WO2022247885A9 - Crystal and salt of triheterocyclic compound and use thereof - Google Patents

Abstract

A crystal of a compound of formula (I), a salt thereof and a crystal of the salt thereof, and the use thereof in the preparation of a medicament for the treatment or prevention of diseases associated with JAKs.

Description

Crystallization and Salts of Triheterocyclic Compounds and Their Applications

References to related applications

This application claims priority to Chinese Patent Application No. 202110578454.7 submitted to the State Intellectual Property Office of the People's Republic of China on May 26, 2021, the entire content of which is hereby incorporated by reference in its entirety.

Technical field

The present application relates to the crystallization of the compound of formula (I), its salts and the crystallization of its salts, and their application in the preparation of drugs for the treatment of diseases related to JAKs.

Background technique

Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transmit cytokine signals from membrane receptors to STAT transcription factors. The JAK family consists of four members: JAK1, JAK2, JAK3 and TYK2. The JAK-STAT pathway transmits extracellular signals from a variety of cytokines, growth factors, and hormones to the 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).

JAK-1, JAK-2 and TYK-2 are expressed in cells of various tissues in the human body. JAK-3 is mainly expressed in cells of various hematopoietic tissues, mainly in bone marrow cells, thymocytes, NK cells and activated B lymphocytes. , in T lymphocytes. JAK1 has become a new target in the fields of immunity, inflammation, cancer and other diseases. A base mutation on the JAK2 gene in humans, JAK2V617F, is associated with polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and chronic myeloproliferative diseases. closely related to the occurrence of myelogenous leukemia (CML), etc. Mutations in either JAK3 or γc can lead to severe combined immunodeficiency. Abnormal JAK3 activity manifests as a massive decrease in T cells and NK cells and loss of B cell function, seriously affecting 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, loss of TYK2 function 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 (John J. O'Shea, 2004 ,Nature Reviews Drug Discovery 3,555-564). Different JAK family members selectively bind to different cytokine receptors, conferring signaling specificity and thereby exerting different physiological effects. This selective mode of action allows JAK inhibitors to be applied to diseases with relative specificity. treat. For example, IL-2 or IL-4 receptors bind to JAK1 and JAK3 along 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 JAK1/2 and TYK2. Type I receptors activated by hormone-like cytokines bind and activate JAK2 kinase. Type II receptors for interferons bind JAK1 and TYK2, whereas receptors of the IL-10 cytokine family bind JAK1/2 and TYK2. Various specific combinations of the cytokines and their receptors with JAK family members trigger different physiological effects, providing possibilities for the treatment of different diseases. JAK1 heterodimerizes with other JAKs to transduce cytokine-driven pro-inflammatory signaling. Therefore, inhibition of JAK1 and/or other JAKs is expected to be of therapeutic benefit for a range of inflammatory conditions and other diseases driven by JAK-mediated signaling (Daniella M. Schwartz, 2017, Nature Reviews Drug Discovery 16, 843-862. )

Contents of the invention

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

In some embodiments, the salt of the compound of formula (I) is selected from the group consisting of phosphates or oxalates.

In another aspect, the present application provides crystallization of a compound of formula (I) or a salt thereof.

In some embodiments, the present application provides crystallization of the phosphate salt of a compound of Formula (I) or crystallization of an oxalate salt of a compound of Formula (I).

On the one hand, the present application provides a type A 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: 5.74±0.20°, 7.23±0.20° and 12.28±0.2 °;

In some embodiments of the present application, the X-ray powder diffraction pattern of the Form A crystal of the compound of formula (I) using Cu Kα 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°, 12.28±0.20° and 14.46±0.2°.

In some embodiments of the present application, the X-ray powder diffraction pattern of the Form A crystal of the compound of formula (I) using Cu Kα 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°, 12.28±0.2°, 14.46±0.2°, 14.89±0.2° and 21.06±0.2°.

In some embodiments of the present application, the X-ray powder diffraction pattern of the Form A crystal of the compound of formula (I) using Cu Kα 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°, 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the Type A crystal of the compound of formula (I) 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern of the Form A crystal of the compound of formula (I) using Cu Kα 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±0.20° and 14.46±0.2°.

In some embodiments of the present application, the X-ray powder diffraction pattern of the Form A crystal of the compound of formula (I) using Cu Kα 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern of the Form A crystal of the compound of formula (I) using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.26±0.20°, 5.74±0.20°, and 21.06±0.20°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the Type A crystal of the compound of formula (I) 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°, 9.64±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°.

On the other hand, the present application provides a type A crystal of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation contains 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks: 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°.

On the other hand, the present application provides a type A crystal of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation contains 3, 4, 5, 6, 7 or 3, 4, 5, 6, 7 or 8 diffraction peaks: 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°.

In some embodiments of the present application, the XRPD pattern of type A crystal of the compound of formula (I) is shown in Figure 1.

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 position and relative intensity of the X-ray powder diffraction pattern using Cu Kα radiation are as shown in Table 1:

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

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	twenty one	27.16	7.08
11	15.75	10.70	​	​	​

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

In some embodiments of the present application, the DSC pattern of Form A crystal of the compound of formula (I) is shown in Figure 2.

In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of the Type A crystal of the compound of formula (I) has a weight loss of 3.13% at 200±3°C.

In some embodiments of the present application, the TGA spectrum of type A crystal of the compound of formula (I) is shown in Figure 3.

In another aspect, the present application provides a method for preparing type A crystals of the compound of formula (I). The method includes the following steps: dissolving the compound of formula (I) in ethanol and precipitating 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 includes the step of isolating the solid and subsequently drying the solid; optionally, drying under vacuum conditions.

On the other hand, the present application also provides a type B 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: 5.08±0.20°, 9.78±0.20° and 13.76 ±0.20°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the B-type crystal of the compound of formula (I) has 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the B-type crystal of the compound of formula (I) 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the B-type crystal of the compound of formula (I) has 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the B-type crystal of the compound of formula (I) 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°.

On the other hand, the present application provides a B-type crystal of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation includes 3, 4, 5, 6, 7, 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks: 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°.

On the other hand, the present application provides a B-type crystal of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation contains 3, 4, 5, 6, 7 or 8 diffraction peaks: 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°.

