Crystals of pyrazolyl-amino-pyrimidinyl derivatives, manufacturing method, and use

Abstract

This invention provides crystals of pyrazolyl-aminopyrimidinyl derivatives, methods for their production, and uses. It provides type I crystals of compound (1), and discloses methods for producing them and their uses. These crystals satisfy one or more effective advantages, including good physical and chemical properties, solid stability, good solubility, low hygroscopicity, and good processability for formulation processes. [Case 1] JPEG2026516185000035.jpg6562

Description

Technical Field

[0001] This application claims the priority of Chinese Patent Application PCT / CN2023 / 095378 with an application date of May 19, 2023. This application incorporates the entire text of the above-mentioned Chinese patent application by reference.

[0002] The present invention relates to crystals of pyrazolyl-amino-pyrimidinyl derivatives, methods for their production, and their uses.

Background Art

[0003] The JAK-STAT pathway mediates intracellular signal transduction of various cytokines in vivo. Previous studies have shown that there is an increase in the levels of multiple inflammatory cytokines in the skin lesions of AD patients. For example, Th1 (γ-interferon), Th2 (IL-4, IL-13, IL-31), and Th22 (IL-22) cytokines are involved, suggesting that the onset of AD is closely related to the JAK-STAT pathway. IL-4 and IL-13 can activate JAK1 / 3 and promote the phosphorylation of STAT3 / 6 after binding to IL-4 receptor α and γ, and IL-13 receptor α1. STAT3 destroys the integrity of the skin barrier by downregulating KC differentiation-related proteins, and STAT6 upregulates chemokines involved in the onset of AD. Th0 cells differentiate into Th2 cells via the JAK1 / 3-STAT6 pathway, causing the onset of AD. Eosinophils are one of the most important effector cells in AD. IL-5, together with its receptor β-chain complex, is involved in the process of controlling the proliferation, survival, and effectiveness of eosinophils via the JAK2-STAT1 / 5 pathway. Activated eosinophils are attracted to the skin by chemokines involved in the onset of AD released from epidermal cells in a high Th2 immune environment, further exacerbating the AD condition.

[0004] The most advanced JAK inhibitors currently under development are Japan Tobacco's delgocitinib (already on the market), Incyte's ruxolitinib (already on the market), and Pfizer's tofacitinib (Phase II). Results show that delgocitinib significantly improved patients' clinical scores in a Phase III clinical trial for the treatment of Alzheimer's disease (AD). Phase II and Phase III trials of ruxolitinib for AD showed that the drug exhibited rapid antipruritic and anti-inflammatory effects and was well-tolerated. In a Phase II trial of tofacitinib, EASI scores significantly improved after 4 weeks of administration of a 2% ointment to AD patients, and the drug demonstrated good local tolerability and safety. Furthermore, in China, research-based JAK inhibitors used for the treatment of Alzheimer's disease (AD) include Jaktinib hydrochloride cream from Suzhou Zelgen Biopharmaceuticals Co., Ltd. and SHR0302 alkaline ointment from Jiangsu Hengrui Pharmaceuticals Co., Ltd., both currently in Phase I / II and Phase II / III trials, respectively. However, current topical treatments for AD still fail to meet clinical needs, and the continued development of safer and more effective JAK inhibitors has great significance and market potential, as it can address the shortcomings of existing treatments and improve the therapeutic efficacy and quality of life for patients with atopic dermatitis.

[0005] Preclinical studies have revealed that LNK01004 (structure shown below) is a potent pan-Janus kinase (JAK) inhibitor that inhibits JAK1, JAK2, and TYK2, and can simultaneously inhibit multiple cytokine-induced p-STAT signaling pathways both in vitro and in vivo. In vitro and in vivo test results show that LNK01004 not only inhibits cytokine-induced p-STAT signaling pathways in immune cells, but also effectively inhibits psoriasis or atopic dermatitis-related cytokine-induced p-STAT signaling pathways in skin tissue when applied topically. Unlike ruxolitinib and tofacitinib, LNK01004 can further inhibit keratinocyte proliferation. [ka] [Overview of the project]

[0006] The present invention provides crystals of pyrazolyl-aminopyrimidinyl derivatives, methods for producing them, and uses thereof, wherein the crystals satisfy one or more effective advantages such as good physical and chemical properties, solid stability, good solubility, low hygroscopicity, and good processability for formulation processes.

