Salts of pyrrolopyrimidine compounds, crystals thereof and uses thereof

Abstract

This disclosure provides salts of pyrrolopyrimidine compounds, their crystals, and uses thereof. Specifically, it provides crystals of the compound represented by formula I, its salts, and hydrates of its salts, as well as methods for producing and using the crystals and salts of the compound represented by formula (I). Furthermore, the salts and crystals of the present invention are stable and have good hygroscopicity, and are expected to be used in pharmaceuticals. JPEG2023553021000065.jpg5961

Description

[Technical field]

[0001] This application claims priority from Chinese patent application No. 202011413463.2, filed on December 4, 2020. This application cites the above-mentioned Chinese patent application in full. The present invention relates to a salt of a pyrrolopyrimidine compound, a crystal thereof and use thereof. [Background technology]

[0002] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that can transmit cytokine signals from membrane receptors to STAT transcription factors. There are four members of the JAK family: JAK1, JAK2, JAK3, and TYK2. The JAK-STAT pathway transmits extracellular signals from various cytokines, growth factors, and hormones to the cell nucleus and is responsible for the expression of thousands of protein-coding genes. Several steps are involved in the conversion of extracellular signals into transcriptional responses by the JAK-STAT pathway. 1) After the cytokine receptors on the cell surface bind to their respective cytokine complexes, they undergo a conformational change that leads to the dimerization of the receptor molecules, which brings the receptor-bound JAK kinases into close proximity to each other and activates them by alternating tyrosine phosphorylation. 2) After activation, JAKs catalyze the phosphorylation modification of tyrosine residues on the receptor, and these phosphorylated tyrosine sites form "docking sites" with the surrounding amino acid sequences, and at the same time, STAT proteins containing SH2 domains are invited to these "docking sites." 3) Finally, the kinase JAK catalyzes the phosphorylation of receptor-bound STAT proteins, which then dissociate from the receptor to form dimers and translocate into the cell nucleus to transcribe specific genes. JAK-STAT intracellular signaling is instrumental in the regulation of the expression of interferons, most interleukins, and various cytokines and endocrine factors, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL (Vainchenker WE T al. (2008)).

[0003] JAK-1, JAK-2 and TYK-2 are expressed in all tissue cells of the human body, while JAK-3 is mainly expressed in all hematopoietic tissue cells, mainly present in bone marrow cells, thymocytes, NK cells and activated B and T lymphocytes. JAK1 can bind to other receptors including IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, IL-6 and γc of the gp130 family, etc. JAK1 has become a new target in the fields of immunity, inflammation, cancer, etc. JAK2 plays an important role in the regulation process of various receptor signals including EPO, GH, PRL, IL-3, IL-5, GM-CSF, etc. in the IFN-γ and βc families. The single base mutation JAK2V617F in the JAK2 gene in the human body is closely related to the occurrence of myeloproliferative diseases such as polycythemia vera (PV), idiopathic thrombocytosis (ET), idiopathic myelofibrosis (IMF), and chronic granulocytic leukemia (CML). JAK3 regulates cell signaling by associating with the gamma chain (γc) in the cytokine receptor complexes of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Either JAK3 or γc mutation can cause severe combined immunodeficiency. Abnormal activity of JAK3 manifests as a massive reduction in T cells and NK cells, loss of B cell function, and severely affects normal biological functions such as the immune system. Based on its functional characteristics and special tissue distribution, JAK3 has become an extremely attractive drug target for immune system-related diseases. TYK2 is the first member of the JAK family and is activated by various receptors such as IFNs, IL-10, IL-6, IL-12, IL-23, and IL-27. In mice, loss of TYK2 function leads to defects in the signaling pathways of various cytokine receptors, leading to increased susceptibility to viral infections, reduced antibacterial immune function, and increased susceptibility to pulmonary infections (John J. O'Shea, 2004, Nature Reviews Drug Discovery 3, 555-564).Different JAK family members selectively bind to different cytokine receptors, conferring signal transduction specificity and exerting different physiological actions, and this selective mode of action allows JAK inhibitors to be used with relative specificity in the treatment of diseases. For example, IL-2 or IL-4 receptors bind to JAK1 and JAK3 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 to JAK1 and TYK2, while receptors of the IL-10 cytokine family bind to JAK1 / 2 and TYK2. The cytokines and their receptors cause different physiological actions through various specific binding to JAK family members, providing the potential 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 have therapeutic effects on a range of inflammatory diseases and other diseases driven by JAK-mediated signaling (Daniella M. Schwartz, 2017, Nature Reviews Drug Discovery 16,843-862.).

[0004] The structural formulae of the compound represented by formula (I-1) and the compound represented by formula (II) are as follows:

[0005] [ka]

[0006] Since the solubility of the compound represented by formula (I-1) and the compound represented by formula (II) is relatively low, in order to further improve the solubility of the compound, a salt formation test of the compound represented by formula (II) was carried out: at present, the salt or crystal of the compound represented by formula (II) has not been reported, and the crystal structure of the active pharmaceutical ingredient may affect the chemical and physical stability of the drug, and the crystal structure of the compound may change due to differences in crystallization conditions and storage conditions, and sometimes may be accompanied by the formation of crystals of other forms. In general, amorphous pharmaceuticals do not have a regular crystal structure and may have other defects such as low thermodynamic stability. Therefore, it is necessary to improve the properties of the above compounds in all aspects. Summary of the Invention [Problem to be solved by the invention]

[0007] The technical problem that the present invention aims to solve is the shortcomings of the prior art such as low solubility of pyrrolopyrimidine compounds, and the present invention provides a salt of pyrrolopyrimidine compounds, its crystals and its use. The salt of pyrrolopyrimidine compounds of the present invention and its crystals have good solubility, stable properties, good hygroscopicity, and good drug forming properties. [Means for solving the problem]

[0008] The present invention provides a salt of a compound represented by formula (I) or a hydrate of the salt.

[0009] [ka]

[0010] however, T 1 is CH or N, D 1 is O or C 0-1 is alkyl, R 1 , H, C 1 ~C 3 Alkyl or "1, 2 or 3 R aC replaced by 1 ~C 3 "Alkyl" R 2 , H, C 1 ~C 3 Alkyl or "1, 2 or 3 R b C replaced by 1 ~C 3 "Alkyl" R 3 is H, fluorine, chlorine, bromine, iodine, -CN, C 1 ~C 3 Alkyl or "1, 2 or 3 R c C replaced by 1 ~C 3 "Alkyl" R a , R b and R c are independently fluorine, chlorine, bromine, iodine and NH 2 is selected from The acid in said salt is selected from maleic acid, hydrochloric acid and sulfuric acid.

[0011] In some embodiments, in the salt of the compound represented by formula (I) or the hydrate of the salt thereof, the definitions of certain groups are as shown below, and the definitions of other groups are as described in any one of the schemes above (hereinafter referred to as "some embodiments"): 1 is H or CH 3 It is.

[0012] In some embodiments, R 2 is H or CH 3 It is.

[0013] In some embodiments, R 3 is hydrogen, halogen or CN, preferably CN.

[0014] In some embodiments, D 1 is CH 2 It is.

[0015] In some embodiments, T 1 is CH.

[0016] In some embodiments, the compound in the salt of the compound represented by formula (I) is a compound represented by formula (II):

[0017] [ka]

[0018] and preferably, the salt of the compound represented by formula (I) is selected from any one of the following compounds:

[0019] [ka]

[0020] In some embodiments, the molar ratio of the acid to the compound represented by formula (I) in the salt is (0.25-1.5):1, preferably (0.5-1):1, more preferably (0.7-1):1, for example, 1:1.

[0021] In some embodiments, the molar ratio of water to the compound represented by formula (I) in the hydrate of the salt is (0-3):1, for example, 1.5.

[0022] In some embodiments, the hydrate of the salt of the compound represented by Formula (I) is selected from the hydrates of the following compounds:

[0023] [ka]

[0024] The present invention provides a type A crystal of a compound represented by formula (II), whose X-ray powder diffraction spectrum (XRPD) expressed in 2θ angles has diffraction peaks at 12.69°, 13.84°, 15.37°, 15.90°, 16.62°, 19.07°, 27.66° and 25.62°.

[0025] In some embodiments, the A-type crystal of the compound represented by formula (II) may have a powder X-ray diffraction spectrum represented by 2θ angles, and the 2θ values ​​may be as shown in Table 1 below:

[0026] [Table 1]

[0027] In some embodiments, the A-type crystal of the compound represented by formula (II) has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0028] In some embodiments, the powder X-ray diffraction spectrum of the A-type crystal of the compound represented by formula (II) is detected under the condition of a Cu-Kα radiation source.

[0029] In some embodiments, the A-type crystals of the compound represented by formula (II) have an absorption peak at a peak temperature of 300.4°C in the differential scanning calorimetry curve.

[0030] In some embodiments, the A-type crystal of the compound represented by formula (II) exhibits a weight loss of 2.1% in the temperature range of 25.1°C to 250°C in its thermogravimetric analysis curve (TGA).

[0031] In some embodiments, the A-type crystals of the compound represented by formula (II) have a differential scanning calorimetry curve (DSC) and a thermogravimetric analysis curve (TGA) as shown in FIG.

[0032] In some embodiments, the A-type crystals of the compound represented by formula (II) have a thermogravimetric analysis curve in the heating interval and are detected under conditions where the heating rate is 10° C. / min.

[0033] In some embodiments, the A-type crystals of the compound represented by formula (II) are detected under conditions where the differential scanning calorimetric curve is in the temperature rise interval and the temperature rise rate is 10° C. / min.

[0034] The present invention provides a B-type crystal of a compound represented by formula (II), whose powder X-ray diffraction spectrum expressed as 2θ angles has diffraction peaks at 12.40°, 13.31°, 15.75°, 22.16°, 23.72°, 25.49°, 26.12° and 26.87°.

[0035] In some embodiments, the B-type crystal of the compound represented by formula (II) may have a powder X-ray diffraction spectrum represented by 2θ angles, and the 2θ values ​​may be as shown in Table 2 below:

[0036] [Table 2]

[0037] In some embodiments, the B-type crystal of the compound represented by formula (II) has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0038] In some embodiments, the powder X-ray diffraction spectrum of the B-type crystal of the compound represented by formula (II) is detected under the condition of a Cu-Kα radiation source.

[0039] The present invention provides a type A crystal of the maleate salt represented by formula (II-1), and the powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 12.24°, 13.14°, 13.73°, 14.56°, 15.52°, 17.54°, 19.54°, 23.19°, 26.55° and 26.91°.

[0040] In some embodiments, the A-type crystal of the maleate salt represented by formula (II-1) may have a powder X-ray diffraction spectrum represented by 2θ angles, and the 2θ values ​​may be as shown in Table 3 below:

[0041] [Table 3]

[0042] In some embodiments, the A-type crystal of the maleate salt represented by formula (II-1) has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0043] In some embodiments, the powder X-ray diffraction spectrum of the A-type crystal of the maleate salt represented by the formula (II-1) is detected under the condition of a Cu-Kα radiation source.