In some embodiments of the present application, the XRPD pattern of type B crystal of the compound of formula (I) is shown in Figure 4.

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 :

Table 2: XRPD data of Form B crystal of compound of formula (I)

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	​	​	​

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

In some embodiments of the present application, the DSC spectrum of type B crystal of the compound of formula (I) is shown in Figure 5.

In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of the Type B crystal of the compound of formula (I) has a weight loss of 5.18% at 150±3°C.

In some embodiments of the present application, the TGA spectrum of type B crystal of the compound of formula (I) is shown in Figure 6.

In another aspect, the present application provides a method for preparing type B crystals of the compound of formula (I). The method includes the following steps: mixing the compound of formula (I) with DMF and MEK, precipitating and separating to obtain a solid.

In some embodiments, the above precipitation process is performed at -20°C to room temperature.

In some embodiments, the above method further includes the step of drying the separated solid; optionally, drying at room temperature.

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°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the C-type crystal of the compound of formula (I) has 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the C-type crystal of the compound of formula (I) has 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°.

On the other hand, the present application provides a C-type crystal of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation contains 3, 4, 5, 6 or 7 selected from the following 2θ angles Diffraction peaks: 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°.

In some embodiments of the present application, the XRPD pattern of type C crystal of the compound of formula (I) is shown in Figure 7.

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 :

Table 3: XRPD spectrum analysis data of type C crystal of compound of formula (I)

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	​	​	​

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.

In some embodiments of the present application, the DSC spectrum of type C crystal of the compound of formula (I) is shown in Figure 8.

In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of the Type C crystal of the compound of formula (I) has a weight loss of 3.10% at 130±3°C.

In some embodiments of the present application, the TGA spectrum of type C crystal of the compound of formula (I) is shown in Figure 9.

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

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

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/minute.

In some embodiments of the present application, the above method further includes the step of isolating the solid and subsequently drying the solid; optionally, drying at room temperature.

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°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the D-form crystal of the compound of formula (I) has 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the D-form crystal of the compound of formula (I) 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°, 21.45±0.20° and 22.71±0.20°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the D-form crystal of the compound of formula (I) 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°.

On the other hand, the present application provides a D-type crystal of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation includes 3, 4, 5, 6, 7, 8, 9 or 10 diffraction peaks: 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°.

On the other hand, the present application provides a D-type crystal of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation contains 3, 4, 5, 6, 7 or 3, 4, 5, 6, 7 or 8 diffraction peaks: 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°.

In some embodiments of the present application, the XRPD pattern of the D-form crystal of the compound of formula (I) is shown in Figure 10.

In some embodiments of the present application, in the XRPD of the D-form 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 as shown in Table 4:

Table 4: XRPD spectrum analysis data of the D-form crystal of the compound of formula (I)

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

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

In some embodiments of the present application, the TGA spectrum of the D-form crystal of the compound of formula (I) is shown in Figure 11.

In another aspect, the present application provides a method for preparing D-type crystals of the compound of formula (I). The method includes the following steps: mixing the compound of formula (I) with maleic acid and acetone, and separating the solid.

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

On the other hand, the present application also provides phosphate salts of compounds of formula (I).

On the other hand, the present application also provides the crystallization of the phosphate salt of the compound of formula (I).

In some embodiments of the present application, in the phosphate salt of the compound of formula (I), the ratio of the number of molecules of the compound of formula (I) to phosphoric acid is 1:(1-1.5); in some embodiments, the ratio of the number of molecules of the compound of formula (I) to phosphoric acid is 1:(1-1.5); in some embodiments, the ratio of the number of molecules of the compound of formula (I) is Ⅰ) The ratio of the number of molecules of the compound to phosphoric acid is 1:1.

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

In some embodiments of the present application, the phosphate salt of the compound of formula (I) is a crystallized phosphate salt of the compound of formula (I).

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

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

In some embodiments of the present application, the X-ray powder diffraction pattern of the crystallized phosphate of the compound of formula (I) using Cu Kα radiation has diffraction peaks at 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern of the crystallized phosphate of the compound of formula (I) using Cu Kα radiation 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° .

In some embodiments of the present application, the X-ray powder diffraction pattern of the crystallized phosphate of the compound of formula (I) using Cu Kα radiation 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern of the crystallized phosphate of the compound of formula (I) using Cu Kα radiation 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°, 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°.

On the other hand, the present application provides a crystal of a phosphate salt of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation contains 3, 4, 5, 6, 7 selected from the following 2θ angles , 8, 9, 10, 11, 12, 13 or 14 diffraction peaks: 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°.

On the other hand, the present application provides a crystal of a phosphate salt of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation contains 3, 4, 5, 6, 7 selected from the following 2θ angles Or 8 diffraction peaks: 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°.

In some embodiments of the present application, the XRPD pattern of the crystallized phosphate salt of the compound of formula (I) is shown in Figure 12.

In some embodiments of the present application, in the XRPD pattern of the crystallized 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 as shown in Table 5 Show:

Table 5: XRPD data of crystallization of phosphate salt of compound of formula (I)

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	​	​	​

In some embodiments of the present application, the differential scanning calorimetry (DSC) spectrum of the crystallization of the phosphate salt of the compound of formula (I) has an origin of an exothermic peak at 141.9±3.0°C.

In some embodiments of the present application, the DSC pattern of the crystallization of the phosphate salt of the compound of formula (I) is shown in Figure 13.

In some embodiments of the present application, the thermogravimetric analysis (TGA) pattern of the crystallized phosphate of the compound of formula (I) has a weight loss of 5.50% at 130±3°C.

In some embodiments of the present application, the TGA spectrum of the crystallization of the phosphate salt of the compound of formula (I) is shown in Figure 14.

In another aspect, the present application provides a method for preparing crystallized phosphate of a compound of formula (I). The method includes the following steps: mixing the compound of formula (I) with phosphoric acid, EtOH and H ₂ O, and separating to obtain a solid.

In some embodiments of the present application, the above preparation method includes stirring under heating conditions after the mixing; optionally, stirring under heating conditions of 40 to 80°C; optionally, stirring under heating conditions to Stir at 50°C.

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

On the other hand, the present application also provides oxalate salts of compounds of formula (I).

