Crystals and salts of tricyclic heterocyclic compounds and their applications

Abstract

The invention relates to the crystal of the compound of formula (I), its salt and the crystal of its salt, and their use in preparing drugs for treating or preventing diseases related to JAKs.

Description

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese Patent Application No. 202110578454.7 filed with the State Intellectual Property Office of the People's Republic of China on May 26, 2021, the entire contents of which are hereby incorporated by reference into this document in their entirety. Technical Field

[0003] The present application relates to the crystal of the compound of formula (I), its salt and the crystal of its salt, and the use thereof in the preparation of drugs for treating diseases related to JAKs. Background Art

[0004] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transmit cytokine signals from membrane receptors to STAT transcription factors. The JAK family contains four members: JAK1, JAK2, JAK3, and TYK2. The JAK-STAT pathway conducts extracellular signals from a variety of cytokines, growth factors, and hormones to the cell nucleus and is responsible for the expression of thousands of protein-coding genes. JAK-STAT intracellular signaling serves interferons, most interleukins, and a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL (Vainchenker W. et al. (2008)).

[0005] JAK-1, JAK-2 and TYK-2 are expressed in all tissue cells of the human body, while JAK-3 is mainly expressed in all hematopoietic tissue cells, mainly in bone marrow cells, thymocytes, NK cells and activated B lymphocytes and T lymphocytes. JAK1 has become a new target in the fields of immunity, inflammation and cancer. A base mutation JAK2V617F on the JAK2 gene in the human body is closely related to the occurrence of myeloproliferative diseases such as polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and chronic myeloid leukemia (CML). JAK3 or γc mutations can lead to severe combined immunodeficiency. Abnormal JAK3 activity is manifested as a large reduction in T cells and NK cells, loss of B cell function, and serious impact on the normal biological functions of the immune system. Based on its functional characteristics and special tissue distribution, JAK3 has become an attractive drug target for immune system-related diseases. In mice, TYK2 functional deficiency can cause defects in the signaling pathways of multiple cytokine receptors, leading to viral infection, decreased antibacterial immune function and increased possibility of lung infection, etc. (John J.O'Shea, 2004, Nature Reviews Drug Discovery 3, 555-564). Different JAK family members selectively bind to different cytokine receptors, conferring signal transduction specificity, thereby exerting different physiological effects. This selective mode of action allows JAK inhibitors to be relatively specifically applied to disease treatment. For example, IL-2 or IL-4 receptors bind to JAK1 and JAK3 together with a common γ chain, while type I receptors with the same β chain bind to JAK2. Type I receptors using gp130 (glycoprotein 130) and type I receptors activated by heterodimeric cytokines preferentially bind to JAK1 / 2 and TYK2. Type I receptors activated by hormone-like cytokines bind to and activate JAK2 kinases. The type II receptor of interferon binds to JAK1 and TYK2, while the receptor of the IL-10 cytokine family binds to JAK1 / 2 and TYK2. The various specific bindings of the cytokines and their receptors to the JAK family members trigger different physiological effects, providing the possibility for the treatment of different diseases. JAK1 is heterodimerized with other JAKs to transduce cytokine-driven pro-inflammatory signaling. Therefore, it is expected that inhibition of JAK1 and / or other JAKs will have therapeutic benefits for a range of inflammatory conditions and other diseases driven by JAK-mediated signal transduction (Daniella M. Schwartz, 2017, Nature Reviews Drug Discovery 16, 843-862.) Summary of the invention

[0006] In one aspect, the present application provides a compound of formula (I) or a salt thereof

[0007] In some embodiments, the salt of the compound of formula (I) is selected from a phosphate or an oxalate.

[0008] In another aspect, the present application provides a crystal of the compound of formula (I) or a salt thereof.

[0009] In some embodiments, the present application provides a crystal of a phosphate salt of the compound of formula (I) or a crystal of an oxalate salt of the compound of formula (I).

[0010] On the one hand, the present application provides a type A crystal of the compound of formula (I), which has diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 5.74±0.20°, 7.23±0.20° and 12.28±0.2°;

[0011]

[0012] In some embodiments of the present application, the Type A crystal of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 9.25±0.20°, 12.28±0.20° and 14.46±0.2°.

[0013] In some embodiments of the present application, the type A crystal of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kαɑ radiation having diffraction peaks at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 9.25±0.20°, 12.28±0.2°, 14.46±0.2°, 14.89±0.2° and 21.06±0.2°.

[0014] In some embodiments of the present application, the X-ray powder diffraction pattern of type A crystals of the compound of formula (I) using Cu Kαɑ radiation has diffraction peaks at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 9.25±0.20°, 1228±0.20°, 14.46±0.20°, 14.89±0.20°, 15.75±0.20°, 16.82±0.20°, 19.37±0.20° and 21.06±0.20°.

[0015] In some embodiments of the present application, the X-ray powder diffraction pattern of the A-type crystal of the compound of formula (I) using Cu Kαɑ radiation has diffraction peaks at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 8.80±0.20°, 9.25±0.20°, 12.28±0.20°, 14.23±0.20°, 14.46±0.20°, 14.89±0.20°, 15.75±0.20°, 16.82±0.20°, 17.32±0.20°, 17.84±0.20°, 19.37±0.20°, 21.06±0.20°, 22.76±0.20°, 24.11±0.20°, 26.16±0.20°, 26.76±0.20° and 27.16±0.20°.

[0016] In some embodiments of the present application, the type A crystal of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kαɑ radiation having diffraction peaks at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 9.25±0.20°, 9.64±0.20°, 10.50±0.20°, 12.28±0.20° and 14.46±0.2°.

[0017] In some embodiments of the present application, the X-ray powder diffraction pattern of type A crystals of the compound of formula (I) using Cu Kαa2 radiation has diffraction peaks at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 9.25±0.20°, 9.64±0.20°, 10.50±0.20°, 12.28±0.2°, 14.46±0.2°, 14.89±0.2° and 21.06±0.2°.

[0018] In some embodiments of the present application, the A-type crystal of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kαɑ radiation having diffraction peaks at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 9.25±0.20°, 9.64±0.20°, 10.50±0.20°, 12.28±0.20°, 14.46±0.20°, 14.89±0.20°, 15.75±0.20°, 16.82±0.20°, 19.37±0.20° and 21.06±0.20°.

[0019] In some embodiments of the present application, the A-type crystal of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kαɑ radiation at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 8.80±0.20°, 9.25±0.20°, 9.64±0.20°, 10.50±0.20°, 12.28±0.20°, 14.23±0.20°, 14.46±0.20°, 1 4.89±0.20°, 15.75±0.20°, 16.82±0.20°, 17.32±0.20°, 17.84±0.20°, 19.37±0.20°, 21.06±0.20°, 22.76±0.20°, 24.11±0.20°, 26.16±0.20°, 26.76±0.20° and 27.16±0.20°.

[0020] On the other hand, the present application provides type A crystals of the compound of formula (I), which has an X-ray powder diffraction pattern using Cu Kαɑ radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks selected from the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 9.25±0.20°, 12.28±0.20°, 14.46±0.20°, 14.89±0.20°, 15.75±0.20°, 16.82±0.20°, 19.37±0.20° and 21.06±0.20°.

[0021] On the other hand, the present application provides type A crystals of a compound of formula (I), which has an X-ray powder diffraction pattern using Cu Kαɑ radiation, comprising 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 9.25±0.20°, 12.28±0.2°, 14.46±0.2°, 14.89±0.2° and 21.06±0.2°.

[0022] In some embodiments of the present application, the XRPD pattern of the type A crystal of the compound of formula (I) is as follows: Figure 1 shown.

[0023] In some embodiments of the present application, in the XRPD pattern of the type A crystal of the compound of formula (I), the diffraction peak positions and relative intensities of the X-ray powder diffraction pattern using Cu Kα radiation are shown in Table 1:

[0024] Table 1: XRPD data of type A crystal of compound of formula (I)

[0025] serial number 2θ[±0.20°] Relative strength [%] serial number 2θ[±0.20°] Relative strength [%] 1 5.26 19.49 12 16.82 10.67 2 5.74 37.39 13 17.32 6.18 3 7.23 100.00 14 17.84 9.24 4 8.80 7.43 15 19.37 11.38 5 9.25 25.32 16 21.06 16.32 6 10.50 5.16 17 22.76 8.73 7 12.28 47.04 18 24.11 5.60 8 14.23 17.55 19 26.16 9.76 9 14.46 39.79 20 26.76 6.91 10 14.89 11.33 21 27.16 7.08 11 15.75 10.70

[0026] In some embodiments of the present application, the differential scanning calorimetry (DSC) spectrum of the Type A crystal of the compound of formula (I) has an exothermic peak starting point at 188.8±3°C.

[0027] In some embodiments of the present application, the DSC spectrum of the type A crystal of the compound of formula (I) is as follows: Figure 2 shown.

[0028] In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of type A crystals of the compound of formula (I) shows a weight loss of 3.13% at 200±3°C.

[0029] In some embodiments of the present application, the TGA spectrum of the type A crystal of the compound of formula (I) is as follows: Figure 3 shown.

[0030] On the other hand, the present application provides a method for preparing type A crystals of a compound of formula (I), the method comprising the following steps: the compound of formula (I) is dissolved in ethanol to precipitate a solid. In some embodiments, the compound of formula (I) is mixed with ethanol, and the solution of the compound of formula (I) is clarified by heating and stirring. In some embodiments, after the compound of formula (I) is dissolved in ethanol, the resulting solution is cooled to precipitate a solid. In some embodiments, the above method further comprises the steps of isolating the solid and then drying the solid; optionally, drying is performed under vacuum conditions.