[0044] In some embodiments, the maleic acid salt A type crystal represented by the formula (II-1) has an absorption peak at a peak temperature of 173.3°C in its differential scanning calorimetry curve (DSC).

[0045] In some embodiments, the A-type crystal of the maleate salt represented by the formula (II-1) exhibits a weight loss of 1.86% in the temperature range of 29.1°C to 150°C in the thermogravimetric analysis curve (TGA).

[0046] In some embodiments, the A-type crystals of the maleate salt represented by formula (II-1) have a differential scanning calorimetry curve (DSC) and a thermogravimetric analysis curve (TGA) as shown in FIG.

[0047] In some embodiments, the A-type crystals of the maleate salt represented by the formula (II-1) have a thermogravimetric analysis curve in the temperature rise interval and are detected under the condition of a temperature rise rate of 10° C. / min.

[0048] In some embodiments, the A-type crystals of the maleate salt represented by the formula (II-1) are detected under conditions where the differential scanning calorimetry curve is in the temperature rise interval and the temperature rise rate is 10° C. / min.

[0049] The present invention provides a type A crystal of the hydrochloride salt represented by formula (II-2), and the powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 7.20°, 7.85°, 8.63°, 10.82°, 21.25°, 21.78°, 24.12°, 25.56°, 26.11° and 27.03°.

[0050] In some embodiments, the A-type crystals of the hydrochloride salt represented by formula (II-2) may have a powder X-ray diffraction spectrum represented by 2θ angles, the 2θ values ​​of which may be as shown in Table 4 below:

[0051] [Table 4]

[0052] In some embodiments, the A-type crystals of the hydrochloride salt represented by formula (II-2) have a powder X-ray diffraction spectrum essentially as shown in FIG.

[0053] In some embodiments, the powder X-ray diffraction spectrum of the A-type crystals of the hydrochloride salt represented by formula (II-2) is detected under the condition of a Cu-Kα radiation source.

[0054] In some embodiments, the A-type crystals of the hydrochloride salt represented by formula (II-2) have three absorption peaks in the differential scanning calorimetric curve, the peak temperatures of which are 78.1° C., 92.2° C., and 274° C., respectively.

[0055] In some embodiments, the A-type crystals of the hydrochloride salt represented by the formula (II-2) show a weight loss of 6.71% in the temperature range of 27.2°C to 100°C in the thermogravimetric analysis curve.

[0056] In some embodiments, the A-type crystals of the hydrochloride salt represented by formula (II-2) have a differential scanning calorimetry curve (DSC) and a thermogravimetric analysis curve (TGA) as shown in FIG.

[0057] The present invention provides a B-type crystal of the hydrochloride salt represented by formula (II-2), and the powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 5.95°, 11.92°, 12.53°, 13.14°, 20.94°, 24.96°, 25.67°, 30.09° and 31.69°.

[0058] In some embodiments, the B-type crystals of the hydrochloride salt represented by formula (II-2) may have a powder X-ray diffraction spectrum represented by 2θ angles, and the 2θ values ​​may be as shown in Table 5 below:

[0059] [Table 5]

[0060] In some embodiments, the B-type crystals of the hydrochloride salt represented by formula (II-2) have a powder X-ray diffraction spectrum essentially as shown in FIG.

[0061] In some embodiments, the powder X-ray diffraction spectrum of the B-type crystals of the hydrochloride salt represented by formula (II-2) is detected under the condition of a Cu-Kα radiation source.

[0062] In some embodiments, the B-type crystals of the hydrochloride salt represented by formula (II-2) have an absorption peak at a peak temperature of 274.7°C in the differential scanning calorimetry curve.

[0063] In some embodiments, the B-type crystals of the hydrochloride salt represented by the formula (II-2) show a weight loss of 2.34% in the temperature range of 31.4°C to 100°C in the thermogravimetric analysis curve.

[0064] In some embodiments, the B-type crystals of the hydrochloride salt represented by the formula (II-2) have a thermogravimetric analysis curve in the heating interval and are detected under conditions where the heating rate is 10° C. / min.

[0065] In some embodiments, the B-type crystals of the hydrochloride salt represented by the formula (II-2) have a differential scanning calorimetric curve in the temperature rise interval and are detected under conditions where the temperature rise rate is 10° C. / min.

[0066] In some embodiments, the B-type crystals of the hydrochloride salt represented by formula (II-2) have a differential scanning calorimetry curve (DSC) and a thermogravimetric analysis curve (TGA) as shown in FIG.

[0067] The present invention provides a C-type crystal of the hydrochloride salt represented by formula (II-2), and its powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 5.89°, 11.77°, 13.21°, 13.52°, 15.75°, 23.51°, 25.51°, 24.65°, 26.31° and 27.15°.

[0068] In some embodiments, the C-type crystals of the hydrochloride salt represented by the formula (II-2) may have a powder X-ray diffraction spectrum represented by 2θ angles, and the 2θ values ​​may be as shown in Table 6 below:

[0069] [Table 6]

[0070] In some embodiments, the C-type crystals of the hydrochloride salt represented by formula (II-2) have a powder X-ray diffraction spectrum essentially as shown in FIG.

[0071] In some embodiments, the powder X-ray diffraction spectrum of the C-type crystal of the hydrochloride salt represented by formula (II-2) is detected under the condition of a Cu-Kα radiation source.

[0072] In some embodiments, the C-type crystals of the hydrochloride salt represented by formula (II-2) have an absorption peak at a peak temperature of 275.1°C in the differential scanning calorimetry curve.

[0073] In some embodiments, the C-type crystals of the hydrochloride salt represented by the formula (II-2) show a weight loss of 1.32% in the temperature range of 33.7°C to 100°C in the thermogravimetric analysis curve.

[0074] In some embodiments, the C-type crystals of the hydrochloride salt represented by the formula (II-2) have a thermogravimetric analysis curve in the heating interval and are detected under conditions where the heating rate is 10° C. / min.

[0075] In some embodiments, the C-type crystals of the hydrochloride salt represented by the formula (II-2) have a differential scanning calorimetric curve in the temperature rise interval and are detected under conditions where the temperature rise rate is 10° C. / min.

[0076] In some embodiments, the C-type crystals of the hydrochloride salt represented by formula (II-2) have a differential scanning calorimetry curve (DSC) and a thermogravimetric analysis curve (TGA) as shown in FIG.

[0077] The present invention provides a D-type crystal of the hydrochloride salt represented by formula (II-2), and the powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 3.08°, 6.07°, 9.05°, 12.06°, 12.73°, 13.23°, 13.78°, 15.08°, 21.28°, 24.94°, 26.06° and 31.72°.

[0078] In some embodiments, the D-type crystals of the hydrochloride salt represented by the formula (II-2) may have a powder X-ray diffraction spectrum represented by 2θ angles, and the 2θ values ​​may be as shown in Table 7 below:

[0079] [Table 7]

[0080] In some embodiments, the D-type crystals of the hydrochloride salt represented by formula (II-2) have a powder X-ray diffraction spectrum essentially as shown in FIG.

[0081] In some embodiments, the powder X-ray diffraction spectrum of the D-type crystal of the hydrochloride salt represented by formula (II-2) is detected under the condition of a Cu-Kα radiation source.

[0082] In some embodiments, the D-type crystals of the hydrochloride salt represented by formula (II-2) have two absorption peaks in their differential scanning calorimetry curve, the peak temperatures of which are 273.7°C and 279.3°C, respectively.

[0083] In some embodiments, the D-type crystals of the hydrochloride salt represented by the formula (II-2) show a weight loss of 2.92% in the temperature range of 28.3°C to 100°C in the thermogravimetric analysis curve.

[0084] In some embodiments, the D-type crystals of the hydrochloride salt represented by formula (II-2) have a differential scanning calorimetry curve (DSC) and a thermogravimetric analysis curve (TGA) as shown in FIG.

[0085] In some embodiments, the D-type crystals of the hydrochloride salt represented by the formula (II-2) have a thermogravimetric analysis curve in the heating interval and are detected under conditions where the heating rate is 10° C. / min.

[0086] In some embodiments, the D-type crystals of the hydrochloride salt represented by the formula (II-2) have a differential scanning calorimetric curve in the temperature rise interval and are detected under conditions where the temperature rise rate is 10° C. / min.

[0087] The present invention provides a type A crystal of the sulfate salt represented by formula (II-3), and the powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 4.16°, 4.46°, 7.56°, 8.02°, 12.65°, 13.36°, 15.75°, 17.91°, 20.43°, 24.54°, 24.94°, 25.90° and 26.99°.

[0088] In some embodiments, the A-type crystal of the sulfate salt represented by formula (II-3) may have a powder X-ray diffraction spectrum represented by 2θ angles, and the 2θ values ​​may be as shown in Table 8 below:

[0089] [Table 8]

[0090] In some embodiments, the A-type crystals of the sulfate salt represented by formula (II-3) have a powder X-ray diffraction spectrum essentially as shown in FIG.

[0091] In some embodiments, the powder X-ray diffraction spectrum of the A-type crystal of the sulfate salt represented by formula (II-3) is detected under the condition of a Cu-Kα radiation source.

[0092] In some embodiments, the A-type crystals of the sulfate salt represented by formula (II-3) have two absorption peaks in their differential scanning calorimetric curve, the peak temperatures of which are 85.1° C. and 126.7° C., respectively.

[0093] In some embodiments, the A-type crystals of the sulfate salt represented by the formula (II-3) show a weight loss of 8.14% in the temperature range of 28.4°C to 150°C in the thermogravimetric analysis curve.

[0094] In some embodiments, the A-type crystals of the sulfate salt represented by formula (II-3) have a differential scanning calorimetry curve (DSC) and a thermogravimetric analysis curve (TGA) as shown in FIG.

[0095] In some embodiments, the A-type crystals of the sulfate salt represented by the formula (II-3) have a thermogravimetric analysis curve in the temperature rise interval and are detected under the condition of a temperature rise rate of 10° C. / min.

[0096] In some embodiments, the A-type crystals of the sulfate salt represented by the formula (II-3) have a differential scanning calorimetric curve in the temperature rise interval and are detected under conditions where the temperature rise rate is 10° C. / min.

[0097] The present invention provides a C-type crystal of the sulfate salt represented by formula (II-3), and the powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 6.09°, 12.17°, 13.25°, 15.60°, 16.09°, 17.45°, 18.66°, 22.61°, 23.62°, 24.44°, 25.04°, 25.89°, 26.30° and 26.62°.

