Crystalline form, salt form, preparation method, pharmaceutical composition, and use of a 5-membered condensed 6-membered compound

Abstract

This invention discloses the crystalline form, salt form, preparation method, pharmaceutical composition, and use of a five-membered condensed six-membered compound. Specifically, this invention discloses the crystalline form, salt form, preparation method, pharmaceutical composition, and use of a five-membered condensed six-membered compound represented by formula I. The crystalline form and salt form of the compound of this invention have inhibitory effects on FLT3 and / or IRAK4. The crystalline form of this invention has a high single melting point, is thermodynamically stable, and has high crystallinity. The crystalline form of this invention exhibits good physical and chemical stability under any conditions of strong light irradiation, high temperature, and high humidity, and has extremely weak hygroscopicity. JPEG2026521654000137.jpg7365

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority to Chinese patent applications 202310748384.4, 202310744684.5, 202310748633.X, 202310746259.X, and 202410756994.3, filed on June 12, 2024. The full texts of the above Chinese patent applications are incorporated into this application by reference.

[0002] This invention relates to the crystalline form, salt form, preparation method, pharmaceutical composition, and use of a five-membered condensed six-membered compound. [Background technology]

[0003] FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase, and mutations in it are one of the most common genetic alterations and poor prognostic factors in patients with acute myeloid leukemia (AML). The main types of FLT3 mutations are internal tandem duplication mutations in the near-membrane domain (FLT3-ITD) and point mutations or deletions in the tyrosine kinase domain (FLT3-TKD), which account for approximately 30% of AML patients (Kiyoi H, Kawashima N, Ishikawa Y. FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development. Cancer Sci. 2020 Feb;111(2):312-322). Activated FLT3 causes abnormalities in multiple intracellular signaling pathways (RAS, PI3K, STAT5, etc.), leading to hematopoietic cell survival, proliferation, differentiation, and anti-apoptosis. Furthermore, the ratio of mutant to wild-type alleles, insertion site, ITD length, karyotype, and presence of NPM1 gene mutations may influence the prognostic role of FLT3-ITD in newly diagnosed FLT3-ITD mutant AML patients (Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019 Feb;33(2):299-312. Doi: 10.1038 / s41375-018-0357-9.). Because high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation do not adequately improve prognosis, and patients have short survival times and are prone to relapse, FLT3 kinase inhibitors have become a focus of research in AML treatment. First-generation FLT3 inhibitors, such as letaurtinib, sunitinib, sorafenib, ponatinib, and midostaurin, are broad-spectrum inhibitors that can inhibit multiple kinases. However, their efficacy is insufficient, and when used in combination with chemotherapy drugs, they do not show clear efficacy and significantly increase toxicity.For example, while midostaurin alone is insufficiently effective, its combination with cytarabine, daunorubicin, or cytarabine (FDA approved) can be used to treat adult FLT3-mutated AML. Second-generation FLT3 kinase inhibitors such as gilteritinib, crenolanib, and quizartinib offer higher selectivity, stronger activity, and lower toxicity, but still have some off-target effects.

[0004] Currently, three FLT3 inhibitors (quizartinib, gilteritinib, and midostaurin) are approved for sale in Japan and / or the United States as monotherapy or in combination with conventional chemotherapy agents for the treatment of AML patients. These inhibitors have shown good therapeutic responses in clinical practice and have improved the prognosis of AML patients to some extent. When used as monotherapy, the disease relapses rapidly, and both target-dependent and non-target-dependent resistance has already developed. Target-dependent mutations are commonly found in the activation loop (e.g., aspartate 835, D835) and gating residues (e.g., phenylalanine 691, F691), with the D835 mutation being the most common site of targeted resistance mutation. Activation of related signaling pathways can compensate for the inhibition of the FLT3 signaling pathway. Currently, some researchers are working to reduce the rate of non-targeted drug resistance by directly inhibiting related signaling pathways (such as PI3K / AKT and RAS / MEK / MAPK) or by inhibiting signaling pathways related to cell survival through drug combination therapy, but the effects remain limited (Rabik CA, Wang J, Pratilas CA. FLT3-IRAK dual targeting: an exciting new therapeutic option guided by adaptive activation of immune response pathways. Ann Transl Med. 2020 Apr;8(7):511.). After administration of quizartinib and gilteritinib for a certain period, pFLT3 and pSTAT5 expression decreased, but no significant inhibition of tumor cells was observed. In relapsed cases, elevated levels of IRAK4 phosphorylation were observed in a large number of cases, and when combined with IRAK4 inhibitors, tumor cell survival rates were again reduced, suggesting that IRAK4 can be used as a non-targeted drug resistance target.

[0005] Interleukin-1 receptor-related kinases (IRAKs) are serine / threonine protein kinases belonging to the tyrosine-like kinase (TLK) family, with IRAK1 and IRAK4 exhibiting kinase activity. IRAKs are located downstream of the Toll-like receptor and the IL-1R pathway and play a crucial role in innate immune signaling. TLR stimulation recruits MYD88, activating the receptor complex, which then forms a complex with IRAK4 to activate IRAK1. Subsequently, TRAF6 is activated by IRAK1, leading to NF-κB activation. Abnormal activation of the IRAK pathway in tumor cells may further accelerate disease progression through inflammatory responses in the tumor microenvironment (Gummadi VR, Boruah A, Ainan BR, Vare BR, Manda S, Gondle HP, Kumar SN, Mukherjee S, Gore ST, Krishnamurthy NR, Marappan S, Nayak SS, Nellore K, Balasubramanian WR, Bhumireddy A, Giri S, Gopinath S, Samiulla DS, Daginakatte G, Basavaraju A, Chelur S, Eswarappa R, Belliappa C, Subramanya HS, Booher RN, Ramachandra M, Samajdar S. Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies. ACS Med Chem Lett. 2020 Oct.) (14;11(12):2374-2381.) The development of dual-target compounds that target FLT3 / IRAK4 has potential clinical value and is expected to improve patient prognosis and reduce the likelihood of drug resistance development. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] This invention provides the crystalline form, salt form, preparation method, pharmaceutical composition, and use of a five-membered condensed six-membered compound. The crystalline form and salt form of the compound of this invention have inhibitory effects on FLT3 and / or IRAK4, and are expected to have potential clinical application value, improving patient prognosis and reducing the possibility of drug resistance development. [Means for solving the problem]

[0007] The present invention provides a crystalline form A of a five-membered condensed six-membered compound represented by formula I, which has characteristic peaks at positions 13.12±0.20°, 19.05±0.20°, 25.85±0.20°, and 26.73±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0008] [ka]

[0009] In some aspects of the present invention, the powder X-ray diffraction pattern is measured using Cu-Kα radiation spectral lines.

[0010] In some aspects of the present invention, the crystal form A has characteristic peaks at one or more of the following positions in a powder X-ray diffraction pattern represented by a 2θ angle: 7.84±0.20°, 10.25±0.20°, 20.96±0.20°, and 24.46±0.20°.

[0011] In some aspects of the present invention, the crystal form A has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 7.84±0.20°, 10.25±0.20°, 13.12±0.20°, 19.05±0.20°, 20.96±0.20°, 24.46±0.20°, 25.85±0.20°, and 26.73±0.20°.

[0012] The present invention provides a crystalline form A of a 5-membered fused 6-membered compound represented by Formula I, which has characteristic peaks at positions of 7.84 ± 0.20°, 10.25 ± 0.20°, 20.96 ± 0.20°, 22.36 ± 0.20°, and 25.85 ± 0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0013]

Chemical formula

[0014] The crystalline form A further has characteristic peaks at one or more positions of 11.33 ± 0.20°, 13.12 ± 0.20°, 14.43 ± 0.20°, 15.52 ± 0.20°, 16.78 ± 0.20°, 17.55 ± 0.20°, 20.77 ± 0.20°, 22.92 ± 0.20°, and 24.46 ± 0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0015] In some embodiments of the present invention, the crystalline form A has diffraction peaks at diffraction angles shown in the following table in a powder X-ray diffraction pattern represented by a 2θ angle.

[0016]

Table 1

[0017]

Table 2

[0018] In some embodiments of the present invention, the diffraction peaks, d values, and peak height percentages in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form A are as shown in the following table.

[0019]

Table 3

[0020] I

Table 4

[0021] In some embodiments of the present invention, the powder X-ray diffraction pattern (XRPD) of crystal form A is basically as shown in Figure 1.

[0022] In some aspects of the present invention, the crystal form A has an endothermic peak starting point at 231.31±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 232.04±2°C, and its enthalpy value is 111.300 J / g.

[0023] In some aspects of the present invention, the crystal form A has an endothermic peak starting point at 237.74±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 244.16±2°C, and its enthalpy value is 69.104 J / g.

[0024] In some aspects of the present invention, the differential scanning calorimetry (DSC) analysis chart of crystal form A is basically as shown in Figure 2.

[0025] In some aspects of the present invention, the crystal form A has a weight loss of 0.428% at 200°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage.

[0026] In some aspects of the present invention, the analysis chart of crystal form A by thermogravimetric analysis (TGA) is basically as shown in Figure 2.

[0027] The present invention provides a crystalline form C of a five-membered condensed six-membered compound represented by formula I, which has characteristic peaks at positions 11.05±0.20°, 14.21±0.20°, 18.83±0.20°, and 28.80±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0028] [ka]

[0029] In some aspects of the present invention, the crystal form C has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 7.02±0.20°, 9.78±0.20°, 20.44±0.20°, and 23.98±0.20°.

[0030] In some aspects of the present invention, the crystal form C has characteristic peaks at the following positions in a powder X-ray diffraction pattern represented by a 2θ angle: 7.02±0.20°, 9.78±0.20°, 11.05±0.20°, 14.21±0.20°, 18.83±0.20°, 20.44±0.20°, 23.98±0.20°, and 28.80±0.20°.

[0031] The present invention provides a crystalline form C of a five-membered condensed six-membered compound represented by formula I, which has characteristic peaks at positions 7.02±0.20°, 9.78±0.20°, 11.05±0.20°, 14.21±0.20°, 18.83±0.20°, and 20.44±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0032] [ka]

[0033] In some aspects of the present invention, the crystal form C has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 11.59±0.20°, 18.19±0.20°, 21.17±0.20°, 22.87±0.20°, 23.98±0.20°, 24.19±0.20°, 25.71±0.20°, and 28.80±0.20°.

[0034] In some aspects of the present invention, the crystal form C has diffraction peaks at the diffraction angles shown in the following table in a powder X-ray diffraction pattern represented by a 2θ angle.

[0035] [Table 5]

[0036] [Table 6]

[0037] In some aspects of the present invention, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form C are as shown in the table below.

[0038] [Table 7]

[0039] [Table 8]

[0040] In some embodiments of the present invention, the powder X-ray diffraction pattern (XRPD) of the crystalline form C is basically as shown in Figure 5.

[0041] In some aspects of the present invention, the crystalline form C has an endothermic peak starting point at 63.69±2°C in an analysis chart by differential scanning calorimetry, further reaching the peak value of the endothermic peak at 82.10±2°C, and its enthalpy value is 61.396 J / g.

[0042] In some aspects of the present invention, the crystalline form C has an endothermic peak starting point at 126.27±2°C in an analysis chart by differential scanning calorimetry, further reaching the peak value of the endothermic peak at 134.20±2°C, and its enthalpy value is 42.089 J / g.

[0043] In some aspects of the present invention, the crystalline form C has an endothermic peak starting point at 230.61±2°C in an analysis chart by differential scanning calorimetry, further reaching the peak value of the endothermic peak at 231.73±2°C, and further having an enthalpy value of 103.46 J / g.

[0044] In some aspects of the present invention, the differential scanning calorimetry (DSC) analysis chart of the crystalline form C is basically as shown in Figure 6.

[0045] In some aspects of the present invention, the crystalline form C has a weight loss of 3.778% at 73.91°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage.

[0046] In some aspects of the present invention, the analysis chart of the crystalline form C by thermogravimetric analysis (TGA) is basically as shown in Figure 6.

[0047] The present invention provides crystalline form B of a five-membered condensed six-membered compound represented by formula I, which has characteristic peaks at positions 9.94±0.20°, 11.81±0.20°, 16.26±0.20°, and 18.47±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0048] [ka]

[0049] In some aspects of the present invention, the crystal form B has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 11.41±0.20°, 14.41±0.20°, 20.73±0.20°, and 23.39±0.20°.

[0050] In some aspects of the present invention, crystal form B has characteristic peaks at the following positions in a powder X-ray diffraction pattern represented by a 2θ angle: 9.94±0.20°, 11.41±0.20°, 11.81±0.20°, 14.41±0.20°, 16.26±0.20°, 18.47±0.20°, 20.73±0.20°, and 23.39±0.20°.

[0051] In some aspects of the present invention, the crystal form B has diffraction peaks at the diffraction angles shown in the following table in a powder X-ray diffraction pattern represented by a 2θ angle.

[0052] [Table 9]

[0053] In some aspects of the present invention, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of crystal form B are as shown in the table below.

[0054] [Table 10]

[0055] In some embodiments of the present invention, the powder X-ray diffraction pattern (XRPD) of crystal form B is basically as shown in Figure 3.

[0056] In some aspects of the present invention, the crystal form B has an endothermic peak starting point at 60.85±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 72.84±2°C, and its enthalpy value is 32.752 J / g.

[0057] In some aspects of the present invention, the crystal form B has an endothermic peak starting point at 151.04±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 153.19±2°C, and its enthalpy value is 4.135 J / g.

[0058] In some aspects of the present invention, the crystal form B has an endothermic peak starting point at 230.51±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 231.37±2°C, and its enthalpy value is 113.950 J / g.

[0059] In some aspects of the present invention, the differential scanning calorimetry (DSC) analysis chart of crystal form B is basically as shown in Figure 4.

[0060] In some aspects of the present invention, crystal form B exhibits a weight loss of 4.741% at 122.68°C in an analysis chart by thermogravimetric analysis, where "%" represents a mass percentage.

[0061] In some aspects of the present invention, the analysis chart of crystal form B by thermogravimetric analysis (TGA) is basically as shown in Figure 4.

[0062] The present invention provides a crystalline form D of a 5-membered condensed 6-membered compound represented by formula I, which has characteristic peaks at positions 9.51±0.20°, 15.35±0.20°, 19.27±0.20°, and 24.20±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0063] [ka]

[0064] In some aspects of the present invention, the crystal form D has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 9.90±0.20°, 20.01±0.20°, 20.75±0.20°, and 29.18±0.20°.

[0065] In some aspects of the present invention, the crystal form D has characteristic peaks at the following positions in a powder X-ray diffraction pattern represented by a 2θ angle: 9.51±0.20°, 9.90±0.20°, 15.35±0.20°, 19.27±0.20°, 20.01±0.20°, 20.75±0.20°, 24.20±0.20°, and 29.18±0.20°.

[0066] In some aspects of the present invention, the crystal form D has diffraction peaks at the diffraction angles shown in the following table in a powder X-ray diffraction pattern represented by a 2θ angle.

[0067] [Table 11]

[0068] In some aspects of the present invention, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form D are as shown in the table below.

[0069] [Table 12]

[0070] In some embodiments of the present invention, the powder X-ray diffraction pattern (XRPD) of crystal form D is basically as shown in Figure 7.

[0071] In some aspects of the present invention, the crystal form D has an endothermic peak starting point at 231.13±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 232.25±2°C, and its enthalpy value is 115.52 J / g.

[0072] In some aspects of the present invention, the differential scanning calorimetry (DSC) analysis chart of the crystal form D is basically as shown in Figure 8.

[0073] In some aspects of the present invention, the crystal form D has a weight loss of 2.826% at 116.38°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage.

[0074] In some aspects of the present invention, the analysis chart of the crystal form D by thermogravimetric analysis (TGA) is basically as shown in Figure 8.

[0075] The present invention provides a crystalline form E of a five-membered condensed six-membered compound represented by formula I, which has characteristic peaks at positions of 9.21±0.20°, 10.61±0.20°, 13.93±0.20°, 18.66±0.20°, and 23.43±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0076] [ka]

[0077] In some aspects of the present invention, the crystal form E has characteristic peaks at one or more positions among 20.06±0.20°, 21.85±0.20°, and 28.25±0.20° in the powder X-ray diffraction pattern represented by the 2θ angle.