[0031] On the other hand, the present application also provides a type B crystal of the compound of formula (I), which has diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 5.08±0.20°, 9.78±0.20° and 13.76±0.20°.

[0032] In some embodiments of the present application, the B-type crystals of the compound of formula (I) have an X-ray powder diffraction pattern using CuKα radiation having diffraction peaks at the following 2θ angles: 5.08±0.20°, 9.78±0.20°, 13.76±0.20°, 18.96±0.20° and 24.34±0.20°.

[0033] In some embodiments of the present application, the X-ray powder diffraction pattern of the B-type crystals of the compound of formula (I) using CuKα radiation has diffraction peaks at the following 2θ angles: 5.08±0.20°, 9.78±0.20°, 13.76±0.20°, 15.80±0.20°, 18.96±0.20°, 19.61±0.20° and 24.34±0.20°.

[0034] In some embodiments of the present application, the B-type crystals of the compound of formula (I) have an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 5.08±0.20°, 6.31±0.20°, 9.78±0.20°, 13.76±0.20°, 15.80±0.20°, 18.96±0.20°, 19.61±0.20° and 24.34±0.20°.

[0035] In some embodiments of the present application, the X-ray powder diffraction pattern of type B crystals of the compound of formula (I) using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.08±0.20°, 6.31±0.20°, 9.78±0.20°, 11.75±0.20°, 13.76±0.20°, 14.17±0.20°, 15.80±0.20°, 18.96±0.20°, 19.61±0.20°, 23.87 / 0.20° and 24.34±0.20°.

[0036] On the other hand, the present application provides a type B crystal of a compound of formula (I), which has an X-ray powder diffraction pattern using Cu Kα radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks selected from the following 2θ angles: 5.08±0.20°, 6.31±0.20°, 9.78±0.20°, 11.75±0.20°, 13.76±0.20°, 14.17±0.20°, 15.80±0.20°, 18.96±0.20°, 19.61±0.20°, 23.87±0.20° and 24.34±0.20°.

[0037] On the other hand, the present application provides a type B crystal of a compound of formula (I), which 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: 5.08±0.20°, 6.31±0.20°, 9.78±0.20°, 13.76±0.20°, 15.80±0.20°, 18.96±0.20°, 19.61±0.20° and 24.34±0.20°.

[0038] In some embodiments of the present application, the XRPD pattern of the type B crystal of the compound of formula (I) is as follows: Figure 4 shown.

[0039] In some embodiments of the present application, in the XRPD pattern of the B-type crystal of the compound of formula (I), the peak position and relative intensity of the diffraction peak of the X-ray powder diffraction pattern using Cu Kα radiation are shown in Table 2:

[0040] Table 2: XRPD data of type B crystal of compound of formula (I)

[0041] serial number 2θ[±0.20°] Relative strength [%] serial number 2θ[±0.20°] Relative strength [%] 1 5.08 100.00 7 15.80 5.51 2 6.31 4.73 8 18.96 7.60 3 9.78 46.35 9 19.61 6.83 4 11.75 3.95 10 23.87 5.59 5 13.76 53.39 11 24.34 9.98 6 14.17 9.88

[0042] In some embodiments of the present application, the differential scanning calorimetry (DSC) spectrum of the Type B crystal of the compound of formula (I) has an endothermic peak starting point at 172.9±3°C.

[0043] In some embodiments of the present application, the DSC spectrum of the type B crystal of the compound of formula (I) is as follows: Figure 5 shown.

[0044] In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of type B crystals of the compound of formula (I) shows a weight loss of 5.18% at 150±3°C.

[0045] In some embodiments of the present application, the TGA spectrum of the type B crystal of the compound of formula (I) is as follows: Figure 6 shown.

[0046] On the other hand, the present application provides a method for preparing type B crystals of the compound of formula (I), the method comprising the following steps: mixing the compound of formula (I) with DMF and MEK, and precipitating and separating to obtain a solid.

[0047] In some embodiments, the precipitation process is carried out at -20°C to room temperature.

[0048] In some embodiments, the above method further comprises the step of drying the separated solid; optionally, drying at room temperature.

[0049] On the other hand, the present application also provides a C-type crystal of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 6.21±0.20°, 9.04±0.20° and 12.38±0.20°.

[0050] In some embodiments of the present application, the C-type crystals of the compound of formula (I) have an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 6.21±0.20°, 9.04±0.20°, 11.54±0.20°, 12.38±0.20° and 23.29±0.20°.

[0051] In some embodiments of the present application, the C-type crystals of the compound of formula (I) have an X-ray powder diffraction pattern using CuKα radiation having diffraction peaks at the following 2θ angles: 6.21±0.20°, 9.04±0.20°, 11.54±0.20°, 12.38±0.20°, 16.27±0.20°, 23.29±0.20° and 25.62±0.20°.

[0052] On the other hand, the present application provides type C crystals of the compound of formula (I), which has an X-ray powder diffraction pattern using Cu Kα radiation, comprising 3, 4, 5, 6 or 7 diffraction peaks selected from the following 2θ angles: 6.21±0.20°, 9.04±0.20°, 11.54±0.20°, 12.38±0.20°, 16.27±0.20°, 23.29±0.20° and 25.62±0.20°.

[0053] In some embodiments of the present application, the XPRDD pattern of the C-type crystal of the compound of formula (I) is as follows: Figure 7 shown.

[0054] In some embodiments of the present application, in the XRPD pattern of the C-type crystal of the compound of formula (I), the peak position and relative intensity of the diffraction peak of the X-ray powder diffraction pattern using Cu Kα radiation are shown in Table 3:

[0055] Table 3: XRPD pattern analysis data of type C crystal of compound of formula (I)

[0056] serial number 2θ[±0.20°] Relative strength [%] serial number 2θ[±0.20°] Relative strength [%] 1 6.21 100.00 5 16.27 3.54 2 9.04 29.07 6 23.29 4.79 3 11.54 6.28 7 25.62 4.26 4 12.38 18.89

[0057] In some embodiments of the present application, the differential scanning calorimetry (DSC) spectrum of the type C crystal of the compound of formula (I) has an endothermic peak starting point at 140.2±3°C.

[0058] In some embodiments of the present application, the DSC spectrum of the type C crystal of the compound of formula (I) is as follows: Figure 8 shown.

[0059] In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of type C crystals of the compound of formula (I) shows a weight loss of 3.10% at 130±3°C.

[0060] In some embodiments of the present application, the TGA spectrum of the type C crystal of the compound of formula (I) is as follows: Fig. 9 shown.

[0061] In another aspect, the present application provides a method for preparing type C crystals of the compound of formula (I), the method comprising the following steps: dissolving the compound of formula (I) in ACN, and cooling to precipitate a solid.

[0062] In some embodiments of the present application, in the above preparation method, after dissolving the compound of formula (I) in ACN, a filtration operation is further included; optionally, a 0.45 micron PTFE filter head is used for the filtration.

[0063] In some embodiments of the present application, the above-mentioned cooling refers to cooling from 50°C to 5°C at a rate of 0.1°C / min.

[0064] In some embodiments of the present application, the above method further comprises the steps of isolating the solid and then drying the solid; optionally, drying at room temperature.

[0065] On the other hand, the present application also provides a D-type crystal of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 7.13±0.20°, 18.22±0.20° and 21.45±0.20°.

[0066] In some embodiments of the present application, the D-type crystals of the compound of formula (I) have an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 7.13±0.20°, 10.04±0.20°, 11.24±0.20°, 15.97±0.20°, 18.22±0.20° and 21.45±0.20°.

[0067] In some embodiments of the present application, the D-type crystals of the compound of formula (I) have an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 7.13±0.20°, 10.04±0.20°, 11.24±0.20°, 15.97±0.20°, 16.94±0.20°, 18.22±0.20°, 21.45±0.20° and 22.71±0.20°.

[0068] In some embodiments of the present application, the D-type crystals of the compound of formula (I) have an X-ray powder diffraction pattern using Cu Kα radiation having diffraction peaks at the following 2θ angles: 7.13±0.20°, 10.04±0.20°, 11.24±0.20°, 15.97±0.20°, 16.94±0.20°, 18.22±0.20°, 20.28±0.20°, 21.45±0.20°, 22.71±0.20° and 26.21±0.20°.

[0069] On the other hand, the present application provides a D-type crystal of a compound of formula (I), which has an X-ray powder diffraction pattern using Cu Kα radiation, comprising 3, 4, 5, 6, 7, 8, 9 or 10 diffraction peaks selected from the following 2θ angles: 7.13±0.20°, 10.04±0.20°, 11.24±0.20°, 15.97±0.20°, 16.94±0.20°, 18.22±0.20°, 20.28±0.20°, 21.45±0.20°, 22.71±0.20° and 26.21±0.20°.

[0070] On the other hand, the present application provides a D-type crystal of a compound of formula (I), which 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: 7.13±0.20°, 10.04±0.20°, 11.24±0.20°, 15.97±0.20°, 16.94±0.20°, 18.22±0.20°, 21.45±0.20° and 22.71±0.20°.

[0071] In some embodiments of the present application, the XRPD pattern of the D-type crystal of the compound of formula (I) is as follows: Fig.10 shown.

