Fused ring nitrogen-containing compound, crystal form thereof, preparation method therefor, and use thereof

Abstract

The present invention provides a fused ring nitrogen-containing compound, a crystal form thereof, a preparation method therefor, and use thereof. Specifically provided are a fused ring nitrogen-containing compound containing a compound represented by formula I and a crystal form thereof. The fused ring nitrogen-containing compound and the crystal form thereof provided by the present invention have good pharmaceutical activity and wide medicinal prospects.

Description

Cyclic nitrogen compounds, their crystal forms, preparation methods and uses

[0001] This application claims priority to Chinese patent application 202410500685X, filed on April 24, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to cyclic nitrogen-containing compounds, their crystal forms, preparation methods, and uses. Background Technology

[0003] DNA damage is a crucial mechanism by which many chemotherapeutic drugs exert their antitumor effects. Double-strand breaks (DSBs) are one of the most common types of cell damage, caused directly by ionizing radiation or induced by ultraviolet radiation, reactive oxygen species (ROS), or other mutagens, such as common chemotherapeutic drugs like cisplatin, 5-FU, and etoposide. Unrepaired DNA damage leads to the arrest of cellular functions such as transcription and replication, inducing apoptosis or necrosis, and is subsequently cleared by immune cells. Tumor cells possess highly efficient damage repair or alternative repair pathways. Targeting key proteins in these DNA damage repair pathways to allow unrepaired DNA damage to accumulate and ultimately lead to cell death is a key strategy in cancer treatment.

[0004] DNA double-strand breaks are typically repaired through three pathways: non-homologous end joining (NHEJ), homologous recombination (HR), and alternative non-homologous recombination end joining (Alt-NHEJ, also known as microhomological end joining (MMEJ) or TMEJ). The HR repair pathway occurs only during the G2 and S phases and is error-free in the presence of sister chromatids. In mammals, over 90% of DSB damage is repaired via the NHEJ pathway. It is an error-prone repair pathway, resulting in deletion mutations <30 bp, insertion mutations <5 bp, or microhomological sequences <2 bp. Recent research indicates that when HR and / or NHEJ are deficient, cells highly rely on the third pathway, MMEJ, to repair broken DNA. Inhibition of MMEJ leads to apoptosis. MMEJ is also an error-prone repair pathway that relies on the DNA polymerase theta-mediated end joining (TMEJ) to repair DNA double-strand breaks.

[0005] DNA polymerase theta (Pol theta, or Polθ) is a key protein in the MMEJ repair pathway. It is a unique multifunctional polymerase composed of an N-terminal helicase domain, a central domain, and a C-terminal polymerase domain. Basic research has revealed that the polymerase domain is essential for DNA elongation at the DSB damage repair site, while the helicase and central domains play a crucial role in the recognition and binding of Polθ to substrates. Polθ can deactivate the interaction between DNA and the damage repair complex (e.g., competitive binding of single-stranded DNA to RAD51), inhibiting the HR repair pathway. Furthermore, the helicase domain of Polθ is involved in DNA replication arrest; its loss of function leads to increased replication pressure in tumor cells, resulting in apoptosis.

[0006] Polθ is not expressed or is expressed at low levels in normal tissues and cells, but it is highly expressed in various tumors, including lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, and colon cancer, and is associated with poor prognosis. In particular, over 70% of breast cancers show Polθ overexpression. These phenomena suggest that Polθ may play an important role in these cancers and is a potential tumor-specific target.

[0007] Studies knocking down or knocking out Polθ in tumor cells have revealed that Polθ deficiency can sensitize these cells to radiation, induce DSB production, enhance replication fork instability, and sensitize tumor cells to genotoxic agents, potentially enhancing the efficacy of radiotherapy and chemotherapy, making it a potential drug target. Research has also found a combined lethal effect between Polθ and HR deficiency; its small-molecule inhibitors can kill HR-deficient tumor cells in vitro and in vivo. Particularly in HR-deficient reversion mutation-resistant tumors resistant to PARP inhibitors (such as Olaparib), Polθ inhibitors can resensitize cells to PARP inhibitors, providing valuable therapeutic opportunities. Furthermore, given that Polθ is a key protein in the MMEJ pathway, its functional deficiency can also lead to increased genomic instability in cancer cells, increasing somatic mutations and facilitating the production of neoantigens. In addition, Polθ has been reported to participate in cGAS-STING-mediated immune activation; therefore, targeting Polθ also has the potential to enhance immunotherapy.

[0008] In summary, Polθ is a highly promising target for cancer treatment. Designing ATPase activity inhibitors targeting the Polθ protein to inhibit intracellular MMEJ, and using them alone or in combination with other chemotherapy, radiotherapy, antibody therapy, immunotherapy, etc., can kill tumor cells and has great potential in the treatment of tumors such as lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, colon cancer, prostate cancer, and pancreatic cancer. Summary of the Invention

[0009] The technical problem to be solved by this invention is to overcome the deficiency of the limited variety of polymerase theta inhibitor compounds in the prior art. To this end, this invention provides cyclic nitrogen-containing compounds, their crystal forms, preparation methods, and uses. The cyclic nitrogen-containing compounds provided by this invention have good efficacy, stable crystal forms, and good drug-like properties.

[0010] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0011] This invention provides a compound represented by Formula II.

[0012] The structure of the compound shown in Formula II is as follows:

[0013] x' (solvent) is water or acetone;

[0014] q (molar equivalent of solvent) is 0.01-2.5.

[0015] Preferably, in the compound represented by Formula II, q (molar equivalent of solvent) is 0.1, 0.5, 0.56, 0.6, 1, 1.5, 2 or 2.5.

[0016] In one embodiment, the compound represented by Formula II is crystal form A of the compound represented by Formula II, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 9.00±0.2°, 10.84±0.2°, 17.91±0.2° and 22.05±0.2°.

[0017] In one embodiment, the crystal form A of the compound represented by Formula II, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, also exhibits diffraction peaks at one or more of the following locations: 5.98±0.2°, 11.94±0.2°, 18.36±0.2°, 21.30±0.2°, 23.29±0.2°, and 27.72±0.2°.

[0018] In one embodiment, the crystal form A of the compound represented by Formula II has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 9.00±0.2°, 10.84±0.2°, 17.91±0.2°, 22.05±0.2°, 5.98±0.2°, 11.94±0.2°, 18.36±0.2°, 21.30±0.2°, and 23.29±0.2°.

[0019] In one embodiment, the crystal form A of the compound represented by Formula II, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ, further exhibits diffraction peaks at one or more of the following locations: 13.46±0.2°, 14.16±0.2°, 14.72±0.2°, 19.99±0.2°, 20.65±0.2°, 24.6±0.2°, 25.62±0.2°, 28.96±0.2°, 29.68±0.2°, 30.29±0.2°, and 31.08±0.2°.

[0020] In one embodiment, the crystal form A of the compound represented by Formula II has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 1.

[0021] In one embodiment, the crystal form A of the compound represented by Formula II has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 1.

[0022] In one embodiment, the differential scanning calorimetry (DSC) curve of the compound represented by Formula II, in crystal form A, has endothermic peaks at peak temperatures of 98.33±3℃ and 206.94±3℃.

[0023] In one embodiment, the differential scanning calorimetry (DSC) curve of crystal form A of the compound represented by Formula II is basically as shown in Figure 2.

[0024] In one embodiment, the crystal form A of the compound represented by Formula II exhibits a weight loss of approximately 0.48% in the temperature range of 34.7±3℃ to 70.0±3℃, approximately 2.11% in the temperature range of 70.0±3℃ to 95.0±3℃, approximately 1.38% in the temperature range of 95.0±3℃ to 140.0±3℃, and approximately 0.34% in the temperature range of 140.0±3℃ to 220.0±3℃.

[0025] In one embodiment, the thermogravimetric analysis (TGA) curve of crystal form A of the compound represented by Formula II is basically as shown in Figure 3.

[0026] In one embodiment, in crystal form A of the compound represented by Formula II, x' is water and q is 1.

[0027] The present invention provides a crystal form C of the compound shown in Formula I, which has diffraction peaks at 11.51±0.2°, 18.01±0.2°, 22.56±0.2° and 25.68±0.2° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0028] In one embodiment, the crystal form C of the compound represented by Formula I has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ, which also has diffraction peaks at one or more of the following locations: 12.88±0.2°, 15.05±0.2°, 20.85±0.2°, 21.68±0.2°, 23.11±0.2°, and 24.79±0.2°.

[0029] Preferably, in the crystal form C of the compound shown in Formula I, the strongest diffraction peak is found at 11.51 ± 0.2° in the X-ray powder diffraction pattern expressed as 2θ angle using Cu-Kα radiation.

[0030] In one embodiment, the crystal form C of the compound represented by Formula I has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 11.51±0.2°, 18.01±0.2°, 22.56±0.2°, 25.68±0.2°, 12.88±0.2°, 15.05±0.2°, 20.85±0.2°, 21.68±0.2°, and 23.11±0.2°.

[0031] In one embodiment, the crystal form C of the compound represented by Formula I, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, further exhibits diffraction peaks at one or more of the following locations: 9.022±0.2°, 10.212±0.2°, 16.163±0.2°, 16.96±0.2°, 17.22±0.2°, 26.937±0.2°, 29.445±0.2°, 30.137±0.2°, and 30.354±0.2°.

[0032] In one embodiment, the crystal form C of the compound represented by Formula I has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 2.

[0033] In one embodiment, the crystal form C of the compound represented by Formula I has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 4.

[0034] In one embodiment, the differential scanning calorimetry (DSC) curve of the compound represented by Formula I, crystal form C, has an endothermic peak at a peak temperature of 238.92 ± 3 °C.

[0035] In one embodiment, the differential scanning calorimetry (DSC) curve of crystal form C of the compound represented by Formula I is basically as shown in Figure 5.

[0036] In one embodiment, the crystal form C of the compound represented by Formula I exhibits a weight loss of approximately 0.81% in the temperature range of 35.56±3℃ to 230.00±3℃ according to thermogravimetric analysis (TGA).