In some embodiments of the present application, in the oxalate salt of the compound of formula (I), the ratio of the number of molecules of the compound of formula (I) to oxalic acid is 1:(1-1.5); in some embodiments, the The ratio of the number of molecules between the compound of formula (I) and oxalic acid is 1:1.1.

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

In some embodiments of the present application, the oxalate salt of the compound of formula (I) is a crystal of the oxalate salt of the compound of formula (I), such as the Form I crystal of the oxalate salt of the compound of formula (I) or the oxalate salt of the compound of formula (I) I) Form II crystals of the oxalate salt of the compound.

On the other hand, the present application also provides a Form I crystal of the oxalate salt of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.06±0.20°, 12.69± 0.20° and 15.21±0.20°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the Form I crystal of the oxalate salt of the compound of formula (I) 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern of the Form I crystal 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°.

On the other hand, the present application provides a Form I crystal of the oxalate salt of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation contains 3, 4, 5 or 3 at the 2θ angle below. 6 diffraction peaks: 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°.

In some embodiments of the present application, the XRPD pattern of the Form I crystal of the oxalate salt of the compound of formula (I) is shown in Figure 15.

In some embodiments of the present application, in the XRPD pattern of the Form I crystal of the oxalate salt 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 is as follows Table 6 shows:

Table 6: XRPD data of Form I crystals of the oxalate salt of the compound of formula (I)

serial number	2θ[±0.20°]	Relative Strength[%]	serial number	2θ[±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	​	​	​

In some embodiments of the present application, the DSC pattern of the Form I crystal of the oxalate salt of the compound of formula (I) is shown in Figure 16.

In some embodiments of the present application, the thermogravimetric analysis (TGA) spectrum of the Form I crystal of the oxalate salt of the compound of formula (I) has a weight loss of 11.44% at 150±3°C.

In some embodiments of the present application, the TGA spectrum of the Form I crystal of the oxalate salt of the compound of formula (I) is shown in Figure 17.

In another aspect, the present application provides a method for preparing Type I crystals of the oxalate salt of the compound of formula (I). The method includes the following steps: mixing the compound of formula (I) with oxalic acid and acetone, and separating the solid.

In some embodiments of the present application, the above preparation method includes stirring under heating after the mixing; optionally, the heating temperature is 40-80°C; optionally, the heating temperature is 50°C.

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

On the other hand, the present application also provides a Type II crystal of the oxalate salt of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.44±0.20°, 11.75± 0.20° and 13.77±0.20°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the Form II crystal of the oxalate salt of the compound of formula (I) 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the Form II crystal of the oxalate salt of the compound of formula (I) 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°.

In some embodiments of the present application, the X-ray powder diffraction pattern using Cu Kα radiation of the Form II crystal of the oxalate salt of the compound of formula (I) 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°.

On the other hand, the present application provides a Type II crystal of the oxalate salt of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 diffraction peaks: 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°.

On the other hand, the present application provides a Type II crystal of the oxalate salt of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation contains 3, 4, 5, 6, 7 or 8 diffraction peaks: 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°.

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 shown in Figure 18.

In some embodiments of the present application, in the XRPD pattern of the Type II crystal of the oxalate salt 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 as follows Table 7 shows:

Table 7: XRPD data of Form II crystals of the oxalate salt of the compound of formula (I)

serial number	2θ[±0.20°]	Relative Strength[%]	serial number	2θ[±0.20°]	Relative Strength[%]
1	5.44	100.00	9	18.39	6.50
2	10.85	15.27	10	20.83	12.17
3	11.75	23.69	11	21.75	12.75

serial number	2θ[±0.20°]	Relative Strength[%]	serial number	2θ[±0.20°]	Relative Strength[%]
4	13.77	33.21	12	23.39	13.01
5	16.01	23.53	13	25.13	8.47
6	16.27	28.41	14	25.61	6.83
7	17.21	5.99	15	27.42	16.16
8	17.85	11.76	​	​	​

In some embodiments of the present application, the DSC pattern of the Form II crystal of the oxalate salt of the compound of formula (I) is shown in Figure 19.

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) has a weight loss of 7.78% at 150±3°C.

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 shown in Figure 20.

In another aspect, the present application provides a method for preparing type II crystals of the oxalate salt of the compound of formula (I). The method includes the following steps: mixing the compound of formula (I) with oxalic acid, EtOH and H ₂ O, and separating. A solid was obtained.

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

In some embodiments of the present application, the above preparation method also includes a drying step; optionally, drying is performed at room temperature and under vacuum conditions.

In another aspect, the present application provides a crystalline composition comprising the crystals described in the present application, wherein the crystals account for more than 50%, preferably more than 80%, and more preferably more than 90% by weight of the crystalline composition, It is best to be above 95%.

In another aspect, the present application provides a pharmaceutical composition, which contains a therapeutically effective amount of the crystal of the compound of formula (I) described in the present application, the salt of the compound of formula (I) or its crystal, or its crystal form. combination. The pharmaceutical composition of the present application may or may not contain pharmaceutically acceptable excipients. In addition, the pharmaceutical compositions 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 pharmaceutical composition contains a therapeutically effective amount of the crystal of the compound of formula (I) described in the present application, the salt of the compound of formula (I) or its crystal, or its crystalline composition.

In another aspect, the present application also provides the crystallization of the compound of formula (I), the salt of the compound of formula (I) or its crystal, its crystal form composition, or its pharmaceutical composition for use in the preparation of treatment or Application in drugs to prevent JAK1 and/or JAK2 related diseases.

In another aspect, this application also provides the use of the crystal of the compound of formula (I), the salt of the compound of formula (I) or its crystal, its crystal form composition, or its pharmaceutical composition in the treatment or prevention of JAK1 and /or applications in JAK2-related diseases.

In another aspect, the present application also provides crystals of the compound of formula (I) described in the present application, salts of the compound of formula (I) or crystals thereof, and combinations of crystal forms thereof for the treatment or prevention of JAK1 and/or JAK2-related diseases. substances, or pharmaceutical compositions thereof.

In another aspect, the present application also provides a method for treating or preventing JAK1 and/or JAK2-related diseases, including administering a therapeutically effective amount of a compound of formula (I) described in the present application to a mammal (preferably a human) in need of such treatment. Crystals, salts of the compound of formula (I) or crystals thereof, crystalline compositions thereof, or pharmaceutical compositions thereof.