[0072] In some embodiments of the present application, in the XRPD of the D-type crystal of the compound of formula (I), the peak position and relative intensity of the diffraction peak of the X-ray powder diffraction pattern using Cu Kα radiation are shown in Table 4:

[0073] Table 4: XRPD pattern analysis data of type D crystal of compound of formula (I)

[0074] serial number 2θ[±0.20°] Relative strength [%] serial number 2θ[±0.20°] Relative strength [%] 1 7.13 100.00 6 18.22 26.78 2 10.04 8.44 7 20.28 7.27 3 11.24 13.76 8 21.45 25.17 4 15.97 12.42 9 22.71 10.84 5 16.94 11.92 10 26.21 8.07

[0075] In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of the D-type crystal of the compound of formula (I) shows a weight loss of 1.83% at 140±3°C.

[0076] In some embodiments of the present application, the TGA spectrum of the D-type crystal of the compound of formula (I) is as follows: Fig.11 shown.

[0077] On the other hand, the present application provides a method for preparing type D crystals of the compound of formula (I), the method comprising the following steps: mixing the compound of formula (I) with maleic acid and acetone, and separating the solid.

[0078] In some embodiments of the present application, the above method further comprises the step of drying the separated solid; optionally, the drying is performed at room temperature under vacuum conditions.

[0079] On the other hand, the present application also provides a phosphate of the compound of formula (I).

[0080] In another aspect, the present application also provides a crystal of the phosphate salt of the compound of formula (I).

[0081] In some embodiments of the present application, in the phosphate of the compound of formula (I), the molecular ratio of the compound of formula (I) to phosphoric acid is 1:(1-1.5); in some embodiments, the molecular ratio of the compound of formula (I) to phosphoric acid is 1:1.

[0082] In some embodiments of the present application, the phosphate salt of the compound of formula (I) is a compound of formula (II),

[0083]

[0084] In some embodiments of the present application, the phosphate salt of the compound of formula (I) is a crystal of the phosphate salt of the compound of formula (I).

[0085] On the other hand, the present application also provides a crystal of phosphate of the compound of formula (I), which has diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 7.87±0.20°, 16.64±0.20° and 20.04±0.20°.

[0086] In some embodiments of the present application, the crystalline phosphate of the compound of formula (I) has a diffraction peak at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 16.64±0.20° and 20.04±0.20°.

[0087] In some embodiments of the present application, the crystalline phosphate of the compound of formula (I) has a diffraction peak at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 16.64±0.20°, 20.04±0.20°, 21.73±0.20°, 26.17±0.20° and 28.11±0.20°.

[0088] In some embodiments of the present application, the crystalline phosphate of the compound of formula (I) has a diffraction peak at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 15.21±0.20°, 16.64±0.20°, 20.04±0.20°, 21.73±0.20°, 22.21±0.20°, 25.07±0.20°, 26.17±0.20°, 26.81±0.20° and 28.11±0.20°.

[0089] In some embodiments of the present application, the crystalline phosphate of the compound of formula (I) has a diffraction peak at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 15.21±0.20°, 16.64±0.20°, 20.04±0.20°, 21.73±0.20°, 2221±0.20°, 23.66±0.20°, 25.07±0.20°, 26.17±0.20°, 26.81±0.20°, 27.50±0.20° and 28.11±0.20°.

[0090] In some embodiments of the present application, the phosphate salt of the compound of formula (I) has a diffraction peak at the following 2θ angles in an X-ray powder diffraction pattern using Cu Kα radiation: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 15.21±0.20°, 16.64±0.20°, 20.04±0.20°, 21.73±0.20°, 22.21±0.20°, 23.66±0.20°, 25.07±0.20°, 25.94±0.20°, 26.17±0.20°, 26.81±0.20°, 27.50±0.20°, 28.11±0.20°, 29.06±0.20° and 29.85±0.20°.

[0091] On the other hand, the present application provides a crystal of a phosphate of a compound of formula (I), which comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 15.21±0.20°, 16.64±0.20°, 20.04±0.20°, 21.73±0.20°, 22.21±0.20°, 23.66±0.20°, 25.07±0.20°, 26.17±0.20°, 26.81±0.20°, 27.50±0.20° and 28.11±0.20°.

[0092] On the other hand, the present application provides a crystal of a phosphate of a compound of formula (I), which 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: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 16.64±0.20°, 20.04±0.20°, 21.73±0.20°, 26.17±0.20° and 28.11±0.20°.

[0093] In some embodiments of the present application, the XRPD pattern of the crystal of the phosphate salt of the compound of formula (I) is as follows: Fig.12 shown.

[0094] In some embodiments of the present application, in the XRPD pattern of the crystal of the phosphate of the compound of formula (I), the peak position and relative intensity of the diffraction peak of the X-ray powder diffraction pattern using Cu Kα radiation are shown in Table 5:

[0095] Table 5: XRPD data of the crystals of the phosphate salt of the compound of formula (I)

[0096] serial number 2θ[±0.20°] Relative strength [%] serial number 2θ[±0.20°] Relative strength [%] 1 6.69 50.68 11 23.66 10.28 2 7.87 100.00 12 25.07 16.28 3 14.15 43.11 13 25.94 13.52 4 15.21 16.29 14 26.17 22.03 5 16.64 80.67 15 26.81 18.85 6 18.28 4.91 16 27.50 12.14 7 20.04 59.77 17 28.11 44.87 8 21.30 6.15 18 29.06 3.59 9 21.73 20.72 19 29.85 3.19 10 22.21 12.94

[0097] In some embodiments of the present application, the differential scanning calorimetry (DSC) spectrum of the crystal of the phosphate salt of the compound of formula (I) has an exothermic peak starting point at 141.9±3.0°C.

[0098] In some embodiments of the present application, the DSC spectrum of the crystal of the phosphate of the compound of formula (I) is as follows: Fig.13 shown.

[0099] In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of the crystals of the phosphate salt of the compound of formula (I) shows a weight loss of 5.50% at 130±3°C.

[0100] In some embodiments of the present application, the TGA spectrum of the crystal of the phosphate of the compound of formula (I) is as follows: Fig.14 shown.

[0101] In another aspect, the present application provides a method for preparing a crystal of a phosphate of a compound of formula (I), the method comprising the following steps: reacting a compound of formula (I) with phosphoric acid, EtOH and H 2 O mixed and a solid was separated.

[0102] In some embodiments of the present application, the preparation method comprises stirring under heating conditions after the mixing; optionally, stirring under heating conditions of 40 to 80° C.; optionally, stirring under heating conditions of 50° C.

[0103] In some embodiments of the present application, the above method further comprises the step of drying the separated solid; optionally, drying at room temperature and vacuum conditions.

[0104] On the other hand, the present application also provides the oxalate of the compound of formula (I).

[0105] In some embodiments of the present application, in the oxalate of the compound of formula (I), the molecular ratio of the compound of formula (I) to oxalic acid is 1:(1-1.5); in some embodiments, the molecular ratio of the compound of formula (I) to oxalic acid is 1:1.1.

[0106] In some embodiments of the present application, the oxalate of the compound of formula (I) is a compound of formula (III),

[0107]

[0108] In some embodiments of the present application, the oxalate of the compound of formula (I) is a crystal of the oxalate of the compound of formula (I), such as type I crystal of the oxalate of the compound of formula (I) or type II crystal of the oxalate of the compound of formula (I).

[0109] On the other hand, the present application also provides type I crystals of oxalate of the compound of formula (I), which has diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 5.06±0.20°, 12.69±0.20° and 15.21±0.20°.

[0110] In some embodiments of the present application, the X-ray powder diffraction pattern of type I crystals of the oxalate salt of the compound of formula (I) using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.06±0.20°, 12.69±0.20°, 15.21±0.20°, 17.92±0.20°, 20.77±0.20° and 27.32±0.20°.

[0111] In some embodiments of the present application, the X-ray powder diffraction pattern of type I crystals of the oxalate salt of the compound of formula (I) using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.06±0.20°, 11.28±0.20°, 12.69±0.20°, 15.21±0.20°, 16.48±0.20°, 17.92±0.20°, 19.52±0.20°, 20.77±0.20°, 22.90±0.20° and 27.32±0.20°.

[0112] On the other hand, the present application provides type I crystals of oxalate of the compound of formula (I), which comprises 3, 4, 5 or 6 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 5.06±0.20°, 12.69±0.20°, 15.21±0.20°, 17.92±0.20°, 20.77±0.20° and 27.32±0.20°.

[0113] In some embodiments of the present application, the XRPD pattern of the type I crystal of the oxalate salt of the compound of formula (I) is as follows: Fig.15 shown.

[0114] In some embodiments of the present application, in the XRPD pattern of the type I crystal of the oxalate of the compound of formula (I), the peak positions and relative intensities of the diffraction peaks of the X-ray powder diffraction pattern using Cu Kα radiation are shown in Table 6:

[0115] Table 6: XRPD data of type I crystal of oxalate salt of compound of formula (I)

[0116] serial number 20[±0.20°] Relative strength [%] serial number 20[±0.20°] Relative strength [%] 1 5.06 100.00 7 17.92 9.17 2 10.03 2.21 8 19.52 3.45 3 11.28 3.74 9 20.77 6.05 4 12.69 16.97 10 22.90 4.48 5 15.21 40.90 11 27.32 8.78 6 16.48 4.02

[0117] In some embodiments of the present application, the DSC spectrum of the type I crystal of the oxalate salt of the compound of formula (I) is as follows: Fig.16 shown.

[0118] In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of type I crystals of the oxalate salt of the compound of formula (I) shows a weight loss of 11.44% at 150±3°C.

[0119] In some embodiments of the present application, the TGA spectrum of the type I crystal of the oxalate salt of the compound of formula (I) is as follows: Fig.17 shown.