[0007] This invention provides a type I crystal of compound 1. [ka]

[0008] The aforementioned Type I crystal, when subjected to Cu-Kα radiation, exhibits a powder X-ray diffraction pattern represented by 2θ, with diffraction peaks at the following positions: 8.60°±0.2°, 10.25°±0.2°, 11.96°±0.2°, 14.35°±0.2°, 15.39°±0.2°, 16.59°±0.2°, 17.06°±0.2°, and 18.16°±0.2°.

[0009] In one embodiment, the powder X-ray diffraction pattern represented by the 2θ angle of the type I crystal is further divided into one or more positions: 12.77°±0.2°, 13.48°±0.2°, 14.04°±0.2°, 17.27°±0.2°, 18.83°±0.2°, 20.52°±0.2°, 20.77°±0.2°, 21.45°±0.2°, 22. Diffraction peaks are observed at 12°±0.2°, 22.79°±0.2°, 23.55°±0.2°, 24.04°±0.2°, 24.40°±0.2°, 25.08°±0.2°, 25.87°±0.2°, 26.51°±0.2°, 26.73°±0.2°, 26.89°±0.2°, 27.36°±0.2°, and 28.29°±0.2°.

[0010] In one embodiment, the powder X-ray diffraction pattern of the type I crystal, represented by a 2θ angle, further has diffraction peaks at one or more of the following positions: 28.93°±0.2°, 29.42°±0.2°, 30.63°±0.2°, 33.00°±0.2°, 33.37°±0.2°, 34.43°±0.2°, and 37.09°±0.2°.

[0011] In one embodiment, the powder X-ray diffraction pattern of the type I crystal, represented by a 2θ angle, has the target diffraction peaks shown in the table below. [Table 1-1] [Table 1-2]

[0012] In one embodiment, the powder X-ray diffraction pattern represented by the 2θ angle of the type I crystal is basically as shown in Figure 1.

[0013] In one embodiment, the differential scanning calorimetry spectrum of the type I crystal has a single endothermic peak between 207.4°C and 209.2°C.

[0014] In one embodiment, the differential scanning calorimetry spectrum of the type I crystal has one endothermic peak between 207.4°C and 209.2°C, and the heat of fusion is 123.76 J / g.

[0015] In one embodiment, the differential scanning calorimetry spectrum of the type I crystal is basically as shown in Figure 2.

[0016] In one embodiment, the thermogravimetric analysis spectrum of the type I crystal ranges from 30.07°C to 208.96°C, with a weight loss of 0.0%, indicating that the type I crystal is an anhydrous compound.

[0017] In one embodiment, the thermogravimetric analysis spectrum of the type I crystal is basically as shown in FIG. 3.

[0018] The present invention further provides a method for producing the above type I crystal which is Scheme 1 or Scheme 2.

[0019] Scheme 1 includes the step of crystallizing a methanol solution of Compound 1 to obtain the type I crystal.

Chemical formula

[0020] Scheme 2 includes the step of cooling a solution of Compound 1 in tetrahydrofuran / methanol and isopropanol to obtain the type I crystal.

[0021] In one embodiment, in Scheme 1, in the crystallization, the mass of the solution is (1:6) to (1:8.5) of the mass of Compound 1, preferably (1:6.3) to (1:8.3).

[0022] In one embodiment, Scheme 1 preferably includes the step of adding methanol to a solution of Compound 1 and tetrahydrofuran at 40°C, concentrating, adding more methanol to the concentrated solution, stirring, and crystallizing to obtain the type I crystal.

[0023] Here, the temperature of the solution formed by dissolving Compound 1 in tetrahydrofuran is preferably 50 to 60°C.

[0024] The mass ratio of Compound 1 to tetrahydrofuran is preferably (1:8) to (1:9), more preferably 1:8.7.

[0025] The mass ratio of Compound 1 to the methanol added for the first time is preferably (1:16) to (1:18), more preferably 1:17.

[0026] The mass of the concentrated liquid is preferably 4 to 6 times the mass of compound 1, more preferably 5 times.

[0027] The mass ratio of compound 1 to methanol added a second time is preferably (1:2) to (1:3), and more preferably 1:2.3.

[0028] In one embodiment, scheme 1 may further include post-processing steps of filtration, washing, vacuum drying, and sieving to obtain the type I crystals.

[0029] In one embodiment, in scheme 2, the mass ratio of compound 1 to tetrahydrofuran / methanol is (1:3) to (1:5), preferably 1:4.

