Crystal form of 7-azaindole compound, and composition, preparation method and application thereof

Abstract

The invention discloses a crystal form of a 7-azaindole compound as well as a composition, a preparation method and application of the 7-azaindole compound. The crystal forms comprise a crystal form II, a crystal form III and a crystal form IV, an X-ray diffraction method is used, and the crystal form II has characteristic diffraction peaks at about 8.4 degrees, 12.8 degrees, 15.8 degrees, 16.8 degrees, 18.6 degrees and 20.3 degrees; the crystal form III has characteristic diffraction peaks at about 9.6 degrees, 14.7 degrees, 19.2 degrees, 20.1 degrees and 21.7 degrees, and the crystal form IV has characteristic diffraction peaks at about 12.1 degrees, 14.5 degrees, 17.9 degrees and 18.7 degrees; the preparation method comprises the following steps: adding a proper solvent into a 7-azaindole compound, stirring, filtering, and drying to obtain the crystal form II, III or IV; the crystal form II or III or IV can be used for preparing drugs for preventing or treating diseases caused by JAK-STAT signal pathway abnormality, wherein the diseases comprise autoimmune diseases, cancers and bone marrow growth diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a crystal form of a 7-azaindole compound with Janus kinase (JAK) inhibitory activity, a composition thereof, a preparation method and an application thereof. Background Art

[0002] Janus kinase (JAK) is a cytoplasmic tyrosine protein kinase responsible for transducing many inflammatory-related cytokine signals from cytokine membrane receptors to STAT transcription factors. Abnormal JAK / STAT signal transduction is associated with many diseases and is involved in immune-inflammatory-related diseases such as organ transplant rejection, multiple sclerosis, rheumatoid arthritis, type I diabetes, lupus, psoriasis, asthma, food allergies, atopic dermatitis and rhinitis, rash, etc. Studies have shown that high selectivity for JAK3 kinase can avoid unnecessary side effects. Therefore, improving the activity and selectivity of JAK3 kinase inhibitors can further improve the clinical use of JAK3 kinase inhibitors, which have significant clinical advantages over the currently clinically used Pan-JAK inhibitors and selective JAK1 and JAK2 inhibitors.

[0003] The prior art (application number: 202211018957.X) discloses a highly selective 7-azaindole JAK3 kinase inhibitor, the structure of which is shown below. The 7-azaindole compound also has a good inhibitory effect on the TEC kinase family, and exhibits a good immunosuppressive effect in the rheumatoid arthritis CIA mouse model, the DSS-induced mouse ulcerative colitis model, and the radiation lung injury mouse model. Therefore, the compound has good application prospects in autoimmune and inflammatory diseases.

[0004]

[0005] Drug polymorphism is one of the important factors affecting drug quality and clinical efficacy. Different crystal forms will lead to differences in stability, absorption and bioavailability, thereby affecting the clinical efficacy of drugs. Therefore, the crystal form of the 7-azaindole compound and its preparation technology are of great significance to the application of the drug. Summary of the invention

[0006] The present invention aims to provide a crystalline form of a 7-azaindole compound, a composition thereof, a preparation method and an application thereof. The crystalline form of the 7-azaindole compound can be used as a JAK kinase inhibitor for the treatment and prevention of clinical applications related to abnormal activity of these kinases, including autoimmune diseases, cancer, myeloproliferative diseases and other diseases.

[0007] The present invention provides a 7-azaindole compound having the structural formula:

[0008]

[0009] The 7-azaindole compound may exist in a variety of different crystal forms.

[0010] A crystalline form I of a 7-azaindole compound has characteristic diffraction peaks at 2θ angles of about 7.3°, 9.5°, 15.6°, 18.2°, and 20.0° using X-ray diffraction.

[0011] A crystal form II of a 7-azaindole compound has characteristic diffraction peaks at 2θ angles of about 8.4°, 12.8°, 15.8°, 16.8°, 18.6° and 20.3° using X-ray diffraction.

[0012] A crystal form III of a 7-azaindole compound has characteristic diffraction peaks at 2θ angles of about 9.6°, 14.7°, 19.2°, 20.1°, and 21.7° using X-ray diffraction.

[0013] A crystalline form IV of a 7-azaindole compound has characteristic diffraction peaks at 2θ angles of about 12.1°, 14.5°, 17.9°, and 18.7° using X-ray diffraction.

[0014] A crystal form V of a 7-azaindole compound has characteristic diffraction peaks at 2θ angles of about 7.3°, 8.9°, 14.5°, and 18.3° using an X-ray diffraction method.

[0015] A crystal form VI of a 7-azaindole compound has characteristic diffraction peaks at 2θ angles of about 6.1°, 6.8°, 7.1°, 18.0°, and 19.9° using X-ray diffraction.

[0016] A crystalline form VII of a 7-azaindole compound has characteristic diffraction peaks at 2θ angles of about 9.1°, 11.6°, 14.3°, 19.4°, and 20.0° using X-ray diffraction.

[0017] A crystalline form VIII of a 7-azaindole compound has characteristic diffraction peaks at 2θ angles of about 7.2°, 9.2°, 18.7°, and 20.7° using X-ray diffraction.

[0018] Furthermore, the crystal form II, using the X-ray diffraction method, has characteristic diffraction peaks at 2θ angles of approximately 11.7°, 16.2°, and 18.3°; further, the 2θ angle has characteristic diffraction peaks at approximately 22.0°, 22.2°, 25.1°, and 26.3°.

[0019] Furthermore, the crystal form III, using X-ray diffraction, has characteristic diffraction peaks at about 10.4°, 14.2°, and 16.3° at 2θ angles, wherein the error range of the 2θ angle is ±0.2°. Furthermore, the crystal form III also has characteristic diffraction peaks at about 22.4°, 24.0°, and 27.3°.

[0020] Furthermore, the crystalline form IV, using X-ray diffraction, has characteristic diffraction peaks at 2θ angles of approximately 15.1°, 15.5°, 21.9°, 22.4°, 22.9°, 22.3°, 26.3°, and 26.6°.

[0021] Furthermore, Form I has Figure 1 The X-ray diffraction pattern shown or Figure 2 Corresponding X-ray diffraction characteristic data; Form II has Figure 8 The X-ray diffraction pattern shown or Fig. 9 Corresponding X-ray diffraction characteristic data; Form III has Fig.15 The X-ray diffraction pattern shown or Fig.16 Corresponding X-ray diffraction characteristic data; Form IV has Fig. 22 The X-ray diffraction pattern shown or Fig.23 Corresponding X-ray diffraction characteristic data; Form V has Fig.29 The X-ray diffraction pattern shown or Fig.30 Corresponding X-ray diffraction characteristic data; Form VI has Fig.37 The X-ray diffraction pattern shown or Fig.38 Corresponding X-ray diffraction characteristic data; Form VII has Fig.46 The X-ray diffraction pattern shown is characterized by: Form VIII has Fig.55 The X-ray diffraction pattern shown or Fig.56 Corresponding X-ray diffraction characteristic data.