In this application, the JAK1 and/or JAK2 related diseases are selected from inflammatory diseases (such as arthritis) and the like.

Technical effect

The compound of the present application, its crystals, its salts and the crystals of its salts showed good selective inhibition of JAK1 and/or JAK2 in the in vitro activity test of the four subtypes of Janus kinase JAK1, JAK2, JAk3 and TYK2; in It can have good oral bioavailability, high exposure, good pharmacokinetic properties, and good in vivo efficacy in animals to be tested. Moreover, the crystallization of the compound of formula (I) of the present application, its salts and the crystallization of its salts can show the advantages of stable physical and chemical properties, little influence by light, heat and humidity, good solubility, and difficulty in crystallization, which is beneficial to the preparation of medicines.

Definition and Description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

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 and the measuring method/conditions. For any particular crystal form, there may be errors in the position of the peak, and the error in the determination of the 2θ value can be ±0.2°. Therefore, this error should be taken into account when determining each crystal form, and values within the error range also belong to the scope of this application.

It should be noted that for the same crystal form, the position of the endothermic peak of DSC may differ due to factors such as measuring instruments, measuring methods/conditions, etc. For any specific crystal form, there may be errors in the position of the endothermic peak, and the error can be ±5°C or ±3°C. Therefore, this error should be taken into account when determining each crystal form, and values within the error range also belong to the scope of this application.

The words "comprise" or "comprise" and their English variants such as compris or comprising should be understood as having an open, non-exclusive meaning, that is, "including but not limited to".

"Pharmaceutically acceptable excipients" refer to inert substances that are administered together with the active ingredients and facilitate the administration of the active ingredients, including but not limited to acceptable substances approved by the State Food and Drug Administration for use in humans or animals (e.g. any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, Isotonic agents, solvents or emulsifiers. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

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

The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients. For example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

Typical routes of administration of the crystals described herein or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous Internal administration.

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

In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.

The therapeutic dosage of a compound of the present application may be determined based, for example, on the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportions or concentrations of the compounds of the present application in pharmaceutical compositions may not be fixed and depend on a variety of factors, including dosage, chemical properties (eg, hydrophobicity), and route of administration. The term "treating" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) To inhibit a disease or disease state, that is, to arrest its progression;

(ii) Alleviation of a disease or condition, i.e. resolution of the disease or condition.

The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in a mammal, in particular when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.

The therapeutically effective amount of the crystals described herein is from about 0.0001 to 20 mg/Kg body weight/day, for example from 0.001 to 10 mg/Kg body weight/day.

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 may be intermittent, for example, wherein during a period of several days the patient receives a daily dose of crystals, followed by a period of several or more days in which the patient does not receive a daily dose of crystals.

In this document, unless the context clearly dictates otherwise, singular terms encompass plural referents and vice versa. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

Unless otherwise stated, parameter values herein should be understood to be modified by the term "about." When the term "about" is used to describe a parameter of the present application, the term "about" means that there is an error value, for example, within a range of ±5%, such as ±1% or ±0.1% of a particular value.

All patents, patent applications, and other identified publications are expressly incorporated by reference herein for purposes of description and disclosure. These publications are provided solely because their disclosures preceded the filing date of this application. All statements as to the date of these documents or representations of the contents of these documents are based on information available to the applicant and do not constitute any admission as to the correctness of the date of these documents or the contents of these documents. Furthermore, any reference herein to these publications does not constitute an admission that the publications form part of the common general knowledge in the art in any country.

The present application will be described in detail through examples below, and these examples do not imply any limitation on the present application.

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

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-butoxycarbonyl; TBS represents tert-butyldimethylsilyl; Et represents ethyl; Ts represents p-toluenesulfonyl; PE represents petroleum ether; EA or EtOAc represents ethyl acetate; ADDP represents azodicarboxyl dipipridine; TBAF represents tetrabutylammonium fluoride; DCM represents dichloromethane; THF represents tetrahydrofuran; TMSI represents trimethylsilyl iodide; AcOH represents acetic acid.

X-ray powder diffraction (XRPD)

Instrument model: Bruker D8 advance X-ray diffractometer

Test method: About 10~20mg sample is used for XRPD detection.

The detailed XRPD parameters are as follows:

Light pipe: Cu,kα,

Light tube voltage: 40kV, light tube current: 40mA

Divergence slit: 0.60mm

Detector slit: 10.50mm

Anti-scatter slit: 7.10mm

Scanning range: 4-40deg (or 3-40deg)

Step distance: 0.02deg

Step size: 0.12 seconds

Sample plate rotation speed: 15rpm

Differential Scanning Calorimetry (DSC)

Instrument model: TA Q2000 differential scanning calorimeter

Test method: Take a sample (~1mg) and place it in a DSC aluminum pot for testing. Under 50mL/min _N2 conditions, heat the sample from 25℃ to 300℃ at a heating rate of 10℃/min.

Thermal Gravimetric Analysis (TGA)

Instrument model: TA Q5000IR thermogravimetric analyzer

Test method: Take a sample (2~5mg) and place it in a TGA platinum pot for testing. Under 25mL/min _N2 conditions, heat the sample from room temperature to a weight loss of 20% at a heating rate of 10°C/min.

Description of the drawings

Figure 1 is the XRPD spectrum of Cu-Kα radiation of type A crystal of the compound of formula (I).

Figure 2 is a DSC spectrum of Form A crystal of the compound of formula (I).

Figure 3 is a TGA spectrum of type A crystal of the compound of formula (I).

Figure 4 is the XRPD spectrum of Cu-Kα radiation of type B crystal of the compound of formula (I).

Figure 5 is a DSC spectrum of type B crystal of the compound of formula (I).

Figure 6 is a TGA spectrum of type B crystal of the compound of formula (I).

Figure 7 is the XRPD spectrum of Cu-Kα radiation of the C-type crystal of the compound of formula (I).

Figure 8 is a DSC spectrum of type C crystal of the compound of formula (I).

Figure 9 is a TGA spectrum of type C crystal of the compound of formula (I).