[0078] In some aspects of the present invention, the crystal form E has characteristic peaks at the following positions in a powder X-ray diffraction pattern represented by a 2θ angle: 9.21±0.20°, 10.61±0.20°, 13.93±0.20°, 18.66±0.20°, 20.06±0.20°, 21.85±0.20°, 23.43±0.20°, and 28.25±0.20°.

[0079] In some aspects of the present invention, the crystal form E has diffraction peaks at the diffraction angles shown in the following table in a powder X-ray diffraction pattern represented by a 2θ angle.

[0080] [Table 13]

[0081] In some aspects of the present invention, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form E are as shown in the table below.

[0082] [Table 14]

[0083] In some embodiments of the present invention, the powder X-ray diffraction pattern (XRPD) of crystal form E is basically as shown in Figure 9.

[0084] In some aspects of the present invention, the crystal form E has an endothermic peak starting point at 48.59±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 51.08±2°C, and its enthalpy value is 5.451 J / g.

[0085] In some aspects of the present invention, the crystal form E has an endothermic peak starting point at 90.07±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 95.66±2°C, and its enthalpy value is 19.797 J / g.

[0086] In some aspects of the present invention, the crystal form E has an endothermic peak starting point at 225.15±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 228.25±2°C, and its enthalpy value is 86.445 J / g.

[0087] In some aspects of the present invention, the differential scanning calorimetry (DSC) analysis chart of the crystal form E is basically as shown in Figure 10.

[0088] In some aspects of the present invention, the crystal form E has a weight loss of 5.585% at 119.49°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage.

[0089] In some aspects of the present invention, the analysis chart of the crystal form E by thermogravimetric analysis (TGA) is basically as shown in Figure 10.

[0090] The present invention provides a crystalline form F of a five-membered condensed six-membered compound represented by formula I, which has characteristic peaks at positions of 5.53±0.20°, 5.93±0.20°, 10.38±0.20°, and 22.37±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0091] [ka]

[0092] In some aspects of the present invention, the crystal form F has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 10.21±0.20°, 11.11±0.20°, 16.72±0.20°, and 25.78±0.20°.

[0093] In some aspects of the present invention, the crystal form F has characteristic peaks at the following positions in a powder X-ray diffraction pattern represented by a 2θ angle: 5.53±0.20°, 5.93±0.20°, 10.21±0.20°, 10.38±0.20°, 11.11±0.20°, 16.72±0.20°, 22.37±0.20°, and 25.78±0.20°.

[0094] In some aspects of the present invention, the crystal form F has diffraction peaks at the diffraction angles shown in the following table in a powder X-ray diffraction pattern represented by a 2θ angle.

[0095] [Table 15]

[0096] In some aspects of the present invention, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form F are as shown in the table below.

[0097] [Table 16]

[0098] In some embodiments of the present invention, the powder X-ray diffraction pattern (XRPD) of the crystalline form F is basically as shown in Figure 11.

[0099] In some aspects of the present invention, the crystalline form F has an endothermic peak starting point at 49.64±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 52.43±2°C, and its enthalpy value is 3.400 J / g.

[0100] In some aspects of the present invention, the crystalline form F has an endothermic peak starting point at 97.99±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 103.02±2°C, and its enthalpy value is 9.028 J / g.

[0101] In some aspects of the present invention, the crystalline form F has an endothermic peak starting point at 225.07±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 226.71±2°C, and its enthalpy value is 92.201 J / g.

[0102] In some aspects of the present invention, the differential scanning calorimetry (DSC) analysis chart of the crystal form F is basically as shown in Figure 12.

[0103] In some aspects of the present invention, the crystal form F has a weight loss of 1.066% at 127.37°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage.

[0104] In some aspects of the present invention, the analysis chart of the crystal form F by thermogravimetric analysis (TGA) is basically as shown in Figure 12.

[0105] The present invention provides a crystalline form G of a five-membered condensed six-membered compound represented by formula I, which has characteristic peaks at positions 9.74±0.20°, 13.56±0.20°, 16.39±0.20°, and 24.51±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0106] [ka]

[0107] In some aspects of the present invention, the crystal form G has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 7.09±0.20°, 18.50±0.20°, 20.94±0.20°, and 23.36±0.20°.

[0108] In some aspects of the present invention, the crystal form G has characteristic peaks at the following positions in a powder X-ray diffraction pattern represented by a 2θ angle: 7.09±0.20°, 9.74±0.20°, 13.56±0.20°, 16.39±0.20°, 18.50±0.20°, 20.94±0.20°, 23.36±0.20°, and 24.51±0.20°.

[0109] The present invention provides a crystalline form G of a five-membered condensed six-membered compound represented by formula I, which has characteristic peaks at positions of 9.74±0.20°, 13.56±0.20°, 11.07±0.20°, 11.45±0.20°, 16.39±0.20°, 20.94±0.20°, and 23.36±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

[0110] [ka]

[0111] In some aspects of the present invention, the crystal form G has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 7.09±0.20°, 14.28±0.20°, 15.61±0.20°, 18.5±0.20°, 20.36±0.20°, and 24.51±0.20°.

[0112] In some aspects of the present invention, the crystal form G has diffraction peaks at the diffraction angles shown in the following table in a powder X-ray diffraction pattern represented by a 2θ angle.

[0113] [Table 17]

[0114] In some aspects of the present invention, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form G are as shown in the table below.

[0115] [Table 18]

[0116] In some embodiments of the present invention, the powder X-ray diffraction pattern (XRPD) of the crystalline form G is basically as shown in Figure 13.

[0117] In some aspects of the present invention, the crystalline form G has an endothermic peak starting point at 63.20±2℃ in an analysis chart by differential scanning calorimetry, further reaching the peak value of the endothermic peak at 76.01±2℃, and its enthalpy value is 25.610 J / g.

[0118] In some aspects of the present invention, the crystalline form G has an endothermic peak starting point at 150.82±2℃ in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 153.33±2℃, and its enthalpy value is 12.882 J / g.

[0119] In some aspects of the present invention, the crystalline form G has an endothermic peak starting point at 230.69±2°C in an analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 231.37±2°C, and its enthalpy value is 111.380 J / g.

[0120] In some aspects of the present invention, the differential scanning calorimetry (DSC) analysis chart of the crystal form G is basically as shown in Figure 14.

[0121] In some aspects of the present invention, the crystal form G has a weight loss of 3.405% at 130.90°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage.

[0122] In some aspects of the present invention, the analysis chart of the crystal form G by thermogravimetric analysis (TGA) is basically as shown in Figure 14.

[0123] The present invention further provides a method for preparing the crystalline form G of an indazole compound represented by formula I, the method comprising the operation of lowering the temperature of a five-membered condensed six-membered compound solution represented by formula I to obtain the crystalline form, wherein the solvent of the solution is an alcohol-based solvent.

[0124] In one embodiment, the alcoholic solvent may be methanol.

[0125] In one embodiment, in the method for preparing crystalline form G, the mass-volume ratio of the 5-membered condensed 6-membered compound represented by formula I to the alcohol-based solvent may be (10-100):1 mg / mL, for example, 50:1 mg / mL.

[0126] In one embodiment, in a method for preparing crystalline form G, the temperature of the solution is 30 to 70°C, for example, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, and 70°C.

[0127] In one embodiment, in the method for preparing crystalline form G, the cooling rate is 3 to 10°C / hour, for example, 5°C / hour.

[0128] In one embodiment, in the method for preparing crystalline form G, the cooling time is 1 to 20 hours, preferably 14 hours.

[0129] The present invention provides a salt of a five-membered condensed six-membered compound represented by formula I, wherein the salt is a hydrochloride salt, a sulfate salt, a phosphate salt, a sodium salt, or a potassium salt.

[0130] [ka]

[0131] In one embodiment, the hydrochloride salt is preferably a monohydrochloride salt (meaning that the molar ratio of hydrochloric acid to compound I in the hydrochloride salt is 1:1).

[0132] In one embodiment, the sulfate is preferably a monosulfate (where the molar ratio of sulfuric acid to compound I in the sulfate is 1:1).

[0133] In one embodiment, the phosphate is preferably a monophosphate (meaning that the molar ratio of phosphoric acid to compound I in the phosphate is 1:1).

[0134] In one embodiment, the sodium salt is preferably a monosodium salt (a monosodium salt means that the molar ratio of sodium ions in the sodium salt to the anions of compound I is 1:1).

[0135] In one embodiment, the potassium salt is preferably a monopotassium salt (meaning that the molar ratio of potassium ions in the potassium salt to the anions of compound I is 1:1).

[0136] In one embodiment, the hydrochloride salt is crystalline form A, and in a powder X-ray diffraction pattern represented by a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 10.81±0.20°, 20.20±0.20°, 22.70±0.20°, 23.74±0.20°, 29.89±0.20°, and 39.32±0.20°.

[0137] In one embodiment, the crystalline form A of the hydrochloride salt has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 11.72±0.20°, 21.88±0.20°, 28.61±0.20°, and 31.26±0.20°.

[0138] In one embodiment, the crystalline form A of the hydrochloride salt has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 10.81±0.20°, 11.72±0.20°, 20.20±0.20°, 21.88±0.20°, 22.70±0.20°, 23.74±0.20°, 28.61±0.20°, 29.89±0.20°, 31.26±0.20°, and 39.32±0.20°.

[0139] In one embodiment, in the case of the crystalline form A of the hydrochloride salt, the diffraction peaks in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form A may further be as shown in the table below.

[0140] [Table 19]

[0141] [Table 20]

[0142] In one embodiment, for the crystalline form A of the hydrochloride salt, the diffraction peaks and relative intensities in the powder X-ray diffraction pattern, represented by the 2θ angle and relative intensity of the crystalline form A, may be as shown in the following table.

[0143] [Table 21]

[0144] [Table 22]

[0145] In one embodiment, the powder X-ray diffraction pattern (XRPD) of crystalline form A of the hydrochloride salt is basically as shown in Figure 17.

[0146] In one embodiment, the crystalline form A of the hydrochloride salt shows a weight loss of 2.070% at 125.06°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage. In an analysis chart by differential scanning calorimetry, it has an endothermic peak starting at 184.04±2°C, and further reaches its peak value at 188.62±2°C, with an enthalpy value of 344.80 J / g.

[0147] In one embodiment, the thermogravimetric spectrum and differential scanning calorimetry chart of crystalline form A of the hydrochloride salt are basically as shown in Figure 18.

[0148] In one embodiment, the hydrochloride salt is crystalline form B, and in a powder X-ray diffraction pattern represented by a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 8.2±0.20°, 13.28±0.20°, 18.87±0.20°, 25.07±0.20°, 34.76±0.20°, and 35.21±0.20°.

[0149] In one embodiment, the crystalline form B of the hydrochloride salt has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 13.93±0.20°, 15.28±0.20°, 27.18±0.20°, and 28.99±0.20°.

[0150] In one embodiment, the crystalline form B of the hydrochloride salt has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 8.2±0.20°, 13.28±0.20°, 13.93±0.20°, 15.28±0.20°, 18.87±0.20°, 25.07±0.20°, 27.18±0.20°, 28.99±0.20°, 34.76±0.20°, and 35.21±0.20°.

[0151] In one embodiment, in the case of crystalline form B of the hydrochloride salt, the diffraction peaks in the powder X-ray diffraction pattern represented by the 2θ angle of crystalline form B may further be as shown in the table below.

[0152] [Table 23]

[0153] [Table 24]

[0154] In one embodiment, for the crystalline form B of the hydrochloride salt, the diffraction peaks and relative intensities in the powder X-ray diffraction pattern, represented by the 2θ angle and relative intensity of the crystalline form B, may further be as shown in the following table.

[0155] [Table 25]

[0156] [Table 26]

[0157] In one embodiment, the powder X-ray diffraction pattern (XRPD) of crystalline form B of the hydrochloride salt is basically as shown in Figure 19.

[0158] In one embodiment, crystalline form B of the hydrochloride salt shows a weight loss of 7.216% at 96.43°C in an analysis chart by thermogravimetric analysis, where "%" represents mass percentage. In an analysis chart by differential scanning calorimetry, it has an endothermic peak starting at 173.54±2°C, and further reaches its peak value at 184.54±2°C, with an enthalpy value of 259.36 J / g.

[0159] In one embodiment, the thermogravimetric spectrum and differential scanning calorimetry chart of crystalline form B of the hydrochloride salt are basically as shown in Figure 20.

[0160] In one embodiment, the sulfate is in crystalline form A, and in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 19.62±0.20°, 27.19±0.20°, 28.70±0.20°, 32.36±0.20°, 33.43±0.20°, and 34.15±0.20°.

[0161] In one embodiment, the crystalline form A of the sulfate has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 14.94±0.20°, 17.42±0.20°, 22.76±0.20°, and 26.46±0.20°.

[0162] In one embodiment, the crystalline form A of the sulfate has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 14.94±0.20°, 17.42±0.20°, 19.62±0.20°, 22.76±0.20°, 26.46±0.20°, 27.19±0.20°, 28.70±0.20°, 32.36±0.20°, 33.43±0.20°, and 34.15±0.20°.

[0163] In one embodiment, in the case of the crystalline form A of the sulfate, the diffraction peaks in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form A may further be as shown in the table below.

[0164] [Table 27]

[0165] [Table 28]

[0166] In one embodiment, for the crystalline form A of the sulfate, the diffraction peaks and relative intensities in the powder X-ray diffraction pattern, represented by the 2θ angle and relative intensity of the crystalline form A, may further be as shown in the table below.

[0167] [Table 29]

[0168] [Table 30]

[0169] In one embodiment, the powder X-ray diffraction pattern (XRPD) of crystalline form A of the sulfate is basically as shown in Figure 21.

[0170] In one embodiment, the crystalline form A of the sulfate shows a weight loss of 3.880% at 118.49°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage. In an analysis chart by differential scanning calorimetry, it has an endothermic peak starting at 149.86±2°C, and further reaches its peak value at 160.23±2°C, with an enthalpy value of 229.21 J / g.

[0171] In one embodiment, the thermogravimetric spectrum and differential scanning calorimetry chart of crystalline form A of the sulfate are basically as shown in Figure 22.

[0172] In one embodiment, the sulfate is in crystalline form B, and in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 15.86±0.20°, 16.53±0.20°, 20.05±0.20°, 28.46±0.20°, and 30.59±0.20°.

[0173] In one embodiment, the crystalline form B of the sulfate has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 9.00±0.20°, 12.52±0.20°, 21.21±0.20°, and 22.36±0.20°.

[0174] In one embodiment, the crystalline form B of the sulfate has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 9.00±0.20°, 12.52±0.20°, 15.86±0.20°, 16.53±0.20°, 20.05±0.20°, 21.21±0.20°, 22.36±0.20°, 28.46±0.20°, and 30.59±0.20°.

[0175] In one embodiment, in the case of the crystalline form B of the sulfate, the diffraction peaks in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form B may further be as shown in the table below.

[0176] [Table 31]

[0177] In one embodiment, for the crystalline form B of the sulfate, the diffraction peaks and relative intensities in the powder X-ray diffraction pattern, represented by the 2θ angle and relative intensity of the crystalline form B, may further be as shown in the table below.

[0178] [Table 32]

[0179] In one embodiment, the powder X-ray diffraction pattern (XRPD) of crystalline form B of the sulfate is basically as shown in Figure 23.

[0180] In one embodiment, crystalline form B of the sulfate shows a weight loss of 6.895% at 92.04°C in an analysis chart by thermogravimetric analysis, where "%" represents mass percentage. In an analysis chart by differential scanning calorimetry, it has an endothermic peak starting at 126.34±2°C, reaches its peak value at 139.98±2°C, and its enthalpy value is 230.50 J / g.

[0181] In one embodiment, the thermogravimetric spectrum and differential scanning calorimetry chart of crystalline form B of the sulfate are basically as shown in Figure 24.

[0182] In one embodiment, the sulfate is in crystalline form C, and in a powder X-ray diffraction pattern represented by a 2θ angle using Cu-Kα rays, it has characteristic peaks at positions 7.70±0.20°, 12.87±0.20°, 19.87±0.20°, 21.55±0.20°, and 25.94±0.20°.

[0183] In one embodiment, the crystalline form C of the sulfate has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 8.74±0.20°, 10.67±0.20°, 18.64±0.20°, and 19.05±0.20°.

