A crystalline form, salt form, preparation method, pharmaceutical composition and application of a pentacyclic hexacyclic compound

Abstract

The application discloses a crystal form and a salt form of a five-membered and six-membered compound, a preparation method, a pharmaceutical composition and application of the five-membered and six-membered compound. Specifically, the application discloses a crystal form and a salt form of a five-membered and six-membered compound as shown in formula I, a preparation method, a pharmaceutical composition and application of the five-membered and six-membered compound. The crystal form and the salt form of the compound have inhibitory effect on FLT3 and / or IRAK4. The crystal form has a high single melting point, is thermodynamically stable, and has high crystallinity. The crystal form has good physical and chemical stability under strong light, high temperature and high humidity conditions, and the crystal form has very weak hygroscopicity.

Description

[0001] This application claims priority to Chinese patent applications 202310748384.4, 202310744684.5, 202310748633.X, 202310746259.X, and 202410756994.3, all filed on June 21, 2023, and filed on June 12, 2024, respectively. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the crystal form, salt form, preparation method, pharmaceutical composition, and application of a pentagonal and hexa-ary compound. Background Technology

[0003] FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase, and its mutations are among 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 repeat mutations in the juxta-membrane domain (FLT3-ITD) and point mutations or deletions in the tyrosine kinase domain (FLT3-TKD), accounting for approximately 30% of AML patients (Kiyoi H, Kawashima N, Ishikawa Y. FLT3 mutations in acute myeloidleukemia: Therapeutic paradigm beyond inhibitor development. Cancer Sci. 2020 Feb; 111(2):312-322). Activated FLT3 induces abnormalities in multiple intracellular signaling pathways (such as RAS, PI3K, and STAT5), 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 the presence of NPM1 gene mutations can affect 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.). Since high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot adequately improve prognosis, resulting in short patient survival and a high relapse rate, FLT3 kinase inhibitors have become a research hotspot in AML treatment. First-generation FLT3 inhibitors are broad-spectrum inhibitors, such as lettaurtinib, sunitinib, sorafenib, ponatinib, and midostaurin, which inhibit multiple kinases. However, their efficacy is poor, and their combined use with chemotherapy drugs has not shown clear efficacy, with significantly increased toxicity. For example, midostaurin monotherapy is ineffective, but its combination with cytarabine, daunorubicin, and cytarabine (FDA approved) can be used to treat adult FLT3-mutant AML. Second-generation FLT3 kinase inhibitors, such as gilteritinib, crenolanib, and quizartinib, are more selective, have stronger activity, and lower toxicity, but still have some off-target effects.

[0004] Currently, three FLT3 inhibitors (Quizartinib, Gilteritinib, and Midostaurin) have been approved for marketing in Japan and / or the United States for monotherapy or in combination with conventional chemotherapy drugs to treat AML patients. These inhibitors have demonstrated good treatment responses in clinical practice and have improved the prognosis of AML patients to some extent. When used as monotherapy, the disease relapses rapidly, and target-dependent and non-target-dependent resistance has emerged. Target-dependent mutations commonly involve activation loops (such as aspartate 835, D835) and gating residues (such as phenylalanine 691, F691), with the D835 mutation being the most common target resistance mutation site. Activation of related signaling pathways can also compensate for the inhibition of FLT3 signaling pathway. Currently, some researchers have reduced the proportion of non-target drug resistance by directly inhibiting related signaling pathways (such as PI3K / AKT and / or RAS / MEK / MAPK) or by combining drugs to jointly inhibit cell survival-related signaling pathways, but the effect is still relatively 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 a period of administration of Quizartinib and Gilteritinib, although the expression of pFLT3 and pSTAT5 was reduced, no significant inhibition of tumor cells was observed. In relapsed cases, the phosphorylation level of IRAK4 was increased in most cases. When combined with IRAK4 inhibitors, the survival rate of tumor cells was reduced again, suggesting that IRAK4 can be used as a non-target drug resistance target.

[0005] Interleukin-1 receptor-associated kinases (IRAKs) are serine / threonine protein kinases belonging to the tyrosine-like kinase (TLK) family, among which IRAK1 and IRAK4 possess kinase activity. IRAKs are located downstream of the toll-like receptor and the IL-1R pathway, playing a crucial role in innate immune signaling. Stimulation of the TLR recruits MYD88 and activates the receptor complex, which then forms a complex with IRAK4, thereby activating IRAK1. Subsequently, TRAF6 is activated by IRAK1, leading to NF-κB activation. Aberrant activation of the IRAK pathway in tumor cells can further promote disease progression through inflammatory responses in the tumor microenvironment (GummadiVR, 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, EswarappaR, Bellippa 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.). A dual-target compound targeting FLT3 / IRAK4 has been developed, which has potential clinical application value and is expected to improve patient prognosis and reduce the possibility of drug resistance. Summary of the Invention

[0006] This invention provides a crystalline form, salt form, preparation method, pharmaceutical composition, and application of a pentagonal compound. The crystalline form and salt form of the compound exhibit inhibitory effects on FLT3 and / or IRAK4, possessing potential clinical application value and expected to improve patient prognosis and reduce the likelihood of drug resistance.

[0007] The present invention provides a crystal form A of a pentagonal compound as shown in Formula I, whose X-ray powder diffraction pattern, expressed in 2θ angle, has characteristic peaks at 13.12±0.20°, 19.05±0.20°, 25.85±0.20° and 26.73±0.20°.

[0008]

[0009] In some embodiments of the present invention, the X-ray powder diffraction pattern is obtained using Cu-Kα radiation spectroscopy.

[0010] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form A, expressed as an angle of 2θ, also has characteristic peaks at one or more of the following locations: 7.84±0.20°, 10.25±0.20°, 20.96±0.20°, and 24.46±0.20°.

[0011] In some embodiments of the present invention, the crystal form A, as expressed in 2θ angle X-ray powder diffraction patterns, exhibits characteristic peaks at 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 crystal form A of a pentagonal compound as shown in Formula I, whose X-ray powder diffraction pattern, expressed in 2θ angle, has characteristic peaks at 7.84±0.20°, 10.25±0.20°, 20.96±0.20°, 22.36±0.20° and 25.85±0.20°.

[0013]

[0014] The crystal form A, as expressed in 2θ angle X-ray powder diffraction pattern, also has characteristic peaks at one or more of the following locations: 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°.

[0015] In some embodiments of the present invention, the crystal form A, whose X-ray powder diffraction pattern, expressed as 2θ angle, has diffraction peaks at the diffraction angles shown in the table below:

[0016]

[0017]

[0018]

[0019] In some embodiments of the present invention, the diffraction peaks, d-values, and peak height percentages of the X-ray powder diffraction pattern of crystal form A, expressed as an angle of 2θ, are shown in the table below:

[0020]

[0021]

[0022] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal form A is substantially as follows: Figure 1 As shown.

[0023] In some embodiments of the present invention, the crystal form A has an endothermic peak starting point at 231.31±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 232.04±2℃; even further, its enthalpy value is 111.300J / g.

[0024] In some embodiments of the present invention, the crystal form A has an endothermic peak starting point at 237.74±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 244.16±2℃; even further, its enthalpy value is 69.104J / g.

[0025] In some embodiments of the present invention, the differential scanning calorimetry (DSC) analysis pattern of crystal form A is substantially as follows: Figure 2 As shown.

[0026] In some embodiments of the present invention, the crystal form A has a weight loss of 0.428% at 200°C according to thermogravimetric analysis; the "%" refers to the mass percentage.

[0027] In some embodiments of the present invention, the thermogravimetric analysis (TGA) chart of crystal form A is essentially as follows: Figure 2 As shown.

[0028] The present invention provides a crystal form C of a pentagonal compound as shown in Formula I, whose X-ray powder diffraction pattern, expressed in 2θ angle, has characteristic peaks at 11.05±0.20°, 14.21±0.20°, 18.83±0.20° and 28.80±0.20°.

[0029]

[0030] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form C, expressed at an angle of 2θ, also has characteristic peaks at one or more of the following locations: 7.02±0.20°, 9.78±0.20°, 20.44±0.20°, and 23.98±0.20°.

[0031] In some embodiments of the present invention, the crystal form C, as expressed in 2θ angle X-ray powder diffraction patterns, exhibits characteristic peaks at 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°.

[0032] The present invention provides a crystal form C of a pentagonal compound as shown in Formula I, whose X-ray powder diffraction pattern, expressed in 2θ angle, has characteristic peaks at 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°.

[0033]

[0034] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form C, expressed at an angle of 2θ, also has characteristic peaks at one or more of the following locations: 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°.

[0035] In some embodiments of the present invention, the crystal form C, whose X-ray powder diffraction pattern, expressed as 2θ angle, has diffraction peaks at the diffraction angles shown in the table below:

[0036]

[0037]

[0038]

[0039] In some embodiments of the present invention, the diffraction peaks, d-values, and peak height percentages of the X-ray powder diffraction pattern of the crystal form C represented by the 2θ angle are shown in the table below:

[0040]

[0041]

[0042] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal form C is substantially as follows: Figure 5 As shown.

[0043] In some embodiments of the present invention, the crystal form C has an endothermic peak starting point at 63.69±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 82.10±2℃; even further, its enthalpy value is 61.396J / g.

[0044] In some embodiments of the present invention, the crystal form C has an endothermic peak starting point at 126.27±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 134.20±2℃; even further, its enthalpy value is 42.089J / g.

[0045] In some embodiments of the present invention, the crystal form C has an endothermic peak starting point at 230.61±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 231.73±2℃; even further, its enthalpy value is 103.46J / g.

[0046] In some embodiments of the present invention, the differential scanning calorimetry (DSC) analysis pattern of the crystal form C is essentially as follows: Figure 6 As shown.

[0047] In some embodiments of the present invention, the crystal form C has a weight loss of 3.778% at 73.91°C according to thermogravimetric analysis; the "%" refers to the mass percentage.

[0048] In some embodiments of the present invention, the thermogravimetric analysis (TGA) chart of the crystal form C is essentially as follows: Figure 6 As shown.

[0049] The present invention provides a crystal form B of a pentagonal compound as shown in Formula I, whose X-ray powder diffraction pattern, expressed in 2θ angle, has characteristic peaks at 9.94±0.20°, 11.81±0.20°, 16.26±0.20° and 18.47±0.20°.

[0050]

[0051] In some embodiments of the present invention, the crystal form B, in the form of X-ray powder diffraction pattern expressed at an angle of 2θ, also has characteristic peaks at one or more of the following locations: 11.41±0.20°, 14.41±0.20°, 20.73±0.20°, and 23.39±0.20°.

[0052] In some embodiments of the present invention, the crystal form B, as expressed in 2θ angle X-ray powder diffraction pattern, has characteristic peaks at 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°.

[0053] In some embodiments of the present invention, the crystal form B, whose X-ray powder diffraction pattern, expressed as 2θ angle, has diffraction peaks at the diffraction angles shown in the table below:

[0054]

[0055]

[0056] In some embodiments of the present invention, the diffraction peaks, d-values, and peak height percentages of the crystal form B in the X-ray powder diffraction pattern expressed at a 2θ angle are shown in the table below:

[0057]

[0058]

[0059] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of crystal form B is substantially as follows: Figure 3 As shown.

[0060] In some embodiments of the present invention, the crystal form B has an endothermic peak starting point at 60.85±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 72.84±2℃; even further, its enthalpy value is 32.752J / g.

[0061] In some embodiments of the present invention, the crystal form B has an endothermic peak starting point at 151.04±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 153.19±2℃; even further, its enthalpy value is 4.135J / g.

[0062] In some embodiments of the present invention, the crystal form B has an endothermic peak starting point at 230.51±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 231.37±2℃; even further, its enthalpy value is 113.950J / g.

[0063] In some embodiments of the present invention, the differential scanning calorimetry (DSC) analysis pattern of crystal form B is substantially as follows: Figure 4 As shown.

[0064] In some embodiments of the present invention, the crystal form B has a weight loss of 4.741% at 122.68°C according to thermogravimetric analysis; the "%" refers to the mass percentage.

[0065] In some embodiments of the present invention, the thermogravimetric analysis (TGA) chart of crystal form B is essentially as follows: Figure 4 As shown.

[0066] The present invention provides a crystal form D of a pentagonal compound as shown in Formula I, whose X-ray powder diffraction pattern, expressed in terms of 2θ angle, has characteristic peaks at 9.51±0.20°, 15.35±0.20°, 19.27±0.20° and 24.20±0.20°.

[0067]

[0068] In some embodiments of the present invention, the crystal form D, in the X-ray powder diffraction pattern expressed at an angle of 2θ, also has characteristic peaks at one or more of the following locations: 9.90±0.20°, 20.01±0.20°, 20.75±0.20°, and 29.18±0.20°.

[0069] In some embodiments of the present invention, the crystal form D, as expressed in 2θ angle X-ray powder diffraction patterns, exhibits characteristic peaks at 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°.

[0070] In some embodiments of the present invention, the crystal form D, whose X-ray powder diffraction pattern, expressed as 2θ angle, has diffraction peaks at the diffraction angles shown in the table below:

[0071]

[0072]

[0073] In some embodiments of the present invention, the diffraction peaks, d-values, and peak height percentages in the X-ray powder diffraction pattern of the crystal form D expressed at an angle of 2θ are shown in the table below:

[0074]

[0075]

[0076] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of the crystal form D is substantially as follows: Figure 7 As shown.

[0077] In some embodiments of the present invention, the crystal form D has an endothermic peak starting point at 231.13±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 232.25±2℃; even further, its enthalpy value is 115.52J / g.

[0078] In some embodiments of the present invention, the differential scanning calorimetry (DSC) analysis pattern of crystal form D is substantially as follows: Figure 8 As shown.

[0079] In some embodiments of the present invention, the crystal form D has a weight loss of 2.826% at 116.38°C according to thermogravimetric analysis; the "%" refers to the mass percentage.

[0080] In some embodiments of the present invention, the thermogravimetric analysis (TGA) chart of crystal form D is essentially as follows: Figure 8 As shown.

[0081] The present invention provides a crystal form E of a pentagonal compound as shown in Formula I, whose X-ray powder diffraction pattern, expressed in terms of 2θ angle, 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°.

[0082]

[0083] In some embodiments of the present invention, the crystal form E, in the X-ray powder diffraction pattern expressed at an angle of 2θ, also has characteristic peaks at one or more of the following locations: 20.06±0.20°, 21.85±0.20°, and 28.25±0.20°.

[0084] In some embodiments of the present invention, the crystal form E, as expressed in 2θ angle X-ray powder diffraction patterns, exhibits characteristic peaks at 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°.

[0085] In some embodiments of the present invention, the crystal form E, whose X-ray powder diffraction pattern, expressed as 2θ angle, has diffraction peaks at the diffraction angles shown in the table below:

[0086]

[0087] In some embodiments of the present invention, the diffraction peaks, d-values, and peak height percentages in the X-ray powder diffraction pattern of the crystal form E expressed at an angle of 2θ are shown in the table below:

[0088]

[0089]

[0090] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of the crystal form E is substantially as follows: Figure 9 As shown.

[0091] In some embodiments of the present invention, the crystal form E has an endothermic peak starting point at 48.59±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 51.08±2℃; even further, its enthalpy value is 5.451J / g.

[0092] In some embodiments of the present invention, the crystal form E has an endothermic peak starting point at 90.07±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 95.66±2℃; even further, its enthalpy value is 19.797J / g.

[0093] In some embodiments of the present invention, the crystal form E has an endothermic peak starting point at 225.15±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 228.25±2℃; even further, its enthalpy value is 86.445J / g.

[0094] In some embodiments of the present invention, the differential scanning calorimetry (DSC) analysis pattern of crystal form E is substantially as follows: Figure 10 As shown.

[0095] In some embodiments of the present invention, the crystal form E has a weight loss of 5.585% at 119.49°C according to thermogravimetric analysis; the "%" refers to the mass percentage.

[0096] In some embodiments of the present invention, the thermogravimetric analysis (TGA) chart of crystal form E is essentially as follows: Figure 10 As shown.