Figure 10 is the XRPD spectrum of Cu-Kα radiation of the D-type crystal of the compound of formula (I).

Figure 11 is a TGA spectrum of the D-form crystal of the compound of formula (I).

Figure 12 is an XRPD spectrum of Cu-Kα radiation of crystallized phosphate of the compound of formula (I).

Figure 13 is a DSC spectrum of the crystallized phosphate salt of the compound of formula (I).

Figure 14 is a TGA spectrum of crystallized phosphate of the compound of formula (I).

Figure 15 is the XRPD spectrum of Cu-Kα radiation of the Form I crystal of the oxalate salt of the compound of formula (I).

Figure 16 is a DSC spectrum of the Form I crystal of the oxalate salt of the compound of formula (I).

Figure 17 is a TGA spectrum of the Form I crystal of the oxalate salt of the compound of formula (I).

Figure 18 is an XRPD spectrum of the Cu-Kα radiation of the Type II crystal of the oxalate salt of the compound of formula (I).

Figure 19 is a DSC spectrum of the Form II crystal of the oxalate salt of the compound of formula (I).

Figure 20 is a TGA spectrum of type II crystal of the oxalate salt of the compound of formula (I).

Detailed ways

In order to better understand the content of the present application, further description will be given below with reference to specific embodiments, but the specific implementations do not limit the content of the present application.

Example 1: Preparation of compounds of formula (I)

Step 1: Under nitrogen protection at -78°C, add n-butyllithium and n-hexane dropwise to a solution of tert-butyldimethyl (2-propynyloxy)silane (200g, 1174.24mmol) in tetrahydrofuran (2L) Alkane solution (2.5M, 427.54mL), 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 (2 L) was added dropwise to the reaction liquid 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. Add saturated ammonium chloride aqueous solution (2L) and water (1L) to the reaction solution to quench the reaction, extract with EA (2L*3), and combine the reactions. The 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 (400MHz, 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).

Step 2: Add hydrazine hydrate (34.71g, 1.03mol, 98%) to a solution of compound 1-2 (400g, 935.44mmol) dissolved in DMF (3L) under an 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 (10L) and extracted with EA (2L*2). The combined reaction solution was washed with saturated brine (2L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain Compounds 1-3. MS(ESI)442[M+H] ⁺ .

Step 3: To a solution of compound 1-3 (432g, 978.18mmol) in THF (3L) under ice bath conditions, NaBH ₄ (77.71g, 2.05mol) was added in portions. Afterwards, methanol (0.6L) was slowly added dropwise, and the reaction solution was stirred and reacted at 25°C for 12 hours. LC-MS showed that the reaction was complete. Under ice bath conditions, add saturated ammonium chloride aqueous solution (300mL) to the reaction solution to quench the reaction, then dilute with water (2L), extract with EA (2L*2), and wash the combined reaction solution with saturated brine (2L) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and obtained compound 1-4 through silica gel column chromatography (DCM:MeOH=50:1~20:1). MS(ESI)400[M+H] ⁺ .

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

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

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

Step 7: To a solution of compound 1-7 (11g, 41.46mmol) dissolved in THF (150mL), add NH ₃ ·H ₂ O (51.89g, 414.61mmol, 57.03mL, 28% purity) and I ₂ (31.57g , 124.38 mmol), the reaction solution was replaced with nitrogen three times, and then stirred at 25°C for 12 hours. LC-MS showed the reaction was complete. Add saturated aqueous sodium sulfite solution to the reaction solution to quench the reaction, add 20 mL of water to dilute, and then extract with ethyl acetate (50 mL*2). The organic phases were combined, washed with saturated brine (30 mL), dried over 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] ⁺ .

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

Step 9: Add p-toluenesulfonyl chloride (27.49g, 144.19mmol, 1.1eq) and DMAP (1.6g, 13.11) to a solution of compound 1-10 (20g, 131.08mmol, 1eq) in DCM (50mL) at 25°C. mmol, 0.1eq) and triethylamine (19.9g, 196, 62mmol, 27.37mL), the resulting solution was stirred at 25°C for 16 hours, the reaction was complete, the solvent was removed under reduced pressure, saturated NaHCO ₃ solution (50mL) was added, and filtered. The filter cake is washed with water and dried to obtain product 1-11. MS(ESI)307[M+H] ⁺ .

Step 10: To a solution of compound 1-11 (10g, 32.60mmol, 1eq) in DCM (50mL), add dropwise tetrabutylammonium nitrate (29.78g, 97.79mmol, 3eq) in dichloromethane ( 50mL) solution, then slowly add trifluoroacetic anhydride (20.54g, 97.79mmol, 13.60mL, 3eq) 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 phases were washed with water (200 mL*2) and brine (200 mL*1), followed by anhydrous sodium sulfate. Dry, filter, and concentrate under reduced pressure, and the resulting concentrate is recrystallized in dichloromethane to obtain product 1-12. MS(ESI)352[M+H] ⁺ .

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

Step 12: Add Fe (9.36g, 167.54mmol) and NH ₄ Cl (12.55g, 234.56mmol) to a solution of compound 1-13 (16g, 33.51mmol) dissolved in THF (200mL) and H ₂ O (50mL). , replaced with nitrogen three times, and stirred at 100°C for 1 hour. LCMS showed the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with H ₂ O (100 mL), and then extracted with ethyl acetate (150 mL*2). The filter cake was washed with DCM:MeOH (20:1, 100mL*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] ⁺ .

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

Step 14: Dissolve compound 1-15 (180 mg, 369.21 μmol) in THF (10 mL), and then add TBAF (1 M, 738.4 μL). The reaction liquid was replaced with nitrogen three times and stirred at 70°C for 12 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated, and then the resulting concentrate was diluted with NaHCO ₃ 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 and separated by preparative HPLC (Phenomenex Gemini NX 80*30mm*3μm; mobile phase: phase A is water (10mM NH ₄ HCO ₃ )-ACN; phase B (ACN)%: 20%-50%, 9min) Compounds of formula (I) are obtained. MS(ESI)334[M+H] ⁺ . ¹ H NMR (400MHz, 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),2.68-2.55(m,1H),2.28(br s,1H ).