[0098] In some embodiments, the C-type crystal of the sulfate salt represented by formula (II-3) may have a powder X-ray diffraction spectrum represented by 2θ angles, and the 2θ values ​​may be as shown in Table 9 below:

[0099] [Table 9]

[0100] In some embodiments, the C-type crystal of the sulfate salt represented by formula (II-3) has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0101] In some embodiments, the powder X-ray diffraction spectrum of the C-type crystal of the sulfate salt represented by formula (II-3) is detected under the condition of a Cu-Kα radiation source.

[0102] In some embodiments, the C-type crystals of the sulfate salt represented by formula (II-3) have two absorption peaks in their differential scanning calorimetric curve, the peak temperatures of which are 69.3°C and 118.1°C, respectively.

[0103] In some embodiments, the C-type crystals of the sulfate salt represented by the formula (II-3) show a weight loss of 6.82% in the temperature range of 28.2°C to 150°C in the thermogravimetric analysis curve.

[0104] In some embodiments, the C-type crystals of the sulfate salt represented by formula (II-3) have a differential scanning calorimetry curve (DSC) and a thermogravimetric analysis curve (TGA) as shown in FIG.

[0105] In some embodiments, the C-type crystals of the sulfate represented by the formula (II-3) have a thermogravimetric analysis curve in the temperature rise interval and are detected under the condition of a temperature rise rate of 10° C. / min.

[0106] In some embodiments, the C-type crystals of the sulfate represented by the formula (II-3) are detected under conditions where the differential scanning calorimetry curve is in the temperature rise interval and the temperature rise rate is 10° C. / min.

[0107] The present invention provides a D-type crystal of the sulfate salt represented by formula (II-3), and the powder X-ray diffraction spectrum expressed in terms of 2θ angles has diffraction peaks at 4.16°, 6.11°, 8.00°, 9.10°, 10.91°, 13.73°, 18.86°, 23.27°, 25.28°, and 25.97°.

[0108] In some embodiments, the D-type crystal of the sulfate salt represented by formula (II-3) may have a powder X-ray diffraction spectrum represented by 2θ angles, and the 2θ values ​​may be as shown in Table 10 below:

[0109] [Table 10]

[0110] In some embodiments, the D-type crystal of the sulfate salt represented by formula (II-3) has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0111] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the D-type crystal of the sulfate salt represented by the formula (II-3) is detected under the condition of a Cu-Kα radiation source.

[0112] In some embodiments, the D-type crystals of the sulfate salt represented by formula (II-3) have two absorption peaks in their differential scanning calorimetric curve, the peak temperatures of which are 78.5° C. and 144.3° C., respectively.

[0113] In some embodiments, the D-type crystals of the sulfate salt represented by the formula (II-3) show a weight loss of 8.13% in the temperature range of 23.3°C to 150°C in the thermogravimetric analysis curve.

[0114] In some embodiments, the sulfate D-type crystals represented by the formula (II-3) have a differential scanning calorimetry curve (DSC) and a thermogravimetric analysis curve (TGA) as shown in FIG.

[0115] In some embodiments, the D-type crystals of the sulfate salt represented by the formula (II-3) have a thermogravimetric analysis curve in the temperature rise interval and are detected under the condition of a temperature rise rate of 10° C. / min.

[0116] In some embodiments, the D-type crystals of the sulfate salt represented by the formula (II-3) have a differential scanning calorimeter curve in the temperature rise interval and are detected under conditions where the temperature rise rate is 10° C. / min.

[0117] The present invention provides a B-type crystal of a hydrate of a sulfate represented by formula (II-3), and the powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 5.18°, 12.03°, 12.92°, 15.54°, 16.09°, 17.74°, 19.06°, 20.71°, 23.99°, 24.82° and 25.79°.

[0118] In some embodiments, the B-type crystal of the hydrate of the sulfate represented by formula (II-3) may have a powder X-ray diffraction spectrum represented by 2θ angles, and the 2θ values ​​may be as shown in Table 11 below:

[0119] [Table 11]

[0120] In some embodiments, the B-type crystal of the hydrate of the sulfate salt represented by formula (II-3) has a powder X-ray diffraction spectrum essentially as shown in FIG.

[0121] In some embodiments, the powder X-ray diffraction spectrum of the B-type crystal of the hydrate of the sulfate represented by formula (II-3) is detected under the condition of a Cu-Kα radiation source.

[0122] In some embodiments, the B-type crystals of the hydrate of the sulfate represented by formula (II-3) have two absorption peaks in their differential scanning calorimetric curve, the peak temperatures of which are 98° C. and 140.2° C., respectively.

[0123] In some embodiments, the B-type crystals of the hydrate of sulfate represented by the formula (II-3) show a weight loss of 6.67% in the temperature range of 28.6°C to 150°C in the thermogravimetric analysis curve.

[0124] In some embodiments, the B-type crystals of the hydrate of the sulfate represented by formula (II-3) have a differential scanning calorimetry curve (DSC) and a thermogravimetric analysis curve (TGA) as shown in FIG.

[0125] In some embodiments, the B-type crystals of the hydrate of the sulfate represented by the formula (II-3) have a thermogravimetric analysis curve in the temperature rise interval and are detected under the condition of a temperature rise rate of 10° C. / min.

[0126] In some embodiments, the B-type crystals of the hydrate of the sulfate represented by the formula (II-3) have a differential scanning calorimetric curve in the temperature rise interval and are detected under conditions where the temperature rise rate is 10° C. / min.

[0127] In some embodiments, the ratio of the number of water molecules to the number of sulfate molecules represented by formula (II-3) in the B-type crystals of the hydrate of the sulfate molecule represented by formula (II-3) may be 1.5.

[0128] The present invention also provides a method for producing a salt of a compound represented by formula (I), comprising the step of carrying out a salt-forming reaction between a compound represented by formula (I) and an acid in a solvent.

[0129] In some embodiments, the solvent is preferably one or more selected from tetrahydrofuran, 2-methylfuran, ethyl acetate, cyclohexane, dimethyl sulfoxide, water, n-butanol, isopropanol, ethanol, N-methylpyrrolidone, acetonitrile, acetone, butanone, methyl isobutyl ketone, toluene, dichloromethane, 1,4-dioxane, anisole, preferably, the solvent is one or more selected from tetrahydrofuran, ethyl acetate, cyclohexane, dimethyl sulfoxide, ethanol, water, n-butanol, N-methylpyrrolidone, acetonitrile, butanone, more preferably, the solvent is selected from tetrahydrofuran, acetone, ethanol, ethyl acetate, and aqueous acetonitrile.

[0130] The present invention also provides a method for producing type A crystals of the compound represented by formula (II), comprising the steps of adding a poor solvent to a solution of the compound represented by formula (II) in tetrahydrofuran at room temperature and precipitating the crystals to obtain type A crystals, wherein the poor solvent is an ester solvent or an alkane solvent.

[0131] In some embodiments, the ester solvent is ethyl acetate or n-butyl acetate, for example, ethyl acetate.

[0132] In some embodiments, the alkane solvent is n-hexane, petroleum ether, or n-heptane, for example, n-hexane.

[0133] In some embodiments, the volume ratio of the tetrahydrofuran to the poor solvent is 1:(0.1 to 10), preferably 1:(0.5 to 3), and more preferably 1:1 or 1.25:1.

[0134] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the tetrahydrofuran is 2 to 6 mg / mL, and preferably 5:1 mg / mL.

[0135] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the poor solvent is 2 to 6 mg / mL, and preferably 5:1 mg / mL or 4:1 mg / mL.

[0136] The present invention also provides a method for producing type B crystals of the compound represented by formula (II), comprising the steps of dissolving type A crystals of the compound represented by formula (II-1) in NMP at room temperature, adding water, and precipitating the crystals to obtain type B crystals.

[0137] In some embodiments, the volume ratio of the NMP to the water is 1:(0.1 to 10), preferably 1:(0.2 to 2), and more preferably 1:0.4.

[0138] In some embodiments, the mass / volume ratio of the A-type crystal of the compound represented by formula (II-1) to the NMP is 1 to 5 mg / mL, and preferably 2:1 mg / mL.

[0139] The present invention also provides a method for producing type A crystals of a compound represented by formula (II-1), comprising the steps of dispersing a compound represented by formula (II) and maleic acid in an ester solvent, carrying out a reaction represented by the following formula, and collecting the solid to obtain type A crystals.

[0140] [ka]

[0141] In some embodiments, the molar ratio of maleic acid to the compound represented by formula (II) is 1.04:1.

[0142] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the ethyl acetate is 10 mg / mL.

[0143] In some embodiments, the ester solvent is a conventional ester solvent in the art, such as ethyl acetate.

[0144] The present invention also provides a method for producing type A crystals of a compound represented by formula (II-2), comprising the steps of adding hydrochloric acid to a solution of a compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain type A crystals, wherein the solvent of the solution is an aqueous acetonitrile solution.

[0145] [ka]

[0146] In some embodiments, the molar ratio of the hydrochloric acid to the compound represented by Formula (II) is 1.05:1.

[0147] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the acetonitrile aqueous solution is 40 mg / mL.

[0148] In some embodiments, the volume ratio of acetonitrile to aqueous solution in the acetonitrile-aqueous solution is 19:1.

[0149] The present invention also provides a method for producing type B crystals of a compound represented by formula (II-2), comprising the steps of adding hydrochloric acid to an ethyl acetate solution of a compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain type B crystals.

[0150] [ka]

[0151] In some embodiments, the molar ratio of the hydrochloric acid to the compound represented by Formula (II) is 1.05:1.

[0152] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the ethyl acetate is 40 mg / mL.

[0153] The present invention also provides a method for producing type C crystals of a compound represented by formula (II-2), comprising the steps of adding hydrochloric acid to an ethanol solution of a compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain type C crystals.

[0154] [ka]

[0155] In some embodiments, the molar ratio of the hydrochloric acid to the compound represented by Formula (II) is 1.05:1.

[0156] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the ethanol is 40 mg / mL.

[0157] The present invention also provides a method for producing type D crystals of a compound represented by formula (II-2), comprising the steps of adding hydrochloric acid to a tetrahydrofuran solution of a compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain type D crystals.

[0158] [ka]

[0159] In some embodiments, the molar ratio of the hydrochloric acid to the compound represented by Formula (II) is 1.05:1.

[0160] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the tetrahydrofuran is 40 mg / mL.

[0161] The present invention also provides a method for producing type A crystals of a compound represented by formula (II-3), comprising the steps of adding sulfuric acid to a solution of a compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain type A crystals, wherein the solvent of the solution is an aqueous acetonitrile solution.

[0162] [ka]

[0163] In some embodiments, the molar ratio of the sulfuric acid to the compound represented by Formula (II) is 1.03:1.

[0164] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the acetonitrile aqueous solution is 30 mg / mL.

[0165] In some embodiments, the volume ratio of acetonitrile to aqueous solution in the acetonitrile-aqueous solution is 19:1.

[0166] In some embodiments, the mass concentration of the sulfuric acid is 4 mol / L.

