A crystal of IRAK4 inhibitor and preparation method thereof

Abstract

Provided are a crystal of a compound of formula (I), a salt thereof, a crystal of the salt thereof, and a method for preparing the crystal, and also include use of the compound and the crystal in preparing a drug for treating IRAK4-related diseases.

Description

[0001] Citations of related applications:

[0002] This application claims the rights and priority of Chinese invention patent application No. 202010071573.9 filed with the State Intellectual Property Office of the People's Republic of China on January 21, 2020, and the rights and priority of Chinese invention patent application No. 202010753615.7 filed with the State Intellectual Property Office of the People's Republic of China on July 30, 2020, the entire contents of which are hereby incorporated by reference into this document in their entirety. Technical Field

[0003] The present application relates to crystals of a compound of formula (I), a salt thereof, crystals of a salt thereof, and methods for preparing the crystals, and specifically to crystals of a compound of formula (I), a compound of formula (II) and its crystals, crystals of a compound of formula (III), crystals of a compound of formula (IV), crystals of a compound of formula (V), crystals of a compound of formula (VI), and methods for preparing the crystals, and also includes uses of the compounds and the crystals in preparing drugs for treating diseases associated with IRAK4. Background Art

[0004] Interleukin 1 receptor kinase 4 (IRAK4) is a serine / threonine-specific protein kinase, a member of the tyrosine kinase (TLK) family, and a key node in the innate immune response involving interleukin-1, 18, 33 receptors and Toll-like receptors. After extracellular signaling molecules bind to interleukin receptors or Toll-like receptors, they recruit to form a MyD88:IRAK4:IRAK1 / 2 multiprotein complex, leading to IRAK1 / 2 phosphorylation, mediating a series of downstream signal transductions, thereby activating the p38, JNK and NF-kB signaling pathways, and ultimately leading to the expression of pro-inflammatory cytokines. Clinical pathological studies have shown that individuals with IRAK4 mutations have a protective effect against chronic lung disease and inflammatory bowel disease. IRAK4 deficiency itself is not lethal, and individuals can survive to adulthood, and the risk of infection decreases with age. Therefore, IRAK4 has become an important therapeutic target and has attracted widespread research and development interest. Summary of the invention

[0005] In one aspect, the present application provides a salt of a compound of formula (I), wherein the salt is selected from hydrochloride, sulfate, methanesulfonate, maleate or p-toluenesulfonate.

[0006]

[0007] On the other hand, the present application provides crystals of the hydrochloride salt of the compound of formula (I), crystals of the sulfate salt of the compound of formula (I), crystals of the methanesulfonate salt of the compound of formula (I), crystals of the maleate salt of the compound of formula (I), or crystals of the p-toluenesulfonate salt of the compound of formula (I).

[0008] On the other hand, the present application provides a compound of formula (II),

[0009]

[0010] In another aspect, the present application also provides a crystal of the compound of formula (II).

[0011] On the other hand, the present application also provides a crystalline A of the compound of formula (II), whose X-ray powder diffraction pattern using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.25±0.20°, 16.15±0.20° and 21.79±0.20°.

[0012] In some embodiments of the present application, the crystalline A of the compound of the above formula (II) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.25±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 20.00±0.20° and 21.79±0.20°.

[0013] In some embodiments of the present application, the crystalline A of the compound of the above formula (II) has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 6.25±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 20.00±0.20°, 21.53±0.20° and 21.79±0.20°.

[0014] In some embodiments of the present application, the crystalline A of the compound of the above formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 20.00±0.20°, 20.57±0.20°, 21.79±0.20° and 28.02±0.20°.

[0015] In some embodiments of the present application, the crystalline A of the compound of the above formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°, 21.79±0.20°, 23.87±0.20°, 27.71±0.20° and 28.02±0.20°.

[0016] In some embodiments of the present application, the crystalline A of the compound of the above formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°, 21.53±0.20°, 21.79±0.20°, 27.71±0.20° and 28.02±0.20°.

[0017] In some embodiments of the present application, the crystalline A of the compound of the above formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.41±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°, 21.53±0.20°, 21.79±0.20°, 27.71±0.20° and 28.02±0.20°.

[0018] In some embodiments of the present application, the crystalline A of the compound of formula (II) above has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 16.41±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°, 21.53±0.20°, 21.79±0.20°, 27.71±0.20° and 28.02±0.20°.

[0019] In some embodiments of the present application, the crystalline A of the compound of the above formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°, 21.79±0.20°, 23.87±0.20°, 28.02±0.20° and 30.81±0.20°.

[0020] In some embodiments of the present application, the crystalline A of the compound of formula (II) above has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25°, 11.95°, 12.58°, 14.33°, 16.15°, 16.41°, 18.20°, 18.75°, 19.46°, 20.00°, 20.57°, 21.53°, 21.79°, 23.11°, 23.87°, 24.31°, 25.26°, 26.14°, 27.71°, 28.02°, 28.50°, 30.06°, 30.81° and 33.21°.

[0021] In some embodiments of the present application, the crystalline A of the compound of formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 16.41±0.20°, 18.20±0.20°, 18.75±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°. °, 21.53±0.20°, 21.79±0.20°, 23.11±0.20°, 23.87±0.20°, 24.31±0.20°, 25.26±0.20°, 26.14±0.20°, 27.71±0.20°, 28.02±0.20°, 28.50±0.20°, 30.06±0.20°, 30.81±0.20° and 33.21±0.20°.

[0022] In some embodiments of the present application, the crystalline A of the compound of formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 18.20±0.20°, 18.75±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57 ±0.20°, 21.53±0.20°, 21.79±0.20°, 23.11±0.20°, 23.87±0.20°, 24.31±0.20°, 25.26±0.20°, 26.14±0.20°, 27.71±0.20°, 28.02±0.20°, 28.50±0.20°, 30.06±0.20°, 30.81±0.20° and 33.21±0.20°.

[0023] In some embodiments of the present application, the crystalline A of the compound of formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.41±0.20°, 18.20±0.20°, 18.75±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57 ±0.20°, 21.53±0.20°, 21.79±0.20°, 23.11±0.20°, 23.87±0.20°, 24.31±0.20°, 25.26±0.20°, 26.14±0.20°, 27.71±0.20°, 28.02±0.20°, 28.50±0.20°, 30.06±0.20°, 30.81±0.20° and 33.21±0.20°.

[0024] In some embodiments of the present application, the crystalline A of the compound of formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 16.41±0.20°, 18.20±0.20°, 18.75±0.20°, 19.46±0.20°, 20.00 ±0.20°, 20.57±0.20°, 21.53±0.20°, 23.11±0.20°, 23.87±0.20°, 24.31±0.20°, 25.26±0.20°, 26.14±0.20°, 27.71±0.20°, 28.02±0.20°, 28.50±0.20°, 30.06±0.20°, 30.81±0.20° and 33.21±0.20°.

[0025] In some embodiments of the present application, the crystalline A of the compound of formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 16.41±0.20°, 18.20±0.20°, 18.75±0.20°, 19.46±0.20°, 20.00 ±0.20°, 20.57±0.20°, 21.79±0.20°, 23.11±0.20°, 23.87±0.20°, 24.31±0.20°, 25.26±0.20°, 26.14±0.20°, 27.71±0.20°, 28.02±0.20°, 28.50±0.20°, 30.06±0.20°, 30.81±0.20° and 33.21±0.20°.

[0026] In some embodiments of the present application, the crystalline A of the compound of formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 16.41±0.20°, 18.20±0.20°, 18.75±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°, 21.53±0.20°, 21.79±0.20°, 23.11±0.20°, 24.80±0.20°, 25.13±0.20°, 26.81±0.20°, 27.90±0.20°, 28.81±0.20°, 29. 0.20°, 23.87±0.20°, 24.31±0.20°, 25.26±0.20°, 26.14±0.20°, 27.71±0.20°, 28.02±0.20°, 28.50±0.20°, 30.06±0.20°, 30.81±0.20° and 33.21±0.20°.

[0027] In some embodiments of the present application, the crystalline A of the compound of formula (II) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.50±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 16.41±0.20°, 18.20±0.20°, 18.75±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°, 21.53 ±0.20°, 21.79±0.20°, 23.11±0.20°, 23.87±0.20°, 24.31±0.20°, 25.26±0.20°, 26.14±0.20°, 26.70±0.20°, 27.71±0.20°, 28.02±0.20°, 28.50±0.20°, 29.09±0.20°, 30.06±0.20°, 30.81±0.20°, 32.39±0.20°, 33.21±0.20° and 33.71±0.20°.

[0028] The present application provides a crystalline compound A of formula (II), which comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.50±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 16.41±0.20°, 18.20±0.20°, 18.75±0.20°, 19.46±0.20°, 20.00±0.20°, 20. 57±0.20°, 21.53±0.20°, 21.79±0.20°, 23.11±0.20°, 23.87±0.20°, 24.31±0.20°, 25.26±0.20°, 26.14±0.20°, 26.70±0.20°, 27.71±0.20°, 28.02±0.20°, 28.50±0.20°, 29.09±0.20°, 30.06±0.20°, 30.81±0.20°, 32.39±0.20°, 33.21±0.20° and 33.71±0.20°.