[0097] The present invention provides a crystal form F of a pentagonal compound as shown in Formula I, whose X-ray powder diffraction pattern, expressed in terms of 2θ angle, has characteristic peaks at 5.53±0.20°, 5.93±0.20°, 10.38±0.20° and 22.37±0.20°.

[0098]

[0099] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form F, expressed in terms of 2θ angle, also has characteristic peaks at one or more of the following locations: 10.21±0.20°, 11.11±0.20°, 16.72±0.20°, and 25.78±0.20°.

[0100] In some embodiments of the present invention, the crystal form F, as expressed in 2θ angle X-ray powder diffraction patterns, exhibits characteristic peaks at 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°.

[0101] In some embodiments of the present invention, the crystal form F, whose X-ray powder diffraction pattern, expressed as 2θ angle, has diffraction peaks at the diffraction angles shown in the table below:

[0102]

[0103]

[0104] In some embodiments of the present invention, the diffraction peaks, d-values, and peak height percentages of the crystal form F expressed in 2θ angle X-ray powder diffraction pattern are shown in the table below:

[0105]

[0106]

[0107] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of the crystal form F is substantially as follows: Figure 11 As shown.

[0108] In some embodiments of the present invention, the crystal form F has an endothermic peak starting point at 49.64±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 52.43±2℃; even further, its enthalpy value is 3.400J / g.

[0109] In some embodiments of the present invention, the crystal form F has an endothermic peak starting point at 97.99±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 103.02±2℃; even further, its enthalpy value is 9.028J / g.

[0110] In some embodiments of the present invention, the crystal form F has an endothermic peak starting point at 225.07±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 226.71±2℃; even further, its enthalpy value is 92.201J / g.

[0111] In some embodiments of the present invention, the differential scanning calorimetry (DSC) analysis plot of the crystal form F is essentially as follows: Figure 12 As shown.

[0112] In some embodiments of the present invention, the crystal form F has a weight loss of 1.066% at 127.37°C according to thermogravimetric analysis; the "%" refers to the mass percentage.

[0113] In some embodiments of the present invention, the thermogravimetric analysis (TGA) chart of crystal form F is essentially as follows: Figure 12 As shown.

[0114] The present invention provides a crystal form G of a pentagonal compound as shown in Formula I, whose X-ray powder diffraction pattern, expressed in terms of 2θ angle, has characteristic peaks at 9.74±0.20°, 13.56±0.20°, 16.39±0.20° and 24.51±0.20°.

[0115]

[0116] In some embodiments of the present invention, the crystal form G, when expressed in terms of 2θ angle, has characteristic peaks at one or more of the following locations: 7.09±0.20°, 18.50±0.20°, 20.94±0.20°, and 23.36±0.20°.

[0117] In some embodiments of the present invention, the crystal form G, as expressed in 2θ angle X-ray powder diffraction patterns, exhibits characteristic peaks at 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°.

[0118] The present invention provides a crystal form G of a pentagonal compound as shown in Formula I, whose X-ray powder diffraction pattern, expressed in 2θ angle, has characteristic peaks at 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°.

[0119]

[0120] In some embodiments of the present invention, the crystal form G, in the form of X-ray powder diffraction pattern expressed at an angle of 2θ, also has characteristic peaks at one or more of the following locations: 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°.

[0121] In some embodiments of the present invention, the crystal form G, whose X-ray powder diffraction pattern, expressed as 2θ angle, has diffraction peaks at the diffraction angles shown in the table below:

[0122]

[0123]

[0124] In some embodiments of the present invention, the diffraction peaks, d-values, and peak height percentages of the crystal form G in the X-ray powder diffraction pattern expressed at an angle of 2θ are shown in the table below:

[0125]

[0126]

[0127] In some embodiments of the present invention, the X-ray powder diffraction (XRPD) pattern of the crystal form G is substantially as follows: Figure 13 As shown.

[0128] In some embodiments of the present invention, the crystal form G has an endothermic peak starting point at 63.20±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 76.01±2℃; even further, its enthalpy value is 25.610 J / g.

[0129] In some embodiments of the present invention, the crystal form G has an endothermic peak starting point at 150.82±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 153.33±2℃; even further, its enthalpy value is 12.882J / g.

[0130] In some embodiments of the present invention, the crystal form G has an endothermic peak starting point at 230.69±2℃ in its differential scanning calorimetry analysis chart, and further reaches the endothermic peak at 231.37±2℃; even further, its enthalpy value is 111.380 J / g.

[0131] In some embodiments of the present invention, the differential scanning calorimetry (DSC) analysis plot of the crystal form G is essentially as follows: Figure 14 As shown.

[0132] In some embodiments of the present invention, the crystal form G has a weight loss of 3.405% at 130.90°C according to thermogravimetric analysis; the "%" refers to the mass percentage.

[0133] In some embodiments of the present invention, the thermogravimetric analysis (TGA) chart of the crystal form G is essentially as follows: Figure 14 As shown.

[0134] The present invention also provides a method for preparing crystal form G of the indazole compound as shown in Formula I, which includes the following operation: cooling a solution of a five-membered and six-membered compound as shown in Formula I to obtain the crystal form; wherein the solvent of the solution is an alcohol solvent.

[0135] In one embodiment, the alcohol solvent may be methanol.

[0136] In one embodiment, in the preparation method of crystal form G, the mass-to-volume ratio of the five- or six-membered compound as shown in Formula I to the alcohol solvent can be (10-100):1 mg / mL, for example, 50:1 mg / mL.

[0137] In one embodiment, in the preparation method of crystal form G, the temperature of the solution is 30-70°C, for example, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C and 70°C.

[0138] In one embodiment, the cooling rate in the preparation method of crystal form G is 3-10℃ / hour, for example, 5℃ / hour.

[0139] In one embodiment, the cooling time in the preparation method of crystal form G is 1-20 hours, preferably 14 hours.

[0140] This invention provides a salt of a pentagonal compound as shown in Formula I, wherein the salt is a hydrochloride, sulfate, phosphate, sodium salt, or potassium salt;

[0141]

[0142] In one embodiment, the hydrochloride is preferably a monohydrochloride (a monohydrochloride means that the molar ratio of hydrochloric acid to compound I in the hydrochloride is 1:1).

[0143] In one embodiment, the sulfate is preferably a monosulfate (a monosulfate means that the molar ratio of sulfuric acid to compound I in the sulfate is 1:1).

[0144] 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).

[0145] In one embodiment, the sodium salt is preferably a monosodium salt (a monosodium salt means that the molar ratio of sodium ions to the anions of the compound of formula I in the sodium salt is 1:1).

[0146] In one embodiment, the potassium salt is preferably a monopotassium salt (a monopotassium salt means that the molar ratio of potassium ions to the anions of the compound of formula I in the potassium salt is 1:1).

[0147] In one embodiment, the hydrochloride is crystal form A, and its X-ray powder diffraction pattern, expressed as a 2θ angle using Cu-Kα radiation, has characteristic peaks at 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°.

[0148] In one embodiment, the crystal form A of the hydrochloride salt has a characteristic peak at one or more locations at 11.72±0.20°, 21.88±0.20°, 28.61±0.20° and 31.26±0.20° in its X-ray powder diffraction pattern expressed at a 2θ angle.

[0149] In one embodiment, the X-ray powder diffraction pattern of the hydrochloride in crystal form A, expressed at an angle of 2θ, has characteristic peaks at 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°.

[0150] In one embodiment, the diffraction peaks of crystal form A of the hydrochloride, expressed as an X-ray powder diffraction pattern at an angle of 2θ, may also be shown in the table below:

[0151]

[0152]

[0153] In one embodiment, the diffraction peaks and relative intensities of crystal form A of the hydrochloride, expressed as 2θ angle and relative intensity, can also be shown in the following table:

[0154]

[0155]

[0156]

[0157] In one embodiment, the crystal form A of the hydrochloride has an X-ray powder diffraction (XRPD) pattern that is substantially as follows: Figure 17 As shown.

[0158] In one embodiment, the hydrochloride crystal form A has a thermogravimetric analysis chromatogram showing a weight loss of 2.070% at 125.06℃; where "%" represents mass percentage; its differential scanning calorimetry chromatogram shows an endothermic peak starting point at 184.04±2℃, and further, reaches the endothermic peak peak at 188.62±2℃; even further, its enthalpy value is 344.80 J / g.

[0159] In one embodiment, the thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of the hydrochloride crystal form A are essentially as follows: Figure 18 As shown.

[0160] In one embodiment, the hydrochloride is crystal form B, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, exhibits characteristic peaks at 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°.

[0161] In one embodiment, the crystal form B of the hydrochloride salt, when expressed at an angle of 2θ, has characteristic peaks at one or more locations at 13.93±0.20°, 15.28±0.20°, 27.18±0.20°, and 28.99±0.20°.

[0162] In one embodiment, the X-ray powder diffraction pattern of the hydrochloride in crystal form B, expressed at an angle of 2θ, has characteristic peaks at 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°.

[0163] In one embodiment, the diffraction peaks of crystal form B of the hydrochloride, expressed as an X-ray powder diffraction pattern at an angle of 2θ, may also be shown in the table below:

[0164]

[0165]

[0166]

[0167] In one embodiment, the diffraction peaks and relative intensities of crystal form B of the hydrochloride, expressed as 2θ angle and relative intensity, are shown in the following table:

[0168]

[0169]

[0170] In one embodiment, the crystal form B of the hydrochloride has an X-ray powder diffraction (XRPD) pattern that is essentially as follows: Figure 19 As shown.

[0171] In one embodiment, the hydrochloride crystal form B has a thermogravimetric analysis (TGA) curve showing a weight loss of 7.216% at 96.43°C (% is mass percentage); its differential scanning calorimetry (DSC) curve shows an endothermic peak starting at 173.54±2°C, and further, reaches the endothermic peak at 184.54±2°C; even further, its enthalpy is 259.36 J / g.

[0172] In one embodiment, the thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of the hydrochloride crystal form B are essentially as follows: Figure 20 As shown.

[0173] In one embodiment, the sulfate is crystal form A, and its X-ray powder diffraction pattern, expressed as a 2θ angle using Cu-Kα radiation, shows characteristic peaks at 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°.

[0174] In one embodiment, the X-ray powder diffraction pattern of the sulfate crystal form A, expressed at an angle of 2θ, also has characteristic peaks at one or more locations at 14.94±0.20°, 17.42±0.20°, 22.76±0.20°, and 26.46±0.20°.

[0175] In one embodiment, the X-ray powder diffraction pattern of the sulfate in crystal form A, expressed at an angle of 2θ, has characteristic peaks at 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°.

[0176] In one embodiment, the diffraction peaks of crystal form A of the sulfate, expressed as an X-ray powder diffraction pattern at an angle of 2θ, may also be shown in the table below:

[0177]

[0178]

[0179]

[0180] In one embodiment, the diffraction peaks and relative intensities of the sulfate in crystal form A, expressed as 2θ angle and relative intensity, can also be shown in the following table:

[0181]

[0182]

[0183] In one embodiment, the crystal form A of the sulfate has an X-ray powder diffraction (XRPD) pattern that is essentially as follows: Figure 21 As shown.

[0184] In one embodiment, the sulfate crystal form A has a weight loss of 3.880% at 118.49℃ according to thermogravimetric analysis (TGA); the percentage is a mass percentage; its differential scanning calorimetry (DSC) chart has an endothermic peak starting point at 149.86±2℃, and further, reaches the endothermic peak peak at 160.23±2℃; even further, its enthalpy value is 229.21 J / g.

[0185] In one embodiment, the thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of the sulfate crystal form A are essentially as follows: Figure 22 As shown.

[0186] In one embodiment, the sulfate is crystal form B, and its X-ray powder diffraction pattern, expressed as a 2θ angle, using Cu-Kα radiation, has characteristic peaks at 15.86±0.20°, 16.53±0.20°, 20.05±0.20°, 28.46±0.20°, and 30.59±0.20°.

[0187] In one embodiment, the X-ray powder diffraction pattern of the sulfate crystal form B, expressed at an angle of 2θ, also has characteristic peaks at one or more locations at 9.00±0.20°, 12.52±0.20°, 21.21±0.20°, and 22.36±0.20°.

[0188] In one embodiment, the X-ray powder diffraction pattern of the sulfate in crystal form B, expressed at an angle of 2θ, exhibits characteristic peaks at 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°.

[0189] In one embodiment, the diffraction peaks of crystal form B of the sulfate, expressed as an X-ray powder diffraction pattern at an angle of 2θ, may also be shown in the table below:

[0190]

[0191]

[0192] In one embodiment, the diffraction peaks and relative intensities of the sulfate in crystal form B, expressed as 2θ angle and relative intensity in the X-ray powder diffraction pattern, can also be shown in the table below:

[0193]

[0194] In one embodiment, the crystal form B of the sulfate has an X-ray powder diffraction (XRPD) pattern that is essentially as follows: Figure 23 As shown.

[0195] In one embodiment, the sulfate crystal form B has a weight loss of 6.895% at 92.04℃ according to thermogravimetric analysis (TGA); the percentage is a mass percentage; its differential scanning calorimetry (DSC) chromatogram has an endothermic peak starting point at 126.34±2℃, and further reaches the endothermic peak peak at 139.98±2℃; even further, its enthalpy value is 230.50 J / g.

[0196] In one embodiment, the thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of the sulfate crystal form B are essentially as follows: Figure 24 As shown.

[0197] In one embodiment, the sulfate is crystalline form C, and its X-ray powder diffraction pattern, expressed as a 2θ angle using Cu-Kα radiation, has characteristic peaks at 7.70±0.20°, 12.87±0.20°, 19.87±0.20°, 21.55±0.20°, and 25.94±0.20°.

[0198] In one embodiment, the X-ray powder diffraction pattern of the sulfate crystal form C, expressed at an angle of 2θ, also has characteristic peaks at one or more locations at 8.74±0.20°, 10.67±0.20°, 18.64±0.20°, and 19.05±0.20°.

[0199] In one embodiment, the X-ray powder diffraction pattern of the sulfate crystal form C, expressed at an angle of 2θ, has characteristic peaks at 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°.

[0200] In one embodiment, the diffraction peaks of crystal form C of the sulfate, expressed as an X-ray powder diffraction pattern at an angle of 2θ, may also be shown in the table below:

[0201]

[0202] In one embodiment, the diffraction peaks and relative intensities of the sulfate in crystal form C, expressed as 2θ angle and relative intensity in the X-ray powder diffraction pattern, can also be shown in the table below:

[0203]

[0204] In one embodiment, the crystal form C of the sulfate has an X-ray powder diffraction (XRPD) pattern that is essentially as follows: Figure 25 As shown.

[0205] In one embodiment, the sulfate crystal form C has a thermogravimetric analysis chromatogram showing a weight loss of 10.471% at 102.19℃; where "%" represents mass percentage; its differential scanning calorimetry chromatogram shows an endothermic peak starting point at 117.30±2℃, and further, reaches the endothermic peak peak at 122.26±2℃; even further, its enthalpy value is 54.426 J / g.

[0206] In one embodiment, the thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of the sulfate crystal form C are essentially as follows: Figure 26 As shown.

[0207] In one embodiment, the phosphate is crystal form A, and its X-ray powder diffraction pattern, expressed as a 2θ angle using Cu-Kα radiation, shows characteristic peaks at 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°.

[0208] In one embodiment, the X-ray powder diffraction pattern of the phosphate crystal form A, expressed at an angle of 2θ, also has characteristic peaks at one or more locations at 6.57±0.20°, 18.53±0.20°, 19.97±0.20°, 22.43±0.20° and 27.18±0.20°.

[0209] In one embodiment, the phosphate crystal form A has characteristic peaks in its X-ray powder diffraction pattern (expressed at 2θ angle) at 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°.