[0167] The present invention also provides a method for producing type C crystals of a compound represented by formula (II-3), comprising the steps of adding sulfuric acid to an ethyl acetate solution of a compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain type C crystals.

[0168] [ka]

[0169] In some embodiments, the molar ratio of the sulfuric acid to the compound represented by Formula (II) is 1.03:1.

[0170] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the ethyl acetate is 30 mg / mL.

[0171] In some embodiments, the mass concentration of the sulfuric acid is 4 mol / L.

[0172] The present invention also provides a method for producing type D crystals of a compound represented by formula (II-3), comprising the steps of adding sulfuric acid to an ethanol solution of a compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain type D crystals.

[0173] [ka]

[0174] In some embodiments, the molar ratio of the sulfuric acid to the compound represented by Formula (II) is 1.03:1.

[0175] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the ethanol is 30 mg / mL.

[0176] In some embodiments, the mass concentration of the sulfuric acid is 4 mol / L.

[0177] The present invention also provides a method for producing type B crystals of a hydrate of a compound represented by formula (II-3), comprising the steps of adding sulfuric acid to an acetone solution of a compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain type B crystals.

[0178] [ka]

[0179] In some embodiments, the molar ratio of the sulfuric acid to the compound represented by Formula (II) is 1.03:1.

[0180] In some embodiments, the mass / volume ratio of the compound represented by formula (II) to the acetone is 30 mg / mL.

[0181] In some embodiments, the mass concentration of the sulfuric acid is 4 mol / L.

[0182] In some embodiments, in the production of A-type crystals of a compound represented by (II-1), A-type crystals, B-type crystals, C-type crystals, and D-type crystals of a compound represented by (II-2), A-type crystals, C-type crystals, and D-type crystals of a compound represented by (II-3), and B-type crystals of a hydrate of a compound represented by (II-3), the compound represented by formula (II) is an A-type crystal of a compound represented by formula (II).

[0183] The present invention also provides the use of a crystal of a compound of Formula I, a salt thereof, a hydrate of a salt thereof, and related crystals thereof in the manufacture of a medicament for treating a disease associated with JAK1 and / or JAK2.

[0184] In some embodiments, the crystal in the use is an A-type crystal or a B-type crystal of the compound represented by (II), an A-type crystal of the compound represented by (II-1), an A-type crystal, a B-type crystal, a C-type crystal, or a D-type crystal of the compound represented by (II-2), an A-type crystal, a C-type crystal, or a D-type crystal of the compound represented by (II-3), or a B-type crystal of a hydrate of the compound represented by (II-3).

[0185] In some embodiments, in said uses, the relevant disease is rheumatoid arthritis. Effect of the Invention

[0186] The positive advances of the present invention are: The A-type crystals and B-type crystals of the compound represented by (II) provided by the present invention, the A-type crystals of the compound represented by (II-1), the A-type crystals, B-type crystals, C-type crystals, and D-type crystals of the compound represented by (II-2), the A-type crystals, C-type crystals, and D-type crystals of the compound represented by (II-3), and the B-type crystal of the hydrate of the compound represented by (II-3) are stable in nature and have good hygroscopicity, and are expected to be used in pharmaceuticals. [Brief description of the drawings]

[0187] [Figure 1] 1 is an XRPD spectrum of Cu-Kα radiation for crystal form A of the compound of formula (II). [Diagram 2] 1 is a TGA / DSC spectrum of type A crystals of the compound represented by formula (II). [Diagram 3] 1 is an XRPD spectrum of Cu-Kα radiation for the B-type crystals of the compound of formula (II). [Figure 4] 1 is an XRPD spectrum of Cu-Kα radiation of the A-type crystal of the compound represented by formula (II-1). [Diagram 5] 1 is a TGA / DSC spectrum of type A crystals of the compound represented by formula (II-1). [Figure 6] 1 is an XRPD spectrum of Cu-Kα radiation of the A-type crystal of the compound represented by formula (II-2). [Figure 7] 1 is a TGA / DSC spectrum of type A crystals of the compound represented by formula (II-2). [Figure 8] 1 is an XRPD spectrum of Cu-Kα radiation of the B-type crystal of the compound represented by formula (II-2). [Figure 9] 1 is a TGA / DSC spectrum of type B crystals of the compound represented by formula (II-2). [Figure 10] 1 is an XRPD spectrum of Cu-Kα radiation of the C-type crystal of the compound represented by formula (II-2). [Figure 11] 1 is a TGA / DSC spectrum of type C crystals of the compound represented by formula (II-2). [Figure 12] 1 is an XRPD spectrum of Cu-Kα radiation of the D-type crystal of the compound represented by formula (II-2). [Figure 13] 1 is a TGA / DSC spectrum of the D-type crystal of the compound represented by formula (II-2). [Figure 14] 1 is an XRPD spectrum of Cu-Kα radiation of the A-type crystal of the compound represented by formula (II-3). [Figure 15]1 is a TGA / DSC spectrum of type A crystals of the compound represented by formula (II-3). [Figure 16] 1 is an XRPD spectrum of Cu-Kα radiation of the B-type crystal of the hydrate of the compound of formula (II-3). [Figure 17] 1 is a TGA / DSC spectrum of type B crystal of the hydrate of the compound represented by formula (II-3). [Figure 18] 1 is an XRPD spectrum of Cu-Kα radiation of the C-type crystal of the compound represented by formula (II-3). [Figure 19] 1 is a TGA / DSC spectrum of type C crystals of the compound represented by formula (II-3). [Figure 20] 1 is an XRPD spectrum of Cu-Kα radiation of the D-type crystal of the compound represented by formula (II-3). [Figure 21] 1 is a TGA / DSC spectrum of the D-type crystal of the compound represented by formula (II-3). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0188] [Definitions and Explanations]

[0189] Unless otherwise stated, the following terms and phrases used herein have the following meanings. A particular phrase or term, unless specifically defined, should be understood to have its ordinary definition, not to be indefinite or unclear. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.

[0190] The intermediate compounds of the present invention can be prepared by various synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention. In the present invention, unless the reaction temperature is specified, the reaction temperature is room temperature, which is generally 20-35°C.

[0191] The chemical reactions of the specific embodiments of the present invention are completed in suitable solvents, which are suitable for and necessary reagents and materials for the chemical transformations of the present invention. In order to obtain the compounds of the present invention, those skilled in the art may need to modify or select synthetic steps or reaction schemes based on the existing embodiments.

[0192] The above preferred conditions can be combined in any manner to obtain each preferred embodiment of the present invention without violating the ordinary skill in the art.

[0193] The reagents and materials used in the present invention are commercially available. EXAMPLES

[0194] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the examples. In the following examples, the experimental methods without specific conditions are selected according to the usual methods and conditions or product instructions.

[0195] In the present invention, Boc: tert-butoxycarbonyl; Cbz: benzyloxycarbonyl; Fmoc: fluorenylmethoxycarbonyl; Alloc: allyloxycarbonyl; Teoc: trimethylsilylethoxycarbonyl; Pht: phthaloyl; Tos: p-toluenesulfonyl; Tfa: trifluoroacetyl; Trt: triphenylmethyl; Dmb: 2,4-dimethoxybenzyl; PMB: p-methoxybenzyl; MOM: methoxymethylene, Bn: benzyl, THP: tetrahydropyranyl, Tr: trityl, Ac: acetyl, Bz: benzoyl, Piv: pivaloyl, TMS: trimethylsilyl, TES: triethylsilyl, TBS: tert-butyldimethylsilyl, TBDPS: tert-butyldiphenylsilyl, Ms: methylsulfonyl, Ts: p-toluenesulfonyl.

[0196] All solvents used in this invention are commercially available and may be used as is without further purification. Reactions are generally carried out in anhydrous solvents under an inert nitrogen gas atmosphere. Proton NMR data are recorded on a Bruker Avance III 400 (400 MHz) spectrometer and chemical shifts are expressed in (ppm) downfield of tetramethylsilane. Mass spectra are measured on an Agilent 1200 series plus 6110 (&1956A). The LC / MS or Shimadzu MS contains one DAD: SPD-M20A (LC) and a Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ion source (ESI) operating in positive or negative mode.

[0197] [Table 12]

[0198] Compounds are named manually or by software; commercially available compounds use the manufacturer's catalogue name.

[0199] X-ray powder diffractometer (XRPD)

[0200] [Table 13]

[0201] TGA and DSC spectra were collected on a TA Q5000 / 5500 thermogravimetric analyzer and a TA Q2000 / 2500 differential scanning calorimeter, respectively, and Table-14 shows the test parameters.

[0202] [Table 14]

[0203] [Table 15]

[0204] Example 1 The method for preparing the compound of formula 10 is as follows:

[0205] [ka]

[0206] Step 1: DCM (220 g) was added to a reactor, stirring was started, then TBSCl (61.5 g) was added and stirred to dissolve, the compound represented by formula 1 (21.8 g) and imidazole (39.7 g) were added, nitrogen gas was passed through, the temperature was raised to -2 to 5°C, and the reaction was carried out while maintaining the temperature for 3 hours. After the reaction was completed, 110.0 g of water was added, stirred for 0.5 hours, allowed to stand, separated, and the organic phase was concentrated to obtain product 2.

[0207] Step 2: The product 2 (72.3 g) obtained in step 1, THF (430 g), and the compound represented by formula (3) (63.8 g) were added to a reactor, stirred, nitrogen gas was passed through, the temperature was raised to 40-50°C, and the reaction was allowed to proceed for 1 hour. Then, butyllithium (88 g) was added, and the reaction was allowed to proceed for 4 hours. After the reaction was completed, water (480 g) and ammonium chloride (30 g) were added, and the reaction was allowed to proceed for 0.5 hours. MTBE (200 g) was added, and the reaction was allowed to proceed for 0.5 hours. The reaction was allowed to proceed, and the organic phase was collected to obtain a solution of product 4; 1 H NMR (400 MHz, CDCl 3 ) δ =4.971 (s,1H),4.33(s,2H),4.177 - 4.144 (m,H),4.100-4.039(m,2H),2.621-2.525 (m,2H),2.054-1.912 (m,2H),1.312 (s,9H),1.172 -1.127 (m,3H),0.781 (s,9H),0.001 (s,6H).

[0208] Step 3: 80% hydrazine hydrate (19.8 g) was added dropwise to the reactor of step 2, and the temperature was maintained at 0-5°C. After the addition was completed, the temperature was raised to 20-30°C and the reaction was allowed to proceed for 4 hours while maintaining the temperature. After the reaction was completed, water (400.0 g) was added, the mixture was stirred for 0.5 hours, allowed to stand, and then separated. The organic phase was concentrated to obtain product 5.