[0184] In one embodiment, the crystalline form C of the sulfate has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 7.70±0.20°, 8.74±0.20°, 10.67±0.20°, 12.87±0.20°, 18.64±0.20°, 19.05±0.20°, 19.87±0.20°, 21.55±0.20°, and 25.94±0.20°.

[0185] In one embodiment, in the case of the crystalline form C of the sulfate, the diffraction peak in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form C is also as shown in the table below.

[0186] [Table 33]

[0187] In one embodiment, for the crystalline form C of the sulfate, the diffraction peaks and relative intensities in the powder X-ray diffraction pattern, represented by the 2θ angle and relative intensity of the crystalline form C, may further be as shown in the table below.

[0188] [Table 34]

[0189] In one embodiment, the powder X-ray diffraction pattern (XRPD) of the crystalline form C of the sulfate is basically as shown in Figure 25.

[0190] In one embodiment, the crystalline form C of the sulfate shows a weight loss of 10.471% at 102.19°C in an analysis chart by thermogravimetric analysis, where "%" represents mass percentage. In an analysis chart by differential scanning calorimetry, it has an endothermic peak starting at 117.30±2°C, and further reaches its peak value at 122.26±2°C, with an enthalpy value of 54.426 J / g.

[0191] In one embodiment, the thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form C of the sulfate are basically as shown in Figure 26.

[0192] In one embodiment, the phosphate is crystalline form A, and in a powder X-ray diffraction pattern represented by a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 10.04±0.20°, 14.10±0.20°, 18.10±0.20°, 22.80±0.20°, 24.57±0.20°, 28.44±0.20°, and 30.82±0.20°.

[0193] In one embodiment, the crystalline form A of the phosphate has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 6.57±0.20°, 18.53±0.20°, 19.97±0.20°, 22.43±0.20°, and 27.18±0.20°.

[0194] In one embodiment, the crystalline form A of the phosphate has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 6.57±0.20°, 10.04±0.20°, 14.10±0.20°, 18.10±0.20°, 18.53±0.20°, 19.97±0.20°, 22.43±0.20°, 22.80±0.20°, 24.57±0.20°, 27.18±0.20°, 28.44±0.20°, and 30.82±0.20°.

[0195] In one embodiment, in the case of the crystalline form A of the phosphate, the diffraction peaks in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form A may further be as shown in the table below.

[0196] [Table 35]

[0197] [Table 36]

[0198] In one embodiment, for the crystalline form A of the phosphate, the diffraction peaks and relative intensities in the powder X-ray diffraction pattern, represented by the 2θ angle and relative intensity of the crystalline form A, may further be as shown in the table below.

[0199] [Table 37]

[0200] [Table 38]

[0201] In one embodiment, the powder X-ray diffraction pattern (XRPD) of crystalline form A of the phosphate is basically as shown in Figure 27.

[0202] In one embodiment, the crystalline form A of the phosphate shows a weight loss of 0.776% at 142.87°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage. In an analysis chart by differential scanning calorimetry, it has an endothermic peak starting at 179.76±2°C, and further reaches its peak value at 180.61±2°C, with an enthalpy value of 265.82 J / g.

[0203] In one embodiment, the thermogravimetric spectrum and differential scanning calorimetry chart of crystalline form A of the phosphate are basically as shown in Figure 28.

[0204] In one embodiment, the phosphate is crystalline form B, and in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 17.96±0.20°, 21.10±0.20°, 21.41±0.20°, 23.38±0.20°, 26.91±0.20°, and 28.9±0.20°.

[0205] In one embodiment, the crystalline form B of the phosphate has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 7.40±0.20°, 17.61±0.20°, 19.69±0.20°, and 24.93±0.20°.

[0206] In one embodiment, the crystalline form B of the phosphate has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 7.40±0.20°, 17.61±0.20°, 17.96±0.20°, 19.69±0.20°, 21.10±0.20°, 21.41±0.20°, 23.38±0.20°, 24.93±0.20°, 26.91±0.20°, and 28.9±0.20°.

[0207] In one embodiment, in the case of crystalline form B of the phosphate, the diffraction peaks in the powder X-ray diffraction pattern represented by the 2θ angle of crystalline form B may further be as shown in the following table.

[0208] [Table 39]

[0209] In one embodiment, for the crystalline form B of the phosphate, the diffraction peaks and relative intensities in the powder X-ray diffraction pattern, represented by the 2θ angle and relative intensity of the crystalline form B, may further be as shown in the table below.

[0210] [Table 40]

[0211] In one embodiment, the powder X-ray diffraction pattern (XRPD) of crystalline form B of the phosphate is basically as shown in Figure 29.

[0212] In one embodiment, the crystalline form B of the phosphate shows a weight loss of 1.071% at 74.52°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage. In an analysis chart by differential scanning calorimetry, it has an endothermic peak starting at 159.94±2°C, and further reaches its peak value at 169.82±2°C, with an enthalpy value of 77.238 J / g.

[0213] In one embodiment, the thermogravimetric spectrum and differential scanning calorimetry chart of crystalline form B of the phosphate are basically as shown in Figure 30.

[0214] In one embodiment, the sodium salt is in crystalline form A, and in a powder X-ray diffraction pattern represented by a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 7.04±0.20°, 11.05±0.20°, 11.55±0.20°, 15.18±0.20°, 17.98±0.20°, 22.09±0.20°, 25.65±0.20°, and 28.76±0.20°.

[0215] In one embodiment, the crystalline form A of the sodium salt has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 9.78±0.20°, 14.20±0.20°, 18.81±0.20°, 19.97±0.20°, and 24.13±0.20°.

[0216] In one embodiment, the crystalline form A of the sodium salt has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 7.04±0.20°, 9.78±0.20°, 11.05±0.20°, 11.55±0.20°, 14.20±0.20°, 15.18±0.20°, 17.98±0.20°, 18.81±0.20°, 19.97±0.20°, 22.09±0.20°, 24.13±0.20°, 25.65±0.20°, and 28.76±0.20°.

[0217] In one form, in the case of the crystal form A of the sodium salt, the diffraction peaks in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form A may further be as shown in the following table.

[0218] [Table 41]

[0219] [Table 42]

[0220] In one form, in the case of the crystal form A of the sodium salt, the diffraction peaks and relative intensities in the powder X-ray diffraction pattern represented by the 2θ angle and relative intensity of the crystal form A may further be as shown in the following table.

[0221] [Table 43]

[0222] [Table 44]

[0223] In one form, the powder X-ray diffraction pattern (XRPD) of the crystal form A of the sodium salt is basically as shown in FIG. 31.

[0224] In one form, the crystal form A of the sodium salt has a weight loss of 6.279% at 116.94 °C in the analysis chart by thermogravimetric analysis, where the “%” is the mass percentage, and has an endothermic peak starting point at 228.53 ± 2 °C and reaches the peak value of the endothermic peak at 230.66 ± 2 °C in the analysis chart by differential scanning calorimetry. Furthermore, its enthalpy value is 107.61 J / g.

[0225] In one embodiment, the thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form A of the sodium salt are basically as shown in Figure 32.

[0226] In one embodiment, the potassium salt is crystalline form A, and in a powder X-ray diffraction pattern represented by a 2θ angle using Cu-Kα rays, it has characteristic peaks at the following positions: 7.04±0.20°, 9.75±0.20°, 11.05±0.20°, 11.49±0.20°, 14.20±0.20°, 15.06±0.20°, 18.06±0.20°, 25.58±0.20°, and 30.93±0.20°.

[0227] In one embodiment, the crystalline form A of the potassium salt has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 19.46±0.20°, 19.96±0.20°, 23.54±0.20°, and 27.92±0.20°.

[0228] In one embodiment, the crystalline form A of the potassium salt has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 7.04±0.20°, 9.75±0.20°, 11.05±0.20°, 11.49±0.20°, 14.20±0.20°, 15.06±0.20°, 18.06±0.20°, 19.46±0.20°, 19.96±0.20°, 23.54±0.20°, 25.58±0.20°, 27.92±0.20°, and 30.93±0.20°.

[0229] In one embodiment, in the case of the crystalline form A of the potassium salt, the diffraction peaks in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form A may further be as shown in the table below.

[0230] [Table 45]

[0231] [Table 46]

[0232] In one form, in the case of crystalline form A of the potassium salt, the diffraction peaks and relative intensities in the powder X-ray diffraction pattern represented by the 2θ angle and relative intensity of crystalline form A may further be as shown in the following table.

[0233] [Table 47]

[0234] [Table 48]

[0235] In one form, the powder X-ray diffraction pattern (XRPD) of crystalline form A of the potassium salt is basically as shown in FIG. 33.

[0236] In one form, crystalline form A of the potassium salt has a weight loss of 8.352% at 183.95 °C in the analysis chart by thermogravimetric analysis, and the “% ” is mass percentage, and has an endothermic peak starting point at 217.76 ± 2 °C in the analysis chart by differential scanning calorimetry, and further reaches the peak value of the endothermic peak at 222.51 ± 2 °C, and furthermore, its enthalpy value is 102.94 J / g.

[0237] In one form, the thermogravimetric analysis spectrum and the chart by differential scanning calorimetry of crystalline form A of the potassium salt are basically as shown in FIG. 34.

[0238] The present invention further provides a pharmaceutical composition comprising one or more of salts, crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, and crystalline form G of the 5-member fused 6-member compound represented by formula I as described above, and a pharmaceutical adjuvant.

[0239] In one form, the pharmaceutical composition comprises crystalline form A or crystalline form C of the 5-member fused 6-member compound represented by formula I as described above, and a pharmaceutical adjuvant.

[0240] In one embodiment, the pharmaceutical composition comprises one or more crystalline forms B, D, E, F, and G of the five-membered condensed six-membered compound represented by the aforementioned formula I, and a pharmaceutical adjuvant.

[0241] In one embodiment, the pharmaceutical composition comprises a salt of a five-membered condensed six-membered compound represented by the above formula I, and a pharmaceutical adjuvant.

[0242] In one embodiment, the pharmaceutical adjuvant may be a conventional pharmaceutical adjuvant in the field, but preferably one or more of DMSO, Twain-80, polyethylene glycol 15-hydroxystearate, and physiological saline. Furthermore, the pharmaceutical adjuvant consists of 5% DMSO, 10% Twain-80, 5% polyethylene glycol 15-hydroxystearate, and 80% physiological saline, where % is a volume ratio.

[0243] In one embodiment, the mass-to-volume ratio of the salt of the 5-membered condensed 6-membered compound represented by formula I to the pharmaceutical adjuvant is 4:1 mg / mL.

[0244] The present invention further provides the use of substance Z in the preparation of FLT3 and / or IRAK4 inhibitors or drugs for treating and / or preventing FLT3 and / or IRAK4-related diseases, wherein substance Z is one or more of the salts, crystalline forms A, B, C, D, E, F, and G of the five-membered condensed six-membered compound represented by formula I described above.

[0245] In one embodiment, the substance Z is crystalline form A or crystalline form C of the 5-membered condensed 6-membered compound represented by the above formula I.

[0246] In one embodiment, substance Z is one or more of the crystalline forms B, D, E, F, and G of the 5-membered condensed 6-membered compound represented by formula I described above.

[0247] In one embodiment, substance Z is a salt of a five-membered condensed six-membered compound represented by the above formula I.

[0248] The aforementioned FLT3-related diseases include hematological malignancies and / or solid tumors.

[0249] The aforementioned hematological malignancies may be one or more selected from acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, acute anaplastic leukemia, anaplastic large cell lymphoma, prolymphoblastic leukemia, juvenile myeloid monocytic leukemia, myelodysplastic syndrome, non-Hodgkin lymphoma, multiple myeloma, myeloproliferative disorders, mantle cell lymphoma, and adult-onset acute myeloid leukemia.

[0250] The solid tumor may be one or more selected from colorectal cancer, renal cell carcinoma, non-small cell lung cancer, bladder cancer, ovarian cancer, breast cancer, pancreatic cancer, gastric adenocarcinoma, prostate cancer, and lung cancer.

[0251] The aforementioned IRAK4-related diseases include autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, or central nervous system diseases.

[0252] The autoimmune disease may be one or more selected from rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes (e.g., type 1 diabetes), psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome.

[0253] The inflammatory disease mentioned above may be one or more selected from rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes (e.g., type 1 diabetes), psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome, but is not limited to these.

[0254] The aforementioned cardiovascular disease may be a stroke or atherosclerosis.

[0255] The present invention further provides a method for treating and / or preventing FLT3 and / or IRAK4-related diseases, the method comprising administering an effective amount of substance Z to a patient, wherein substance Z is one or more of the salts, crystalline forms A, B, C, D, E, F, and G of the five-membered condensed six-membered compound represented by the aforementioned formula I.

[0256] In one embodiment, the substance Z is crystalline form A or crystalline form C of the 5-membered condensed 6-membered compound represented by the above formula I.

[0257] In one embodiment, substance Z is one or more of the crystalline forms B, D, E, F, and G of the 5-membered condensed 6-membered compound represented by formula I described above.

[0258] In one embodiment, substance Z is a salt of a five-membered condensed six-membered compound represented by the above formula I.

[0259] In one embodiment, the FLT3-related disease is the FLT3-related disease described in any of the above embodiments.

[0260] In one embodiment, the IRAK4-related disease is the IRAK4-related disease described in any of the above embodiments.

[0261] The present invention further provides the use of substance Z in the preparation of a drug, wherein substance Z is one or more of the salts, crystalline forms A, B, C, D, E, F, and G of the five-membered condensed six-membered compound represented by formula I described above, and the drug is used to treat and / or prevent one or more of the following: hematological malignancies, solid tumors, autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and central nervous system diseases.

[0262] In one embodiment, the substance Z is crystalline form A or crystalline form C of the 5-membered condensed 6-membered compound represented by the above formula I.

[0263] In one embodiment, substance Z is one or more of the crystalline forms B, D, E, F, and G of the 5-membered condensed 6-membered compound represented by formula I described above.

[0264] In one embodiment, substance Z is a salt of a five-membered condensed six-membered compound represented by the above formula I.

[0265] In one embodiment, the hematological malignancy is the hematological malignancy described in any of the above embodiments.

[0266] In one embodiment, the solid tumor is a solid tumor as described in any of the above embodiments.

[0267] In one embodiment, the autoimmune disease is the autoimmune disease described in any of the above embodiments.

[0268] In one embodiment, the inflammatory disease is an inflammatory disease described in any of the above embodiments.

[0269] In one embodiment, the cardiovascular disease is the cardiovascular disease described in any of the above embodiments.

[0270] The present invention further provides a method for treating and / or preventing a disease, the method comprising administering an effective amount of substance Z to a patient, wherein substance Z is one or more of salts, crystalline forms A, B, C, D, E, F, and G of the five-membered condensed six-membered compound represented by the aforementioned formula I, and the disease is one or more selected from hematological malignancies, solid tumors, autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and central nervous system diseases. In one embodiment, substance Z is crystalline form A or crystalline form C of the five-membered condensed six-membered compound represented by the aforementioned formula I.

[0271] In one embodiment, substance Z is one or more of the crystalline forms B, D, E, F, and G of the 5-membered condensed 6-membered compound represented by formula I described above.

[0272] In one embodiment, substance Z is a salt of a five-membered condensed six-membered compound represented by the above formula I.

[0273] In one embodiment, the hematological malignancy is the hematological malignancy described in any of the above embodiments.

[0274] In one embodiment, the solid tumor is a solid tumor as described in any of the above embodiments.

[0275] In one embodiment, the autoimmune disease is the autoimmune disease described in any of the above embodiments.

[0276] In one embodiment, the inflammatory disease is an inflammatory disease described in any of the above embodiments.

[0277] In one embodiment, the cardiovascular disease is the cardiovascular disease described in any of the above embodiments.

[0278] The present invention relates to the compound represented by formula II-49-3.

[0279] [ka]

[0280] To provide.

[0281] The present invention further provides a method for preparing the crystalline form A of the five-membered condensed six-membered compound represented by formula I, comprising the steps of adding a poor solvent to a solution of the five-membered condensed six-membered compound represented by formula I, and lowering the temperature to crystallize it in order to obtain the crystalline form A.

[0282] In one embodiment, in the method for preparing crystalline form A, the solvent for the solution of the 5-membered condensed 6-membered compound represented by formula I is a mixture of a sulfoxide solvent and an alcohol solvent.

