Salt form and crystal form of JAK inhibitor as well as preparation method and application of salt form and crystal form

Abstract

The invention provides a salt form and a crystal form of a JAK inhibitor as well as a preparation method and application of the salt form and the crystal form. An X-ray powder diffraction pattern of the crystal form A of the compound shown in the formula I has characteristic diffraction peaks at the following angles of 2 theta: 5.9 degrees + / -0.2 degrees, 7.4 degrees + / -0.2 degrees, 11.6 degrees + / -0.2 degrees, 21.7 degrees + / -0.2 degrees and 23.8 degrees + / -0.2 degrees; # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with the national application number CN202180061258.0 and the invention-creation name "Salt forms, crystal forms of JAK inhibitors and their preparation methods and uses". The patent application with the application number CN202180061258.0 is the application of the PCT application with the international filing date of August 12, 2021 and the international application number PCT / CN2021 / 112278 in the Chinese national phase, and the entry date into China is January 13, 2023. This application claims the priority of the priority date of August 14, 2020 and the priority number PCT / CN2020 / 109279, and the priority of the priority date of February 3, 2021 and the priority number PCT / CN2021 / 075086. Technical Field

[0002] The present invention relates to salt forms, crystal forms of JAK inhibitors and their preparation methods and uses. Background Art

[0003] The Janus kinase (JAK) signaling pathway, which is found in interferon-induced receptor-mediated gene expression, has been shown to be a common signaling pathway used by many cytokines and growth factors. The mammalian JAK family of intracellular tyrosine kinases has four members: Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). JAKs range in size from 120 to 140 kDa and contain seven conserved JAK homology (JH) domains that define this kinase superfamily.

[0004] Each JAK isoform can be used by multiple cytokine pathways, and the biological activities of many cytokines can be inhibited and regulated by one or more JAKs. Inhibition of JAK can be used to prevent, inhibit, or treat the development or onset of various diseases and disorders, including hyperproliferative diseases and cancers such as leukemia and lymphoma, and immune and inflammatory disorders such as transplant rejection, asthma, chronic obstructive pulmonary disease, allergies, rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis, and multiple sclerosis.

[0005] It is disclosed in WO2016119700A1 that the compound shown in Formula I is an effective JAK inhibitor for preventing or treating one or more symptoms of Janus kinase-mediated diseases;

[0006]

[0007] The free base form of the compound shown in Formula I has too low solubility in water, which will affect its dissolution and absorption in vivo, resulting in too low bioavailability and making it unsuitable for further drug development. At the same time, due to its too low water solubility, it is not easily purified during the production process, bringing certain difficulties to industrial production. Summary of the Invention

[0008] The present invention provides salt forms, crystal forms of JAK inhibitors, and their preparation methods and applications. The salt forms and crystal forms have good JAK kinase inhibitory activity, solubility, stability and bioavailability, enhancing the developability of the oral preparation of the compound shown in Formula I.

[0009] The present invention provides crystal form A of the hydrochloride hydrate of the compound shown in Formula I, and its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 5.9° ± 0.2°, 7.4° ± 0.2°, 11.6° ± 0.2°, 21.7° ± 0.2° and 23.8° ± 0.2°;

[0010]

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.9° ± 0.2°, 7.4° ± 0.2°, 11.6° ± 0.2°, 17.7° ± 0.2°, 17.8° ± 0.2°, 21.7° ± 0.2°, 23.6° ± 0.2°, 23.8° ± 0.2°, 29.0° ± 0.2°, 30.4° ± 0.2° and 34.9° ± 0.2°.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.9° ± 0.2°, 7.4° ± 0.2°, 8.9° ± 0.2°, 11.6° ± 0.2°, 14.6° ± 0.2°, 17.7° ± 0.2°, 17.8° ± 0.2°, 18.7° ± 0.2°, 19.5° ± 0.2°, 21.0° ± 0.2°, 21.7° ± 0.2°, 21.9° ± 0.2°, 22.6° ± 0.2°, 23.6° ± 0.2°, 23.8° ± 0.2°, 29.0° ± 0.2°, 30.4° ± 0.2°, 33.3° ± 0.2°, 34.9° ± 0.2° and 37.7° ± 0.2°.

[0013] In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A has characteristic diffraction peaks at the following 2θ angles: 5.9° ± 0.2°, 6.6° ± 0.2°, 7.4° ± 0.2°, 8.9° ± 0.2°, 10.5° ± 0.2°, 11.6° ± 0.2°, 12.3° ± 0.2°, 13.9° ± 0.2°, 14.2° ± 0.2°, 14.6° ± 0.2°, 17.1° ± 0.2°, 17.7° ± 0.2°, 17.8° ± 0.2°, 18.7 ° ± 0.2°, 19.5° ± 0.2°, 20.4° ± 0.2°, 21.0° ± 0.2°, 21.2° ± 0.2°, 21.7° ± 0.2°, 21.9° ± 0.2°, 22.6° ± 0.2°, 23.6° ± 0.2°, 23.8° ± 0.2°, 24.9° ± 0.2°, 26.6° ± 0.2°, 26.8° ± 0.2°, 28.3° ± 0.2°, 29.0° ± 0.2°, 30.4° ± 0.2°, 31.2° ± 0.2°, 32.3° ± 0.2°, 33.3° ± 0.2°, 34.2° ± 0.2°, 34.9° ± 0.2°, 35.6° ± 0.2°, 35.9° ± 0.2°, 36.4° ± 0.2°, 36.9° ± 0.2°, 37.7° ± 0.2°, 39.3° ± 0.2° and 39.8° ± 0.2°.

[0014] In some embodiments of the present invention, the X-ray powder diffraction pattern of Form A has characteristic diffraction peaks at the following 2θ angles: 5.9°, 6.6°, 7.4°, 8.9°, 10.5°, 11.6°, 12.3°, 13.9°, 14.2°, 14.6°, 17.1°, 17.7°, 17.8°, 18.7°, 19.5°, 20.4°, 21.0°, 21.2°, 21.7°, 21.9°, 22.6°, 23.6°, 23.8°, 24.9°, 26.6°, 26.8°, 28.3°, 29.0°, 30.4°, 31.2°, 32.3°, 33.3°, 34.2°, 34.9°, 35.6°, 35.9°, 36.4°, 36.9°, 37.7°, 39.3° and 39.8°.

[0015] In some embodiments of the present invention, the XRPD pattern analysis data of Form A are shown in Table 1:

[0016] Table 1. X-ray powder diffraction pattern analysis data of Form A

[0017]

[0018]

[0019] In some embodiments of the present invention, the XRPD pattern of polymorph A is as Figure 1 shown.

[0020] In some embodiments of the present invention, for the thermogravimetric analysis curve of polymorph A, there is a weight loss of 8.31 ± 0.50% before 148°C; and a weight loss of 4.76 ± 0.50% between 148°C and 228°C.

[0021] In some embodiments of the present invention, for the thermogravimetric analysis curve of polymorph A, there is a weight loss of 8.31% before 148°C; and a weight loss of 4.76% between 148°C and 228°C.

[0022] In some embodiments of the present invention, for the thermogravimetric analysis curve of polymorph A, there is a weight loss of 8.3143% before 148°C; and a weight loss of 4.7637% between 148°C and 228°C.

[0023] In some embodiments of the present invention, the thermogravimetric analysis curve of polymorph A is as Figure 3 shown.

[0024] In some embodiments of the present invention, the thermogravimetric analysis curve is detected under the conditions of a temperature rising range of 10°C - 300°C and a temperature rising rate of 10°C / min.

[0025] In some embodiments of the present invention, the differential scanning calorimetry (DSC) analysis chart of polymorph A has absorption peaks at 165°C ± 3°C and 198°C ± 3°C respectively.

[0026] In some embodiments of the present invention, the differential scanning calorimetry analysis chart of polymorph A has absorption peaks at 165.14°C and 197.70°C respectively.

[0027] In some embodiments of the present invention, the differential scanning calorimetry analysis chart of polymorph A has absorption peaks with starting temperatures of 141°C ± 3°C and 179°C ± 3°C respectively.

[0028] In some embodiments of the present invention, the differential scanning calorimetry analysis chart of polymorph A has absorption peaks with starting temperatures of 140.82°C and 179.20°C respectively.

[0029] In some embodiments of the present invention, the differential scanning calorimetry analysis chart of polymorph A is as Figure 2 shown.

[0030] In some embodiments of the present invention, the differential scanning calorimetry analysis chart is detected under the conditions of a temperature rising range of 25°C - 300°C and a temperature rising speed of 10°C / min.

[0031] In some embodiments of the present invention, the crystalline form A is a single crystal.

[0032] In some embodiments of the present invention, the single crystal of the crystalline form A belongs to the monoclinic system, space group P21 / c.

[0033] In some embodiments of the present invention, the unit cell parameters of the crystalline form A are α = 90°, β = 101.262(3)°, γ = 90°.