[0120] On the other hand, the present application provides a method for preparing type I crystals of oxalate of the compound of formula (I), the method comprising the following steps: mixing the compound of formula (I) with oxalic acid and acetone, and separating the solid.

[0121] In some embodiments of the present application, the preparation method comprises stirring under heating after the mixing; optionally, the heating temperature is 40 to 80°C; optionally, the heating temperature is 50°C.

[0122] In some embodiments of the present application, the above method further comprises the step of drying the separated solid; optionally, the drying is performed at room temperature under vacuum conditions.

[0123] On the other hand, the present application also provides type II crystals of oxalate of the compound of formula (I), which has diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 5.44±0.20°, 11.75±0.20° and 13.77±0.20°.

[0124] In some embodiments of the present application, the X-ray powder diffraction pattern of type II crystals of the oxalate salt of the compound of formula (I) using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.44±0.20°, 10.85±0.20°, 11.75±0.20°, 13.77±0.20°, 16.27±0.20° and 27.42±0.20°.

[0125] In some embodiments of the present application, the X-ray powder diffraction pattern of type II crystals of the oxalate salt of the compound of formula (I) using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.44±0.20°, 10.85±0.20°, 11.75±0.20°, 13.77±0.20°, 16.01±0.20°, 16.27±0.20°, 23.39±0.20° and 27.42±0.20°.

[0126] In some embodiments of the present application, the X-ray powder diffraction pattern of type II crystals of the oxalate salt of the compound of formula (I) using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.44±0.20°, 10.85±0.20°, 11.75±0.20°, 13.77±0.20°, 16.01±0.20°, 16.27±0.20°, 17.85±0.20°, 18.39±0.20°, 20.83±0.20°, 21.75±0.20°, 23.39±0.20°, 25.13±0.20° and 27.42±0.20°.

[0127] On the other hand, the present application provides Type II crystals of oxalate of the compound of formula (I), which comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 diffraction peaks selected from the following 2θ angles in its X-ray powder diffraction pattern using Cu Kα radiation: 5.44±0.20°, 10.85±0.20°, 11.75±0.20°, 13.77±0.20°, 16.01±0.20°, 16.27±0.20°, 17.85±0.20°, 18.39±0.20°, 20.83±0.20°, 21.75±0.20°, 23.39±0.20°, 25.13±0.20° and 27.42±0.20°.

[0128] On the other hand, the present application provides Type II crystals of the oxalate salt of the compound of formula (I), which 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: 5.44±0.20°, 10.85±0.20°, 11.75±0.20°, 13.77±0.20°, 16.01±0.20°, 16.27±0.20°, 23.39±0.20° and 27.42±0.20°.

[0129] In some embodiments of the present application, the XRPD pattern of the type II crystal of the oxalate salt of the compound of formula (I) is as follows: Fig.18 shown.

[0130] In some embodiments of the present application, in the XRPD pattern of the type II crystal of the oxalate of the compound of formula (I), the peak position and relative intensity of the diffraction peak of the X-ray powder diffraction pattern using Cu Kα radiation are shown in Table 7:

[0131] Table 7: XRPD data of type II crystals of oxalate salt of compound of formula (I)

[0132]

[0133]

[0134] In some embodiments of the present application, the DSC spectrum of the type II crystal of the oxalate salt of the compound of formula (I) is as follows: Fig.19 shown.

[0135] In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of the type II crystal of the oxalate salt of the compound of formula (I) shows a weight loss of 7.78% at 150±3°C.

[0136] In some embodiments of the present application, the TGA spectrum of the type II crystal of the oxalate salt of the compound of formula (I) is as follows: Fig. 20 shown.

[0137] In another aspect, the present application provides a method for preparing type II crystals of oxalate of a compound of formula (I), the method comprising the following steps: reacting the compound of formula (I) with oxalic acid, EtOH and H 2 O mixed and a solid was separated.

[0138] In some embodiments of the present application, the preparation method comprises stirring under heating after the mixing; optionally, stirring at 40 to 80° C.; optionally, stirring at 50° C.

[0139] In some embodiments of the present application, the above-mentioned preparation method further includes a drying step; optionally, the drying is performed at room temperature under vacuum conditions.

[0140] On the other hand, the present application provides a crystalline composition comprising the crystals described in the present application, wherein the crystals account for more than 50% of the weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.

[0141] On the other hand, the present application provides a pharmaceutical composition, which comprises a therapeutically effective amount of a crystal of a compound of formula (I) described in the present application, a salt of a compound of formula (I) or its crystal, or a crystal composition thereof. The pharmaceutical composition of the present application may contain or not contain a pharmaceutically acceptable excipient. In addition, the pharmaceutical composition of the present application may further include one or more other therapeutic agents. In some embodiments, the present application provides a solid pharmaceutical composition, which comprises a therapeutically effective amount of a crystal of a compound of formula (I) described in the present application, a salt of a compound of formula (I) or its crystal, or a crystal composition thereof.

[0142] On the other hand, the present application also provides the use of the crystals of the compound of formula (I), the salt of the compound of formula (I) or its crystals, their crystalline compositions, or their pharmaceutical compositions described in the present application in the preparation of drugs for treating or preventing JAK1 and / or JAK2 related diseases.

[0143] On the other hand, the present application also provides the use of the crystals of the compound of formula (I), the salts of the compound of formula (I) or its crystals, their crystalline compositions, or their pharmaceutical compositions described in the present application in the treatment or prevention of JAK1 and / or JAK2 related diseases.

[0144] In another aspect, the present application also provides crystals of the compound of formula (I), salts of the compound of formula (I) or crystals thereof, crystal compositions thereof, or pharmaceutical compositions thereof as described in the present application for treating or preventing JAK1 and / or JAK2 related diseases.

[0145] On the other hand, the present application also provides a method for treating or preventing JAK1 and / or JAK2 related diseases, comprising administering a therapeutically effective amount of a crystal of a compound of formula (I) described in the present application, a salt of the compound of formula (I) or its crystals, a crystalline composition thereof, or a pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment.

[0146] In the present application, the JAK1 and / or JAK2 related diseases are selected from inflammatory disorders (eg, arthritis) and the like.

[0147] Technical Effects

[0148] The compounds, crystals, salts and crystals of their salts of the present application show good selective inhibition of JAK1 and / or JAK2 in the in vitro activity tests of the four subtypes of Janus kinases, JAK1, JAK2, JAK3 and TYK2; they can have good oral bioavailability, high exposure, good pharmacokinetic properties and good in vivo efficacy in the animals to be tested. The crystals of the compound of formula (I) of the present application, its salts and crystals of its salts can show advantages such as stable physicochemical properties, little influence by light, heat and humidity, good solubility, and not easy to undergo crystal transformation, which is conducive to drug development.

[0149] Definition and Description

[0150] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term 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.

[0151] 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 form, there may be an error in the position of the peak, and the measurement error of the 2θ value may be ±0.2°. Therefore, when determining each crystal form, this error should be taken into account, and the value within the error range also belongs to the scope of this application.

[0152] It should be noted that for the same crystal form, 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 form, the position of the endothermic peak may have an error, which may be ±5°C or ±3°C. Therefore, when determining each crystal form, this error should be taken into account, and the value within the error range also belongs to the scope of this application.

[0153] The word “comprise” or “comprises” and its English variations such as comprises or comprising should be construed as having an open and non-exclusive meaning, ie, “including but not limited to”.

[0154] "Pharmaceutically acceptable excipients" refer to inert substances that are administered together with the active ingredient and are conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is acceptable for human or animal (e.g., livestock) and approved by the State Food and Drug Administration. Non-limiting examples of the excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0155] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0156] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0157] Typical routes of administration of the crystals described herein or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0158] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0159] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0160] The therapeutic dose of the compounds of the present application may be determined, for example, based on the specific purpose of the treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. The term "treatment" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0161] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0162] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0163] 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.

[0164] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or 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.

[0165] The therapeutically effective amount of the crystals described herein is from about 0.0001 to 20 mg / Kg body weight / day, such as from 0.001 to 10 mg / Kg body weight / day.

[0166] The dosage frequency of the crystals described herein is determined by the needs of the individual patient, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, wherein during a period of several days, the patient receives a daily dose of the crystals, and then during a period of several days or more days, the patient does not receive a daily dose of the crystals.

[0167] Herein, singular terms encompass plural referents and vice versa unless the context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0168] Unless otherwise indicated, in this article, parameter values ​​should be understood as modified by the term "about". When the term "about" is used to describe a parameter of the present application, the term "about" indicates an error value that exists, such as a change within the range of ±5%, such as ±1% or ±0.1% of a particular value.

[0169] For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

[0170] The present application will be described in detail below through examples, which do not imply any limitation to the present application.

[0171] All solvents used in this application were commercially available and used without further purification.

[0172] The following abbreviations are used in this application: DCM represents dichloromethane; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; MeOH represents methanol; TsOH represents p-toluenesulfonic acid; ATP represents adenosine triphosphate; MEK represents methyl ethyl ketone; ACN represents acetonitrile; Boc represents tert-butyloxycarbonyl; TBS represents tert-butyldimethylsilyl; Et represents ethyl; Ts represents p-toluenesulfonyl; PE represents petroleum ether; EA or EtOAc represents ethyl acetate; ADDP represents azodicarbonyl dipyridine; TBAF represents tetrabutylammonium fluoride; DCM represents dichloromethane; THF represents tetrahydrofuran; TMSI represents trimethylsilane iodide; AcOH represents acetic acid.

[0173] X-ray powder diffraction (XRPD)

[0174] Instrument model: Bruker D8 advance X-ray diffractometer

[0175] Test method: About 10-20 mg of sample was used for XRPD detection.