[0283] In one embodiment, in the method for preparing crystalline form A, the sulfoxide solvent may be dimethyl sulfoxide.

[0284] In one embodiment, in the method for preparing crystalline form A, the alcoholic solvent may be ethanol and / or isopropanol.

[0285] In one embodiment, in the method for preparing crystalline form A, the poor solvent may be an alcoholic solvent and / or water, such as ethanol and / or isopropanol.

[0286] In one embodiment, in the method for preparing crystalline form A, the mass-volume ratio of the five-membered condensed six-membered compound represented by formula I to the solvent in the solution of the five-membered condensed six-membered compound represented by formula I may be 1:(1~10) g / mL, for example, 1:5 g / mL.

[0287] In one embodiment, in a method for preparing crystalline form A, the volume ratio of the sulfoxide solvent to the alcohol solvent in the solvent of the solution of the 5-membered condensed 6-membered compound represented by formula I may be (1-5):1, for example, 2:1.

[0288] In one embodiment, in the method for preparing crystalline form A, the volume ratio of the solution of the 5-membered condensed 6-membered compound represented by formula I to the poor solvent may be (1-10):18.3, for example, 5:18.3.

[0289] In one embodiment, in the method for preparing crystalline form A, the temperature at which the poor solvent is added may be 20 to 65°C, for example, 50°C.

[0290] In one embodiment, in the method for preparing crystalline form A, the cooling temperature of the solution is 30 to 70°C, for example, 30°C, 40°C, 50°C, and 65°C.

[0291] In one embodiment, in the method for preparing crystalline form A, the cooling rate is 5 to 15°C / hour, for example, 10°C / hour.

[0292] In one embodiment, in the method for preparing crystalline form A, the cooling time is 10 to 30 hours.

[0293] The present invention further provides a method for preparing the crystalline form C of the five-membered condensed six-membered compound represented by formula I, comprising the step of volatilizing a suspension of the five-membered condensed six-membered compound represented by formula I to obtain the crystalline form C.

[0294] In one embodiment, in a method for preparing crystalline form C, the solvent of the suspension is a mixture of an organic solvent and water.

[0295] In one embodiment, in a method for preparing crystalline form C, the organic solvent may be one or more of alcohol-based solvents, ketone-based solvents, and nitrile-based solvents, such as ethanol, acetone, or acetonitrile.

[0296] In one embodiment, in the method for preparing crystalline form C, the volume ratio of the organic solvent to water may be 60:40 to 99:1, for example, 95:5.

[0297] In one embodiment, in the method for preparing crystalline form C, the mass-volume ratio of the 5-membered condensed 6-membered compound represented by formula I to the solvent in the suspension may be (10-100):1 mg / mL, for example, 50:1 mg / mL.

[0298] In one embodiment, in the method for preparing crystalline form C, the volatilization temperature is room temperature.

[0299] In one embodiment, in the method for preparing crystalline form C, the volatilization time is 1 to 5 days, preferably 3 days.

[0300] The terms “compound” and “pharmaceutically acceptable salt” may exist in the form of a single tautomer or a mixture thereof, if tautomers are present, and preferably in the form of a more stable tautomer.

[0301] The term "basically" means that slight variations in measuring instruments, measurement conditions, and batches of the product being measured may cause slight changes in the position of each peak in the figure, and therefore should not be considered absolute values.

[0302] The term "pharmaceutical adjuvants" refers to excipients and additives used in the manufacture and preparation of pharmaceuticals, and includes all substances contained in pharmaceutical preparations except for the active ingredient. For further details, refer to the *Pharmacopoeia of the People's Republic of China* (2020 edition) or the *Handbook of Pharmaceutical EMcipients* (Raymond C Rowe, 2009).

[0303] The term "treatment" means any of the following: (1) alleviating one or more biological symptoms of a disease; (2) interfering with one or more points in the biological cascade that causes the disease; or (3) slowing the progression of one or more biological symptoms of a disease.

[0304] The term "prevention" refers to reducing the risk of developing a disease.

[0305] The term “patient” refers to any animal that has received or is seeking treatment, preferably a mammal, most preferably a human. Mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0306] The term "room temperature" refers to 20-30°C, preferably 25°C.

[0307] The aforementioned preferred conditions can be combined in any way, without violating the ordinary knowledge of the art, to obtain various preferred embodiments of the present invention.

[0308] The reagents and raw materials used in this invention are commercially available. [Effects of the Invention]

[0309] The key advantages of the present invention are as follows: The salts and crystalline forms of the compounds of the present invention have inhibitory effects on FLT3 and / or IRAK4. Some of the crystalline forms and salt forms of the present invention have a high single melting point, are thermodynamically stable, and have high crystallinity. The crystalline forms exhibit good physical and chemical stability under conditions of strong light irradiation, high temperature, and high humidity, and have extremely weak hygroscopicity. Some of the salt forms of the present invention can significantly increase the blood drug concentration and exposure of the compounds in rats compared to free bases. [Brief explanation of the drawing]

[0310] [Figure 1] This is the powder X-ray diffraction spectrum of crystal form A. [Figure 2] These are the differential scanning calorimetry and thermogravimetric analysis spectra of crystal form A. [Figure 3] This is the powder X-ray diffraction spectrum of crystal form B. [Figure 4] These are the differential scanning calorimetry and thermogravimetric analysis spectra of crystal form B. [Figure 5] This is the powder X-ray diffraction spectrum of crystalline form C. [Figure 6] These are differential scanning calorimetry and thermogravimetric analysis spectra of crystal form C. [Figure 7] This is the powder X-ray diffraction spectrum of crystal form D. [Figure 8] These are the differential scanning calorimetry and thermogravimetric analysis spectra of crystal form D. [Figure 9] This is the powder X-ray diffraction spectrum of crystal form E. [Figure 10] These are the differential scanning calorimetry and thermogravimetric analysis spectra of crystal form E. [Figure 11] This is the powder X-ray diffraction spectrum of crystal form F. [Figure 12] These are the differential scanning calorimetry and thermogravimetric analysis spectra of crystal form F. [Figure 13] This is the powder X-ray diffraction spectrum of crystal form G. [Figure 14] These are the differential scanning calorimetry and thermogravimetric analysis spectra of crystal form G. [Figure 15] This is the dynamic water vapor (DVS) adsorption spectrum used in the detection of hygroscopicity of crystal form A. [Figure 16] These are the powder X-ray diffraction spectra of crystal form A before and after detection of hygroscopicity. [Figure 17] This is the powder X-ray diffraction spectrum of crystalline form A of the hydrochloride salt. [Figure 18] These are the differential scanning calorimetry and thermogravimetric analysis spectra of crystalline form A of the hydrochloride salt. [Figure 19] This is the powder X-ray diffraction spectrum of crystalline form B of the hydrochloride salt. [Figure 20] These are differential scanning calorimetry and thermogravimetric analysis spectra of crystalline form B of the hydrochloride salt. [Figure 21] This is the powder X-ray diffraction spectrum of crystalline form A of the sulfate. [Figure 22] These are differential scanning calorimetry and thermogravimetric analysis spectra of crystalline form A of sulfate. [Figure 23] This is the powder X-ray diffraction spectrum of crystalline form B of the sulfate. [Figure 24] These are differential scanning calorimetry and thermogravimetric analysis spectra of crystalline form B of sulfate. [Figure 25] This is the powder X-ray diffraction spectrum of crystalline form C of sulfate. [Figure 26] These are differential scanning calorimetry and thermogravimetric analysis spectra of crystalline form C of sulfate. [Figure 27] This is the powder X-ray diffraction spectrum of phosphate crystalline form A. [Figure 28] These are differential scanning calorimetry and thermogravimetric analysis spectra of phosphate crystal form A. [Figure 29] This is the powder X-ray diffraction spectrum of phosphate crystalline form B. [Figure 30] These are differential scanning calorimetry and thermogravimetric analysis spectra of phosphate crystalline form B. [Figure 31] This is the powder X-ray diffraction spectrum of crystalline form A of the sodium salt. [Figure 32] These are differential scanning calorimetry and thermogravimetric analysis spectra of crystalline form A of the sodium salt. [Figure 33]This is the powder X-ray diffraction spectrum of crystalline form A of the potassium salt. [Figure 34] These are differential scanning calorimetry and thermogravimetric analysis spectra of crystalline form A of potassium salt. [Figure 35] This is a dynamic water vapor adsorption (DVS) spectral diagram of phosphate. [Figure 36] This is a dynamic water vapor adsorption (DVS) spectrum diagram of hydrochloride salts. [Modes for carrying out the invention]

[0311] The present invention will be further described below by providing examples, but the present invention is not limited to the scope of the above examples. In the experimental methods in the following examples, if specific conditions are not explicitly stated, conventional methods and conditions should be followed, or selected according to the product description.

[0312] Comparison table of Chinese and English names:

[0313] [Table 49]

[0314] Equipment, devices, and test conditions

[0315] For crystalline products, powder X-ray diffraction (XRPD) is performed, approximately 10 mg of the product is placed on a glass slide, flattened, and then set in the instrument and the program is started. For differential scanning calorimeters (DSCs), 1-3 mg of the sample is weighed into an aluminum dish, sealed, and perforated. The aluminum dish is then placed on the sample stage, the program is set, and it is executed. For thermogravimetric analyzers (TGAs), the weight of the aluminum dish is first zeroed, then 3-10 mg of the sample is weighed, the aluminum dish is placed on the sample stage, the program is set, and it is executed. For polarizing microscopes (PLMs), a small amount of sample is placed on a clean glass slide, dispersed with a small amount of silicone oil, set in the instrument, the magnification and exposure intensity are adjusted, and the data is saved by taking photographs while observing.

[0316] [Table 50]

[0317] The counterions and solvents used in this invention are as shown in the table below.

[0318] [Table 51]

[0319] [Table 52]

[0320] (Example 1: Preparation of the compound)

[0321] [ka]

[0322] Step 1: Synthesis of II-8-1

[0323] A mixed solution of 2-(trifluoromethyl)pyridine-4-boronic acid pinacol ester (286.32 mg, 1.05 mmol), 2-bromoxazole-4-carboxylate methyl (0.18 g, 873.81 μmol), Pd(dppf)Cl2 (115.24 mg, 0.16 mmol), cesium carbonate (569.41 mg, 1.75 mmol), and anhydrous 1,4-dioxane (6 mL) was stirred at 80°C under a nitrogen atmosphere for 4 hours to allow complete reaction. The reaction solution was diluted with H2O (10 mL), extracted by stirring with EA (10 mL x 3), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography, and eluted at PE / EA = 10:3 to obtain 0.23 g of the white solid product II-8-1 in 84.66% yield. MS(ESI)m / z:272.0[M+H] + .

[0324] Step 2: Synthesis of II-8-2

[0325] Lithium hydroxide (40.48 mg, 1.69 mmol) was added to a solution of II-8-1 (0.23 g, 845.03 μmol), H2O (1 mL), and THF (3 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 3 hours to allow complete reaction. The reaction mixture was diluted with H2O (10 mL), and the solution was acidified to pH 3-4 while stirring. The mixture was extracted with EA (10 mL x 3), the combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and vacuum concentrated to obtain 0.2 g of the white solid product II-8-2 as the crude product. MS(ESI)m / z:259.0[M+H] + .

[0326] Step 3: Synthesis of II-49-1-P2

[0327] A mixture of methyl 5-nitro-2H-indazole-6-carboxylate (1 g, 4.52 mmol) and DMF (10 mL) at 25°C, to which Cs₂CO₃ (2.62 g, 13.56 mmol) and 4-bromo-2-methylbutan-2-ol (1.13 g, 6.78 mmol) was added, and the mixture was stirred at 100°C for 16 hours to allow complete reaction. The reaction mixture was diluted with H₂O (30 mL) and then extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 6.00 g of a yellow solid crude product. The crude product was purified by silica gel column chromatography (PE:siRNA = 2:1) to obtain 510.00 mg, 1.66 mmol, of the pale yellow solid product II-49-1-P2 in 35.24% yield. MS(ESI)m / z:308.1 [M+H] + II-49-1-P1: 1H NMR (400 MHz, Chloroform-d) δ 8.46 (s, 1H), 8.21 (s, 1H), 7.74 (s, 1H), 4.61 (t, J = 8.0Hz, 2H), 3.95 (s, 3H), 2.11 (t, J = 8.0Hz, 2H), 1.30 (s, 6H). II-49-1-P2: 1 H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.23 ​​(s, 1H), 8.01 (s, 1H), 4.68 (t, J = 8.0Hz, 2H), 3.92 (s, 3H), 2.22 (t, J = 8.0Hz, 2H), 1.30 (s, 6H).

[0328] Step 4: Synthesis of II-49-2

[0329] A mixture of II-49-1-P2 (0.5 g, 1.63 mmol), EtOH (6 mL), and H2O (2.5 mL) was mixed with NH4Cl (43.00 mg, 811.32 μmol) and iron powder (908.72 mg, 16.27 mmol). The mixture was stirred at 80°C for 16 hours to allow complete reaction. The reaction mixture was diluted with H2O (20 mL) and then extracted with EA (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. 400.00 mg of the yellow solid product II-49-2 was obtained. MS(ESI) m / z: 278.1[M+H] + .

[0330] Step 5: Synthesis of II-49-3

[0331] A mixture of II-49-2 (400 mg, 1.44 mmol) and THF (10 mL) was stirred at 0°C, then methylchloromagnesium (539.40 mg, 7.21 mmol) was added. The mixture was stirred for a further 16 hours to allow for complete reaction. The reaction mixture was diluted with H₂O (20 mL), the pH of the solution was adjusted to 7-8 with NH₄Cl aqueous solution (1 M), and then extracted with EA (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was subjected to reverse-phase preparative HPLC (Prep-C18, 5 μM Xbridge column, 19 × 150 mm, both solvents containing 0.1% ammonium bicarbonate) to obtain 210.00 mg, 681.42 μmol, of the yellow oily product II-49-3 in 47.24% yield. MS(ESI)m / z:278.2[M+H] + .

[0332] Step 6: Synthesis of the 5-membered condensed 6-membered compound shown in formula I

[0333] Under the condition of 25 °C, II-49-3 (21.49 mg, 77.47 μmol, 1.0 eq), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (60 mg, 232.42 μmol, 3.0 eq), and DIPEA (80 mg, 77.47 μmol, 1.0 eq) were added to a mixture of II-8-2 (20 mg, 77.47 μmol, 1.0 eq) and DCM (2 mL). After the addition was completed, the resulting mixed solution was stirred for 1 hour to react completely. The reaction mixture was concentrated under reduced pressure until dry, H2O (10 mL) was added to the residue for dilution, and then it was extracted with EA (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and then filtered and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to reverse-phase preparative HPLC (Prep-C18, 5 μM Xbridge column, 19 × 150 mm, Waters; both of the two solvents in the mobile phase (water and acetonitrile) contained 0.1% ammonium bicarbonate), and 23.90 mg, 47.34 μmol of a white solid product (i.e., the 5-membered condensed 6-membered compound represented by Formula I) was obtained in a yield of 61.11%, and the purity was 98%. MS (ESI) m / z: 518.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 11.38 (s, 1H), 8.91 (d, J = 4.0 Hz, 1H), 8.71 (s, 1H), 8.45 (s, 1H), 8.30 (s, 1H), 8.14 (dd, J = 4.0, 1.2 Hz, 1H), 7.90 (s, 1H), 7.68 (s, 1H), 4.57 (t, J = 8.0 Hz, 2H), 2.68 (s, 1H), 2.37 (s, 1H), 2.18 (t, J = 8.0 Hz, 2H), 1.79 (s, 6H), 1.31 (s, 6H).

[0334] (Example 2: Inhibition Evaluation against Compound Kinase Activity)

[0335] Using an experimental method based on fluorescence microfluidic mobility detection, the IC50 of compounds against competitive binding between kinases IRAK4 and FLT3 and ATP was investigated. 50 The values ​​were measured. The initial detection concentration of the compound was set to 10 μM, diluted to 0.38 nM using a 4x gradient, and detected in a double replication well. Commercially available staurosporine was used as the standard control in this experiment.