[0034] In some embodiments of the present invention, the unit cell volume of the crystalline form A is

[0035] The unit cell parameters and / or unit cell volume of the single crystal of the crystalline form A can be obtained by X-ray single crystal diffraction. The X-ray wavelength λ of the X-ray single crystal diffraction can be

[0036] In some embodiments of the present invention, in the crystalline form A, the molar ratio of the compound of formula I, HCl and water is 1:x:y, where x is greater than 0 and not greater than 3, and y is greater than 0 and not greater than 3.

[0037] In some embodiments of the present invention, in the crystalline form A, the molar ratio of the compound of formula I, HCl and water is 1:2:2.

[0038] The present invention also provides a method for preparing the crystalline form A of the hydrochloride hydrate of the compound of formula I, which comprises the following steps: precipitating crystals from a hydrochloride solution of the compound of formula I, and the crystals are the crystalline form A; wherein, the hydrochloride solution of the compound of formula I contains the hydrochloride of the compound of formula I, an organic solvent and water, and the organic solvent is one or a mixture of two or more selected from methanol, ethanol, n-propanol, n-butanol, isopropanol, isobutanol and tert-butanol. Two or more herein should be understood to include two. Those skilled in the art should be clear that the hydrochloride solution of the compound of formula I does not contain other organic solvents, unless it is an inevitable impurity or solvent residue.

[0039] Wherein, in the hydrochloride of the compound of formula I, the molar ratio of the compound of formula I and HCl is 1:x, x is greater than 0 and not greater than 3, for example 1:2.

[0040] In some embodiments, the organic solvent is ethanol.

[0041] In some embodiments, the volume ratio of the organic solvent to water is 5 - 15:0.5 - 1.5, for example 10:1 to 6:1, or for example 10:1 to 8:1, or for example 9:1.

[0042] In some embodiments, the temperature of the hydrochloride solution of the compound represented by formula I is 30 - 70 °C.

[0043] In some embodiments, the step of precipitating crystals from the hydrochloride solution of the compound represented by formula I includes: cooling the hydrochloride solution of the compound represented by formula I, for example, the cooling is to cool to 20 °C to 30 °C.

[0044] In some embodiments, the step of precipitating crystals from the hydrochloride solution of the compound represented by formula I includes: stirring the hydrochloride solution of the compound represented by formula I at 20 °C to 30 °C to precipitate crystals; the stirring time is for example 48 - 96 hours, or for example 48 hours.

[0045] In some embodiments, the preparation method further includes: after precipitating crystals from the hydrochloride solution of the compound represented by formula I, filtering, washing and drying the obtained filter cake to obtain polymorph A.

[0046] In some embodiments, the preparation method further includes: cooling the solution of polymorph A of the hydrochloride hydrate of the compound represented by formula I for crystallization to obtain single crystals of polymorph A of the hydrochloride hydrate of the compound represented by formula I, wherein the solvent of the solution of polymorph A of the hydrochloride hydrate of the compound represented by formula I is a mixture of ethanol and water; for example, the temperature of the solution of polymorph A of the hydrochloride hydrate of the compound represented by formula I is 55 - 75 °C, or for example 60 - 70 °C, or for example 64 - 66 °C; for example, the volume ratio of ethanol to water in the mixture of ethanol and water is 5 - 15:0.5 - 1.5, or for example 10:1 to 6:1, or for example 10:1 to 8:1, or for example 9:1; for example, the cooling is to cool to 20 °C to 30 °C.

[0047] In some embodiments, the hydrochloride solution of the compound represented by formula I is obtained by mixing raw materials including the hydrochloride hydrate of the compound represented by formula I, an organic solvent and water; for example, the hydrochloride solution of the compound represented by formula I is a mixture of the hydrochloride hydrate of the compound represented by formula I, an organic solvent and water. For example, the volume ratio of the organic solvent to water is 5 - 15:0.5 - 1.5, or for example 10:1 to 6:1, or for example 10:1 to 8:1, or for example 9:1; for example, the dosage ratio of the hydrochloride hydrate of the compound represented by formula I to water is 250 - 450 mg:1 mL, or for example 300 - 400 mg:1 mL, or for example 350 mg:1 mL.

[0048] In some embodiments, the hydrochloride solution of the compound represented by Formula I is obtained by mixing raw materials including the compound represented by Formula I, an organic solvent, water, and a concentrated hydrochloric acid solution. For example, the hydrochloride solution of the compound represented by Formula I is a mixture of the compound represented by Formula I, an organic solvent, water, and a concentrated hydrochloric acid solution. For example, the preparation method further includes: mixing the compound represented by Formula I, an organic solvent, and water, heating the resulting mixture to 30-70 °C, and adding a concentrated hydrochloric acid solution to obtain the hydrochloride solution of the compound represented by Formula I.

[0049] Among them, the ratio of the concentrated hydrochloric acid solution to the compound represented by Formula I can be, for example, 0.38 mL - 0.57 mL: 1 g, for example, 0.4 mL - 0.5 mL: 1 g, and also, for example, 0.38 mL - 0.40 mL: 1 g, 0.40 mL - 0.42 mL: 1 g, 0.42 mL - 0.44 mL: 1 g, 0.44 mL - 0.46 mL: 1 g, 0.46 mL - 0.48 mL: 1 g, 0.48 mL - 0.50 mL: 1 g, 0.50 mL - 0.52 mL: 1 g, 0.52 mL - 0.54 mL: 1 g, or 0.54 mL - 0.57 mL: 1 g.

[0050] Among them, the ratio of the organic solvent to the compound represented by Formula I can be, for example, 5 mL - 15 mL: 1 g, for example, 8 mL - 12 mL: 1 g, and also, for example, 5 mL - 6 mL: 1 g, 6 mL - 7 mL: 1 g, 7 mL - 8 mL: 1 g, 8 mL - 9 mL: 1 g, 9 mL - 10 mL: 1 g, 10 mL - 11 mL: 1 g, 11 mL - 12 mL: 1 g, 12 mL - 13 mL: 1 g, 13 mL - 14 mL: 1 g, or 14 mL - 15 mL: 1 g.

[0051] Among them, the volume ratio of the organic solvent to water can be, for example, 5 - 15: 0.5 - 1.5, and also, for example, 10:1 to 6:1, and also, for example, 10:1 to 8:1, and also, for example, 9:1.

[0052] Among them, the ratio of water to the compound represented by Formula I can be, for example, 0.5 mL - 1.5 mL: 1 g; for example, 0.8 mL - 1.2 mL: 1 g, and also, for example, 0.5 mL - 0.6 mL: 1 g, 0.6 mL - 0.7 mL: 1 g, 0.7 mL - 0.8 mL: 1 g, 0.8 mL - 0.9 mL: 1 g, 0.9 mL - 1.0 mL: 1 g, 1.0 mL - 1.1 mL: 1 g, 1.1 mL - 1.2 mL: 1 g, 1.2 mL - 1.3 mL: 1 g, 1.3 mL - 1.4 mL: 1 g, or 1.4 mL - 1.5 mL: 1 g.

[0053] Among them, the ratio of the organic solvent, water, and the compound shown in Formula I can be, for example, 5 mL - 15 mL : 0.5 mL - 1.5 mL : 1 g, or for another example, 8 mL - 12 mL : 0.8 mL - 1.2 mL : 1 g, or for another example, 9 mL : 1 mL : 1 g.

[0054] Among them, the ratio of the organic solvent, water, concentrated hydrochloric acid solution, and the compound shown in Formula I can be, for example, 5 mL - 15 mL : 0.5 mL - 1.5 mL : 0.38 mL - 0.57 mL : 1 g, or for another example, 8 mL - 12 mL : 0.8 mL - 1.2 mL : 0.38 mL - 0.48 mL : 1 g, or for another example, 9 mL : 1 mL : 0.41 mL : 1 g.

[0055] Among them, the concentration of the concentrated hydrochloric acid solution can be, for example, 8 mol / L - 12 mol / L, or for another example, 10 mol / L - 12 mol / L, or for another example, 12 mol / L.

[0056] Among them, in the hydrochloride solution of the compound shown in Formula I, the molar ratio of HCl to the compound shown in Formula I can be, for example, 2:1 to 3:1, or for another example, 2.0:1 to 2.5:1, or for another example, 2.1:1 to 2.3:1.

[0057] In some embodiments, the hydrochloride solution of the compound shown in Formula I is obtained by mixing raw materials including the solution of the compound shown in Formula I and the concentrated hydrochloric acid solution; for example, the hydrochloride solution of the compound shown in Formula I is a mixture of the solution of the compound shown in Formula I and the raw materials composed of the concentrated hydrochloric acid solution.

[0058] For example, the solvent of the solution of the compound shown in Formula I is a mixture of an organic solvent and water; for another example, the solution of the compound shown in Formula I is a mixture of the compound shown in Formula I, an organic solvent, and water.

[0059] For example, the volume ratio of the organic solvent to water is 5 - 15 : 0.5 - 1.5, or for another example, 10:1 to 6:1, or for another example, 10 : 1 to 8 : 1, or for another example, 9:1.

[0060] For example, the solution of the compound shown in Formula I is obtained by mixing the compound shown in Formula I and the solvent at a temperature of 30 - 70 °C, and the temperature is, for another example, 40 - 60 °C, or for another example, 45 - 55 °C.