[0037] In one embodiment, the thermogravimetric analysis (TGA) curve of crystal form C of the compound represented by Formula I is basically as shown in Figure 6.

[0038] In one embodiment, the crystal form C of the compound represented by Formula I is solvent-free.

[0039] This invention provides a compound represented by formula IX.

[0040] Wherein, d (molar equivalent of p-toluenesulfonic acid) is 1-2;

[0041] g (solvent) is water, tetrahydrofuran, isopropanol, 1,4-dioxane or methyl tert-butyl ether;

[0042] h is (solvent molar equivalent) 0-3.

[0043] In one embodiment, in the compound represented by Formula IX, d is 1, 1.1, 1.2, 1.02, or 1.5.

[0044] In one embodiment, h is 0 (solvent-free) in the compound represented by formula IX.

[0045] In one embodiment, in the compound represented by Formula IX, h is 0.1-3. For example, if g is water, h is 3; if g is tetrahydrofuran, h is 0.2, 0.1, or 0.16; if g is isopropanol, h is 0.9, 0.98, or 1; if g is 1,4-dioxane, h is 3, 2.96, or 2.9; if g is methyl tert-butyl ether, h is 0.4, 0.45, or 0.5.

[0046] In one embodiment, the compound represented by Formula IX is crystal form A of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 5.96±0.2°, 16.71±0.2°, 17.79±0.2°, 20.33±0.2°, and 24.66±0.2°.

[0047] In one embodiment, the crystal form A of the compound represented by Formula IX, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, also exhibits diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern: 10.57±0.2°, 12.34±0.2°, 12.77±0.2°, 14.06±0.2°, 14.40±0.2°, 14.97±0.2°, 19.88±0.2°, 22.64±0.2°, 23.18±0.2°, and 24.22±0.2°.

[0048] In one embodiment, the crystal form A of the compound pair represented by Formula IX has X-ray powder diffraction patterns using Cu-Kα radiation, expressed in 2θ angles, with diffraction peaks at 5.96±0.2°, 16.71±0.2°, 17.79±0.2°, 20.33±0.2°, 24.66±0.2°, 10.57±0.2°, 12.34±0.2°, 12.77±0.2°, 14.06±0.2°, 14.40±0.2°, and 14.97±0.2°.

[0049] In one embodiment, the crystal form A of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ, further exhibits diffraction peaks at one or more of the following locations: 9.93±0.2°, 10.13±0.2°, 11.03±0.2°, 11.88±0.2°, 17.56±0.2°, 18.41±0.2°, 18.70±0.2°, 20.68±0.2°, 22.11±0.2°, 25.43±0.2°, 25.98±0.2°, 27.35±0.2°, 27.52±0.2°, 28.08±0.2°, and 29.17±0.2°.

[0050] In one embodiment, the crystal form A of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 3.

[0051] In one embodiment, the crystal form A of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 7.

[0052] In one embodiment, the differential scanning calorimetry (DSC) curve of the compound represented by Formula IX, in crystal form A, has endothermic peaks at peak temperatures of 95.83±3℃ and 194.7±3℃.

[0053] In one embodiment, the differential scanning calorimetry (DSC) curve of crystal form A of the compound represented by formula IX is basically as shown in Figure 8.

[0054] In one embodiment, the crystal form A of the compound represented by Formula IX exhibits a weight loss of approximately 2.03% in the temperature range of 30.52±3℃ to 60.0±3℃, approximately 5.13% in the temperature range of 60.0±3℃ to 100.0±3℃, and approximately 0.5% in the temperature range of 100.0±3℃ to 190.0±3℃.

[0055] In one embodiment, the thermogravimetric analysis (TGA) curve of crystal form A of the compound represented by formula IX is basically as shown in Figure 9.

[0056] In one embodiment, in crystal form A of the compound represented by formula IX, g is water, d is 1, and h is 3.

[0057] In one embodiment, the compound represented by formula IX is a single crystal of the compound represented by formula IX, wherein...

[0058] g represents water, h represents 3, and d represents 1;

[0059] It has the following unit cell parameters: Triclinic system, space group p-1; α = 89.299(7)°, β=86.519(6)°, γ=84.364(6)°, The number of asymmetric units within the unit cell is Z = 2, and the crystal density is 1.46 mg / m³. 3 .

[0060] In one embodiment, the compound represented by Formula IX is crystal form B of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 5.34±0.2°, 9.34±0.2°, 9.92±0.2°, 12.84±0.2°, and 16.61±0.2°.

[0061] In one embodiment, the crystal form B of the compound represented by Formula IX, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, also exhibits diffraction peaks at one or more of the following locations: 8.20±0.2°, 10.13±0.2°, 11.12±0.2°, 13.18±0.2°, 16.13±0.2°, 18.67±0.2°, 19.47±0.2°, and 19.85±0.2°.

[0062] In one embodiment, the crystal form B of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.34±0.2°, 9.34±0.2°, 9.92±0.2°, 12.84±0.2°, 16.61±0.2°, 8.20±0.2°, 10.13±0.2°, 13.18±0.2°, and 16.13±0.2°.

[0063] In one embodiment, the crystal form B of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further exhibits diffraction peaks at one or more of the following locations: 11.47±0.2°, 16.36±0.2°, 18.60±0.2°, and 21.53±0.2°.

[0064] In one embodiment, the crystal form B of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 4.

[0065] In one embodiment, the crystal form B of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 11.

[0066] In one embodiment, in crystal form B of the compound represented by formula IX, d is 1.

[0067] In one embodiment, in crystal form B of the compound represented by formula IX, h is 0.

[0068] In one embodiment, the compound represented by Formula IX is crystal form C of the compound represented by Formula IX, and its X-ray powder diffraction pattern, radiated by Cu-Kα radiation and expressed in 2θ angle, shows diffraction peaks at 5.23±0.2° and 19.82±0.2°.

[0069] In one embodiment, the crystal form C of the compound represented by Formula IX, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, also exhibits diffraction peaks at one or more of the following locations: 9.21±0.2°, 16.11±0.2°, 16.57±0.2°, 19.39±0.2°, and 20.01±0.2°.

[0070] Preferably, the crystal form C of the compound represented by Formula IX has a relative intensity of 60%-100% for its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation, and is more preferably 70%-80%, for example 71.2%, at a diffraction peak at 19.82±0.2°.

[0071] In one embodiment, the crystal form C of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.23±0.2°, 19.82±0.2°, 9.21±0.2°, 16.11±0.2°, 16.57±0.2°, 19.39±0.2°, 9.80±0.2°, 11.12±0.2°, and 20.01±0.2°.

[0072] In one embodiment, the crystal form C of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ, further exhibits diffraction peaks at one or more of the following locations: 8.07±0.2°, 8.26±0.2°, 9.80±0.2°, 11.12±0.2°, 12.72±0.2°, 15.24±0.2°, 15.48±0.2°, 18.20±0.2°, 18.71±0.2°, 21.52±0.2°, 23.51±0.2°, and 23.83±0.2°.

[0073] In one embodiment, the crystal form C of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 5, obtained by Cu-Kα radiation.

[0074] In one embodiment, the crystal form C of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 12.

[0075] In one embodiment, the crystal form C and d of the compound represented by Formula IX is 1, 1.1, or 1.02, for example, 1.02.

[0076] In one embodiment, the crystal form C of the compound represented by Formula IX is tetrahydrofuran, g is 1, and h is 0.2; or g is tetrahydrofuran, d is 1.02, and h is 0.16; or d is 1 and h is 0.

[0077] In one embodiment, the compound represented by Formula IX is crystal form D of the compound represented by Formula IX, and its X-ray powder diffraction pattern, radiated by Cu-Kα radiation and expressed in 2θ angle, shows diffraction peaks at 6.13±0.2°, 10.87±0.2°, and 18.38±0.2°.

[0078] In one embodiment, the crystal form D of the compound represented by Formula IX, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, also exhibits diffraction peaks at one or more of the following locations: 8.52±0.2°, 12.18±0.2°, 13.12±0.2°, 16.60±0.2°, 20.07±0.2°, and 24.00±0.2°.

[0079] Preferably, the crystal form D of the compound shown in Formula IX has a relative intensity of 80%-100% for its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation, with the diffraction peak at 6.13±0.2°, and preferably the diffraction peak at 6.13±0.2° is the strongest peak.

[0080] In one embodiment, the crystal form D of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.13±0.2°, 10.87±0.2°, 18.38±0.2°, 8.52±0.2°, 12.18±0.2°, 13.12±0.2°, 16.60±0.2°, 20.07±0.2°, and 24.00±0.2°.

[0081] In one embodiment, the crystal form D of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ, further exhibits diffraction peaks at one or more of the following locations: 14.25±0.2°, 14.42±0.2°, 17.00±0.2°, 19.09±0.2°, 19.34±0.2°, 21.12±0.2°, 21.28±0.2°, 21.59±0.2°, 21.72±0.2°, 23.14±0.2°, and 24.27±0.2°.

[0082] In one embodiment, the crystal form D of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 6.

[0083] In one embodiment, the crystal form D of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 13.

[0084] In one embodiment, the crystal form D of the compound represented by Formula IX is 1 / 3.

[0085] In one embodiment, the crystal form D of the compound represented by Formula IX is D, g is water, d is 1, and h is 0, 1, or 3.

[0086] In one embodiment, the compound represented by Formula IX is crystal form E of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 5.66±0.2°, 11.50±0.2°, 17.97±0.2°, 19.83±0.2°, 23.95±0.2°, and 26.58±0.2°.

[0087] In one embodiment, the crystal form E of the compound represented by Formula IX, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, also exhibits diffraction peaks at one or more of the following locations: 13.85±0.2°, 14.30±0.2°, 17.74±0.2°, 19.04±0.2°, 21.93±0.2°, 22.25±0.2°, 23.08±0.2°, and 23.43±0.2°.

[0088] In one embodiment, the crystal form E of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.66±0.2°, 11.50±0.2°, 17.97±0.2°, 19.83±0.2°, 23.95±0.2°, 13.85±0.2°, 14.30±0.2°, 17.74±0.2°, 19.04±0.2°, and 21.93±0.2°.