[0336] The information regarding reagents and consumables is as follows:

[0337] IRAK4 kinase (Carna, Catalog No.: 09-145, Lot No.: 14CBS-0020 H)

[0338] FLT3 kinase (Carna, Catalog No.: 08-154, Lot No.: 07CBS-2350)

[0339] Substrate peptide FAM-P2 (GL Biochem, catalog number: 112394, lot number: P131014-XP112394)

[0340] Substrate peptide FAM-P8 (GL Biochem, catalog number: 112396, lot number: P170731-SY112396)

[0341] ATP (adenosine triphosphate, Sigma, catalog number: A7699-1G, CAS registry number: 987-65-5)

[0342] DMSO (Dimethyl sulfoxide, Sigma, Catalog number: D2650)

[0343] EDTA (Ethylenediaminetetraacetic acid, Sigma, Catalog number: E5134, CAS registry number: 60-00-4)

[0344] Staurosporine (Selleckchem, catalog number: S1421)

[0345] HEPES (4-(2-hydroxyethyl)-1-piperazine ethanol sulfonic acid, Gibco, catalog number: 15630-080)

[0346] Brij-35 solution (polyethylene glycol monododecyl ether, Sigma, catalog number: B41840-100mL)

[0347] DTT (DL-Dithiothreitol, Sigma, Catalog Number: D0632-20G)

[0348] 0.2% Coating Reagent #3 (Perkin Elmer, Catalog No.: 760050)

[0349] 96-well plate (Corning, catalog number: 3365)

[0350] 384-well plate (Corning, catalog number: 3573)

[0351] Experimental procedure:

[0352] 1) FLT3 kinase and IRAK4 kinase were dissolved in kinase buffer (50 mM HEPES (pH 7.5), 10 mM MgCl2, 2 mM DTT, 0.01% Brij-35), respectively, to final concentrations of 0.9 nM, 30 nM, and 6 nM, respectively.

[0353] 2) Substrate peptides FAM-P2 and FAM-P8 were dissolved together with ATP in the kinase buffer described above. The final concentrations of substrate peptide FAM-P2 and ATP used for measuring FLT3 were 3 μM and 97 μM, respectively, while the final concentrations of substrate peptide FAM-P8 and ATP used for measuring IRAK4 were 3 μM and 10 μM, respectively.

[0354] 3) Dilution of the compound: The compound was first diluted to 50 μM, and then diluted fourfold using DMSO. Here, a solution without the compound and kinase served as a blank control (corresponding to the "minimum value" below), while a solution without the compound but containing kinase, adenosine triphosphate, DMSO, and buffer served as a positive control (corresponding to the "maximum value" below).

[0355] 4) Kinase reaction and termination: 10 μL of kinase buffer was added to a 384-well plate containing 5 μL of the test compound and incubated at room temperature for 10 minutes. Then, 10 μL of buffer containing the substrate peptide and adenosine triphosphate was added to the 384-well plate and incubated at 28°C for 1 hour. Finally, 25 μL of reaction termination solution (100 mM HEPES (pH 7.5), 50 mM EDTA, 0.2% Coating Reagent #3, 0.015% Brij-35) was added to each well to terminate the reaction.

[0356] 5) Data Reading: Conversion rate data was read using CaliperEZ Reader II. The conditions were set as follows: downstream voltage -500V, upstream voltage -2250V, reference pressure -0.5PSI, and screening pressure -1.2PSI.

[0357] 6) Data Calculation: The conversion rate data was copied from CaliperEZ Reader II and converted to inhibition rate data. The calculation formula is as follows:

[0358] Inhibition rate (%) = (Maximum value - Conversion rate) / (Maximum value - Minimum value) * 100%

[0359] Using XLFit Excel add-in version 5.4.0.8 for IC 50 The values ​​were fitted.

[0360] Fitting formula: Y = Bottom + (Top - Bottom) / (1 + (IC) 50 / X)^HillSlope)

[0361] The compound kinase activity data is as follows:

[0362] [Table 53]

[0363] (Example 3: IC of compound's toxic activity against MV4-11 cells) 50 (Measurement of values)

[0364] The reagents and consumables are as follows: MV4-11 cells (ATCC, catalog number: CRL-9591) DPBS (Dulbeccio phosphate-buffered saline, Biosera, catalog number: LM-S2041 / 500) IMDM medium (Thermo, catalog number: 12440053) Fetal bovine serum (Biological, Catalog number: 04-002-1A) Penicillin-streptomycin solution (Invitrogen, catalog number: 15140122) Dimethyl sulfoxide (Sigma, catalog number: D2650) CellTiter-Glo Luminescent Cell Viability Assay (Promega, Catalog No.: G7573) 96-well plate (Corning, catalog number: 3903)

[0365] CTG Experiment Steps

[0366] 1. MV-4-11 cells were cultured in IMDM complete medium (IMDM + 10% fetal bovine serum + 1% penicillin-streptomycin).

[0367] 2. MV-4-11 cells in good condition were collected and washed twice with DPBS (Dulbeccio phosphate-buffered saline).

[0368] 3. Resuspend MV-4-11 cells in IMDM complete medium and increase the cell density to 1.11 × 10⁶. 6 The solution was adjusted to cells / mL and added to a 96-well plate at a density of 90 μL per well.

[0369] 4. A 10-fold compound solution was prepared using IMDM complete medium. 10 μL of this 10-fold compound solution was added to 96-well cells, mixed thoroughly, and then incubated in a 37°C, 5% CO2 incubator for 72 hours.

[0370] 5. After incubation was complete, the 96-well plate was removed and allowed to equilibrate at room temperature for 30 minutes. Then, 100 μL of CellTiter Glo reagent was added to each well and mixed thoroughly with a horizontal shaker for 2 minutes.

[0371] The 6 and 96-well plates were removed and allowed to equilibrate at room temperature for 10 minutes, after which the chemiluminescence values ​​were detected using an ELISA reader.

[0372] Conclusion: The cytotoxic activity data of the compound is equivalent to that of MV4-11 IC. 50 The value is 21 nM.

[0373] (Example 4: Preparation of crystalline form)

[0374] 4.1 Preparation of crystal form A 1 g of the 5-membered condensed 6-membered compound represented by formula I, prepared in Example 1, was weighed into a reaction vessel. 5 V DMSO / IPA (volume ratio 2:1, where V represents 1 mL of solvent per 1 g of solute) was added, and the mixture was heated to 65°C while stirring to obtain a clear solution. The mixture was then cooled to 50°C and stirred for 0.5 hours. At 50°C, 18.3 V IPA was added and the mixture was reacted for 3 hours. The mixture was then cooled to 20°C at a rate of 10°C / hour and stirred overnight (approximately 16 hours) at 20°C to obtain a solid. The filtered cake was washed with 2 V IPA and dried under vacuum at 50°C to obtain crystalline form A of the free base.

[0375] 4.2 Preparation of crystal form B 30 mg of the 5-membered condensed 6-membered compound represented by formula I, prepared in Example 1, was weighed out, 0.6 mL of methanol was added, and the mixture was suspended at room temperature for 3 days. After filtration, solid crystalline form B was obtained.

[0376] 4.3 Preparation of crystal form C 30 mg of the 5-membered condensed 6-membered compound represented by formula I, prepared in Example 1, was weighed out, 0.6 mL of acetone / water = 95 / 5 (volume ratio) was added, and the mixture was suspended at room temperature for 3 days. After filtration, solid crystalline form C was obtained.

[0377] 4.4 Preparation of crystal form D 30 mg of the 5-membered condensed 6-membered compound represented by formula I, prepared in Example 1, was weighed out, 0.6 mL of methanol was added, and the mixture was suspended at room temperature for 3 days. After filtering to obtain a saturated solution, it was slowly evaporated at room temperature to obtain solid crystalline form D.

[0378] 4.5 Preparation of crystal form E 30 mg of the 5-membered condensed 6-membered compound represented by formula I, prepared in Example 1, was weighed out, 0.6 mL of ethanol was added, and the mixture was suspended at room temperature for 3 days. After filtering to obtain a saturated solution, it was slowly evaporated at room temperature to obtain solid crystalline form E.

[0379] 4.6 Preparation of crystal form F 30 mg of the 5-membered condensed 6-membered compound represented by formula I, prepared in Example 1, was weighed out, 0.6 mL of acetone-water 95 / 5 (volume ratio) was added, the mixture was suspended at room temperature for 3 days, filtered to obtain a saturated solution, and then slowly evaporated at room temperature to obtain solid crystalline form F.

[0380] 4.7 Preparation of crystal form G 30 mg of the 5-membered condensed 6-membered compound represented by formula I, prepared in Example 1, was weighed out, 0.6 mL of methanol was added, and the mixture was dissolved at 70°C until clear. The mixture was then cooled to 5°C at a rate of 5°C / hour, and the suspension was filtered to obtain the solid crystalline form G.

[0381] (Example 5: Simulated granulation test)

[0382] Dry method: Crystal form A of the 5-membered condensed 6-membered compound represented by formula I was directly pulverized for 30 minutes.

[0383] Wet method: Ethanol, a granulation solvent, was dropped onto the surface of the crystalline form A of the 5-membered condensed 6-membered compound represented by formula I until the solid was completely wet, and then pulverized for 30 minutes. The resulting solid was evaluated using XRPD and DSC to characterize its crystalline form and crystallinity. The purpose was to determine whether polymorphs, solvates, or amorphous compounds were likely to form. As can be seen from the results of the simulated granulation experiment, the crystalline form remained unchanged from crystalline form A, and no new crystalline forms were observed.

[0384] (Example 6: High-voltage characteristics test)

[0385] Approximately 10 mg of crystalline form A of the 5-membered condensed 6-membered compound represented by formula I was weighed out and placed on a 13 mm diameter hydraulic press plate. A high-pressure properties test was then performed using a manual hydraulic press with a hydraulic pressure of 10 tons and a pressing time of 5 minutes. The resulting solid was subjected to property evaluation such as XRPD to observe the stability of the crystalline form under high pressure. As can be seen from the results of the high-pressure treatment experiment, the crystalline form remained unchanged from crystalline form A, and no new crystalline forms were observed.

[0386] (Example 7: Research on crystal transformation relationships)

[0387] To study the interconversion relationships between polymorphs, polymorphs were prepared under repeated conditions, and a series of suspension competition experiments were conducted in different solvent systems for crystalline forms A, C, D, E, and G. The specific experimental steps are as follows.

[0388] 20 mg each of crystal forms A, C, D, E, and G were weighed out and placed in 5 mL glass vials. A suspension was prepared by adding a solvent (EtOH / H2O = 1 / 1 (v / v) or DMSO (dimethyl sulfoxide) / EtOH = 1 / 8 (v / v)). The vials were then transferred to 25°C and stirred for 72 hours. After filtration at different times, the XRPD of the filtered cakes was measured.

[0389] EtOH / H2O1 / 1 solvent system

[0390] [Table 54]

[0391] As can be seen from the suspension experiment using the EtOH / H2O 1 / 1 solvent system, after 24 hours of suspension, the solid sample is in crystalline form C.

[0392] DMSO / EtOH 1 / 8 solvent system

[0393] [Table 55]

[0394] As can be seen from the suspension experiment using the DMSO / EtOH 1 / 8 solvent system, after 24 hours of suspension, the solid sample is in crystalline form A.

[0395] (Example 8: Analysis of polymorphic products)

[0396] Products obtained through polymorphism screening were subjected to tests such as powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and high-performance liquid chromatography (HPLC). The newly emerging crystalline forms were summarized, and the relevant spectral diagrams can be found in Figures 1-14.

[0397] [Table 56]

[0398] As can be seen from the summary of the experimental results, of the seven crystal forms discovered, crystal form A has a high melting point and low loss in weight.

[0399] (Example 9: Solid Stability Study - Testing of Influencing Factors)

[0400] To investigate the solid stability of crystal form A, changes in crystal form, purity, and color were examined under various conditions.

[0401] 60 mg of crystal form A was weighed out and placed in a glass dish or vial. This glass dish or vial was then placed in a constant temperature and humidity chamber under the following conditions: light irradiation: 4500 ± 500 Lux, high temperature: 60°C (sealed), high humidity: 25°C, relative humidity RH = 90 ± 5% (open). The results of the study on the solid stability of crystal form A are shown in the table below.

[0402] [Table 57]

[0403] As can be seen from the evaluation results of solid stability, crystal form A exhibited excellent physical and chemical properties under all conditions of high temperature, high humidity, and strong light irradiation.

[0404] (Example 10: Study on hygroscopic properties)

[0405] The important hygroscopic properties of this compound were tested using a dynamic measurement method, a dynamic water vapor adsorption (DVS) system. During the measurement, the sample weight changed, and as with other research methods, the DVS recorded the change in sample mass as the sample changed with relative humidity. The relevant spectral diagrams can be found in Figures 15-16. As can be seen from the DVS curve results shown in Figure 15, the initial water adsorption of the sample in the two adsorption / desorption curves at 25°C / 90%RH (relative humidity) was less than 0.04% in both cases, indicating that the sample has low hygroscopicity.

[0406] [Table 58]

[0407] Conclusion: XRPD testing was performed on samples before and after DVS testing. As can be seen from Figure 16, the crystal form did not change.

[0408] (Example 11: Preparation of salt mold)

[0409] Free bases possess multiple basic sites, and we selected inorganic / organic acids and free bases commonly used in drug research to study salt formation. Nine different salts, including hydrochloride, sulfate, and phosphate salts, were prepared in the study. The experimental process for salt formation is summarized below.

[0410] (1) API (i.e., the 5-membered condensed 6-membered compound represented by formula I prepared in Example 1) (30 mg) and solvent (0.3 mL) were placed in a reaction flask. The reaction system was stirred at room temperature (approximately 25°C) to obtain a clear solution or suspension. (2) First, the counterion reagent (1.1 eq. or 3.0 eq.) and solvent (0.3 mL) were placed in a reaction flask and stirred at room temperature to obtain a clear solution or suspension. Then, under stirring conditions, this system was slowly added to the clear solution or suspension from (1). (3) The reaction system was heated to 50°C and stirred at 50°C for 2 hours. (4) The reaction system was cooled to 25°C at a cooling rate of 10°C / hour and held there for 15 hours. (5) The suspension reaction system was centrifuged, and the filtered cake was vacuum-dried at room temperature for 15 hours. For reaction systems in which no solid precipitate was formed, the solvent was evaporated by purging with nitrogen gas at 25°C to obtain a solid sample. The results are as follows.

[0411] [Table 59]

[0412] [Table 60]

[0413] Note: Samples marked with "*" indicate a solid obtained by evaporating a clear solution under a nitrogen atmosphere, while " / / " indicates that evaporation did not occur or only a small amount of solid was obtained.

[0414] In the table, HC represents hydrochloride, SF represents sulfate, PH represents phosphate, NA represents sodium salt, and KA represents potassium salt.

[0415] Based on nine different salt forms that could be obtained, and considering the characterization results by XRPD, TGA, and DSC, the crystallinity, melting point, and weight loss by TGA of the salts were comprehensively compared, and hydrochloride crystal form A (HC-crystal form A), sulfate crystal form A (SF-crystal form A), and phosphate crystal form A (PH-crystal form A) were selected as the dominant salt forms, and subsequent solid stability tests and DVS hygroscopicity tests were conducted.

[0416] (Example 12: Detection of salt type)

[0417] 5.1 Experimental Objective: The chloride ion, sulfate ion, and phosphate ion content in hydrochloride crystal form A, sulfate crystal form A, and phosphate crystal form A was measured by ion chromatography.