[0210] In one embodiment, the diffraction peaks of crystal form A of the phosphate, expressed as an X-ray powder diffraction pattern at an angle of 2θ, may also be shown in the table below:

[0211]

[0212]

[0213] In one embodiment, the diffraction peaks and relative intensities of crystal form A of the phosphate, expressed as 2θ angle and relative intensity, can also be shown in the following table:

[0214]

[0215]

[0216] In one embodiment, the phosphate crystal form A has an X-ray powder diffraction (XRPD) pattern that is essentially as follows: Figure 27 As shown.

[0217] In one embodiment, the phosphate crystal form A has a weight loss of 0.776% at 142.87℃ according to thermogravimetric analysis (TGA); the percentage is a mass percentage; its differential scanning calorimetry (DSC) chromatogram has an endothermic peak starting point at 179.76±2℃, and further reaches the endothermic peak peak at 180.61±2℃; even further, its enthalpy is 265.82 J / g.

[0218] In one embodiment, the thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of the phosphate crystal form A are essentially as follows: Figure 28 As shown.

[0219] In one embodiment, the phosphate is crystal form B, and its X-ray powder diffraction pattern, expressed as a 2θ angle using Cu-Kα radiation, has characteristic peaks at 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°.

[0220] In one embodiment, the X-ray powder diffraction pattern of the phosphate crystal form B, expressed at an angle of 2θ, also has characteristic peaks at one or more locations at 7.40±0.20°, 17.61±0.20°, 19.69±0.20°, and 24.93±0.20°.

[0221] In one embodiment, the phosphate crystal form B has characteristic peaks in its X-ray powder diffraction pattern (expressed at 2θ angle) at 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°.

[0222] In one embodiment, the diffraction peaks of crystal form B of the phosphate, as shown in the X-ray powder diffraction pattern of crystal form B (expressed at an angle of 2θ), may also be as shown in the table below:

[0223]

[0224]

[0225] In one embodiment, the diffraction peaks and relative intensities of crystal form B of the phosphate, expressed as 2θ angle and relative intensity in the X-ray powder diffraction pattern, can also be shown in the table below:

[0226]

[0227]

[0228] In one embodiment, the crystal form B of the phosphate has an X-ray powder diffraction (XRPD) pattern that is essentially as follows: Figure 29 As shown.

[0229] In one embodiment, the phosphate crystal form B has a weight loss of 1.071% at 74.52℃ according to thermogravimetric analysis (TGA); the percentage is a mass percentage; its differential scanning calorimetry (DSC) chart shows an endothermic peak starting at 159.94±2℃, and further, reaches the endothermic peak at 169.82±2℃; even further, its enthalpy is 77.238 J / g.

[0230] In one embodiment, the thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of the phosphate crystal form B are essentially as follows: Figure 30 As shown.

[0231] In one embodiment, the sodium salt is crystal form A, and its X-ray powder diffraction pattern, expressed as a 2θ angle using Cu-Kα radiation, exhibits characteristic peaks at 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°.

[0232] In one embodiment, the X-ray powder diffraction pattern of the sodium salt in crystal form A, expressed at an angle of 2θ, also has characteristic peaks at one or more locations at 9.78±0.20°, 14.20±0.20°, 18.81±0.20°, 19.97±0.20° and 24.13±0.20°.

[0233] In one embodiment, the X-ray powder diffraction pattern of the sodium salt in crystal form A, expressed at an angle of 2θ, has characteristic peaks at 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°.

[0234] In one embodiment, the diffraction peaks of crystal form A of the sodium salt, expressed as an X-ray powder diffraction pattern at an angle of 2θ, may also be shown in the table below:

[0235]

[0236]

[0237]

[0238] In one embodiment, the diffraction peaks and relative intensities of crystal form A of the sodium salt, expressed as 2θ angle and relative intensity, can also be shown in the following table:

[0239]

[0240]

[0241]

[0242] In one embodiment, the crystal form A of the sodium salt has an X-ray powder diffraction (XRPD) pattern that is essentially as follows: Figure 31 As shown.

[0243] In one embodiment, the sodium salt, crystal form A, has a weight loss of 6.279% at 116.94℃ according to thermogravimetric analysis (TGA); the percentage is a mass percentage; its differential scanning calorimetry (DSC) chart shows an endothermic peak starting at 228.53±2℃, and further, reaches the endothermic peak at 230.66±2℃; even further, its enthalpy is 107.61 J / g.

[0244] In one embodiment, the thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of the sodium salt, crystal form A, are essentially as follows: Figure 32 As shown.

[0245] In one embodiment, the potassium salt is crystal form A, and its X-ray powder diffraction pattern, expressed as a 2θ angle using Cu-Kα radiation, exhibits characteristic peaks 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°.

[0246] In one embodiment, the X-ray powder diffraction pattern of the potassium salt in crystal form A, expressed at an angle of 2θ, also has characteristic peaks at one or more locations at 19.46±0.20°, 19.96±0.20°, 23.54±0.20° and 27.92±0.20°.

[0247] In one embodiment, the X-ray powder diffraction pattern of the potassium salt in crystal form A, expressed at an angle of 2θ, has characteristic peaks 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°.

[0248] In one embodiment, the diffraction peaks of crystal form A of the potassium salt, expressed as an X-ray powder diffraction pattern at an angle of 2θ, may also be shown in the table below:

[0249]

[0250]

[0251] In one embodiment, the diffraction peaks and relative intensities of crystal form A of the potassium salt, expressed as 2θ angle and relative intensity in the X-ray powder diffraction pattern, can also be shown in the table below:

[0252]

[0253]

[0254] In one embodiment, the crystal form A of the potassium salt has an X-ray powder diffraction (XRPD) pattern that is essentially as follows: Figure 33 As shown.

[0255] In one embodiment, the potassium salt, crystal form A, has a weight loss of 8.352% at 183.95℃ according to thermogravimetric analysis (TGA); the percentage is a mass percentage; its differential scanning calorimetry (DSC) curve shows an endothermic peak starting at 217.76±2℃, and further, reaches the endothermic peak at 222.51±2℃; even further, its enthalpy is 102.94 J / g.

[0256] In one embodiment, the thermogravimetric analysis (TGA) spectrum and differential scanning calorimetry (DSC) spectrum of the potassium salt, crystal form A, are essentially as follows: Figure 34 As shown.

[0257] The present invention also provides a pharmaceutical composition comprising one or more of a salt of a pentagonal compound as shown in Formula I, crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, and crystal form G, and a pharmaceutical excipient.

[0258] In one embodiment, the pharmaceutical composition comprises crystal form A or crystal form C of a pentagonal compound as shown in Formula I as described above, and pharmaceutical excipients.

[0259] In one embodiment, the pharmaceutical composition comprises one or more of the following crystal forms: crystal form B, crystal form D, crystal form E, crystal form F and crystal form G of the aforementioned pentagonal and hexavalent compounds as shown in Formula I, as well as pharmaceutical excipients.

[0260] In one embodiment, the pharmaceutical composition comprises a salt of the aforementioned pentagonal compound as shown in Formula I, and pharmaceutical excipients.

[0261] In one embodiment, the pharmaceutical excipient may be a conventional pharmaceutical excipient in the art, preferably one or more of DMSO, Tween-80, polyethylene glycol 15-hydroxystearate, and physiological saline; further, the pharmaceutical excipient is composed of 5% DMSO, 10% Tween-80, 5% polyethylene glycol 15-hydroxystearate, and 80% physiological saline, wherein % is a volume ratio.

[0262] In one embodiment, the mass-to-volume ratio of the salt of the pentaneous and hexane compound as shown in Formula I to the pharmaceutical excipient is 4:1 mg / mL.

[0263] The present invention also provides the use of substance Z in the preparation of FLT3 and / or IRAK4 inhibitors or medicaments for the treatment and / or prevention of FLT3 and / or IRAK4-related diseases, wherein substance Z is one or more of the following: salts of the aforementioned pentagonal compounds as shown in Formula I, crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, and crystal form G.

[0264] In one embodiment, the substance Z is crystal form A or crystal form C of the aforementioned pentagonal compound as shown in Formula I.

[0265] In one embodiment, the substance Z is one or more of the following crystal forms: B, D, E, F, and G, of the aforementioned pentagonal and hexavalent compounds as shown in Formula I.

[0266] In one embodiment, substance Z is a salt of a pentagonal compound as shown in Formula I.

[0267] The FLT3-related diseases include hematologic malignancies and / or solid tumors.

[0268] The hematologic malignancy may be selected from one or more of the following: acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, anaplastic large cell lymphoma, prolymphocytic leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma, multiple myeloma, myeloproliferative disorders, mantle cell lymphoma, and new-onset acute myeloid leukemia in adults.

[0269] The solid tumor may be selected from one or more of 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.

[0270] The IRAK4-related diseases include autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, or central nervous system diseases.

[0271] The autoimmune disease may be selected from one or more of the following: rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes (such as type 1 diabetes), psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome.

[0272] The inflammatory disease may be selected from one or more of the following, but not limited to: rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes (such as type 1 diabetes), psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome.

[0273] The cardiovascular disease mentioned can be stroke or atherosclerosis.

[0274] The present invention also provides a method for treating and / or preventing FLT3 and / or IRAK4-related diseases, comprising administering an effective amount of substance Z to a patient, said substance Z being one or more of the following: a salt of the aforementioned pentagonal compound as shown in Formula I, crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, and crystal form G.

[0275] In one embodiment, the substance Z is crystal form A or crystal form C of the aforementioned pentagonal compound as shown in Formula I.

[0276] In one embodiment, the substance Z is one or more of the following crystal forms: B, D, E, F, and G, of the aforementioned pentagonal and hexavalent compounds as shown in Formula I.

[0277] In one embodiment, substance Z is a salt of a pentagonal compound as shown in Formula I.

[0278] In one of the schemes, the FLT3-related disease is the FLT3-related disease described in any of the above schemes.

[0279] In one embodiment, the IRAK4-related disease is the IRAK4-related disease described in any of the above embodiments.

[0280] The present invention also provides the application of substance Z in the preparation of a drug, wherein substance Z is one or more of the salts, crystal forms A, B, C, D, E, F, and G of the aforementioned pentagonal and hexavalent compounds as shown in Formula I; the drug is used to treat and / or prevent one or more of hematologic malignancies, solid tumors, autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and central nervous system diseases.

[0281] In one embodiment, the substance Z is crystal form A or crystal form C of the aforementioned pentagonal compound as shown in Formula I.

[0282] In one embodiment, the substance Z is one or more of the following crystal forms: B, D, E, F, and G, of the aforementioned pentagonal and hexavalent compounds as shown in Formula I.

[0283] In one embodiment, substance Z is a salt of a pentagonal compound as shown in Formula I.

[0284] In one embodiment, the hematoma is the hematoma described in any of the above embodiments.

[0285] In one embodiment, the solid tumor is the solid tumor described in any of the above embodiments.

[0286] In one of the schemes, the autoimmune disease is the autoimmune disease described in any of the above schemes.

[0287] In one embodiment, the inflammatory disease is the inflammatory disease described in any of the above embodiments.

[0288] In one of the embodiments, the cardiovascular disease is the cardiovascular disease described in any of the above embodiments.

[0289] The present invention also provides a method for treating and / or preventing a disease, comprising administering an effective amount of substance Z to a patient, said substance Z being one or more of a salt, crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, and crystal form G of the aforementioned pentagonal compound as shown in Formula I; said disease being one or more selected from hematologic malignancies, solid tumors, autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and central nervous system diseases. In one embodiment, said substance Z is crystal form A or crystal form C of the aforementioned pentagonal compound as shown in Formula I.

[0290] In one embodiment, the substance Z is one or more of the following crystal forms: B, D, E, F, and G, of the aforementioned pentagonal and hexavalent compounds as shown in Formula I.

[0291] In one embodiment, substance Z is a salt of a pentagonal compound as shown in Formula I.

[0292] In one embodiment, the hematoma is the hematoma described in any of the above embodiments.

[0293] In one embodiment, the solid tumor is the solid tumor described in any of the above embodiments.

[0294] In one of the schemes, the autoimmune disease is the autoimmune disease described in any of the above schemes.

[0295] In one embodiment, the inflammatory disease is the inflammatory disease described in any of the above embodiments.

[0296] In one of the embodiments, the cardiovascular disease is the cardiovascular disease described in any of the above embodiments.

[0297] This invention provides a compound as shown in Formula II-49-3.

[0298] The present invention also provides a method for preparing crystal form A of the aforementioned penta-hexa-component compound as shown in Formula I, which includes the following steps: adding a poor solvent to a solution of the penta-hexa-component compound as shown in Formula I, and cooling to crystallize to obtain crystal form A.

[0299] In one embodiment, in the preparation method of crystal form A, the solvent for the solution of the pentagonal compound as shown in Formula I can be a mixed solvent of sulfoxide solvent and alcohol solvent.

[0300] In one embodiment, in the preparation method of crystal form A, the sulfoxide solvent may be dimethyl sulfoxide.

[0301] In one embodiment, in the method for preparing crystal form A, the alcohol solvent may be ethanol and / or isopropanol.

[0302] In one embodiment, in the method for preparing crystal form A, the undesirable solvent may be an alcohol solvent and / or water, such as ethanol and / or isopropanol.

[0303] In one embodiment, in the preparation method of crystal form A, in the solution of the pentagonal compound as shown in Formula I, the mass-to-volume ratio of the pentagonal compound as shown in Formula I to the solvent of the solution of the pentagonal compound as shown in Formula I can be 1:(1-10) g / mL, for example 1:5 g / mL.

[0304] In one embodiment, in the preparation method of crystal form A, the volume ratio of the sulfoxide solvent to the alcohol solvent in the solvent of the solution of the penta-hexa-part compound as shown in Formula I can be (1-5):1, for example 2:1.

[0305] In one embodiment, in the preparation method of crystal form A, the volume ratio of the solution of the pentagonal compound as shown in Formula I to the undesirable solvent can be (1-10):18.3, for example 5:18.3.

[0306] In one embodiment, during the preparation of crystal form A, the temperature at which the undesirable solvent is added can be 20-65°C, for example, 50°C.

[0307] In one embodiment, in the preparation method of crystal form A, the cooling temperature of the solution is 30-70℃, for example, 30℃, 40℃, 50℃ and 65℃.

[0308] In one embodiment, in the preparation method of crystal form A, the cooling rate is 5-15℃ / hour, for example 10℃ / hour.

[0309] In one embodiment, the cooling time in the preparation method of crystal form A is 10-30 hours.

[0310] The present invention also provides a method for preparing crystal form C of the aforementioned penta-hexa-component compound as shown in Formula I, which includes the following steps: evaporating a suspension of the penta-hexa-component compound as shown in Formula I to obtain the crystal form C.

[0311] In one embodiment, in the preparation method of crystal form C, the solvent of the suspension is a mixture of organic solvent and water.

[0312] In one embodiment, in the method for preparing crystal form C, the organic solvent may be one or more of alcohol solvents, ketone solvents, and nitrile solvents, such as ethanol, acetone, or acetonitrile.

[0313] In one embodiment, in the preparation method of crystal form C, the volume ratio of the organic solvent to water can be 60:40 to 99:1, for example, 95:5.

[0314] In one embodiment, in the preparation method of crystal form C, the mass-to-volume ratio of the pentagonal compound as shown in Formula I to the solvent in the suspension can be (10-100):1 mg / mL, for example 50:1 mg / mL.

[0315] In one embodiment, the evaporation temperature in the preparation method of crystal form C is room temperature.

[0316] In one embodiment, the evaporation time in the preparation method of crystal form C is 1-5 days, preferably 3 days.

[0317] The terms “compound” and “pharmaceutically acceptable salt” may exist in the form of a single tautomer or a mixture thereof, preferably in the form of the more stable tautomer.

[0318] The term "basically" means that the positions of the peaks in the graph may vary slightly with slight variations in measuring equipment, measuring conditions, and batches of the product being measured, and are not considered absolute values.

[0319] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Emcipients (Raymond C. Rowe, 2009) for details.

[0320] The term “treatment” refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that triggers the disease; or (3) slowing the development of one or more biological manifestations of a disease.

[0321] The term "prevention" refers to reducing the risk of developing a disease.