[0089] In one embodiment, the crystal form E of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ, further exhibits diffraction peaks at one or more of the following locations: 8.45±0.2°, 9.02±0.2°, 9.84±0.2°, 11.19±0.2°, 12.70±0.2°, 15.59±0.2°, 16.56±0.2°, 16.93±0.2°, 18.75±0.2°, 20.55±0.2°, 25.05±0.2°, and 26.98±0.2°.

[0090] In one embodiment, the crystal form E of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in 2θ angles, with the diffraction peaks shown in Table 7.

[0091] In one embodiment, the crystal form E of the compound represented by formula IX is shown in Figure 14 using Cu-Kα radiation and X-ray powder diffraction patterns.

[0092] In one embodiment, the differential scanning calorimetry (DSC) curve of the compound represented by Formula IX, in crystal form E, has endothermic peaks at peak temperatures of 102.94±3℃ and 183.71±3℃.

[0093] In one embodiment, the differential scanning calorimetry (DSC) curve of crystal form E of the compound represented by formula IX is basically as shown in Figure 15.

[0094] In one embodiment, the crystal form E of the compound represented by Formula IX exhibits a weight loss of approximately 3.11% in the temperature range of 33.06±3℃ to 55.0±3℃, approximately 3.82% in the temperature range of 55.0±3℃ to 120.0±3℃, and approximately 1.21% in the temperature range of 120.0±3℃ to 190.0±3℃.

[0095] In one embodiment, the thermogravimetric analysis (TGA) curve of crystal form E of the compound represented by formula IX is basically as shown in Figure 16.

[0096] In one embodiment, the crystal form E, d of the compound represented by Formula IX is 1, 1.1, or 1.02, for example, 1.02.

[0097] In one embodiment, in the crystal form E of the compound represented by Formula IX, d is 1, g is isopropanol, and h is 1; or, d is 1.02, g is isopropanol, and h is 0.98.

[0098] In one embodiment, the compound represented by Formula IX is crystal form F of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 6.15±0.2°, 16.55±0.2°, 17.30±0.2° and 21.48±0.2°.

[0099] In one embodiment, the crystal form F of the compound represented by Formula IX, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, also exhibits diffraction peaks at one or more of the following locations: 10.34±0.2°, 15.73±0.2°, 16.34±0.2°, 20.42±0.2°, 20.72±0.2°, 24.34±0.2°, and 25.74±0.2°.

[0100] In one embodiment, the crystal form F of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.15±0.2°, 16.55±0.2°, 17.30±0.2°, 21.48±0.2°, 10.34±0.2°, 15.73±0.2°, 16.34±0.2°, 20.42±0.2°, and 20.72±0.2°.

[0101] In one embodiment, the crystal form F of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ, further exhibits diffraction peaks at one or more of the following locations: 6.99±0.2°, 11.85±0.2°, 12.27±0.2°, 12.57±0.2°, 13.97±0.2°, 18.42±0.2°, 20.98±0.2°, 21.22±0.2°, 21.83±0.2°, 21.97±0.2°, 26.02±0.2°, and 26.83±0.2°.

[0102] In one embodiment, the crystal form F of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 8.

[0103] In one embodiment, the crystal form F of the compound represented by formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 17.

[0104] In one embodiment, the crystal form F of the compound represented by Formula IX has an endothermic peak at a peak temperature of 266.84 ± 3 °C in its differential scanning calorimetry (DSC) curve.

[0105] In one embodiment, the differential scanning calorimetry (DSC) curve of crystal form F of the compound represented by formula IX is basically as shown in Figure 18.

[0106] In one embodiment, the crystal form F of the compound represented by Formula IX exhibits a weight loss of approximately 2.2% in the temperature range of 34.19±3℃ to 260.0±3℃ according to thermogravimetric analysis (TGA).

[0107] In one scheme, the thermogravimetric analysis (TGA) curve of crystal form F of the compound represented by formula IX is basically as shown in Figure 19.

[0108] In one embodiment, in the crystal form F of the compound represented by Formula IX, d is 1, 1.1, or 1.02, for example, 1.02.

[0109] In one embodiment, in the crystal form F of the compound represented by formula IX, d is 1 and h is 0.

[0110] In one embodiment, the compound represented by Formula IX is crystal form G of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 7.65±0.2°, 13.76±0.2°, 20.35±0.2°, 21.01±0.2°, and 21.57±0.2°.

[0111] g is 1,4-dioxane.

[0112] In one scheme, the crystal form G of the compound shown in Formula IX has a Cu-Kα radiation X-ray powder diffraction pattern expressed in 2θ angles with one or more diffraction peaks at the following locations: 23.83±0.2°, 25.37±0.2°, 25.63±0.2° and 27.60±0.2°.

[0113] In one scheme, the crystal form G of the compound shown in Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 7.65±0.2°, 13.76±0.2°, 20.35±0.2°, 21.01±0.2°, 21.57±0.2°, 23.83±0.2°, 25.37±0.2°, 25.63±0.2°, and 27.60±0.2°.

[0114] In one scheme, the crystal form G of the compound shown in Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further exhibits diffraction peaks at one or more of the following locations: 11.87±0.2°, 12.60±0.2°, 12.76±0.2°, 16.07±0.2°, 20.05±0.2°, 22.75±0.2°, and 23.83±0.2°.

[0115] In one scheme, the crystal form G of the compound represented by Formula IX has X-ray powder diffraction patterns using Cu-Kα radiation and expressed in 2θ angles, which show the diffraction peaks as shown in Table 9.

[0116] In one scheme, the crystal form G of the compound represented by formula IX is basically shown in Figure 20 using Cu-Kα radiation and X-ray powder diffraction patterns.

[0117] In one scheme, in the crystal form G of the compound represented by Formula IX, d is 1, 1.1, or 1.2, for example, 1.1.

[0118] In one scheme, in the crystal form G of the compound represented by Formula IX, d is 1, g is 1,4-dioxane, and h is 3, or d is 1.1, g is 1,4-dioxane, and h is 2.96.

[0119] In one embodiment, the compound represented by Formula IX is crystal form H of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 8.27±0.2°, 9.70±0.2°, 16.55±0.2° and 19.78±0.2°.

[0120] g represents methyl tert-butyl ether.

[0121] In one embodiment, the crystal form H of the compound represented by Formula IX, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, also exhibits diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern: 10.39±0.2°, 11.07±0.2°, 11.60±0.2°, 12.56±0.2°, 17.07±0.2°, 19.09±0.2°, 21.12±0.2°, 21.46±0.2°, 25.23±0.2°, and 27.27±0.2°.

[0122] In one embodiment, the crystal form H of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 8.27±0.2°, 9.70±0.2°, 16.55±0.2°, 19.78±0.2°, 11.07±0.2°, 12.56±0.2°, 17.07±0.2°, 19.09±0.2°, and 21.46±0.2°.

[0123] In one embodiment, the crystal form H of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further exhibits diffraction peaks at one or more of the following locations: 5.21±0.2°, 11.60±0.2°, 15.29±0.2°, 18.79±0.2°, and 23.36±0.2°.

[0124] In one embodiment, the crystal form H of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in 2θ angles, with the diffraction peaks shown in Table 10.

[0125] In one embodiment, the crystal form H of the compound represented by formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 21.

[0126] In one embodiment, the differential scanning calorimetry (DSC) curve of the compound represented by Formula IX, in crystal form H, exhibits endothermic peaks at peak temperatures of 45.53±3℃, 155.23±3℃, and 191.45±3℃.

[0127] In one embodiment, the differential scanning calorimetry (DSC) curve of crystal form H of the compound represented by formula IX is basically as shown in Figure 22.

[0128] In one embodiment, the crystal form H of the compound represented by Formula IX exhibits a weight loss of approximately 1.74% in the temperature range of 32.99±3℃ to 100.0±3℃ and a weight loss of approximately 5.38% in the temperature range of 100.0±3℃ to 180.0±3℃.

[0129] In one scheme, the thermogravimetric analysis (TGA) curve of crystal form H of the compound represented by formula IX is basically as shown in Figure 23.

[0130] In one embodiment, the crystal form H of the compound represented by Formula IX, g is methyl tert-butyl ether, and h is 0.5, 0.4, or 0.45, for example, 0.45.

[0131] In one embodiment, the crystal form H and d of the compound represented by Formula IX is 1:1 (i.e., 1).

[0132] In one embodiment, the crystal form H of the compound represented by Formula IX, g is methyl tert-butyl ether, h is 0.5, and d is 1.

[0133] In one embodiment, the compound represented by Formula IX is crystal form I of the compound represented by Formula IX, and its X-ray powder diffraction pattern, radiated by Cu-Kα radiation and expressed in 2θ angle, shows diffraction peaks at 6.01±0.2°, 10.63±0.2°, and 12.79±0.2°.

[0134] In one embodiment, the crystal form I of the compound represented by Formula IX, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, also exhibits diffraction peaks at one or more of the following locations: 14.20±0.2°, 16.67±0.2°, 18.00±0.2°, 18.74±0.2°, 20.07±0.2°, and 24.06±0.2°.

[0135] Preferably, the crystal form I of the compound represented by Formula IX has a relative intensity of 80%-100% for its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation, with the diffraction peak at 6.01±0.2° being the strongest peak.

[0136] In one embodiment, the crystal form I of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.01±0.2°, 10.63±0.2°, 12.79±0.2°, 14.20±0.2°, 16.67±0.2°, 18.00±0.2°, 20.07±0.2°, and 24.06±0.2°.

[0137] In one embodiment, the crystal form I of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further exhibits diffraction peaks at one or more of the following locations: 11.99±0.2°, 17.84±0.2°, and 23.22±0.2°.

[0138] In one embodiment, the crystal form I of the compound represented by Formula IX has X-ray powder diffraction patterns using Cu-Kα radiation and expressed at 2θ angles, which show the diffraction peaks as shown in Table 11.

[0139] In one embodiment, the crystal form I of the compound represented by formula IX is shown in Figure 24 using Cu-Kα radiation and X-ray powder diffraction patterns.

[0140] In one embodiment, the crystal form I of the compound represented by formula IX has a d of 1.