[0418] 5.2 Equipment and apparatus:

[0419] [Table 61]

[0420] 5.3 Reagents and materials:

[0421] [Table 62]

[0422] 5.4 Sample Configuration:

[0423] [Table 63]

[0424] SPL-Cl -Accurately weigh 15.65 mg of hydrochloride crystalline form A sample and place it in a 15 mL plastic centrifuge tube. First, accurately add 8.0 mL of pure water, then add 7.0 mL of ethyl acetate and dissolve with sonication until clear. After standing and liquid-liquid separation, remove the upper organic phase by aspirate. Next, add 1.0 mL of methyl-tert-butyl ether to the aqueous phase, shake well, and after standing and liquid-liquid separation, accurately transfer 1.0 mL from the aqueous phase to a 5 mL volumetric flask, and use SPL-Cl - He wrote:

[0425] SPL-SO4 2- Accurately weigh 16.70 mg of sulfate crystalline form A sample and place it in a 15 mL plastic centrifuge tube. First, accurately add 8.0 mL of pure water, then add 7.0 mL of ethyl acetate and dissolve with sonication until clear. After standing and separating, remove the upper organic phase. Next, add 1.0 mL of methyl tert-butyl ether to the aqueous phase, shake well, and after standing and separating, accurately transfer 1.0 mL from the aqueous phase to a 5 mL volumetric flask and set aside in SPL-SO4. 2- He wrote:

[0426] SPL-PO4 3- Accurately weigh 13.81 mg of phosphate crystalline form A sample and place it in a 15 mL plastic centrifuge tube. First, accurately add 8.0 mL of pure water, then add 7.0 mL of ethyl acetate and dissolve it with sonication until clear. After standing and separating, remove the upper organic phase by aspirate. Next, add 1.0 mL of methyl tert-butyl ether to the aqueous phase, shake well, and after standing and separating, accurately transfer 1.0 mL from the aqueous phase to a 5 mL volumetric flask and use SPL-PO4. 3- He wrote:

[0427] 5.5 Method Parameters:

[0428] [Table 64]

[0429] 5.6 Experimental Results

[0430] [Table 65]

[0431] Calculation: The molar ratio of chloride ions to free base in the hydrochloride salt is (5.95 / 35.5) / (100 / (517.5+36.5))=0.93:1. The molar ratio of sulfate to free base in a sulfate solution is (15.67 / 96) / (100 / (517.5+98))=1:1. The molar ratio of phosphate to free base in a phosphate is (14.98 / 95) / (100 / (517.5+98))=0.97:1.

[0432] Conclusion: The results of the verification showed that the acid-base ratio of all the salts obtained above was 1:1.

[0433] (Example 13: Characterization of crystal form)

[0434] The solid salts obtained through screening were characterized using methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and powder X-ray diffraction (XRPD). Based on a comprehensive consideration of the crystallinity, TGA loss, melting point, and HPLC purity of the salts obtained through screening, a superior salt type was selected, and scale-up preparation was carried out.

[0435] The solid properties of the salt-type obtained through screening were characterized using methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and powder X-ray diffraction (XRPD). Relevant spectral diagrams can be found in Figures 17-34. The experimental results are as follows.

[0436] [Table 66]

[0437] (Example 14: Solid Stability Test)

[0438] 60 mg each of hydrochloride crystalline form A, sulfate crystalline form A, and phosphate crystalline form A were weighed out and placed in glass dishes or vials. Next, the glass dishes or vials were placed in different environments within a constant temperature and humidity chamber, including light irradiation: 4500 ± 500 lux (open), high temperature: 60°C (closed), high humidity: 25°C, relative humidity 90 ± 5% (open).

[0439] The results of the solid stability studies of phosphates, hydrochlorides, and sulfates are shown below.

[0440] [Table 67]

[0441] As can be seen from the results of the solid stability evaluation test, hydrochloride crystalline form A showed good physical and chemical stability under all conditions of strong light irradiation, high temperature, and high humidity.

[0442] (Example 15: Solubility Test)

[0443] The solubility of the dominant salt was measured in different pH buffers, water, and physiological saline. The specific steps for solubility measurement are as follows:

[0444] 15 mg of each hydrochloride crystal form A sample was accurately weighed out and transferred to a 20 mL screw-top vial. 3 mL of the solution (water, pH buffer, SGF, FaSSIF, FeSSIF) was added to each vial. The vials were sealed and placed in a magnetic stirrer, where they were maintained at 25°C and a stirring speed of 500 rpm for 24 hours. The solubility of the samples in the vials was recorded during the test period. After 24 hours, approximately 1 mL of the suspension was filtered, the filtrate was collected, and a solubility test was performed by HPLC. The pH value of the filtrate sample was measured using a pH meter. Phosphate crystal form A and sulfate crystal form A were determined according to the above procedure.

[0445] The experimental results are summarized in the table below.

[0446] [Table 68]

[0447] As the results show, all crystalline forms exhibited good solubility in a pH 1 buffer solution.

[0448] (Example 16: DVS test)

[0449] Experimental method: 1. First, the weight of the instrument's sample tray was set to zero to achieve equilibrium. 2. 30 mg of each sample (phosphate crystalline form A and hydrochloride crystalline form A) was weighed out and placed in a sample tray. 3. Program operation: Starting from a point where the humidity was 0%, the first cycle was completed when the humidity slowly increased to 90% and then returned to 0%. The second cycle was completed when the humidity increased again to 90% and then returned to 0% (as shown in Figures 35-36).

[0450] The results of the DVS data are shown in the following table.

[0451] [Table 69]

[0452] As can be seen from the test results, both hydrochloride crystalline form A and phosphate crystalline form A have low hygroscopicity, and no changes were observed in the samples before and after the DVS test.

[0453] (Example 17: Pharmacokinetic study)

[0454] 10.1 Solvent Information and Preparation of Test Sample Dosage Formulations Solvent information:

[0455] [Table 70]

[0456] 5% DMSO + 10% Tween 80 + 5% Kolliphor HS 15 + 80% physiological saline, where % represents volume ratio.

[0457] Preparation procedure for a 4 mg / mL formulation of hydrochloride (5% DMSO + 10% Tween 80 + 5% Kolliphor HS15 + 85% physiological saline): Accurately measure 41.97 mg of hydrochloride into a 15 mL centrifuge tube, add 488 μL of DMSO and vortex for 30 seconds to completely dissolve the compound, add 976 μL of Tween 80 and vortex for 30 seconds, then add 488 μL of Kolliphor HS15 (use after heating and dissolving Kolliphor HS15 at 50°C) and vortex for 30 seconds, finally add 7808 μL of physiological saline and vortex for 30 seconds, and finally sonicate for 10 seconds to remove air bubbles. This drug is a suspension.

[0458] Preparation procedure for a 4 mg / mL formulation of free base (5% DMSO + 10% Tween 80 + 5% Kolliphor HS15 + 85% physiological saline): Accurately weigh 41.35 mg of the 5-membered condensed 6-membered compound shown in Formula I, prepared in Example 1, into a 15 mL centrifuge tube. Add 517 μL of DMSO and vortex for 30 seconds to completely dissolve the compound. Add 1034 μL of Tween 80 and vortex for 30 seconds. Next, add 517 μL of Kolliphor HS15 (used after heating and dissolving Kolliphor HS15 at 50°C) and vortex for 30 seconds. Finally, add 8270 μL of physiological saline and vortex for 30 seconds. Lastly, sonicate for 10 seconds to remove air bubbles. This drug is a suspension.

[0459] 10.2 Experimental System 10.2.1 Laboratory animals Species and lineage: Sprague-Dawley rat (SD rat) (Zhejiang Weitong Lihua Laboratory Animal Technology Co., Ltd.) Animal grade: SPF grade Setting the animal body weight at the start of administration: 200-250g for males; the actual animal body weight will be recorded in the original record. Number of animals and sex: 3 (3 per group), male

[0460] 10.2.2 Rearing In the barrier-free animal enclosure, the animals had free access to food and water. Environmental conditions were controlled to a room temperature of 20°C to 26°C, relative humidity of 40% to 70%, and lighting with alternating light and dark cycles every 12 hours. The animals were housed in polycarbonate cages, with dimensions of 466mm (length) x 314mm (width) x 200mm (height), and no more than 5 animals per cage.

[0461] 10.2.3 Drinking water Animals can drink water freely.

[0462] 10.2.4 Marking Animal identification: Serial numbers were written on the tail of each rat using a marker pen, so that each animal had a unique identification number, and each group was housed in a single cage.

[0463] 10.3 Experimental Design 10.3.1 Animal grouping and dosage Based on measured body weight, animals of similar weight were divided into groups of three. The group divisions and dosages are shown in the table below. The blank group animals were used to collect blank biological substrates.

[0464] [Table 71]

[0465] 10.3.2 Administration Route of administration: Intragastric administration Dosage: 10 mL / kg Frequency of administration: Single dose Method of administration: The test substance is administered orally into the stomach using an appropriate syringe and oral tube. When using a 2 mL or 5 mL syringe, the dose is recorded to one decimal place. If the smallest mark on the syringe is 0.2 mL and the administered volume falls between two marks, the dose was drawn up to the upper mark. Reason for selecting the dosage: Standard dose in pharmacokinetic studies.

[0466] 10.3.3 Collection and Processing of Specimens Sample collection: At each time point, approximately 0.30 mL of whole blood was collected from the orbital vein of the animals in Group 1.

[0467] The experimental animals were fasted for 12 hours prior to administration, but water intake was permitted. Blood samples were collected from the first group (intragastric administration group) at 5, 15, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration.

[0468] Sample processing: The collected venous blood was immediately transferred to an EDTA-Na2 coated Ep tube (stored in a refrigerator at 2-8°C or in an icebox with crushed ice before use), mixed uniformly by inverting the tube at least five times, and then temporarily stored in an icebox with crushed ice. The collected whole blood was centrifuged at 2000g for 10 minutes at 2-8°C within 2 hours to separate the plasma, and then transferred to a newly labeled centrifuge tube. Both samples were stored at -20°C.

[0469] Specimen labeling: Collected whole blood / plasma samples are labeled as R-HPB-M20221013-07~09-WB / P-Po-5min / 15min / 30min / 1h / 2h / 4h / 6h / 8h / 24h, where "R" represents rat, "HPB" represents the project number, "M20221013" represents the animal's sex (male) and the experiment date, "07~09" represents the animal's abbreviation, "WB" represents whole blood, and "P" represents plasma.

[0470] 10.4 Data Collection and Statistical Analysis The pharmacokinetics team of the Pharmacology and Toxicology Department analyzed and measured all samples and compiled the data. Plasma concentration data was analyzed using the metabolic dynamics data analysis software WinNonlin. 1 / 2 , C max , T max , V d CL, AUC 0-24Pharmacokinetic parameters such as F were calculated using a non-compartmental model (NCA). The specific results are shown in the table below.

[0471] [Table 72]

[0472] Conclusion: Compared to free bases, hydrochloride salts can significantly increase the blood concentration and exposure of the compound in rats.

[0473] Although specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative descriptions and that various changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Accordingly, the scope of protection of the present invention is limited by the appended claims.

Claims

1. Crystal form A, crystal form C, or crystal form G of a five-membered condensed six-membered compound represented by formula I, The aforementioned crystal form A has characteristic peaks at 13.12±0.20°, 19.05±0.20°, 25.85±0.20°, and 26.73±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle. The aforementioned crystal form C has characteristic peaks at 11.05±0.20°, 14.21±0.20°, 18.83±0.20°, and 28.80±0.20° in the powder X-ray diffraction pattern represented by a 2θ angle. The aforementioned crystal form G has characteristic peaks at 9.74±0.20°, 13.56±0.20°, 16.39±0.20°, and 24.51±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle. 【Chemistry 1】 Preferably, The aforementioned crystal form A has characteristic peaks at one or more of the following positions in its powder X-ray diffraction pattern, represented by a 2θ angle: 7.84±0.20°, 10.25±0.20°, 20.96±0.20°, and 24.46±0.20°. and / or, the crystalline form C has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 7.02±0.20°, 9.78±0.20°, 20.44±0.20°, and 23.98±0.20°. and / or, the crystal form G has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 7.09±0.20°, 18.50±0.20°, 20.94±0.20°, and 23.36±0.20°. more, The aforementioned crystal form A has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 7.84±0.20°, 10.25±0.20°, 13.12±0.20°, 19.05±0.20°, 20.96±0.20°, 24.46±0.20°, 25.85±0.20°, and 26.73±0.20°. The aforementioned crystal form C has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 7.02±0.20°, 9.78±0.20°, 11.05±0.20°, 14.21±0.20°, 18.83±0.20°, 20.44±0.20°, 23.98±0.20°, and 28.80±0.20°. The crystalline form G is characterized by having characteristic peaks at the positions of 7.09±0.20°, 9.74±0.20°, 13.56±0.20°, 16.39±0.20°, 18.50±0.20°, 20.94±0.20°, 23.36±0.20°, and 24.51±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle, and is a crystalline form A, crystalline form C, or crystalline form G of the 5-membered condensed 6-membered compound represented by formula I.

2. A crystalline form of a 5-membered condensed 6-membered compound represented by formula I, which is crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, or crystalline form G, The aforementioned crystal form A has characteristic peaks at the positions of 7.84±0.20°, 10.25±0.20°, 20.96±0.20°, 22.36±0.20°, and 25.85±0.20° in the powder X-ray diffraction pattern represented by a 2θ angle. The aforementioned crystal form C has characteristic peaks at the positions of 7.02±0.20°, 9.78±0.20°, 11.05±0.20°, 14.21±0.20°, 18.83±0.20°, and 20.44±0.20° in the powder X-ray diffraction pattern represented by a 2θ angle. The aforementioned crystal form B has characteristic peaks at 9.94±0.20°, 11.81±0.20°, 16.26±0.20°, and 18.47±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle. The aforementioned crystal form D has characteristic peaks at 9.51±0.20°, 15.35±0.20°, 19.27±0.20°, and 24.20±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle. The aforementioned crystal form E has characteristic peaks at 9.21±0.20°, 10.61±0.20°, 13.93±0.20°, 18.66±0.20°, and 23.43±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle. The aforementioned crystal form F has characteristic peaks at 5.53±0.20°, 5.93±0.20°, 10.38±0.20°, and 22.37±0.20° in the powder X-ray diffraction pattern represented by a 2θ angle. The aforementioned crystal form G has characteristic peaks at 9.74±0.20°, 13.56±0.20°, 16.39±0.20°, and 24.51±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle. 【Chemistry 2】 Preferably, The aforementioned crystal form A has characteristic peaks at one or more of the following positions in its powder X-ray diffraction pattern, represented by a 2θ angle: 11.33±0.20°, 13.12±0.20°, 14.43±0.20°, 15.52±0.20°, 16.78±0.20°, 17.55±0.20°, 20.77±0.20°, 22.92±0.20°, and 24.46±0.20°. The aforementioned crystal form C has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 11.59±0.20°, 18.19±0.20°, 21.17±0.20°, 22.87±0.20°, 23.98±0.20°, 24.19±0.20°, 25.71±0.20°, and 28.80±0.20°. The aforementioned crystal form B has characteristic peaks at one or more of the following positions in its powder X-ray diffraction pattern, represented by a 2θ angle: 11.41±0.20°, 14.41±0.20°, 20.73±0.20°, and 23.39±0.20°. The aforementioned crystal form D has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 9.90±0.20°, 20.01±0.20°, 20.75±0.20°, and 29.18±0.20°. The aforementioned crystal form E has characteristic peaks at one or more positions among 20.06±0.20°, 21.85±0.20°, and 28.25±0.20° in the powder X-ray diffraction pattern represented by a 2θ angle. The aforementioned crystal form F has characteristic peaks at one or more of the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 10.21±0.20°, 11.11±0.20°, 16.72±0.20°, and 25.78±0.20°. The aforementioned crystal form G has characteristic peaks at one or more of the following positions in its powder X-ray diffraction pattern, represented by a 2θ angle: 7.09±0.20°, 14.28±0.20°, 15.61±0.20°, 18.5±0.20°, 20.36±0.20°, and 24.51±0.20°. more, The aforementioned crystal form B has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 9.94±0.20°, 11.41±0.20°, 11.81±0.20°, 14.41±0.20°, 16.26±0.20°, 18.47±0.20°, 20.73±0.20°, and 23.39±0.20°. The aforementioned crystal form D has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 9.51±0.20°, 9.90±0.20°, 15.35±0.20°, 19.27±0.20°, 20.01±0.20°, 20.75±0.20°, 24.20±0.20°, and 29.18±0.20°. The aforementioned crystal form E has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 9.21±0.20°, 10.61±0.20°, 13.93±0.20°, 18.66±0.20°, 20.06±0.20°, 21.85±0.20°, 23.43±0.20°, and 28.25±0.20°. The crystalline form F of the five-membered condensed six-membered compound represented by formula I is characterized by having characteristic peaks at the positions of 5.53±0.20°, 5.93±0.20°, 10.21±0.20°, 10.38±0.20°, 11.11±0.20°, 16.72±0.20°, 22.37±0.20°, and 25.78±0.20° in a powder X-ray diffraction pattern represented by a 2θ angle.