[0029] In some embodiments of the present application, the crystalline A of the compound of formula (II) above comprises 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.25±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°, 21.79±0.20°, 23.87±0.20°, 28.02±0.20° and 30.81±0.20°.

[0030] In some embodiments of the present application, the crystalline A of the compound of the above formula (II) has an X-ray powder diffraction pattern using Cu Kα radiation, comprising 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 6.25±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 20.00±0.20°, 20.57±0.20°, 21.79±0.20° and 28.02±0.20°.

[0031] In some embodiments of the present application, the crystal A of the compound of formula (II) has an XRPD pattern using Cu Kα radiation as shown in Figure 1 shown.

[0032] In some embodiments of the present application, the XRPD spectrum analysis data of the crystal A of the compound of formula (II) using Cu Kα radiation is shown in Table 1.

[0033] Table 1: XRPD pattern analysis data of crystal A of compound of formula (II)

[0034]

[0035]

[0036] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (II) has a starting point of an endothermic peak at 262.9±5.0°C.

[0037] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (II) has an endothermic peak at 270.0±5.0°C.

[0038] In some embodiments of the present application, the crystal A of the compound of formula (II) has a DSC spectrum as shown in Figure 2 shown.

[0039] In some embodiments of the present application, the thermogravimetric analysis curve of the crystalline A of the compound of formula (II) above shows a weight loss of 2.23% at 100.0±3.0°C.

[0040] In some embodiments of the present application, the crystal A of the compound of formula (II) has a TGA spectrum as shown in Figure 3 shown.

[0041] On the other hand, the present application also provides a method for preparing crystal A of the compound of formula (II), comprising: a step of precipitating the compound of formula (II) from methanol.

[0042] On the other hand, the present application also provides a method for preparing the above-mentioned crystal A of the compound of formula (I), comprising: freeing the crystal A of the compound of formula (II) in an alkaline aqueous solution; then extracting with an organic solvent, concentrating under reduced pressure and then adding it to the solvent; stirring and filtering to obtain the crystal A of the compound of formula (I).

[0043] In some embodiments of the present application, the alkaline aqueous solution is an aqueous sodium carbonate solution, the organic solvent is dichloromethane, and the solvent is methanol.

[0044] On the other hand, the present application also provides a method for preparing crystal A of compound of formula (II), comprising:

[0045]

[0046] (a) adding the compound of formula (I) into a solvent and dissolving it;

[0047] (b) adding a methanol solution of hydrochloric acid under stirring;

[0048] (c) stirring at 20 to 30° C. for 0.5 to 3 hours;

[0049] (d) filtering and drying;

[0050] Wherein, the solvent is methanol, and the concentration of the hydrochloric acid methanol solution is 4 mol / L.

[0051] On the other hand, the present application also provides a crystal of a compound of formula (I),

[0052]

[0053] On the other hand, the present application provides a crystalline form A of the compound of formula (I), which has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 16.63±0.20°, 18.54±0.20° and 19.27±0.20°.

[0054] In some embodiments of the present application, the crystalline A of the compound of formula (I) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.40±0.20°, 16.63±0.20°, 18.54±0.20° and 19.27±0.20°.

[0055] In some embodiments of the present application, the crystalline A of the compound of the above formula (I) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.40±0.20°, 8.75±0.20°, 9.86±0.20°, 16.63±0.20°, 18.54±0.20°, 19.27±0.20°, 19.87±0.20° and 20.85±0.20°.

[0056] In some embodiments of the present application, the crystalline A of the compound of the above formula (I) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.40±0.20°, 13.11±0.20°, 16.10±0.20°, 16.63±0.20°, 18.54±0.20°, 19.27±0.20°, 19.87±0.20° and 20.85±0.20°.

[0057] In some embodiments of the present application, the crystalline A of the compound of the above formula (I) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.40±0.20°, 12.31±0.20°, 13.11±0.20°, 13.64±0.20°, 16.10±0.20°, 16.63±0.20°, 18.54±0.20°, 19.27±0.20°, 19.87±0.20°, 20.85±0.20°, 22.18±0.20° and 23.55±0.20°.

[0058] In some embodiments of the present application, the crystalline A of the compound of the above formula (I) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.40±0.20°, 8.75±0.20°, 9.86±0.20°, 12.31±0.20°, 13.11±0.20°, 13.64±0.20°, 16.10±0.20°, 16.63±0.20°, 18.54±0.20°, 19.27±0.20°, 19.87±0.20°, 20.61±0.20°, 20.85±0.20°, 22.18±0.20° and 23.55±0.20°.

[0059] In some embodiments of the present application, the crystalline A of the compound of formula (I) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.40±0.20°, 8.75±0.20°, 9.86±0.20°, 10.46±0.20°, 11.10±0.20°, 12.31±0.20°, 13.11±0.20°, 13.64±0.20°, 14.01±0.20°, 16.10±0.20°, 16.63±0.20°, 17.05 ±0.20°, 18.54±0.20°, 19.27±0.20°, 19.87±0.20°, 20.61±0.20°, 20.85±0.20°, 21.95±0.20°, 22.18±0.20°, 23.55±0.20°, 24.73±0.20°, 27.50±0.20°, 28.61±0.20°, 30.05±0.20° and 31.58±0.20°.

[0060] The present application provides a crystalline compound A of formula (I), which comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.40±0.20°, 8.75±0.20°, 9.86±0.20°, 10.46±0.20°, 11.10±0.20°, 12.31±0.20°, 13.11±0.20°, 13.64±0.20°, 14.01±0.20°, 16.10±0.20°, 16.63±0.20°, 17.05±0.20°, 18.54±0.20°, 19.27±0.20°, 19.87±0.20°, 20.61±0.20°, 20.85±0.20°, 21.95±0.20°, 22.18±0.20°, 23.55±0.20°, 24.73±0.20°, 27.50±0.20°, 28.61±0.20°, 30.05±0.20° and 31.58±0.20°.

[0061] In some embodiments of the present application, the crystalline A of the compound of the above formula (I) comprises 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.40±0.20°, 12.31±0.20°, 13.11±0.20°, 13.64±0.20°, 16.10±0.20°, 16.63±0.20°, 18.54±0.20°, 19.27±0.20°, 19.87±0.20°, 20.85±0.20°, 22.18±0.20° and 23.55±0.20°.

[0062] In some embodiments of the present application, the crystalline A of the compound of the above formula (I) comprises 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.40±0.20°, 13.11±0.20°, 16.10±0.20°, 16.63±0.20°, 18.54±0.20°, 19.27±0.20°, 19.87±0.20° and 20.85±0.20°.

[0063] In some embodiments of the present application, the crystal A of the compound of formula (I) has an XRPD pattern using Cu Kα radiation as shown in Figure 4 shown.

[0064] In some embodiments of the present application, the XRPD spectrum analysis data of the crystal A of the compound of formula (I) using Cu Kα radiation is shown in Table 2.

[0065] Table 2: XRPD pattern analysis data of crystal A of compound of formula (I)

[0066]

[0067] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (I) has an onset point of an endothermic peak at 281.8±5.0°C.

[0068] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (I) has an endothermic peak at 282.6±5.0°C.

[0069] In some embodiments of the present application, the crystal A of the compound of formula (I) above has a DSC spectrum as shown in Figure 5 shown.

[0070] In some embodiments of the present application, the thermogravimetric analysis curve of the crystalline A of the compound of formula (I) above shows a weight loss of 1.27% at 100.0±3.0°C.

[0071] In some embodiments of the present application, the crystal A of the compound of formula (I) has a TGA spectrum as shown in Figure 6 shown.

[0072] On the other hand, the present application also provides a compound of formula (III),

[0073]

[0074] In another aspect, the present invention also provides a crystal of the compound of formula (III).

[0075] On the other hand, the present application provides a crystalline A of the compound of formula (III), whose X-ray powder diffraction pattern using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.82±0.20°, 7.98±0.20° and 18.02±0.20°.

[0076] In some embodiments of the present application, the crystalline A of the compound of the above formula (III) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.82±0.20°, 7.98±0.20°, 15.55±0.20°, 18.02±0.20°, 19.34±0.20°, 20.69±0.20°, 22.91±0.20° and 24.08±0.20°.

[0077] In some embodiments of the present application, the crystalline A of the compound of the above formula (III) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.82±0.20°, 7.98±0.20°, 15.55±0.20°, 18.02±0.20°, 19.34±0.20°, 20.69±0.20°, 22.91±0.20°, 24.08±0.20° and 24.93±0.20°.