[0322] The term "patient" refers to any animal that has received or is about to receive treatment, preferably a mammal, and 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.

[0323] The term "room temperature" refers to 20-30°C, preferably 25°C.

[0324] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0325] The reagents and raw materials used in this invention are all commercially available.

[0326] The significant advantages of this invention are as follows: the salts and crystal forms of the compounds of this invention have inhibitory effects on FLT3 and / or IRAK4. Some crystal forms and salt forms of this invention have high single melting points, are thermodynamically stable, and have high crystallinity. The crystal forms exhibit good physicochemical stability under strong light, high temperature, and high humidity conditions, and have very weak hygroscopicity. Compared to the free base, some salt forms of this invention can significantly increase the blood drug concentration and exposure of the compound in rats. Attached Figure Description

[0327] Figure 1 The X-ray powder diffraction pattern is for crystal form A.

[0328] Figure 2 Differential scanning calorimetry and thermogravimetric analysis spectra for crystal form A.

[0329] Figure 3 The X-ray powder diffraction pattern is for crystal form B.

[0330] Figure 4 Differential scanning calorimetry and thermogravimetric analysis spectra for crystal form B.

[0331] Figure 5 The X-ray powder diffraction pattern is for crystal form C.

[0332] Figure 6 Differential scanning calorimetry and thermogravimetric analysis spectra for crystal form C.

[0333] Figure 7 The image shows the X-ray powder diffraction pattern of crystal form D.

[0334] Figure 8 Differential scanning calorimetry and thermogravimetric analysis spectra of crystal form D.

[0335] Figure 9 The image shows the X-ray powder diffraction pattern of crystal form E.

[0336] Figure 10 Differential scanning calorimetry and thermogravimetric analysis spectra of crystal form E.

[0337] Figure 11 The image shows the X-ray powder diffraction pattern of crystal form F.

[0338] Figure 12 Differential scanning calorimetry and thermogravimetric analysis spectra for crystal form F.

[0339] Figure 13 The X-ray powder diffraction pattern is for crystal form G.

[0340] Figure 14 Differential scanning calorimetry and thermogravimetric analysis spectra for crystal form G.

[0341] Figure 15 Dynamic vapor adsorption (DVS) spectrum for hygroscopicity detection of crystal form A.

[0342] Figure 16 The X-ray powder diffraction patterns of crystal form A before and after the hygroscopicity test are shown.

[0343] Figure 17 The X-ray powder diffraction pattern of crystal form A of hydrochloride is shown.

[0344] Figure 18 Differential scanning calorimetry and thermogravimetric analysis spectra of crystal form A of hydrochloride.

[0345] Figure 19 The X-ray powder diffraction pattern is for crystal form B of hydrochloride.

[0346] Figure 20 Differential scanning calorimetry and thermogravimetric analysis spectra of crystal form B of hydrochloride.

[0347] Figure 21 The X-ray powder diffraction pattern is for crystal form A of sulfate.

[0348] Figure 22 Differential scanning calorimetry and thermogravimetric analysis spectra of sulfate crystal form A.

[0349] Figure 23 The X-ray powder diffraction pattern is for crystal form B of sulfate.

[0350] Figure 24 Differential scanning calorimetry and thermogravimetric analysis spectra of sulfate crystal form B.

[0351] Figure 25 X-ray powder diffraction pattern of crystal form C of sulfate.

[0352] Figure 26 Differential scanning calorimetry and thermogravimetric analysis spectra of the crystal form C of sulfate.

[0353] Figure 27 X-ray powder diffraction pattern of phosphate crystal form A.

[0354] Figure 28 Differential scanning calorimetry and thermogravimetric analysis spectra of phosphate crystal form A.

[0355] Figure 29 X-ray powder diffraction pattern of phosphate crystal form B.

[0356] Figure 30 Differential scanning calorimetry and thermogravimetric analysis spectra of phosphate crystal form B.

[0357] Figure 31 The X-ray powder diffraction pattern is for crystal form A of the sodium salt.

[0358] Figure 32 Differential scanning calorimetry and thermogravimetric analysis spectra of sodium salt crystal form A.

[0359] Figure 33 The X-ray powder diffraction pattern of crystal form A of the potassium salt is shown.

[0360] Figure 34 Differential scanning calorimetry and thermogravimetric analysis spectra of potassium salt crystal form A.

[0361] Figure 35 This is the dynamic water adsorption (DVS) spectrum of phosphate.

[0362] Figure 36 This is the dynamic water adsorption (DVS) spectrum of hydrochloride. Detailed Implementation

[0363] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0364] Chinese-English Name Comparison Table:

[0365]

[0366]

[0367] Instruments and testing conditions

[0368] For X-ray powder diffraction (XRPD) of crystalline products, place approximately 10 mg of product on a glass slide, flatten it, and place it in the instrument to start the program. For differential scanning calorimetry (DSC), weigh 1-3 mg of sample onto an aluminum disk, seal it, punch a hole, and then place the aluminum disk on the sample stage to be tested. Set and run the program. For thermogravimetric analysis (TGA), first remove the tare from the aluminum disk, then weigh 3-10 mg of sample onto the aluminum disk, and then place the aluminum disk on the sample stage to be tested. Set and run the program. For polarizing microscope (PLM), take a small amount of sample onto a clean glass slide, add a small amount of silicone oil to disperse it, place it on the instrument, adjust the magnification and exposure intensity, observe, and take pictures to save the data.

[0369]

[0370]

[0371] The counterions and solvents used in this application are shown in the table below:

[0372]

[0373]

[0374] Example 1: Preparation of the compound

[0375]

[0376] Step 1: Synthesis of II-8-1

[0377] A mixed solution of 2-(trifluoromethyl)pyridine-4-boronic acid pinacol ester (286.32 mg, 1.05 mmol), methyl 2-bromooxazol-4-carboxylate (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 nitrogen protection for 4 hours until the reaction was complete. The reaction solution was diluted with 10 mL of H2O, extracted with EA (10 mL x 3) with stirring, and the combined organic phases were washed with 10 mL of brine. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography, eluting with PE / EA at a ratio of 10:3, to give a white solid product II-8-1, 0.23 g, yield 84.66%, MS (ESI) m / z: 272.0 [M+H]. + .

[0378] Step 2: Synthesize II-8-2

[0379] 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 nitrogen protection for 3 hours until the reaction was complete. The reaction mixture was diluted with H₂O (10 mL), and the solution was acidified to pH 3-4 with stirring. The mixture was extracted with EA (10 mL x 3), washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give a white solid product II-8-2, 0.2 g, crude product, MS (ESI) m / z: 259.0 [M+H]. + .

[0380] Step 3: Synthesis of II-49-1-P2

[0381] Cs₂CO₃ (2.62 g, 13.56 mmol) and 4-bromo-2-methyl-6-carboxylic acid methyl ester (1 g, 4.52 mmol) and DMF (10 mL) were added to a solution at 25 °C. The mixture was stirred at 100 °C for 16 hours until the reaction was complete. 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 give 6.00 g of crude yellow solid. The crude product was purified by silica gel column chromatography (PE:EtOAc = 2:1) to give a pale yellow solid product II-49-1-P2 510.00 mg, 1.66 mmol, with a yield of 35.24% and MS (ESI) m / z: 308.1 [M+H]. + II-49-1-P1: 1 H NMR(400MHz,Chloroform-d)δ8.46(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 (400MHz, Chloroform-d) δ8.40(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).

[0382] Step 4: Synthesize II-49-2

[0383] To a mixture of II-49-1-P2 (0.5 g, 1.63 mmol), EtOH (6 mL), and H2O (2.5 mL), NH4Cl (43.00 mg, 811.32 μmol) and iron powder (908.72 mg, 16.27 mmol) were added, and the mixture was stirred at 80 °C for 16 hours until the reaction was complete. The reaction mixture was diluted with H2O (20 mL) and then extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. A yellow solid product, II-49-2, was given at 400.00 mg, MS (ESI) m / z: 278.1 [M+H]. + .

[0384] Step 5: Synthesize II-49-3

[0385] Methylmagnesium chloride (539.40 mg, 7.21 mmol) was added to a stirred solution of II-49-2 (400 mg, 1.44 mmol) and THF (10 mL) at 0 °C, and the mixture was stirred for 16 hours until the reaction was complete. 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 layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was subjected to reversed-phase preparative HPLC (Prep-C18, 5 μM Xbridge column, 19 × 150 mm, both solvents containing 0.1% ammonium bicarbonate) to give a yellow oily product II-49-3, 210.00 mg, 681.42 μmol, yield 47.24%, MS (ESI) m / z: 278.2 [M+H]. + .

[0386] Step 6: Synthesize the pentagonal compound as shown in Formula I

[0387] II-49-3 (21.49 mg, 77.47 μmol, 1.0 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea 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 DIPEA (80 mg, 77.47 μmol, 1.0 eq) at 25 °C. The mixture was stirred for 1 hour until the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with 10 mL of H2O and then extracted with EA (10 mL x 3). The combined organic layers were washed with 10 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was subjected to reverse-phase preparative HPLC (Prep-C18, 5 μM Xbridge column, 19 × 150 mm, Waters; mobile phase containing 0.1% ammonium bicarbonate in both solvents (water and acetonitrile)) to yield a white solid product (i.e., the penta-hexa-membered compound as shown in Formula I) in a yield of 23.90 mg (47.34 μmol), with a purity of 98% (61.11%). MS (ESI) m / z: 518.2 [M+H). + . 1 HNMR(400MHz,Chloroform-d)δ11.38(s,1H),8.91(d,J=4.0Hz,1H),8.71(s,1H),8.45(s,1H),8.30(s,1H),8.14(dd,J=4.0,1.2Hz ,1H),7.90(s,1H),7.68(s,1H),4.57(t,J=8.0Hz,2H),2.68(s,1H),2.37(s,1H),2.18(t,J=8.0Hz,2H),1.79(s,6H),1.31(s,6H).

[0388] Example 2: Evaluation of the inhibitory effect of the compound on kinase activity

[0389] An experimental method based on fluorescence microfluidic mobility detection was used to determine the IC50 of compounds in competitive binding of ATP to kinases IRAK4 and FLT3. 50 The initial detection concentration of the compound was 10 μM, with a 4-fold serial dilution down to 0.38 nM, and detection was performed in duplicate. Commercially available staurosporine was used as the standard control in this experiment.

[0390] The reagent and consumable information is as follows:

[0391] IRAK4 kinase (Carna, Cat. No. 09-145, Lot. No. 14CBS-0020H)

[0392] FLT3 kinase (Carna, Cat. No. 08-154, Lot. No. 07CBS-2350)

[0393] Substrate peptide FAM-P2 (GL Biochem, Cat. No. 112394, Lot. No. P131014-XP112394)

[0394] Substrate peptide FAM-P8 (GL Biochem, Cat. No. 112396, Lot. No. P170731-SY112396)

[0395] ATP (Adenosine triphosphate, Sigma, Cat. No. A7699-1G, CAS No. 987-65-5)

[0396] DMSO (Dimethyl sulfoxide, Sigma, Cat. No. D2650)

[0397] EDTA (ethylenediaminetetraacetic acid, Sigma, Cat. No. E5134, CAS No. 60-00-4)

[0398] Staurosporine (Selleckchem, Cat. No. S1421)

[0399] HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid, Gibco, Cat. No. 15630-080)

[0400] Brij-35 solution (polyethylene lauroyl ether, Sigma, Cat. No. B41840-100mL)

[0401] DTT (Dithiothreitol, Sigma, Cat. No. D0632-20G)

[0402] 0.2% Coating Reagent #3 (Perkin Elmer, Cat. No. 760050)

[0403] 96-well plate (Corning, Cat. No. 3365)

[0404] 384-well plate (Corning, Cat. No. 3573)

[0405] Experimental procedure:

[0406] 1) FLT3 and IRAK4 kinases were dissolved in kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01% Brij-35) to obtain final concentrations of 0.9 nM, 30 nM and 6 nM, respectively.

[0407] 2) Substrate peptides FAM-P2 and FAM-P8 were dissolved in ATP in the above-mentioned kinase buffer, respectively. The final concentrations of substrate peptide FAM-P2 and ATP used to determine FLT3 were 3 μM and 97 μM, respectively; the final concentrations of substrate peptide FAM-P8 and ATP used to determine IRAK4 were 3 μM and 10 μM, respectively.

[0408] 3) Compound dilution: Dilute the compound to 50 μM first, then dilute it down 4-fold with DMSO. The solution without the compound and kinase is the blank control, corresponding to the "minimum value" below; the solution without the compound but containing kinase, adenosine triphosphate, DMSO and buffer is the positive control, corresponding to the "maximum value" below.

[0409] 4) Kinase reaction and termination: Add 10 μL of kinase buffer to a 384-well plate containing 5 μL of the test compound and incubate at room temperature for 10 minutes; add another 10 μL of buffer containing substrate peptide and adenosine triphosphate to a 384-well plate and incubate at 28°C for one hour. Then, add 25 μL of stop solution (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2% Coating Reagent#3 and 0.015% Brij-35) to each well to terminate the reaction.

[0410] 5) Data reading: Use the CaliperEZ ReaderⅡ instrument to read the conversion rate data. Set the conditions as follows: downstream voltage -500V, upstream voltage -2250V, reference pressure -0.5PSI, screening pressure -1.2PSI.

[0411] 6) Data Calculation: Copy the conversion rate data from CaliperEZ ReaderⅡ and convert the conversion rate into inhibition rate data. The calculation formula is as follows:

[0412] Inhibition percentage (%) = (Maximum value - Conversion rate) / (Maximum value - Minimum value) * 100%

[0413] Fitting ICs using XLFit excel add-in version 5.4.0.8 50 value,

[0414] Fitting formula: Y = Bottom + (Top - Bottom) / (1 + (IC) 50 / X)^HillSlope)

[0415] The compound kinase activity data are shown below:

[0416]

[0417] Example 3: Killing power of compound against MV4-11 cells (IC50) 50 Value determination

[0418] The reagent and consumable information is as follows:

[0419] MV4-11 cells (ATCC, Cat. No. CRL-9591)

[0420] DPBS (Duborough Phosphate Buffer, Biosera, Cat. No. LM-S2041 / 500)

[0421] IMDM medium (Thermo, Cat. No. 12440053)

[0422] Fetal bovine serum (Biological, Cat. No. 04-002-1A)

[0423] Penicillin-streptomycin solution (Invitrogen, Cat. No. 15140122)

[0424] Dimethyl sulfoxide (Sigma, Cat. No. D2650)

[0425] CellTiter-Glo Luminescent Cell Viability Assay (CellTiter-Glo chemiluminescence assay for cell viability, Promega, Cat. No. G7573)

[0426] 96-well plate (Corning, Cat. No. 3903)

[0427] CTG Experimental Procedure

[0428] 1. Culture MV-4-11 cells in IMDM complete medium (IMDM + 10% fetal bovine serum + 1% penicillin-streptomycin mixture).

[0429] 2. Collect healthy MV-4-11 cells and wash them twice with DPBS (Dubor's phosphate buffered saline).

[0430] 3. Resuspend MV-4-11 cells in IMDM complete medium and adjust the cell density to 1.11 × 10⁻⁶. 6Add cells / mL to 90 μL per well of a 96-well plate.

[0431] 4. Prepare a 10-fold concentration of the compound solution using IMDM complete medium. Add 10 μL of the 10-fold concentration of the compound solution to the 96-well cells, mix well, and then incubate the 96-well plate in a 37°C 5% CO2 incubator for 72 hours.

[0432] 5. After incubation, remove the 96-well plate and allow it to equilibrate at room temperature for 30 minutes. Then, add 100 μL of CellTiterGlo reagent to each well and mix on a horizontal shaker for 2 minutes.

[0433] 6. Remove the 96-well plate, allow it to equilibrate at room temperature for 10 minutes, and then measure the chemiluminescence value using an ELISA reader.

[0434] Conclusion: The cytotoxic activity data of the compound is MV4-11 IC50. 50 The value is 21nM.