Example 2

Take 1 gram of the compound of formula (I) and place it in a 100 ml glass vial, add 40 ml of ethanol, heat to reflux, stir at 78°C until the solution is clear, cool to room temperature, and stir overnight. The solid was obtained by filtration, and the solid was vacuum dried for 8 hours to obtain Type A crystals of the compound of formula (I).

Example 3

Take 19.9 mg of the compound of formula (I) and place it in a 5.0 ml glass vial, and add 0.2 ml of DMF to dissolve the solid. Add 3 ml of MEK dropwise to the clear solution while magnetically stirring at room temperature (rotation speed is about 750 rpm). The resulting clear solution is still clarified after magnetic stirring at room temperature overnight. Continue to transfer to 5°C. After magnetic stirring overnight, it was still clear. Then, after magnetic stirring overnight at -20°C, a turbid sample was obtained. The solid was obtained by centrifugation. 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). .

Example 4

Put 19.8 mg of the compound of formula (I) into a 5.0 ml glass vial, add 2.5 ml of ACN, leave it overnight at 50°C, and filter using a 0.45 micron PTFE filter to obtain a clear solution. After cooling the clear solution from 50°C to 5°C at a rate of 0.1°C/min, it was magnetically stirred at 5°C overnight to obtain a turbid sample. The solid was obtained by centrifugal separation, and the solid was transferred to room temperature and dried overnight to obtain Form C crystals of the compound of formula (I).

Example 5

Put 20.1 mg of the compound of formula (I) into an HPLC glass vial, add 8.5 mg of maleic acid and 0.5 ml of acetone to obtain a turbid sample. The sample was magnetically stirred at 50°C for two days, but the sample was still turbid. The solid was obtained by centrifugal separation, and the solid was transferred to room temperature and vacuum dried for about four hours to obtain Form D crystals of the compound of formula (I).

Example 6

Put 20.3 mg of the compound of formula (I) into an HPLC glass vial, add 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, but the sample was still turbid. The solid was obtained by centrifugal separation, and the solid was transferred to room temperature and vacuum dried for about four hours to obtain crystals of the phosphate salt of the compound of formula (I).

Example 7

Put 20.3 mg of the compound of formula (I) into an HPLC glass vial, add 9.3 mg of oxalic acid and 0.5 ml of acetone to obtain a turbid sample. The sample was magnetically stirred at 50°C for two days, but the sample was still turbid. The solid was obtained by centrifugal separation, and the solid was transferred to room temperature and vacuum dried for about four hours to obtain Form I crystals of the oxalate salt of the compound of formula (I).

Example 8

Put 20.1 mg of the compound of formula (I) into an HPLC glass vial, add 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, but the sample was still turbid. The solid was obtained by centrifugal separation, and the solid was transferred to room temperature and vacuum dried for about four hours to obtain Type II crystals of the oxalate salt of the compound of formula (I).

Bioactivity testing

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

Experimental Materials

Recombinant human JAK1, JAK2, JAK3, and TYK2 proteases, main instruments, and reagents are all provided by the British company Eurofins.

experimental method

JAK2, JAK3, and TYK2 were diluted in a solution prepared from: 20mM 3-(N-morpholine)propanesulfonic acid (MOPS), 1mM EDTA, 0.01% Brij-35.5% glycerol, 0.1% β-mercaptoethanol, 1mg/ mLBSA. JAK1 was diluted in a solution prepared as follows: 20mM TRIS, 0.2mM EDTA, 0.1% β-mercaptoethanol, 0.01% Brij-35.5% 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 subsequent determinations. The tested compound of formula (I) was diluted 3 times in a concentration gradient to obtain a total of 9 concentrations ranging from 10 μM to 0.001 μM. The content of DMSO in the detection reaction system was 2%. The working stock solution of this compound is added to the corresponding assay well as the first component of the reaction, followed by the remaining components following the assay protocol detailed below.

JAK1(h) enzyme reaction

JAK1 (h) was incubated with 20mM Tris/HCl pH 7.5, 0.2mM EDTA, 500μM MGEEPLYWSFPAKKK (SEQ ID NO: 1), 10mM magnesium acetate, and [γ- ³³ P]-ATP (activity and concentration as required). The reaction was started by adding the Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. 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 counted by scintillation.

JAK2(h) enzyme reaction

JAK2(h) was incubated with 8mM MOPS pH 7.0, 0.2mM EDTA, 100μM KTFCGTPEYLAPEVRREPRILSEEEQEM FRDFDYIADWC (SEQ ID NO:2), 10mM magnesium acetate, and [γ- ^33P ]-ATP (activity and concentration as required). The reaction was started by adding the Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. 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 counted by scintillation.

JAK3(h) enzyme reaction

JAK3(h) was incubated with 8mM MOPS pH 7.0, 0.2mM EDTA, 500μM GGEEEEYFELVKKKK (SEQ ID NO:3), 10mM magnesium acetate, and [γ- ³³ P]-ATP (activity and concentration as required). The reaction was started by adding the Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. 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 counted by scintillation.

TYK2(h) enzyme reaction

TYK2(h) was incubated with 8mM MOPS pH 7.0, 0.2mM EDTA, 250μM GGMEDIYFEFMGGKKK (SEQ ID NO:4), 10mM magnesium acetate and [γ- ^33P ]-ATP (activity and concentration as required). The reaction was started by adding the Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphoric acid. 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 counted by scintillation.

data analysis

The IC ₅₀ results were analyzed using IDBS's XLFIT5 (205 formula). See Table 8 for details.

Table 8. In vitro screening test results for compounds of formula (I)

Experimental Example 2: Pharmacokinetic (PK) test

After the compound of formula (I) of Example 1 was dissolved in 5% DMSO and 95% (v:v) SBE-β-CD with a mass concentration of 12%, the obtained clear solution was injected through the tail vein. and intragastric administration into male SD rats (fast overnight before administration, 7 to 8 weeks old). After administration of the test compound, the intravenous injection group (1mg/kg) rats were at 0.117, 0.333, 1, 2, 4, 7 and 24 hours, and the intragastric group (5mg/kg) rats were at 0.25, 0.5, 1 , 2, 4, 8 and 24 hours, blood was collected from the mandibular vein of each rat and centrifuged to obtain plasma. The blood drug concentration was measured using the LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated using the non-compartmental model linear logarithmic trapezoidal method using WinNonlin ^TM Version 6.3 pharmacokinetic software. The test results are as follows:

Table 9 PK test results of compounds of formula (I) in rats

PK parameters	Compounds of formula (I)
T 1/2 (hr)	3.65
C max (nM)	10152
AUC 0-inf (nM.hr)	67786
bioavailability(%)	119%

Note: T _1/2 : half-life; C _max : peak concentration;

AUC _0-inf : Area under the plasma concentration-time curve from time 0 to extrapolation to infinity.