[0141] In one embodiment, in crystal form I of the compound represented by formula IX, h is 0.

[0142] In one embodiment, in crystal form I of the compound represented by formula IX, d is 1 and h is 0.

[0143] In one embodiment, the compound represented by Formula IX is crystal form J of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 5.27±0.2°, 8.18±0.2°, 9.72±0.2°, 10.54±0.2°, 11.06±0.2°, 12.44±0.2°, 18.79±0.2°, and 20.21±0.2°.

[0144] In one embodiment, the crystal form J of the compound represented by Formula IX, when subjected to Cu-Kα radiation and expressed at an angle of 2θ, also exhibits diffraction peaks at one or more of the following locations: 15.30±0.2°, 16.41±0.2°, 18.79±0.2°, 19.07±0.2°, 19.66±0.2°, and 21.25±0.2°.

[0145] In one embodiment, the crystal form J of the compound represented by Formula IX has X-ray powder diffraction patterns using Cu-Kα radiation and expressed at 2θ angles, which show the diffraction peaks as shown in Table 12.

[0146] In one embodiment, the crystal form J of the compound represented by formula IX is shown in Figure 25 using Cu-Kα radiation and X-ray powder diffraction patterns.

[0147] In one embodiment, the crystal form J of the compound represented by formula IX is 1.

[0148] In one embodiment, the crystal form J of the compound represented by formula IX has d = 1 and h = 0.

[0149] The present invention provides a method for preparing the compound shown in Formula II, comprising the following steps: reacting the compound shown in Formula II (e.g., crystal form A of the compound shown in Formula II) with a mixed solvent of a ketone solvent (e.g., acetone) and water to obtain the compound shown in Formula II. Preferably, the mixed solvent of the ketone solvent (e.g., acetone) and water is a mixed solution of acetone and water with a volume ratio of 19:1 (acetone / water).

[0150] The present invention provides a method for preparing the compound shown in Formula IX, comprising the following steps: in a ketone solvent (e.g., acetone) and water, and a nitrile solvent (e.g., acetonitrile), the compound shown in Formula I and p-toluenesulfonic acid are subjected to a salt-forming reaction to obtain the compound shown in Formula IX. Preferably, the mixed solvent of the ketone solvent (e.g., acetone) and water is a mixed solution of acetone and water with a volume ratio of 19:1 (acetone / water).

[0151] Alternatively, the compound of Formula IX can be mixed with a solvent and dried to obtain the compound of Formula IX; the solvent is one or more of the following: ether solvents (e.g., tetrahydrofuran, 1,4-dioxane or methyl tert-butyl ether), alcohol solvents (e.g., isopropanol), and nitrile solvents (e.g., acetonitrile).

[0152] The present invention provides a method for preparing crystal form C of the compound shown in Formula I, crystal form A of the compound shown in Formula IX, and crystal form B of the compound shown in Formula IX, comprising the following steps: cooling a mixture of the compound and a solvent to crystallize, drying, and obtaining the crystal form;

[0153] in,

[0154] The compound is the compound shown in Formula II, and the solvent is ethyl acetate or acetonitrile, to obtain the crystal form C of the compound shown in Formula I;

[0155] The compound is the compound shown in Formula IX, and the solution is a mixture of acetone and water to obtain crystal form A of the compound shown in Formula IX;

[0156] The compound is the compound shown in Formula IX, and the solution is acetonitrile, yielding crystal form B of the compound shown in Formula IX.

[0157] The present invention provides a method for preparing crystal forms C, E, F, G and H of the compound shown in Formula IX, which includes the following steps: drying and crystallizing a mixture of the compound and a solvent to obtain the crystal forms;

[0158] The compound is the compound shown in Formula IX (preferably crystal form A of the compound shown in Formula IX), and the solution is tetrahydrofuran to obtain crystal form C of the compound shown in Formula IX.

[0159] The compound is the compound shown in Formula IX (preferably crystal form A of the compound shown in Formula IX), and the solution is isopropanol, to obtain crystal form E of the compound shown in Formula IX;

[0160] The compound is the compound shown in Formula IX (preferably crystal form A of the compound shown in Formula IX), and the solution is acetonitrile and n-heptane to obtain crystal form F of the compound shown in Formula IX;

[0161] The compound is the compound shown in Formula IX (preferably crystal form A of the compound shown in Formula IX), and the solution is 1,4-dioxane to obtain crystal form G of the compound shown in Formula IX;

[0162] The compound is the compound shown in Formula IX (preferably crystal form A of the compound shown in Formula IX), and the solution is a mixed solution of acetonitrile and methyl tert-butyl ether to obtain crystal form H of the compound shown in Formula IX.

[0163] In the preparation method, the cooling crystallization is, for example, cooling from 50°C to 25°C.

[0164] In the preparation method, the acetone and water mixture can be a volume ratio of 19:1 (acetone / water) acetone and water mixture.

[0165] In the preparation method, the drying is, for example, centrifugal drying and / or vacuum drying.

[0166] Preferably, the method for preparing crystal form C of the compound shown in Formula I includes the following steps: crystallizing crystal form A of the compound shown in Formula II with a mixture of ethyl acetate or acetonitrile (e.g., a suspension) to obtain crystal form C of the compound shown in Formula I.

[0167] In one embodiment, the crystallization of the compound represented by Formula I in the preparation method of crystal form C is performed by cooling crystallization (e.g., cooling from 50°C to 25°C) and drying (e.g., centrifugation and / or vacuum drying).

[0168] Preferably, the method for preparing crystal form A of the compound shown in Formula IX and crystal form B of the compound shown in Formula IX includes the following steps: crystallizing a mixture of the compound shown in Formula I, a solvent, and an acid to obtain the crystal form;

[0169] in,

[0170] The solution is a mixture of acetone and water, and the acid is p-toluenesulfonic acid, to obtain crystal form A of the compound shown in Formula IX;

[0171] The solution is acetonitrile, and the acid is p-toluenesulfonic acid, yielding crystal form B of the compound shown in Formula IX.

[0172] Preferably, in the preparation method, the crystallization is performed by cooling crystallization (e.g., cooling from 50°C to 25°C) and drying (e.g., vacuum drying).

[0173] Preferably, in the preparation method, the acetone and water mixture is a volume ratio of 19:1 (acetone / water) of acetone and water.

[0174] Preferably, the method for preparing crystal forms C, E, F, G, and H of the compound represented by Formula IX includes the following steps: crystallizing a mixture of crystal form A of the compound represented by Formula IX and a solvent;

[0175] The solution is tetrahydrofuran, yielding crystal form C of the compound shown in Formula IX;

[0176] The solution is isopropanol, yielding crystal form E of the compound shown in Formula IX;

[0177] The solution is acetonitrile and n-heptane, yielding crystal form F of the compound shown in Formula IX;

[0178] The solution is 1,4-dioxane, yielding crystal form G of the compound shown in Formula IX;

[0179] The solution is a mixture of acetonitrile and methyl tert-butyl ether (e.g., a mixture of acetonitrile and methyl tert-butyl ether in a volume ratio of 1:4), yielding the crystal form H of the compound shown in Formula IX.

[0180] In one embodiment, the crystallization in the preparation method is dry crystallization (e.g., vacuum drying at 50°C).

[0181] In one embodiment, during the preparation method, when the crystal form G of the compound represented by Formula IX is obtained, the crystallization is performed by filtration.

[0182] In one embodiment, the preparation method, when obtaining crystal form F of the compound represented by Formula IX, comprises the following steps: adding n-heptane to a mixed solvent of crystal form A of the compound represented by Formula IX and acetonitrile, and crystallizing.

[0183] In one embodiment, the preparation method, when obtaining crystal form H of the compound represented by Formula IX, comprises the following steps: adding methyl tert-butyl ether to a mixed solvent of crystal form A of the compound represented by Formula IX and acetonitrile, and crystallizing.

[0184] The present invention provides a method for preparing crystal form I of the compound shown in Formula IX, which includes the following steps: heating crystal form A of the compound shown in Formula IX at 25°C (preferably under nitrogen protection) to obtain crystal form I of the compound shown in Formula IX.

[0185] Preferably, the method for preparing crystal form D of the compound shown in Formula IX includes the following steps: heating crystal form A of the compound shown in Formula IX at 55°C (preferably under nitrogen protection) to obtain crystal form D of the compound shown in Formula IX.

[0186] Preferably, the method for preparing crystal form J of the compound shown in Formula IX includes the following steps: heating crystal form H of the compound shown in Formula IX at 170°C (preferably under nitrogen protection) to obtain crystal form J of the compound shown in Formula IX.

[0187] This invention provides a method for preparing a single crystal of the compound shown in Formula IX, comprising the following steps:

[0188] Step (1): Mix the mixture of the compound shown in Formula I, acetone and water with crystal form A of the compound shown in Formula IX;

[0189] Step (2): Add a mixture of toluene-4-sulfonic acid, acetone and water, and crystallize to obtain a single crystal of the compound shown in Formula IX.

[0190] In the method for preparing a single crystal of the compound represented by Formula IX, in step (1), the mass ratio of the compound represented by Formula I to acetone can be (0.5-2):(8-12), for example 1.63:10.3.

[0191] In the method for preparing a single crystal of the compound shown in Formula IX, in step (1), the mass ratio of acetone to water can be (9-11):(0.5-1.5), for example, 10.3:1.3.

[0192] In the method for preparing single crystals of the compound shown in Formula IX, in step (1), the mixing can be performed at 45-55°C.

[0193] In the method for preparing a single crystal of the compound represented by Formula IX, in step (1), the mass ratio of crystal form A of the compound represented by Formula IX to the compound represented by Formula I can be 1:100 to 1:10, for example 8:163.

[0194] In the method for preparing a single crystal of the compound shown in Formula IX, in step (2), the mass ratio of toluene-4-sulfonic acid, acetone and water can be (1-2.5):(5-10):(0.5-1.5), for example 0.58:2.57:0.32.

[0195] In the method for preparing a single crystal of the compound shown in Formula IX, in step (2), the toluene-4-sulfonic acid can be toluene-4-sulfonic acid monohydrate.