[0030] In one embodiment, in the tetrahydrofuran / methanol mixture in Scheme 2, the mass ratio of tetrahydrofuran to methanol is (2:1) to (1:2), preferably 1:1.

[0031] In one embodiment, in scheme 2, the mass ratio of compound 1 to isopropanol is (1:11) to (1:13), preferably 1:12.

[0032] In one embodiment, in scheme 2, the temperature at which compound 1 dissolves in tetrahydrofuran / methanol and isopropanol is 50-60°C, preferably 55°C.

[0033] In one embodiment, in scheme 2, the cooling is to cool the temperature to 0-5°C, preferably 0°C.

[0034] In one embodiment, in scheme 2, the temperature holding time after cooling is related to the reaction scale, and generally the reaction endpoint is defined as the point at which the product no longer increases, and the temperature holding time is preferably 15 to 30 hours, more preferably 24 hours.

[0035] In one embodiment, scheme 2 preferably includes the steps of heating compound 1 and tetrahydrofuran / methanol, adding isopropanol and dissolving it, adding more isopropanol and cooling to form a suspension and obtain the type I crystal.

[0036] In one embodiment, scheme 2 may further include post-processing steps of filtration, washing, vacuum drying, and sieving to obtain the type I crystals.

[0037] The present invention further provides a pharmaceutical composition comprising the above-mentioned type I crystal and pharmaceutical adjuvants.

[0038] The present invention also provides the use of the type I crystal in the manufacture of a pharmaceutical product for treating and / or preventing JAK kinase-related diseases.

[0039] In one embodiment, the JAK kinase-related disease is inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, or ovarian cancer.

[0040] The aforementioned preferred conditions can be combined in any way, without violating the ordinary knowledge of the art, to obtain each preferred embodiment of the present invention.

[0041] The reagents and raw materials used in this invention are commercially available.

[0042] Positive advancements of the present invention: Type I crystals possess good physical and chemical properties, good high temperature (e.g., 60°C) and high humidity (92.5% RH) stability, high pressure (10 MPa) solid state stability, good solubility (significantly exceeding 8 μg / mL), low hygroscopicity, uniform particle size distribution, good solid form and processability in formulation processes, and good development prospects. [Brief explanation of the drawing]

[0043] [Figure 1] This is the XRPD spectrum of a type I crystal. [Figure 2] This is the DSC spectrum of a type I crystal. [Figure 3] This is the TGA spectrum of a type I crystal. [Figure 4] This is the PLM spectrum of a type I crystal. [Figure 5] This is the SEM spectrum of a type I crystal. [Figure 6A] and [Figure 6B] This is the DVS spectrum of a type I crystal. [Figure 7] These are the XRPD spectra of type I crystals before and after DVS testing. [Figure 8] This is the XRPD spectrum of a type II crystal. [Figure 9] This is the DSC spectrum of a type II crystal. [Figure 10] This is the TGA spectrum of a type II crystal. [Figure 11] This is the PLM spectrum of a type II crystal. [Figure 12] This is the XRPD spectrum of a type III crystal. [Figure 13] This is the DSC spectrum of a type III crystal. [Figure 14] This is the TGA spectrum of a type III crystal. [Figure 15] This is the PLM spectrum of a type III crystal. [Figure 16] This is the XRPD spectrum of a type IV crystal. [Figure 17] This is the DSC spectrum of a type IV crystal. [Figure 18] This is the TGA spectrum of a type IV crystal. [Figure 19] This is the PLM spectrum of a type IV crystal. [Figure 20] This is the XRPD spectrum of a V-type crystal. [Figure 21] This is the DSC spectrum of a V-type crystal. [Figure 22]This is the TGA spectrum of a V-type crystal. [Figure 23] This is the PLM spectrum of a V-type crystal. [Figure 24] This is the XRPD spectrum of a type VI crystal. [Figure 25] This is the DSC spectrum of a type VI crystal. [Figure 26] This is the TGA spectrum of a type VI crystal. [Figure 27] This is the PLM spectrum of a type VI crystal. [Figure 28] This is an amorphous XRPD spectrum. [Figure 29] This is an amorphous DSC spectrum. [Modes for carrying out the invention]

[0044] The present invention will be further described below with reference to the embodiments described, but this does not limit the present invention to the scope of the embodiments described above. In the following embodiments, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or according to the product description.