[0061] The present invention also provides a method for preparing crystalline form A of the hydrochloride hydrate of the compound represented by formula I, which comprises the following steps: Crystals are precipitated from a hydrochloride solution of the compound represented by formula I, and the crystals are crystalline form A; wherein, the hydrochloride solution of the compound represented by formula I contains the compound represented by formula I, an organic solvent, water and a concentrated hydrochloric acid solution, and the organic solvent is one or a mixture of two or more selected from methanol, ethanol, n-propanol, n-butanol, isopropanol, isobutanol and tert-butanol. Two or more herein should be understood to include two. Those skilled in the art should be clear that the hydrochloride solution of the compound represented by formula I does not contain other organic solvents, unless it is an inevitable impurity or solvent residue.

[0062] In some embodiments, the organic solvent is ethanol.

[0063] In some embodiments, the hydrochloride solution of the compound represented by formula I is a mixture of the compound represented by formula I, an organic solvent, water and a concentrated hydrochloric acid solution.

[0064] In some embodiments, the ratio of the concentrated hydrochloric acid solution to the compound represented by formula I is 0.38 mL - 0.57 mL: 1 g, for example 0.4 mL - 0.5 mL: 1 g, and further for example 0.38 mL - 0.40 mL: 1 g, 0.40 mL - 0.42 mL: 1 g, 0.42 mL - 0.44 mL: 1 g, 0.44 mL - 0.46 mL: 1 g, 0.46 mL - 0.48 mL: 1 g, 0.48 mL - 0.50 mL: 1 g, 0.50 mL - 0.52 mL: 1 g, 0.52 mL - 0.54 mL: 1 g or 0.54 mL - 0.57 mL: 1 g.

[0065] In some embodiments, the ratio of the organic solvent to the compound represented by formula I is 5 mL - 15 mL: 1 g, for example 8 mL - 12 mL: 1 g, and further for example 5 mL - 6 mL: 1 g, 6 mL - 7 mL: 1 g, 7 mL - 8 mL: 1 g, 8 mL - 9 mL: 1 g, 9 mL - 10 mL: 1 g, 10 mL - 11 mL: 1 g, 11 mL - 12 mL: 1 g, 12 mL - 13 mL: 1 g, 13 mL - 14 mL: 1 g or 14 mL - 15 mL: 1 g.

[0066] In some embodiments, the ratio of the water to the compound shown in Formula I is 0.5 mL - 1.5 mL : 1 g; for example, 0.8 mL - 1.2 mL : 1 g, and for another example, 0.5 mL - 0.6 mL : 1 g, 0.6 mL - 0.7 mL : 1 g, 0.7 mL - 0.8 mL : 1 g, 0.8 mL - 0.9 mL : 1 g, 0.9 mL - 1.0 mL : 1 g, 1.0 mL - 1.1 mL : 1 g, 1.1 mL - 1.2 mL : 1 g, 1.2 mL - 1.3 mL : 1 g, 1.3 mL - 1.4 mL : 1 g, or 1.4 mL - 1.5 mL : 1 g.

[0067] In some embodiments, the volume ratio of the organic solvent to the water is 5 - 15 : 0.5 - 1.5, preferably 10:1 to 6:1, more preferably 10 : 1 to 8:1, and even more preferably 9:1.

[0068] In some embodiments, the ratio of the organic solvent, water, and the compound shown in Formula I is 5 mL - 15 mL : 0.5 mL - 1.5 mL : 1 g, preferably 8 mL - 12 mL : 0.8 mL - 1.2 mL : 1 g, and further preferably 9 mL : 1 mL : 1 g.

[0069] In some embodiments, the ratio of the organic solvent, water, concentrated hydrochloric acid solution, and the compound shown in Formula I is 5 mL - 15 mL : 0.5 mL - 1.5 mL : 0.38 mL - 0.57 mL : 1 g, preferably 8 mL - 12 mL : 0.8 mL - 1.2 mL : 0.38 mL - 0.48 mL : 1 g, and further preferably 9 mL : 1 mL : 0.41 mL : 1 g.

[0070] In some embodiments, the concentration of the concentrated hydrochloric acid solution is 8 mol / L - 12 mol / L, preferably 10 mol / L - 12 mol / L, and more preferably 12 mol / L.

[0071] In some embodiments, in the hydrochloride solution of the compound shown in Formula I, the molar ratio of HCl to the compound shown in Formula I is 2:1 to 3:1, preferably 2.0:1 to 2.5:1, and further preferably 2.1:1 to 2.3:1.

[0072] In some embodiments, the hydrochloride solution of the compound shown in Formula I is a mixture of the solution of the compound shown in Formula I and the concentrated hydrochloric acid solution.

[0073] In some embodiments, the hydrochloride solution of the compound shown in Formula I is obtained by adding (for example, by dropwise addition) the concentrated hydrochloric acid solution to the solution of the compound shown in Formula I.

[0074] In some embodiments, the solvent of the solution of the compound represented by Formula I is a mixture of an organic solvent and water.

[0075] In some embodiments, the solution of the compound represented by Formula I is obtained by mixing the compound represented by Formula I and the solvent at a temperature of 30 - 70 °C, preferably 40 - 60 °C, and more preferably 45 - 55 °C.

[0076] In some embodiments, the solution of the compound represented by Formula I is a mixture of the compound represented by Formula I, an organic solvent, and water.

[0077] In some embodiments, in the solvent of the solution of the compound represented by Formula I, the volume ratio of the organic solvent to water is 10:1 to 6:1, preferably 10:1 to 8:1, and more preferably 9:1.

[0078] In some embodiments, the preparation method further includes: mixing the compound represented by Formula I, an organic solvent, and water, heating the resulting mixture to 30 - 70 °C (preferably 40 - 60 °C, and more preferably 45 - 55 °C), and adding a concentrated hydrochloric acid solution (for example, by dropwise addition) to obtain a hydrochloride solution of the compound represented by Formula I.

[0079] In some embodiments, the preparation method further includes: stirring the hydrochloride solution of the compound represented by Formula I at 30 - 70 °C. The step of stirring the hydrochloride solution of the compound represented by Formula I at 30 - 70 °C is carried out before the step of precipitating crystals from the hydrochloride solution of the compound represented by Formula I. The stirring time is, for example, 1 - 5 hours, or for example, 1 hour.

[0080] In some embodiments, the step of precipitating crystals from the hydrochloride solution of the compound represented by Formula I includes: cooling the hydrochloride solution of the compound represented by Formula I, preferably, the cooling is to 20 °C to 30 °C.

[0081] In some embodiments, the step of precipitating crystals from the hydrochloride solution of the compound represented by Formula I includes: stirring the hydrochloride solution of the compound represented by Formula I at 20 °C to 30 °C to precipitate crystals. The stirring time is, for example, 48 - 96 hours, or for example, 48 hours.

[0082] In some embodiments, the preparation method further includes: after precipitating crystals from the hydrochloride solution of the compound represented by Formula I, filtering, washing and drying the obtained filter cake to obtain Polymorph A.

[0083] In some embodiments, the raw materials of the preparation method only include the compound represented by Formula I, absolute ethanol, water, and a concentrated hydrochloric acid solution.

[0084] In some embodiments, the method for preparing crystalline form A of the hydrochloride hydrate of the compound represented by formula I further comprises: cooling a solution of crystalline form A of the hydrochloride hydrate of the compound represented by formula I for crystallization to obtain single crystals of crystalline form A of the hydrochloride hydrate of the compound represented by formula I, wherein the solvent of the solution of crystalline form A of the hydrochloride hydrate of the compound represented by formula I is a mixture of ethanol and water.

[0085] Wherein, the temperature of the mixture of ethanol and water can be 55 - 75 °C, more preferably 60 - 70 °C, and even more preferably 64 - 66 °C.

[0086] Wherein, the volume ratio of ethanol to water in the mixture of ethanol and water can be 10:1 to 6:1, preferably 10:1 to 8:1, and more preferably 9:1.

[0087] Wherein, the cooling can be to 20 °C to 30 °C.

[0088] The present invention also provides a hydrochloride hydrate of the compound represented by formula I, wherein in the hydrochloride hydrate, the molar ratio of the compound of formula I, HCl and water is 1:x:y, x is greater than 0 and not greater than 3, and y is greater than 0 and not greater than 3.

[0089] In some embodiments, in the hydrochloride hydrate, the molar ratio of the compound of formula I, HCl and water is 1:2:2.

[0090] The present invention also provides a pharmaceutical composition, which comprises at least one of the hydrochloride hydrate of the compound represented by formula I and crystalline form A of the hydrochloride hydrate of the compound represented by formula I according to any one of the above - mentioned schemes, and at least one pharmaceutically acceptable carrier.

[0091] In some embodiments, the carrier is at least one of an excipient, a diluent and a solvent.

[0092] The present invention also provides the use of the hydrochloride hydrate of the compound represented by formula I, crystalline form A or the pharmaceutical composition according to any one of the above - mentioned schemes in the preparation of a drug for preventing or treating a disorder, disease or condition mediated by Janus kinase.