[0078] In some embodiments of the present application, the crystalline A of the compound of the above formula (III) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.82±0.20°, 7.98±0.20°, 15.55±0.20°, 18.02±0.20°, 19.34±0.20°, 20.69±0.20°, 21.33±0.20°, 22.14±0.20°, 22.91±0.20°, 24.08±0.20°, 24.93±0.20° and 26.04±0.20°.

[0079] In some embodiments of the present application, the crystalline A of the compound of formula (III) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.82±0.20°, 7.98±0.20°, 11.61±0.20°, 15.55±0.20°, 17.39±0.20°, 18.02±0.20°, 18.78±0.20°, 19.34±0.20°, 20.26±0.20°. °, 20.69±0.20°, 21.02±0.20°, 21.33±0.20°, 22.14±0.20°, 22.91±0.20°, 24.08±0.20°, 24.34±0.20°, 24.93±0.20°, 25.18±0.20°, 26.04±0.20° and 27.61±0.20°.

[0080] In some embodiments of the present application, the crystalline A of the compound of formula (III) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.82±0.20°, 7.98±0.20°, 9.02±0.20°, 9.64±0.20°, 11.61±0.20°, 12.13±0.20°, 13.44±0.20°, 15.55±0.20°, 16.61±0.20°, 17.39±0.20°, 18.02±0.20°, 18.78±0.20°, 19.34±0.20°, 20.26 ±0.20°, 20.69±0.20°, 21.02±0.20°, 21.33±0.20°, 22.14±0.20°, 22.91±0.20°, 24.08±0.20°, 24.34±0.20°, 24.93±0.20°, 25.18±0.20°, 26.04±0.20°, 26.80±0.20°, 27.27±0.20°, 27.61±0.20°, 29.55±0.20° and 31.57±0.20°.

[0081] The present application provides a crystalline compound A of formula (III), which comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.82±0.20°, 7.98±0.20°, 9.02±0.20°, 9.64±0.20°, 11.61±0.20°, 12.13±0.20°, 13.44±0.20°, 15. 55±0.20°、16.61±0.20°、17.39±0.20°、18.02±0.20°、18.78±0.20°、19.34±0.20°、20.26±0.20°、20.69±0.20°、21.02±0.20°、21.33±0.20°、22.14±0.20°、22.91±0.20°、 24.08±0.20°, 24.34±0.20°, 24.93±0.20°, 25.18±0.20°, 26.04±0.20°, 26.80±0.20°, 27.27±0.20°, 27.61±0.20°, 29.55±0.20° and 31.57±0.20°.

[0082] In some embodiments of the present application, the crystalline A of the compound of the above formula (III) comprises 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.82±0.20°, 7.98±0.20°, 15.55±0.20°, 18.02±0.20°, 19.34±0.20°, 20.69±0.20°, 21.33±0.20°, 22.14±0.20°, 22.91±0.20°, 24.08±0.20°, 24.93±0.20° and 26.04±0.20°.

[0083] In some embodiments of the present application, the crystalline A of the compound of the above formula (III) comprises 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.82±0.20°, 7.98±0.20°, 15.55±0.20°, 18.02±0.20°, 19.34±0.20°, 20.69±0.20°, 22.91±0.20° and 24.08±0.20°.

[0084] In some embodiments of the present application, the crystal A of the compound of formula (III) has an XRPD pattern using Cu Kα radiation as shown in Figure 7 shown.

[0085] In some embodiments of the present application, the XRPD spectrum analysis data of the crystal A of the compound of formula (III) using Cu Kα radiation are shown in Table 3.

[0086] Table 3: XRPD pattern analysis data of crystal A of compound of formula (III)

[0087]

[0088] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (III) has a peak value of the endothermic peak at 88.0±3.0°C and a starting point of the endothermic peak at 176.3±5.0°C.

[0089] In some embodiments of the present application, the crystal A of the compound of formula (III) has a DSC spectrum as shown in Figure 8 shown.

[0090] In some embodiments of the present application, the thermogravimetric analysis curve of the crystalline A of the compound of formula (III) above shows a weight loss of 4.45% at 100.0±3.0°C.

[0091] In some embodiments of the present application, the crystal A of the compound of formula (III) has a TGA spectrum as shown in Fig. 9 shown.

[0092] On the other hand, the present application also provides a compound of formula (IV),

[0093]

[0094] On the other hand, the present application also provides a crystal of the compound of formula (IV).

[0095] On the other hand, the present application provides a crystalline A of the compound of formula (IV), whose X-ray powder diffraction pattern using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.78±0.20°, 18.09±0.20° and 21.72±0.20°.

[0096] In some embodiments of the present application, the crystalline A of the compound of formula (IV) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.78±0.20°, 13.52±0.20°, 18.09±0.20° and 21.72±0.20°.

[0097] In some embodiments of the present application, the crystalline A of the compound of the above formula (IV) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.78±0.20°, 7.24±0.20°, 7.87±0.20°, 13.52±0.20°, 18.09±0.20°, 19.65±0.20°, 21.01±0.20° and 21.72±0.20°.

[0098] In some embodiments of the present application, the crystalline A of the compound of the above formula (IV) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.78±0.20°, 13.52±0.20°, 18.09±0.20°, 19.65±0.20°, 21.01±0.20°, 21.72±0.20°, 23.22±0.20° and 23.60±0.20°.

[0099] In some embodiments of the present application, the crystalline A of the compound of the above formula (IV) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.78±0.20°, 7.24±0.20°, 7.87±0.20°, 13.52±0.20°, 18.09±0.20°, 19.25±0.20°, 19.65±0.20°, 20.30±0.20°, 21.01±0.20°, 21.72±0.20°, 23.22±0.20° and 23.60±0.20°.

[0100] In some embodiments of the present application, the crystalline A of the compound of the above formula (IV) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.78±0.20°, 7.87±0.20°, 13.52±0.20°, 16.69±0.20°, 18.09±0.20°, 19.65±0.20°, 20.30±0.20°, 21.01±0.20°, 21.72±0.20°, 23.22±0.20°, 23.60±0.20° and 27.04±0.20°.

[0101] In some embodiments of the present application, the crystalline A of the compound of formula (IV) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.78±0.20°, 7.24±0.20°, 7.87±0.20°, 12.06±0.20°, 12.74±0.20°, 12.96±0.20°, 13.52±0.20°, 18.09±0.20°, 18.87±0.20°, 19.25±0.20°, 19.65±0.20°, 20.30±0.20°, 21.01±0.20°, 21.72±0.20°, 22.86±0.20° , 23.22±0.20°, 23.60±0.20°, 25.09±0.20°, 25.42±0.20°, 25.59±0.20°, 26.04±0.20°, 27.04±0.20°, 27.80±0.20°, 28.82±0.20°, 30.06±0.20°, 30.72±0.20°, 31.32±0.20°, 32.57±0.20°, 33.13±0.20°, 34.59±0.20°, 36.00±0.20° and 37.63±0.20°.

[0102] The present application provides a crystalline compound A of formula (IV), which has an X-ray powder diffraction pattern using Cu Kα radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following 2θ angles: 6.78±0.20°, 7.24±0.20°, 7.87±0.20°, 12.06±0.20°, 12.74±0.20°, 12.96±0.20°, 13.52±0.20°, 18.09±0.20°, 18.87±0.20°, 19.25±0.20°, 19.65±0.20°, 20.30±0.20°, 21.01±0.20°, 21.72±0.20°, 22.86±0.20°, 23.22±0.20°, 23.60±0.20°, 25.09±0.20° 0.20°, 25.42±0.20°, 25.59±0.20°, 26.04±0.20°, 27.04±0.20°, 27.80±0.20°, 28.82±0.20°, 30.06±0.20°, 30.72±0.20°, 31.32±0.20°, 32.57±0.20°, 33.13±0.20°, 34.59±0.20°, 36.00±0.20° and 37.63±0.20°.

[0103] In some embodiments of the present application, the crystalline A of the compound of formula (IV) above comprises 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.78±0.20°, 7.87±0.20°, 13.52±0.20°, 16.69±0.20°, 18.09±0.20°, 19.65±0.20°, 20.30±0.20°, 21.01±0.20°, 21.72±0.20°, 23.22±0.20°, 23.60±0.20° and 27.04±0.20°.

[0104] In some embodiments of the present application, the crystalline A of the compound of the above formula (IV) comprises 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.78±0.20°, 13.52±0.20°, 18.09±0.20°, 19.65±0.20°, 21.01±0.20°, 21.72±0.20°, 23.22±0.20° and 23.60±0.20°.

[0105] In some embodiments of the present application, the crystal A of the compound of formula (IV) has an XRPD pattern using Cu Kα radiation as shown in Fig.10shown.

[0106] In some embodiments of the present application, the XRPD spectrum analysis data of the crystal A of the compound of formula (IV) using Cu Kα radiation are shown in Table 4.

[0107] Table 4: XRPD pattern analysis data of crystal A of compound of formula (IV)

[0108]

[0109] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (IV) has an onset of an endothermic peak at 247.4±5.0°C.