[0045] XRPD analysis method 1. Exam preparation [Table 2]

[0046] 2. Parameter settings [Table 3]

[0047] 3. Reporting of the test and results A suitable amount of sample (e.g., 20-50 mg, adjustable) is packed into a single-crystal silicon plate, and the sample is uniformly spread in the central region of the single-crystal silicon plate as shown in the diagram below. If the sample contains large particles, a back-loading sample plate can be used. If there is no requirement for response intensity, both flat and recessed-row single-crystal silicon plates can be used; otherwise, a recessed-row single-crystal silicon plate should be used to match the packing height.

[0048] If necessary, a thin layer of petroleum jelly or silicone oil can be applied to the surface of a single-crystal silicon plate, the sample can be attached, and any excess sample can be gently tapped off. The sample plate is then mounted in an XRPD sample holder, scanned to collect the spectrum, and the results are reported.

[0049] DSC Test Method 1. Exam preparation [Table 4]

[0050] 2. Parameter settings [Table 5]

[0051] 3. Reporting of the test and results Take an appropriate amount of sample (do not fill completely to prevent overflow during heating), place it in the expansion tray, close the lid, and seal it with a pressure lid. Use an empty expansion tray as a blank control. The expansion tray and cover used for the blank control must be identical to those used for the sample. Set the expansion tray in the corresponding sample holder, place the sample expansion tray in the sample holder, and place the blank expansion tray in the control holder. Select a method, process the data using workstation software, and report the results.

[0052] TGA Test Method 1. Exam preparation [Table 6]

[0053] 2. Parameter settings [Table 7]

[0054] 3. Reporting of the test and results Place an empty sample tray in the target position on the Auto Sampler, and click "TARE" on the workstation. The device will automatically place the tray, close the furnace, and then remove the weight from the container. Precisely weigh approximately 2-10 mg of sample and leave it in the sample tray after weight removal. Edit the sample information, select the method, and click "Sta" to start the sample analysis. The workstation will automatically record the sample weight percentage curve in response to temperature changes. Click "Analysis," select "Weight change" from the drop-down menu to analyze the command, and click "Analyze." The workstation will automatically calculate the percentage of sample weight loss (%) and report the results.

[0055] PLM (Polarizing Microscopy) Test Method 1. Exam preparation [Table 8]

[0056] 2. Reporting of the test and results A suspension is formed by placing several particles of the sample in mineral oil (e.g., silicone oil) and placing it on a clean glass slide. An appropriate amount of the suspension is placed on the slide glass and covered with a coverslip. For particles with irregular shapes, particle information must be included in the characterization of particle size. The uniformity of the powder should be examined using appropriate magnification. The results of the microscopic images are reported.

[0057] Example 1: Manufacturing and Characterization of Type I Crystals LNK01004 (amorphous, prepared according to Example 113 of CN113227074A) (net weight: 1.73 kg, 1.00 ± 0.02 X) and tetrahydrofuran (15 kg, 8.7 X) were added to reactor R1, the temperature was raised to 50-60°C, and the mixture was stirred for 1-3 hours to completely dissolve it.

[0058] The temperature was controlled to 40°C, methanol (30 kg, 17X) was added, and the mixture was concentrated to 4.0-6.0X under reduced pressure. Then, methanol (4 kg, 2.3X) was added, and the mixture was stirred for 1-3 hours.

[0059] The suspension was filtered, and the cake was washed with methanol (2 kg, 1.2X). It was dried under reduced pressure at 40-50°C until moisture and solvent residues met the specifications (tetrahydrofuran). < 720 ppm methanol < (5000 ppm). After drying, sieving was performed to obtain 1.362 kg of the final product LNK01004I type crystal (JR-C200212007-FPF21001), the XRPD pattern of which is shown in Figure 1, the purity was 99.91%, and the yield was 90%. [Table 9-1] [Table 9-2]

[0060] Characterization of Type I Crystals Typical characterization data for Type I crystals obtained from JR-C200212007-FPF21001 are shown below. According to the characterization data, Type I crystals are highly stable solvent-free crystals that exhibit very high purity, a stable melting point, solvent-free encapsulation, good morphology and particle size distribution, and no significant hygroscopicity. These characteristics are advantageous for the subsequent development and production of active pharmaceutical ingredients and formulations. [Table 10]

[0061] Type I crystal manufacturing example 2: In reactor R1, LNK01004 (amorphous, prepared according to Example 113 of CN113227074A) (net weight: 5 kg, 1.00 ± 0.02 X) and tetrahydrofuran / methanol = 1:1 (20 kg, 4.0 X) were added, the temperature was raised to 50-60°C, isopropanol (5 kg, 1.0 X) was added, and the mixture was stirred for 1-3 hours to completely dissolve the substances.