[0176] The detailed XRPD parameters are as follows:

[0177] Light pipe: Cu, kα,

[0178] Light tube voltage: 40kV, light tube current: 40mA

[0179] Divergence slit: 0.60mm

[0180] Detector slit: 10.50mm

[0181] Anti-scatter slit: 7.10mm

[0182] Scanning range: 4-40deg (or 3-40deg)

[0183] Step diameter: 0.02deg

[0184] Step length: 0.12 seconds

[0185] Sample plate speed: 15rpm

[0186] Differential Scanning Calorimetry (DSC)

[0187] Instrument model: TA Q2000 differential scanning calorimeter

[0188] Test method: Take a sample (~1 mg) and place it in a DSC aluminum pan for testing at 50 mL / min N 2 Under the same conditions, the sample was heated from 25°C to 300°C at a heating rate of 10°C / min.

[0189] Thermogravimetric Analysis (TGA)

[0190] Instrument model: TA Q5000IR thermogravimetric analyzer

[0191] Test method: Take a sample (2-5 mg) and place it in a TGA platinum pan for testing at 25 mL / min N 2 Under the conditions, the sample was heated from room temperature to a weight loss of 20% at a heating rate of 10°C / min. BRIEF DESCRIPTION OF THE DRAWINGS

[0192] Figure 1 The XRPD spectrum of Type A crystal of the compound of formula (I) using Cu-Kα radiation.

[0193] Figure 2 It is the DSC spectrum of type A crystal of the compound of formula (I).

[0194] Figure 3 This is the TGA spectrum of type A crystal of the compound of formula (I).

[0195] Figure 4The XRPD spectrum of type B crystal of the compound of formula (I) using Cu-Kα radiation.

[0196] Figure 5 It is the DSC spectrum of type B crystal of the compound of formula (I).

[0197] Figure 6 This is the TGA spectrum of type B crystal of the compound of formula (I).

[0198] Figure 7 The XRPD spectrum of type C crystal of the compound of formula (I) using Cu-Kα radiation.

[0199] Figure 8 It is the DSC spectrum of type C crystal of the compound of formula (I).

[0200] Fig. 9 This is the TGA spectrum of type C crystals of the compound of formula (I).

[0201] Fig.10 The XRPD spectrum of the D-type crystal of the compound of formula (I) using Cu-Kα radiation.

[0202] Fig.11 This is the TGA spectrum of the D-type crystal of the compound of formula (I).

[0203] Fig.12 The XRPD spectrum of the crystal of the phosphate of the compound of formula (I) using Cu-Kα radiation.

[0204] Fig.13 It is the DSC spectrum of the crystal of the phosphate salt of the compound of formula (I).

[0205] Fig.14 It is the TGA spectrum of the crystal of the phosphate salt of the compound of formula (I).

[0206] Fig.15 This is the XRPD spectrum of Type I crystals of the oxalate salt of the compound of formula (I) using Cu-Kα radiation.

[0207] Fig.16 This is the DSC spectrum of type I crystals of the oxalate salt of the compound of formula (I).

[0208] Fig.17 This is the TGA spectrum of type I crystal of the oxalate salt of the compound of formula (I).

[0209] Fig.18 This is the XRPD spectrum of Type II crystals of the oxalate salt of the compound of formula (I) using Cu-Kα radiation.

[0210] Fig.19 It is the DSC spectrum of type II crystals of the oxalate salt of the compound of formula (I).

[0211] Fig. 20 This is the TGA spectrum of type II crystals of the oxalate salt of the compound of formula (I). DETAILED DESCRIPTION

[0212] In order to better understand the content of this application, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not limitations on the content of this application.

[0213] Example 1: Preparation of the compound of formula (I)

[0214]

[0215] Step 1: Under nitrogen protection at -78°C, a solution of n-butyl lithium in n-hexane (2.5M, 427.54 mL) was added dropwise to a solution of tert-butyldimethyl (2-propynyloxy) silane (200 g, 1174.24 mmol) in tetrahydrofuran (2L), and the reaction solution was stirred at -78°C for 30 minutes. Then, a solution of compound 1-1 (250 g, 971.7 mmol) in tetrahydrofuran (2L) was added dropwise to the reaction solution at -78°C. The reaction solution was reacted at -78°C for 3 hours. TLC (PE: EA = 3: 1, volume ratio) showed that the reaction was complete, and a saturated aqueous ammonium chloride solution (2L) and water (1L) were added to the reaction solution to quench the reaction, and EA (2L*3) was used for extraction. The combined reaction solution was washed with saturated brine (2L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 1-2. 1 H NMR (400 MHz, CDCl 3 )δ=5.11 (br d, J=7.3Hz, 1H), 4.48 (s, 2H), 4.35-4.27 (m, 1H), 4.21 (q, J=7.2Hz, 2H), 2.80-2.59 (m, 2H), 2.30-2.13 (m, 1H), 1.98 (br dd, J=6.4, 14.2Hz, 1H), 1.55-1.42 (s, 9H), 1.36-1.27 (m, 3H), 0.93 (s, 9H), 0.19-0.07 (s, 6H).

[0216] Step 2: Add hydrazine hydrate (34.71 g, 1.03 mol, 98%) to a DMF (3 L) solution containing compound 1-2 (400 g, 935.44 mmol) under ice bath. The reaction was carried out at 25°C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (10 L), extracted with EA (2 L*2), and the combined reaction solution was washed with saturated brine (2 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 1-3. MS (ESI) 442 [M+H] + .

[0217] Step 3: Under ice bath conditions, NaBH 4 (77.71g, 2.05mol). Then, methanol (0.6L) was slowly added dropwise, and the reaction solution was stirred at 25°C for 12 hours. LC-MS showed that the reaction was complete. Under ice bath conditions, saturated aqueous ammonium chloride solution (300mL) was added to the reaction solution to quench the reaction, and then diluted with water (2L), extracted with EA (2L*2), and the combined reaction solution was washed with saturated brine (2L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and compound 1-4 was obtained by silica gel column chromatography (DCM: MeOH = 50: 1 to 20: 1). MS (ESI) 400 [M+H] + .

[0218] Step 4: Under ice bath conditions, tributylphosphine (340.24 g, 1.68 mol) was added to a tetrahydrofuran (4 L) solution of compound 1-4 (336 g, 840.84 mmol). The reaction solution was stirred under ice bath conditions for 30 minutes, and ADDP (424.31 g, 1.68 mol) was added to the reaction solution. The reaction solution was stirred at 20°C for 12 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (2 L), extracted with EA (2 L * 2), and the combined reaction solution was washed with saturated brine (1.5 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and compound 1-5 was obtained by silica gel column chromatography (PE: EA = 20: 1 to 2: 1, volume ratio). MS (ESI) 382 [M + H] + .

[0219] Step 5: At room temperature, TBAF (1M, 1.02L, 1.02mol) was added to a tetrahydrofuran (1L) solution containing compound 1-5 (390g, 1.02mol). The reaction was carried out at 20°C for 1.5 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (1L) and saturated with NaHCO 3 The aqueous solution was adjusted to pH = 8, extracted with EA (1L*3), the combined reaction solution was washed with saturated brine (1L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then the concentrate was dissolved in ethyl acetate (1L), HCl / EtOAc (4M, 200mL) was slowly added dropwise to the solution, stirred for 1 hour, solid was generated, filtered to obtain compound 1-6. MS (ESI) 268 [M+H] + .

[0220] Step 6: Add manganese dioxide (37.40 g, 430.19 mmol) to a solution of DCM (150 mL) and MeOH (15 mL) containing compound 1-6 (11.5 g, 43.02 mmol), replace with nitrogen three times, and then stir at 65°C for 12 hours. LC-MS showed that the reaction was complete. The reaction solution was filtered and concentrated to obtain compound 1-7. MS (ESI) 266 [M+H] + .

[0221] Step 7: To a solution of compound 1-7 (11 g, 41.46 mmol) in THF (150 mL) was added NH 3 ·H 2 O (51.89g, 414.61mmol, 57.03mL, 28% purity) and I 2 (31.57g, 124.38mmol), the reaction solution was replaced with nitrogen three times, and then stirred at 25°C for 12 hours. LC-MS showed that the reaction was complete. Saturated aqueous sodium sulfite solution was added to the reaction solution to quench the reaction, 20mL of water was added to dilute, and then extracted with ethyl acetate (50mL*2). The organic phases were combined, washed with saturated brine (30mL), dried with sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA=3:1) to obtain compound 1-8. MS (ESI)263[M+H] + .

[0222] Step 8: At 0°C, add TMSI (10.91 g, 54.52 mmol, 7.42 mL) to a DCM (150 mL) solution of compound 1-8 (11 g, 41.94 mmol). The reaction solution was stirred at 0°C for 1 hour. TLC showed that the starting material disappeared and new spots were generated. The reaction solution was concentrated under reduced pressure to obtain the hydroiodide of compound 1-9. MS (ESI) 163 [M+H] + .

[0223] Step 9: p-Toluenesulfonyl chloride (27.49 g, 144.19 mmol, 1.1 eq), DMAP (1.6 g, 13.11 mmol, 0.1 eq) and triethylamine (19.9 g, 196.62 mmol, 27.37 mL) were added to a solution of compound 1-10 (20 g, 131.08 mmol, 1 eq) in DCM (50 mL) at 25 °C, respectively. The resulting solution was stirred at 25 °C for 16 hours. The reaction was complete, the solvent was removed under reduced pressure, and saturated NaHCO was added. 3 The solution (50 mL) was filtered, the filter cake was washed with water and dried to obtain product 1-11. MS (ESI) 307 [M+H] + .