3. The aforementioned crystal form A has diffraction peaks at the diffraction angles shown in the following table in the powder X-ray diffraction pattern represented by a 2θ angle. Table 1 Table 2 and / or, the crystalline form C has diffraction peaks at the diffraction angles shown in the following table in the powder X-ray diffraction pattern represented by a 2θ angle, Table 3 Table 4 And / or, in the powder X-ray diffraction pattern represented by a 2θ angle, the crystal form B has diffraction peaks at the diffraction angles shown in the following table, Table 5 And / or, the crystal form D has diffraction peaks at the diffraction angles shown in the following table in the powder X-ray diffraction pattern represented by a 2θ angle, Table 6 And / or, the crystal form E has diffraction peaks at the diffraction angles shown in the following table in the powder X-ray diffraction pattern represented by a 2θ angle, Table 7 And / or, the crystal form F has diffraction peaks at the diffraction angles shown in the following table in the powder X-ray diffraction pattern represented by a 2θ angle, Table 8 And / or, the crystal form G has diffraction peaks at the diffraction angles shown in the following table in the powder X-ray diffraction pattern represented by a 2θ angle, Table 9 moreover, The diffraction peaks, d values, and peak height percentages in the powder X-ray diffraction pattern represented by the 2θ angle of the aforementioned crystal form A are as shown in the table below. Table 10 Table 11 And / or, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form C are as shown in the table below. Table 12 Table 13 And / or, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form B are as shown in the table below. Table 14 And / or, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form D are as shown in the table below. Table 15 And / or, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form E are as shown in the table below. Table 16 And / or, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form F are as shown in the table below. Table 17 And / or, the diffraction peak, d value, and peak height percentage in the powder X-ray diffraction pattern represented by the 2θ angle of the crystal form G are as shown in the table below. Table 18 The crystal form according to claim 1 or 2.

4. The powder X-ray diffraction pattern of the aforementioned crystal form A is basically as shown in Figure 1. And / or, the powder X-ray diffraction pattern of the crystalline form C is basically as shown in Figure 5. And / or, the powder X-ray diffraction pattern of crystal form B is basically as shown in Figure 3. And / or, the powder X-ray diffraction pattern of the crystal form D is basically as shown in Figure 7. And / or, the powder X-ray diffraction pattern of the crystal form E is basically as shown in Figure 9. And / or, the powder X-ray diffraction pattern of the crystal form F is basically as shown in Figure 11. And / or, the powder X-ray diffraction pattern of the crystalline form G is basically as shown in Figure 13. And / or, in the analysis chart by differential scanning calorimetry, the crystal form A has an endothermic peak starting point at 231.31 ± 2°C, and further reaches the peak value of the endothermic peak at 232.04 ± 2°C, and its enthalpy value is 111.300 J / g. And / or, in the differential scanning calorimetry analysis chart, the crystal form A has an endothermic peak starting point at 237.74 ± 2°C, and further reaches the peak value of the endothermic peak at 244.16 ± 2°C, and its enthalpy value is 69.104 J / g. And / or, in the differential scanning calorimetry analysis chart, the crystalline form C has an endothermic peak starting point at 63.69 ± 2°C, further reaching the peak value of the endothermic peak at 82.10 ± 2°C, and further having an enthalpy value of 61.396 J / g. And / or, in the differential scanning calorimetry analysis chart, the crystalline form C has an endothermic peak starting point at 126.27 ± 2°C, and further reaches the peak value of the endothermic peak at 134.20 ± 2°C, and its enthalpy value is 42.089 J / g. And / or, in the differential scanning calorimetry analysis chart, the crystalline form C has an endothermic peak starting point at 230.61 ± 2°C, further reaching the peak value of the endothermic peak at 231.73 ± 2°C, and furthermore, its enthalpy value is 103.46 J / g. And / or, the crystalline form A has a weight loss of 0.428% at 200°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage. And / or, the crystalline form C shows a weight loss of 3.778% at 73.91°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage. And / or, in the differential scanning calorimetry analysis chart, the crystal form B has an endothermic peak starting point at 60.85 ± 2°C, further reaching the peak value of the endothermic peak at 72.84 ± 2°C, and furthermore, its enthalpy value is 32.752 J / g. And / or, in the analysis chart by differential scanning calorimetry, crystal form B has an endothermic peak starting point at 151.04 ± 2°C, and further reaches the peak value of the endothermic peak at 153.19 ± 2°C, and its enthalpy value is 4.135 J / g. And / or, in the analysis chart by differential scanning calorimetry, the crystal form B has an endothermic peak starting point at 230.51 ± 2°C, and further reaches the peak value of the endothermic peak at 231.37 ± 2°C, and its enthalpy value is 113.950 J / g. And / or, in the differential scanning calorimetry analysis chart, the crystalline form D has an endothermic peak starting point at 231.13 ± 2°C, and further reaches the peak value of the endothermic peak at 232.25 ± 2°C, and its enthalpy value is 115.520 J / g. And / or, in the analysis chart by differential scanning calorimetry, the crystal form E has an endothermic peak starting point at 48.59 ± 2°C, and further reaches the peak value of the endothermic peak at 51.08 ± 2°C, and its enthalpy value is 5.451 J / g. And / or, in the differential scanning calorimetry analysis chart, the crystal form E has an endothermic peak starting point at 90.07 ± 2°C, and further reaches the peak value of the endothermic peak at 95.66 ± 2°C, and its enthalpy value is 19.797 J / g. And / or, in the differential scanning calorimetry analysis chart, the crystal form E has an endothermic peak starting point at 225.15 ± 2°C, and further reaches the peak value of the endothermic peak at 228.25 ± 2°C, and its enthalpy value is 86.445 J / g. And / or, in the analysis chart by differential scanning calorimetry, the crystalline form F has an endothermic peak starting point at 49.64 ± 2°C, further reaching the peak value of the endothermic peak at 52.43 ± 2°C, and furthermore, its enthalpy value is 3.400 J / g. And / or, in the differential scanning calorimetry analysis chart, the crystalline form F has an endothermic peak starting point at 97.99 ± 2°C, and further reaches the peak value of the endothermic peak at 103.02 ± 2°C, and its enthalpy value is 9.028 J / g. And / or, in the analysis chart by differential scanning calorimetry, the crystalline form F has an endothermic peak starting point at 225.07 ± 2°C, further reaching the peak value of the endothermic peak at 226.71 ± 2°C, and furthermore, its enthalpy value is 92.201 J / g. And / or, in the differential scanning calorimetry analysis chart, the crystalline form G has an endothermic peak starting point at 63.20 ± 2°C, further reaching the peak value of the endothermic peak at 76.01 ± 2°C, and further having an enthalpy value of 25.610 J / g. And / or, in the differential scanning calorimetry analysis chart, the crystalline form G has an endothermic peak starting point at 150.82 ± 2°C, further reaching the peak value of the endothermic peak at 153.33 ± 2°C, and its enthalpy value is 12.882 J / g. And / or, in the analysis chart by differential scanning calorimetry, the crystalline form G has an endothermic peak starting point at 230.69 ± 2°C, and further reaches the peak value of the endothermic peak at 231.37 ± 2°C, and its enthalpy value is 111.380 J / g. And / or, the crystalline form B shows a weight loss of 4.741% at 122.68°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage. And / or, the crystalline form D shows a weight loss of 2.826% at 116.38°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage. And / or, the crystalline form E has a weight loss of 5.585% at 119.49°C in the analysis chart by thermogravimetric analysis, where "%" is a mass percentage. And / or, the crystalline form F has a weight loss of 1.066% at 127.37°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage. And / or, the crystalline form G has a weight loss of 3.405% at 130.90°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage. Preferably, The analysis chart of the aforementioned crystal form A by differential scanning calorimetry is basically as shown in Figure 2. And / or, the differential scanning calorimetry analysis chart for the crystalline form C is basically as shown in Figure 6. And / or, the analysis chart of the crystal form A by thermogravimetric analysis is basically as shown in Figure 2. And / or, the analysis chart of the crystalline form C by thermogravimetric analysis is basically as shown in Figure 6. And / or, the differential scanning calorimetry analysis chart for the crystal form B is basically as shown in Figure 4. And / or, the differential scanning calorimetry analysis chart for the crystal form D is basically as shown in Figure 8. And / or, the differential scanning calorimetry analysis chart for the crystal form E is basically as shown in Figure 10. And / or, the differential scanning calorimetry analysis chart for the crystal form F is basically as shown in Figure 12. And / or, the differential scanning calorimetry analysis chart of the crystal form G is basically as shown in Figure 14. And / or, the analysis chart of the crystal form B by thermogravimetric analysis is basically as shown in Figure 4. And / or, the analysis chart of the crystal form D by thermogravimetric analysis is basically as shown in Figure 8. And / or, the analysis chart of the crystal form E by thermogravimetric analysis is basically as shown in Figure 10. And / or, the analysis chart of the crystal form F by thermogravimetric analysis is basically as shown in Figure 12. The crystal form according to any one of claims 1 to 3, characterized in that the analysis chart of the crystal form G by thermogravimetric analysis is basically as shown in Figure 14.

5. A salt of a five-membered condensed six-membered compound represented by formula I, which is a hydrochloride, sulfate, phosphate, sodium salt, or potassium salt. 【Transformation 3】 Preferably, (1) The condition that the hydrochloride salt is monohydrochloride salt, (2) The condition that the sulfate is monosulfate, (3) The condition that the phosphate is a monophosphate, (4) The condition that the sodium salt is a monosodium salt, (5) A salt of a five-membered condensed six-membered compound represented by formula I, characterized in that the potassium salt satisfies one or more of the conditions for being a monopotassium salt.

6. The aforementioned salt is (1) The hydrochloride salt is of crystalline form A, and in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 10.81±0.20°, 20.20±0.20°, 22.70±0.20°, 23.74±0.20°, 29.89±0.20°, and 39.32±0.20°. (2) The hydrochloride salt is of crystalline form B, and in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 8.2±0.20°, 13.28±0.20°, 18.87±0.20°, 25.07±0.20°, 34.76±0.20°, and 35.21±0.20°. (3) The sulfate is of crystalline form A, and in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 19.62±0.20°, 27.19±0.20°, 28.70±0.20°, 32.36±0.20°, 33.43±0.20°, and 34.15±0.20°. (4) The sulfate is of crystalline form B, and in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 15.86±0.20°, 16.53±0.20°, 20.05±0.20°, 28.46±0.20°, and 30.59±0.20°. (5) The sulfate is in crystalline form C, and in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays, it has characteristic peaks at the positions of 7.70±0.20°, 12.87±0.20°, 19.87±0.20°, 21.55±0.20°, and 25.94±0.20°. (6) The phosphate is of crystalline form A and has characteristic peaks at the following positions in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays: 10.04±0.20°, 14.10±0.20°, 18.10±0.20°, 22.80±0.20°, 24.57±0.20°, 28.44±0.20°, and 30.82±0.20°. (7) The phosphate is of crystalline form B and has characteristic peaks at the positions of 17.96±0.20°, 21.10±0.20°, 21.41±0.20°, 23.38±0.20°, 26.91±0.20°, and 28.9±0.20° in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays. (8) The sodium salt is of crystalline form A, and in a powder X-ray diffraction pattern expressed as a 2θ angle using Cu-Kα rays, it has characteristic peaks at the following positions: 7.04±0.20°, 11.05±0.20°, 11.55±0.20°, 15.18±0.20°, 17.98±0.20°, 22.09±0.20°, 25.65±0.20°, and 28.76±0.20°. (9) The salt according to claim 5, wherein the potassium salt is in crystalline form A and satisfies one or more of the conditions that, in a powder X-ray diffraction pattern represented by a 2θ angle using Cu-Kα rays, characteristic peaks are located at 7.04±0.20°, 9.75±0.20°, 11.05±0.20°, 11.49±0.20°, 14.20±0.20°, 15.06±0.20°, 18.06±0.20°, 25.58±0.20°, and 30.93±0.20°.

7. The aforementioned salt is (1) The crystalline form A of the hydrochloride salt has a characteristic peak at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 11.72±0.20°, 21.88±0.20°, 28.61±0.20°, and 31.26±0.20°. (2) The crystalline form B of the hydrochloride salt has a characteristic peak at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 13.93±0.20°, 15.28±0.20°, 27.18±0.20°, and 28.99±0.20°. (3) The crystalline form A of the sulfate has a characteristic peak at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 14.94±0.20°, 17.42±0.20°, 22.76±0.20°, and 26.46±0.20°. (4) The crystalline form B of the sulfate has a characteristic peak at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 9.00±0.20°, 12.52±0.20°, 21.21±0.20°, and 22.36±0.20°. (5) The crystalline form C of the sulfate has a characteristic peak at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 8.74±0.20°, 10.67±0.20°, 18.64±0.20°, and 19.05±0.20°. (6) The crystalline form A of the phosphate has a characteristic peak at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 6.57±0.20°, 18.53±0.20°, 19.97±0.20°, 22.43±0.20°, and 27.18±0.20°. (7) The crystalline form B of the phosphate has a characteristic peak at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 7.40±0.20°, 17.61±0.20°, 19.69±0.20°, and 24.93±0.20°. (8) The crystalline form A of the sodium salt has a characteristic peak at one or more of the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 9.78±0.20°, 14.20±0.20°, 18.81±0.20°, 19.97±0.20°, and 24.13±0.20°, and (9) The crystalline form A of the potassium salt satisfies one or more of the conditions that the powder X-ray diffraction pattern represented by the 2θ angle has characteristic peaks at one or more of the following positions: 19.46±0.20°, 19.96±0.20°, 23.54±0.20°, and 27.92±0.20°. Furthermore, the salt is (1) The crystalline form A of the hydrochloride salt has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 10.81±0.20°, 11.72±0.20°, 20.20±0.20°, 21.88±0.20°, 22.70±0.20°, 23.74±0.20°, 28.61±0.20°, 29.89±0.20°, 31.26±0.20°, and 39.32±0.20°. (2) The crystalline form B of the hydrochloride salt has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 8.2±0.20°, 13.28±0.20°, 13.93±0.20°, 15.28±0.20°, 18.87±0.20°, 25.07±0.20°, 27.18±0.20°, 28.99±0.20°, 34.76±0.20°, and 35.21±0.20°. (3) The crystalline form A of the sulfate has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 14.94±0.20°, 17.42±0.20°, 19.62±0.20°, 22.76±0.20°, 26.46±0.20°, 27.19±0.20°, 28.70±0.20°, 32.36±0.20°, 33.43±0.20°, and 34.15±0.20°. (4) The crystalline form B of the sulfate has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 9.00±0.20°, 12.52±0.20°, 15.86±0.20°, 16.53±0.20°, 20.05±0.20°, 21.21±0.20°, 22.36±0.20°, 28.46±0.20°, and 30.59±0.20°. (5) The crystalline form C of the sulfate has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 7.70±0.20°, 8.74±0.20°, 10.67±0.20°, 12.87±0.20°, 18.64±0.20°, 19.05±0.20°, 19.87±0.20°, 21.55±0.20°, and 25.94±0.20°. (6) The crystalline form A of the phosphate has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 6.57±0.20°, 10.04±0.20°, 14.10±0.20°, 18.10±0.20°, 18.53±0.20°, 19.97±0.20°, 22.43±0.20°, 22.80±0.20°, 24.57±0.20°, 27.18±0.20°, 28.44±0.20°, and 30.82±0.20°. (7) The crystalline form B of the phosphate has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by the 2θ angle: 7.40±0.20°, 17.61±0.20°, 17.96±0.20°, 19.69±0.20°, 21.10±0.20°, 21.41±0.20°, 23.38±0.20°, 24.93±0.20°, 26.91±0.20°, and 28.9±0.20°. (8) The crystalline form A of the sodium salt has characteristic peaks at the following positions in the powder X-ray diffraction pattern represented by a 2θ angle: 7.04±0.20°, 9.78±0.20°, 11.05±0.20°, 11.55±0.20°, 14.20±0.20°, 15.18±0.20°, 17.98±0.20°, 18.81±0.20°, 19.97±0.20°, 22.09±0.20°, 24.13±0.20°, 25.65±0.20°, and 28.76±0.20°, and (9) The salt according to 6, characterized in that the crystalline form A of the potassium salt satisfies one or more of the conditions that, in the powder X-ray diffraction pattern represented by a 2θ angle, characteristic peaks are located at 7.04±0.20°, 9.75±0.20°, 11.05±0.20°, 11.49±0.20°, 14.20±0.20°, 15.06±0.20°, 18.06±0.20°, 19.46±0.20°, 19.96±0.20°, 23.54±0.20°, 25.58±0.20°, 27.92±0.20°, and 30.93±0.20°.