[0196] In the method for preparing single crystals of the compound represented by Formula IX, in step (2), the mixture can be added in two parts. Preferably, the first addition is made at 45-55°C, and the mass ratio of toluene-4-sulfonic acid to the compound represented by Formula I is 1:(2-4), for example, 0.58:1.63. The second addition is made at 20-30°C, and the mass ratio of toluene-4-sulfonic acid to the compound represented by Formula I is 1:(4-8), for example, 0.29:1.63.

[0197] In one embodiment, the method for preparing a single crystal of the compound represented by Formula IX involves filtering after crystallization to obtain a single crystal of the compound represented by Formula IX.

[0198] The present invention provides a pharmaceutical composition comprising substance X and pharmaceutical excipients, wherein substance X is a compound of formula II or IX (e.g., a crystal form of a compound of formula II or IX) or a crystal form C of a compound of formula I.

[0199] The present invention provides the use of substance X or the above-described pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, or colon cancer; wherein substance X is a compound of formula II or IX (e.g., a crystal form of a compound of formula II or IX) or crystal form C of a compound of formula I.

[0200] Preferably, the substance X is a crystal form A of the compound shown in Formula II, a crystal form B of the compound shown in Formula XI, a crystal form C of the compound shown in Formula IX, a crystal form D of the compound shown in Formula IX, a crystal form E of the compound shown in Formula IX, a crystal form F of the compound shown in Formula IX, a crystal form G of the compound shown in Formula IX, a crystal form H of the compound shown in Formula IX, a crystal form I of the compound shown in Formula IX, or a crystal form J of the compound shown in Formula IX.

[0201] Terminology Explanation:

[0202] As used herein and unless otherwise stated, the term "solvent" refers to a crystal form of a substance whose crystal structure contains a solvent. The term "hydrate" refers to a solvate whose crystal structure contains water as the solvent.

[0203] As used herein and unless otherwise stated, the terms “about” and “approximately” when used together to provide a range of the following numerical values ​​or values ​​characterizing a particular solid form indicate that the value or range may deviate to a degree that would be reasonable to a person skilled in the art (e.g., taking error into account) while still describing the particular solid form: for example, a specific temperature or temperature range describing the melting, dehydration, desolvation, or glass transition temperature; a change in mass, such as a change in mass with temperature or humidity; a solvent content or water content in, for example, by mass or percentage; or, for example, a peak position in an analysis by IR or Raman spectroscopy or XRPD, or a peak position (temperature of thermal behavior) in an analysis by, for example, DSC or TGA. For example, in a particular embodiment, the terms “about” and “approximately” when used in this context indicate that the numerical value or range may vary within the range of 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of said value or value. The tilde (i.e., “~”) preceding a range of numerical values ​​or values ​​used herein indicates “about” or “approximately”.

[0204] As used herein and unless otherwise stated, the positions or relative intensities of diffraction peaks in X-ray powder diffraction patterns may vary due to factors such as the measuring instrument, method / conditions, etc. For any given crystal form, the peak positions may have errors, for example, a 2θ value measurement error of ±0.2°. Therefore, this error should be taken into account when determining each crystal form, and is within the scope of this application.

[0205] As used herein, when referring to a specific salt, composition, or excipient as "pharmaceutically acceptable," it means that the salt, composition, or excipient is generally non-toxic, safe, and suitable for use by subjects, preferably mammalian subjects, and more preferably human subjects.

[0206] As used herein, the structure of the compound represented by Formula I is as follows:

[0207] As used herein and unless otherwise stated, the term "excipient" refers to those excipients widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration of the composition to a subject. Excipients may be inert fillers or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient in the composition.

[0208] 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.

[0209] The reagents and raw materials used in this invention are all commercially available.

[0210] The positive and progressive effects of this invention are as follows: the salt form and crystal form of the cyclic nitrogen-containing compound provided by this invention have good drug activity, good stability and solubility, and have good pharmaceutical prospects. Attached Figure Description

[0211] Figure 1 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula II.

[0212] Figure 2 shows the differential scanning calorimeter of crystal form A of the compound represented by formula II.

[0213] Figure 3 shows the thermogravimetric analysis spectrum of crystal form A of the compound represented by formula II.

[0214] Figure 4 shows the X-ray powder diffraction pattern of crystal form C of the compound shown in Formula I.

[0215] Figure 5 shows the differential scanning calorimeter of the crystal form of the compound represented by Formula I.

[0216] Figure 6 shows the thermogravimetric analysis (TGA) spectrum of the crystal form of the compound represented by Formula I.

[0217] Figure 7 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula IX.

[0218] Figure 8 shows the differential scanning calorimeter of crystal form A of the compound represented by formula IX.

[0219] Figure 9 shows the thermogravimetric analysis (TGA) spectrum of crystal form A of the compound represented by formula IX.

[0220] Figure 10 shows the molecular structure of a single crystal of the compound represented by Formula IX.

[0221] Figure 11 is an X-ray powder diffraction pattern of crystal form B of the compound represented by formula IX.

[0222] Figure 12 shows the X-ray powder diffraction pattern of crystal form C of the compound represented by formula IX.

[0223] Figure 13 is an X-ray powder diffraction pattern of crystal form D of the compound represented by formula IX.

[0224] Figure 14 is an X-ray powder diffraction pattern of crystal form E of the compound represented by formula IX.

[0225] Figure 15 shows the differential scanning calorimeter of the crystal form E of the compound represented by formula IX.

[0226] Figure 16 shows the thermogravimetric analysis (TGA) spectrum of the crystal form E of the compound represented by formula IX.

[0227] Figure 17 shows the X-ray powder diffraction pattern of crystal form F of the compound represented by formula IX.

[0228] Figure 18 shows the differential scanning calorimeter of the crystal form F of the compound represented by formula IX.

[0229] Figure 19 shows the thermogravimetric analysis (TGA) spectrum of crystal form F of the compound represented by formula IX.

[0230] Figure 20 shows the X-ray powder diffraction pattern of crystal form G of the compound represented by formula IX.

[0231] Figure 21 is an X-ray powder diffraction pattern of crystal form H of the compound represented by formula IX.

[0232] Figure 22 shows the differential scanning calorimeter of the crystal form H of the compound represented by formula IX.

[0233] Figure 23 shows the thermogravimetric analysis (TGA) spectrum of crystal form H of the compound represented by formula IX.

[0234] Figure 24 shows the X-ray powder diffraction pattern of crystal form I of the compound represented by formula IX.

[0235] Figure 25 shows the X-ray powder diffraction pattern of crystal form J of the compound represented by formula IX.

[0236] Figure 26 shows the XRPD images of crystal form C of the compound shown in Formula I after being placed under open and closed conditions at 25°C / 60%RH.

[0237] Figure 27 shows the XRPD images of crystal form A of the compound shown in Formula IX after being placed under open and closed conditions at 25°C / 60%RH.

[0238] Figure 28 shows the XRPD images of crystal form F of the compound represented by formula IX after being placed under open and closed conditions at 25°C / 60%RH. Detailed Implementation

[0239] 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.

[0240] The X-ray powder diffraction (XRPD) testing methods involved in this invention are shown in the table below:

[0241] The single-crystal testing method involved in this invention is as follows:

[0242] Model: Bruker A8 Advance X-ray Diffractometer

[0243] X-ray source: High-intensity micro-focused Cu / Mo automatic switching dual light source system, using diamond thermal conductivity technology, Mo light source power 70W, Cu light source power 60W.

[0244] Micro-focal spot light source, with a spot size no larger than 100mm.

[0245] X-ray optical system, multilayer film micro-focusing optical system.

[0246] Angle measuring instrument: Kappa (Kappa, ω, 2θ, φ) quadriaxial angle measuring instrument, equipped with an automatic angle measuring head.

[0247] Detector: A brand-new semiconductor two-dimensional imaging technology detector, featuring both photon counting and integration functions; detection area 208×128mm 2 Pixel size: ≤135μm×135μm, 1:1 coupling with the chip, no beam ratio.

[0248] Low-temperature cooling system: Supports testing in the temperature range of 80K to 500K.

[0249] The test methods for thermogravimetric analysis (TGA) curves and differential scanning calorimetry (DSC) curves involved in this invention are shown in the table below:

[0250] This invention relates to the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Guidelines for Hygroscopic Testing of Drugs, Part IV, Chinese Pharmacopoeia 2020 Edition):

[0251] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0252] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0253] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0254] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0255] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0256] The method for testing moisture content is as follows: Fischer titration (KF).

[0257] The ion chromatograph testing conditions involved in this application are as follows:

[0258] The nuclear magnetic resonance (NMR) testing conditions involved in this application are as follows:

[0259] The testing conditions for polarizing microscopes (PLM) involved in this application are as follows:

[0260] The high-performance liquid chromatography (HPLC) testing conditions involved in this application are as follows:

[0261] Example 1. Preparation method of the compound shown in Formula II

[0262] Intermediate 1: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0263] Step 1: (2-chloro-5-methoxypyridin-4-yl)boronic acid

[0264] 2-Chloro-5-methoxypyridine (10.0 g, 69.5 mmol) was dissolved in 250 mL of tetrahydrofuran and cooled to 65 °C under nitrogen protection. While maintaining the temperature below -60 °C, 2 mol / L lithium diisopropylamino (70 mL) was slowly added dropwise. The reaction was maintained at this low temperature for 2 hours. Then, triisopropyl borate (26.2 g, 139 mmol) was slowly added dropwise at -65 °C, and the mixture was stirred for another hour while maintaining the temperature at -65 °C. The mixture was then allowed to rise to room temperature overnight. The reaction solution was quenched with 100 mL of water in an ice-water bath. The resulting aqueous solution was extracted twice with ethyl acetate. The organic phase was discarded, and the pH of the aqueous phase was adjusted to 5-6 with 2 M hydrochloric acid. A large amount of solid precipitated. The solid phase was filtered under reduced pressure and dried to give the title compound (11.4 g, white solid, yield 88.1%). LC / MS (ESI) m / z: 188.0 [M+H] + .