[0062] The temperature was controlled to 55°C, and isopropanol (55 kg, 11.0X) was added simultaneously and maintained for 1 to 3 hours.

[0063] The reaction temperature was cooled to 0°C within 5.0 hours. The mixture was then maintained at 0°C for 24 hours to form a suspension.

[0064] The suspension was filtered, and the cake was washed with isopropanol (10 kg, 2.0X).

[0065] Dried under reduced pressure at 40-50°C until moisture and solvent residues met the specifications (tetrahydrofuran). < 720 ppm methanol < 5000 ppm, isopropanol < (5000 ppm). After drying, sieving was performed to obtain 4.7 kg of type I crystals of the final product LNK01004 (its characteristic data was consistent with that of type I crystals in Production Example 1), with a purity of 100.0% and a yield of 94%.

[0066] Effect of Type I Crystals Example 1: Water activity experiment at 1.25℃ 20 mg of type I crystals were weighed, and 1 mL of acetone / aqueous system with different water activity was added. The mixture was stirred at 25°C for 10, 12, or 22 days. The resulting solid was filtered and characterized by XRPD. [Table 11]

[0067] According to these water activity experiment results, anhydrous type I crystals remain stable for a long period (up to 22 days) across a wide range of water activity levels (1% to 100%), without conversion to hydrates or other crystals. This is advantageous for maintaining a stable crystalline form after the formulation enters the body, and is also advantageous for temperature absorption and exposure after the drug enters the body.

[0068] 2. Stability test results Type I crystals were left for 30 days under high temperature (60°C) and high humidity (92.5% RH), and then subjected to light irradiation (1 × ICH, total illuminance 1.2 × 10⁻¹⁰). 6 Lux·hr or higher, near-ultraviolet energy 200 W·hr / m 2 (As described above) After storage for 6 months under accelerated conditions (40±2℃ / 75±5%RH) and 18 months under long-term conditions (25±2℃ / 60±5%RH), there were no changes in appearance, related substances, content (anhydrous and solvent-free), moisture, crystals, content, and microbial limits. [Table 12-1] [Table 12-2]

[0069] Example 2 of the effects of type I crystals: Dynamic solubility study of type I crystals Approximately 20 mg of type I crystals were weighed and placed in a 40 mL glass bottle. 10 mL of simulated gastrointestinal fluid was added, and the mixture was stirred at 400 rpm at 37°C. Approximately 1 mL of suspension was collected at 1 hour, 4 hours, and 24 hours, and the suspension was centrifuged at 37°C to measure the solubility of type I crystals at each time point. After 24 hours, the pH of the suspension was measured, the remaining suspension was centrifuged, and the remaining solid was characterized by XRPD. [Table 13]

[0070] The results showed that Type I crystals exhibited good solubility in simulated gastrointestinal fluid (significantly exceeding 8 μg / mL), confirming that the stability and absorption of the formulation were maintained during subsequent formulation development and manufacturing processes.

[0071] Effect of Type I Crystals Example 3: Pressure Test of Type I Crystals Approximately 10 mg of type I crystals (sample number: FR00970-12-SU1) were weighed and tabletized using a hydraulic press at a pressure of 10 MPa for 5 minutes. Crystal deformation and changes in crystallinity were then evaluated by XRPD characterization. The results indicate that superior type I crystals maintain stability under high pressure (10 MPa), which is advantageous for subsequent stable production of formulations. [Table 14]

[0072] Effect of Type I Crystals Example 4: Simulated Dry Grinding of Type I Crystals Approximately 10 mg of type I crystals (sample number: FR00970-12-SU1) were weighed, ground in a mortar for 3 minutes, and crystal deformation and changes in crystallinity were evaluated by XRPD characterization. The results showed that type I crystals maintained stability under dry grinding conditions, which is advantageous for subsequent formulation production. [Table 15]