[0093] The present invention also provides a method for preventing or treating a disorder, disease or condition mediated by Janus kinase in a subject in need thereof, which comprises administering to the subject a prophylactically or therapeutically effective amount of the hydrochloride hydrate of the compound represented by formula I, crystalline form A or the pharmaceutical composition according to any one of the above - mentioned schemes.

[0094] The present invention also provides the hydrochloride hydrate, crystalline form A of the compound represented by formula I or the pharmaceutical composition according to any of the above - mentioned solutions for preventing or treating disorders, diseases or conditions mediated by Janus kinases.

[0095] In some embodiments, the Janus kinase is at least one of JAK1, JAK2, JAK3 and TyK2.

[0096] In some embodiments, the diseases mediated by Janus kinases are at least one of hyperproliferative diseases, cancers (such as leukemia and lymphoma), immune and inflammatory disorders (such as transplant rejection, asthma, chronic obstructive pulmonary disease, allergies, rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis and multiple sclerosis).

[0097] In some embodiments, the diseases mediated by Janus kinases are at least one of leukemia, lymphoma, transplant rejection, asthma, chronic obstructive pulmonary disease, allergies, rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis and multiple sclerosis.

[0098] On the basis of not violating the common sense in the art, the above - mentioned preferred conditions can be combined arbitrarily to obtain the preferred examples of the present invention.

[0099] The reagents and raw materials used in the present invention are all commercially available.

[0100] The positive and progressive effects of the present invention are as follows: the salt form and crystalline form of the present invention have good JAK kinase inhibitory activity, solubility, stability and bioavailability, enhancing the developability of the oral preparation of the compound represented by formula I.

[0101] Definitions and Explanations

[0102] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this text, it is intended to refer to its corresponding product or its active ingredient.

[0103] The term "pharmaceutically acceptable carrier" used herein refers to pharmaceutical excipients, which means all substances contained in a pharmaceutical preparation except the active ingredient, such as the pharmaceutical excipients specified in Part IV of the Pharmacopoeia of the People's Republic of China (2015 Edition or 2020 Edition).

[0104] The term "pharmaceutical composition" used herein refers to a composition containing a specified active ingredient and can be prepared into the same dosage form.

[0105] As used herein, the term "subject" refers to any animal, preferably a mammal, and most preferably a human, that is about to receive or has received administration of the compound or composition according to an embodiment of the present invention. As used herein, the term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.

[0106] As used herein, the term "prophylactically or therapeutically effective amount" refers to the amount of a compound that is sufficient to effectively prevent or treat the disorder, disease or condition described herein when administered to a subject. The amount of the compound that constitutes a "prophylactically or therapeutically effective amount" will vary depending on the compound, the type and severity of the disorder, disease or condition, and the age of the subject, but can be adjusted by those skilled in the art as needed.

[0107] As used herein, the term "treatment" refers to therapeutic treatment. When referring to a specific disease or condition, "treatment" means at least one of the following: (1) alleviating one or more biological manifestations of the disorder, disease or condition, (2) interfering with one or more biological manifestations of the disorder, disease or condition, (3) improving or eliminating one or more symptoms, effects or side effects associated with the disorder, disease or condition, or one or more symptoms, effects or side effects associated with the treatment of the disorder, disease or condition; and (4) slowing the development of one or more biological manifestations of the disorder, disease or condition.

[0108] The present invention uses the following abbreviations:

[0109] XRPD X-ray powder diffraction

[0110] DSC Differential scanning calorimetry

[0111] TGA Thermogravimetric analysis

[0112] rpm Revolutions per minute

[0113] ATP Adenosine triphosphate

[0114] DTT DL-Dithiothreitol

[0115] SEB Supplier of Enzymatic Buffer, additive for enzymatic reaction buffer

[0116] AUClast Area under the plasma concentration-time curve

[0117] Cmax Peak concentration

[0118] min Minute

[0119] -RH Relative humidity

[0120] XRPD Characterization Method

[0121] Unless otherwise specified, the XRPD data (including but not limited to the XRPD patterns shown in Figure 1 , 4 -5, 8-12) of the present invention are measured under the following conditions:

[0122] Sample preparation: Take an appropriate amount of the sample to be measured and evenly distribute it in the sample holder, and press it flat with a clean glass plate so that the surface of the sample is flush with the surface of the sample holder.

[0123] The instrument used is a Bruker D2 Phaser X-ray powder diffractometer, where the detector: PSD LynxEye detector

[0124] Diffractometer parameter settings: Goniometer diameter, 282.2 mm; Divergence slit, 1.0 mm; Main Soller slit, 2.5 degrees; Secondary Soller slit, 2.5 degrees; Anti-air scattering component, 1.0 mm; X-ray tube element, copper; X-ray tube parameters, voltage 30 kV, current 10 mA;

[0125] Scanning parameter settings: Scanning type, Locked coupled; Scanning mode, Continuous PSD fast mode; Rotation speed, 20 degrees / min; Scanning range, 3 degrees to 40 degrees (2θ); Scanning step, 0.02 degrees (2θ); Scanning speed, 0.2 seconds / step; Detector aperture, 4.5 degrees.

[0126] DSC Characterization Method

[0127] Unless otherwise specified, the DSC data of the present invention are measured under the following conditions:

[0128] Instrument: Discovery DSC250 differential scanning calorimeter, sample pan type is perforated;

[0129] Temperature rising range is 25°C - 300°C, temperature rising rate is 10°C / min;

[0130] TGA Characterization Method

[0131] Unless otherwise specified, the TGA data of the present invention are measured under the following conditions:

[0132] Instrument: Discovery 55 thermogravimetric analyzer

[0133] Sample pan type: Default open aluminum pan;

[0134] Temperature rising range: 10°C - 300°C, temperature rising rate is 10°C / min. Description of the Drawings

[0135] Figure 1 XRPD pattern of Polymorph A;

[0136] Figure 2 DSC pattern of Polymorph A;

[0137] Figure 3 TGA pattern of Polymorph A;

[0138] Figure 4 XRPD pattern of Polymorph C;

[0139] Figure 5 XRPD pattern of Polymorph D;

[0140] Figure 6 XRPD pattern of Polymorph E;

[0141] Figure 7 XRPD pattern of Polymorph F;

[0142] Figure 8 XRPD pattern of Polymorph A after being placed in a stability chamber at 40 °C / 60%-RH for 30 days;

[0143] Figure 9 XRPD pattern of Polymorph A after being placed in a stability chamber at 25 °C / 75%-RH for 30 days;

[0144] Figure 10 XRPD pattern of the solid precipitated after adding Polymorph A to the saturated solution system in Example 5;

[0145] Figure 11 XRPD pattern of the solid precipitated after adding Polymorph E to the saturated solution system in Example 5;

[0146] Figure 12 XRPD pattern of the solid precipitated after adding Polymorph F to the saturated solution system in Example 5;

[0147] Figure 13 Single crystal shape of Polymorph A obtained in Example 8;

[0148] Figure 14 XRPD pattern of the single crystal of Polymorph A obtained in Example 8;

[0149] Figure 15 Schematic diagram of the asymmetric structural unit of the single crystal of Polymorph A obtained in Example 8.

[0150] Figure 1 and 4 In Figures 5, 8-12, and 14, the unit of the ordinate intensity is counts, and the unit of the abscissa 2θ angle is degree (°). Figures 6 - 7 The unit of the abscissa 2θ angle in Figure 14 is degree (°). Detailed implementation mode

[0151] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0152] In the following examples, unless otherwise specified, the mass spectrometry was detected by a Waters Acquity Xevo G2-XS QTof UPLC / MS ultra-high performance liquid chromatography high-resolution mass spectrometry combined system. 1 1H-NMR was detected by a Bruker AVANCE III 400 MHz nuclear magnetic resonance spectrometer or a Bruker AVANCE III HD 300 MHz nuclear magnetic resonance spectrometer, and HPLC was detected by an Agilent 1260 high performance liquid chromatography instrument.

[0153] Unless otherwise specified, the concentrated hydrochloric acid solution described in the present invention refers to an aqueous solution of hydrogen chloride (HCl), and its concentration is not less than 8 mol / L.

[0154] Unless otherwise specified, the room temperature in the present invention refers to 20-30 °C.

[0155] Example 1. Synthesis of the compound shown in Formula I

[0156] Synthesis of compound 4

[0157]

[0158] Add SM1-1 (54.60 g, 175.0 mmol) and dichloromethane (1 L) to a 3 L round-bottom flask. After cooling to 0 °C, slowly add trifluoroacetic acid (200 mL). After dropping, stir at room temperature for 10 hours. HPLC shows that the reaction is complete. Remove trifluoroacetic acid under vacuum, and then dilute with dichloromethane (500 mL). The obtained solution was washed with an aqueous solution of NaHCO 3 After drying and concentrating, it was purified by silica gel column chromatography to obtain white solid compound 4 (23.00 g, yield 62.0%).

[0159] Nuclear magnetic data of compound 4: 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.24 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 1.1 Hz, 6.8 Hz, 1H), 6.97 - 7.01 (m, 2H), 5.31 (br, 2H).