[0209] Step 4: Product 5 (250 g) and MTBE (400 g) were added to a reactor, nitrogen gas was passed through, the mixture was cooled to 0-5°C, sodium borohydride (30 g) was slowly added, then methanol (120 g) was added, the mixture was warmed to room temperature, and the mixture was reacted while maintaining the temperature for 20 hours. After the reaction was completed, water (480 g) and ammonium chloride (40 g) were added, the mixture was stirred for 0.5 hours, allowed to stand, and separated. The organic phase was concentrated to obtain product 6.

[0210] Step 5: Product 6 (145 g) and THF (630 g) were added to a reactor, nitrogen gas was passed through, the mixture was cooled to 0-5°C, tributylphosphine (40 g) was added, the mixture was stirred, ADDP was added in batches, the mixture was warmed to room temperature, and the mixture was allowed to react for 20 hours while maintaining the temperature. After the reaction was completed, the mixture was filtered and concentrated to obtain product 7.

[0211] Step 6: A reactor was charged with 30% (HCl / EtOH, 180 g) and cooled to 0-5°C. Product 7 (160 g) was then added and warmed to room temperature. The reaction was allowed to proceed for 4 hours. After the reaction was completed, the reaction was allowed to proceed to room temperature, filtered, and dried to obtain product 8.

[0212] Step 7: Product 8 (32 g), water (320 g), and a sodium carbonate solution (mass fraction: 10%, 180 g) were added to a reactor, stirred, and cooled to 0-5°C. Next, a Boc anhydride / methanol solution (Boc anhydride 50 g, methanol 150 g) was added dropwise. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out while maintaining the temperature for 10 hours. After the reaction was completed, the mixture was allowed to stand, separated, and the organic phase was concentrated to obtain product 9.

[0213] Step 8: THF (90 ml) was added to a reactor, nitrogen gas was passed through, and the mixture was cooled to 0-5°C. Lithium aluminum hydride (3.4 g) was then added, and the mixture was heated to 50°C. Product 9 / THF solution (6 g / 30 ml) was then added dropwise. After the addition was completed, the mixture was heated to 70°C and reacted for 3 hours while maintaining the temperature. After the reaction was completed, the mixture was cooled to 5-10°C, water (30 g) was added, and the mixture was stirred, filtered, and dried to obtain product 10.

[0214] Example 2 The compound of formula (II) can be synthesized as follows:

[0215] [ka]

[0216] Step 9: Product 10 (0.01 eq) of Example 1, the compound represented by formula (II) (0.00103 eq), DMSO (100 ml), and DIPEA (0.02 eq) were added to a reactor, and the mixture was heated to 100-110°C and stirred for 4 hours while maintaining the temperature. Then, the mixture was cooled to 20-30°C, water (150 ml) was added, and the mixture was stirred for 1 hour. The mixture was filtered and dried to obtain product 12.

[0217] Step 10: Dichloromethane (200 g), product 12 (15 g), 2,2,6,6-tetramethylpiperidine-oxyl (TEMPO, 0.52 g), and iodobenzene diacetate (11.7 g) were added to a reactor and reacted at room temperature for 10 h. After completion of the reaction, triethylamine (12 g) was added, stirred for 1 h, filtered, and dried to obtain product 13.

[0218] Step 11: Product 13 (73 g), aqueous ammonia (25 ml), and iodine (12.4 g) were added to a reactor and stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate (100 ml) was added and stirred for 0.5 hours. The mixture was allowed to stand and separated. The organic phase was concentrated to obtain product 14.

[0219] Step 12: Product 14 (11 g), THF (100 ml), and TBAF (0.1 mol) were added to a reactor, heated to 70 °C, and reacted for 12 h. After the reaction was completed, the mixture was cooled to room temperature and diluted with 10% NaHCO 3 An aqueous solution (100 ml) was added and the mixture was stirred at 20° C. for 2 h, filtered and dried to give product 15, i.e., the compound of formula (II).

[0220] MS (ESI) Calculated value C 15 H 15 N 7 293, Measurement value 294 [M + H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ = 12.80 - 12.56 (m,1H),8.43 - 8.32 (m,1H),7.49 - 7.38 (m,1H),7.01 - 6.88 (m,1H),6.88 - 6.74 (m,1H),5.31 - 5.17 (m,1H),4.52 - 4.36 (m,2H),3.45 - 3.41 (m,3H),3.13 - 3.04 (m,1H),3.01 - 2.91 (m,1H),2.38 - 2.29 (m,1H),2.17 - 2.09(m,1H).

[0221] Example 3 Method for preparing type A crystals of the compound represented by formula (II): 20 mg of the compound represented by formula (II) and 4 mL of tetrahydrofuran were added to a reactor, and the mixture was stirred at room temperature until it became transparent to dissolve it. Then, 4 mL of ethyl acetate was slowly added dropwise, and the mixture was stirred at room temperature for 24 hours, filtered, and dried to obtain type A crystals of the compound represented by formula (II).

[0222] Example 4 Method for preparing type A crystals of the compound represented by formula (II): 20 mg of the compound represented by formula (II) and 4 mL of tetrahydrofuran were added to a reactor, and the mixture was stirred at room temperature until it became transparent and dissolved. Then, 5 mL of cyclohexane was slowly added dropwise, and the mixture was stirred at room temperature for 24 hours, filtered, and dried to obtain type A crystals of the compound represented by formula (II).

[0223] The XRPD spectrum is shown in FIG. 1, and the results of TGA and DSC are shown in FIG. 2. The TGA result showed that the weight of the sample decreased by 2.1% when heated from 25.1° C. to 250° C., and the DSC curve showed an endothermic peak at 330.46±5° C.

[0224] Example 5 Method for preparing B-type crystals of the compound represented by formula (II): Weigh out 20 mg of maleate A-type crystals and place them in the reactor. Add NMP (10 ml) to dissolve them, then add poor solvent H to the flask. 2 O (4 ml) was added dropwise and magnetically stirred while adding dropwise to precipitate a solid, which was then stirred for 0.5 h and filtered to obtain type B crystals of the compound represented by formula (II).

[0225] The XRPD spectrum is shown in FIG.

[0226] Example 6 Method for producing A-type crystals of the compound represented by formula (II-1): 399.1 mg of the starting sample, the A-type crystal sample of the compound represented by formula (II), and 164.7 mg of maleic acid were weighed into a 20 mL glass vial (the molar ratio of maleic acid to the A-type crystal sample of the compound represented by formula (II) was 1.04:1), and dispersed into a uniform suspension by adding 10 mL of EtOAc with magnetic stirring (~750 rpm). The suspension was stirred at room temperature for 2 days, and then the solid was collected by vacuum filtration and dried under vacuum at room temperature for 20 hours to obtain 490 mg of solid (yield: 88.0%).

[0227] The XRPD spectrum is shown in Figure 4, and the TGA and DSC results are shown in Figure 5. The TGA results showed that the weight of the sample decreased by 2.0% when heated to 150°C, and the DSC curve showed five endothermic signals at 50.7°C, 54.8°C, 59.0°C, 75.9°C and 167.7°C (peak temperature). The molar ratio of acid to base was 1:1.

[0228] Example 7 Method for producing A-type crystals of the compound represented by formula (II-2): Weigh 399.0 mg of the starting sample of type A crystals of compound (II) into a 20 mL glass vial and add 10 mL of ACN / H2O with magnetic stirring (~750 rpm). 2 O (v:v=19:1) was added to disperse the mixture into a uniform suspension, and 120 μL of concentrated hydrochloric acid (specific concentration of concentrated hydrochloric acid: 37%) (the molar ratio of concentrated hydrochloric acid to the A-type crystal sample of the compound represented by formula (II) is 1.05:1) was slowly added, and the mixture was suspended and stirred at room temperature for 6 days, and then the solid was collected by vacuum filtration and dried in vacuum at room temperature for 20 hours to obtain 270 mg of solid.

[0229] The XRPD spectrum is shown in Figure 6, and the TGA / DSC results of the hydrochloride salt crystals of Form A are shown in Figure 7. The TGA results showed that the sample lost 6.7% weight when heated to 100°C, and the DSC curve showed endothermic peaks at 78.1°C, 92.2°C, and 274.0°C (peak temperature). The IC / HPLC test results showed that the molar ratio of acid to base was 1:1.

[0230] Example 8 Method for producing B-type crystals of the compound represented by formula (II-2): 399.0 mg of the starting sample of the A-type crystals of the compound represented by formula (II) was weighed into a 20 mL glass vial, and 10 mL of ethyl acetate was added with magnetic stirring (~750 rpm) to disperse the mixture into a uniform suspension. 120 μL of concentrated hydrochloric acid (the molar ratio of concentrated hydrochloric acid to the A-type crystals of the compound represented by formula (II) was 1.05:1) was slowly added, and the mixture was suspended and stirred at room temperature for 6 days. The solid was then collected by vacuum filtration and dried under vacuum at room temperature for 20 hours to obtain 281 mg of solid.

[0231] The XRPD spectrum is shown in Figure 8, and the TGA / DSC spectrum of the hydrochloride salt B-type crystals is shown in Figure 9. The TGA results showed that the sample lost 2.3% weight when heated to 100°C, and the DSC curve showed two endothermic peaks at 68.3°C and 274.7°C (peak temperatures). The IC / HPLC test results showed that the molar ratio of the acid to the base was 1:1.

[0232] Example 9 Method for producing C-type crystals of the compound represented by formula (II-2): 399.0 mg of the starting sample, the A-type crystal sample of the compound represented by formula (II), was weighed into a 20 mL glass vial, and dispersed into a uniform suspension by adding 10 mL of EtOH with magnetic stirring (~750 rpm). 120 μL of concentrated hydrochloric acid (the molar ratio of concentrated hydrochloric acid to the A-type crystal sample of the compound represented by formula (II) was 1.05:1) was slowly added, and the suspension was stirred at room temperature for 6 days. After that, the solid was collected by vacuum filtration and dried under vacuum at room temperature for 20 hours to obtain 280 mg of solid.

[0233] The XRPD spectrum is shown in Figure 10, and the TGA / DSC results of the hydrochloride salt C-type crystals are shown in Figure 11. The TGA results showed that the sample lost 1.3% weight when heated to 100°C, and the DSC curve showed one endothermic peak at 275.1°C (peak temperature). The IC / HPLC test results showed that the molar ratio of the acid to the base was 1:1.

[0234] Example 10 Method for producing D-type crystals of the compound represented by formula (II-2): 399.0 mg of the starting sample of A-type crystals of compound represented by formula (II) was weighed into a 20 mL glass vial, and dispersed into a uniform suspension by adding 10 mL of tetrahydrofuran with magnetic stirring (~750 rpm). 120 μL of concentrated hydrochloric acid (the molar ratio of concentrated hydrochloric acid to A-type crystals of compound represented by formula (II) was 1.05:1) was slowly added, and the suspension was stirred at room temperature for 6 days. The solid was then collected by vacuum filtration and dried under vacuum at room temperature for 20 hours to obtain 273 mg of solid.