[0110] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (IV) has an endothermic peak at 249.8±5.0°C.

[0111] In some embodiments of the present application, the crystal A of the compound of formula (IV) has a DSC spectrum as shown in Fig.11 shown.

[0112] In some embodiments of the present application, the thermogravimetric analysis curve of the crystalline A of the compound of formula (IV) above shows a weight loss of 3.11% at 120.0±3.0°C.

[0113] In some embodiments of the present application, the crystal A of the compound of formula (IV) has a TGA spectrum as shown in Fig.12 shown.

[0114] On the other hand, the present application also provides a compound of formula (V),

[0115]

[0116] On the other hand, the present application also provides a crystal of the compound of formula (V).

[0117] On the other hand, the present application provides a crystalline A of the compound of formula (V), which has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 17.72±0.20°, 19.73±0.20° and 22.32±0.20°.

[0118] The present application provides a crystalline form A of the compound of formula (V), which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 17.72±0.20°, 19.50±0.20° and 22.32±0.20°.

[0119] The present application provides a crystalline form A of the compound of formula (V), which has characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 19.50±0.20°, 19.73±0.20°, and 22.32±0.20°.

[0120] In some embodiments of the present application, the crystalline A of the compound of formula (V) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 17.72±0.20°, 19.50±0.20°, 19.73±0.20°, 21.32±0.20° and 22.32±0.20°.

[0121] In some embodiments of the present application, the crystalline A of the compound of formula (V) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 17.72±0.20°, 19.50±0.20°, 19.73±0.20°, 21.05±0.20° and 22.32±0.20°.

[0122] In some embodiments of the present application, the crystalline A of the compound of formula (V) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 17.72±0.20°, 19.73±0.20°, 21.05±0.20°, 21.32±0.20° and 22.32±0.20°.

[0123] In some embodiments of the present application, the crystalline A of the compound of formula (V) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 17.72±0.20°, 19.50±0.20°, 21.05±0.20°, 21.32±0.20° and 22.32±0.20°.

[0124] In some embodiments of the present application, the crystalline A of the compound of the above formula (V) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 17.72±0.20°, 19.50±0.20°, 19.73±0.20°, 21.05±0.20°, 21.32±0.20° and 22.32±0.20°.

[0125] In some embodiments of the present application, the crystalline A of the compound of the above formula (V) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 16.67±0.20°, 17.72±0.20°, 18.17±0.20°, 19.73±0.20°, 21.05±0.20°, 22.32±0.20°, 23.45±0.20°, and 24.89±0.20°.

[0126] In some embodiments of the present application, the crystalline A of the compound of the above formula (V) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 12.54±0.20°, 13.04±0.20°, 15.96±0.20°, 16.67±0.20°, 17.72±0.20°, 18.17±0.20°, 19.73±0.20°, 21.05±0.20°, 22.32±0.20°, 23.45±0.20°, 24.89±0.20° and 25.61±0.20°.

[0127] In some embodiments of the present application, the crystalline A of the compound of formula (V) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.23±0.20°, 8.37±0.20°, 10.02±0.20°, 12.54±0.20°, 13.04±0.20°, 13.73±0.20°, 15.96±0.20°, 16.67±0.20°, 17.7 2±0.20°, 18.17±0.20°, 19.50±0.20°, 19.73±0.20°, 21.05±0.20°, 21.32±0.20°, 22.32±0.20°, 23.45±0.20°, 24.89±0.20°, 25.61±0.20° and 26.80±0.20°.

[0128] In some embodiments of the present application, the crystalline A of the compound of formula (V) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 4.23±0.20°, 8.37±0.20°, 10.02±0.20°, 10.90±0.20°, 11.85±0.20°, 12.54±0.20°, 13.04±0.20°, 13.73±0.20°, 14.48±0.20°, 15.05±0.20°, 15.96±0.20°, 16.67±0.20°. °, 17.72±0.20°, 18.17±0.20°, 19.50±0.20°, 19.73±0.20°, 21.05±0.20°, 21.32±0.20°, 22.32±0.20°, 23.45±0.20°, 24.89±0.20°, 25.61±0.20°, 26.80±0.20°, 27.32±0.20°, 30.42±0.20° and 33.09±0.20°.

[0129] The present application provides a crystalline A of a compound of formula (V), which comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 4.23±0.20°, 8.37±0.20°, 10.02±0.20°, 10.90±0.20°, 11.85±0.20°, 12.54±0.20°, 13.04±0.20°, 13.73±0.20°, 14.48±0.20°, 15.05±0.20°, 15.96±0. 0°, 20°, 16.67±0.20°, 17.72±0.20°, 18.17±0.20°, 19.50±0.20°, 19.73±0.20°, 21.05±0.20°, 21.32±0.20°, 22.32±0.20°, 23.45±0.20°, 24.89±0.20°, 25.61±0.20°, 26.80±0.20°, 27.32±0.20°, 30.42±0.20° and 33.09±0.20°.

[0130] In some embodiments of the present application, the crystalline A of the compound of the above formula (V) comprises 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 12.54±0.20°, 13.04±0.20°, 15.96±0.20°, 16.67±0.20°, 17.72±0.20°, 18.17±0.20°, 19.73±0.20°, 21.05±0.20°, 22.32±0.20°, 23.45±0.20°, 24.89±0.20° and 25.61±0.20°.

[0131] In some embodiments of the present application, the crystalline A of the compound of the above formula (V) comprises 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 16.67±0.20°, 17.72±0.20°, 18.17±0.20°, 19.73±0.20°, 21.05±0.20°, 22.32±0.20°, 23.45±0.20°, and 24.89±0.20°.

[0132] In some embodiments of the present application, the crystal A of the compound of formula (V) has an XRPD pattern using Cu Kα radiation as shown in Fig.13 shown.

[0133] In some embodiments of the present application, the XRPD spectrum analysis data of the crystalline A of the compound of formula (V) using Cu Kα radiation are shown in Table 5.

[0134] Table 5: XRPD pattern analysis data of crystal A of compound of formula (V)

[0135]

[0136]

[0137] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (V) has the starting points of the endothermic peaks at 182.2±5.0°C and 194.2±5.0°C, respectively.

[0138] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (V) has endothermic peaks at 185.9±5.0°C and 199.5±5.0°C, respectively.

[0139] In some embodiments of the present application, the crystal A of the compound of formula (V) has a DSC spectrum as shown in Fig.14 shown.

[0140] In some embodiments of the present application, the thermogravimetric analysis curve of the crystalline A of the compound of formula (V) shows a weight loss of 3.62% at 100.0±3.0°C.

[0141] In some embodiments of the present application, the crystal A of the compound of formula (V) has a TGA spectrum as shown in Fig.15 shown.

[0142] On the other hand, the present application also provides a compound of formula (VI),

[0143]

[0144] In another aspect, the present application also provides a crystal of the compound of formula (VI).

[0145] On the other hand, the present application provides a crystalline A of the compound of formula (VI), whose X-ray powder diffraction pattern using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.66±0.20°, 20.15±0.20° and 23.34±0.20°.

[0146] The present application also provides a crystalline form A of the compound of formula (VI), which has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 20.15±0.20°, 23.34±0.20° and 24.77±0.20°.

[0147] In some embodiments of the present application, the crystalline A of the compound of formula (VI) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 7.66±0.20°, 20.15±0.20°, 23.34±0.20° and 24.77±0.20°.

[0148] In some embodiments of the present application, the crystalline A of the compound of formula (VI) above has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 7.66±0.20°, 12.15±0.20°, 16.56±0.20°, 18.90±0.20°, 20.15±0.20°, 22.02±0.20°, 23.34±0.20° and 24.77±0.20°.

[0149] In some embodiments of the present application, the crystalline A of the compound of the above formula (VI) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 7.66±0.20°, 12.15±0.20°, 16.56±0.20°, 18.90±0.20°, 20.15±0.20°, 21.73±0.20°, 23.34±0.20° and 24.77±0.20°.

[0150] In some embodiments of the present application, the crystalline A of the compound of the above formula (VI) has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 7.66±0.20°, 12.15±0.20°, 16.56±0.20°, 18.90±0.20°, 20.15±0.20°, 21.73±0.20°, 22.02±0.20°, 23.34±0.20° and 24.77±0.20°.

[0151] In some embodiments of the present application, the crystalline A of the compound of the above formula (VI) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 7.66±0.20°, 12.15±0.20°, 16.13±0.20°, 16.56±0.20°, 17.08±0.20°, 17.62±0.20°, 18.90±0.20°, 20.15±0.20°, 22.02±0.20°, 23.34±0.20°, 24.77±0.20° and 30.00±0.20°.

[0152] In some embodiments of the present application, the crystalline A of the compound of the above formula (VI) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 7.66±0.20°, 8.23±0.20°, 12.15±0.20°, 16.13±0.20°, 16.56±0.20°, 17.08±0.20°, 17.62±0.20°, 18.90±0.20°, 20.15±0.20°, 21.73±0.20°, 22.02±0.20°, 23.34±0.20°, 24.77±0.20° and 30.00±0.20°.