[0160] Synthesis of compound 5

[0161]

[0162] To a 2 L round-bottom flask, add compound 4 (23.00 g, 108.5 mmol), triethylamine (39.46 g, 390.0 mmol), and acetonitrile (400 mL). After cooling to 0 °C, slowly add cyclopropylcarbonyl chloride (40.23 g, 384.9 mmol) dropwise. After the addition, stir at room temperature for 8 hours. HPLC shows that the reaction is complete. Concentrate the resulting reaction solution to dryness, then add water for washing, filter to obtain a solid, and the obtained solid is subjected to column chromatography to obtain white solid compound 5 (29.46 g, yield 97.0%).

[0163] NMR data of compound 5: 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.14 (br, 1H), 8.05 (s, 1H), 7.50 - 7.52 (m, 1H), 7.19 - 7.28 (m, 2H), 1.92 - 1.99 (m, 1H), 0.82 - 0.84 (m, 4H).

[0164] Synthesis of the compound shown in Formula I

[0165]

[0166] To a 2 L round-bottom flask, add compound 5 (29.46 g, 105.2 mmol), SM2-1 (41.88 g, 113.4 mmol), K 2 CO 3 (26.12 g, 189.0 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (6.91 g, 8.5 mmol), H 2 O (120 mL), and 1,4-dioxane (600 mL). Heat under reflux for 10 hours under N 2 protection. HPLC shows that the reaction is complete. Add ice water to quench the reaction, and filter to obtain a solid. The obtained solid is subjected to column chromatography to obtain the compound shown in Formula I (27.42 g, yield 58.9%), which is a white solid.

[0167] Characterization data of the compound shown in Formula I: 1 H (400 Hz, DMSO-d 6)δ ppm: 8.08 (1H, dd, J = 9.2, 7.3 Hz), 8.03 (1H, dd, J = 9.3, 1.6 Hz), 7.84 - 7.78 (3H, m), 7.60 (1H, dd, J = 7.1, 1.6 Hz), 4.66 (2H, s), 3.90 - 3.89, (4H, m), 3.70 - 3.68 (4H, m), 1.97 - 1.94 (1H, m), 1.08 - 1.04 (4H, m). LC / MS m / z: 443.2 (M + H).

[0168] Example 2. Preparation of Crystal Form A of the Hydrochloride Hydrate of the Compound Shown by Formula I

[0169] Add the compound shown by Formula I (1.5 g, 3.4 mmol) to a round-bottom flask, then add 13.5 mL of absolute ethanol and 1.5 mL of pure water, and stir and heat the resulting mixture to 50 °C. Then, add dropwise 0.62 mL of concentrated hydrochloric acid solution (12 mol / L, 7.4 mmol). After the addition is complete, keep the hydrochloride salt solution of the compound shown by Formula I at 50 °C and stir for 1 hour, then naturally cool it to 25 °C at room temperature, and then keep it at 25 °C and stir for 48 hours to precipitate crystals, and stop stirring. Filter, wash the obtained filter cake with a small amount of ethanol, collect it, and dry it under vacuum at 40 °C for 6 hours. The obtained crystals are Crystal Form A.

[0170] The XRPD pattern of Crystal Form A is as Figure 1 shown, and the X-ray powder diffraction peaks expressed in 2θ angles are shown in Table 1.

[0171] The DSC result of Crystal Form A is as Figure 2 shown. DSC shows the first endothermic peak at 165.14 °C, with an enthalpy value of 180.63 J / g and a starting temperature of 140.82 °C; another endothermic peak is at 197.70 °C, with an enthalpy value of 23.689 J / g and a starting temperature of 179.20 °C.

[0172] The TGA result of Crystal Form A is as Figure 3 shown, showing that the sample has a weight loss of 8.3143% before 148.00 °C; and a weight loss of 4.7637% between 148 - 228 °C.

[0173] The chloride content was determined using a Mettler Toledo T5 potentiometric titrator. The result showed that the chloride content in the sample was 12.3%, which was basically consistent with the sample containing two chloride ions (the theoretical value of chloride ions in the sample containing two hydrochlorides was 12.9%). The water content was determined using a Mettler Toledo KF titrator V30S. The result showed that the water content in the sample was 8.0%, which was basically consistent with the sample containing two crystal waters (the theoretical value of water in the sample containing two crystal waters was 6.5%). Thus, it can be determined that the crystalline form A is a hydrochloride hydrate of the compound of formula I, and in this hydrochloride hydrate, the molar ratio of the compound of formula I, HCl, and water is 1:2:2.

[0174] Comparative Example 1. Attempts to prepare crystalline form A using other solvent systems

[0175] (1) Crystallization in the THF / water system

[0176] Add the compound shown in formula I (1.0 g, 2.3 mmol) to a round-bottom flask, then add 9 mL of THF and 1 mL of pure water. The resulting mixture was stirred and heated to 60 °C. Then, 0.41 mL of concentrated hydrochloric acid solution (12 mol / L, 4.9 mmol) was added dropwise. After the addition was complete, the hydrochloride solution of the compound shown in formula I was kept at 60 °C and stirred for 1 hour, then naturally cooled to 25 °C at room temperature, and then kept at 25 °C and stirred for 48 hours to precipitate crystals, and the stirring was stopped. Filtration was carried out, and the obtained filter cake was washed with a small amount of THF and dried. The obtained solid was crystalline form C, and its XRPD pattern was as Figure 4 shown, indicating that the obtained crystalline form C is different from crystalline form A.

[0177] (2) Crystallization in the DCM / MeOH system

[0178] Add the compound shown in formula I (0.5 g, 1.1 mmol) to a round-bottom flask, then add 10 mL of DCM and 10 mL of MeOH. The resulting mixture was stirred and heated to 40 °C. Then, 4M hydrochloric acid solution (0.6 mL, 2.4 mmol) was added dropwise. After the addition was complete, the hydrochloride solution of the compound shown in formula I was kept at 40 °C and stirred for 1 hour, then naturally cooled to 25 °C at room temperature, and then kept at 25 °C and stirred for 48 hours to precipitate crystals, and the stirring was stopped. Filtration was carried out, and the obtained filter cake was washed with a small amount of DCM and dried. The obtained solid was crystalline form D, and its XRPD pattern was as Figure 5 shown. It can be seen that the obtained crystalline form D is different from crystalline form A.

[0179] Comparative Example 2. Preparation of crystalline form E of the hydrochloride of the compound shown in formula I

[0180] Take 10 mg of crystalline form A of the hydrochloride hydrate of the compound shown in formula I and add it to 0.3 mL of acetonitrile. Stir at room temperature for 3 days, and filter to obtain crystalline form E. Its crystalline form XRPD pattern was asFigure 6 as shown

[0181] The attached Figure 6 The detection instrument used for the XRPD pattern shown in the present invention is a Bruker D8 Advance X-ray diffractometer. Among them, the X-ray tube parameters are set as follows: X-ray wavelength, Cu:K-Alpha Voltage, 40 kV; current, 40 mA; sample rotation speed: 15 rpm; scanning range: 3 to 40 degrees (2θ); scanning speed: 10 degrees / minute.

[0182] Comparative Example 3. Preparation of crystalline form F of the hydrochloride salt of the compound shown in Formula I

[0183] 10 mg of crystalline form A of the hydrochloride hydrate of the compound shown in Formula I was added to a 4 mL vial, and 0.5 mL of DMSO was added and stirred until dissolved. Another 40 mL round-bottom flask was taken and 4 mL of acetonitrile was added. The vial was placed in the round-bottom flask, the round-bottom flask was capped, and slow crystallization was carried out at room temperature. After 3 days, crystalline form F was obtained by filtration, and its XRPD is as Figure 7 shown

[0184] The attached Figure 7 The detection instrument used for the XRPD pattern shown in the present invention is a Bruker D8 Advance X-ray diffractometer. Among them, the X-ray tube parameters are set as follows: X-ray wavelength, Cu:K-Alpha Voltage, 40 kV; current, 40 mA; sample rotation speed: 15 rpm; scanning range: 3 to 40 degrees (2θ); scanning speed: 10 degrees / minute.

[0185] Example 3. JAK kinase inhibitory activity test of crystalline form A of the hydrochloride hydrate of the compound shown in Formula I

[0186] Using Cisbio's (Homogeneous Time-Resolved Fluorescence) kit (HTRF kinEASE-TK kit, catalog number: 62TKOPEC) to perform in vitro enzymatic biochemical assays of the compound. The substrate, kinase reaction buffer, detection buffer, streptavidin labeled with allophycocyanin modifier (XL-665), europium (EU)-labeled specific phosphorylation antibody, and SEB used in the test are all included in the kit. JAK1 used in the assay was purchased from Invitrogen (catalog number PV4774), and JAK2, JAK3, and TYK2 were all purchased from Carna Biosciences, Inc. (catalog numbers: 08-045, 08-046, 08-147 respectively), and DTT was purchased from Sigma (catalog number 43816).

[0187] The compound (the hydrochloride hydrate crystal form A of the compound shown by formula I prepared according to the method of Example 2 or tofacitinib citrate (Shanghai Haoyuan Chemical Technology Co., Ltd., HY-40354A)) was serially diluted 10 times at 3-fold in DMSO, and the concentration of the resulting compound dilution was 100 times the final test concentration. Then, the concentration of the compound dilution was further diluted to 2.5 times the final test concentration with kinase reaction buffer to obtain the compound solution to be tested.