[0265] Step 2: Methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0266] 4-Bromo-6-methylnicotinic acid methyl ester (5 g, 21.7 mmol), (2-chloro-5-methoxypyridin-4-yl)boronic acid (4.07 g, 21.7 mmol), and potassium carbonate (9 g, 65.2 mmol) were dissolved in a mixture of 180 mL of 1,4-dioxane and 36 mL of water. Under nitrogen protection, bis(triphenylphosphine)palladium dichloride (1.59 g, 2.17 mmol) was added, and the mixture was heated to 80 °C for 2 hours. The reaction solution was cooled to room temperature, filtered, and extracted separately with water and ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate system: 0-50% ethyl acetate) to give the title compound (5.20 g, white solid, yield 81.7%). LC / MS (ESI) m / z: 293.0 [M+H] + .

[0267] Step 3: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0268] Methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (5.2 g, 17.7 mmol) was dissolved in 50 mL of tetrahydrofuran and 50 mL of water. Lithium hydroxide (0.64 g, 26.6 mmol) was added, and the mixture was stirred overnight at room temperature. After concentrating under reduced pressure to remove the tetrahydrofuran, the pH was adjusted to 5-6 with hydrogen chloride, resulting in the precipitation of a large amount of white solid. The solid was filtered under reduced pressure, and the resulting filter cake was dried to give the title compound (4.82 g, white solid, yield 96.7%). LC / MS (ESI) m / z: 279.1 [M+H] + .

[0269] 2'-Chloro-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-fluorothiazo[4,5-c]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0270] Step 1: O-((9H-fluorene-9-yl)methyl)carbonate isothiocyanate

[0271] At 0 °C, a solution of chloroformate-9-fluorenyl methyl ester (50 g, 193 mmol) in ethyl acetate (160 mL) was added dropwise to a solution of potassium thiocyanate (20.7 g, 213 mmol) in ethyl acetate (160 mL). The mixture was stirred at room temperature for 16 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20, v / v) to give the title compound (yellow oil, 16.0 g, yield 29.4%). 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=7.6Hz,2H),7.69(d,J=7.6Hz,2H),7.45-7.39(m,2H),7.36-7.31(m,2H),4.30-4.23(m,2H),4.23-4.18(m,1H).

[0272] Step 2: (6-chloro-5-fluoropyridin-3-yl)tert-butyl carbamate

[0273] To a solution of 2-chloro-3-fluoro-5-bromopyridine (8.00 g, 38.0 mmol), tert-butyl carbamate (4.90 g, 41.8 mmol), cesium carbonate (24.8 g, 76.0 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (880 mg, 1.52 mmol) in 1,4-dioxane (160 mL), tris(dibenzylacetone)dipalladium (1.04 g, 1.14 mmol) was added. The mixture was stirred at 85 °C for 20 hours under nitrogen protection. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4, V / V) to give the title compound (yellow solid, 6.10 g, yield 65.0%). LC / MS (ESI) m / z: 246.9 [M+H] + .

[0274] Step 3: (4-bromo-6-chloro-5-fluoropyridine)-3-carbamate tert-butyl ester

[0275] (6-chloro-5-fluoropyridin-3-yl)tert-butyl carbamate (6.10 g, 24.7 mmol) and N,N,N',N'-tetramethylethylenediamine (8.62 g, 74.2 mmol) were dissolved in diethyl ether (130 mL). Under nitrogen protection, the reaction mixture was cooled to -60 °C, and 1.6 M n-butyllithium (46.4 mL, 74.2 mmol) was added dropwise. After the addition was complete, the mixture was heated to -20 °C and stirred for 1.5 hours. The reaction mixture was then cooled to -60 °C, and 1,2-dibromotetrafluoroethane (19.9 g, 76.7 mmol) was added dropwise. After the addition was complete, the mixture was slowly heated to room temperature, and the reaction was quenched with 1 N HCl (92 mL). The mixture was extracted with ethyl acetate, the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The mixture was concentrated under reduced pressure to give the title compound (yellow solid, 8.0 g, 99.4% yield). LC / MS (ESI) m / z: 326.9 [M+H] + .

[0276] Step 4: 4-Bromo-6-chloro-5-fluoropyridine-3-amine

[0277] (4-Bromo-6-chloro-5-fluoropyridine)-3-carbamate tert-butyl ester (8.0 g, 24.6 mmol) was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (50 mL), and the reaction mixture was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure to obtain a residue, which was then dissolved in ethyl acetate, neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The mixture was concentrated under reduced pressure to give the title compound (yellow solid, 5.7 g, yield 103%). LC / MS (ESI) m / z: 224.8 [M+H] + .

[0278] Step 5: (9H-fluorene-9-yl)methyl(6-chloro-7-fluorothiazo[4,5-c]pyridin-2-yl)carbamate hydrobromide

[0279] 4-Bromo-6-chloro-5-fluoropyridin-3-amine (5.7 g, 25.3 mmol) was dissolved in acetone (100 mL), and O-((9H-fluorene-9-yl)methyl)carbonate isothiocyanate (8.54 g, 30.3 mmol) was added. The mixture was stirred overnight at 50 °C. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with acetone. The solid was dried under reduced pressure to give the title compound (7.7 g, white solid, yield 60.1%). LC / MS (ESI) m / z: 426.0 [M+H] + .

[0280] Step 6: 6-Chloro-7-fluorothiazo[4,5-c]pyridine-2-amine

[0281] To a solution of (9H-fluorene-9-yl)methyl(6-chloro-7-fluorothiazo[4,5-c]pyridin-2-yl)carbamate hydrobromide (7.7 g, 18.1 mmol) in dichloromethane (80 mL), piperidine (17.9 mL, 181 mmol) was added, and the mixture was stirred at room temperature for one hour. Water was added to the reaction mixture, and the mixture was back-extracted with ethyl acetate and concentrated under reduced pressure in aqueous phase. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10, v / v) followed by slurrying with dichloromethane to give the title compound (white solid, 1.45 g, yield 39.4%). LC / MS (ESI) m / z: 204.1 [M+H] + .

[0282] Step 7: 6-Chloro-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-7-fluorothiazo[4,5-c]pyridine

[0283] To a solution of 6-chloro-7-fluorothiazo[4,5-c]pyridin-2-amine (1.45 g, 7.12 mmol), acetone-acetone (1.65 g, 14.5 mmol), and toluene (30 mL), p-toluenesulfonic acid hydrate (0.25 g, 1.42 mmol) was added. The mixture was then refluxed at 140 °C for two hours to remove water. The reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate solution, followed by washing with saturated brine. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10, V / V) to give the title compound (white solid, 1.5 g, 74.8% yield). LC / MS (ESI) m / z: 282.1 [M+H] + .

[0284] Step 8: 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-7-fluorothiazo[4,5-c]pyridine

[0285] To a xylene (30 mL) solution of 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-7-fluorothiazo[4,5-c]pyridine (1.5 g, 5.32 mmol) and 1,4-dimethyl-5-(tributyltinyl)-1H-1,2,3-triazole (3.08 g, 7.99 mmol), tetraphenylphosphine palladium (1.85 g, 1.60 mmol) was added. The mixture was stirred at 150 °C for 5 hours under nitrogen protection. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3, V / V) to give the title compound (pale yellow solid, 1.25 g, yield 68.7%). LC / MS (ESI) m / z: 343.1 [M+H] + .

[0286] Step 9: 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-fluorothiazo[4,5-c]pyridine-2-amine hydrochloride

[0287] 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-7-fluorothiazo[4,5-c]pyridine (1.25 g, 3.65 mmol) was dissolved in 2N HCl (15 mL), and the reaction mixture was stirred at 80 °C for two hours. The mixture was concentrated under reduced pressure, and the residue was slurried with acetonitrile to give the title compound (pale yellow solid, 1.0 g, yield 91.1%). LC / MS (ESI) m / z: 265.1 [M+H] + .

[0288] Step 10: 2'-Chloro-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-fluorothiazo[4,5-c]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0289] 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-fluorothiazo[4,5-c]pyridine-2-amine hydrochloride (1.0 g, 3.78 mmol), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (1.16 g, 4.16 mmol), and N-methylimidazolium (2.17 g, 26.5 mmol) were dissolved in acetonitrile (20 mL) and stirred at 70 °C for five minutes. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (5.31 g, 18.9 mmol) was added to the reaction solution and stirred at 70 °C for two hours. Before the reactants were completely reacted, N-methylimidazole (0.62 g, 7.56 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (1.06 g, 3.78 mmol) were added to the reaction solution. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, concentrated under reduced pressure, and the residue was first subjected to silica gel column chromatography (eluent: dichloromethane / methanol = 20, v / v), and then slurried with ethyl acetate to give the title compound (834.7 mg, white solid, yield 42.0%). 1 H NMR(400MHz,DMSO-d6)δ13.63(s,1H),9.14(d,J=2.0Hz,1H),8.90(s,1H),8.18(s,1H),7.62(s,1H),7 .51(s,1H),4.03(s,3H),3.61(s,3H),2.62(s,3H),2.26(d,J=1.6Hz,3H).LC / MS(ESI)m / z:525.2[M+H] + .

[0290] The resulting white solid is crystal form A of the compound shown in Formula II, and its XRPD pattern is shown in Figure 1. It has the diffraction peaks shown in Table 1 below.

[0291] Table 1

[0292] The DSC spectrum of crystal form A of the compound shown in Formula II is shown in Figure 2. Two endothermic peaks were observed in the DSC curve at peak temperatures of 98.33℃ (enthalpy 121.36 J / g) and 206.94℃ (enthalpy 66.798 J / g), with onset x values ​​of 72.55℃ and 200.15℃, respectively. The TGA spectrum is shown in Figure 3. The sample lost 0.48% weight when heated from 34.69℃ to 70.0℃, 2.11% weight when heated from 70.0℃ to 95.0℃, 1.38% weight when heated from 95.0℃ to 140.0℃, and approximately 0.34% weight in the temperature range of 140.0℃ to 220.0℃. DSC and TGA analyses indicate that crystal form A is a monohydrate.