[0073] Effect of Type I Crystals Example 5: Simulated Dry Grinding of Type I Crystals Approximately 10 mg of type I crystals (sample number: FR00970-12-SU1) were weighed, 40 μL of water or ethanol was added to each, and the crystals were ground in a mortar for 3 minutes. Crystal deformation and changes in crystallinity were evaluated by XRPD characterization. The results showed that favorable type I crystals maintained stability under wet grinding conditions and were advantageous for subsequent formulation production. [Table 16]

[0074] Effect of Type I Crystals Example 6: Pharmacodynamic Data of Type I Crystals This study used migration detection technology to measure the half-inhibitory concentrations (IC50) of type I crystals of compound LNK01004, ruxolitinib, tofacitinib, and upadacitinib for JAK1, JAK2, JAK3, and TYK2 kinase activity. In the study, the initial concentration for detecting type I crystals of compound LNK01004, ruxolitinib, tofacitinib, and upadacitinib for JAK1, JAK2, JAK3, and TYK2 kinase activity was 10 μM. Ten concentrations were then 3-fold gradient diluted and detected in replication wells, with an ATP concentration of 1 mM. The detection results are shown in the table below: [Table 17]

[0075] The test results show that type I crystals of compound LNK01004 exhibited more potent kinase inhibitory activity compared to ruxolitinib, tofacitinib, and upadacitinib in JAK1, JAK2, JAK3, and TYK2 activity tests, indicating that type I crystals of LNK01004 possess superior pharmaceutical properties at the same concentration and dosage.

[0076] Comparative Example 1: Manufacturing and Characterization of Type II Crystals Approximately 50 mg of LNK01004 (amorphous, prepared according to Example 113 of CN113227074A) was weighed, 2 ml of acetone / water (v:v=1:1) was added, and the mixture was completely dissolved at 50°C. The solution was then filtered through a 0.45 μm filter to obtain a clear solution. The resulting clear solution was cooled to 5°C at a rate of 0.1°C / min. The resulting solid was collected by filtration to obtain type II crystals. The type I crystals (sample number: FR00970-7-SC12) contained 0.3% acetone residue and had a water content of 12.2%. The type II crystals had a lower dehydration temperature and T onset The temperature was 56.8°C, and it was a highly crystalline metastable hydrate. [Table 18]

[0077] Comparative Example 2: Manufacturing and Characterization of Type III Crystals Approximately 50 mg of LNK01004 (amorphous, prepared according to Example 113 of CN113227074A) was weighed and placed in a 2 mL glass bottle. 1 mL of methanol / dichloromethane (v:v=1:1) solvent was added, and the suspension was incubated at 50°C and 400 rpm for 1 week. The resulting suspension was filtered, and the resulting solid portion was characterized to obtain type III crystals. The type III crystals (sample number: FR00970-7-SC6) were free of residual solvent, had a water content of 6.6%, and were metastable hydrates with high crystalline properties. [Table 19]

[0078] Comparative Example 3: Manufacturing and Characterization of Type IV Crystals Approximately 50 mg of LNK01004 (amorphous, prepared according to Example 113 of CN113227074A) was weighed and placed in a 2 mL glass bottle. 1 mL of tetrahydrofuran / water (v:v=1:1) solvent was added, and the suspension was allowed to stand at 25°C and 400 rpm for 1 week. The resulting suspension was filtered, and the obtained solid was characterized; it was a type IV crystal (Figure 24). The type IV crystal (sample number: FR00970-12-SU3) contained 3% tetrahydrofuran residue and had a water content of 5.4%. The type IV crystal transformed into a type VI crystal when left in an external environment (20-25°C, 80-95% RH) for 2 days. This indicates that the type IV crystal is a highly crystalline metastable hydrate. [Table 20]

[0079] Comparative Example 4: Manufacturing and Characterization of V-type Crystals Approximately 20 mg of LNK01004 (amorphous, prepared according to Example 113 of CN113227074A) was weighed, and 1 ml of DMF / n-heptane (v:v=1:1) solvent was added to completely dissolve it. The solution was then filtered through a 0.45 μm filter to obtain a clear solution. The resulting clear solution was then slowly evaporated at room temperature, and the resulting solid was a V-type crystal. The V-type crystal (sample number: FR00970-11-VD3) contained 1.6 equivalents of DMF. The V-type crystal was heated to 150°C to remove the solvent and converted to a I-type crystal (its XRPD data matched that of the I-type crystal preparation example 1). [Table 21]