[0153] In some embodiments of the present application, the crystalline A of the compound of the above formula (VI) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.05°, 7.66°, 8.23°, 12.15°, 13.16°, 13.78°, 14.20°, 14.73°, 15.35°, 16.13°, 16.56°, 17.08°, 17.62°, 18.02°, 18.90°, 20.15°, 20.90°, 21.73°, 22.02°, 23.34°, 24.77°, 26.47°, 27.50°, 28.43°, 29.29° and 30.00°.

[0154] In some embodiments of the present application, the crystalline A of the compound of formula (VI) has a characteristic diffraction peak at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.05±0.20°, 7.66±0.20°, 8.23±0.20°, 12.15±0.20°, 13.16±0.20°, 13.78±0.20°, 14.20±0.20°, 14.73±0.20°, 15.35±0.20°, 16.13±0.20°, 16.56±0.20°, 17.08±0.20°, 17.62±0.20°, 18.02±0.20°, 18.90 ±0.20°, 20.15±0.20°, 20.90±0.20°, 21.73±0.20°, 22.02±0.20°, 23.34±0.20°, 24.77±0.20°, 26.47±0.20°, 27.50±0.20°, 28.43±0.20°, 29.29±0.20°, 30.00±0.20°, 30.86±0.20°, 32.62±0.20°, 36.10±0.20°, 37.01±0.20° and 38.49±0.20°.

[0155] The present application provides a crystalline compound A of formula (VI), which comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.05±0.20°, 7.66±0.20°, 8.23±0.20°, 12.15±0.20°, 13.16±0.20°, 13.78±0.20°, 14.20±0.20°, 14.73±0.20°, 15.35±0.20°, 16.13±0.20°, 16.56±0.20°, 17.08±0.20°, 17.62±0.20°, 18. 0°, 02±0.20°, 18.90±0.20°, 20.15±0.20°, 20.90±0.20°, 21.73±0.20°, 22.02±0.20°, 23.34±0.20°, 24.77±0.20°, 26.47±0.20°, 27.50±0.20°, 28.43±0.20°, 29.29±0.20°, 30.00±0.20°, 30.86±0.20°, 32.62±0.20°, 36.10±0.20°, 37.01±0.20° and 38.49±0.20°.

[0156] In some embodiments of the present application, the crystalline A of the compound of the above formula (VI) comprises 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 7.66±0.20°, 12.15±0.20°, 16.13±0.20°, 16.56±0.20°, 17.08±0.20°, 17.62±0.20°, 18.90±0.20°, 20.15±0.20°, 22.02±0.20°, 23.34±0.20°, 24.77±0.20° and 30.00±0.20°.

[0157] In some embodiments of the present application, the crystalline A of the compound of the above formula (VI) comprises 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 7.66±0.20°, 12.15±0.20°, 16.56±0.20°, 18.90±0.20°, 20.15±0.20°, 22.02±0.20°, 23.34±0.20° and 24.77±0.20°.

[0158] In some embodiments of the present application, the crystal A of the compound of formula (VI) has an XRPD pattern using Cu Kα radiation as shown in Fig.16 shown.

[0159] In some embodiments of the present application, the XRPD spectrum analysis data of the crystal A of the compound of formula (VI) using Cu Kα radiation are shown in Table 6.

[0160] Table 6: XRPD pattern analysis data of crystal A of compound of formula (VI)

[0161]

[0162] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (VI) has an onset of an endothermic peak at 262.9±5.0°C.

[0163] In some embodiments of the present application, the differential scanning calorimetry curve of the crystalline A of the compound of formula (VI) has an endothermic peak at 264.2±5.0°C.

[0164] In some embodiments of the present application, the crystal A of the compound of formula (VI) has a DSC spectrum as shown in Fig.17 shown.

[0165] In some embodiments of the present application, the thermogravimetric analysis curve of the crystalline A of the compound of formula (VI) above shows a weight loss of 2.17% at 250.0±3.0°C.

[0166] In some embodiments of the present application, the crystal A of the compound of formula (VI) has a TGA spectrum as shown in Fig.18 shown.

[0167] The present invention also provides a method for preparing the above-mentioned crystals A of the compound of formula (III), the above-mentioned crystals A of the compound of formula (IV), the above-mentioned crystals A of the compound of formula (V), and the above-mentioned crystals A of the compound of formula (VI), comprising: adding the crystals A of the compound of formula (I) to a solvent, then adding an acid, heating and stirring, cooling and filtering, to obtain each crystal.

[0168] In some embodiments of the present application, the solvent is methanol; the heating temperature is 40-60°C, preferably 50°C.

[0169] On the other hand, the present application provides a crystalline composition comprising a crystalline A of a compound of formula (I), a crystalline A of a compound of formula (II), a crystalline A of a compound of formula (III), a crystalline A of a compound of formula (IV), a crystalline A of a compound of formula (V), or a crystalline A of a compound of formula (VI), wherein the crystalline A of a compound of formula (I), a crystalline A of a compound of formula (II), a crystalline A of a compound of formula (III), a crystalline A of a compound of formula (IV), a crystalline A of a compound of formula (V), or a crystalline A of a compound of formula (VI) accounts for more than 50% by weight of the crystalline composition, preferably more than 75%, more preferably more than 90%, and most preferably more than 95%. Each of the crystalline compositions may also contain a small amount of other crystalline or non-crystalline forms of the compound of formula (I), the compound of formula (II), the compound of formula (III), the compound of formula (IV), the compound of formula (V), or the compound of formula (VI).

[0170] On the other hand, the present application provides a pharmaceutical composition, which comprises a therapeutically effective amount of the above-mentioned compound of formula (I), compound of formula (II), compound of formula (III), compound of formula (IV), compound of formula (V) or compound of formula (VI), or a crystal thereof, or a crystalline composition thereof; the pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier or other excipient. In addition, the pharmaceutical composition of the present application may further include one or more other therapeutic agents.

[0171] On the other hand, the present application provides the use of the above-mentioned compound of formula (I), compound of formula (II), compound of formula (III), compound of formula (IV), compound of formula (V) or compound of formula (VI) or their crystals, or the above-mentioned crystalline composition, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating or preventing diseases related to IRAK4.

[0172] On the other hand, the present application provides the use of the above-mentioned compound of formula (I), compound of formula (II), compound of formula (III), compound of formula (IV), compound of formula (V) or compound of formula (VI) or their crystals, or the above-mentioned crystalline composition, or the above-mentioned pharmaceutical composition in a drug for treating or preventing diseases related to IRAK4.

[0173] On the other hand, the present application provides a method for treating or preventing a disease associated with IRAK4, comprising administering to a mammal in need thereof a therapeutically effective amount of the above-mentioned compound of formula (I), compound of formula (II), compound of formula (III), compound of formula (IV), compound of formula (V) or compound of formula (VI) or their crystals, or the above-mentioned crystalline composition, or the above-mentioned pharmaceutical composition.

[0174] On the other hand, the present application provides the above-mentioned compound of formula (I), compound of formula (II), compound of formula (III), compound of formula (IV), compound of formula (V) or compound of formula (VI) or its crystal, or the above-mentioned crystalline composition, or the above-mentioned pharmaceutical composition for treating or preventing diseases related to IRAK4. In some embodiments of the present application, the mammal is a human.

[0175] The present application also provides a method for preparing a compound of formula (I), comprising the following synthetic route:

[0176]

[0177] In the present application, the pharmaceutical composition can be prepared into a certain dosage form for administration, preferably oral administration, parenteral administration (including subcutaneous, intramuscular and intravenous), rectal administration, etc. For example, dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, syrups or suspensions; dosage forms suitable for parenteral administration include aqueous or non-aqueous injection solutions or emulsions; dosage forms suitable for rectal administration include suppositories using hydrophilic or hydrophobic carriers. As needed, the above dosage forms can also be prepared into dosage forms suitable for rapid release, delayed release or regulated release of the active ingredient.

[0178] The crystals described in the present application may be in the form of a non-solvate or a solvate, such as a hydrate.

[0179] In this application, the X-ray powder diffraction spectrum of the sample was measured under the following conditions: instrument: Bruker D8advance X-ray diffractometer; target: Cu:Kα; wavelength 2θ angle range: 4-40°; scattering slit: 0.6mm; detector slit: 10.5mm; anti-scattering slit: 7.10mm; Cu target tube voltage and tube current: 40KV, 40mA; step diameter: 0.02°; step length: 0.12 seconds; sample plate rotation speed: 15rpm.

[0180] In the present application, the DSC spectrum is measured under the following conditions: instrument: TA Q2000 differential scanning calorimeter; temperature range: 30-300° C.; heating rate: 10° C. / min.

[0181] In the present application, TGA thermogravimetric analysis is measured under the following conditions: instrument: TA Q5000IR thermogravimetric analyzer; gas flow rate: 25 mL / min; temperature range: 30-350°C; heating rate: 10°C / min.