[0022] Further, Form I has a crystal transformation peak at 148°C-165°C, and a melting point of about 216°C. The melting point of Form II is 222-224°C, and more specifically, the melting point of Form II is about 223°C. The melting point of Form III is 218-220°C, and more specifically, the melting point of Form III is about 219°C. The melting point of Form IV is 213-215°C, and more specifically, the melting point of Form IV is about 214°C. Form V has an endothermic peak at 120°C-165°C, and a melting point of about 214°C. Form VI has an endothermic peak at 115°C-160°C, and a melting point of 203°C. The melting point of Form VII is about 203°C. Form VIII has an endothermic peak at 125°C-170°C, and a melting point of about 219°C.

[0023] Another object of the present invention is to provide a combination of crystalline forms of 7-azaindole compounds, which can be used as JAK kinase inhibitors for the treatment and prevention of clinical applications related to abnormal activity of these kinases, including autoimmune diseases, inflammatory diseases, cancer and other diseases.

[0024] A composition of crystalline forms of a 7-azaindole compound, comprising one or a combination of two or more of the crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V, crystalline form VI, crystalline form VII, and crystalline form VIII; and the crystalline form II or / and crystalline form III or / and crystalline form IV account for more than 50% of the weight of the crystalline composition. Preferably, the composition comprises one or two of the crystalline form II, crystalline form III, and crystalline form IV; and the crystalline form II or / and crystalline form III or / and crystalline form IV account for more than 50% of the weight of the composition.

[0025] Another object of the present invention is to provide a combination of crystalline forms of 7-azaindole compounds, which can be used as JAK kinase inhibitors for the treatment and prevention of clinical applications related to abnormal activity of these kinases, including autoimmune diseases, inflammatory diseases, cancer and other diseases.

[0026] A composition of crystalline forms of a 7-azaindole compound, comprising one or a combination of two or more of the crystalline forms I, II, III, IV, V, VI, VII and VIII; and the crystalline form II or / and the crystalline form III or / and the crystalline form IV account for more than 80% of the weight of the crystalline composition. Preferably, the composition comprises one or two of the crystalline form II or / and the crystalline form III or / and the crystalline form IV; and the crystalline form II or / and the crystalline form III or / and the crystalline form IV account for more than 80% of the weight of the composition.

[0027] Another object of the present invention is to provide a combination of crystalline forms of 7-azaindole compounds, which can be used as JAK kinase inhibitors for the treatment and prevention of clinical applications related to abnormal activity of these kinases, including autoimmune diseases, inflammatory diseases, cancer and other diseases.

[0028] A composition of crystalline forms of a 7-azaindole compound, comprising one or a combination of two or more of the crystalline forms I, II, III, IV, V, VI, VII and VIII; and the weight of the composition of the crystalline form II or / and III or / and IV is more than 90%. As a further preference, the composition comprises one or two of the crystalline forms II, III and IV; and the crystalline form II or / and III or / and IV account for more than 90% of the weight of the composition.

[0029] Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned crystal form for use in the treatment and prevention of clinical applications related to abnormal activity of these kinases, including autoimmune diseases, inflammatory diseases, cancer and other diseases.

[0030] A pharmaceutical composition comprising the crystal form II and / or the crystal form III and / or the crystal form IV, and a pharmaceutically acceptable excipient.

[0031] Further, for the above-mentioned pharmaceutical composition, the weight of the crystal form II or / and the crystal form III or / and the crystal form IV accounts for more than 50% of the total weight of the composition. Further, the weight of the crystal form II or / and the crystal form III or / and the crystal form IV accounts for more than 80% of the total weight of the composition. Further, the weight of the crystal form II or / and the crystal form III or / and the crystal form IV accounts for more than 95% of the total weight of the composition.

[0032] The "7-azaindole compound" mentioned in the following method of the present invention refers to the compound represented by formula (I), or a crude product or a refined sample containing the compound represented by formula (I). The content of the compound represented by formula (I) in the crude product or the refined sample is greater than 80%; or further greater than 90%; further greater than 95%.

[0033] Another object of the present invention is to provide a method for preparing form II, comprising adding a solvent to the 7-azaindole compound to form a suspension, stirring at room temperature, separating the solid from the liquid (by filtration or centrifugation), and drying to obtain a white solid.

[0034] Further, when preparing Form II, the solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, butyl acetate, and water, and the amount of the organic solvent is 3 to 50 times the weight of the 7-azaindole compound. Further, when the solvent contains butyl acetate, ethyl acetate or water, the solvent is a combination of two or more of methanol, ethanol, acetone, acetonitrile, ethyl acetate, butyl acetate, and water. Further, the solvent is one or more of methanol, ethanol, acetone, acetonitrile, or a mixed solvent of one of methanol, ethanol, acetone, acetonitrile and a second solvent, and the second solvent is butyl acetate, ethyl acetate or water. More specifically, the solvent is one or more of methanol, ethanol, acetone, acetonitrile, or any combination of one of methanol, ethanol, acetone, acetonitrile and one or two of butyl acetate and water.

[0035] Preferably, a method for preparing Form II comprises adding a solvent to the 7-azaindole compound to form a suspension, stirring at room temperature, separating the solid from the liquid (by filtration or centrifugation), and drying to obtain a white solid Form II; the solvent is selected from methanol and ethanol. For 1 mg of 7-azaindole compound, the required solvent volume is 0.01 to 0.5 mL.

[0036] Another object of the present invention is to provide a method for preparing the crystal form II, which comprises adding a solvent to the 7-azaindole compound to dissolve it and evaporate it to dryness.

[0037] Furthermore, the solvent is one or a combination of two or more of methanol, ethanol, butanone, tetrahydrofuran and water.

[0038] Another object of the present invention is to provide a method for preparing crystal form II, comprising adding an organic solvent to the 7-azaindole compound, heating to dissolve, filtering, stirring, cooling and crystallizing; and then solid-liquid separation (filtration or centrifugation) and drying.

[0039] Further, the organic solvent is one of acetone, methanol, ethanol, n-propanol, sec-butanol, acetonitrile, butanone, or a combination of two or more thereof; methanol is further preferred. The amount of the organic solvent used is 10 to 50 times the weight of the 7-azaindole compound. When methanol is selected as the organic solvent, the volume of methanol required for 1 mg of the 7-azaindole compound is 0.1 to 0.5 mL.

[0040] Another object of the present invention is to provide a method for preparing form III, comprising adding a solvent to the 7-azaindole compound to form a suspension, stirring at room temperature, separating the solid from the liquid (by filtration or centrifugation), and drying to obtain a white solid.

[0041] Furthermore, when preparing Form III, the solvent is one or a combination of two or more of water, methyl tert-butyl ether, ethyl acetate, isopropanol, isopropyl acetate, toluene, and n-heptane, and the amount of the organic solvent used is 3 to 50 times the weight of the 7-azaindole compound.

[0042] Preferably, a method for preparing Form III comprises adding a solvent to the 7-azaindole compound to form a suspension, stirring at room temperature, separating the solid from the liquid (by filtration or centrifugation), and drying to obtain a white solid Form III; the solvent is selected from water and ethyl acetate. For 1 mg of 7-azaindole compound, the required solvent volume is 0.01 to 0.5 mL.

[0043] Another object of the present invention is to provide a method for preparing the crystal form III, which comprises adding a solvent to the 7-azaindole compound to dissolve it and evaporate it to dryness.

[0044] Furthermore, the solvent is one of acetone, trifluoroethanol, methanol, and chloroform, or a combination of two or more thereof.