[0293] Preparation of crystal form C of the compound shown in Formula I in Examples 1-2

[0294] Weigh approximately 30 mg of the compound of formula II, crystal form A, and place it in a 2 mL glass bottle. Add 0.5 mL of ethyl acetate or acetonitrile for suspension. The resulting sample is suspended at 50 °C for 2 hours, then allowed to cool naturally to 25 °C and suspended at 25 °C for 3 days. The resulting suspension is centrifuged through a 0.45 μm nylon filter membrane at 14,000 rpm. The resulting solid is then vacuum dried at 50 °C for 2 hours to obtain crystal form C.

[0295] The resulting white solid is crystalline form C of the compound shown in Formula I, and its XRPD pattern is shown in Figure 4. It exhibits the diffraction peaks shown in Table 2 below. The DSC pattern of crystalline form C of the compound shown in Formula I is shown in Figure 5. An endothermic peak was observed in the DSC curve at a peak temperature of 238.92℃ (enthalpy of 106.67 J / g). The TGA pattern is shown in Figure 6. The sample lost 0.81% of its weight when heated from 35.56℃ to 230.0℃. DSC and TGA analyses indicate that the free basal crystalline form C of the compound shown in Formula I is an anhydrous hydrate.

[0296] Table 2

[0297] Example 2 Crystal form A of the compound shown in Formula IX

[0298] 30 mg of the compound shown in Formula I and 10.44 mg of p-toluenesulfonic acid were added to 0.5 mL of acetone / water (95:5, v:v), and the mixture was heated to 50 °C. The entire system was stirred at 50 °C for 2 hours, then cooled to 25 °C and stirred again. After filtration, the resulting wet product was dried under vacuum at 50 °C for 2 hours to obtain crystal form A of the compound shown in Formula IX. The XRPD pattern of crystal form A of the compound shown in Formula I is shown in Figure 7, and it exhibits the diffraction peaks shown in Table 3 below.

[0299] MRI: 1H NMR (400MHz, DMSO-d6) δ13.64(s,1H),9.15(d,J=2.0Hz,1H),8.91(s,1H),8.18(s,1H),7.63(s,1H),7.53(s,1H),7.4 7(d,J=8.4Hz,2H),7.11(d,J=7.6Hz,2H),4.03(s,3H),3.61(s,3H),2.63(s,3H),2.29(s,3H),2.26(d,J=1.6Hz,3H).

[0300] Table 3

[0301] The DSC spectrum of crystal form A of the compound represented by Formula IX is shown in Figure 8. Two endothermic peaks were observed in the DSC curve at peak temperatures of 95.83℃ (enthalpy 244.34 J / g) and 194.7℃ (enthalpy 34.862 J / g), with onset x values ​​of 57.37℃ and 181.84℃, respectively. The TGA spectrum is shown in Figure 9. The sample lost 2.03% weight when heated from 30.52℃ to 60.0℃, 5.13% weight when heated from 60.0℃ to 100.0℃, and 0.50% weight when heated from 100.0℃ to 190.0℃. NMR data show that the molar ratio of water to the compound represented by Formula I and p-toluenesulfonic acid in crystal form A of the compound represented by Formula IX is 3:1:1.

[0302] Example 2-1 Single crystal of the compound shown in Formula IX

[0303] The compound shown in Formula I (1.63 kg, 3.11 mol) was added to a mixed solution of 10.3 kg acetone and 1.30 kg water, and the temperature was controlled at 45-55 °C. Then, 80 g of crystal form A of the compound shown in Formula IX was added to obtain a mixture. 0.58 kg of toluene-4-sulfonic acid monohydrate was dissolved in 2.57 kg acetone and 0.32 kg water, and added dropwise to the above mixture. The mixture was stirred at 45-55 °C for 2 hours. The temperature was then lowered to 20-30 °C, and the mixture was stirred for 2 hours. 0.29 kg of toluene-4-sulfonic acid monohydrate was dissolved in 1.28 kg acetone and 0.16 kg water, and added dropwise to the above mixture. The mixture was stirred at 20-30 °C for 2 hours. The mixture was filtered to obtain a single crystal of the compound shown in Formula IX, wherein the molar ratio of water to the compound shown in Formula I and p-toluenesulfonic acid was 3:1:1.

[0304] The molecular structure of a single crystal of the compound represented by Formula IX is shown in Figure 10, and the unit cell parameters are shown in the table below:

[0305] Example 3 Crystal form B of the compound shown in Formula IX

[0306] 30 mg of the compound shown in Formula I and 10.44 mg of p-toluenesulfonic acid were added to 0.5 mL of acetonitrile, and the mixture was heated to 50 °C. The entire system was stirred at 50 °C for 2 hours, then cooled to 25 °C and stirred again. After filtration, the resulting wet product was dried under vacuum at 50 °C for 2 hours to obtain crystal form B of the compound shown in Formula IX. The molar ratio of the compound shown in Formula I to p-toluenesulfonic acid was 1:1.00. The XRPD pattern of crystal form B of the p-toluenesulfonate of the compound shown in Formula I (crystal form B of the compound shown in Formula IX) is shown in Figure 11, and it exhibits the diffraction peaks shown in Table 4 below.

[0307] MRI: 1 H NMR (400MHz, DMSO-d6) δ13.65(s,1H),9.15(d,J=2.0Hz,1H),8.92(s,1H),8.19(s,1H),7.63(s,1H),7.54(s,1H),7.4 7(d,J=8.4Hz,2H),7.11(d,J=7.6Hz,2H),4.03(s,3H),3.61(s,3H),2.63(s,3H),2.29(s,3H),2.26(d,J=1.6Hz,3H).

[0308] Table 4

[0309] Example 4 Crystal form C of the compound shown in Formula IX

[0310] 199.4 mg of the p-toluenesulfonate crystal form A of the compound shown in Formula I (crystal form A of the compound shown in Formula IX) was added to 5.2 mL of tetrahydrofuran. After stirring at 25 °C, the mixture was filtered and dried under vacuum at 50 °C for 2 hours to obtain crystal form C of the compound shown in Formula IX, which is a solvate of tetrahydrofuran. The molar ratio of the compound shown in Formula I to p-toluenesulfonic acid and tetrahydrofuran was 1:1.02:0.16. The XRPD pattern of crystal form C of the compound shown in Formula IX is shown in Figure 12, and it exhibits the diffraction peaks shown in Table 5 below.

[0311] Table 5

[0312] Crystal form D of the compound shown in Formula IX in Example 5

[0313] The crystal form A of the compound shown in Formula IX was heated at 55 °C under a nitrogen atmosphere to obtain the crystal form D of the compound shown in Formula IX. The molar ratio of the compound shown in Formula I to p-toluenesulfonic acid was 1:1. The XRPD pattern of the p-toluenesulfonate crystal form D of the compound shown in Formula I (crystal form D of the compound shown in Formula IX) is shown in Figure 13, and it has the diffraction peaks shown in Table 6 below.

[0314] Table 6

[0315] Crystal form E of the compound shown in Formula IX in Example 6

[0316] 40 mg of crystal form A of the compound shown in Formula IX was added to 0.2 mL of isopropanol, heated to 50 °C and shaken, filtered, and dried under vacuum at 50 °C for 2 hours to obtain crystal form E of the p-toluenesulfonate isopropanol solvate of the compound shown in Formula I (crystal form E of the compound shown in Formula IX). Its 1H NMR spectrum showed that this crystal form contained 0.98 equivalents of isopropanol. In crystal form E of the compound shown in Formula IX, the molar ratio of the compound shown in Formula I, p-toluenesulfonic acid, and isopropanol was 1:1.02:0.98. The XRPD pattern of crystal form E of the compound shown in Formula IX is shown in Figure 14, and it exhibits the diffraction peaks shown in Table 7 below.

[0317] MRI: 1 H NMR (400MHz, DMSO-d6) δ13.65(s,1H),9.15(d,J=2.0Hz,1H),8.92(s,1H),8.19(s,1H),7.63(s,1H),7.54(s,1H),7.47(d,J=8.4Hz,2H),7.11 (d,J=7.6Hz,2H),4.03(s,3H),3.78(sept,J=7.0Hz,1H),3.61(s,3H),2.63(s,3H),2.29(s,3H),2.26(d,J=1.6Hz,3H),1.09(d,J=7.0Hz,6H).

[0318] Table 7

[0319] The DSC spectrum of crystal form E of the compound shown in Formula IX is shown in Figure 15. Two endothermic peaks were observed in the DSC curve at peak temperatures of 102.94 °C (enthalpy 207.35 J / g) and 183.71 °C (enthalpy 34.855 J / g), with onset points (Onset x) of 65.61 °C and 176.33 °C, respectively. The TGA spectrum is shown in Figure 16. The sample lost 3.11% weight when heated from 33.06 °C to 55.0 °C, 3.82% weight when heated from 55.0 °C to 120.00 °C, and 1.21% weight when heated from 120.0 °C to 190.0 °C.

[0320] Example 7 Crystal form F of the compound shown in Formula IX

[0321] 40 mg of crystal form A of the compound shown in Formula IX was added to 1.6 mL of acetonitrile, dissolved, and filtered. The filtrate was kept at 25 °C, and 3.2 mL of n-heptane was added. A solid precipitated in the system. The mixture was filtered and dried under vacuum at 50 °C for 2 hours to obtain crystal form F of the compound shown in Formula IX. The molar ratio of the compound shown in Formula I to p-toluenesulfonic acid was 1:1.02. The XRPD pattern of crystal form F of the compound shown in Formula IX is shown in Figure 17, and it exhibits the diffraction peaks shown in Table 8 below.

[0322] 1 H NMR (400MHz, DMSO-d6) δ13.64(s,1H),9.15(d,J=2.0Hz,1H),8.91(s,1H),8.19(s,1H),7.63(s,1H),7.53(s,1H),7.4 7(d,J=8.4Hz,2H),7.12(d,J=7.6Hz,2H),4.02(s,3H),3.61(s,3H),2.63(s,3H),2.29(s,3H),2.26(d,J=1.6Hz,3H).

[0323] Table 8

[0324] The DSC spectrum of crystal form F of compound IX is shown in Figure 18. An endothermic peak was observed at the peak temperature of 266.84 °C (enthalpy of 70.167 J / g) in the DSC curve, with the onset point (Onset x) of the endothermic peak at 263.55 °C. The TGA spectrum is shown in Figure 19. The sample lost 2.2% of its weight when heated from 34.19 °C to 260.0 °C.