[0182] It should be noted that in the powder X-ray diffraction spectrum, the position of the peak or the relative intensity of the peak may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal, there may be an error in the position of the peak, and the measurement error of the 2θ value is ±0.2. Therefore, when determining each crystal, this error should be taken into account, and it also belongs to the scope of this application within the error.

[0183] It should be noted that for the same type of crystal, the position of the endothermic peak of DSC may be different due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal, the position of the endothermic peak may have an error, which may be ±5°C. Therefore, when determining each crystal, this error should be taken into account, and the error is also within the scope of this application.

[0184] It should be noted that for the same type of crystal, the position of the weight loss temperature of TGA may be different due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal, the position of the weight loss temperature may have an error, and the error may be ±3°C. Therefore, when determining each crystal, this error should be taken into account, and the error is also within the scope of this application.

[0185] Technical Effects

[0186] The salt or crystal described in the present application has good solubility and good pharmacokinetic (PK) properties. The crystals are stable, have good hygroscopicity, are less affected by light and heat, and have high thermal stability.

[0187] Definition and Description

[0188] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0189] "Mammal" includes humans and domestic animals such as laboratory mammals and household pets (e.g., cats, dogs, pigs, sheep, cattle, goats, horses, rabbits), and non-domesticated mammals, such as wild mammals, etc.

[0190] The term "pharmaceutical composition" refers to a preparation of the present invention compound and a medium generally accepted in the art for delivering biologically active compounds to mammals, such as humans. The medium includes all pharmaceutically acceptable carriers for its use. The pharmaceutical composition facilitates the administration of the compound to an organism.

[0191] The term "therapeutically effective amount" refers to a sufficient amount of a drug or pharmaceutical agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0192] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0193] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0194] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0195] The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0196] In the present application, "pharmaceutically acceptable carrier" refers to those carriers that are administered together with the active ingredient, have no significant irritation to the organism, and do not impair the biological activity and performance of the active compound. For other information about the carrier, reference may be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0197] In this application, "eq" stands for molar equivalent.

[0198] In this application, "FA" stands for trifluoroacetic acid.

[0199] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0200] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0201] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0202] All solvents used in this application were commercially available and used without further purification.

[0203] The solvents used in this application can be obtained commercially, and the commercially available compounds are named in the supplier's catalog. When adding the mixed solvent to the reaction solution, the individual solvents can be mixed first and then added to the reaction solution; or the individual solvents can be added to the reaction solution in sequence and mixed in the reaction system.

[0204] Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names. BRIEF DESCRIPTION OF THE DRAWINGS

[0205] Figure 1 It is the XRPD spectrum of the crystal A of the compound of formula (II) using Cu-Kα radiation.

[0206] Figure 2 It is the DSC spectrum of the crystal A of the compound of formula (II).

[0207] Figure 3 This is the TGA spectrum of crystal A of compound of formula (II).

[0208] Figure 4 It is the Cu-Kα radiation XRPD spectrum of the crystal A of the compound of formula (I).

[0209] Figure 5 It is the DSC spectrum of the crystal A of the compound of formula (I).

[0210] Figure 6 This is the TGA spectrum of crystal A of compound of formula (I).

[0211] Figure 7 It is the Cu-Kα radiation XRPD spectrum of the crystal A of the compound of formula (III).

[0212] Figure 8 It is the DSC spectrum of the crystal A of the compound of formula (III).

[0213] Fig. 9 This is the TGA spectrum of crystal A of compound of formula (III).

[0214] Fig.10 It is the Cu-Kα radiation XRPD spectrum of the crystal A of the compound of formula (IV).

[0215] Fig.11 It is the DSC spectrum of the crystal A of the compound of formula (IV).

[0216] Fig.12 This is the TGA spectrum of crystal A of compound of formula (IV).

[0217] Fig.13 It is the Cu-Kα radiation XRPD spectrum of the crystal A of the compound of formula (V).

[0218] Fig.14 It is the DSC spectrum of crystal A of compound of formula (V).

[0219] Fig.15 This is the TGA spectrum of crystal A of compound of formula (V).

[0220] Fig.16 It is the Cu-Kα radiation XRPD spectrum of the crystal A of the compound of formula (VI).

[0221] Fig.17 It is the DSC spectrum of the crystal A of the compound of formula (VI).

[0222] Fig.18 This is the TGA spectrum of crystal A of compound of formula (VI). DETAILED DESCRIPTION

[0223] The present application is described in detail below by way of examples, but this does not mean any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0224] Example 1: Preparation of the compound of formula (I)

[0225]

[0226] Synthesis route:

[0227]

[0228] first step:

[0229] Compound 2 (100.0 g, 466.6 mmol) was added to a bottle containing isopropanol (1.5 L), and then compound 1 (125.3 g, 466.6 mmol) and sodium bicarbonate (156.8 g, 1.9 mol) were added to the reaction system, and the reaction was stirred at 90 ° C (internal temperature) for 12 hours. The raw material reaction was complete according to LCMS detection, the reaction temperature was lowered to 50 ° C, and the filter cake was rinsed with 1 L of tetrahydrofuran while filtering, and the organic phase was concentrated to dryness under reduced pressure. The crude product was homogenized with (methyl tert-butyl ether: petroleum ether = 2:1, 800.0 mL), and the filter cake was rinsed with methyl tert-butyl ether (50.0 mL*2) after filtering, and the filter cake was concentrated to remove the solvent to obtain compound 3.

[0230] LCMS (ESI) m / z: 374.3 [M+H] +

[0231] 1 H NMR (400MHz, CDCl3) δ7.27-7.34(m,5H),4.36(s,1H),3.53(s,1H),3.38(s,1H),2.22-2.60(m,8H),2.20-2 .22(m,1H),2.06-2.09(m,2H),1.92-1.95(m,2H),1.40-1.46(m,9H),1.30-1.36(m,3H),1.10-1.17(m,2H).

[0232] Step 2:

[0233] Under argon protection, palladium hydroxide (31.2 g, 44.4 mmol) was slowly added to the hydrogenation bottle in batches, and ethanol (800 mL) was slowly added under argon protection, and then compound 3 (78.0 g, 208.8 mmol) was added to the reaction system, and the reaction was stirred at 50 Psi hydrogen pressure and 50 ° C for 2 hours. LCMS detected that the raw material reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter cake was rinsed with ethanol (5.0 L), and the filtrate was concentrated to dryness under reduced pressure to obtain compound 4.

[0234] LCMS (ESI) m / z: 284.2 [M+H] +

[0235] 1H NMR (400MHz, CDCl3) δ4.29-4.47(m,1H),3.25-3.46(m,1H),2.79-2.98(m,4H),2.43-2.62(m,4 H),2.13-2.25(m,1H),1.98-2.11(m,2H),1.83-1.95(m,2H),1.65-1.71(m,1H),1.39-1.57(m,9 H),1.23-1.38(m,2H),1.03-1.17(m,2H).

[0236] Step 3:

[0237] Compound 4 (150.0 g, 529.3 mmol) and sodium bicarbonate (33.4 g, 1.6 mol) were added to tetrahydrofuran (1.5 mL) and water (800.0 mL), cooled to 0°C, and methyl chloroformate (295.5 g, 3.1 mol) was added dropwise to the reaction system. The reaction was stirred at 25°C for 0.5 hours, and the reaction was completed by LCMS. Ethyl acetate (500.0 mL) and water (500.0 mL) were added to the reaction solution for extraction, and the aqueous phase was extracted with ethyl acetate (500.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5.

[0238] LCMS (ESI) m / z: 342.3 [M+H] +

[0239] 1 H NMR (400MHz, CDCl3) δ4.31-4.44(m,1H),3.66-3.74(m,3H),3.44-3.58(m,4H),3.25-3.42(m,1H),2.46-2.58(m,4H) ,2.20-2.32(m,1H),2.02-2.11(m,2H),1.81-1.93(m,2H),1.51-1.81(m,9H),1.26-1.40(m,2H),1.01-1.21(m,2H).

[0240] Step 4:

[0241] Compound 5 (100.0 g, 292.9 mmol) was added to methanol (1.0 L), and 4M hydrochloric acid / methanol (732.2 mL) was added to the reaction system. The reaction was stirred at 25°C for 4 hours. The reaction was completed as detected by TLC and LCMS, and the reaction solution was concentrated under reduced pressure to dryness to obtain compound 6. LCMS (ESI) m / z: 242.1 [M+H] +

[0242] Step 5:

[0243] Compound 7 (40.0 g, 181.8 mmol), sodium carbonate (77.1 g, 727.0 mmol) and compound 6 (60.6 g, 218.1 mmol) were added to a reaction bottle containing acetonitrile (600.0 mL), and the reaction was stirred at 80° C. for 12 hours. LCMS detected that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure to dryness. Dichloromethane (1.0 L) and water (1.0 L) were added to the bottle containing the crude product for extraction and separation. The aqueous phase was extracted once with dichloromethane (1.0 L), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 8.