[0045] Another object of the present invention is to provide a method for preparing form III, comprising adding a first organic solvent to the 7-azaindole compound to form a solution, and then adding a second organic solvent; stirring to crystallize; and then solid-liquid separation (filtration or centrifugation) and drying.

[0046] Further, the first organic solvent is one or a combination of two or more selected from dimethyl sulfoxide, methanol, ethanol, acetonitrile, n-propanol, and sec-butanol; ethanol is further preferred. The amount of the first organic solvent is 10 to 50 times the weight of the 7-azaindole compound. The second organic solvent is one or a combination of two or more selected from water, methyl tert-butyl ether, and isopropyl ether; water is further preferred. The amount of the second organic solvent is 10 to 50 times the weight of the 7-azaindole compound. Further, when the first organic solvent is dimethyl sulfoxide, the second solvent is water; when the first organic solvent is methanol, the second solvent is methyl tert-butyl ether. When the first organic solvent is ethanol or DMSO, the volume of ethanol or DMSO required for 1 mg of 7-azaindole compound is 0.1 to 0.5 mL; when the second organic solvent is water, the volume of water required for 10 mg of 7-azaindole compound is 0.1 to 0.5 mL. The volume ratio of water to ethanol or DMSO is 0.5 to 3:1, more preferably 1 to 1.5:1.

[0047] Another object of the present invention is to provide a method for preparing form IV, comprising adding a first organic solvent to the 7-azaindole compound to form a solution, and then adding a second organic solvent; stirring to crystallize; and then solid-liquid separation (filtration or centrifugation) and drying.

[0048] Further, when preparing Form IV, the first organic solvent is one of ethanol and acetone or a combination of two or more thereof. The amount of the first organic solvent is 10 to 50 times the weight of the 7-azaindole compound. The second organic solvent is n-heptane, and the amount of the second organic solvent is 10 to 50 times the weight of the 7-azaindole compound.

[0049] As a further preferred method, when preparing the crystal form IV, the first organic solvent is ethanol or acetone; the second organic solvent is n-heptane. For 1 mg of 7-azaindole compound, the volume of the first organic solvent required is 0.1 to 0.3 mL; the volume of the second organic solvent required is 0.3 to 0.8 mL; the volume ratio of the second organic solvent to the first organic solvent is 1 to 8:1; more preferably 2 to 3:1.

[0050] Another object of the present invention is to provide a use of the above-mentioned crystal form in the preparation of a drug for preventing or treating diseases caused by abnormal JAK-STAT signaling pathway. The drug can be used for autoimmune diseases, cancer, and myeloproliferative diseases.

[0051] Furthermore, the autoimmune disease is selected from one or more of alopecia areata, lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, rheumatoid arthritis, psoriasis, complications caused by organ transplantation, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, vitiligo, autoimmune kidney damage, autoimmune liver damage, and chronic obstructive pulmonary disease; the cancer is selected from one or more of colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, CNS (central nervous system) cancer, and malignant glioma; the bone marrow proliferation disease is selected from one or more of chronic myelomonocytic leukemia, atypical chronic myelomonocytic leukemia, and juvenile myelomonocytic leukemia.

[0052] The 7-azaindole compounds of the present invention have polymorphic phenomena, and a total of 8 crystal forms, i.e., crystal forms I to VIII, have been found. When using hot stage XRPD to study the crystal form of the compound, it is found that the sample is easily transformed into a thermodynamically more stable crystal form II, crystal form III, or crystal form IV, or a mixture of two or three of the above three crystal forms, see Fig.70 .

[0053] It can be seen that the 7-azaindole compound applied for in the present invention has polymorphism and most of the crystal forms are solvates. Under most preparation conditions, anhydrous crystal forms cannot be obtained, so the preparation of anhydrous crystal form II, crystal form III or crystal form IV has great technical difficulty. Solvates (including crystal form I of the prior art) have toxic and side effects due to high organic solvent content, and there is a problem of easy desolvation and crystal form transformation during storage. The crystal form composition ratio of the compound under different storage times is different, which will lead to unstable compound quality. Crystal form II, crystal form III or crystal form IV provided by the present invention is not easy to change crystal form during storage, which can overcome the above-mentioned defects of the prior art.

[0054] At the same time, the researchers conducted competitive tests on the above-mentioned crystal forms in water, acetone and ethanol to examine the transformation of various crystal forms in solvents. The results showed that crystal form II is the most stable in water, acetone and ethanol.

[0055] The researchers tested the saturated solubility of the prior art crystal form I and the crystal forms II, III, and IV for protection in different dissolution media and physiological media. The results showed that the dissolution ability of crystal forms II, III, and IV was significantly better than that of crystal form I, especially the solubility of crystal form II in simulated fasting state intestinal fluid and simulated postprandial state intestinal fluid was more than three times that of crystal form I. The technical solution for protection in the present invention has the technical effect of significantly improving solubility and bioavailability. The present invention further investigated the stability of crystal forms I and II under the conditions of influencing factors. The results showed that not only did crystal form I undergo a crystal transformation, but also its solubility in physiological media changed significantly. In comparison, crystal form II neither underwent a crystal transformation nor a significant change in solubility. Therefore, crystal form II has stable crystal form and stable absorption under different environmental conditions, and can overcome the technical defects of crystal form I. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 It is the X-ray diffraction pattern of Form I in the present invention.

[0057] Figure 2 It is the X-ray diffraction peak data diagram of the crystal form I in the present invention.

[0058] Figure 3 This is the TG diagram of Form I in the present invention.

[0059] Figure 4 This is the DSC diagram of Form I in the present invention.

[0060] Figure 5 This is the PLM diagram of Form I in the present invention.

[0061] Figure 6 This is the XRPD pattern of Form 1b in the present invention.

[0062] Figure 7 For the crystal form I of the present invention 1 H-NMR spectrum.

[0063] Figure 8 It is the X-ray diffraction pattern of Form II in the present invention.

[0064] Fig. 9 It is the X-ray diffraction peak data diagram of Form II in the present invention.

[0065] Fig.10 This is the TG diagram of Form II in the present invention.

[0066] Fig.11 It is the DSC diagram of Form II in the present invention.

[0067] Fig.12 It is the DVS diagram of Form II in the present invention.

[0068] Fig.13 It is the isotherm curve diagram of Form II in the present invention.

[0069] Fig.14 This is the PLM diagram of Form II in the present invention.

[0070] Fig.15 It is the X-ray diffraction pattern of Form III in the present invention.

[0071] Fig.16 It is the X-ray diffraction peak data diagram of Form III in the present invention.

[0072] Fig.17 This is the TG diagram of Form III in the present invention.

[0073] Fig.18 It is the DSC diagram of Form III in the present invention.

[0074] Fig.19 It is the DVS diagram of Form III in the present invention.

[0075] Fig. 20 It is the isotherm curve diagram of Form III in the present invention.

[0076] Fig.21 It is the PLM diagram of Form III in the present invention.

[0077] Fig. 22 It is the X-ray diffraction pattern of the crystal form IV in the present invention.

[0078] Fig.23 It is the X-ray diffraction peak data diagram of the crystal form IV in the present invention.

[0079] Fig.24 This is the TG diagram of Form IV in the present invention.

[0080] Fig.25 This is the DSC diagram of Form IV in the present invention.