[0224] Step 10: At -5°C, a solution of compound 1-11 (10 g, 32.60 mmol, 1 eq) in DCM (50 mL) was added dropwise with a solution of tetrabutylammonium nitrate (29.78 g, 97.79 mmol, 3 eq) in dichloromethane (50 mL), and then trifluoroacetic anhydride (20.54 g, 97.79 mmol.13.60 mL, 3 eq) was slowly added dropwise. The resulting solution was stirred at -5°C for 30 min, then stirred for 16 h. The reaction was complete, extracted with ethyl acetate (500 mL*3), and the combined organic phase was washed with water (200 mL*2) and brine (200 mL*1) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was recrystallized from dichloromethane to obtain product 1-12. MS (ESI) 352 [M+H] + .

[0225] Step 11: Add DIEA (26.73 g, 206.82 mmol, 36.0 mL) to a solution of compound 1-9 (12 g, 41.36 mmol, hydroiodide) and compound 1-12 (11.64 g, 33.09 mmol) in isopropanol (200 mL). Replace the reaction solution with nitrogen three times and then stir at 90 ° C for 12 hours. LC-MS showed that the reaction was complete. Cool the reaction solution and add H 2 O (200 mL), filtered and dried to obtain compound 1-13. MS (ESI) 478 [M+H] + .

[0226] Step 12: Compound 1-13 (16 g, 33.51 mmol) was dissolved in THF (200 mL) and H 2 O (50 mL) solution was added with Fe (9.36 g, 167.54 mmol) and NH 4 Cl (12.55 g, 234.56 mmol), replaced with nitrogen three times, and stirred at 100 ° C for 1 hour. LCMS showed that the reaction was complete. The reaction solution was filtered and the filtrate was washed with H 2 O (100 mL), then extracted with ethyl acetate (150 mL * 2). The filter cake was washed with DCM: MeOH (20: 1, 100 mL * 3). The extract and the washing liquid of the filter cake were combined, dried over sodium sulfate, filtered, and concentrated to obtain compound 1-14. MS (ESI) 448 [M + H] + .

[0227] Step 13: Add tetramethyl orthocarbonate (456.4 mg, 3.35 mmol) to a solution of compound 1-14 (150 mg, 335.19 μmol) and TsOH (5.8 mg, 33.52 μmol) in AcOH (5 mL). Replace the reaction solution with nitrogen three times and stir at 50 °C for 2 hours. LCMS showed that the reaction was complete. Concentrate the reaction solution to remove the solvent, and add H 2 O (5mL), and extracted with dichloromethane (5mL*3). The organic phases were combined, washed with saturated brine, dried with sodium sulfate, filtered, and concentrated to obtain compound 1-15. MS (ESI) 488 [M+H] + .

[0228] Step 14: Compound 1-15 (180 mg, 369.21 μmol) was dissolved in THF (10 mL), and then TBAF (1 M, 738.4 μL) was added. The reaction solution was replaced with nitrogen three times and stirred at 70 °C for 12 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated, and the concentrate was washed with NaHCO 3 The mixture was diluted with aqueous solution (15 mL), extracted with DCM (15 mL*3), the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini NX 80*30 mm*3 μm; mobile phase: phase A was water (10 mM NH 4 HCO 3 )-ACN; Phase B (ACN)%: 20%-50%, 9min) was purified to obtain the compound of formula (I). MS (ESI) 334 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ=11.72 (br s, 1H), 8.38 (br s, 1H), 7.42 (br s, 1H), 6.85 (br s, 1H), 6.71 (br s, 1H), 5.41 (br s, 1H), 4.69 (br s, 2H), 4.09 (br s, 3H), 3.05 (br s, 2H), 268-2.55 (m, 1H), 2.28 (br s, 1H).

[0229] Example 2

[0230] 1 g of the compound of formula (I) was placed in a 100 ml glass vial, 40 ml of ethanol was added, heated to reflux, stirred at 78°C until the solution was clear, cooled to room temperature, and stirred overnight. The solid was filtered and vacuum dried for 8 hours to obtain type A crystals of the compound of formula (I).

[0231] Example 3

[0232] 19.9 mg of the compound of formula (I) was placed in a 5.0 ml glass vial, and 0.2 ml of DMF was added to dissolve the solid. 3 ml of MEK was added dropwise to the clear solution under room temperature while magnetically stirring (at a speed of about 750 rpm), and the obtained clear solution was transferred to room temperature and magnetically stirred overnight, and still clear, and then transferred to 5° C. and magnetically stirred overnight, and then transferred to -20° C. and magnetically stirred overnight to obtain a turbid sample, which was centrifuged to obtain a solid, and the solid was transferred to room temperature and dried in the open for three days to obtain type B crystals of the compound of formula (I).

[0233] Example 4

[0234] 19.8 mg of the compound of formula (I) was placed in a 5.0 ml glass vial, 2.5 ml of ACN was added, and the mixture was placed at 50°C overnight, and filtered using a 0.45 μm PTFE filter to obtain a clear solution. The clear solution was cooled from 50°C to 5°C at a rate of 0.1°C / min, and magnetically stirred at 5°C overnight to obtain a turbid sample. The solid was obtained by centrifugation, and the solid was transferred to room temperature and dried overnight to obtain type C crystals of the compound of formula (I).

[0235] Example 5

[0236] 20.1 mg of the compound of formula (I) was placed in a HPLC glass vial, and 8.5 mg of maleic acid and 0.5 ml of acetone were added to obtain a turbid sample. The sample was magnetically stirred at 50°C for two days, and the sample was still turbid. The solid was centrifuged and the solid was transferred to room temperature and vacuum dried for about four hours to obtain type D crystals of the compound of formula (I).

[0237] Example 6

[0238] 20.3 mg of the compound of formula (I) was placed in a HPLC glass vial, and 3.5 μl of phosphoric acid and 0.5 ml of EtOH / H 2 O (19: 1, v / v) to obtain a turbid sample. The sample was magnetically stirred at 50°C for two days, and the sample was still turbid. A solid was obtained by centrifugation, and the solid was transferred to room temperature and vacuum dried for about four hours to obtain a crystal of the phosphate of the compound of formula (I).

[0239] Example 7

[0240] 20.3 mg of the compound of formula (I) was placed in a HPLC glass vial, and 9.3 mg of oxalic acid and 0.5 ml of acetone were added to obtain a turbid sample. The sample was magnetically stirred at 50° C. for two days, and the sample was still turbid. A solid was obtained by centrifugation, and the solid was transferred to room temperature and vacuum dried for about four hours to obtain type I crystals of the oxalate of the compound of formula (I).

[0241] Example 8

[0242] 20.1 mg of the compound of formula (I) was placed in a HPLC glass vial, and 9.6 mg of oxalic acid and 0.5 ml of EtOH / H 2 O (19: 1, v / v) to obtain a turbid sample. The sample was magnetically stirred at 50°C for two days, and the sample was still turbid. A solid was obtained by centrifugation, and the solid was transferred to room temperature and vacuum dried for about four hours to obtain type II crystals of the oxalate of the compound of formula (I).

[0243] Biological activity test

[0244] Experimental Example 1: In vitro activity test of JAK1, JAK2, JAK3, and TYK2 kinases

[0245] Experimental Materials

[0246] Recombinant human JAK1, JAK2, JAK3, TYK2 proteases, major instruments and reagents were provided by Eurofins in the UK.

[0247] Experimental methods

[0248] JAK2, JAK3 and TYK2 were diluted in a solution prepared as follows: 20 mM 3-(N-morpholino)propanesulfonic acid (MOPS), 1 mM EDTA, 0.01% Brij-3 5.5% glycerol, 0.1% β-mercaptoethanol, 1 mg / mL BSA. JAK1 was diluted in a solution prepared as follows: 20 mM TRIS, 0.2 mM EDTA, 0.1% β-mercaptoethanol, 0.01% Brij-3 5.5% glycerol. The compound of formula (I) of Example 1 was prepared as a solution in 100% DMSO and its concentration reached 50 times the concentration in the subsequent assay. The tested compound of formula (I) was diluted 3 times to obtain a final concentration of 9 concentrations ranging from 10 μM to 0.001 μM, and the content of DMSO in the detection reaction system was 2%. The working stock solution of the compound was added to the corresponding assay well as the first component of the reaction, and then the remaining components were added according to the assay protocol detailed below.

[0249] JAK1(h) enzyme reaction

[0250] JAK1(h) was mixed with 20 mM Tris / HCl pH 7.5, 0.2 mM EDTA, 500 μM MGEEPLYWSFPAKKK (SEQ ID NO: 1), 10 mM magnesium acetate and [γ- 33P]-ATP (activity and concentration as required). The reaction was started by adding the Mg / ATP mixture and incubated at room temperature for 40 minutes before adding 0.5% phosphoric acid to terminate the reaction. Then 10 μL of the reaction was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried, and scintillation counted.

[0251] JAK2(h) enzyme reaction

[0252] JAK2(h) was mixed with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μM KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (SEQ ID NO: 2), 10 mM magnesium acetate and [γ- 33 P]-ATP (activity and concentration as required). The reaction was started by adding the Mg / ATP mixture and incubated at room temperature for 40 minutes before adding 0.5% phosphoric acid to terminate the reaction. Then 10 μL of the reaction was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried, and scintillation counted.