[0235] The XRPD spectrum is shown in Figure 12, and the TGA / DSC results of the hydrochloride salt D-type crystals are shown in Figure 13. The TGA results showed that the sample lost 2.9% weight when heated to 100°C, and the DSC curve showed overlapping endothermic peaks at 273.7°C and 279.3°C (peak temperatures). The IC / HPLC test results showed that the acid to base molar ratio was 1:1.

[0236] Example 11 Method for producing A-type crystals of the compound represented by formula (II-3): Weigh 399.3 mg of the Form A crystal sample of compound (II) into a 20 mL glass vial and add it to 13 mL of ACN / H2O with magnetic stirring (~750 rpm). 2 O (v:v=19:1) was added to disperse the mixture into a uniform suspension, and 350 μL of 4 M sulfuric acid (the molar ratio of sulfuric acid to the A-type crystal sample of the compound represented by formula (II) was 1.03:1) was added dropwise, and the mixture was suspended and stirred at room temperature for 2 days. The solid was then collected by vacuum filtration and dried in vacuum at room temperature for 20 hours to obtain 350 mg of solid.

[0237] The XRPD spectrum is shown in Figure 14, and the TGA / DSC results of the sulfate salt A-type crystals are shown in Figure 15. The TGA results showed that the sample lost 8.1% weight when heated to 150°C, and the DSC curve showed two endothermic peaks at 85.1°C and 126.7°C (peak temperatures). The IC / HPLC test results showed that the acid to base molar ratio was 1:1.

[0238] Example 12 Method for producing B-type crystals of the hydrate of the compound represented by formula (II-3) 399.3 mg of the A-type crystals of compound (II) were weighed into a 20 mL glass vial, and dispersed into a uniform suspension by adding 13 mL of acetone with magnetic stirring (~750 rpm). 350 μL of 4 M sulfuric acid (the molar ratio of sulfuric acid to the A-type crystals of compound (II) was 1.03:1) was added dropwise, and the mixture was suspended and stirred at room temperature for 2 days. The solid was then collected by vacuum filtration and dried in vacuum at room temperature for 20 hours to obtain 350 mg of solid (yield 65.7%).

[0239] The XRPD spectrum is shown in Figure 16, and the TGA / DSC results of the sulfate salt B-type crystals are shown in Figure 17. The TGA results showed that the sample lost 6.67% weight when heated to 150°C, and the DSC curve showed two endothermic peaks at 98.0°C and 140.2°C (peak temperatures). According to the 6.67% TGA weight loss, it was preliminarily determined that the sample contained 1.5 crystal water. The IC / HPLC test results showed that the molar ratio of acid to base was 1:1.

[0240] Example 13 Method for producing C-type crystals of the compound represented by formula (II-3) 399.3 mg of the A-type crystal sample of compound represented by formula (II) was weighed into a 20 mL glass vial, and dispersed into a uniform suspension by adding 13 mL of ethyl acetate with magnetic stirring (~750 rpm). 350 μL of 4 M sulfuric acid (the molar ratio of sulfuric acid to the A-type crystal sample of compound represented by formula (II) was 1.03:1) was added dropwise, and the suspension was stirred at room temperature for 2 days. The solid was then collected by vacuum filtration and dried under vacuum at room temperature for 20 hours to obtain 351 mg of solid.

[0241] The XRPD spectrum is shown in Figure 18, and the TGA / DSC results of the sulfate salt C-type crystals are shown in Figure 19. The TGA results showed that the sample lost 6.8% weight when heated to 150°C, and the DSC curve showed two endothermic peaks at 69.3°C and 118.1°C (peak temperatures). The IC / HPLC test results showed that the acid-base molar ratio was 1:1.

[0242] Example 14 Method for producing D-type crystals of the compound represented by formula (II-3) 399.3 mg of the A-type crystal sample of the compound represented by formula (II) was weighed into a 20 mL glass vial, and dispersed into a uniform suspension by adding 13 mL of ethanol with magnetic stirring (~750 rpm). 350 μL of 4 M sulfuric acid (the molar ratio of sulfuric acid to the A-type crystal sample of the compound represented by formula (II) was 1.03:1) was added dropwise, and the suspension was stirred at room temperature for 2 days. The solid was then collected by vacuum filtration and dried in vacuum at room temperature for 20 hours to obtain 350 mg of solid.

[0243] The XRPD spectrum is shown in Figure 20, and the TGA / DSC results of the D-type crystals of the sulfate salt are shown in Figure 21. The TGA results showed that the weight of the sample was reduced by 8.1% when heated to 150°C, and the DSC curve showed two endothermic peaks at 78.5°C and 144.3°C (peak temperatures). The IC / HPLC test results showed that the molar ratio of the acid to the base was 1:1.

[0244] Example 15 Dynamic solubility evaluation The kinetic solubilities of the sulfate type B crystals, the maleate type A crystals, and the hydrochloride type C crystals in water and three biological solvents were evaluated.

[0245] The solids were mixed at 37°C by spinning at a solid dosage concentration of 10 mg / mL (calculated in the free state, 40 mg of solids were added to 4 mL of solvent) and the solubility of each sample was measured in four reaction systems: water, SGF, FaSSIF and FeSSIF at different time points (1, 2, 4 and 24 hours).

[0246] [Table 16]

[0247] Example 16 Hygroscopicity Evaluation The hygroscopicity of the sulfate salt type B crystals, the maleate salt type A crystals, and the hydrochloride salt type C crystals was evaluated by DVS. The water adsorption rates (second adsorption curve) of the three salts at 25°C / 80% RH were 7.62%, 1.35%, and 4.77%, respectively.

[0248] Example 17 Solid State Stability The sulfate salt type B crystals, the maleate salt type A crystals, and the hydrochloride salt type C crystals were left at 25°C / 60% RH and 40°C / 75% RH conditions for one week, respectively, and then the chemical stability of the samples was detected by HPLC. For the maleate salt, stability data was collected after storage at 25°C / 60% RH and 40°C / 75% RH (open) for one month and two months, and further, stability data was collected after storage at 60°C (closed) for 24 hours using the maleate salt type A crystals as the starting sample. The purity data are shown in Table-18. The results showed that none of the three salt forms were significantly decomposed under the corresponding conditions, and none of the crystals were changed.

[0249] [Table 17]

[0250] Example 18 Biological activity measurement Experimental Example 18-1: In vitro activity measurement of Jak1, Jak2, Jak3, and Tyk2 kinases Experimental materials The recombinant human JAK1, JAK2, JAK3, and Tyk2 proteases are used, and all major equipment and reagents are provided by Eurofins, UK.

[0251] Experimental Method

[0252] Dilution of JAK2, JAK3 and TYK2: 20 mM 3-(N-morpholino)propanesulfonic acid (MOPS), 1 mM EDTA, 0.01% Brij~35.5% glycerin, 0.1% β-mercaptoethanol, 1 mg / mL BSA; Dilution of JAK1: 20 mM TRIS, 0.2 mM EDTA, 0.1% β-mercaptoethanol, 0.01% Brij~35.5% glycerin. All compounds were prepared in 100% DMSO solution, 50 times the final measurement concentration. The measurement compounds were gradient diluted to 3-fold concentration, with a total of 9 concentrations with final concentrations ranging from 10 μM to 0.001 μM, and the content of DMSO in the detection reaction was 2%. The working stock solution of the compound was added to the measurement well as the first component of the reaction, and then other components were added according to the detailed measurement form below.

[0253] JAK1(h) enzyme reaction JAK1(h) was incubated in 20 mM Tris / HCl pH 7.5, 0.2 mM EDTA, 500 μM MGEEPLYWSFPAKKK, 10 mM magnesium acetate and [γ- 33 The reaction was incubated with [P]-ATP (activity and concentration to be determined as required). The reaction was initiated by the addition of Mg / ATP mixture and incubated at room temperature for 40 min before being terminated by the addition of 0.5% phosphoric acid. 10 μL of the reaction was then dropped onto a P30 filter pad, washed three times with 0.425% phosphoric acid and once with methanol within 4 min, dried, and counted by scintillation.

[0254] JAK2(h) enzyme reaction JAK2(h) was incubated in 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μM KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10 mM magnesium acetate and [γ- 33The reaction was incubated with [P]-ATP (activity and concentration to be determined as required). The reaction was initiated by the addition of Mg / ATP mixture and incubated at room temperature for 40 min before being terminated by the addition of 0.5% phosphoric acid. 10 μL of the reaction was then dropped onto a P30 filter pad, washed three times with 0.425% phosphoric acid and once with methanol within 4 min, dried, and counted by scintillation.

[0255] JAK3(h) enzyme reaction JAK3(h) was incubated in 8 mM MOPS pH 7.0, 0.2 mM EDTA, 500 μM GGEEEEYFELVKKKK, 10 mM magnesium acetate and [γ- 33 The reaction was incubated with [P]-ATP (activity and concentration to be determined as required). The reaction was initiated by the addition of Mg / ATP mixture and incubated at room temperature for 40 min before being terminated by the addition of 0.5% phosphoric acid. 10 μL of the reaction was then dropped onto a P30 filter pad, washed three times with 0.425% phosphoric acid and once with methanol within 4 min, dried, and counted by scintillation.

[0256] TYK2(h) enzyme reaction TYK2(h) was incubated in 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM GGMEDIYFEFMGGKKK, 10 mM magnesium acetate and [γ- 33 The reaction was incubated with [P]-ATP (activity and concentration to be determined as required). The reaction was initiated by the addition of Mg / ATP mixture and incubated at room temperature for 40 min before being terminated by the addition of 0.5% phosphoric acid. 10 μL of the reaction was then dropped onto a P30 filter pad, washed three times with 0.425% phosphoric acid and once with methanol within 4 min, dried, and counted by scintillation.

[0257] Data analysis I C 50 The results were analyzed using IDBS's XLFIT5 (205 formula), and are specifically shown in Table 19.

[0258] [Table 18]

[0259] Conclusion: The compounds of the present invention show good selectivity for inhibition of JAK1 and / or JAK2 in in vitro activity assays of the four subtypes of kinases JAK1, JAK2, JAK3 and TYK2.

[0260] Experimental Example 18-2: Permeability test Experimental materials The transport buffer was HBSS (Hank's balanced salt solution) and 10 mM HEPES [N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) solution], with a pH value of 7.40 ± 0.05; Caco-2 cells were purchased from ATCC.