[0081] Fig.26 This is the DVS diagram of Form IV in the present invention.

[0082] Fig. 27 It is the isotherm curve diagram of Form IV in the present invention.

[0083] Fig.28 This is the PLM diagram of Form IV in the present invention.

[0084] Fig.29 It is the X-ray diffraction pattern of the crystal form V in the present invention.

[0085] Fig.30It is the X-ray diffraction peak data diagram of the crystal form V in the present invention.

[0086] Fig.31 This is the TG diagram of Form V in the present invention.

[0087] Fig.32 It is the DSC graph of Form V in the present invention.

[0088] Fig.33 This is the DVS diagram of Form V in the present invention.

[0089] Fig.34 It is the isotherm curve diagram of the crystal form V in the present invention.

[0090] Fig.35 This is the PLM diagram of Form V in the present invention.

[0091] Fig.36 This is the hot stage XRPD pattern of Form V in the present invention.

[0092] Fig.37 It is the X-ray diffraction pattern of the crystal form VI in the present invention.

[0093] Fig.38 It is the X-ray diffraction peak data diagram of the crystal form VI in the present invention.

[0094] Fig.39 This is the TG diagram of Form VI in the present invention.

[0095] Fig.40 It is the DSC diagram of the crystal form VI in the present invention.

[0096] Fig.41 This is the DVS diagram of Form VI in the present invention.

[0097] Fig.42 It is the isotherm curve diagram of Form VI in the present invention.

[0098] Fig.43 This is the PLM diagram of Form VI in the present invention.

[0099] Fig.44 This is the hot stage XRPD pattern of Form VI in the present invention.

[0100] Fig.45 is the hot stage of the crystal form VI in the present invention 1 H-NMR spectrum.

[0101] Fig.46 It is the X-ray diffraction pattern of the crystalline form VII in the present invention.

[0102] Fig.47 It is the X-ray diffraction peak data diagram of Form VII in the present invention.

[0103] Fig.48 This is the TG diagram of Form VII in the present invention.

[0104] Fig.49 It is the DSC chart of Form VII in the present invention.

[0105] Fig.50 It is the DVS diagram of Form VII in the present invention.

[0106] Fig.51 It is the isotherm curve diagram of Form VII in the present invention.

[0107] Fig.52 This is the PLM diagram of Form VII in the present invention.

[0108] Fig.53 This is the hot stage XRPD pattern of Form VII in the present invention.

[0109] Fig.54 is the hot stage of the crystal form VII of the present invention 1 H-NMR spectrum.

[0110] Fig.55 This is the X-ray diffraction pattern of the crystal form VIII in the present invention.

[0111] Fig.56 This is the X-ray diffraction peak data diagram of the crystal form VIII in the present invention.

[0112] Fig.57 This is the TG diagram of the crystal form VIII in the present invention.

[0113] Fig.58 This is the DSC diagram of the crystal form VIII in the present invention.

[0114] Fig.59 This is the DVS diagram of Form VIII in the present invention.

[0115] Fig.60 It is the isotherm curve diagram of the crystal form VIII in the present invention.

[0116] Fig.61 This is the PLM diagram of Form VIII in the present invention.

[0117] Fig.62 This is the hot stage XRPD diagram of Form VIII in the present invention.

[0118] Fig.63 The hot plate of the crystal form VIII of the present invention 1 H-NMR spectrum.

[0119] Fig.64 This is XRPD Figure 1 of the 7-day experiment of crystal transformation in the present invention.

[0120] Fig.65 This is XRPD Figure 2 of the 7-day experiment of crystal transformation in the present invention.

[0121] Fig.66 This is the XRPD pattern of Form II in the present invention at high humidity for 5 days.

[0122] Fig.67 This is the XRPD diagram of Form II in the present invention at high temperature for 5 days.

[0123] Fig.68 This is the XRPD pattern of Form I in the present invention subjected to high humidity for 5 days.

[0124] Fig.69 This is the XRPD diagram of Form I in the present invention at high temperature for 5 days.

[0125] Fig.70 This is a diagram showing the crystal relationship of the compound.

[0126] Fig.71 This is the standard curve of 7-azaindole compounds. DETAILED DESCRIPTION

[0127] In order to explain the present invention more clearly, the present invention is further described below in conjunction with preferred embodiments. It should be understood by those skilled in the art that the following specific description is illustrative rather than restrictive, and should not be used to limit the scope of protection of the present invention.

[0128] All numerical designations of the present invention (e.g., temperature, time, concentration, and weight, including ranges of each thereof) are generally approximate values ​​that can be appropriately changed by increments of 0.1 or 1.0 (+) or (-). All numerical designations can be understood as being preceded by the term "about". The present invention mainly uses the expression of "crystal form + Roman numerals" to describe different crystal forms, which is equivalent to the expression of "Form + Arabic numerals" in the accompanying drawings, for example, Form I and Form 1 refer to the same crystal form, Form II and Form 2 refer to the same crystal form, and so on.

[0129] In the present invention, the X-ray diffraction spectrum is measured by the following method: Instrument: Bruker D8AdvanceDiffractometer; Technical indicators: Copper target wavelength is Kα radiation (40KV, 40mA), θ-2θ goniometer, nickel filter, Lynxeye detector; detection angle: 3°-40°2θ / 3°-30°2θ (hot stage XRPD); step size: 0.02°2θ; speed: 0.2s.step -1 .

[0130] Example 1 (Comparative Example): 7-Azaindole Compounds

[0131] The 7-azaindole compound was prepared according to the method of Example 2 of the prior art (application number: 202211018957.X):

[0132]

[0133] Step 1: Add intermediate 8d-IM3 (3g, 9.9mmol), cyclopropylboronic acid (1.7g, 19.8mmol), copper acetate (1.8g, 9.9mmol), DMAP (4.8g, 39.8mmol), pyridine (1.9g, 24.8mmol) into a 500mL three-necked flask containing 100mL 1,4-dioxane in sequence, and place the reaction system at 105°C for 24 hours with sufficient stirring. After the reaction is completed, pour the reaction solution into water, extract with ethyl acetate three times, combine the organic layers, wash twice with saturated sodium chloride, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography to obtain 1.2g intermediate M as a yellow solid with a yield of 34.8%. ESI (M+H) + =342.

[0134] Step 2: Under nitrogen protection, add intermediate M (1g, 2.9mmol), tetrakis(triphenylphosphine)palladium (0.3g, 0.29mmol), intermediate SM3 (1.1g, 4.3mmol) and potassium carbonate (1.2g, 8.7mmol) in turn into a 200ml three-necked flask containing 100mL 1,4-dioxane, and place the reaction system at 95°C for full stirring and reaction overnight. After the reaction is completed, cool to room temperature, pour the reaction solution into 100mL water, extract with ethyl acetate 3 times, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography to obtain 0.88g of intermediate N as a light yellow solid with a yield of 79.2%, ESI (M+H) + =380.

[0135] Step 3: Dissolve the intermediate N (0.8 g, 2.1 mmol) in dichloromethane, add an equal volume of trifluoroacetic acid, react at room temperature overnight, adjust the pH to 8-9 after the reaction is complete, extract with dichloromethane three times, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography to obtain 0.46 g of intermediate O as a white solid, with a yield of 78.2%. ESI (M+H) + =280.