[0188] The enzymatic reaction was carried out in a white 384-well polypropylene plate (Greniner, catalog number: 784075). The total reaction volume was 10 μL, containing 500 ng / mL JAK1, 6 ng / mL JAK2, 37 ng / mL JAK3, 100 ng / mL TYK2, 1 μM substrate, and 1 mM ATP (Sigma-Aldrich, catalog number: A7699).

[0189] Add 4 μL of the compound solution to be tested into the wells of the 384-well polypropylene plate, and then add 2 μL of JAK1 diluted in kinase reaction buffer (with additional buffer additives MgCl 2 , MnCl 2 and DTT, with final concentrations of 5 mM, 1 mM, and 1 mM respectively), JAK2 (with additional buffer additives MgCl 2 and DTT, with final concentrations of 5 mM and 1 mM respectively), JAK3 (with additional buffer additives MgCl 2 and DTT, with final concentrations of 5 mM and 1 mM respectively), TYK2 (with additional buffer additives MgCl 2 , MnCl 2, DTT, and SEB, with their respective final concentrations being 5 mM, 1 mM, 1 mM, and 12.5 nM), were pre-incubated at room temperature for 15 minutes. The enzymatic reaction was initiated by adding a mixture of 2 μL of the substrate prepared in the kinase reaction buffer and 2 μL of ATP. After a 30-minute reaction at room temperature, 5 μL of the streptavidin labeled with allophycocyanin modifier (XL-665) prepared in the detection buffer and 5 μL of the europium-labeled specific phosphorylation antibody prepared in the detection buffer were added to stop the enzymatic reaction and generate a signal. After incubation at room temperature for 1 hour, the plate was read in a Molecular Devices SpectraMAX Paradigm multimode microplate reader with the following settings: excitation at 340 nm / emission 1 at 616 nm / emission 2 at 665 nm. The ratio (Ratio) of the emission light signals of the acceptor and donor for each well was calculated according to the following formula: Ratio = signal 665 nm / signal 616 nm * 10000, where signal 665 nm is the signal at 665 nm and signal 616 nm is the signal at 616 nm. The percentage of inhibition was calculated according to the following formula: percentage of inhibition = 100% - (ratio value of the treated compound / ratio value of the DMSO vehicle treated) * 100% (the DMSO vehicle is the blank control group without the drug).

[0190] A dose-response curve was generated, and the IC was calculated by non-linear sigmoidal curve fitting using GraphPad Prism software 50 . The results obtained were as follows:

[0191] Table 2. IC of crystalline form A of the hydrochloride hydrate of the compound of formula I 50 Data

[0192]

[0193] Example 4. Solubility test of the compound of formula I and crystalline form A

[0194] Weigh the sample ground into fine powder and add it to a certain volume of solvent respectively (ambient temperature: 25°C ± 5°C). Vigorously shake it for 30 seconds every 5 minutes and observe the dissolution situation within 30 minutes. If there are no visually observable solute particles or droplets, it is regarded as completely dissolved. Observe the dissolution situations of crystalline form A of the hydrochloride hydrate of the compound shown in Formula I and the free base form of the compound shown in Formula I in common solvents according to this method, and the results are shown in Table 3. Among them, "freely soluble" means that 1 g (mL) of solute can dissolve in a solvent with a volume of 1 mL ≤ V < 10 mL; "soluble" means that 1 g (mL) of solute can dissolve in a solvent with a volume of 10 mL ≤ V < 30 mL; "sparingly soluble" means that 1 g (mL) of solute can dissolve in a solvent with a volume of 30 mL ≤ V < 100 mL; "slightly soluble" means that 1 g (mL) of solute can dissolve in a solvent with a volume of 100 mL ≤ V < 1000 mL; "very slightly soluble" means that 1 g (mL) of solute can dissolve in a solvent with a volume of 1000 mL ≤ V < 10000 mL; "almost insoluble" or "insoluble" means that 1 g (mL) of solute cannot be completely dissolved in a solvent with a volume of 10000 mL.

[0195] Table 3. Solubility of the free base of the compound shown in Formula I and crystalline form A of its hydrochloride hydrate

[0196] Solvent Free base of the compound shown in Formula I Crystal Form A Methanol Sparingly soluble Freely soluble Ethanol Sparingly soluble Dissolve Water Very slightly soluble Dissolve Simulated gastric fluid Insoluble Slightly soluble

[0197] Example 5. Stability test of different crystalline forms

[0198] Test whether the test temperature and humidity have an impact on the stability of crystalline form A of the hydrochloride hydrate of the compound shown in Formula I:

[0199] Place crystalline form A in a stability chamber and control the temperature and humidity at 40°C / 60%-RH and 25°C / 75%-RH respectively. After 30 days, compare the obtained solid with its initial crystalline form A: there is no obvious change in its appearance, and there is no obvious change in the content of the compound shown in Formula I measured by HPLC (as shown in Table 4), and there is also no obvious change in XRPD (the XRPD patterns obtained after treatment at 40°C / 60%-RH and 25°C / 75%-RH are shown in Figure 8 and Figure 9 ) either, indicating that crystalline form A has good stability.

[0200] Table 4. Content of the compound shown in Formula I before and after placing crystalline form A

[0201] Sample Content of the compound shown in Formula I Initial Crystal A 99.901％ After Crystal A is placed at 40°C / 75%-RH for 30 days 99.905％ After Crystal A is placed at 25°C / 75%-RH for 30 days 99.899％

[0202] Comparison of the thermodynamic stabilities of crystalline form A, crystalline form E and crystalline form F:

[0203] Polymorph A, polymorph E, and polymorph F were separately dissolved in a mixed solvent of ethanol / water (volume ratio = 9:1) to prepare saturated solutions. The solutions were heated to 50 °C, and 10 mg of polymorph A, polymorph E, and polymorph F were separately added under stirring. After stirring at 50 °C for 24 hours, filtration was carried out, and the XRPD of the obtained crystals was measured respectively (the XRPD patterns of the crystals precipitated by adding polymorph A, E, and F are shown in Figure 10 , 11 and 12, respectively). The obtained XRPD patterns were compared and analyzed with the XRPD pattern of polymorph A shown in Figure 1 . It was found that the crystals precipitated from the system with polymorph A added were still polymorph A, while both polymorph E and polymorph F were transformed into polymorph A, indicating that polymorph A has better thermodynamic stability than polymorph E and polymorph F.

[0204] Example 6. Single-dose PK study

[0205] Two groups of SD rats (3 female rats in each group) were separately administered a single oral dose of 3 mg / kg of the free base of the compound shown in Formula I and a single oral dose of 3 mg / kg of polymorph A of the hydrochloride hydrate of the compound shown in Formula I. The drug was administered in the form of a 0.5% CMC-Na suspension. Samples were taken at different times until 24 hours, and the drug concentration of the compound shown in Formula I in plasma was analyzed by LC-MS / MS method. The final calculated results are shown in Table 8.

[0206] Chromatographic conditions for the LC-MS / MS method of the compound shown in Formula I:

[0207] Instrument model, SHIMADZU LC-30AD liquid phase system; chromatographic column, ACQUITY BEH C18 (2.1×50 mm, 1.7 μm); column temperature, 40 °C; injection volume, 1 μL; flow rate 0.6 mL / min; running time 6 min; mobile phase gradient settings are shown in Table 5.

[0208] Table 5.

[0209]

[0210] Mass spectrometry conditions:

[0211] Instrument model, AB SCIEX TRIPLE QUAD 6500 mass spectrometer; ion source, electrospray ionization (ESI); ionization mode, positive ion scan; multiple reaction monitoring (MRM) ion pairs are shown in Table 6; instrument parameters are shown in Table 7.

[0212] Table 6.

[0213] Analyte Q1 mass-to-charge ratio (m / Z) Q3 mass-to-charge ratio (m / Z) Scan interval (milliseconds) Compound shown in Formula I 443.2 375.3 100 GLPG0634* 426.1 291.2 100

[0214] *: The internal standard compound, purchased from MedChemExpress (Catalog No.: HY-18300), the same in Table 7.

[0215] Table 7.

[0216] Parameter Compound shown in Formula I GLPG0634 Spray voltage (v) 5000 5000 Ion source temperature (°C) 550 550 Collision gas (psi) 10 10 Curtain gas (psi) 40 40 Nebulizing gas (psi) 50 50 Auxiliary gas (psi) 40 40 Declustering voltage (v) 110 110 Entrance voltage (v) 12 12 Collision voltage (v) 47 39 Collision cell exit voltage (v) 10 10

[0217] Table 8. PK Data of Crystal Form A of the Hydrochloride Hydrate of the Compound Shown in Formula I and the Free Base of the Compound Shown in Formula I

[0218] Solid form AUClast Cmax Free base 987 h*ng / mL 352 ng / mL Crystal Form A 1390 h*ng / mL 456 ng / mL

[0219] Example 7. Hygroscopicity Study of Crystal Form A, Crystal Form C, Crystal Form D, Crystal Form E and Crystal Form F

[0220] Take about 500 mg of each of Crystal Form A, Crystal Form C, Crystal Form D, Crystal Form E and Crystal Form F, accurately weigh them and place them in a constant humidity sealed container. Place them for 5 days under the conditions of 25 °C / 75%-RH, and then take them out to measure their weight gain due to moisture absorption. The results are shown in Table 9, indicating that the hygroscopicity of Crystal Form A is the lowest.