Experimental Example 3: In vivo efficacy study of collagen-induced arthritis (CIA) in rats

experiment procedure:

The rat collagen-induced arthritis model was used to verify the effect of the compound of formula (I) in treating arthritis. Lewis rats were immunized, and the day of the first immunization was recorded as day 0, and subsequent days were marked in sequence. After Lewis rats were anesthetized with isoflurane, 50 μl of prepared collagen emulsion (containing 200 μg CII) was injected subcutaneously in the tail (2-3 cm from the base of the tail). On the 21st day, the same volume of collagen emulsion was subcutaneously injected into the tail using the same method. Lewis rats in the normal group do 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. Rats were given different doses (see Table 11 for specific doses) of 0.5% dissolved in water. The compound of formula (I) in a mixed vehicle of HPMC E5, 0.5% PVP K30 and 0.2% SLS was administered orally twice a day (the number of test animals in each dose group was 8). Administration was continued for 14 days, during which the status of the rats was observed, foot volume swelling was recorded and scored. The scoring standards are shown in Table 10.

Table 10. Clinical scoring criteria for arthritis

Points	Clinical symptoms
0	No erythema or swelling
1	Red spots or mild swelling near the tarsal bones or on the ankle or metatarsal bones or red spots and swelling on one toe
2	Mild erythema and swelling on the ankle and metatarsal bones, and redness and erythema on more than two toes
3	Moderate erythema and swelling of ankles, wrists, and metatarsals
4	Severe redness and swelling of all ankles, wrists, metatarsals, and toes

Experimental results:

When the compound of formula (I) was administered BID at doses of 1 and 3 mg/kg, the clinical score of arthritic rats was reduced in a dose-dependent trend, with a significant difference compared with the vehicle control group by the end of the 14th day of administration. At , the clinical scores of rats in the 3 mg/kg BID group dropped to zero (Table 11). At the same time, the degree of foot volume swelling also decreased 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 foot volume swelling of rats in the 3 mg/kg BID group dropped to 1.28 μL. The body weight of the rats in the treatment group (the group administered with the compound of formula (I)) also recovered 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 returned to that of the normal group. rat level.

Table 11 Main parameters of in vivo pharmacodynamic studies of CIA in rats*

*Note: Compared with the vehicle control group, P<0.001 for each group (two-factor analysis of variance).

Experimental Example 4: Stability Test

Relevant determinations were performed on each crystal of the compound described in this application according to each method described below.

Determination of relevant substances HPLC method chromatographic conditions:

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

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

Mobile phase B: 100% ACN

Flow rate: 0.8ml/min

Column temperature: 40℃

Detection wavelength: 230nm.

Content determination HPLC method chromatographic conditions:

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

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

Flow rate: 0.8ml/min

Column temperature: 40℃

Detection wavelength: 220nm.

Enantiomer determination HPLC method chromatographic conditions:

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

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

Flow rate: 1.5ml/min

Column temperature: 40℃

Detection wavelength: 220nm.

Sample preparation: Use a mixed solvent of acetonitrile and water (acetonitrile: water = 50:50 (v/v)) to dissolve the sample.

Moisture determination method:

Determined by Karl Fischer volumetric method, solvent: methanol.

Solid Stability Staking Method

Examine the stability of each crystal of the compound described in this application when placed under the following conditions, and take samples at different time points to detect relevant substances, content, enantiomers and crystal forms.

Accurately weigh different crystals into open flat weighing bottles in triplicate.

Spread into a thin layer as a formal test sample and place it under the influencing factors test conditions [40°C, 60°C, (25°C, relative humidity 75%), (25°C, relative humidity 92.5%), light (total Illumination 1.2×10 ⁶ Lux·hr/near ultraviolet 200w·hr/m ² )], each sample is fully exposed, and two additional portions (1.2g each) are added under the conditions of "25°C, relative humidity 92.5%" Pack the samples. Each sample is put into a double-layer medicinal low-density polyethylene bag. Each layer of medicinal low-density polyethylene bag is buckled and sealed separately, and then the medicinal low-density polyethylene bag is placed in a package of dry Place the agent in an aluminum foil bag and heat seal. Add 2 control samples under lighting conditions (total illumination 1.2×10 ⁶ Lux·hr/near ultraviolet 200w·hr/m ² ). The packaging method of the control samples is the same as that of the lighting samples, but the outside of the watch glass is covered with aluminum film. The above samples were sampled and analyzed on days 5, 10, and 30 respectively. Samples placed under light conditions (visible light 1,200,000 Lux, ultraviolet 200W) are fully exposed to room temperature.

In addition, different crystals of the compound are put into a double-layer medicinal low-density polyethylene bag. Each layer of medicinal low-density polyethylene bag is buckled and sealed separately, and then the medicinal low-density polyethylene bag is placed in a package of dry agent in an aluminum foil bag and heat-sealed as a formal test sample, placed under accelerated conditions (40°C, relative humidity 75%), long-term test conditions (25°C, relative humidity 60%) and 5°C. Sampling and analysis were conducted in January, March, June, September, December, 18, and 24 months. The sampling points for the accelerated test were January, March, and June, and the sampling points for the long-term test were March, June, September, December, 18, and 24 months. The hygroscopicity data of the above crystal forms were investigated using a dynamic vapor adsorption instrument.

Each crystal described in this 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 individual impurities and total impurities, basically unchanged moisture content, and no crystallization. Form transformation, and the hygroscopicity of the crystal form is small.

Those skilled in the art will realize that the scope of the present disclosure is not limited to the various specific implementations and examples described above, but can make various modifications and substitutions without departing from the spirit and concept of the disclosure. , or recombination, which all fall within the protection scope of the present disclosure.