[0136] Step 4: Dissolve the intermediate O (200 mg, 0.7 mmol) in 20 ml of dichloromethane, add triethylamine (217 mg, 2.15 mmol), slowly add acryloyl chloride (64 mg, 0.7 mmol) under ice bath, react at room temperature for 1 hour, add saturated sodium bicarbonate aqueous solution, extract with dichloromethane 3 times, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography to obtain 112 mg of white solid with a yield of 46.7%. 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.23(d,J=5.4Hz,1H),7.43(d,J=3.0Hz,1H),6.91(d,J=4.9Hz,3H),6.11(d,J=15.0Hz,1H),5.70(d,J=10. 5Hz,1H),4.77(d,J=16.1Hz,2H),4.04–3.80(m,2H),3.67–3.53(m,1H),2 .88(d,J=5.6Hz,2H),1.13(d,J=3.6Hz,2H),1.08–0.89(m,2H).ESI(M+H) + =334.

[0137] The 7-azaindole compound obtained by the above preparation method is a crystalline form I. The obtained white solid X-ray diffraction pattern shows that the 2θ angle has characteristic diffraction peaks at 7.3°, 9.5°, 15.6°, 18.2°, and 20.0° (see Figure 1 , Figure 2 ); TGA / DSC thermal analysis results show that there is an endothermic peak at 90℃-148℃, a crystal transformation peak at 148℃-165℃, and a melting point of 216℃; the weight loss before 60℃ is about 1.0%, and the weight loss before 150℃ is about 10.8%, which is about 0.5 dichloromethane molecules (theoretical value 11.3%), and the decomposition temperature is about 371℃ (see Figure 3 , Figure 4 ); 1 The H-NMR graph shows that the peak is the peak position of dichloromethane (see Figure 7 ). PLM shows that the sample is a blocky crystal (see Figure 5 ); Hot stage XRPD showed that Form I sample was converted to Form 1b when heated to 75°C (see Figure 6 ), and then continue to heat up to 160°C to transform into Form II + Form III, and then cool down to room temperature to still be Form II + Form III; the hot stage XRPD shows that the Form I sample degrades after heating to melting.

[0138] According to the TGA weight loss of about 10.8% before 150°C and the presence of a dichloromethane solvent peak in the H-NMR spectrum, it can be determined that the 7-azaindole compound crystal form I prepared according to the prior art (application number: 202211018957.X) is a dichloromethane solvate. Dichloromethane is an unstable halogenated hydrocarbon with mutagenicity or genotoxicity. Studies have shown that dichloromethane damages DNA due to its toxic effects caused by its metabolic conversion to formaldehyde, resulting in DNA breakage, cross-linking and adduct formation. In the Ames test, dichloromethane has a significant mutagenic effect on the test strains TA98 and TA100 (Edited by the Ministry of Environmental Protection. National List of Environmental Health Risks of Pollutants - Chemistry - Volume 1 [M]. 2009).

[0139] In addition, according to the ICH guideline Q3C, dichloromethane is a Class 2 solvent, which is a "non-genotoxic animal carcinogen, or a solvent that may cause other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents that may have other serious but reversible toxicities." According to the above guidelines, it must be controlled at a PDE limit of 6mg / day. The dichloromethane content in Form I is as high as about 10%, which obviously poses a serious safety risk to human health and is not suitable for development as a pharmaceutical crystal form. On the other hand, the solvate has poor stability and is prone to crystal transformation at around 75°C, and transforms into a mixed crystal. Different crystal forms have different bioavailability. During the storage process of Form I, there will inevitably be problems such as unstable crystal composition ratio and unstable quality, which will affect the efficacy and safety of the drug.

[0140] Example 2

[0141] Weigh 30 mg of the 7-azaindole compound prepared in Example 1, add 4 ml of dichloromethane, dissolve under ultrasonication, and evaporate to dryness at 40° C. to obtain a solid.

[0142] The obtained solid X-ray diffraction pattern showed that it was Form I.

[0143] Example 3

[0144] 30 mg of the 7-azaindole compound prepared in Example 1 was weighed, 1 ml of acetonitrile and 1 ml of water were added to form a suspension, which was stirred at room temperature for 4 days and centrifuged. The obtained solid was dried at 45° C. to obtain a white solid.

[0145] The obtained white solid X-ray diffraction pattern shows that the 2θ angle has characteristic diffraction peaks at 8.4°, 12.8°, 15.8°, 16.8°, 18.6°, 20.3°, etc. (see Figure 8 , Fig. 9 ); TGA / DSC thermal analysis results show that the melting point is 223°C, the weight loss before 100°C is about 0.7%, it is a surface solvent, and the decomposition temperature is about 371°C (see Fig.10 , Fig.11 ). DVS hygroscopicity analysis results show that the weight change is <0.2% (w / w) in an environment with humidity of 0%RH-80%RH, and it is almost non-hygroscopic (see Fig.12 , Fig.13 ); PLM shows that the sample is fine crystals (see Fig.14 ); The white solid obtained by the above preparation method is crystal form II.

[0146] Example 4

[0147] 30 mg of the 7-azaindole compound prepared in Example 1 was weighed, and 2 ml of methanol was added to form a suspension. The suspension was stirred at room temperature for 4 days and centrifuged. The obtained solid was dried at 45° C. to obtain a white solid.

[0148] The obtained solid X-ray diffraction pattern showed that it was Form II.

[0149] Example 5

[0150] 30 mg of the 7-azaindole compound prepared in Example 1 was weighed, and 2 ml of ethanol was added to form a suspension. The suspension was stirred at room temperature for 4 days, centrifuged, and the obtained solid was dried at 45° C. to obtain a white solid.

[0151] The obtained solid X-ray diffraction pattern showed that it was Form II.

[0152] Example 6

[0153] 30 mg of the 7-azaindole compound prepared in Example 1 was weighed, and 2 ml of acetone was added to form a suspension. The suspension was stirred at room temperature for 4 days, centrifuged, and the obtained solid was dried at 45° C. to obtain a white solid.

[0154] The obtained solid X-ray diffraction pattern showed that it was Form II.

[0155] Example 6B

[0156] 30 mg of the 7-azaindole compound prepared in Example 1 was weighed, 1 ml of acetonitrile and 1 ml of butyl acetate were added to form a suspension, which was stirred at room temperature for 4 days and centrifuged. The obtained solid was dried at 45° C. to obtain a white solid.

[0157] The obtained solid X-ray diffraction pattern showed that it was Form II.

[0158] Example 7

[0159] Weigh 30 mg of the 7-azaindole compound prepared in Example 1, add 4 ml of methanol, dissolve under ultrasonication, and evaporate to dryness in an open air at 40° C. to obtain a solid.

[0160] The obtained solid X-ray diffraction pattern showed that it was Form II.

[0161] Example 8

[0162] Weigh 30 mg of the 7-azaindole compound prepared in Example 1, add 3 ml of methanol, heat to 60° C. to dissolve, filter, and stir at 4° C. overnight; precipitate a solid, centrifuge, and vacuum dry at 45° C. overnight to obtain a solid.

[0163] The obtained solid X-ray diffraction pattern showed that it was Form II.