[0221] Table 9: Hygroscopicity Data of Each Crystal Form

[0222] Crystal form Crystal Form A Crystal Form C Crystal Form D Crystal Form E Crystal Form F Moisture gain 2.4％ 6.1％ 8.1％ 5.3％ 4.9％

[0223] Example 8. Single Crystal Test and Structure Analysis of Crystal Form A

[0224] Weigh 35 mg of the sample of Crystal Form A of the hydrochloride hydrate of the compound shown in Formula I prepared in Example 2, dissolve it in 1 mL of ethanol / water (9:1, v / v) at 65 °C, and cool it to room temperature for cooling crystallization to obtain long rod-shaped crystals ( Figure 13 ). Then select some crystals for XRPD diffraction study ( Figure 14 ), Figure 14 Among them, characteristic diffraction peaks are present at the following 2θ angles: 5.9°±0.2°, 7.4°±0.2°, 11.6°±0.2°, 21.7°±0.2° and 23.8°±0.2°, which are in agreement with Figure 1 , proving that it is Crystal Form A. Select this crystal for single crystal test and structure analysis. The results of single crystal structure analysis show that Crystal Form A belongs to the monoclinic system, space group P21 / c, and its unit cell parameters are α = 90°, β = 101.262(3)°, γ = 90°, Figure 15 is the schematic diagram of the asymmetric structural unit of this crystal. This asymmetric unit contains 1 cation of the compound shown in Formula I, 2 chloride ions and 2 water molecules of crystallization.

[0225] Instruments, software and methods used in the experiment:

[0226] X-ray powder diffraction (XRPD)

[0227] The solid samples obtained from the experiment were analyzed using an X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2θ scanning angle ranged from 3° to 45°, the scanning step size was 0.02°, and the exposure time was 0.12 s. When testing the samples, the tube voltage and current were 40 kV and 40 mA respectively, and the sample holder was a zero-background sample holder.

[0228] Single-crystal X-ray diffraction (SCXRD)

[0229] A single crystal with appropriate morphology and size was selected from the cultivated single-crystal samples. The single crystal was glued onto a Loop, and then the single-crystal sample was placed on the crystal stage. The preliminary experiment of the single-crystal sample and the collection of single-crystal diffraction data were carried out using a SuperNova (Rigaku, JPN) single-crystal diffractometer (Cu target light source, ) at a temperature of 253.0 K. The diffraction data were analyzed and processed using the CrysAlisPro software package.

[0230] At a temperature of 253.0 K, the angular range for collecting diffraction data was 4.4340° < θ < 73.8890°. A total of 8128 diffraction points were collected within this angular range. After analyzing them using the CrysAlisPro program and refining them by the least-squares method, the unit cell parameters and orientation matrix of the crystal were obtained. The completeness of the data collection corresponding to the highest θ angle (θ = 66.97°) was 99.94%.

[0231] Data reduction

[0232] The CrysAlisPro 1.171.39.46 (Rigaku Oxford Diffraction, 2018) program was used to reduce and integrate each frame of diffraction images collected by the detector. A total of 16159 diffraction points were collected, among which 4275 were independent diffraction points. The SCALE3 ABSPACK scaling algorithm was used to correct the absorption of the diffraction data. The linear absorption coefficient of the X-ray with a wavelength by the crystal sample was 3.404 mm -1 , the minimum transmission coefficient (Tmin) was 0.586, and the maximum transmission coefficient (Tmax) was 1.000. The intensities of all equivalent diffraction points were basically equal within the experimental error range, and the Rint was 4.30%.

[0233] Structure analysis and refinement

[0234] The single-crystal structure analysis was carried out using the OLEX2 software. The XS (Sheldrick, 2008) initial solution program was used to perform the initial structure solution of the diffraction data and determine that the space group to which the crystal belongs is P21 / c. Subsequently, the XH (Sheldrick, 2008) program was used for structure refinement. The coordinates of all non-hydrogen atoms were determined by several rounds of difference Fourier synthesis, and then all non-hydrogen atoms were anisotropically refined by the full-matrix least-squares method. All hydrogen atoms were calculated by the method of theoretical hydrogenation.

[0235] Crystal structure diagram

[0236] The crystal structure diagram and the atomic thermal vibration ellipsoid diagram were drawn using the Diamond software.

[0237] Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that this is only an example. The protection scope of the present invention is defined by the appended claims. Without departing from the principle and essence of the present invention, those skilled in the art can make various changes or modifications to these embodiments, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. Crystal form A of the hydrochloride hydrate of the compound represented by formula I, characterized in that, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.9° ± 0.2°, 7.4° ± 0.2°, 11.6° ± 0.2°, 21.7° ± 0.2° and 23.8° ± 0.2°; 2. Crystal form A of the hydrochloride hydrate of the compound represented by formula I according to claim 1, characterized in that, the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.9° ± 0.2°, 7.4° ± 0.2°, 11.6° ± 0.2°, 17.7° ± 0.2°, 17.8° ± 0.2°, 21.7° ± 0.2°, 23.6° ± 0.2°, 23.8° ± 0.2°, 29.0° ± 0.2°, 30.4° ± 0.2° and 34.9° ± 0.2°.

3. Crystal form A of the hydrochloride hydrate of the compound represented by formula I according to claim 1 or 2, characterized in that, The X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 5.9° ± 0.2°, 7.4° ± 0.2°, 8.9° ± 0.2°, 11.6° ± 0.2°, 14.6° ± 0.2°, 17.7° ± 0.2°, 17.8° ± 0.2°, 18.7° ± 0.2°, 19.5° ± 0.2°, 21.0° ± 0.2°, 21.7° ± 0.2°, 21.9° ± 0.2°, 22.6° ± 0.2°, 23.6° ± 0.2°, 23.8° ± 0.2°, 29.0° ± 0.2°, 30.4° ± 0.2°, 33.3° ± 0.2°, 34.9° ± 0.2° and 37.7° ± 0.2°; for example, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 5.9° ± 0.2°, 6.6° ± 0.2°, 7.4° ± 0.2°, 8.9° ± 0.2°, 10.5° ± 0.2°, 11.6° ± 0.2°, 12.3° ± 0.2°, 13.9° ± 0.2°, 14.2° ± 0.2°, 14.6° ± 0.2°, 17.1° ± 0.2°, 17.7° ± 0.2°, 17.8° ± 0.2°, 18.7° ± 0.2°, 19.5° ± 0.2°, 20.4° ± 0.2°, 21.0° ± 0.2°, 21.2° ± 0.2°, 21.7° ± 0.2°, 21.9° ± 0.2°, 22.6° ± 0.2°, 23.6° ± 0.2°, 23.8° ± 0.2°, 24.9° ± 0.2°, 26.6° ± 0.2°, 26.8° ± 0.2°, 28.3° ± 0.2°, 29.0° ± 0.2°, 30.4° ± 0.2°, 31.2° ± 0.2°, 32.3° ± 0.2°, 33.3° ± 0.2°, 34.2° ± 0.2°, 34.9° ± 0.2°, 35.6° ± 0.2°, 35.9° ± 0.2°, 36.4° ± 0.2°, 36.9° ± 0.2°, 37.7° ± 0.2°, 39.3° ± 0.2° and 39.8° ± 0.2°; and for another example, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 5.9°, 6.6°, 7.4°, 8.9°, 10.5°, 11.6°, 12.3°, 13.9°, 14.2°, 14.6°, 17.1°, 17.7°, 17.8°, 18.7°, 19.5°, 20.4°, 21.0°, 21.2°, 21.7°, 21.9°, 22.6°, 23.6°, 23.8°, 24.9°, 26.6°, 26.8°, 28.3°, 29.0°, 30.4°, 31.2°, 32.3°, 33.3°, 34.2°, 34.9°, 35.6°, 35.9°, 36.4°, 36.9°, 37.7°, 39.3° and 39.8°.

4. Crystal form A of the hydrochloride hydrate of the compound represented by formula I according to at least one of claims 1-3, characterized in that, the XRPD pattern analysis data of the crystal form A are shown in the following table: For example, the XRPD pattern of the crystal form A is shown in Figure 1.

5. Crystal form A of the hydrochloride hydrate of the compound represented by formula I according to at least one of claims 1-4, characterized in that, the thermogravimetric analysis curve of the crystal form A has a weight loss of 8.31 ± 0.50% before 148°C; and a weight loss of 4.76 ± 0.50% between 148°C and 228°C.