[0261] Experimental Method 1 × 10 Caco-2 cells 5 cells / cm 2 The cells were seeded into polyethylene membrane (PET) 96-well BD insert plates at 10 °C and the medium was renewed once every 4-5 days from day 21 to day 28 to form a confluent cell monolayer. Test compounds were tested bidirectionally at 2 μM in two wells. Digoxin was added in both directions at 10 μM, and nadolol and metoprolol were added in both directions at 2 μM. The final DMSO concentration was adjusted to less than 1%. The culture plates were incubated at 37 ± 1 °C in CO 2 Incubate the plates for 2 h in an incubator with 5% CO at saturated humidity. 2 The samples were incubated at 4000 rpm for 10 min without shaking. All samples were mixed with acetonitrile containing internal standard, then centrifuged at 4000 rpm for 10 min, and 100 μL of the supernatant was diluted with 100 μL of distilled water for LC / MS / MS analysis. The LC / MS / MS method was used to determine the concentrations of the test and control in the initial solution, test solution and test solution of the test article by the peak area ratio of analyte / internal standard. After the transport test, the monolayer integrity of Caco-2 cells was measured by fluorescein yellow exclusion reaction test, and the apparent permeability coefficient and efflux rate were calculated. The experimental results are shown in Table 20.

[0262] [Table 19]

[0263] Conclusion: The compounds of the present invention have characteristic high permeability, which is favorable for achieving good target tissue concentrations and oral bioavailability. Note: ND: not detected.

[0264] Experimental Example 18-3: Pharmacokinetic (PK) study The clear solution obtained after dissolving the test compound was administered to male mice (C57BL / 6) or rats (SD) (fasted overnight, 7-8 weeks old) by tail vein injection and intragastric administration, respectively. After administration of the test compound, blood was collected from the submandibular vein at 0.117, 0.333, 1, 2, 4, 7, and 24 hours for the intravenous injection group (1 mg / kg) and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours for the intragastric administration group (3 mg / kg), respectively, and plasma was obtained after centrifugation. Plasma drug concentrations were measured by LC-MS / MS and analyzed by WinNonlin. TM The relevant pharmacokinetic parameters were calculated using the non-compartment linear-logarithmic trapezoidal method using Version 6.3 pharmacokinetic software. The results are as follows:

[0265] [Table 20]

[0266] Conclusion: The compounds of the present invention have good oral bioavailability and high exposure in mice, which is favorable for the occurrence of good in vivo efficacy.

[0267] Experimental Example 18-4: Study of the in vivo efficacy of adjuvant-induced arthritis (AIA) in rats Testing Procedure: The arthritis treatment effect of the compound of the present invention was verified using a rat adjuvant arthritis model. Female Lewis rats weighing 160-180g were anesthetized with isoflurane, and then 0.1ml of Mycobacterium tuberculosis suspension was subcutaneously injected into the left hind paw. After 13 days of modeling, the rats were divided into groups and administered with the corresponding test compounds, for example, different doses were administered to the rats (specific doses are shown in Table 4-2, and test compounds 1-13 were dissolved in a mixed solvent of [5% DMSO, 95% (12% SBE-β-CD), 0.5% MC)] and orally administered twice a day to female Lewis rats (the number of test animals in each dose group was 8). The rats were continuously administered for 2 weeks, during which the condition of the rats was observed, and the swelling of the paw volume was recorded and scored, and the scoring criteria are shown in Table 22.

[0268] [Table 21]

[0269] Test Results: The two dose treatment groups of compound 1-13 had a significant alleviating effect on the weight loss tendency of animals due to the onset of the disease, and the low and medium dose groups (3 mg / kg and 10 mg / kg) showed a significant difference from the solvent control group from the 20th day, showing a good weight recovery effect. Compound 1-13 suppressed the increase in arthritis clinical score and paw volume, and this inhibitory effect was dose-dependent. The effect of compound 1-13 10 mg / kg was the most significant (significant difference from the 15th day compared to the solvent control group). The average arthritis clinical score of this group decreased from a peak value of 6 points on the 13th day to 1.4 points on the 27th day, which was the end point of the experiment, and showed a significant difference compared to the solvent control group.

[0270] [Table 22]

[0271] Conclusion: The compound represented by formula (II) obtained in Example 2 of the present invention showed significant therapeutic effects at the dosages (3 mg / kg and 10 mg / kg) (the inhibition rate was P<0.0001 compared with the solvent control group), and the compound represented by formula (II) obtained in Example 2 of the present invention showed good dose-effect positive correlation (3 mg / kg and 10 mg / kg).

[0272] Comparative Example 1 The present invention also carried out salt formation screening for L-aspartic acid, fumaric acid, L-tartaric acid, and citric acid. Using the A-type crystals of compound represented by formula (II) as raw material, L-aspartic acid, fumaric acid, L-tartaric acid, and citric acid were selected based on the basic pKa (4.47) of the compound and the crude solubility of the starting sample in different solvents at room temperature, and the specific steps of the screening test of the acidic ligand (free state / acidic ligand molar dosage ratio is 1:1) and the five solvent reaction systems in Table 24 are as follows: about 20 mg of the starting A-type crystals of compound represented by formula (II) and an equimolar amount of the above acid were weighed into an HPLC vial, and 0.5 mL of the following solvent mixture was added to obtain a suspension. The suspension was stirred at room temperature for 3 days, centrifuged to separate the solid, and vacuum dried at room temperature for about 4 hours, and the results are shown in Table 24.

[0273] [Table 23]

[0274] As is clear from Table 24, when the acid was L-aspartic acid, fumaric acid, or L-tartaric acid, a salt could not be formed with the compound represented by formula (II) even when any one of the above five solvents was used. When the acid was citric acid, a salt could be formed only when the solvent was ethanol, and none of the other four solvents could form a salt.

[0275] Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative and may make various changes and modifications to these embodiments without departing from the principles and substance of the present invention. Therefore, the scope of protection of the present invention is limited by the appended claims.

Claims

1. A salt of a compound represented by formula (II), the acid in said salt is selected from maleic acid, hydrochloric acid and sulfuric acid; A salt of a compound represented by formula (II), wherein the molar ratio of the acid to the compound represented by formula (II) in the salt is (0.25-1.5):

1. 【Chemistry 1】

2. The salt of the compound represented by formula (II) according to claim 1, wherein the salt of the compound represented by formula (II) is selected from a salt of any one of a maleate represented by formula (II-1) below, a hydrochloride represented by formula (II-2) below, and a sulfate represented by formula (II-3) below. 【Chemistry 2】

3. A crystal of a compound represented by formula (II) or a crystal of a salt of a compound represented by formula (II), 【Chemistry 3】 The salt of the compound represented by formula (II) is selected from a salt of any one of a maleate represented by formula (II-1) below, a hydrochloride represented by formula (II-2) below, and a sulfate represented by formula (II-3) below: 【Chemistry 4】 The crystal of the compound represented by formula (II) is an A-type crystal, and its powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 12.69°, 13.84°, 15.37°, 15.90°, 16.62°, 19.07°, 27.66°, and 25.62°, or The crystal of the compound represented by formula (II) is a B-type crystal, and its powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 12.40°, 13.31°, 15.75°, 22.16°, 23.72°, 25.49°, 26.12°, and 26.87°, and the maleate salt represented by the formula (II-1) is an A-type crystal of the maleate salt, and its powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 12.24°, 13.14°, 13.73°, 14.56°, 15.52°, 17.54°, 19.54°, 23.19°, 26.55° and 26.91°, and the hydrochloride represented by the formula (II-2) is an A-type crystal of the hydrochloride, and its powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 7.20°, 7.85°, 8.63°, 10.82°, 21.25°, 21.78°, 24.12°, 25.56°, 26.11°, and 27.03°, or The hydrochloride represented by the formula (II-2) is a B-type crystal of the hydrochloride, and its powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 5.95°, 11.92°, 12.53°, 13.14°, 20.94°, 24.96°, 25.67°, 30.09° and 31.69°, or The hydrochloride represented by the formula (II-2) is a C-type crystal of the hydrochloride, and its powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 5.89°, 11.77°, 13.21°, 13.52°, 15.75°, 23.51°, 25.51°, 24.65°, 26.31°, and 27.15°, or The hydrochloride represented by the formula (II-2) is a D-type crystal of the hydrochloride, and its powder X-ray diffraction spectrum represented by 2θ angles is 3.08°, 6.07°, 9.05°, 12.06°, 1 having diffraction peaks at 2.73°, 13.23°, 13.78°, 15.08°, 21.28°, 24.94°, 26.06° and 31.72°; and the sulfate represented by the formula (II-3) is an A-type crystal of the sulfate, and its powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 4.16°, 4.46°, 7.56°, 8.02°, 12.65°, 13.36°, 15.75°, 17.91°, 20.43°, 24.54°, 24.94°, 25.90°, and 26.99°, or The sulfate represented by the formula (II-3) is a C-type crystal of sulfate, and its powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 6.09°, 12.17°, 13.25°, 15.60°, 16.09°, 17.45°, 18.66°, 22.61°, 23.62°, 24.44°, 25.04°, 25.89°, 26.30°, and 26.62°, or The sulfate represented by the formula (II-3) is a D-type crystal of sulfate, and its powder X-ray diffraction spectrum represented by 2θ angles has diffraction peaks at 4.61°, 6.11°, 8.00°, 9.10°, 10.91°, 13.73°, 18.86°, 23.27°, 25.28°, and 25.97°. A crystal of the compound represented by formula (II) or a crystal of a salt of the compound represented by formula (II).