[0253] JAK3(h) enzyme reaction

[0254] JAK3(h) was mixed with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 500 μM GGEEEEYFELVKKKK (SEQ ID NO: 3), 10 mM magnesium acetate and [γ- 33 P]-ATP (activity and concentration as required). The reaction was started by adding the Mg / ATP mixture and incubated at room temperature for 40 minutes before adding 0.5% phosphoric acid to terminate the reaction. Then 10 μL of the reaction was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried, and scintillation counted.

[0255] TYK2(h) enzyme reaction

[0256] TYK2(h) was mixed with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM GGMEDIYFEFMGGKKK (SEQ ID NO: 4), 10 mM magnesium acetate and [γ- 33 P]-ATP (activity and concentration as required). The reaction was started by adding the Mg / ATP mixture and incubated at room temperature for 40 minutes before adding 0.5% phosphoric acid to terminate the reaction. Then 10 μL of the reaction was spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol within 4 minutes, dried, and scintillation counted.

[0257] Data analysis

[0258] IC 50 The results were obtained by analysis using XLFIT5 (205 formula) from IDBS, as shown in Table 8.

[0259] Table 8. In vitro screening test results of compounds of formula (I)

[0260]

[0261] Experimental Example 2: Pharmacokinetic (PK) test

[0262] After dissolving the compound of formula (I) of Example 1 in 5% DMSO and 95% (v:v) SBE-β-CD with a mass percentage concentration of 12%, the obtained clear solution was injected into the male SD rats (fasted overnight before administration, 7-8 weeks old) via tail vein injection and oral gavage, respectively. After administration of the test compound, blood was collected from the mandibular vein of each rat at 0.117, 0.333, 1, 2, 4, 7 and 24 hours for the rats in the intravenous injection group (1 mg / kg) and at 0.25, 0.5, 1, 2, 4, 8 and 24 hours for the rats in the oral gavage group (5 mg / kg), and plasma was obtained after centrifugation. The blood drug concentration was determined by LC-MS / MS, and WinNonlin TM Version 6.3 pharmacokinetic software uses the non-compartmental linear logarithmic trapezoidal method to calculate relevant pharmacokinetic parameters. The test results are as follows:

[0263] Table 9 PK test results of the compound of formula (I) in rats

[0264] PK parameters Compound of formula (I) <![CDATA[T 1 / 2 (hr)]]> 3.65 <![CDATA[C max (nM)]]> 10152 <![CDATA[AUC 0-inf (nM.hr)]]> 67786 Bioavailability (%) 119％

[0265] Note: 1 / 2 : half-life; C max : peak concentration;

[0266] AUC 0-inf : The area under the plasma concentration-time curve from time 0 extrapolated to infinity.

[0267] Experimental Example 3: In vivo efficacy study on collagen-induced arthritis (CIA) in rats

[0268] Experimental process:

[0269] The rat collagen-induced arthritis model was used to verify the therapeutic effect of the compound of formula (I) on arthritis. Lewis rats were immunized, and the first immunization day was recorded as day 0, and the subsequent days were marked in sequence. After Lewis rats were anesthetized with isoflurane, 50 microliters of the prepared collagen emulsion (containing 200 micrograms of CII) were injected subcutaneously at the tail (2-3 cm from the base of the tail). On the 21st day, the same volume of collagen emulsion was injected subcutaneously at the tail in the same way. Lewis rats in the normal group did not need to be immunized. On the 27th day of modeling, the animals after modeling were divided into groups and given the corresponding compound of formula (I) of Example 1. The rats were given different doses (specific doses are shown in Table 11) of the compound of formula (I) dissolved in a mixed solvent of 0.5% HPMC E5, 0.5% PVP K30 and 0.2% SLS in water, and were orally administered twice a day (the number of animals tested in each dose group was 8). The drug was administered continuously for 14 days. During this period, the condition of the rats was observed, and the paw volume swelling was recorded and scored. The scoring criteria are shown in Table 10.

[0270] Table 10. Clinical scoring criteria for arthritis

[0271] Points Clinical symptoms 0 No erythema or swelling 1 Redness or mild swelling near the tarsal bones or at the ankle or metatarsal bones, or redness and swelling on one toe 2 Mild erythema and swelling of the ankle joint and metatarsal bones, and redness and swelling of more than two toes 3 Moderate erythema and swelling of the ankles, wrists, and metatarsals 4 Severe swelling and redness of the ankles, wrists, metatarsals, and toes

[0272] Experimental results:

[0273] When the compound of formula (I) was administered BID at a dose of 1 and 3 mg / kg, the clinical score of the arthritis rats was reduced in a dose-dependent manner, which was significantly different from the vehicle control group. By the end of the 14th day of administration, the clinical score of the rats in the 3 mg / kg BID group was reduced to zero (Table 11). At the same time, the degree of paw volume swelling was also reduced in a dose-dependent manner. By the end of the 14th day of administration, there was a significant difference compared with the vehicle control group. The paw volume swelling of the rats in the 3 mg / kg BID group was reduced to 1.28 μL. The body weight of the rats in the treatment group (the group administered with the compound of formula (I)) was also restored in a dose-dependent manner. By the end of the 14th day of administration, the body weight of the rats in the 3 mg / kg BID group was restored to the level of the rats in the normal group.

[0274] Table 11 Main parameters of in vivo efficacy study of CIA in rats*

[0275]

[0276] * Note: Compared with the vehicle control group, each group had P < 0.001 (two-way ANOVA).

[0277] Experimental Example 4: Stability Test

[0278] According to the methods described below, the crystals of the compounds described in the present application were subjected to relevant measurements.

[0279] Chromatographic conditions of HPLC method for determination of related substances:

[0280] Column: Waters XBridge C18, 4.6 mm × 150 mm, 3.5 μm

[0281] Mobile phase A: 10mmol / L ammonium formate solution (adjust pH to 3.5 with formic acid)

[0282] Mobile phase B: 100% ACN

[0283] Flow rate: 0.8ml / min

[0284] Column temperature: 40°C

[0285] Detection wavelength: 230nm.

[0286] Content determination HPLC method Chromatographic conditions:

[0287] Column: Waters XBridge C18, 4.6 mm × 150 mm, 3.5 μm

[0288] Mobile phase: 10mmol / L ammonium formate solution (adjust pH to 3.5 with formic acid): acetonitrile (78:22)

[0289] Flow rate: 0.8ml / min

[0290] Column temperature: 40°C

[0291] Detection wavelength: 220nm.

[0292] Enantiomer determination HPLC method Chromatographic conditions:

[0293] Column: Chiral CD-Ph, 4.6mm×250mm, 5μm

[0294] Mobile phase: 0.1% trifluoroacetic acid solution: acetonitrile (65:35)

[0295] Flow rate: 1.5ml / min

[0296] Column temperature: 40°C

[0297] Detection wavelength: 220nm.

[0298] Sample preparation: The sample was dissolved in a mixed solvent of acetonitrile and water (acetonitrile: water = 50:50 (v / v)).

[0299] Moisture determination method:

[0300] The content was determined by Karl Fischer volumetric method, solvent: methanol.

[0301] Solid Stability Lofting Method

[0302] The stability of each crystal of the compound described in the present application under the following conditions was investigated, and samples were taken at different time points to detect related substances, content, enantiomers and crystal forms.

[0303] Accurately weigh different crystals and place them in open flat weighing bottles in triplicate.

[0304] The samples were spread into a thin layer as the formal test samples and placed under the test conditions of influencing factors [40℃, 60℃, (25℃, relative humidity 75%), (25℃, relative humidity 92.5%), light (total illumination 1.2×10 6 Lux·hr / Near UV 200w·hr / m 2 )], each sample was completely exposed and placed. In addition, two samples (1.2 g each) were added under the condition of "25°C, relative humidity 92.5%". Each sample was placed in a double-layer medicinal low-density polyethylene bag, each layer of which was sealed with a buckle. The medicinal low-density polyethylene bag was then placed in an aluminum foil bag containing a pack of desiccant and heat-sealed. Light (total illumination 1.2×10 6 Lux·hr / Near UV 200w·hr / m 2 ) conditions, two control samples were added. The control samples were packaged in the same way as the light samples, but the surface of the watch glass was covered with aluminum film. The above samples were sampled and analyzed at 5 days, 10 days, and 30 days. The samples placed under light (visible light 1200000Lux, UV 200W) conditions were fully exposed at room temperature.

[0305] Different crystals of the compound were put into double-layer medicinal low-density polyethylene bags, each layer of the medicinal low-density polyethylene bags was sealed with buckles, and then the medicinal low-density polyethylene bags were placed in an aluminum foil bag containing a pack of desiccant and heat-sealed as formal test samples, placed under accelerated conditions (40°C, relative humidity 75%), long-term test conditions (25°C, relative humidity 60%) and 5°C, and sampled and analyzed at 1, 3, 6, 9, 12, 18, and 24 months, respectively, where the accelerated test sampling points were 1, 3, and 6 months, and the long-term test sampling points were 3, 6, 9, 12, 18, and 24 months. The hygroscopicity data of the above crystal forms were investigated using a dynamic vapor adsorption instrument.

[0306] The crystals described in the present application can exhibit the following favorable properties under light, high temperature, high humidity and accelerated test conditions: stable physical and chemical properties, stable content of each single impurity and total impurity, basically unchanged water content, no crystal form transformation, and low hygroscopicity of the crystal.

[0307] Those skilled in the art will recognize that the scope of the present disclosure is not limited to the various specific implementations and examples described above, but that various modifications, substitutions, or re-combinations can be made without departing from the spirit and concept of the present disclosure, which all fall within the scope of protection of the present disclosure.