[0435] Example 4: Preparation of Crystal Form

[0436] 4.1 Preparation of Crystal Form A

[0437] Weigh 1g of the penta-hexa-ary compound of Formula I prepared in Example 1 into a reaction vessel, and add 5V DMSO / IPA (volume ratio 2:1, where V represents 1g of solute to 1mL of solvent). Heat to 65°C with stirring to obtain a clear solution. Then cool to 50°C and stir for 0.5 hours. Add 18.3V IPA at 50°C and react for 3 hours. Cool to 20°C at 10°C / hour and stir overnight at 20°C (about 16 hours) to obtain a solid. Wash the filter cake with 2V IPA and dry under vacuum at 50°C to obtain crystal form A of the free base.

[0438] 4.2 Preparation of crystal form B

[0439] Weigh 30 mg of the pentagonal compound I prepared in Example 1, add 0.6 mL of methanol, suspend at room temperature for 3 days, and filter to obtain the solid crystal form B.

[0440] 4.3 Preparation of Crystal Form C

[0441] Weigh 30 mg of the pentagonal and hexa-ary compound prepared in Example 1 as shown in Formula I, add 0.6 mL of acetone / water = 95 / 5 (volume ratio), suspend at room temperature for 3 days, and filter to obtain the solid crystal form C.

[0442] 4.4 Preparation of Crystal Form D

[0443] Weigh 30 mg of the penta-hexa-ary compound prepared in Example 1 as shown in Formula I, add 0.6 mL of methanol, suspend at room temperature for 3 days, filter to obtain a saturated solution, and slowly evaporate at room temperature to obtain the solid crystal form D.

[0444] 4.5 Preparation of Crystal Form E

[0445] Weigh 30 mg of the penta-hexa-ary compound prepared in Example 1 as shown in Formula I, add 0.6 mL of ethanol, suspend at room temperature for 3 days, filter to obtain a saturated solution, and slowly evaporate at room temperature to obtain the solid crystal form E.

[0446] 4.6 Preparation of crystal form F

[0447] Weigh 30 mg of the penta-hexa-ary compound prepared in Example 1 as shown in Formula I, add 0.6 mL of acetone-water 95 / 5 (volume ratio), suspend at room temperature for 3 days, filter to obtain a saturated solution, and slowly evaporate at room temperature to obtain the solid crystal form F.

[0448] 4.7 Preparation of crystal form G

[0449] Weigh 30 mg of the penta-hexa-ary compound prepared in Example 1 as shown in Formula I, add 0.6 mL of methanol, dissolve at 70 degrees Celsius, cool to 5 degrees Celsius at 5 degrees Celsius per hour, and filter the suspension to obtain the solid crystal form G.

[0450] Example 5: Simulated Granulation Test

[0451] Dry method: directly grind crystal form A of the pentagonal compound shown in Formula I for 30 minutes.

[0452] Wet method: Ethanol, the granulation solvent, was added dropwise to the surface of crystal form A of the five- and six-membered compound shown in Formula I until the solid was fully wetted, followed by grinding for 30 minutes. The resulting solid was then characterized by XRPD and DSC to assess its crystal form and crystallinity. The purpose was to determine whether polymorphs, solvates, or amorphous compounds were easily formed. Simulated granulation experiments showed that the crystal forms remained unchanged, all being crystal form A, and no new crystal forms were observed.

[0453] Example 6 High Voltage Property Test

[0454] Approximately 10 mg of crystal form A of the pentagonal compound shown in Formula I was weighed and added to a hydraulic pan with a diameter of 13 mm. A high-pressure property test was performed using a manual hydraulic press at a pressure of 10 tons for 5 minutes. The resulting solid was characterized by XRPD and other methods to observe its crystal stability under high pressure. The results of the high-pressure treatment experiment showed that the crystal form remained unchanged, remaining crystal form A, and no new crystal form was found.

[0455] Example 7: Study on Crystal Transformation Relationship

[0456] To investigate the interconversion relationships between polymorphs, polymorphs were prepared under repeated conditions, and a series of suspension competition experiments were conducted on polymorphs A, C, D, E, and G in different solvent systems. The specific experimental steps are as follows:

[0457] Weigh 20 mg of each of crystal forms A, C, D, E, and G into 5 mL glass vials, and add solvent (EtOH / H₂O = 1 / 1 (v / v) or DMSO (dimethyl sulfoxide) / EtOH = 1 / 8 (v / v)) to form suspensions. Then transfer the vials to 25 °C and stir for 72 hours. After filtration at different time points, perform XRPD testing on the filter cakes.

[0458] EtOH / H2O 1 / 1 solvent system

[0459] Table 1. Suspension competition in EtOH / H2O 1 / 1 solvent system

[0460]

[0461] The suspension experiment in the EtOH / H2O 1 / 1 solvent system showed that after 24 hours of suspension, the solid sample was in crystalline form C.

[0462] DMSO / EtOH 1 / 8 solvent system

[0463] Table 2. Suspension competition in DMSO / EtOH 1 / 8 solvent system

[0464]

[0465] The suspension experiment in the DMSO / EtOH 1 / 8 solvent system showed that after 24 hours of suspension, the solid sample was crystal form A.

[0466] Example 8 Polymorphic Product Analysis

[0467] The products obtained from polymorph screening were subjected to X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and high-performance liquid chromatography (HPLC). The newly discovered polymorphs were summarized, and the relevant spectra are shown in [reference needed]. Figures 1 to 14 .

[0468] Table 3 Polymorph Characterization Analysis

[0469]

[0470] The experimental results show that among the seven crystal forms discovered, crystal form A has a high melting point and less weight loss.

[0471] Example 9 Solid-state stability study - influencing factor test

[0472] To investigate the solid-state stability of crystal form A, it was placed under different conditions to study the changes in its crystal form, purity, and color.

[0473] 60 mg of crystal form A was weighed and placed in a glass dish or vial. The dish or vial was then placed in a constant temperature and humidity chamber under different conditions, including: light intensity: 4500±500 Lux; high temperature: 60℃ (sealed); high humidity: 25℃, relative humidity RH=90±5% (open). The results of the solid-state stability study of crystal form A are shown in the table below:

[0474] Table 4 Solid-state stability study

[0475]

[0476] Solid-state stability evaluation results show that crystal form A exhibits good physical and chemical properties under high temperature, high humidity and strong light conditions.

[0477] Example 10 Hygroscopicity Study

[0478] The important hygroscopic property of this compound was tested using dynamic vapor adsorption (DVS). DVS is a dynamic measurement method, therefore the sample undergoes weight changes during the measurement process. Like other research methods, DVS records the mass change of the sample as relative humidity changes. See the relevant spectra. Figure 15-16 .Depend on Figure 15 The DVS curve results show that the water adsorption of the initial sample in both adsorption-desorption curves at 25℃ / 90% RH (relative humidity) is less than 0.04%, indicating that the sample has low hygroscopicity.

[0479] Table 5. Hygroscopicity Study

[0480]

[0481] Conclusion: XRPD testing was performed on samples before and after DVS testing. Figure 16 It can be seen that the crystal form has not changed.

[0482] Example 11 Preparation of Salt Form

[0483] Free bases contain multiple basic sites. Salt formation studies were conducted using inorganic / organic acids and free bases commonly used in drug research. During the study, nine salt forms, including hydrochloride, sulfate, and phosphate, were prepared. The experimental process for salt formation studies is summarized below:

[0484] (1) 30 mg of API (i.e., the penta-hexa-ary compound prepared in Example 1 as shown in Formula I) and 0.3 mL of solvent were loaded into a reaction flask. The reaction system was stirred at room temperature (about 25 °C) to obtain a clear solution or suspension.

[0485] (2) First add the counterion reagent (1.1 eq. or 3.0 eq.) and solvent (0.3 mL) into the reaction flask, and obtain a clear solution or suspension system under stirring at room temperature. Then, slowly add this system to the clear solution or suspension system in (1) under stirring.

[0486] (3) Heat the reaction system to 50°C and stir at 50°C for 2 hours.

[0487] (4) Cool the reaction system to 25°C at a cooling rate of 10°C / hour and keep it for 15 hours.

[0488] (5) The suspended reaction system was centrifuged, and the filter cake was vacuum dried at room temperature for 15 hours. For the reaction system without solid precipitation, nitrogen purging was performed at 25°C to evaporate the solvent and obtain a solid sample. The results are as follows:

[0489]

[0490]

[0491] Note: Samples marked with "*" indicate solids obtained by evaporation of a transparent solution under a nitrogen atmosphere; " / / " indicates no evaporation or a small amount obtained.

[0492] solid.

[0493] In the table, HC represents hydrochloride, SF represents sulfate, PH represents phosphate, NA represents sodium salt, and KA represents potassium salt.

[0494] Based on the nine possible salt forms, and considering the XRPD, TGA, and DSC characterization results, the crystallinity, melting point, and TGA weight loss of the salts were comprehensively compared. 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 for subsequent solid-state stability testing and DVS hygroscopicity studies.

[0495] Example 12 Detection of Salt Type

[0496] 5.1 Experimental Objective: To determine the contents of chloride, sulfate, and phosphate ions in hydrochloride crystal form A, sulfate crystal form A, and phosphate crystal form A by ion chromatography.

[0497] 5.2 Instruments and Equipment:

[0498]

[0499] 5.3 Reagents and Materials:

[0500]

[0501] 5.4 Sample configuration:

[0502]

[0503] SPL-Cl - Accurately weigh 15.65 mg of hydrochloride crystal form A sample into a 15 mL plastic centrifuge tube. First, accurately add 8.0 mL of pure water, then add 7.0 mL of ethyl acetate. Sonicate to dissolve completely, allow to stand and separate into layers, then remove the upper organic phase. Next, add 1.0 mL of methyl tert-butyl ether to the aqueous phase, shake thoroughly, and allow to stand and separate into layers. Accurately transfer 1.0 mL from the aqueous phase to a 5 mL volumetric flask, labeled SPL-Cl. - .

[0504] SPL-SO4 2- Accurately weigh 16.70 mg of sulfate crystal form A sample into a 15 mL plastic centrifuge tube. First, accurately add 8.0 mL of pure water, then add 7.0 mL of ethyl acetate. Sonicate to dissolve completely, allow to stand and separate into layers, then remove the upper organic phase. Next, add 1.0 mL of methyl tert-butyl ether to the aqueous phase, shake thoroughly, and allow to stand and separate into layers. Accurately transfer 1.0 mL from the aqueous phase to a 5 mL volumetric flask and label it SPL-SO4. 2- .

[0505] SPL-PO4 3- Accurately weigh 13.81 mg of phosphate crystal form A sample into a 15 mL plastic centrifuge tube. First, accurately add 8.0 mL of pure water, then add 7.0 mL of ethyl acetate. Sonicate to dissolve completely, allow to stand and separate into layers, then remove the upper organic phase. Next, add 1.0 mL of methyl tert-butyl ether to the aqueous phase, shake thoroughly, and allow to stand and separate into layers. Accurately transfer 1.0 mL from the aqueous phase to a 5 mL volumetric flask and label it SPL-PO4. 3- .

[0506] 5.5 Method Parameters:

[0507]

[0508]

[0509] 5.6 Experimental Results

[0510]

[0511] calculate:

[0512] The molar ratio of chloride ions to free base in hydrochloride is (5.95 / 35.5) / (100 / (517.5+36.5)) = 0.93:1

[0513] The molar ratio of sulfate ions to free base in sulfate is (15.67 / 96) / (100 / (517.5+98)) = 1:1

[0514] The molar ratio of phosphate to free base in phosphate is (14.98 / 95) / (100 / (517.5+98)) = 0.97:1

[0515] Conclusion: Verification showed that the acid-base ratio in the salts obtained above was 1:1.

[0516] Example 13 Crystal form characterization

[0517] The solid substances of the salt forms obtained by screening were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray powder diffraction (XRPD). Taking into account the crystallinity, TGA weight loss, melting point, and HPLC purity of the salt forms obtained by screening, the dominant salt forms were selected for scale-up preparation.

[0518] The solid-state properties of the selected salt types were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray powder diffraction (XRPD). Relevant spectra can be found in [reference needed]. Figures 17 to 34 The experimental results are as follows:

[0519]

[0520]

[0521] Example 14 Solid-state stability test

[0522] Weigh 60 mg of each of the following crystal forms: hydrochloride (form A), sulfate (form A), and phosphate (form A), and place them in glass dishes or vials. Then place the glass dishes or vials in different environments within a constant temperature and humidity chamber, with the following conditions: light: 4500±500 Lux (open); high temperature: 60℃ (sealed); high humidity: 25℃; RH=90±5% (open).

[0523] The results of the solid stability studies for phosphates, hydrochlorides, and sulfates are shown below:

[0524]

[0525]

[0526] Solid-state stability evaluation results show that hydrochloride crystal form A exhibits good physicochemical stability under strong light, high temperature and high humidity conditions.

[0527] Example 15 Solubility Test

[0528] The solubility of the dominant salt in different pH buffer solutions, water, and physiological solutions was determined. The specific steps for the solubility determination are as follows:

[0529] Accurately weigh 15 mg of hydrochloride crystal form A sample and transfer it to a 20 mL screw-top bottle. Add 3 mL of solution (water, pH buffer, SGF, FaSSIF, FeSSIF) to each bottle. Seal the bottles and transfer them to a magnetic stirrer. Maintain the stirring rate at 500 rpm at 25°C for 24 hours. Record the dissolution of the sample bottles during the test. After 24 hours, filter approximately 1 mL of the suspension, collect the filtrate, and perform solubility testing by HPLC. Measure the pH value of the filtrate sample using a pH meter. Determine the phosphate crystal form A and sulfate crystal form A following the same procedure.

[0530] The experimental results are summarized in the table below:

[0531]

[0532] The results showed that all crystal forms had good solubility in a buffer solution at pH 1.

[0533] Example 16 DVS Test

[0534] Experimental methods:

[0535] 1. First, tare and balance the sample tray of the instrument;

[0536] 2. Weigh 30 mg of each sample (phosphate crystal form A and hydrochloride crystal form A sample) and place them in the sample tray;

[0537] 3. Program Operation: Starting from 0% humidity, the system slowly rises to 90%, then returns to 0% to complete the first cycle; it then rises to 90% again and falls back to 0% to end the second cycle. Figures 35-36 (As shown).

[0538] The DVS data results are shown in the table below:

[0539]

[0540]

[0541] The test results show that both hydrochloride crystal form A and phosphate crystal form A have low hygroscopicity, and the samples did not change before and after the DVS test.

[0542] Example 17 Pharmacokinetic Test

[0543] 10.1 Solvent Information and Preparation of Test Sample Dosage Formulation

[0544] Solvent information:

[0545]

[0546] 5% DMSO + 10% Tween 80 + 5% Kolliphor HS15 + 80% Saline, where % is the volume ratio.

[0547] Preparation of a 4 mg / mL hydrochloride formulation (5% DMSO + 10% Tween 80 + 5% Kolliphor HS15 + 85% Saline): Accurately weigh 41.97 mg of hydrochloride into a 15 mL centrifuge tube. Add 488 μL of DMSO and vortex for 30 seconds to ensure complete dissolution. Add 976 μL of Tween 80 and vortex for 30 seconds. Then add 488 μL of Kolliphor HS15 (Kolliphor HS15 is melted at 50°C before use) and vortex for 30 seconds. Finally, add 7808 μL of physiological saline and vortex for 30 seconds. Finally, sonicate for 10 seconds to remove air bubbles. This formulation is a suspension.

[0548] Preparation of a 4 mg / mL dosage form of free base (5% DMSO + 10% Tween 80 + 5% Kolliphor HS15 + 85% Saline): Accurately weigh 41.35 mg of the pentagonal and hexaagonal compound prepared in Example 1 as shown in Formula I into a 15 mL centrifuge tube. Add 517 μL of DMSO and vortex for 30 seconds to ensure complete dissolution of the compound. Add 1034 μL of Tween 80 and vortex for 30 seconds. Then add 517 μL of Kolliphor HS15 (Kolliphor HS15 is used after being melted by heating at 50 °C) and vortex for 30 seconds. Finally, add 8270 μL of physiological saline and vortex for 30 seconds. Finally, sonicate for 10 seconds to remove air bubbles. This dosage form is a suspension.