[0164] Example 9

[0165] Weigh 30 mg of the 7-azaindole compound prepared in Example 1, add 3 ml of acetone and 2 ml of water, heat to 60°C to dissolve, filter, and stir at 4°C overnight; precipitate a solid, centrifuge, and vacuum dry at 45°C overnight to obtain a solid.

[0166] The obtained solid X-ray diffraction pattern showed that it was Form II.

[0167] Example 10

[0168] Weigh 30 mg of the 7-azaindole compound prepared in Example 1, add 4 ml of n-propanol and 1 ml of ethyl acetate, heat to 60°C to dissolve, filter, and stir at 4°C overnight; precipitate a solid, centrifuge, and vacuum dry at 45°C overnight to obtain a solid.

[0169] The obtained solid X-ray diffraction pattern showed that it was Form II.

[0170] Embodiment 11

[0171] 200 mg of the 7-azaindole compound prepared in Example 1 was weighed, and 13.5 ml of ethyl acetate was added to form a suspension. The suspension was stirred at room temperature for 4 days and centrifuged. The obtained solid was dried at 45° C. to obtain a white solid.

[0172] The obtained white solid X-ray diffraction pattern shows that the 2θ angle has characteristic diffraction peaks at 9.6°, 14.7°, 19.2°, 20.1°, 21.7°, etc. (see Fig.15 , Fig.16 ); TGA / DSC thermal analysis results show that the melting point is 219°C, the weight loss before 100°C is about 0.1%, and the decomposition temperature is about 370°C (see Fig.17 , Fig.18 ). DVS hygroscopicity analysis results show that the weight gain is 0.3% (w / w) in an environment with humidity of 0% RH-80% RH, and it is slightly hygroscopic (see Fig.19 , Fig. 20 ); PLM shows that the sample is fine crystals (see Fig.21 ); The white solid obtained by the above preparation method is Form III.

[0173] Example 12

[0174] 30 mg of the 7-azaindole compound prepared in Example 1 was weighed, and 2 ml of water was added to form a suspension. The suspension was stirred at room temperature for 4 days, centrifuged, and the obtained solid was dried at 45° C. to obtain a white solid.

[0175] The obtained solid X-ray diffraction pattern showed that it was Form III.

[0176] Example 13

[0177] 30 mg of the 7-azaindole compound prepared in Example 1 was weighed, and 2 ml of ethyl acetate was added to form a suspension. The suspension was stirred at room temperature for 4 days and centrifuged. The obtained solid was dried at 45° C. to obtain a white solid.

[0178] The obtained solid X-ray diffraction pattern showed that it was Form III.

[0179] Embodiment 14

[0180] 30 mg of the 7-azaindole compound prepared in Example 1 was weighed, 0.5 ml of isopropanol and 1.0 ml of methyl tert-butyl ether were added to form a suspension, which was stirred at room temperature for 4 days and centrifuged. The obtained solid was dried at 45° C. to obtain a white solid.

[0181] The obtained solid X-ray diffraction pattern showed that it was Form III.

[0182] Embodiment 15

[0183] Weigh 30 mg of the 7-azaindole compound prepared in Example 1, add 0.4 ml of DMSO, heat and dissolve, and filter; add the above solution dropwise to 7 ml of water, stir at room temperature overnight, centrifuge, and dry the obtained solid at 45° C. to obtain a white solid.

[0184] The obtained solid X-ray diffraction pattern showed that it was Form III.

[0185] Example 16

[0186] Weigh 30 mg of the 7-azaindole compound prepared in Example 1, add 3 ml of methanol, heat and dissolve, filter; add 12 ml of methyl tert-butyl ether dropwise at room temperature, stir at room temperature overnight, centrifuge, and dry the obtained solid at 45°C to obtain a white solid.

[0187] The obtained solid X-ray diffraction pattern showed that it was Form III.

[0188] Embodiment 17

[0189] Weigh 15 mg of the sample prepared in Example 1, add 3 ml of ethanol, heat to dissolve, filter into 7 ml of n-heptane, stir at room temperature for 5 hours, centrifuge, and dry the obtained solid at 45° C. to obtain a white solid.

[0190] The obtained white solid X-ray diffraction pattern shows that the 2θ angle has characteristic diffraction peaks at 12.1°, 14.5°, 17.9°, and 18.7° (see Fig. 22 , Fig.23 ); TGA / DSC thermal analysis results show that the melting point is 214°C, the weight loss before 100°C is about 0.2%, and the decomposition temperature is about 370°C (see Fig.24 , Fig.25 ). DVS hygroscopicity analysis results show that the weight change is <0.2% (w / w) in an environment with humidity of 0%RH-80%RH, and it is almost non-hygroscopic (see Fig.26 , Fig. 27 ); PLM shows that the sample is fine crystals (see Fig.28 ); The white solid obtained by the above preparation method is Form IV.

[0191] Embodiment 18

[0192] Weigh 30 mg of the sample prepared in Example 1, add 7 ml of acetone, heat to dissolve, and filter; add 13 ml of n-heptane dropwise to the above solution, stir overnight at room temperature, centrifuge, and dry the obtained solid at 45°C to obtain a white solid.

[0193] The obtained solid X-ray diffraction pattern showed that it was Form IV.

[0194] Embodiment 19

[0195] Weigh 180 mg of the sample prepared in Example 1, add 48 mL of tetrahydrofuran, heat to dissolve, add 24 mL of n-heptane, keep the solution clear, filter, stir at 4°C overnight, centrifuge, and vacuum dry the obtained solid at 45°C overnight to obtain a solid.

[0196] The obtained white solid X-ray diffraction pattern shows that the 2θ angle has characteristic diffraction peaks at 7.3°, 8.9°, 14.5°, and 18.3° (see Fig.29 , Fig.30 ), TGA / DSC thermal analysis results show that there is an endothermic peak at 120℃-165℃, the melting point is 214℃, the weight loss before 150℃ is about 10.1%, which is about 0.5 tetrahydrofuran molecules (theoretical value 9.8%), and the decomposition temperature is about 369℃ (see Fig.31 , Fig.32 ). DVS hygroscopicity analysis results show that the weight gain is 0.4% (w / w) in an environment with humidity of 0% RH-80% RH, and it is slightly hygroscopic (see Fig.33 , Fig.34 ); PLM shows that the sample is a block crystal (see Fig.35); Hot stage XRPD detection shows that when the temperature of Form V sample is raised to 165°C, it turns into Form II + Form III, and when it is lowered to room temperature, it is still Form II + Form III (see Fig.36 ); The white solid obtained by the above preparation method is crystal form V.

[0197] Embodiment 20

[0198] Weigh 30 mg of the sample prepared in Example 1, add it to 3 mL of chloroform and 2 ml of toluene, dissolve it by ultrasonication, filter it, and evaporate it to dryness at 40° C. The obtained solid is vacuum dried at 45° C. overnight to obtain Form VI.