Claims (15)

1. Crystals of compounds of formula (I), salts of compounds of formula (I) or crystals thereof, wherein the salt of compounds of formula (I) is phosphate or oxalate,

   
2. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1, wherein, in the X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation, Contains 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°;

   Alternatively, the X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.74±0.20°, 7.23±0.20° and 12.28±0.2°;

   Or, have diffraction peaks at the following 2θ angles: 5.74±0.20°, 5.26±0.20°, 7.23±0.20°, 9.25±0.20°, 12.28±0.20° and 14.46±0.2°;

   Alternatively, have 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° ;

   Or, have 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°;

   Or, have 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°;

   Alternatively, the XRPD pattern of the crystal of the compound of formula (I) is as shown in Figure 1.
3. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1 or 2, wherein the differential scanning calorimetry curve of the crystal of the compound of formula (I) is 188.8±3 There is an starting point of the exothermic peak at ℃;

   Alternatively, the DSC spectrum of the crystallization of the compound of formula (I) is as shown in Figure 2.
4. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1, wherein, in the X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation, Contains 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°;

   Alternatively, the X-ray powder diffraction pattern using Cu Kα radiation of the crystal of the compound of formula (I) has diffraction peaks at the following 2θ angles: 5.08±0.20°, 9.78±0.20°, 13.76±0.20°;

   Or, have 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°;

   Or, have 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°, 24.34±0.20° ;

   Or, have 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°;

   Alternatively, the XRPD pattern of the crystal of the compound of formula (I) is as shown in Figure 4.
5. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1 or 4, wherein the differential scanning calorimetry curve of the crystal of the compound of formula (I) is 172.9±3 There is a starting point of an endothermic peak at ℃;

   Alternatively, the DSC spectrum of the crystallization of the compound of formula (I) is as shown in Figure 5.
6. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1, wherein, in the X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation, Contains 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°;

   Alternatively, the X-ray powder diffraction pattern of the crystal of the compound of formula (I) 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°;

   Or, have 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°;

   Or, have 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°;

   Alternatively, the XRPD pattern of the crystal of the compound of formula (I) is as shown in Figure 7.
7. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1 or 6, wherein the differential scanning calorimetry curve of the crystal of the compound of formula (I) is at 140.2±3 There is a starting point of an endothermic peak at ℃;

   Alternatively, the DSC spectrum of the crystallization of the compound of formula (I) is as shown in Figure 8.
8. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1, wherein, in the X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation, Contains 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°; alternatively, the X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation has a diffraction peak at the following 2θ angle: 7.13±0.20°, 18.22±0.20° and 21.45±0.20°;

   Or, have 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°;

   Alternatively, have 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° ;

   Or, have 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°;

   Alternatively, the XRPD pattern of the crystal of the compound of formula (I) is as shown in Figure 10.
9. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1, wherein the salt of the compound of formula (I) is a phosphate, and the compound of formula (I) and phosphoric acid The ratio of the number of molecules is 1:(1-1.5), or the ratio of the number of molecules of the compound of formula (I) to phosphoric acid is 1:1.
10. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1 or 9, wherein the crystal of the salt of the compound of formula (I) is the phosphate salt of the compound of formula (I) The X-ray powder diffraction pattern of the phosphate crystal using Cu Kα radiation contains 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°;

    Alternatively, the X-ray powder diffraction pattern of the crystallized phosphate using Cu Kα radiation has diffraction peaks at the following 2θ angles: 7.87±0.20°, 16.64±0.20° and 20.04±0.20°;

    Or, have diffraction peaks at the following 2θ angles: 6.69±0.20°, 7.87±0.20°, 14.15±0.20°, 16.64±0.20° and 20.04±0.20°;

    Alternatively, have diffraction peaks at 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° ;

    Or, have 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°;

    Or, have 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°;

    Alternatively, the XRPD pattern of the crystallization of the phosphate is shown in Figure 12.
11. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1 or 10, wherein the differential scanning calorimetry curve of the crystal of the phosphate salt is at 141.9±3.0°C. The starting point of an exothermic peak;

    Alternatively, the DSC spectrum of the crystallization of the phosphate is shown in Figure 13.
12. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1, wherein the salt of the compound of formula (I) is an oxalate, and the compound of formula (I) and The ratio of the number of molecules of oxalic acid is 1:(1-1.5); or the ratio of the number of molecules of the compound of formula (I) to oxalic acid is 1:1.1.
13. The crystal of the compound of formula (I), the salt of the compound of formula (I) or the crystal thereof according to claim 1 or 12, wherein the crystal of the salt of the compound of formula (I) is oxalic acid of the compound of formula (I) Salt, the X-ray powder diffraction pattern of the oxalate crystal using Cu Kα radiation includes 3, 4, 5 or 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°;

    Alternatively, the X-ray powder diffraction pattern of the crystallized oxalate using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.06±0.20°, 12.69±0.20° and 15.21±0.20°;

    Or, have 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°;

    Or, have 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°;

    Alternatively, the XRPD pattern of the crystallization of the oxalate is as shown in Figure 15;

    Or wherein, the crystallization of the salt of the compound of formula (I) is the oxalate salt of the compound of formula (I), and the X-ray powder diffraction pattern of the crystallization of the oxalate salt using Cu Kα radiation includes a compound selected from the following 3, 4, 5, 6, 7 or 8 diffraction peaks at 2θ angle: 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°;

    Alternatively, the X-ray powder diffraction pattern of the crystallized oxalate using Cu Kα radiation has diffraction peaks at the following 2θ angles: 5.44±0.20°, 11.75±0.20° and 13.77±0.20°;

    Or, have 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°;

    Alternatively, have 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° ;

    Or, have 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°; or, the XRPD pattern of the crystallization of the oxalate is shown in Figure 18.
14. A pharmaceutical composition comprising a therapeutically effective amount of a crystal of a compound of formula (I), a salt of a compound of formula (I) or a crystal thereof according to any one of claims 1 to 13.
15. The crystal of the compound of formula (I) according to any one of claims 1 to 13, the salt of the compound of formula (I) or the crystal thereof, or the crystal of the compound of formula (I) or the crystal of claim 14 for the treatment or prevention of JAK1 and/or JAK2 related diseases pharmaceutical compositions.

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