[0549] 10.2 Experimental System

[0550] 10.2.1 Laboratory Animals

[0551] Species and strain: Sprague-Dawley rat (SD rat) (Zhejiang Vital River Laboratory Animal Technology Co., Ltd.)

[0552] Animal rating: SPF

[0553] Planned starting weight for administration: 200-250g for males; actual animal weight will be listed in the original record.

[0554] Animal number and sex: 3 (3 per group), male

[0555] 10.2.2 Feeding

[0556] The animal enclosures are designed to provide barrier-free access to food and water. Environmental conditions are maintained at a room temperature of 20℃-26℃, relative humidity of 40%-70%, and alternating light and dark cycles of 12 hours per day. Animals are housed in polycarbonate plastic containers measuring 466mm × 314mm × 200mm (length × width × height), with no more than 5 animals per cage.

[0557] 10.2.3 Drinking water

[0558] Animals have free access to water.

[0559] 10.2.4 Marking

[0560] Animal individual marking: The rats were marked with serial numbers written on their tails using a marker pen. Each animal had a unique mark number, and each group was housed in a cage.

[0561] 10.3 Experimental Design

[0562] 10.3.1 Animal grouping and drug dosage

[0563] Based on measured body weight, animals with similar body weights were grouped into groups of three, with the grouping and drug dosages shown in the table below. Animals in the control group were used for collecting blank biological substrates.

[0564]

[0565] 10.3.2 Administration

[0566] Route of administration: gavage;

[0567] Dosage volume: 10 mL / kg;

[0568] Dosage frequency: single dose

[0569] Administration method: Administer the test sample orally via gavage using a suitable syringe and gavage tube. When using a 2 mL or 5 mL syringe, retain the dose to one decimal place. If the smallest division of the syringe is 0.2 mL and the administered volume falls between two divisions, aspirate the uppermost volume.

[0570] Reason for choosing the dosage: the standard dosage in pharmacokinetic studies.

[0571] 10.3.3 Sample Collection and Processing

[0572] 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.

[0573] Experimental animals were fasted for 12 hours before administration, but water was allowed. Blood samples were collected from the first group of animals (gavage group) at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration.

[0574] Sample processing: Immediately transfer the collected venous blood to EDTA-Na2 coated Eppendorf tubes (store at 2-8°C or in an icebox with crushed ice before use), invert at least 5 times to mix thoroughly, and temporarily store in an icebox with crushed ice. Centrifuge the collected whole blood at 2000g at 2-8°C for 10 minutes within 2 hours to separate the plasma, and place it in newly labeled centrifuge tubes. All samples should be stored at -20°C.

[0575] Sample labeling: Collected whole blood / plasma samples were 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 sex (male) and the experimental date, "07~09" represents the abbreviated animal number, "WB" represents whole blood, and "P" represents plasma.

[0576] 10.4 Data Collection and Statistical Analysis

[0577] The Pharmacokinetics Group of the Pharmacology and Toxicology Department analyzed and determined all samples and summarized the data. Plasma concentration data were analyzed using the WinNonlin metabolic data analysis software. The t-value was calculated using the non-compartmental model (NCA). 1 / 2 C max T max V d CL, AUC 0-24 Pharmacokinetic parameters such as F were also analyzed. Specific results are shown in the table below:

[0578]

[0579] Conclusion: Compared with the free base, the hydrochloride can significantly increase the blood concentration and exposure of the compound in rats.

[0580] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A crystal form A of a pentagonal compound as shown in Formula I, characterized in that, The crystal form A, which has 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 13.12±0.20°, 19.05±0.20°, 25.85±0.20°, and 26.73±0.20°. 。 2. The crystal form A of the pentagonal compound as shown in Formula I as described in claim 1, characterized in that, The crystal form A, which has 2 The X-ray powder diffraction pattern, expressed in angle, also shows characteristic peaks at one or more of the following locations: 7.84±0.20°, 10.25±0.20°, 20.96±0.20°, and 24.46±0.20°.

3. The crystal form A of the pentagonal compound as shown in Formula I as described in claim 1, characterized in that, The crystal form A, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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°.

4. A crystal form of a pentagonal compound as shown in Formula I, wherein the crystal form is C or G, characterized in that, The crystal form C, which has 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 11.05±0.20°, 14.21±0.20°, 18.83±0.20°, and 28.80±0.20°. The crystal form G, which has 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 9.74±0.20°, 13.56±0.20°, 16.39±0.20°, and 24.51±0.20°. 。 5. The crystal form of the pentagonal compound as shown in Formula I as described in claim 4, characterized in that, The crystal form C, which has 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more of the following locations: 7.02±0.20°, 9.78±0.20°, 20.44±0.20°, and 23.98±0.20°. The crystal form G, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more of the following locations: 7.09±0.20°, 18.50±0.20°, 20.94±0.20°, and 23.36±0.20°.

6. The crystal form of the pentagonal compound as shown in Formula I as described in claim 4, characterized in that, The crystal form C, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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 crystal form G, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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°.

7. A crystal form of a pentagonal compound as shown in Formula I, wherein crystal form A is characterized in that, The crystal form A, which has 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 7.84±0.20°, 10.25±0.20°, 20.96±0.20°, 22.36±0.20°, and 25.85±0.20°. 。 8. The crystal form of the pentagonal compound as shown in Formula I as described in claim 7, characterized in that, The crystal form A, with 2 The X-ray powder diffraction pattern, expressed in angle, also shows characteristic peaks at one or more of the following locations: 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°.

9. A crystal form of a pentagonal compound as shown in Formula I, wherein the crystal form is crystal form B, crystal form C, crystal form D, crystal form E, crystal form F or crystal form G, characterized in that, The crystal form C, which has 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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°. The crystal form B, which has 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 9.94±0.20°, 11.81±0.20°, 16.26±0.20°, and 18.47±0.20°. The crystal form D, which has 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 9.51±0.20°, 15.35±0.20°, 19.27±0.20°, and 24.20±0.20°. The crystal form E, which is 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 9.21±0.20°, 10.61±0.20°, 13.93±0.20°, 18.66±0.20°, and 23.43±0.20°. The crystal form F, which has 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 5.53±0.20°, 5.93±0.20°, 10.38±0.20°, and 22.37±0.20°. The crystal form G, which has 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 9.74±0.20°, 13.56±0.20°, 16.39±0.20°, and 24.51±0.20°. 。 10. The crystal form of the pentagonal compound as shown in Formula I as described in claim 9, characterized in that, The crystal form C, with 2 The X-ray powder diffraction pattern, expressed in angle, also shows characteristic peaks at one or more of the following locations: 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 crystal form B, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more of the following locations: 11.41±0.20°, 14.41±0.20°, 20.73±0.20°, and 23.39±0.20°. The crystal form D, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more of the following locations: 9.90±0.20°, 20.01±0.20°, 20.75±0.20°, and 29.18±0.20°. The crystal form E, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more of the following locations: 20.06±0.20°, 21.85±0.20°, and 28.25±0.20°. The crystal form F, with 2 The X-ray powder diffraction pattern represented by angle also has characteristic peaks at one or more of the following locations: 10.21±0.20°, 11.11±0.20°, 16.72±0.20°, and 25.78±0.20°. The crystal form G, with 2 The X-ray powder diffraction pattern, expressed in angle, also shows characteristic peaks at one or more of the following locations: 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°.

11. The crystal form of the pentagonal compound as shown in Formula I as described in claim 9, characterized in that, The crystal form B, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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 crystal form D, with 2 The X-ray powder diffraction pattern, expressed in angle, shows characteristic peaks at 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 crystal form E, with 2 The X-ray powder diffraction pattern, expressed in angle, shows characteristic peaks at 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 crystal form F, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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°.

12. The crystal form as described in any one of claims 1-3 and 7-8, characterized in that, The crystal form A, which has 2 The X-ray powder diffraction patterns represented by angles show diffraction peaks at the diffraction angles shown in the table below: 。 13. The crystal form as described in claim 12, characterized in that, The crystal form A, which has 2 The diffraction peaks, d-values, and peak height percentages in the X-ray powder diffraction patterns represented by angles are shown in the table below: 。 14. The crystal form according to any one of claims 1-3 and 7-8, characterized in that, The X-ray powder diffraction pattern of crystal form A is shown in Figure 1; and / or, said Form A, has a differential scanning calorimetry profile substantially the same as depicted in Figure 2, having an onset of an endothermic peak at 231.31 ± 2 o C; and / or, a peak at 8.8 ± 0.2 °2Θ. And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form A is at 237.74 ± 2. o Point C is the starting point of the endothermic peak; and / or, said Form A, has a thermogravimetric analysis profile comprising an onset of weight loss at 200 o C Weight loss 0.428%; the "%" is a mass percent.

15. The crystal form as described in claim 14, characterized in that, The differential scanning calorimetry (DSC) chromatogram of crystal form A is 231.31 ± 2. o The endothermic peak begins at point C, at 232.04±2. o The endothermic peak is reached at point C; And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form A is at 237.74 ± 2. o The endothermic peak begins at point C, at 244.16±2. o The endothermic peak is reached at point C.

16. The crystal form as described in claim 15, characterized in that, The differential scanning calorimetry (DSC) chromatogram of crystal form A is 231.31 ± 2. o The endothermic peak begins at point C, at 232.04±2. o The endothermic peak is reached at point C, with an enthalpy of 111.300 J / g. And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form A is at 237.74 ± 2. o The endothermic peak begins at point C, at 244.16±2. o The endothermic peak is reached at point C, with an enthalpy of 69.104 J / g.

17. The crystal form as described in claim 16, characterized in that, The differential scanning calorimetry analysis diagram of crystal form A is shown in Figure 2; And / or, the thermogravimetric analysis diagram of crystal form A is shown in Figure 2.

18. The crystal form as described in any one of claims 4-6 and 9-11, characterized in that, The crystal form C, which has 2 The X-ray powder diffraction patterns represented by angles show diffraction peaks at the diffraction angles shown in the table below: ； And / or, the crystal form B, which is 2 The X-ray powder diffraction patterns represented by angles show diffraction peaks at the diffraction angles shown in the table below: ； And / or, the crystal form D, which is 2 The X-ray powder diffraction patterns represented by angles show diffraction peaks at the diffraction angles shown in the table below: ； And / or, the crystal form E, which is 2 The X-ray powder diffraction patterns represented by angles show diffraction peaks at the diffraction angles shown in the table below: ； And / or, the crystal form F, which is 2 The X-ray powder diffraction patterns represented by angles show diffraction peaks at the diffraction angles shown in the table below: ； And / or, the crystal form G, which is 2 The X-ray powder diffraction patterns represented by angles show diffraction peaks at the diffraction angles shown in the table below: 。 19. The crystal form as described in claim 18, characterized in that, The crystal form C, which has 2 The diffraction peaks, d-values, and peak height percentages in the X-ray powder diffraction patterns represented by angles are shown in the table below: ； And / or, the crystal form B, which is 2 The diffraction peaks, d-values, and peak height percentages in the X-ray powder diffraction patterns represented by angles are shown in the table below: ； And / or, the crystal form D, which is 2 The diffraction peaks, d-values, and peak height percentages in the X-ray powder diffraction patterns represented by angles are shown in the table below: ； And / or, the crystal form E, which is 2 The diffraction peaks, d-values, and peak height percentages in the X-ray powder diffraction patterns represented by angles are shown in the table below: ； And / or, the crystal form F, which is 2 The diffraction peaks, d-values, and peak height percentages in the X-ray powder diffraction patterns represented by angles are shown in the table below: ； And / or, the crystal form G, which is 2 The diffraction peaks, d-values, and peak height percentages in the X-ray powder diffraction patterns represented by angles are shown in the table below: 。 20. The crystal form according to any one of claims 4-6 and 9-11, characterized in that, The X-ray powder diffraction pattern of the crystal form C is shown in Figure 5. And / or, the X-ray powder diffraction pattern of the crystal form B is shown in Figure 3; And / or, the X-ray powder diffraction pattern of the crystal form D is shown in Figure 7; And / or, the X-ray powder diffraction pattern of the crystal form E is shown in Figure 9; And / or, the X-ray powder diffraction pattern of the crystal form F is shown in Figure 11; And / or, the X-ray powder diffraction pattern of the crystal form G is shown in Figure 13; and / or, said Form C, has an onset of an endothermic peak at 63.69±2 o the onset of the endothermic peak at C. and / or, said Form C, has an onset of an endothermic peak at 126.27±2 o the onset of the endothermic peak at C. and / or, said Form C has a differential scanning calorimetry profile comprising an endothermic peak at 230.61 ± 2 o the onset of the endothermic peak at C. And / or, the thermogravimetric analysis chromatogram of crystal form C is at 73.

91. o C. Weight loss: 3.778%; the "%" refers to the percentage by mass. and / or, said Form B has a differential scanning calorimetry profile comprising an endothermic peak at 60.85±2 o the onset of the endothermic peak at C. and / or, said Form B has a differential scanning calorimetry profile with an endothermic peak at 151.04±2 o C; and / or, said Form B has a differential scanning calorimetry profile with an endothermic peak at 230.51±2 o C. and / or, said Form D, has an onset of an endothermic peak at 231.13 ± 2 o C; and / or, said Form D, has an onset of an endothermic peak at 231.13 ± 2 o C. And / or, the crystal form E, whose differential scanning calorimetry chromatogram is at 48.59±2 o The endothermic peak begins at point C; and / or, the differential scanning calorimetry (DSC) chromatogram of crystal form E is at 90.07 ± 2°C. o Point C is the starting point of the endothermic peak; and / or, said Form E has a differential scanning calorimetry profile substantially the same as depicted in Figure 25, having an onset of the endothermic peak at 225.15±2 o C; and / or, a thermogravimetric analysis profile substantially the same as depicted in Figure 26. o C; and / or, a thermogravimetric analysis profile substantially And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form F is at 49.64 ± 2. o The endothermic peak begins at point C; and / or, the differential scanning calorimetry (DSC) chromatogram of crystal form F is at 97.99 ± 2 ppm. o Point C is the starting point of the endothermic peak; And / or, the crystal form F, whose differential scanning calorimetry chromatogram is at 225.07±2 o The endothermic peak begins at point C; and / or, the differential scanning calorimetry (DSC) chromatogram of crystal form G is at 63.20 ± 2. o The endothermic peak begins at point C; and / or, the differential scanning calorimetry (DSC) chromatogram of crystal form G is at 150.82 ± 2. o Point C is the starting point of the endothermic peak; And / or, the crystal form G, whose differential scanning calorimetry (DSC) chromatogram is at 230.69 ± 2 ppm. o Point C is the starting point of the endothermic peak; And / or, the thermogravimetric analysis chromatogram of crystal form B is at 122.

68. o C. Weight loss: 4.741%; the "%" refers to the percentage by mass. And / or, the thermogravimetric analysis chromatogram of crystal form D is at 116.

38. o C. Weight loss 2.826%; the "%" refers to the mass percentage. And / or, the thermogravimetric analysis chromatogram of crystal form E is at 119.

49. o C. Weight loss 5.585%; the "%" refers to the percentage by mass. And / or, the thermogravimetric analysis chromatogram of crystal form F is at 127.

37. o C. Weight loss 1.066%; the "%" refers to the mass percentage. And / or, the thermogravimetric analysis chromatogram of the crystal form G is at 130.

90. o C. Weight loss 3.405%; the "%" refers to the mass percentage.