[0244] LCMS (ESI) m / z: 425.3 [M+H] +

[0245] 1 H NMR(400MHz,DMSO-d6)δ6.97-7.03(m,1H),4.03-4.14(m,1H),3.55-3.63(m,3H),3.33-3.39(m,6H),2.75-2.83(m,3H ),2.40-2.48(m,2H),2.28-2.39(m,1H),1.93-2.02(m,2H),1.78-1.88(m,2H),1.52-1.65(m,2H),1.30-1.45(m,2H).

[0246] Step 6:

[0247] Compound 8 (70.0 g, 164.7 mmol), compound 9 (30.3 g, 181.2 mmol) and p-toluenesulfonic acid monohydrate (109.7 g, 576.5 mmol) were added to a reaction bottle containing dioxane (1.1 L) in sequence, and the reaction was stirred at 100°C for 10 hours. LCMS detected that the raw materials reacted completely, the reaction solution was concentrated under reduced pressure to remove dioxane, water (550.0 mL) was added to the reaction solution until it was completely dissolved, saturated sodium hydroxide solution was added under stirring to adjust the pH to 11-12, a large amount of solid precipitated, stirred at room temperature for 30 minutes, filtered, the filter cake was rinsed with water (500 mL), and the filter cake was concentrated under reduced pressure to remove excess water to obtain the compound of formula (I).

[0248] LCMS (ESI) m / z: 556.4 [M+H] +

[0249] Example 2: Preparation of Crystalline Compound A of Formula (II)

[0250]

[0251] Methanol (600 mL) and 4 mol / L methanol solution of hydrochloric acid (108 mL) were added to a reaction flask containing the compound of formula (I) (60.0 g, 108.0 mmol). The reaction was stirred at 25 °C for 1 hour. A large amount of solid precipitated. The reaction solution was filtered, and the filter cake was rinsed with ethyl acetate (200.0 mL). The filter cake was dried to remove excess methanol to obtain crystalline A of the compound of formula (II).

[0252] 1 H NMR (400MHz, DMSO-d6)δ=11.35(brs,1H),9.29(s,1H),7.92(s,1H),7.60(s,1H),6.33-6.22(m,1H),4.44-4.37(m,1H),4.18-4.05(m,3H),4 .04-3.93(m,2H),3.71(s,3H),3.68-3.63(m,5H),3.28–2.99(m,4H), 2.71(s,3H),2.33-2.19(m,4H),2.05-1.85(m,4H),1.77-1.54(m,4H).

[0253] According to IC (ion chromatography) test, the Cl ion content of the compound of formula (II) crystal A is 11%. According to the IC calculation formula = N*Cl(MW) / [compound of formula (I) (MW)+N*Cl(MW) / ]=11%, it is calculated that N=2, so it is determined that the compound of formula (II) crystal A contains two molecules of hydrochloric acid.

[0254] Example 3: Preparation of Crystalline Compound A of Formula (I)

[0255] The compound of formula (II) crystal A (6.2 g, 9.9 mmol) was added to 50 mL of water, and the pH was adjusted to 8 with saturated sodium carbonate aqueous solution, followed by extraction with 50 mL*4 of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The combined organic phases were then added to 30 mL of methanol, stirred for 1 hour, filtered, and the filter cake was concentrated under reduced pressure to remove the solvent to obtain formula (I) crystal A.

[0256] Example 4: Preparation of Crystal A of Compound of Formula (III)

[0257]

[0258] 100 mg of the crystal A of the compound of formula (I) was weighed into 2 mL of anhydrous methanol at room temperature, and then 1.1 eq of sulfuric acid was added. It was observed that the mixed solution first became clear and a white solid precipitated after 30 seconds. The mixed system was stirred at room temperature for 4 hours and then heated to 50°C and stirred for 16 hours. There was no obvious change in the system phenomenon. Cool to room temperature, filter and concentrate to remove the solvent to obtain the crystal A of the compound of formula (III).

[0259] Example 5: Preparation of Crystal A of Compound of Formula (IV)

[0260]

[0261] 100 mg of crystal A of compound (I) was weighed at room temperature and added to 2 mL of anhydrous methanol, followed by the addition of 1.1 eq of methanesulfonic acid. A small amount of precipitation was observed in the mixed solution at first, and a white solid was precipitated after 5 minutes. The mixed system was stirred at room temperature for 4 hours and then heated to 50°C and stirred for 16 hours. There was no obvious change in the system phenomenon. The mixture was cooled to room temperature, filtered and concentrated to remove the solvent to obtain crystal A of compound (IV).

[0262] Example 6: Preparation of Crystalline A of Compound of Formula (V)

[0263]

[0264] 100 mg of the crystal A of the compound of formula (I) was weighed at room temperature and added to 2 mL of anhydrous methanol, followed by the addition of 1.1 eq of maleic acid. A very small amount of precipitation was observed in the mixed solution at first, and a white solid was precipitated after 30 seconds. The mixed system was stirred at room temperature for 4 hours and then heated to 50°C and stirred for 16 hours. There was no obvious change in the system phenomenon. The mixture was cooled to room temperature, filtered and concentrated to remove the solvent to obtain the crystal A of the compound of formula (V).

[0265] Example 7: Preparation of Crystal A of Compound of Formula (VI)

[0266]

[0267] 500 mg of the crystal A of the compound of formula (I) was weighed into 5 mL of anhydrous methanol at room temperature, and then 1.1 eq of p-toluenesulfonic acid was added. It was observed that the mixed solution became clear one minute after the addition of p-toluenesulfonic acid, and a white solid precipitated after about 30 seconds. After the mixed solution was reacted at 25°C for 4 hours, it was heated to 50°C and stirred for 12 hours to become clear. After continuing to stir for 24 hours, a white solid precipitated. Cool to room temperature, filter and concentrate to remove the solvent to obtain the crystal A of the compound of formula (VI).

[0268] Example 8: Polycrystalline Study

[0269] According to Table 7, the crystals of compound A of formula (II) were weighed into 5 mL reaction bottles, and a single solvent or a mixed solvent in Table 7 was added to form a suspension. The suspension samples were then placed on a constant temperature heating stirrer at 50°C and stirred for 2 days. After cooling to room temperature, the mixture was filtered and concentrated to remove the solvent, and the samples were arranged for XRPD testing.

[0270] Table 7. Solution suspension crystallization method for polymorphic studies

[0271] serial number Solvents Added mass (mg) Add volume (mL) 1 Methanol 100.3mg 2.0 2 Ethanol 100.1mg 2.0 3 Acetonitrile 100.5mg 2.0 4 acetone 100.7mg 2.0 5 Ethyl acetate 100.2mg 2.0 6 Tetrahydrofuran 100.5mg 2.0 7 Methanol: tert-butyl methyl ether (1:1) 100.8mg 2.0 8 Tert-butyl methyl ether 100.9mg 2.0 9 Toluene 100.3mg 2.0 10 n-Hexane 100.5mg 2.0 11 Methanol:water (v / v=93 / 7) 100.1mg 1.0 12 Methanol:water (v / v=85 / 15) 100.5mg 1.0 13 Ethanol: water (v / v = 95 / 5) 100.8mg 1.0

[0272] Experimental conclusion: XRPD results show that the diffraction peak positions of the above 13 batches of samples are consistent with those of the solid crystalline A of the compound of formula (II) in Example 2, and it is judged that all of them are crystalline A of the compound of formula (II).

[0273] Example 9: Study on the equilibrium solubility and biological media solubility of the crystal A of the compound of formula (II)

[0274] 1. Equilibrium solubility experiments in biological media and pH buffers

[0275] Weigh 12 portions of about 2 mg of the crystal A of compound (II) into a 2 mL glass bottle, add 1 mL of the medium after adding a magnetic rod, heat and stir on a stirrer at 37°C, if dissolved, add more compound until the concentration reaches 10 mg / mL, stir for 24 hours and take a sample, centrifuge the sample, take the upper layer of the clear liquid to determine its pH value, and then dilute it to a suitable multiple and determine its concentration using UPLC.

[0276] 2. Preparation of diluent and mobile phase

[0277] Diluent: Acetonitrile: Water (1:1) as diluent

[0278] For example: Mix 1L pure water and 1L pure acetonitrile in a glass bottle, degas by ultrasonic for 20 minutes, and cool to room temperature.

[0279] Mobile phase A: 0.1% FA aqueous solution

[0280] For example: Measure 2.0 mL of FA and add it to 2000 mL of water, sonicate for 20 minutes, mix well, and cool to room temperature as mobile phase A.

[0281] Mobile phase B: 0.1% FA ACN / MeOH (1:1) solution

[0282] For example: Mix 1L of methanol and 1L of pure acetonitrile in a glass bottle, measure 2.0mL of FA and add it to 2000mL of acetonitrile / methanol (1:1) solution, ultrasonicate for 20 minutes, mix well, and cool to room temperature as mobile phase B.