8. The aforementioned salt is (1) In the case of the crystalline form A of the hydrochloride salt, the diffraction peaks in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form A may be as shown in the table below, under the following conditions: Table 19 Table 20 (2) In the case of the crystalline form B of the hydrochloride salt, the diffraction peak in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form B may be as shown in the table below, under the following conditions: Table 21 Table 22 (3) In the case of the crystalline form A of the sulfate, the diffraction peak in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form A may be as shown in the table below, under the following conditions. Table 23 Table 24 (4) In the case of the crystalline form B of the sulfate, the diffraction peak in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form B may be as shown in the table below, under the following conditions: Table 25 (5) In the case of the crystalline form C of the sulfate, the diffraction peak in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form C may be as shown in the table below, under the following conditions. Table 26 (6) In the case of the crystalline form A of the phosphate, the diffraction peak in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form A may be as shown in the table below, Table 27 Table 28 (7) In the case of the crystalline form B of the phosphate, the diffraction peak in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form B may be as shown in the table below, under the following conditions: Table 29 (8) In the case of the crystalline form A of the sodium salt, the diffraction peaks in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form A may be as shown in the following table, under the following conditions, Table 30 Table 31 (9) In the case of the crystalline form A of the potassium salt, the diffraction peak in the powder X-ray diffraction pattern represented by the 2θ angle of the crystalline form A further satisfies one or more of the conditions shown in the table below. Table 32 Furthermore, the salt is (1) In the case of the crystalline form A of the hydrochloride salt, the diffraction peak and relative intensity in the powder X-ray diffraction pattern represented by the 2θ angle and relative intensity of the crystalline form A may be as shown in the table below, Table 33 Table 34 (2) In the case of the crystalline form B of the hydrochloride salt, the diffraction peak and relative intensity in the powder X-ray diffraction pattern represented by the 2θ angle and relative intensity of the crystalline form B may be as shown in the table below, Table 35 Table 36 (3) In the case of the crystalline form A of the sulfate, the diffraction peak and relative intensity in the powder X-ray diffraction pattern represented by the 2θ angle and relative intensity of the crystalline form A may be as shown in the table below, Table 37 Table 38 (4) In the case of the crystalline form B of the sulfate, the diffraction peak and relative intensity in the powder X-ray diffraction pattern represented by the 2θ angle and relative intensity of the crystalline form B may be as shown in the table below, Table 39 (5) In the case of the crystalline form C of the sulfate, the diffraction peak and relative intensity in the powder X-ray diffraction pattern represented by the 2θ angle and relative intensity of the crystalline form C may be as shown in the table below, Table 40 (6) In the crystalline form A of the phosphate, the diffraction peak and relative intensity in the powder X-ray diffraction pattern, which are represented by the 2θ angle and relative intensity of the crystalline form A, may be as shown in the table below, Table 41 Table 42 (7) In the crystalline form B of the phosphate, the diffraction peak and relative intensity in the powder X-ray diffraction pattern, represented by the 2θ angle and relative intensity of the crystalline form B, may be as shown in the table below, Table 43 (8) In the crystalline form A of the sodium salt, the diffraction peak and relative intensity in the powder X-ray diffraction pattern, which are represented by the 2θ angle and relative intensity of the crystalline form A, may be as shown in the table below, Table 44 Table 45 (9) In the crystalline form A of the potassium salt, the diffraction peak and relative intensity in the powder X-ray diffraction pattern represented by the 2θ angle and relative intensity of the crystalline form A further satisfy one or more of the conditions shown in the table below. Table 46 Furthermore, the salt is (1) The powder X-ray diffraction pattern (XRPD) of the crystalline form A of the hydrochloride salt is basically as shown in Figure 17, (2) The powder X-ray diffraction pattern (XRPD) of the crystalline form B of the hydrochloride salt is basically as shown in Figure 19, (3) The powder X-ray diffraction pattern (XRPD) of the crystalline form A of the sulfate is basically as shown in Figure 21, (4) The powder X-ray diffraction pattern (XRPD) of the crystalline form B of the sulfate is basically as shown in Figure 23, (5) The powder X-ray diffraction pattern (XRPD) of the crystalline form C of the sulfate is basically as shown in Figure 25, (6) The powder X-ray diffraction pattern (XRPD) of the crystalline form A of the phosphate is basically as shown in Figure 27, (7) The powder X-ray diffraction pattern (XRPD) of the crystalline form B of the phosphate is basically as shown in Figure 29, (8) The conditions under which the powder X-ray diffraction pattern (XRPD) of the crystalline form A of the sodium salt is basically as shown in Figure 31, and (9) The salt according to claim 6 or 7, characterized in that the powder X-ray diffraction pattern (XRPD) of the crystalline form A of the potassium salt satisfies one or more of the conditions shown in Figure 33.

9. The aforementioned salt is (1) The crystalline form A of the hydrochloride salt has a weight loss of 2.070% at 125.06°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage, and / or, in an analysis chart by differential scanning calorimetry, it has the starting point of an endothermic peak at 184.04±2°C, further reaching the peak value of the endothermic peak at 188.62±2°C, and furthermore, its enthalpy value is 344.80 J / g. (2) The crystalline form B of the hydrochloride salt has a weight loss of 7.216% at 96.43°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage, and / or, in an analysis chart by differential scanning calorimetry, it has an endothermic peak starting point at 173.54±2°C, further reaching the peak value of the endothermic peak at 184.54±2°C, and furthermore, its enthalpy value is 259.36 J / g. (3) The crystalline form A of the sulfate has a weight loss of 3.880% at 118.49°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage, and / or, in an analysis chart by differential scanning calorimetry, it has the starting point of an endothermic peak at 149.86±2°C, further reaching the peak value of the endothermic peak at 160.23±2°C, and furthermore, its enthalpy value is 229.21 J / g. (4) The crystalline form B of the sulfate has a weight loss of 6.895% at 92.04°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage, and / or, in an analysis chart by differential scanning calorimetry, it has an endothermic peak starting at 126.34±2°C, and further reaches the peak value of the endothermic peak at 139.98±2°C, and further has an enthalpy value of 230.50 J / g. (5) The crystalline form C of the sulfate has a weight loss of 10.471% at 102.19°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage, and / or, in an analysis chart by differential scanning calorimetry, it has an endothermic peak starting at 117.30±2°C, and further reaches the peak value of the endothermic peak at 122.26±2°C, and further has an enthalpy value of 54.426 J / g. (6) The crystalline form A of the phosphate has a weight loss of 0.776% at 142.87°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage, and / or, in an analysis chart by differential scanning calorimetry, it has an endothermic peak starting point at 179.76±2°C, and further reaches the peak value of the endothermic peak at 180.61±2°C, and further has an enthalpy value of 265.82 J / g. (7) The crystalline form B of the phosphate has a weight loss of 1.071% at 74.52°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage, and / or, in an analysis chart by differential scanning calorimetry, it has an endothermic peak starting point at 159.94±2°C, and further reaches the peak value of the endothermic peak at 169.82±2°C, and further has an enthalpy value of 77.238 J / g. (8) The crystalline form A of the sodium salt has a weight loss of 6.279% at 116.94°C in an analysis chart by thermogravimetric analysis, where "%" is a mass percentage, and / or, in an analysis chart by differential scanning calorimetry, it has the starting point of an endothermic peak at 228.53±2°C, further reaching the peak value of the endothermic peak at 230.66±2°C, and furthermore, its enthalpy value is 107.61 J / g, and (9) The crystalline form A of the potassium salt satisfies one or more of the following conditions: in the analysis chart by thermogravimetric analysis, it has a weight loss of 8.352% at 183.95°C, where "%" is a mass percentage; in the analysis chart by differential scanning calorimetry, it has the starting point of an endothermic peak at 217.76±2°C, further reaching the peak value of the endothermic peak at 222.51±2°C, and furthermore, its enthalpy value is 102.94 J / g. Specifically, the salt is (1) The thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form A of the hydrochloride salt are basically as shown in Figure 18, (2) The thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form B of the hydrochloride salt are basically as shown in Figure 20, (3) The thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form A of the sulfate are basically as shown in Figure 22, (4) The thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form B of the sulfate are basically as shown in Figure 24, (5) The thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form C of the sulfate are basically as shown in Figure 26, under the following conditions: (6) The thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form A of the phosphate are basically as shown in Figure 28, under the following conditions: (7) The thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form B of the phosphate are basically as shown in Figure 30, (8) The thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form A of the sodium salt are basically as shown in Figure 32, (9) The salt according to any one of claims 6 to 8, characterized in that the thermogravimetric spectrum and differential scanning calorimetry chart of the crystalline form A of the potassium salt satisfy one or more of the conditions shown in Figure 34.

10. A crystalline form of a five-membered condensed six-membered compound represented by formula I as described in any one of claims 1 to 4, or a salt of a five-membered condensed six-membered compound represented by formula I as described in any one of claims 5 to 9, and a pharmaceutical adjuvant, The aforementioned pharmaceutical adjuvant is one or more of DMSO, Twain-80, polyethylene glycol 15-hydroxystearate, and physiological saline. Furthermore, the pharmaceutical adjuvant consists of 5% DMSO, 10% Twain-80, 5% polyethylene glycol 15-hydroxystearate, and 80% physiological saline, where % represents the volume ratio. Preferably, the pharmaceutical composition is characterized in that the mass-volume ratio of the salt of the five-membered condensed six-membered compound represented by formula I to the pharmaceutical adjuvant is 4:1 mg / mL.

11. The use of substance Z or the pharmaceutical composition according to claim 10 in the preparation of a drug for treating and / or preventing FLT3 and / or IRAK4-related disease, The substance Z is a crystalline form of a five-membered condensed six-membered compound represented by formula I as described in any one of claims 1 to 4, or a salt of a five-membered condensed six-membered compound represented by formula I as described in any one of claims 5 to 9. Preferably, the FLT3-related diseases include hematological malignancies and / or solid tumors. and / or, the use is characterized in that the IRAK4-related disease includes autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancers, or central nervous system diseases.

12. (1) The hematological malignancy is one or more selected from acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, acute anaplastic leukemia, anaplastic large cell lymphoma, prolymphoblastic leukemia, juvenile myeloid monocytic leukemia, myelodysplastic syndrome, non-Hodgkin lymphoma, multiple myeloma, myeloproliferative disorders, mantle cell lymphoma, and adult-onset acute myeloid leukemia. (2) The solid tumor is one or more selected from colorectal cancer, renal cell carcinoma, bladder cancer, ovarian cancer, breast cancer, pancreatic cancer, gastric adenocarcinoma, prostate cancer, and lung cancer. (3) The autoimmune disease is one or more selected from rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes mellitus, psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome. (4) The inflammatory disease is one or more selected from rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes mellitus, psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome, and (5) The use according to claim 11, characterized in that the cardiovascular disease satisfies one or more of the conditions of being a stroke or atherosclerosis.

13. The use of substance Z in the preparation of a drug, wherein substance Z is a crystalline form of a five-membered condensed six-membered compound represented by formula I as described in any one of claims 1 to 4, or a salt of a five-membered condensed six-membered compound represented by formula I as described in any one of claims 5 to 9, wherein the drug is used to treat and / or prevent one or more of the following: hematological malignancies, solid tumors, autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and central nervous system diseases, preferably, (1) The hematological tumor is as described in claim 12, (2) The solid tumor is as described in claim 12, (3) The autoimmune disease is as described in claim 12, (4) The inflammatory disease is as described in claim 12, (5) Use that satisfies one or more of the conditions described in claim 12 for the cardiovascular disease.

14. A method for treating and / or preventing a disease, The method comprises administering an effective amount of substance Z or the pharmaceutical composition according to claim 10 to a patient, wherein substance Z is a crystalline form of a five-membered condensed six-membered compound represented by formula I according to any one of claims 1 to 4, or a salt of a five-membered condensed six-membered compound represented by formula I according to any one of claims 5 to 9, and the disease is one or more selected from hematological malignancies, solid tumors, autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and central nervous system diseases, preferably, (1) The hematological tumor is as described in claim 12, (2) The solid tumor is as described in claim 12, (3) The autoimmune disease is as described in claim 12, (4) The inflammatory disease is as described in claim 12, and (5) A method characterized in that the cardiovascular disease satisfies one or more of the conditions described in claim 12.

15. A method for preparing the crystalline form of a five-membered condensed six-membered compound represented by formula I according to any one of claims 1 to 4, The method for preparing the aforementioned crystal form A includes the steps of adding a poor solvent to a solution of a five-membered condensed six-membered compound represented by formula I, and then lowering the temperature to crystallize and obtain the aforementioned crystal form A. The method for preparing the crystalline form C includes the step of volatilizing a suspension of a five-membered condensed six-membered compound represented by formula I to obtain the crystalline form C. When the crystalline form is crystalline form G, the procedure includes lowering the temperature of a five-membered condensed six-membered compound solution represented by formula I to obtain the crystalline form, wherein the solvent of the solution is an alcohol-based solvent. Preferably, the preparation method is (1) In the method for preparing crystalline form A, the solvent of the solution of the five-membered condensed six-membered compound represented by formula I is a mixed solvent of a sulfoxide solvent and an alcohol solvent, the sulfoxide solvent is dimethyl sulfoxide, the alcohol solvent is ethanol and / or isopropanol, and the volume ratio of the sulfoxide solvent to the alcohol solvent may be (1-5):1, for example 2:

1. (2) In the method for preparing crystalline form A, the poor solvent is an alcohol-based solvent and / or water, for example, ethanol and / or isopropanol. (3) In the method for preparing crystalline form A, in the solution of the five-membered condensed six-membered compound represented by formula I, the mass-volume ratio of the five-membered condensed six-membered compound represented by formula I to the solvent of the solution of the five-membered condensed six-membered compound represented by formula I is 1:(1-10) g / mL, for example, 1:5 g / mL. (4) In the method for preparing crystalline form A, the volume ratio of the solution of the five-membered condensed six-membered compound represented by formula I to the poor solvent is (1-10):18.3, for example, 5:18.

3. (5) In the method for preparing crystalline form A, the temperature at which the poor solvent is added is 20 to 65°C, for example, 50°C. (6) In the method for preparing crystalline form A, the cooling temperature of the solution is 30 to 70°C, for example, 30°C, 40°C, 50°C, and 65°C. (7) In the method for preparing crystal form A, the cooling rate is set to 5 to 15°C / hour, for example, 10°C / hour. (8) In the method for preparing crystal form A, the cooling time is set to 10 to 30 hours. (9) In a method for preparing crystalline form C, the solvent of the suspension is a mixture of an organic solvent and water, the organic solvent is one or more of alcohol-based solvents, ketone-based solvents, and nitrile-based solvents, for example ethanol, acetone, or acetonitrile, and the volume ratio of the organic solvent to water is 60:40 to 99:1, for example 95:

5. (10) In a method for preparing crystalline form C, the mass-volume ratio of the 5-membered condensed 6-membered compound represented by formula I to the solvent in the suspension is (10-100):1 mg / mL, for example, 50:1 mg / mL. (11) In the method for preparing crystalline form C, the volatilization temperature is set to room temperature, (12) In the method for preparing crystalline form C, the volatilization time is 1 to 5 days, preferably 3 days. (13) In the method for preparing crystalline form G, the alcohol-based solvent is methanol, (14) In the method for preparing crystalline form G, the mass-volume ratio of the 5-membered condensed 6-membered compound represented by formula I to the alcohol-based solvent is (10-100):1 mg / mL, for example, 50:1 mg / mL. (15) In the method for preparing crystalline form G, the temperature of the solution is 30 to 70°C, for example, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, and 70°C. (16) In the method for preparing crystalline form G, the cooling rate is 3 to 10°C / hour, for example, 5°C / hour, and (17) A method for preparing crystalline form G, characterized in that the cooling time satisfies one or more of the conditions that are 1 to 20 hours, preferably 14 hours.

16. A compound represented by formula II-49-3. 【Chemistry 4】

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