Claims

1. Crystallization of a compound of formula (I), in, The X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation comprises 8 diffraction peaks selected from the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 9.25±0.20°, 12.28±0.2°, 14.46±0.2°, 14.89±0.2° and 21.06±0.2°.

2. The crystal of the compound of formula (I) according to claim 1 has diffraction peaks at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 9.25±0.20°, 12.28±0.20°, 14.46±0.20°, 14.89±0.20°, 15.75±0.20°, 16.82±0.20°, 19.37±0.20° and 21.06±0.20°.

3. The crystal of the compound of formula (I) according to claim 1 has diffraction peaks at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, 7.23±0.20°, 8.80±0.20°, 9.25±0.20°, 10.50±0.20°, 12.28±0.20°, 14.23±0.20°, 14.46±0.20°, 14 .89±0.20°, 15.75±0.20°, 16.82±0.20°, 17.32±0.20°, 17.84±0.20°, 19.37±0.20°, 21.06±0.20°, 22.76±0.20°, 24.11±0.20°, 26.16±0.20°, 26.76±0.20° and 27.16±0.20°.

4. The crystal of the compound of formula (I) according to claim 1, the XRPD pattern of the crystal of the compound of formula (I) is shown in Figure 1.

5. The crystal of the compound of formula (I) according to claim 1, wherein The differential scanning calorimetry curve of the crystal of the compound of formula (I) has an exothermic peak starting point at 188.8±3°C.

6. The crystal of the compound of formula (I) according to claim 1, wherein the DSC spectrum of the crystal of the compound of formula (I) is shown in Figure 2.

7. Crystallization of the compound of formula (I), in, The X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation comprises 8 diffraction peaks selected from the following 2θ angles: 5.08±0.20°, 6.31±0.20°, 9.78±0.20°, 13.76±0.20°, 15.80±0.20°, 18.96±0.20°, 19.61±0.20° and 24.34±0.20°.

8. The crystal of the compound of formula (I) according to claim 7 has diffraction peaks at the following 2θ angles: 5.08±0.20°, 6.31±0.20°, 9.78±0.20°, 11.75±0.20°, 13.76±0.20°, 14.17±0.20°, 15.80±0.20°, 18.96±0.20°, 19.61±0.20°, 23.87±0.20° and 24.34±0.20°.

9. The crystal of the compound of formula (I) according to claim 7, the XRPD pattern of the crystal of the compound of formula (I) is shown in Figure 4.

10. The crystal of the compound of formula (I) according to claim 7, wherein The differential scanning calorimetry curve of the crystal of the compound of formula (I) has an endothermic peak starting point at 172.9±3°C.

11. The crystal of the compound of formula (I) according to claim 7, the DSC spectrum of the crystal of the compound of formula (I) is shown in Figure 5.

12. Crystallization of a compound of formula (I), in, The X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation comprises 7 diffraction peaks selected from the following 2θ angles: 6.21±0.20°, 9.04±0.20°, 11.54±0.20°, 12.38±0.20°, 16.27±0.20°, 23.29±0.20° and 25.62±0.20°.

13. The crystal of the compound of formula (I) according to claim 12, wherein the XRPD pattern of the crystal of the compound of formula (I) is shown in FIG7.

14. The crystal of the compound of formula (I) according to claim 12, wherein The differential scanning calorimetry curve of the crystal of the compound of formula (I) has an endothermic peak starting point at 140.2±3°C. 15 . The crystal of the compound of formula (I) according to claim 12 , wherein the DSC spectrum of the crystal of the compound of formula (I) is shown in FIG8 .

16. Crystallization of a compound of formula (I), in, The X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation comprises 8 diffraction peaks selected from the following 2θ angles: 7.13±0.20°, 10.04±0.20°, 11.24±0.20°, 15.97±0.20°, 16.94±0.20°, 18.22±0.20°, 21.45±0.20° and 22.71±0.20°.

17. The crystal of the compound of formula (I) according to claim 16 has diffraction peaks at the following 2θ angles: 7.13±0.20°, 10.04±0.20°, 11.24±0.20°, 15.97±0.20°, 16.94±0.20°, 18.22±0.20°, 20.28±0.20°, 21.45±0.20°, 22.71±0.20° and 26.21±0.20°.

18. The crystal of the compound of formula (I) according to claim 16, wherein the XRPD pattern of the crystal of the compound of formula (I) is shown in FIG10.

19. A salt of a compound of formula (I), wherein The salt of the compound of formula (I) is a phosphate or an oxalate, 20. The salt of the compound of formula (I) according to claim 19, wherein The salt of the compound of formula (I) is a phosphate, and the molecular ratio of the compound of formula (I) to phosphoric acid is 1:(1-1.5).

21. The salt of the compound of formula (I) according to claim 19, wherein the molecular ratio of the compound of formula (I) to phosphoric acid is 1:

1.

22. Crystallization of the phosphate salt of the compound of formula (I), in, The X-ray powder diffraction pattern of the phosphate crystals using Cu Kα radiation comprises 8 diffraction peaks selected from the following 2θ angles: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 16.64±0.20°, 20.04±0.20°, 21.73±0.20°, 26.17±0.20° and 28.11±0.20°.

23. The crystal of the phosphate of the compound of formula (I) according to claim 22 has diffraction peaks at the following 2θ angles: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 15.21±0.20°, 16.64±0.20°, 20.04±0.20°, 21.73±0.20°, 22.21±0.20°, 25.07±0.20°, 26.17±0.20°, 26.81±0.20° and 28.11±0.20°.

24. The crystal of the phosphate of the compound of formula (I) according to claim 22 has diffraction peaks at the following 2θ angles: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 15.21±0.20°, 16.64±0.20°, 20.04±0.20°, 21.73±0.20°, 22.21±0.20°, 23.66±0.20°, 25.07±0.20°, 26.17±0.20°, 26.81±0.20°, 27.50±0.20° and 28.11±0.20°.

25. The crystal of the phosphate salt of the compound of formula (I) according to claim 22, the XRPD pattern of the crystal of the phosphate salt is shown in Figure 12.

26. The crystal of the phosphate salt of the compound of formula (I) according to claim 22, wherein: The differential scanning calorimetry curve of the crystallization of the phosphate has an exothermic peak starting point at 141.9±3.0°C.

27. The crystal of the phosphate of the compound of formula (I) according to claim 22, the DSC spectrum of the crystal of the phosphate is shown in Figure 13.

28. The salt of the compound of formula (I) according to claim 19, wherein The salt of the compound of formula (I) is oxalate, and the molecular ratio of the compound of formula (I) to oxalic acid is 1:(1-1.5).

29. The salt of the compound of formula (I) according to claim 19, wherein the molecular ratio of the compound of formula (I) to oxalic acid is 1:1.

1.

30. Crystallization of the oxalate salt of the compound of formula (I), in, The X-ray powder diffraction pattern of the oxalate crystal using Cu Kα radiation comprises 6 diffraction peaks selected from the following 2θ angles: 5.06±0.20°, 12.69±0.20°, 15.21±0.20°, 17.92±0.20°, 20.77±0.20° and 27.32±0.20°.

31. The crystal of oxalate of the compound of formula (I) according to claim 30 has diffraction peaks at the following 2θ angles: 5.06±0.20°, 11.28±0.20°, 12.69±0.20°, 15.21±0.20°, 16.48±0.20°, 17.92±0.20°, 19.52±0.20°, 20.77±0.20°, 22.90±0.20° and 27.32±0.20°.

32. The crystal of oxalate of the compound of formula (I) according to claim 30, wherein the XRPD pattern of the crystal of oxalate is shown in FIG15.

33. The crystal of the oxalate of the compound of formula (I) according to claim 30, wherein the X-ray powder diffraction pattern of the crystal of the oxalate using Cu Kα radiation comprises 8 diffraction peaks selected from the following 2θ angles: 5.44±0.20°, 10.85±0.20°, 11.75±0.20°, 13.77±0.20°, 16.01±0.20°, 16.27±0.20°, 23.39±0.20° and 27.42±0.20°.

34. The crystal of the oxalate salt of the compound of formula (I) according to claim 30 has diffraction peaks at the following 2θ angles: 5.44±0.20°, 10.85±0.20°, 11.75±0.20°, 13.77±0.20°, 16.01±0.20°, 16.27±0.20°, 17.85±0.20°, 18.39±0.20°, 20.83±0.20°, 21.75±0.20°, 23.39±0.20°, 25.13±0.20° and 27.42±0.20°.

35. The crystal of oxalate of the compound of formula (I) according to claim 30, wherein the XRPD pattern of the crystal of oxalate is shown in Figure 18.

36. A pharmaceutical composition comprising a therapeutically effective amount of crystals of the compound of formula (I) according to any one of claims 1-18, a salt of the compound of formula (I) according to any one of claims 19-21, 28-29, crystals of the phosphate salt of the compound of formula (I) according to any one of claims 22-27, or crystals of the oxalate salt of the compound of formula (I) according to any one of claims 30-35.

37. Use of a crystal of the compound of formula (I) according to any one of claims 1 to 18, a salt of the compound of formula (I) according to any one of claims 19 to 21 and 28 to 29, a crystal of the phosphate of the compound of formula (I) according to any one of claims 22 to 27, a crystal of the oxalate of the compound of formula (I) according to any one of claims 30 to 35, or a pharmaceutical composition according to claim 36 in the preparation of a medicament for treating or preventing JAK1 and / or JAK2 related diseases.

38. The use according to claim 37, wherein the JAK1 and / or JAK2 related disease is selected from inflammatory diseases.

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