[0199] The obtained white solid X-ray diffraction pattern shows that the 2θ angle has characteristic diffraction peaks at 6.1°, 6.8°, 7.1°, 18.0°, and 19.9° (see Fig.37 , Fig.38 ), TGA / DSC thermal analysis results show that there are two endothermic peaks at 20℃-100℃ and 115℃-160℃, the melting point is 203℃, the weight loss before 150℃ is about 10.0%, and the decomposition temperature is about 369℃ (see Fig.39 , Fig.40 ). The presence of toluene solvent peaks in the H-NMR spectrum determined that it was a toluene solvate; DVS hygroscopicity analysis results showed that the weight change was about 1.7% (w / w) under 0% RH-80% RH ambient humidity, and it was slightly hygroscopic (see Fig.41 , Fig.42 ); PLM shows that the sample is a block crystal (see Fig.43 ); Hot stage XRPD detection shows that when the temperature of Form VI sample is raised to 160°C, it turns into Form II + Form III + Form IV, and when it is lowered back to room temperature, it turns into Form II + Form III (see Fig.44 ); The white solid obtained by the above preparation method is Form VI.

[0200] Embodiment 21

[0201] Weigh 120 mg of the sample prepared in Example 1, add 4.0 mL of trifluoroethanol, sonicate to dissolve, add 4 mL of ethyl acetate, keep the solution clear, filter, and evaporate to dryness at 40° C. to obtain a solid.

[0202] The obtained white solid X-ray diffraction pattern shows that the 2θ angle has characteristic diffraction peaks at 9.1°, 11.6°, 14.3°, 19.4°, and 20.0° (see Fig.46 , Fig.47 ); TGA / DSC thermal analysis results show that there are two endothermic peaks at 15℃-80℃ and 85℃-172℃, the melting point is 203℃, the weight loss before 150℃ is about 16.0%, and the decomposition temperature is about 369℃ (see Fig.48 , Fig.49The DVS hygroscopicity analysis results show that the weight change is about 4.9% (w / w) in the environment humidity of 0% RH-80% RH, which is hygroscopic ( Figures 50-51 ); Hot stage XRPD detection shows that when the temperature of Form VII sample is raised to 172°C, it turns into Form III, and when it is lowered to room temperature, it is still Form III (see Fig.53 ). PLM shows that the sample is a rod-shaped crystal (see Fig.52 ); 1 The H-NMR graph shows that the peak at the marked position is the ethyl acetate peak (see Fig.54 ), which is 0.5 parts of ethyl acetate solvate, and is determined to be half ethyl acetate solvate; the white solid obtained by the above preparation method is Form VII.

[0203] Embodiment 22

[0204] Weigh 30 mg of the sample prepared in Example 1, add 5.0 mL of tetrahydrofuran and 3.0 mL of isopropyl acetate, dissolve at 60° C., filter, and evaporate to dryness at room temperature to obtain a solid.

[0205] The obtained white solid X-ray diffraction pattern shows that the 2θ angle has characteristic diffraction peaks at 7.2°, 9.2°, 18.7°, and 20.7° (see Fig.55 , Fig.56 ); TGA / DSC thermal analysis results show that there are two endothermic peaks at 75℃-113℃ and 125℃-170℃, the melting point is 219℃, the weight loss before 50℃ is about 1.2%, the weight loss before 80℃ is about 8.3%, the weight loss before 150℃ is about 11.5%, and the decomposition temperature is about 370℃ (see Fig.57 , Fig.58 ); Hot stage XRPD detection shows that when the temperature of Form VIII sample is raised to 175°C, it turns into Form II + Form III, and when it is lowered to room temperature, it is still Form II + Form III ( Fig.59 , Fig.60 and Fig.62 ). PLM shows that the sample is blocky crystals (see Fig.61 ); 1 The H-NMR graph shows that the peaks are tetrahydrofuran and isopropyl acetate (see Fig.63 ), is a cosolvate of isopropyl acetate\tetrahydrofuran; the white solid obtained by the above preparation method is Form VIII.

[0206] Embodiment 23

[0207] Weigh 60 mg each of the 7-azaindole compounds of Form II, Form III and Form IV, mix them evenly, and take samples for XRD characterization.

[0208] Divide the mixed sample into 6 portions;

[0209] Take 2.0 ml of the corresponding solvent (2 parts ethanol, 2 parts water, 2 parts acetone), add appropriate amount of Form I to each, and place under corresponding conditions for about 10 minutes (room temperature / 60°C). A suspension is formed, and filtered to obtain the corresponding saturated solution;

[0210] The saturated solution was added to 6 mixed samples respectively, stirred at a specified temperature, and samples were taken at different times for XRD characterization.

[0211]

[0212] See also Fig.64 and Fig.65 Through the above crystal transformation test, it can be seen that in the range of room temperature to 60°C, crystal form II is the most stable crystal form in water, ethanol, and acetone systems. In particular, water vapor is an unavoidable environmental condition in drug production, storage, and use. Crystal form II can better ensure the quality stability of drugs during production and storage compared to other crystal forms.

[0213] Embodiment 24

[0214] (1) Drawing of standard curve:

[0215] Instrument: High performance liquid chromatography (Agilent 1260 InfinityⅡ)

[0216] Chromatographic column: Agilent Poroshell HPH-C18 150×4.6mm, 4μm or equivalent

[0217] Mobile phase A: 0.1% triethylamine solution-methanol (90:10) (adjust pH to 7.0 with phosphoric acid)

[0218] Mobile phase B: methanol

[0219] Detection wavelength: 225nm

[0220] Flow rate: 0.8ml / min

[0221] Column temperature: 30°C

[0222] Injection volume: 10 μl

[0223] Run time: 26 minutes

[0224] Run the gradient table:

[0225]

[0226] Diluent: 70% methanol

[0227] Reference substance stock solution: Accurately weigh 10.09 mg of 7-azaindole compound reference substance into a 10 ml volumetric flask, add 70% methanol solution to dissolve by ultrasonication and dilute to the scale, and shake well. (about 1 mg / ml)

[0228] 0.10% limit solution: Accurately measure 1 ml of 10% limit solution into a 100 ml volumetric flask, dilute to scale with diluent, and shake well. (0.001 mg / ml)

[0229] 1.0% limit solution: Accurately measure 1 ml of 10% limit solution into a 10 ml volumetric bottle, dilute to the mark with diluent, and shake well. (0.01 mg / ml)

[0230] 10% limit solution: Accurately measure 1 ml of reference stock solution into a 100 ml volumetric flask, dilute to scale with diluent, and shake well. (0.1 mg / ml)

[0231] 100% limit solution: Accurately measure 1 ml of reference stock solution into a 10 ml volumetric flask, dilute to scale with diluent, and shake well. (0.1 mg / ml)

[0232] 200% limit solution: Accurately measure 2 ml of reference stock solution into a 10 ml volumetric bottle, dilute to scale with diluent, and shake well. (0.2 mg / ml)

[0233] The above limit solution was subjected to HPLC determination, with the solution concentration as the x-axis and the chromatographic peak area as the y-axis. The standard curve obtained by fitting is as follows: Fig.71 .