21. The crystal form as described in claim 20, characterized in that, The differential scanning calorimetry (DSC) chromatogram of the aforementioned crystal form C is 63.69 ± 2. o The endothermic peak begins at point C, at 82.10±2. o The endothermic peak is reached at point C; And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form C is at 126.27 ± 2. o The endothermic peak begins at point C, at 134.20±2. o The endothermic peak is reached at point C; And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form C is at 230.61 ± 2. o The endothermic peak begins at point C, at 231.73±2. o The endothermic peak is reached at point C; And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form B is at 60.85 ± 2. o The endothermic peak begins at point C, at 72.84±2. o The endothermic peak is reached at point C; And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form B is at 151.04 ± 2. o The endothermic peak begins at point C, at 153.19±2. o The endothermic peak is reached at point C; And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form B is at 230.51 ± 2. o The endothermic peak begins at point C, at 231.37±2. o The endothermic peak is reached at point C; And / or, the crystal form D, whose differential scanning calorimetry (DSC) chromatogram is at 231.13 ± 2 ppm. o The endothermic peak begins at point C, at 232.25±2. o The endothermic peak is reached at point C; And / or, the crystal form E, whose differential scanning calorimetry chromatogram is at 48.59±2 o The endothermic peak begins at point C, at 51.08±2. o The endothermic peak is reached at point C; And / or, the crystal form E, whose differential scanning calorimetry chromatogram is within 90.07±2 o The endothermic peak begins at point C, at 95.66±2. o The endothermic peak is reached at point C; And / or, the crystal form E, whose differential scanning calorimetry chromatogram is at 225.15±2 o The endothermic peak begins at point C, at 228.25±2. o The endothermic peak is reached at point C; And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form F is at 49.64 ± 2. o The endothermic peak begins at point C, at 52.43±2. o The endothermic peak is reached at point C; And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form F is within 97.99 ± 2 ppm. o The endothermic peak begins at point C, at 103.02±2. o The endothermic peak is reached at point C; And / or, the crystal form F, whose differential scanning calorimetry chromatogram is at 225.07±2 o The endothermic peak begins at point C, at 226.71±2. o The endothermic peak is reached at point C; And / or, the crystal form G, whose differential scanning calorimetry (DSC) chromatogram is at 63.20 ± 2 ppm. o The endothermic peak begins at point C, at 76.01±2. o The endothermic peak is reached at point C; And / or, the crystal form G, whose differential scanning calorimetry (DSC) chromatogram is at 150.82 ± 2 ppm. o The endothermic peak begins at point C, at 153.33±2. o The endothermic peak is reached at point C; And / or, the crystal form G, whose differential scanning calorimetry (DSC) chromatogram is at 230.69 ± 2 ppm. o The endothermic peak begins at point C, at 231.37±2. o The endothermic peak is reached at point C.

22. The crystal form as described in claim 21, characterized in that, The differential scanning calorimetry (DSC) chromatogram of the aforementioned crystal form C is 63.69 ± 2. o The endothermic peak begins at point C, at 82.10±2. o The endothermic peak is reached at point C, with an enthalpy of 61.396 J / g. And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form C is at 126.27 ± 2. o The endothermic peak begins at point C, at 134.20±2. o The endothermic peak is reached at point C, with an enthalpy of 42.089 J / g. And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form C is at 230.61 ± 2. o The endothermic peak begins at point C, at 231.73±2. o The endothermic peak is reached at point C, with an enthalpy of 103.46 J / g. And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form B is at 60.85 ± 2. o The endothermic peak begins at point C, at 72.84±2. o The endothermic peak is reached at point C, with an enthalpy of 32.752 J / g. And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form B is at 151.04 ± 2. o The endothermic peak begins at point C, at 153.19±2. o The endothermic peak is reached at point C, with an enthalpy of 4.135 J / g. And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form B is at 230.51 ± 2. o The endothermic peak begins at point C, at 231.37±2. o The endothermic peak is reached at point C, with an enthalpy of 113.950 J / g. And / or, the crystal form D, whose differential scanning calorimetry (DSC) chromatogram is at 231.13 ± 2 ppm. o The endothermic peak begins at point C, at 232.25±2. o The endothermic peak is reached at point C, with an enthalpy of 115.520 J / g. And / or, the crystal form E, whose differential scanning calorimetry chromatogram is at 48.59±2 o The endothermic peak begins at point C, at 51.08±2. o The endothermic peak is reached at point C, with an enthalpy of 5.451 J / g. And / or, the crystal form E, whose differential scanning calorimetry chromatogram is within 90.07±2 o The endothermic peak begins at point C, at 95.66±2. o The endothermic peak is reached at point C, with an enthalpy of 19.797 J / g. And / or, the crystal form E, whose differential scanning calorimetry chromatogram is at 225.15±2 o The endothermic peak begins at point C, at 228.25±2. o The endothermic peak is reached at point C, with an enthalpy of 86.445 J / g. And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form F is at 49.64 ± 2. o The endothermic peak begins at point C, at 52.43±2. o The endothermic peak is reached at point C, with an enthalpy of 3.400 J / g. And / or, the differential scanning calorimetry (DSC) chromatogram of crystal form F is within 97.99 ± 2 ppm. o The endothermic peak begins at point C, at 103.02±2. o The endothermic peak is reached at point C, with an enthalpy of 9.028 J / g. And / or, the crystal form F, whose differential scanning calorimetry chromatogram is at 225.07±2 o The endothermic peak begins at point C, at 226.71±2. o The endothermic peak is reached at point C, with an enthalpy of 92.201 J / g. And / or, the crystal form G, whose differential scanning calorimetry (DSC) chromatogram is at 63.20 ± 2 ppm. o The endothermic peak begins at point C, at 76.01±2. o The endothermic peak is reached at point C, with an enthalpy of 25.610 J / g. And / or, the crystal form G, whose differential scanning calorimetry (DSC) chromatogram is at 150.82 ± 2 ppm. o The endothermic peak begins at point C, at 153.33±2. o The endothermic peak is reached at point C, with an enthalpy of 12.882 J / g. And / or, the crystal form G, whose differential scanning calorimetry (DSC) chromatogram is at 230.69 ± 2 ppm. o The endothermic peak begins at point C, at 231.37±2. o The endothermic peak is reached at point C, with an enthalpy of 111.380 J / g.

23. The crystal form as described in claim 22, characterized in that, The differential scanning calorimetry analysis diagram of the crystal form C is shown in Figure 6; And / or, the thermogravimetric analysis diagram of the crystal form C is shown in Figure 6; And / or, the differential scanning calorimetry analysis diagram of the crystal form B is shown in Figure 4; And / or, the differential scanning calorimetry analysis diagram of the crystal form D is shown in Figure 8; And / or, the differential scanning calorimetry analysis diagram of the crystal form E is shown in Figure 10; And / or, the differential scanning calorimetry analysis diagram of the crystal form F is shown in Figure 12; And / or, the differential scanning calorimetry analysis diagram of the crystal form G is shown in Figure 14; And / or, the thermogravimetric analysis results of the crystal form B are shown in Figure 4; And / or, the thermogravimetric analysis diagram of the crystal form D is shown in Figure 8; And / or, the thermogravimetric analysis diagram of the crystal form E is shown in Figure 10; And / or, the thermogravimetric analysis diagram of the crystal form F is shown in Figure 12; And / or, the thermogravimetric analysis diagram of the crystal form G is shown in Figure 14.

24. A salt of a pentagonal compound as shown in Formula I, characterized in that, It is a hydrochloride, sulfate, phosphate, sodium salt, or potassium salt; 。 25. The salt of the pentagonal compound as shown in Formula I as described in claim 24, characterized in that, It meets one or more of the following conditions: (1) The hydrochloride salt is a hydrochloride salt; (2) The sulfate mentioned is a monosulfate; (3) The phosphate mentioned is a monophosphate; (4) The sodium salt is a monosodium salt; and (5) The potassium salt is a monopotassium salt.

26. The salt as claimed in claim 25, characterized in that, The salt satisfies one or more of the following conditions: (1) The hydrochloride is of crystal form A, which uses Cu-K Radiation, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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 is of crystal form B, which uses Cu-K Radiation, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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 crystal form A, which uses Cu-K Radiation, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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 crystal form B, which uses Cu-K Radiation, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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 it uses Cu-K Radiation, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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 crystal form A, which uses Cu-K Radiation, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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 crystal form B, which uses Cu-K Radiation, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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°. (8) The sodium salt is of crystal form A, which uses Cu-K Radiation, with 2 The X-ray powder diffraction pattern, expressed in angle, shows characteristic peaks at 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°; and (9) The potassium salt is of crystal form A, which uses Cu-K Radiation, with 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks 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°.

27. The salt as claimed in claim 26, characterized in that, The salt satisfies one or more of the following conditions: (1) In the crystal form A of the hydrochloride, it is in the form of 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more locations at 11.72±0.20°, 21.88±0.20°, 28.61±0.20°, and 31.26±0.20°. (2) In the crystal form B of the hydrochloride, it is in the form of 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more locations at 13.93±0.20°, 15.28±0.20°, 27.18±0.20°, and 28.99±0.20°. (3) In the sulfate crystal form A, it is 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more locations at 14.94±0.20°, 17.42±0.20°, 22.76±0.20°, and 26.46±0.20°. (4) In the sulfate crystal form B, it is 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more locations at 9.00±0.20°, 12.52±0.20°, 21.21±0.20°, and 22.36±0.20°. (5) In the crystal form C of the sulfate, it is in the form of 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more locations at 8.74±0.20°, 10.67±0.20°, 18.64±0.20°, and 19.05±0.20°. (6) In the crystal form A of the phosphate, it is in the form of 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more locations at 6.57±0.20°, 18.53±0.20°, 19.97±0.20°, 22.43±0.20°, and 27.18±0.20°. (7) In the crystal form B of the phosphate, it is in the form of 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more locations at 7.40±0.20°, 17.61±0.20°, 19.69±0.20°, and 24.93±0.20°. (8) In the sodium salt crystal form A, it is 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more locations at 9.78±0.20°, 14.20±0.20°, 18.81±0.20°, 19.97±0.20° and 24.13±0.20°. (9) In the potassium salt crystal form A, it is 2 The X-ray powder diffraction pattern, expressed in terms of angle, also shows characteristic peaks at one or more locations at 19.46±0.20°, 19.96±0.20°, 23.54±0.20°, and 27.92±0.20°.

28. The salt as claimed in claim 27, characterized in that, The salt satisfies one or more of the following conditions: (1) In the crystal form A of the hydrochloride, it is in the form of 2 The X-ray powder diffraction pattern, expressed in angle, shows characteristic peaks at 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) In the crystal form B of the hydrochloride, it is in the form of 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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) In the sulfate crystal form A, it is 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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) In the sulfate crystal form B, it is 2 The X-ray powder diffraction pattern, expressed in angle, shows characteristic peaks at 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) In the crystal form C of the sulfate, it is in the form of 2 The X-ray powder diffraction pattern, expressed in angle, shows characteristic peaks at 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) In the crystal form A of the phosphate, it is in the form of 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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) In the crystal form B of the phosphate, it is in the form of 2 The X-ray powder diffraction pattern, expressed in terms of angle, shows characteristic peaks at 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) In the sodium salt crystal form A, it is 2 The X-ray powder diffraction pattern, expressed in angle, shows characteristic peaks at 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°. (9) In the potassium salt crystal form A, it is 2 The X-ray powder diffraction pattern, expressed in angle, shows characteristic peaks 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°.

29. The salt as claimed in claim 26, characterized in that, The salt satisfies one or more of the following conditions: (1) In the crystal form A of the hydrochloride, the diffraction peaks of the crystal form A in the X-ray powder diffraction pattern represented by the 2θ angle are shown in the table below: ； (2) In the crystal form B of the hydrochloride, the diffraction peaks of the crystal form B in the X-ray powder diffraction pattern represented by the 2θ angle are shown in the table below: ； (3) In the crystal form A of the sulfate, the diffraction peaks of crystal form A expressed as 2θ angle are shown in the table below: ； (4) In the crystal form B of the sulfate, the diffraction peaks of the crystal form B, expressed as an angle of 2θ, are shown in the table below: ； (5) In the crystal form C of the sulfate, the diffraction peaks of the crystal form C represented by the 2θ angle are shown in the table below: ； (6) In the crystal form A of the phosphate, the diffraction peaks of crystal form A expressed in terms of 2θ angle are shown in the table below: ； (7) In the crystal form B of the phosphate, the diffraction peaks of the crystal form B, expressed in terms of 2θ angle, are shown in the table below: ； (8) In the crystal form A of the sodium salt, the diffraction peaks of crystal form A expressed in terms of 2θ angle are shown in the table below: ； (9) In the crystal form A of the potassium salt, the diffraction peaks of crystal form A expressed in terms of 2θ angle are shown in the table below: 。 30. The salt as claimed in claim 29, characterized in that, The salt satisfies one or more of the following conditions: (1) In the crystal form A of the hydrochloride, the diffraction peaks and relative intensities of the crystal form A expressed in terms of 2θ angle and relative intensity are shown in the table below: ； (2) In the crystal form B of the hydrochloride, the diffraction peaks and relative intensities of the crystal form B expressed in terms of 2θ angle and relative intensity are shown in the table below: ； (3) In the crystal form A of the sulfate, the diffraction peaks and relative intensities of the crystal form A expressed in terms of 2θ angle and relative intensity are shown in the table below: ； (4) In the crystal form B of the sulfate, the diffraction peaks and relative intensities of the crystal form B expressed in terms of 2θ angle and relative intensity are shown in the table below: ； (5) In the crystal form C of the sulfate, the diffraction peaks and relative intensities of the crystal form C expressed in terms of 2θ angle and relative intensity are shown in the table below: ； (6) In the crystal form A of the phosphate, the diffraction peaks and relative intensities of the crystal form A expressed in terms of 2θ angle and relative intensity are shown in the table below: ； (7) In the crystal form B of the phosphate, the diffraction peaks and relative intensities of the crystal form B expressed in terms of 2θ angle and relative intensity are shown in the table below: ； (8) In the crystal form A of the sodium salt, the diffraction peaks and relative intensities of the crystal form A expressed in terms of 2θ angle and relative intensity are shown in the table below: ； (9) In the crystal form A of the potassium salt, the diffraction peaks and relative intensities of the crystal form A expressed in terms of 2θ angle and relative intensity are shown in the table below: 。 31. The salt as described in claim 30, characterized in that, The salt satisfies one or more of the following conditions: (1) The crystal form A of the hydrochloride, its X-ray powder diffraction pattern (XRPD) is shown in Figure 17; (2) The crystal form B of the hydrochloride has an X-ray powder diffraction (XRPD) pattern as shown in Figure 19; (3) The crystal form A of the sulfate is shown in Figure 21 by X-ray powder diffraction (XRPD). (4) The crystal form B of the sulfate has an X-ray powder diffraction (XRPD) pattern as shown in Figure 23; (5) The crystal form C of the sulfate, its X-ray powder diffraction pattern (XRPD) is shown in Figure 25; (6) The crystal form A of the phosphate is shown in Figure 27 by X-ray powder diffraction (XRPD). (7) The crystal form B of the phosphate has an X-ray powder diffraction (XRPD) pattern as shown in Figure 29; (8) The crystal form A of the sodium salt, its X-ray powder diffraction pattern (XRPD) is shown in Figure 31; and (9) The crystal form A of the potassium salt has an X-ray powder diffraction (XRPD) pattern as shown in Figure 33.

32. The salt according to any one of claims 26-29, characterized in that, The salt satisfies one or more of the following conditions: (1) The crystal form A of the hydrochloride, its thermogravimetric analysis chromatogram is at 125.

06. o C weight loss 2.070%; the "%" is mass percentage; and / or, its differential scanning calorimetry chromatogram is at 184.04±2. o Point C is the starting point of the endothermic peak; (2) The crystal form B of the hydrochloride, its thermogravimetric analysis chromatogram is at 96.

43. o C weight loss 7.216%; the "%" is a mass percentage; and / or, its differential scanning calorimetry chromatogram is at 173.54±2 o Point C is the starting point of the endothermic peak; (3) The thermogravimetric analysis chromatogram of the sulfate crystal form A is at 118.

49. o C weight loss 3.880%; the "%" is mass percentage; and / or, its differential scanning calorimetry chromatogram is at 149.86±2 o Point C is the starting point of the endothermic peak; (4) The thermogravimetric analysis chromatogram of the sulfate crystal form B is at 92.