6. Crystal form A of the hydrochloride hydrate of the compound represented by formula I according to at least one of claims 1-5, characterized in that, the thermogravimetric analysis curve of the crystal form A has a weight loss of 8.31% before 148°C, and a weight loss of 4.76% between 148°C and 228°C; for example, the thermogravimetric analysis curve of the crystal form A has a weight loss of 8.3143% before 148°C, and a weight loss of 4.7637% between 148°C and 228°C; and for another example, the thermogravimetric analysis curve of the crystal form A is shown in Figure 3.

7. Crystal form A of the hydrochloride hydrate of the compound represented by formula I according to at least one of claims 1-6, characterized in that, the differential scanning calorimetry chart of the crystal form A has absorption peaks at 165°C ± 3°C and 198°C ± 3°C respectively; for example, the differential scanning calorimetry chart of the crystal form A has absorption peaks at 165.14°C and 197.70°C respectively; and / or, the differential scanning calorimetry chart of the crystal form A has absorption peaks with starting temperatures of 141°C ± 3°C and 179°C ± 3°C respectively; for example, the differential scanning calorimetry chart of the crystal form A has absorption peaks with starting temperatures of 140.82°C and 179.20°C respectively.

8. Crystal form A of the hydrochloride hydrate of the compound represented by formula I according to at least one of claims 1-7, characterized in that, the differential scanning calorimetry chart of the crystal form A is shown in Figure 2.

9. Crystal form A of the hydrochloride hydrate of the compound of formula I as described in at least one of claims 1 - 8, characterized in that, The crystal form A is a single crystal, which belongs to the monoclinic crystal system, space group P21 / c, and the unit cell parameters are α = 90°, β = 101.262(3)°, γ = 90°, and the unit cell volume is 10. Crystal form A of the hydrochloride hydrate of the compound of formula I as described in at least one of claims 1 - 9, characterized in that, in the said crystal form A, the molar ratio of the compound of formula I, HCl and water is 1:x:y, where x is greater than 0 and not greater than 3, and y is greater than 0 and not greater than 3; preferably, in the said crystal form A, the molar ratio of the compound of formula I, hydrochloric acid and water is 1:2:

2.

11. Preparation method of crystal form A of the hydrochloride hydrate of the compound of formula I as described in at least one of claims 1 - 10, characterized in that, comprises the following steps: Crystals are precipitated from the hydrochloride solution of the compound of formula I, and the said crystals are crystal form A; wherein, the hydrochloride solution of the compound of formula I contains the hydrochloride of the compound of formula I, an organic solvent and water, and the said organic solvent is one or a mixture of two or more selected from methanol, ethanol, n - propanol, n - butanol, isopropanol, isobutanol and tert - butanol; for example, the said organic solvent is ethanol.

12. Preparation method of crystal form A of the hydrochloride hydrate of the compound of formula I as described in claim 11, characterized in that, in the hydrochloride of the compound of formula I, the molar ratio of the compound of formula I and HCl is 1:x, x is greater than 0 and not greater than 3, for example, the molar ratio of the compound of formula I and HCl is 1:2; and / or, the volume ratio of the organic solvent and water is 5 - 15: 0.5 - 1.5, for example 10:1 to 6:1, for example 10:1 to 8:1, for example 9:1; and / or, the temperature of the hydrochloride solution of the compound of formula I is 30 - 70 °C; and / or, the step of precipitating crystals from the hydrochloride solution of the compound of formula I comprises: cooling the hydrochloride solution of the compound of formula I, for example, the said cooling is to cool to 20 °C to 30 °C; and / or, the step of precipitating crystals from the hydrochloride solution of the compound of formula I comprises: stirring the hydrochloride solution of the compound of formula I at 20 °C to 30 °C to precipitate crystals; the said stirring time is for example 48 - 96 hours; and / or, the said preparation method further comprises: after precipitating crystals from the hydrochloride solution of the compound of formula I, filtering, washing and drying the obtained filter cake to obtain crystal form A; And / or, the preparation method further includes: cooling a solution of crystalline form A of the hydrochloride hydrate of the compound represented by formula I for crystallization to obtain single crystals of crystalline form A of the hydrochloride hydrate of the compound represented by formula I, wherein the solvent of the solution of crystalline form A of the hydrochloride hydrate of the compound represented by formula I is a mixture of ethanol and water; for example, the temperature of the solution of crystalline form A of the hydrochloride hydrate of the compound represented by formula I is 55 - 75 °C, for another example, it is 60 - 70 °C, and for yet another example, it is 64 - 66 °C; for example, the volume ratio of ethanol to water in the mixture of ethanol and water is 5 - 15:0.5 - 1.5, for another example, it is 10:1 to 6:1, for yet another example, it is 10:1 to 8:1, and for yet another example, it is 9:1; for example, the cooling is to cool to 20 °C to 30 °C.

13. The preparation method of crystalline form A of the hydrochloride hydrate of the compound represented by formula I according to claim 11 or 12, characterized in that, the hydrochloride solution of the compound represented by formula I is obtained by mixing raw materials including the hydrochloride hydrate of the compound represented by formula I, an organic solvent and water; for example, the dosage ratio of the hydrochloride hydrate of the compound represented by formula I to water is 250 - 450 mg:1 mL, for another example, it is 300 - 400 mg:1 mL.

14. The preparation method of crystalline form A of the hydrochloride hydrate of the compound represented by formula I according to claim 11 or 12, characterized in that, the hydrochloride solution of the compound represented by formula I is obtained by mixing raw materials including the compound represented by formula I, an organic solvent, water and a concentrated hydrochloric acid solution; for example, the preparation method further includes: mixing the compound represented by formula I, an organic solvent and water, heating the obtained mixture to 30 - 70 °C, and adding a concentrated hydrochloric acid solution to obtain the hydrochloride solution of the compound represented by formula I.

15. The preparation method of crystalline form A of the hydrochloride hydrate of the compound represented by formula I according to claim 14, characterized in that, the ratio of the concentrated hydrochloric acid solution to the compound represented by formula I is 0.38 mL - 0.57 mL:1 g, for example, it is 0.4 mL - 0.5 mL:1 g, for another example, it is 0.38 mL - 0.40 mL:1 g, 0.40 mL - 0.42 mL:1 g, 0.42 mL - 0.44 mL:1 g, 0.44 mL - 0.46 mL:1 g, 0.46 mL - 0.48 mL:1 g, 0.48 mL - 0.50 mL:1 g, 0.50 mL - 0.52 mL:1 g, 0.52 mL - 0.54 mL:1 g or 0.54 mL - 0.57 mL:1 g; and / or, the ratio of the organic solvent to the compound of formula I is 5 mL - 15 mL: 1 g, for example 8 mL - 12 mL: 1 g, and further for example 5 mL - 6 mL: 1 g, 6 mL - 7 mL: 1 g, 7 mL - 8 mL: 1 g, 8 mL - 9 mL: 1 g, 9 mL - 10 mL: 1 g, 10 mL - 11 mL: 1 g, 11 mL - 12 mL: 1 g, 12 mL - 13 mL: 1 g, 13 mL - 14 mL: 1 g or 14 mL - 15 mL: 1 g; and / or, the concentration of the concentrated hydrochloric acid solution is 8 mol / L - 12 mol / L, for example 10 mol / L - 12 mol / L, and further for example 12 mol / L.

16. The method for preparing crystalline form A of the hydrochloride hydrate of the compound of formula I as claimed in claim 11 or 12, characterized in that the hydrochloride solution of the compound of formula I is obtained by mixing raw materials including a solution of the compound of formula I and a concentrated hydrochloric acid solution; for example, the solvent of the solution of the compound of formula I is a mixture of an organic solvent and water; for example, the solution of the compound of formula I is obtained by mixing the compound of formula I and the solvent at a temperature of 30 - 70 °C, and the temperature is further for example 40 - 60 °C, and further for example 45 - 55 °C.

17. The hydrochloride hydrate of the compound of formula I, characterized in that in the hydrochloride hydrate, the molar ratio of the compound of formula I, HCl and water is 1: x: y, where x is greater than 0 and not greater than 3, and y is greater than 0 and not greater than 3; preferably, in the hydrochloride hydrate, the molar ratio of the compound of formula I, HCl and water is 1: 2: 2; 18. A pharmaceutical composition comprising at least one of the hydrochloride hydrate of the compound of formula I as claimed in claim 17 and crystalline form A of the hydrochloride hydrate of the compound of formula I as claimed in at least one of claims 1 - 10, and at least one pharmaceutically acceptable carrier; preferably, the carrier is at least one of an excipient, a diluent and a solvent.

19. Use of the hydrochloride hydrate of the compound of formula I as claimed in claim 17, crystalline form A of the hydrochloride hydrate of the compound of formula I as claimed in at least one of claims 1 - 10, or the pharmaceutical composition as claimed in claim 18 in the preparation of a drug for preventing or treating a Janus kinase-mediated disorder, disease or condition; preferably, the Janus kinase is at least one of JAK1, JAK2, JAK3 and TyK2.

20. The use as claimed in claim 19, characterized in that the Janus kinase-mediated disease is at least one of a hyperproliferative disease, cancer, immune and inflammatory disorders; preferably, the Janus kinase-mediated disease is at least one of leukemia, lymphoma, transplant rejection, asthma, chronic obstructive pulmonary disease, allergy, rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis and multiple sclerosis.

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