4. When the crystal of the compound represented by formula (II) is an A-type crystal, the 2θ values ​​in the powder X-ray diffraction spectrum represented by the 2θ angles are as shown in the following table: 【Table 1】 and / or, the A-type crystal of the compound represented by formula (II) has an absorption peak at a peak temperature of 300.4°C in its differential scanning calorimetry curve (DSC), and / or, the A-type crystal of the compound represented by formula (II) has a thermogravimetric analysis curve showing a weight loss of 2.1% in the temperature range of 25.1°C to 250°C, And / or, when the crystal of the compound represented by formula (II) is a B-type crystal, the 2θ values ​​in the powder X-ray diffraction spectrum represented by the 2θ angles are as shown in the following table: 【Table 2】 And / or, when the maleate represented by the formula (II-1) is an A-type crystal of the maleate, the 2θ values ​​in the powder X-ray diffraction spectrum represented by the 2θ angles are as shown in the following table: 【Table 3】 and / or, the A-type crystal of the maleate salt represented by the formula (II-1) has an absorption peak at a peak temperature of 173.3°C in its differential scanning calorimetry curve, and / or, the A-type crystal of the maleate salt represented by the formula (II-1) has a weight loss of 1.86% in the temperature range of 29.1°C to 150°C in its thermogravimetric analysis curve, And / or, when the hydrochloride represented by the formula (II-2) is an A-type crystal of the hydrochloride represented by the formula (II-2), the A-type crystal of the hydrochloride represented by the formula (II-2) has a 2θ value in a powder X-ray diffraction spectrum represented by 2θ angles as shown in the following table: 【Table 4】 and / or, the A-type crystals of the hydrochloride represented by formula (II-2) have three absorption peaks in their differential scanning calorimetry curve, the peak temperatures of which are 78.1°C, 92.2°C and 274°C, respectively, and / or, the A-type crystals of the hydrochloride represented by formula (II-2) have a thermogravimetric analysis curve showing a weight loss of 6.71% in the temperature range of 27.2°C to 100°C, And / or, when the hydrochloride represented by the formula (II-2) is a B-type crystal of the hydrochloride, the 2θ values ​​in the powder X-ray diffraction spectrum represented by the 2θ angles are as shown in the following table: 【Table 5】 and / or, the B-type crystals of the hydrochloride represented by formula (II-2) have an absorption peak at a peak temperature of 274.7°C in their differential scanning calorimetry curve, and / or, the B-type crystals of the hydrochloride represented by formula (II-2) have a weight loss of 2.34% in the temperature range of 31.4°C to 100°C in their thermogravimetric analysis curve, And / or, when the hydrochloride represented by the formula (II-2) is a C-type crystal of the hydrochloride represented by the formula (II-2), the C-type crystal of the hydrochloride represented by the formula (II-2) has a 2θ value in a powder X-ray diffraction spectrum represented by 2θ angles as shown in the following table: 【Table 6】 and / or, the C-type crystals of the hydrochloride represented by formula (II-2) have an absorption peak at a peak temperature of 275.1°C in their differential scanning calorimetry curve, and / or, the C-type crystals of the hydrochloride represented by formula (II-2) have a thermogravimetric analysis curve showing a weight loss of 1.32% in the temperature range of 33.7°C to 100°C; And / or, when the hydrochloride represented by the formula (II-2) is a D-type crystal of the hydrochloride, the 2θ values ​​in the powder X-ray diffraction spectrum represented by the 2θ angles are as shown in the following table: 【Table 7】 and / or, the D-type crystals of the hydrochloride represented by formula (II-2) have two absorption peaks at peak temperatures of 273.7°C and 279.3°C in their differential scanning calorimetry curve, and / or, the D-type crystals of the hydrochloride represented by formula (II-2) have a thermogravimetric analysis curve in which the weight is reduced by 2.92% in the temperature range of 28.3°C to 100°C; And / or, when the sulfate represented by the formula (II-3) is an A-type crystal of the sulfate, the 2θ values ​​in the powder X-ray diffraction spectrum represented by the 2θ angles are as shown in the following table: 【Table 8】 and / or, the A-type crystals of the sulfate represented by the formula (II-3) have two absorption peaks in their differential scanning calorimetry curve, the peak temperatures of which are 85.1°C and 126.7°C, respectively, and / or, the A-type crystals of the sulfate represented by the formula (II-3) have a thermogravimetric analysis curve in which the weight is reduced by 8.14% in the temperature range of 28.4°C to 150°C, And / or, when the crystalline salt of the sulfate represented by the formula (II-3) is a C-type crystal of the sulfate, the 2θ values ​​in the powder X-ray diffraction spectrum represented by the 2θ angles are as shown in the following table: 【Table 9】 and / or, the C-type crystals of the sulfate represented by the formula (II-3) have two absorption peaks at peak temperatures of 69.3°C and 118.1°C in their differential scanning calorimetric curve, and / or, the C-type crystals of the sulfate represented by the formula (II-3) have a thermogravimetric analysis curve in which the weight is reduced by 6.82% in the temperature range of 28.2°C to 150°C; And / or, when the sulfate represented by the formula (II-3) is a D-type crystal of the sulfate, the 2θ values ​​in the powder X-ray diffraction spectrum represented by the 2θ angles are as shown in the following table: 【Table 10】 And / or, the D-type crystal of the sulfate represented by the formula (II-3) has two absorption peaks at peak temperatures of 78.5°C and 144.3°C in its differential scanning calorimetry curve, and / or, the D-type crystal of the sulfate represented by the formula (II-3) has a thermogravimetric analysis curve in which the weight is reduced by 8.13% in the temperature range of 23.3°C to 150°C. The crystal according to claim 3.

5. A method for producing the salt according to claim 1 or 2, comprising the steps of: A method for producing a compound represented by formula (II) according to claim 1 and an acid according to claim 1 in a solvent, the method comprising the step of carrying out a salt-forming reaction.

6. When the compound represented by formula (II) is an A-type crystal, the method for producing the A-type crystal of the compound represented by formula (II) comprises the steps of adding a poor solvent to a tetrahydrofuran solution of the compound represented by formula (II) at room temperature to precipitate crystals to obtain A-type crystals, wherein the poor solvent is an ester solvent or an alkane solvent; and / or, when the compound represented by formula (II) is a B-type crystal, the method for producing the B-type crystal of the compound represented by formula (II) comprises the steps of dissolving the A-type crystal of the compound represented by formula (II-1) in NMP at room temperature, adding water, and precipitating the crystal to obtain the B-type crystal; and / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a type A crystal of the hydrochloride, the method for producing the same includes the steps of adding hydrochloric acid to a solution of the compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain a type A crystal, wherein the solvent of the solution is an aqueous acetonitrile solution; 【Chemistry 5】 And / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a B-type crystal of the hydrochloride, the production method thereof includes the steps of adding hydrochloric acid to an ethyl acetate solution of the compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain a B-type crystal: 【Chemistry 6】 And / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a C-type crystal of the hydrochloride, the production method thereof includes the steps of adding hydrochloric acid to an ethanol solution of the compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain a C-type crystal: 【Chemistry 7】 And / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a D-type crystal of the hydrochloride, the production method thereof includes the steps of adding hydrochloric acid to a tetrahydrofuran solution of the compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain a D-type crystal: 【Chemistry 8】 and / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the sulfate represented by formula (II-3) is an A-type crystal of the sulfate, the method for producing the sulfate comprises adding sulfuric acid to a solution of the compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain an A-type crystal, wherein the solvent of the solution is an aqueous acetonitrile solution; 【Chemistry 9】 And / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the sulfate represented by formula (II-3) is a C-type crystal of the sulfate, the production method thereof includes the steps of adding sulfuric acid to an ethyl acetate solution of the compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain a C-type crystal: 【Chemistry 10】 And / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the sulfate represented by formula (II-3) is a D-type crystal of a sulfate, the production method thereof includes the steps of adding sulfuric acid to an ethanol solution of the compound represented by formula (II) to carry out a reaction represented by the following formula, and collecting the solid to obtain a D-type crystal: 【Chemistry 11】 A method for producing the crystal according to claim 3 or 4.

7. When the compound represented by formula (II) is an A-type crystal, the volume ratio of the tetrahydrofuran to the poor solvent is 1:(0.1 to 10); and / or, when the compound represented by formula (II) is an A-type crystal, the mass / volume ratio of the compound represented by formula (II) to the tetrahydrofuran is 2 to 6 mg / mL; and / or, when the compound represented by formula (II) is an A-type crystal, the mass / volume ratio of the compound represented by formula (II) to the poor solvent is 2 to 6 mg / mL; and / or, when the compound represented by formula (II) is a B-type crystal, the mass / volume ratio of the A-type crystal of the compound represented by formula (II-1) to the NMP is 1 to 5 mg / mL; and / or, when the compound represented by formula (II) is a B-type crystal, the volume ratio of the NMP to the water is 1:(0.1 to 10); and / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a type A crystal of the hydrochloride, the molar ratio of the hydrochloric acid to the compound represented by formula (II) is 1.05:1 in the method for preparing the type A crystal of the hydrochloride, and / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a hydrochloride A-type crystal, the mass / volume ratio of the compound represented by formula (II) to the acetonitrile aqueous solution is 40 mg / mL; and / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is an A-type crystal of the hydrochloride, the volume ratio of acetonitrile to water in the acetonitrile aqueous solution is 19:1; and / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a B-type crystal of the hydrochloride, the molar ratio of the hydrochloric acid to the compound represented by formula (II) is 1.05:1 in the method for preparing the B-type crystal of the hydrochloride, and / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a B-type crystal of the hydrochloride, the mass / volume ratio of the compound represented by formula (II) to the ethyl acetate is 40 mg / mL; and / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a C-type crystal of the hydrochloride, the molar ratio of the hydrochloric acid to the compound represented by formula (II) is 1.05:1 in the method for preparing the C-type crystal of the hydrochloride, and / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a C-type crystal of the hydrochloride, the mass / volume ratio of the compound represented by formula (II) to the ethanol is 40 mg / mL; and / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a D-type crystal of the hydrochloride, the molar ratio of the hydrochloric acid to the compound represented by formula (II) is 1.05:1 in the method for preparing the D-type crystal of the hydrochloride, and / or, when the salt of the compound represented by formula (II) is a hydrochloride represented by formula (II-2), and the hydrochloride represented by formula (II-2) is a D-type crystal of the hydrochloride, the mass / volume ratio of the compound represented by formula (II) to the tetrahydrofuran is 40 mg / mL; and / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the sulfate represented by formula (II-3) is an A-type crystal of a sulfate, the molar ratio of the sulfuric acid to the compound represented by formula (II) is 1.03:1 in the method for preparing the A-type crystal of the sulfate, and / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the sulfate represented by formula (II-3) is an A-type crystal of a sulfate, the mass / volume ratio of the compound represented by formula (II) to the acetonitrile aqueous solution is 30 mg / mL; and / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the sulfate represented by formula (II-3) is an A-type crystal of a sulfate, the volume ratio of acetonitrile to water in the acetonitrile aqueous solution is 19:1; and / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the sulfate represented by formula (II-3) is an A-type crystal of a sulfate, the molar concentration of the sulfuric acid is 4 mol / L; and / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the crystalline salt of the sulfate represented by formula (II-3) is a C-type crystal of the sulfate, the molar ratio of the sulfuric acid to the compound represented by formula (II) is 1.03:1 in the method for preparing the C-type crystal of the sulfate, and / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the crystalline salt of the sulfate represented by formula (II-3) is a C-type crystal of the sulfate, the mass / volume ratio of the compound represented by formula (II) to the ethyl acetate is 30 mg / mL; and / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the crystalline salt of the sulfate represented by formula (II-3) is a C-type crystal of the sulfate, the molar concentration of the sulfuric acid is 4 mol / L; and / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the sulfate represented by formula (II-3) is a D-type crystal of a sulfate, the molar ratio of the sulfuric acid to the compound represented by formula (II) is 1.03:1 in the method for preparing the D-type crystal of the sulfate, and / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the sulfate represented by formula (II-3) is a D-type crystal of a sulfate, the mass / volume ratio of the compound represented by formula (II) to the ethanol is 30 mg / mL; And / or, when the salt of the compound represented by formula (II) is a sulfate represented by formula (II-3), and the sulfate represented by formula (II-3) is a D-type crystal of a sulfate, the molar concentration of the sulfuric acid is 4 mol / L. The production method according to claim 6.

8. 10. Use of a salt according to claim 1 or 2, or a crystal according to claim 3 or 4, in the manufacture of a medicament for treating a disease associated with JAK1 and / or JAK2.

9. The use according to claim 8, characterized in that in said use, the disease associated with JAK1 and / or JAK2 is rheumatoid arthritis.

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