[0080] Comparative Example 5: Manufacturing and Characterization of Type VI Crystals Approximately 50 mg of LNK01004 (amorphous, prepared according to Example 113 of CN113227074A) was weighed and placed in a 2 mL glass vial. 1 mL of tetrahydrofuran / water (v:v=1:1) solvent was added, and the mixture was suspended at 25°C and 400 rpm for 1 week. The resulting suspension was filtered, and the obtained solid was characterized. It was a type IV crystal, which was left in an external environment (20-25°C, 80-95% RH) for 2 days to crystallize and obtain a type VI crystal. The type VI crystal (sample number: FR00970-9-TC17) contained 2.3% THF residue and had a water content of 4.8%. The type VI crystal is unstable and may transform into other crystals under certain conditions. Exposure to 0 humidity resulted in a type VII crystal, and heating to 120°C followed by cooling to room temperature converted it to a type III crystal. [Table 22]

[0081] Comparative Example 6: Manufacturing and Characterization of Type VII Crystals Approximately 50 mg of LNK01004 (amorphous, prepared according to Example 113 of CN113227074A) was weighed and placed in a 2 mL glass vial. 1 mL of tetrahydrofuran / water (v:v=1:1) solvent was added, and the suspension was allowed to stand at 25°C and 400 rpm for 1 week. The resulting suspension was filtered, and the resulting solid was characterized. It was a type IV crystal, which converted to a type VII crystal after equilibration at 0% RH for 12 days. The type VII crystal was stable only under low RH conditions and converted to a type III crystal within 2 hours upon recovery to 60% RH. The type VII and type III crystals showed similar XRPD spectra, except for slight shifts in the positions of some peaks.

[0082] Comparative Example 7: Manufacturing and Characterization of Amorphous Materials Approximately 50 mg of LNK01004 (amorphous, prepared according to Example 113 of CN113227074A) was weighed and placed in a 2 mL glass bottle. 1 mL of acetonitrile / water (v:v=1:1) solvent was added, and the mixture was completely dissolved at 50°C. The solution was then filtered through a 0.45 μm filter to obtain a clear solution. The resulting clear solution was cooled to 5°C at a rate of 0.1°C / min. The resulting solid was collected by filtration to obtain an amorphous (sample number: FR00970-7-SC8). The crystals were studied by DSC heating (heated at a rate of 10°C / min until melted at 30°C, then cooled from melt to -20°C at a rate of 20°C / min): it was found that the amorphous material was converted to a type I crystal when the solvent was removed between 30°C and 110°C, and continued heating to 140°C and 190°C (the characterization data is the same as in "Example 1 of Production and Characterization of Type I Crystals"). [Table 23]

[0083] Although specific embodiments of the present invention have been described above, those skilled in the art will know that these are merely illustrative descriptions and that various changes and modifications can be made to these embodiments, provided that they do not contradict the principles of the present invention in substance. Accordingly, the scope of protection of this disclosure is defined by the appended claims.

Claims

1. A type I crystal of compound 1, characterized in that, using Cu-Kα rays, the powder X-ray diffraction pattern represented by 2θ has diffraction peaks at the following positions: 8.60°±0.2°, 10.25°±0.2°, 11.96°±0.2°, 14.35°±0.2°, 15.39°±0.2°, 16.59°±0.2°, 17.06°±0.2°, and 18.16°±0.2°. 【Chemistry 1】

2. The type I crystal according to claim 1, characterized in that it satisfies one or more of the following conditions. (1) The powder X-ray diffraction pattern represented by the 2θ angle of the type I crystal is further divided into one or more of the following positions: 12.77°±0.2°, 13.48°±0.2°, 14.04°±0.2°, 17.27°±0.2°, 18.83°±0.2°, 20.52°±0.2°, 20.77°±0.2°, 21.45°±0.2°, 22.12°±0.2°, 22.79°±0.2°, 23.55°±0.2°, 24.04°±0.2°, 24.40°±0.2°, 25.08°±0. The diffraction peaks are present at 2°, 25.87°±0.2°, 26.51°±0.2°, 26.73°±0.2°, 26.89°±0.2°, 27.36°±0.2° and 28.29°±0.2°, preferably also at one or more of the following positions: 28.93°±0.2°, 29.42°±0.2°, 30.63°±0.2°, 33.00°±0.2°, 33.37°±0.2°, 34.43°±0.2° and 37.09°±0.2°. (2) The differential scanning calorimetry spectrum of the type I crystal has one endothermic peak between 207.4°C and 209.2°C. (3) The thermogravimetric analysis spectrum of the type I crystal is obtained under the condition that the weight loss is 0.0% between 30.07°C and 208.96°C.