[0283] 3. Preparation of reference solution

[0284] Accurately weigh two 5 mg portions of the working standard of compound (II) crystal A into a sample bottle, add 10 mL of diluent, vortex mix for 5 min, and mix evenly. Prepare 2 portions in parallel and mark them as STD#1 and STD#2 respectively.

[0285] 4. Preparation of Linearization Solution

[0286] The reference solution STD#1 was diluted 1, 5, 10, 100, 1000, 2000 times, and recorded as linear solutions L1, L2, L3, L4, L5, and L6. The sample diluted 2000 times was recorded as LOQ.

[0287] 5 Experimental results

[0288] Table 8. Solubility test results in pH buffer and biological media

[0289]

[0290] Experimental conclusion: Referring to Table 9 for the description of solubility, when the compound of formula (II) crystalline A is added to 10 mg / mL of the compound at pH=1.00, pH=2.00, pH=3.8, water and SGF, the solution exhibits an opalescent state, and the solubility of the compound at pH=1.00, pH=2.00, pH=3.8, water and SGF is greater than 10 mg / mL; the solubility at pH=4.50 is slightly soluble, the solubility at pH=6.00 and FeSSIF is slightly soluble, the solubility at pH=5.00 and FaSSIF is very slightly soluble, and the solubility at pH=6.80 and pH=7.40 is almost insoluble or insoluble.

[0291] Table 9 Solubility description in Chinese Pharmacopoeia

[0292] describe Amount of solvent required for 1g of solute (mL) Solubility (mg / mL) Very soluble Less than 1 >1000 Soluble 1～10 100～1000 Dissolve 10～30 33.3～100 Slightly soluble 30～100 10～33.3 Slightly soluble 100～1000 1～10 Very slightly soluble 1000～10,000 0.1～1 Almost insoluble or insoluble >10,000 <0.1

[0293] Example 11: Approximate Solubility Studies

[0294] Weigh about 2.0 mg of sample into a 1.5 mL glass vial, gradually add water with a pipette, and sonicate to dissolve. The test is carried out at room temperature, and the dissolution is judged by the naked eye. The approximate solubility is shown in Table 10.

[0295] Table 10

[0296] Test compound Approximate solubility (mg / mL) Compound of formula (I) ＜1 Crystalline A of compound of formula (II) ＞100

[0297] Experimental conclusion: The approximate solubility of the compound of formula (II) crystal A in water is significantly improved compared with the compound of formula (I).

[0298] Example 12: Solid Stability Study

[0299] According to the "Guidelines for Stability Testing of APIs and Preparations" (Chinese Pharmacopoeia 2015 Edition Part IV General Rules 9001), the stability of the crystals of compound A of formula (II) under accelerated experimental conditions was investigated. About 10 mg of the crystals of compound A of formula (II) was weighed and placed at the bottom of a glass sample bottle, spread into a thin layer, sealed with aluminum foil and pierced with small holes, placed at (40°C / 75%RH) for 2 months and 3 months and (60°C / 75%RH) for 1 month and 2 months, and the samples after placement were characterized by XRPD, and the test results were compared with the initial test results of day 0. The results are shown in Table 11. The crystal form of the crystals of compound A of formula (II) did not change under all stability conditions.

[0300] The test results are shown in Table 11 below:

[0301] Table 11: Solid stability test results of crystal A of compound of formula (II)

[0302]

[0303] Experimental conclusion: Crystal A of compound of formula (II) has good stability.

[0304] Example 13: Hygroscopicity Study

[0305] 1. Operation process:

[0306] 1) Take two dry stoppered glass weighing bottles (outer diameter 50 mm, height 30 mm), place them in a drug stability test chamber (set temperature 25°C, relative humidity 80%) for balance, and accurately weigh the weight m1 of the weighing bottles after balance;

[0307] 2) Take an appropriate amount of the test sample and spread it flat in the two weighing bottles mentioned above. The thickness of the test sample is generally about 1mm. Accurately weigh the total weight m2;

[0308] 3) Open the weighing bottle and place it with the bottle cap under the above constant temperature and humidity conditions for 24 hours. Cover the weighing bottle cap and accurately weigh the total weight m3.

[0309] 2. Calculation and judgment basis

[0310] Calculation: Weight gain percentage = (m3-m2) / (m2-m1)×100%

[0311] Table 12: Basis for judging hygroscopicity

[0312] Description of hygroscopic characteristics Hygroscopic weight gain deliquescence Absorb enough water to form a liquid Highly hygroscopic The weight gain due to moisture absorption is not less than 15% Hygroscopic The weight gain due to moisture absorption is less than 15% but not less than 2%

[0313] Slightly hygroscopic The weight gain due to moisture absorption is less than 2% but not less than 0.2% No or almost no hygroscopicity The weight gain due to moisture absorption is less than 0.2%

[0314] 3. Test results

[0315] Table 13: Hygroscopicity test results of compound A of formula (II)

[0316]

[0317] Experimental conclusion: Crystal A of compound of formula (II) is slightly hygroscopic.

[0318] Test Example 1. Pharmacokinetic study of crystal A of compound of formula (II) in SD rats

[0319] Purpose

[0320] The pharmacokinetic study of the compound of formula (II) crystalline A in SD rats was evaluated to investigate the bioavailability after oral administration.

[0321] Experimental operation

[0322] The test compound was mixed with 5% dimethyl sulfoxide / 10% polyethylene glycol stearate / 85% aqueous solution, vortexed, and a 3 mg / mL clear solution was prepared for use. SD male rats aged 7 to 10 weeks were selected and orally administered with a solution of the candidate compound at a dose of 30 mg / kg. Whole blood was collected for a certain period of time to prepare plasma, and the drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in Table 14:

[0323] Table 14. Pharmacokinetic results of the tested compounds

[0324]

[0325] The results showed that the crystalline compound A of formula (II) had excellent solubility, could reach the peak quickly after oral administration at 30 mpk, and exhibited high oral absorption bioavailability.

Claims

1. A salt of a compound of formula (I), wherein the salt is selected from hydrochloride The hydrochloride salt of the compound of formula (I) is a compound of formula (II), 2. Crystallization of the compound of formula (II), Its X-ray powder diffraction pattern using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.25±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 20.00±0.20°, 21.53±0.20° and 21.79±0.20°.

3. The crystal of the compound of formula (II) according to claim 2, wherein the X-ray powder diffraction pattern using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°, 21.53±0.20°, 21.79±0.20°, 27.71±0.20° and 28.02±0.20°.

4. The crystal of the compound of formula (II) according to claim 3, wherein the X-ray powder diffraction pattern using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 16.41±0.20°, 19.46±0.20°, 20.00±0.20°, 20.57±0.20°, 21.53±0.20°, 21.79±0.20°, 27.71±0.20° and 28.02±0.20°.

5. The crystal of the compound of formula (II) according to claim 4, wherein the X-ray powder diffraction pattern using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.25±0.20°, 8.06±0.20°, 9.29±0.20°, 11.95±0.20°, 12.58±0.20°, 14.33±0.20°, 16.15±0.20°, 16.41±0.20°, 18.20±0.20°, 18.75±0.20°, 19.46±0.20°, 20.00±0.20° , 20.57±0.20°, 21.53±0.20°, 21.79±0.20°, 23.11±0.20°, 23.87±0.20°, 24.31±0.20°, 25.26±0.20°, 26.14±0.20°, 27.71±0.20°, 28.02±0.20°, 28.50±0.20°, 30.06±0.20°, 30.81±0.20° and 33.21±0.20°. 6 . The crystal of the compound of formula (II) according to any one of claims 2 to 5 , whose XRPD pattern using Cu Kα radiation is shown in FIG1 .

7. The crystal of the compound of formula (II) according to any one of claims 2 to 5, wherein the differential scanning calorimetry curve thereof has an onset of an endothermic peak at 262.9±5.0°C.

8. A crystalline composition comprising crystals of the compound of formula (II) according to any one of claims 2 to 7, wherein the crystals account for more than 50% by weight of the crystalline composition.

9. The crystalline composition according to claim 8, wherein the crystals account for more than 75% by weight of the crystalline composition.

10. The crystalline composition according to claim 9, wherein the crystals account for more than 90% by weight of the crystalline composition.

11. The crystalline composition according to claim 10, wherein the crystals account for more than 95% by weight of the crystalline composition.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (II) according to claim 1, or a crystal of a compound of formula (II) according to any one of claims 2 to 7, or a crystalline composition according to any one of claims 8 to 11; optionally, the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier or other excipient.

13. Use of the compound of formula (II) according to claim 1, or the crystal of the compound of formula (II) according to any one of claims 2 to 7, or the crystalline composition according to any one of claims 8 to 11, or the pharmaceutical composition according to claim 12 in the preparation of a drug for treating or preventing diseases associated with IRAK4.

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