04. o C weight loss 6.895%; the "%" is a mass percentage; and / or, its differential scanning calorimetry chromatogram is at 126.34±2. o Point C is the starting point of the endothermic peak; (5) The crystalline form C of the sulfate, its thermogravimetric analysis chromatogram is at 102.

19. o C weight loss 10.471%; the "%" is mass percentage; and / or, its differential scanning calorimetry chromatogram is at 117.30±2 o Point C is the starting point of the endothermic peak; (6) The thermogravimetric analysis chromatogram of the phosphate crystal form A is at 142.

87. o C weight loss 0.776%; the "%" is mass percentage; and / or, its differential scanning calorimetry chromatogram is at 179.76±2 o Point C is the starting point of the endothermic peak; (7) The thermogravimetric analysis chromatogram of the phosphate crystal form B is at 74.

52. o C weight loss 1.071%; the "%" is mass percentage; and / or, its differential scanning calorimetry chromatogram is at 159.94±2 o Point C is the starting point of the endothermic peak; (8) The thermogravimetric analysis chromatogram of the sodium salt in crystal form A is at 116.

94. o C weight loss 6.279%; the "%" is mass percentage; and / or, its differential scanning calorimetry chromatogram is at 228.53±2 o Point C is the starting point of the endothermic peak; and (9) The thermogravimetric analysis chromatogram of the potassium salt in crystal form A is at 183.

95. o The weight loss was 8.352%; the percentage (%) is by mass; its differential scanning calorimetry (DSC) chromatogram was at 217.76 ± 2. o Point C is the starting point of the endothermic peak.

33. The salt as described in claim 32, characterized in that, The salt satisfies one or more of the following conditions: (1) The differential scanning calorimetry (DSC) chromatogram of the hydrochloride salt, crystal form A, is at 184.04 ± 2. o The endothermic peak begins at point C, at 188.62±2. o The endothermic peak is reached at point C; (2) The differential scanning calorimetry (DSC) chromatogram of the hydrochloride salt, crystal form B, is at 173.54 ± 2. o The endothermic peak begins at point C, at 184.54±2. o The endothermic peak is reached at point C; (3) The differential scanning calorimetry (DSC) chromatogram of the sulfate crystal form A is at 149.86 ± 2. o The endothermic peak begins at point C, at 160.23±2. o The endothermic peak is reached at point C; (4) The differential scanning calorimetry (DSC) chromatogram of the sulfate crystal form B is at 126.34 ± 2. o The endothermic peak begins at point C, at 139.98±2. o The endothermic peak is reached at point C; (5) The differential scanning calorimetry (DSC) chromatogram of the sulfate crystal form C is at 117.30 ± 2. o The endothermic peak begins at point C, at 122.26±2. o The endothermic peak is reached at point C; (6) The differential scanning calorimetry (DSC) chromatogram of the phosphate crystal form A is at 179.76 ± 2. o The endothermic peak begins at point C, at 180.61±2. o The endothermic peak is reached at point C; (7) The differential scanning calorimetry (DSC) chromatogram of the phosphate crystal form B is at 159.94 ± 2. o The endothermic peak begins at point C, at 169.82±2. o The endothermic peak is reached at point C; (8) The differential scanning calorimetry (DSC) chromatogram of the sodium salt in crystal form A is at 228.53 ± 2. o The endothermic peak begins at point C, at 230.66±2. o The endothermic peak is reached at point C; (9) The differential scanning calorimetry (DSC) chromatogram of the potassium salt in crystal form A is at 217.76 ± 2. o The endothermic peak begins at point C, at 222.51±2. o The endothermic peak is reached at point C.

34. The salt as described in claim 33, characterized in that, The salt satisfies one or more of the following conditions: (1) The differential scanning calorimetry (DSC) chromatogram of the hydrochloride salt, crystal form A, is at 184.04 ± 2. o The endothermic peak begins at point C, at 188.62±2. o The endothermic peak is reached at point C, with an enthalpy of 344.80 J / g. (2) The differential scanning calorimetry (DSC) chromatogram of the hydrochloride salt, crystal form B, is at 173.54 ± 2. o The endothermic peak begins at point C, at 184.54±2. o The endothermic peak is reached at point C, with an enthalpy of 259.36 J / g. (3) The differential scanning calorimetry (DSC) chromatogram of the sulfate crystal form A is at 149.86 ± 2. o The endothermic peak begins at point C, at 160.23±2. o The endothermic peak is reached at point C, with an enthalpy of 229.21 J / g. (4) The differential scanning calorimetry (DSC) chromatogram of the sulfate crystal form B is at 126.34 ± 2. o The endothermic peak begins at point C, at 139.98±2. o The endothermic peak is reached at point C, with an enthalpy of 230.50 J / g. (5) The differential scanning calorimetry (DSC) chromatogram of the sulfate crystal form C is at 117.30 ± 2. o The endothermic peak begins at point C, at 122.26±2. o The endothermic peak is reached at point C, with an enthalpy of 54.426 J / g. (6) The differential scanning calorimetry (DSC) chromatogram of the phosphate crystal form A is at 179.76 ± 2. o The endothermic peak begins at point C, at 180.61±2. o The endothermic peak is reached at point C, with an enthalpy of 265.82 J / g. (7) The differential scanning calorimetry (DSC) chromatogram of the phosphate crystal form B is at 159.94 ± 2. o The endothermic peak begins at point C, at 169.82±2. o The endothermic peak is reached at point C, with an enthalpy of 77.238 J / g. (8) The differential scanning calorimetry (DSC) chromatogram of the sodium salt in crystal form A is at 228.53 ± 2. o The endothermic peak begins at point C, at 230.66±2. o The endothermic peak is reached at point C, with an enthalpy of 107.61 J / g. (9) The differential scanning calorimetry (DSC) chromatogram of the potassium salt in crystal form A is at 217.76 ± 2. o The endothermic peak begins at point C, at 222.51±2. o The endothermic peak is reached at point C, with an enthalpy of 102.94 J / g.

35. The salt as described in claim 34, characterized in that, The salt satisfies one or more of the following conditions: (1) The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the crystal form A of the hydrochloride are shown in Figure 18; (2) The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the crystal form B of the hydrochloride are shown in Figure 20; (3) The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the sulfate crystal form A are shown in Figure 22; (4) The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the sulfate crystal form B are shown in Figure 24; (5) The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the sulfate crystal form C are shown in Figure 26; (6) The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the phosphate crystal form A are shown in Figure 28; (7) The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the phosphate B crystal form are shown in Figure 30; (8) The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the sodium salt crystal form A are shown in Figure 32; (9) The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the potassium salt crystal form A are shown in Figure 34.

36. A pharmaceutical composition, characterized in that, It comprises the crystal form of the pentagonal compound of Formula I as described in any one of claims 1-23, and pharmaceutical excipients.

37. A pharmaceutical composition, characterized in that, It comprises a pentagonal compound salt as shown in Formula I as described in any one of claims 24-35, and a pharmaceutical excipient.

38. The pharmaceutical composition of claim 37, characterized in that, It meets one or more of the following conditions: (1) The pharmaceutical excipients are selected from one or more of DMSO, Tween-80, polyethylene glycol 15-hydroxystearate and physiological saline; (2) The mass-to-volume ratio of the salt of the pentagonal compound shown in Formula I to the pharmaceutical excipient is 4:1 mg / mL.

39. The pharmaceutical composition of claim 37, characterized in that, The pharmaceutical excipients consist of 5% DMSO, 10% Tween-80, 5% polyethylene glycol 15-hydroxystearate and 80% physiological saline, where % is the volume ratio.

40. The use of substance Z or the pharmaceutical composition according to any one of claims 36-39 in the preparation of an FLT3 and / or IRAK4 inhibitor or a medicament for treating and / or preventing FLT3 and / or IRAK4-related diseases, characterized in that, The substance Z is a crystalline form of a pentagonal compound as shown in Formula I as described in any one of claims 1-23, or a pentagonal compound salt as shown in Formula I as described in any one of claims 24-35.

41. The application as described in claim 40, characterized in that, It meets one or more of the following conditions: (1) The FLT3-related diseases include hematologic malignancies and / or solid tumors; (2) The IRAK4-related diseases include autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, or central nervous system diseases.

42. The application as described in claim 41, characterized in that, It satisfies one or more of the following conditions: (1) The hematologic malignancy is selected from one or more of the following: acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, anaplastic large cell lymphoma, prolymphocytic leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, non-Hodgkin lymphoma, multiple myeloma, myeloproliferative disorders, mantle cell lymphoma, and new-onset acute myeloid leukemia in adults; (2) The solid tumor is selected from one or more of 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 selected from one or more of the following: rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes, psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis and irritable bowel syndrome; (4) The inflammatory disease is selected from one or more of the following: rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes, psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome; and (5) The cardiovascular disease mentioned is stroke or atherosclerosis.

43. The use of a substance Z in the preparation of a medicament, wherein the substance Z is a crystal form of a pentagonal compound of formula I as described in any one of claims 1-23 or a salt of a pentagonal compound of formula I as described in any one of claims 24-35; the medicament is used to treat and / or prevent one or more of hematologic malignancies, solid tumors, autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and central nervous system diseases.

44. The application as described in claim 43, characterized in that, It meets one or more of the following conditions: (1) The hematologic malignancy is selected from one or more of the following: acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, anaplastic large cell lymphoma, prolymphocytic leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, non-Hodgkin lymphoma, multiple myeloma, myeloproliferative disorders, mantle cell lymphoma, and new-onset acute myeloid leukemia in adults; (2) The solid tumor is selected from one or more of 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 selected from one or more of the following: rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes, psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis and irritable bowel syndrome; (4) The inflammatory disease is selected from one or more of the following: rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes, psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome; and (5) The cardiovascular disease mentioned is stroke or atherosclerosis.

45. A method for preparing the crystal form of a pentagonal compound as shown in Formula I according to any one of claims 1-23, characterized in that, The method for preparing crystal form A includes the following steps: adding a poor solvent to a solution of a pentagonal compound as shown in Formula I, and cooling to crystallize to obtain crystal form A; The method for preparing crystal form C includes the following steps: evaporating a suspension of a pentagonal compound as shown in Formula I to obtain crystal form C; When the crystal form is crystal form G, it includes the following operation: cooling a solution of a pentagonal compound as shown in Formula I to obtain the crystal form; wherein the solvent of the solution is an alcohol solvent.

46. ​​The method for preparing the crystal form of the pentagonal compound as shown in Formula I as described in claim 45, characterized in that, It meets one or more of the following conditions: (1) In the preparation method of crystal form A, the solvent of the solution of the five-membered and six-membered compound as shown in Formula I is a mixed solvent of sulfoxide solvent and alcohol solvent; (2) In the preparation method of crystal form A, the undesirable solvent is an alcohol solvent and / or water; (3) In the preparation method of crystal form A, in the solution of the five-membered hexa-membered compound as shown in Formula I, the mass-volume ratio of the five-membered hexa-membered compound as shown in Formula I to the solvent of the solution of the five-membered hexa-membered compound as shown in Formula I is 1: (1-10) g / mL. (4) In the preparation method of crystal form A, the volume ratio of the solution of the five-membered and six-membered compound as shown in Formula I to the undesirable solvent is (1-10):18.3; (5) In the preparation method of crystal form A, the temperature at which the undesirable solvent is added is 20-65℃; (6) In the preparation method of crystal form A, the cooling temperature of the solution is 30-70℃; (7) In the preparation method of crystal form A, the cooling rate is 5-15℃ / hour; (8) In the preparation method of crystal form A, the cooling time is 10-30 hours; (9) In the method for preparing crystal form C, the solvent of the suspension is a mixture of organic solvent and water; (10) In the preparation method of crystal form C, the mass-volume ratio of the five-membered and six-membered compound as shown in Formula I to the solvent in the suspension is (10-100):1 mg / mL; (11) In the preparation method of crystal form C, the volatilization temperature is room temperature; (12) In the preparation method of crystal form C, the volatilization time is 1-5 days; (13) In the preparation method of crystal form G, the alcohol solvent is methanol; (14) In the preparation method of crystal form G, the mass-volume ratio of the five-membered and six-membered compound as shown in Formula I to the alcohol solvent is (10-100):1 mg / mL; (15) In the preparation method of crystal form G, the temperature of the solution is 30-70℃; (16) In the method for preparing crystal form G, the cooling rate is 3-10 °C / hour; and (17) In the preparation method of crystal form G, the cooling time is 1-20 hours.

47. The method for preparing the crystal form of the pentagonal compound as shown in Formula I as described in claim 46, characterized in that, It meets one or more of the following conditions: (1) In the preparation method of crystal form A, the solvent of the solution of the five-membered and six-membered compound as shown in Formula I is a mixed solvent of sulfoxide solvent and alcohol solvent, wherein the sulfoxide solvent is dimethyl sulfoxide. (2) In the preparation method of crystal form A, the solvent of the solution of the five-membered and six-membered compound as shown in Formula I is a mixed solvent of sulfoxide solvent and alcohol solvent, wherein the alcohol solvent is ethanol and / or isopropanol. (3) In the preparation method of crystal form A, the solvent of the solution of the five-membered and six-membered compound as shown in Formula I is a mixed solvent of sulfoxide solvent and alcohol solvent, and the volume ratio of the sulfoxide solvent to the alcohol solvent is (1-5):

1. (4) In the preparation method of crystal form A, the undesirable solvent is ethanol and / or isopropanol; (5) In the preparation method of crystal form A, in the solution of the five-membered hexa-membered compound as shown in Formula I, the mass-volume ratio of the five-membered hexa-membered compound as shown in Formula I to the solvent of the solution of the five-membered hexa-membered compound as shown in Formula I is 1:5 g / mL. (6) In the preparation method of crystal form A, the volume ratio of the solution of the five-membered and six-membered compound as shown in Formula I to the undesirable solvent is 5:18.3; (7) In the preparation method of crystal form A, the temperature at which the undesirable solvent is added is 50°C; (8) In the preparation method of crystal form A, the cooling temperature of the solution is 30°C, 40°C, 50°C or 65°C; (9) In the method for preparing crystal form A, the cooling rate is 10℃ / hour; (10) In the method for preparing crystal form C, the solvent of the suspension is a mixture of an organic solvent and water, wherein the organic solvent is selected from one or more of alcohol solvents, ketone solvents and nitrile solvents; (11) In the preparation method of crystal form C, the solvent of the suspension is a mixture of organic solvent and water, and the volume ratio of organic solvent to water is 60:40~99:1; (12) In the preparation method of crystal form C, the mass-volume ratio of the five-membered and six-membered compound as shown in Formula I to the solvent in the suspension is 50:1 mg / mL. (13) In the method for preparing crystal form C, the volatilization time is 3 days; (14) In the preparation method of crystal form G, the mass-volume ratio of the five-membered and six-membered compound as shown in Formula I to the alcohol solvent is 50:1 mg / mL; (15) In the preparation method of crystal form G, the temperature of the solution is 40°C, 45°C, 50°C, 55°C, 60°C, 65°C or 70°C; (16) In the method for preparing crystal form G, the cooling rate is 5°C / hour; and (17) In the preparation method of crystal form G, the cooling time is 14 hours.

48. The method for preparing the crystal form of the pentagonal compound as shown in Formula I as described in claim 47, characterized in that, It meets one or more of the following conditions: (1) In the preparation method of crystal form A, the solvent of the solution of the five-membered and six-membered compound as shown in Formula I is a mixed solvent of sulfoxide solvent and alcohol solvent, and the volume ratio of the sulfoxide solvent to the alcohol solvent is 2:

1. (2) In the preparation method of crystal form C, the solvent of the suspension is a mixture of organic solvent and water, wherein the organic solvent is ethanol, acetone or acetonitrile; (3) In the preparation method of crystal form C, the solvent of the suspension is a mixture of organic solvent and water, and the volume ratio of organic solvent to water is 95:

5.

49. A compound as shown in Formula II-49-3, 。

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