3. The type I crystal according to claim 2, characterized in that it satisfies one or more of the following conditions. (1) The powder X-ray diffraction pattern of the type I crystal, represented by the 2θ angle, has the following diffraction peaks: Table 1-1 Table 1-2 (2) The differential scanning calorimetry spectrum of the type I crystal has one endothermic peak between 207.4°C and 209.2°C, and the heat of fusion is 123.76 J / g. (3) The thermogravimetric analysis spectrum of the type I crystal is basically as shown in Figure 3.

4. The type I crystal according to claim 3, characterized in that it satisfies one or more of the following conditions. (1) The powder X-ray diffraction pattern represented by the 2θ angle of the type I crystal is basically as shown in Figure 1. (2) The differential scanning calorimetry spectrum of the type I crystal is basically as shown in Figure 2.

5. A method for producing a type I crystal according to any one of claims 1 to 4, characterized in that it is scheme 1 or scheme 2, Scheme 1 includes the step of crystallizing a methanol solution of compound 1 to obtain the type I crystal, 【Chemistry 2】 Scheme 2 is a production method comprising the step of cooling compound 1 in a solution of tetrahydrofuran / methanol and isopropanol to obtain the type I crystal.

6. A method for producing a type I crystal according to claim 5, characterized in that it satisfies one or more of the following conditions. (1) In scheme 1, the crystallization is carried out under the condition that the mass of the solution is (1:6) to (1:8.5), preferably (1:6.3) to (1:8.3), of the mass of compound 1. (2) Scheme 1 includes the steps of adding methanol to the solution of compound 1 and tetrahydrofuran at 40°C, concentrating the solution, adding more methanol to the concentrate, stirring, and crystallizing to obtain the type I crystal, Here, the temperature of the solution formed when compound 1 dissolves in tetrahydrofuran is preferably 50 to 60°C. The mass ratio of compound 1 to tetrahydrofuran is preferably (1:8) to (1:9), and more preferably 1:8.

7. The mass ratio of compound 1 to methanol added for the first time is preferably (1:16) to (1:18), and more preferably 1:

17. The mass of the concentrated liquid is preferably 4 to 6 times the mass of compound 1, and more preferably 5 times. The mass ratio of compound 1 to methanol added a second time is preferably (1:2) to (1:3), and more preferably 1:2.

3. (3) The scheme 1 is a condition that further includes a post-processing step of performing filtration, washing, vacuum drying and sieving to obtain the type I crystals, (4) In scheme 2, the mass ratio of compound 1 to tetrahydrofuran / methanol is (1:3) to (1:5), preferably 1:

4. (5) In Scheme 2, the mass ratio of tetrahydrofuran to methanol in the tetrahydrofuran / methanol mixture is (2:1) to (1:2), preferably 1:

1. (6) In scheme 2, the mass ratio of compound 1 to isopropanol is (1:11) to (1:13), preferably 1:

12. (7) In Scheme 2, the temperature at which compound 1 dissolves in tetrahydrofuran / methanol and isopropanol is 50 to 60°C, preferably 55°C. (8) In scheme 2, the cooling is to cool the temperature to 0 to 5°C, preferably under the condition that the temperature is 0°C. (9) In scheme 2, the temperature retention time after cooling is 15 to 30 hours, more preferably 24 hours. (10) The scheme 2 is a condition that further includes a post-processing step of filtration, washing, vacuum drying and sieving to obtain the type I crystals.

7. The method for producing type I crystals according to claim 6, characterized in that scheme 2 includes the steps of heating compound 1 and tetrahydrofuran / methanol, adding isopropanol and dissolving it, adding more isopropanol, cooling to form a suspension and obtain the type I crystals.

8. A pharmaceutical composition comprising a type I crystal and a pharmaceutical adjuvant according to any one of claims 1 to 4.

9. The use of type I crystals according to any one of claims 1 to 4 in the manufacture of a pharmaceutical product for treating and / or preventing JAK kinase-related diseases, The aforementioned JAK kinase-related diseases include inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, myelofibrosis, breast cancer, or ovarian cancer.

10. The use of type I crystals according to any one of claims 1 to 4 in the manufacture of a pharmaceutical product for treating and / or preventing a disease, characterized in that the disease is inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, myelofibrosis, breast cancer, or ovarian cancer.

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