[0234] (2) Saturation solubility test:

[0235] Take 10 mL of each of different 0.1 mol / L hydrochloric acid, pH 6.8 PBS solution, simulated gastric juice (manufacturer: Biorelevant), simulated fasting intestinal juice (manufacturer: Biorelevant) and simulated postprandial intestinal juice (manufacturer: Biorelevant), add excess crystal form I, crystal form II, crystal form III and crystal form IV samples, shake at 100 rpm for 10 min in a 37°C constant temperature shaker, filter and take the supernatant after shaking, use HPLC to detect, obtain chromatograms of saturated solutions of different crystal forms in different media, substitute the peak area in the chromatogram into the standard curve to calculate the saturated solubility. The results are shown in the following table:

[0236]

[0237] The test results show that different crystal forms are not degraded in various media and are relatively stable. In hydrochloric acid media and simulated gastric fluid at pH 1.0 or so, the solubility of crystal forms II, III, and IV is slightly better than that of crystal form I. In pH 6.8 PBS media and simulated intestinal fluid, the solubility of crystal forms II, III, and IV is significantly better than that of crystal form I, especially the solubility of crystal form II in simulated fasting state intestinal fluid and simulated postprandial state intestinal fluid is more than three times that of crystal form I, which has significant technical effects. The solubility of different crystal forms in physiological states cannot be predicted, and the technical effect is also unexpected. The small intestine is the main absorption site of the drug, and the solubility of the drug in the small intestine directly affects the in vivo exposure of the drug. Therefore, the crystal forms II, III, and IV provided by the present invention have better solubility characteristics and better bioavailability than the crystal form I of the prior art, and are more suitable for development as a medicinal crystal form for oral solid preparations.

[0238] Embodiment 25

[0239] Stability test of factors affecting crystal form I and crystal form II:

[0240] Take appropriate amount of the crystal form I in Example 1 and the crystal form II in Example 3, and place them naked at high temperature 60°C ± 2°C (humidity 60% RH ± 5% RH) for 5 days; take appropriate amount of the crystal form I in Example 1 and the crystal form II in Example 3, and place them naked at high humidity 90% ± 5% RH (temperature 25°C ± 2°C) for 5 days. After 5 days, take samples for XRD characterization.

[0241]

[0242] The test results show that Form II is stable under high temperature and high humidity conditions, and Form I undergoes crystal transformation under high temperature and high humidity conditions. Form I prepared by the method of Example 1 (reference prior art application number: 202211018957.X) is prone to crystal transformation in the environment.

[0243] The crystalline form placed under the above high temperature and high humidity conditions was taken and the saturated solubility was measured by referring to the method of Example 24. The data are shown below

[0244]

[0245] *:NT means not tested

[0246] The test results show that after the crystal form I of the comparative document was placed in the influencing factor test conditions for 5 days, its solubility in intestinal fluid changed by more than 50% due to the change of the crystal form, and the degree of change in the intestinal fluid in the simulated post-meal state was about 2 times. In comparison, the solubility of the crystal form II in the intestinal fluid was very stable. Therefore, the crystal form I prepared by the prior art is prone to crystal transformation during actual application, and then there are problems of unstable absorption and unstable efficacy. The crystal form II of the present invention has stable crystal form and stable absorption under different environmental conditions, which can overcome the above technical defects.

Claims

1. A crystalline form of a 7-azaindole compound, characterized in that: The structural formula of the 7-azaindole compound is: The crystal form is: Form II, using X-ray diffraction, has characteristic diffraction peaks at 2θ angles of 8.4°, 12.8°, 15.8°, 16.8°, 18.6°, and 20.3°; Form III, using X-ray diffraction, has characteristic diffraction peaks at 2θ angles of 9.6°, 14.7°, 19.2°, 20.1°, and 21.7°; Form IV, using X-ray diffraction, has characteristic diffraction peaks at 2θ angles of 12.1°, 14.5°, 17.9°, and 18.7°; The error range of the 2θ angle is ±0.2°.

2. The crystal form according to claim 1, characterized in that: The crystal form II, using the X-ray diffraction method, also has characteristic diffraction peaks at 2θ angles of 11.7°, 16.2°, and 18.3°; The crystal form III, using X-ray diffraction method, also has characteristic diffraction peaks at 2θ angles of 10.4°, 14.2°, and 16.3°; The error range of the 2θ angle is ±0.2°.

3. A pharmaceutical composition, characterized in that: The composition comprises one or two of the crystalline form II, crystalline form III, and crystalline form IV as described in claim 1 or 2; and a pharmaceutically acceptable carrier or excipient, and the percentage of the crystalline form II, crystalline form III, and / or crystalline form IV in the total weight of the composition is more than 50%.

4. The pharmaceutical composition according to claim 3, characterized in that: The percentage of the crystal form II, crystal form III and / or crystal form IV in the total weight of the composition is above 80%.

5. The pharmaceutical composition according to claim 3, characterized in that: The percentage of the crystal form II, crystal form III and / or crystal form IV in the total weight of the composition is above 90%.

6. A method for preparing the crystal form II according to claim 1 or 2, characterized in that: Adding a solvent to the 7-azaindole compound to form a suspension, stirring at room temperature, separating the solid and the liquid, and drying to obtain Form II; the solvent is one or a combination of two or more of methanol, ethanol, acetone, acetonitrile, ethyl acetate, butyl acetate, and water; when the solvent includes ethyl acetate or water, the solvent is a mixed solvent of two or more of methanol, ethanol, acetone, acetonitrile, ethyl acetate, butyl acetate, and water; Or, adding a solvent to the 7-azaindole compound, dissolving it, and evaporating it to dryness; the solvent is one or a mixed solvent of two or more of methanol, ethanol, butanone, tetrahydrofuran, and water; Alternatively, an organic solvent is added to the 7-azaindole compound, heated to dissolve, filtered, stirred, cooled and crystallized; solid-liquid separation, and dried to obtain Form II; the organic solvent is one or a combination of two or more of acetone, methanol, ethanol, n-propanol, sec-butanol, acetonitrile and butanone.

7. A method for preparing the crystal form III according to claim 1 or 2, characterized in that: Adding a solvent to the 7-azaindole compound to form a suspension, stirring at room temperature, separating the solid and the liquid, and drying to obtain Form III; the solvent is one or a combination of two or more of water, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, isopropanol, toluene, and n-heptane; Or, add a first organic solvent to the 7-azaindole compound to form a solution, and then add a second organic solvent; stir to crystallize; separate the solid and liquid, and dry to obtain Form III; the first organic solvent is one of dimethyl sulfoxide, methanol, ethanol, and isopropanol, or a combination of two or more; the second organic solvent is one of water, methyl tert-butyl ether, and isopropyl ether, or a combination of two or more.

8. A method for preparing the crystalline form IV according to claim 1 or 2, characterized in that: A first organic solvent is added to the 7-azaindole compound to form a solution, and then a second organic solvent is added; stirring and crystallization is performed; solid-liquid separation is performed, and drying is performed to obtain Form IV; the first organic solvent is one or two of ethanol and acetone; and the second organic solvent is n-heptane.

9. Use of the crystal form according to claim 1 or 2 in the preparation of a drug for preventing or treating a disease caused by an abnormal JAK-STAT signaling pathway, wherein the abnormal JAK-STAT signaling pathway refers to abnormal expression of JAK3 kinase or changes in the JAK-STAT signaling pathway caused by its abnormal expression.

10. The use according to claim 9, characterized in that: The disease is selected from one or more autoimmune diseases, and the disease is selected from one or more of alopecia areata, lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, rheumatoid arthritis, psoriasis, complications caused by organ transplantation, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, vitiligo, autoimmune kidney damage, and autoimmune liver damage.

11. The use according to claim 9, characterized in that: The disease caused by abnormal JAK-STAT signaling pathway is lung injury, and the lung injury refers to radiation lung injury and acute lung injury.

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