[0325] Crystal form G of the compound shown in Formula IX in Example 8

[0326] 40 mg of crystal form A of the compound shown in Formula IX was added to 0.2 mL of 1,4-dioxane, heated to 50 °C and shaken, filtered, and dried under vacuum at 50 °C for 2 hours to obtain crystal form G of the compound shown in Formula IX. NMR analysis showed that this crystal form contained 3 equivalents of dioxane. The molar ratio of the compound shown in Formula I, p-toluenesulfonic acid, and 1,4-dioxane was 1:1.10:2.96. The XRPD pattern of crystal form G of the compound shown in Formula IX is shown in Figure 20, and it exhibits the diffraction peaks shown in Table 9 below.

[0327] MRI: 1H NMR (400MHz, DMSO-d6) δ13.65(s,1H),9.15(d,J=2.0Hz,1H),8.92(s,1H),8.19(s,1H),7.63(s,1H),7.54(s,1H),7.47(d,J= 8.4Hz,2H),7.11(d,J=7.6Hz,2H),4.03(s,3H),3.57(s,24H),3.61(s,3H),2.63(s,3H),2.29(s,3H),2.26(d,J=1.6Hz,3H).

[0328] Table 9

[0329] Example 9: Crystal form H of the compound shown in Formula IX

[0330] 40 mg of crystal form A of the compound shown in Formula IX was added to 3.0 mL of acetonitrile, dissolved, and filtered. 12 mL of methyl tert-butyl ether was added to the filtrate, resulting in the precipitation of a solid. After filtration, crystal form H of the compound shown in Formula IX was obtained, containing 0.45 equivalents of methyl tert-butyl ether as determined by NMR. The molar ratio of the compound shown in Formula I, p-toluenesulfonic acid, and the solvent methyl tert-butyl ether was 1:1.00:0.5. The XRPD pattern of crystal form H of the compound shown in Formula IX is shown in Figure 21, exhibiting the diffraction peaks shown in Table 10 below.

[0331] MRI: 1 H NMR (400MHz, DMSO-d6) δ13.65(s,1H),9.15(d,J=2.0Hz,1H),8.92(s,1H),8.19(s,1H),7.63(s,1H),7.54(s,1H),7.47(d,J=8.4Hz, 2H),7.11(d,J=7.6Hz,2H),4.03(s,3H),3.61(s,3H),3.08(s,1.5H)2.63(s,3H),2.29(s,3H),2.26(d,J=1.6Hz,3H),1.11(s,4.5H).

[0332] Table 10

[0333] The DSC spectrum of crystal form H of compound IX is shown in Figure 22. Endothermic peaks were observed at peak temperatures of 45.53℃ (enthalpy 10.478 J / g), 155.23℃ (enthalpy 29.331 J / g), and 191.45℃ (enthalpy 23.665 J / g), with onset x values ​​of 29.17℃, 134.74℃, and 184.26℃, respectively. The TGA spectrum is shown in Figure 23. The sample lost 1.74% weight when heated from 32.99℃ to 100.0℃ and 5.38% weight when heated from 100.0℃ to 180.0℃.

[0334] Crystal form I of the compound shown in Formula IX in Example 10

[0335] The crystal form A of the compound shown in Formula IX was heated at 25°C under a nitrogen atmosphere to obtain the crystal form I of the compound shown in Formula IX. The molar ratio of the compound shown in Formula I to p-toluenesulfonic acid was 1:1. The XRPD pattern of crystal form I of the compound shown in Formula I is shown in Figure 24, and it exhibits the diffraction peaks shown in Table 11 below.

[0336] Table 11

[0337] Example 11 Crystal form J of the compound shown in Formula IX

[0338] The crystal form H of the compound shown in Formula IX was heated at 170 °C under a nitrogen atmosphere to remove the solvent, yielding the crystal form J of the compound shown in Formula IX. The molar ratio of the compound shown in Formula I to p-toluenesulfonic acid was 1:1.01. The XRPD pattern of crystal form J of the compound shown in Formula IX is shown in Figure 25, and it exhibits the diffraction peaks shown in Table 12 below.

[0339] Table 12

[0340] Test Example 1

[0341] The crystal form C of the compound of formula I in Examples 1-2, the crystal form A of the compound of formula IX obtained in Example 2, and the crystal form F of the compound of formula IX obtained in Example 7 were placed under open conditions at 25°C / 60%RH and closed conditions at 60°C for two weeks, as shown in Figures 26, 27, and 28. The crystal form stability was good.

[0342] Test Example 2

[0343] Test method: Gradient setting 40-0-95-0-40%RH, dm / dt 0.002 / s, for every 10% change in RH, it will be balanced for 60-360 minutes, and the test temperature is 25℃.

[0344] Test results show that crystal form C of the compound shown in Formula I is non-hygroscopic, and the crystal form remains unchanged before and after the test. Crystal form A of the compound shown in Formula IX absorbs 0.2% water.

[0345] Test Example 3

[0346] The solubility of the crystal form C of the compound shown in Formula I and the crystal form A of the compound shown in Formula IX obtained in the above examples was tested using the following method:

[0347] Weigh 8 mg of crystal form C of compound I and 11.7 mg of crystal form A of compound IX into 20 mL glass bottles, add 4 mL of solvent, and stir the resulting suspension or clear solution at 37 °C and 400 rpm. Take samples at 0.5 h and 2 h, 0.5 mL each time, and centrifuge at 37 °C and 14,000 rpm for 5 min. Finally, perform content testing on the obtained filtrate.

[0348] The results show that the crystal form obtained in this application has good solubility, as shown in the table below:

[0349] A represents a solubility of 0.01-0.1 mg / mL, and B represents a solubility of 0.1-1 mg / L.

[0350] Rat PK Assay

[0351] The purpose of this experiment was to study the pharmacokinetic effects of the test compound administered orally to SD rats (SPF grade, Vital River Pharmaceuticals, Beijing). The experimental procedure is as follows:

[0352] 1) The compound was uniformly dispersed in a mixture of 99.9% (0.5% MC (450cp) / water) + 0.1% Tween 80 to a concentration of 5.0 mg / mL, and then administered orally (10 mL / kg);

[0353] 2) Collect blood samples at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, adding EDTA-K2. After collection, place the blood samples on ice and centrifuge to separate the plasma within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8℃). Store plasma samples at -80℃ before analysis.

[0354] 3) Sample analysis: The concentration of compounds in plasma samples will be analyzed using LC-MS / MS. Pharmacokinetic parameters will be calculated from the plasma assay results using WinNonlin (Phoenix, version 8.2.0) or other similar software.

[0355] The results are shown in the table below:

[0356] The crystal form of this application has high exposure and good metabolic performance.

[0357] Test Example 4

[0358] 1. Biochemical activity assay of Polθ inhibitors (ADP Glo assay)

[0359] The N-terminus of the Polθ protein contains a helicase domain with ATPase activity, capable of hydrolyzing ATP to ADP, which can be detected by the ADP-Glo ​​assay kit (ADP-Glo). TM The Kinase Assay (Promega, V9102) was used to analyze the ATPase activity of Polθ protein and the inhibitory effect of small molecule compounds on the protein. The specific detection method is as follows:

[0360] 1) The helicase domain of the Polθ protein was purified using an insect system to obtain protein with a purity >90%. ssDNA (SEQ ID NO.1:5'-CCAGTGAATTGTTGCTCGGTACCTGCTAAC-3', Hangzhou Youkang Biotechnology Co., Ltd.) was ordered as the substrate for the Polθ protein; a reaction buffer containing 10 mM DTT (dithiothreitol), 20 mM MgCl2, Tris-HCl, and pH 7.5 was prepared.

[0361] 2) Prepare 2x ssDNA-Polθ premix and perform the reaction in a 384-well plate. Set up a control group with only buffer and add the premix to the other groups. Add the compound using an automated pipette (Thermo, Multidrop 8), starting at a concentration of 10 μM and diluting by 1 / 3. Set up a total of 9 detection sites, with 2 replicates per group.

[0362] 3) Prepare 2x ATP solution, add an equal volume of 2x ATP solution to all wells, and let stand at room temperature for 60 min;

[0363] 4) Following the Promega reagent instructions, add ADP-Glo ​​Detection Reagent to the reaction system and let it stand at room temperature for 60 minutes;

[0364] 5) Following the Promega reagent instructions, add Kinase Detection Reagent to the reaction system, let it stand at room temperature for 60 min, and use a microplate reader (Thermo, Varioskan LUX) to detect the chemiluminescence signal. Set the reading time interval for each well to 1000 ms.

[0365] Data analysis was performed on the measurement results: the CV% of the control group test results should be less than 10%, and the z' value should be greater than 0.5. Data meeting the above quality control requirements were used to calculate the inhibition rate of the compound (inhibition rate (%) = 100 * (control group average, experimental group) / (control group average - buffer group average). A nonlinear regression was used to fit the inhibition rate curve of the compound and the IC50 value was obtained.

[0366] 2. Cell viability assay for Polθ inhibitors

[0367] The in vitro efficacy of the inhibitor was assessed using a cell viability assay, specifically the commonly used CTG assay, with CellTiter Glo reagent (Promega, G7573). The specific assay method is as follows:

[0368] 1) Culture DLD1 and DLD1- / - cells. One day before the assay, digest the cells with trypsin (0.025% Trypsin-EDTA, Hyclone), centrifuge at 1000 rpm for 3 min, and collect the cells. Count the cells using a cell counter (Shanghai Mengwei Biomedical Technology Co., Ltd., SmartCell600A.SC1006), and seed them into 96-well white culture plates at an appropriate seeding ratio.

[0369] 2) Drug treatment was performed 24 hours after cell seeding, which was recorded as Day 0. The compound was added using an automated pipette (Thermo, Multidrop8). The plate was set as a 96-well plate with an initial concentration of 30 μM. The cells were diluted by 1 / 3 of the initial concentration, and a total of 9 detection points were set up, with 2 replicates per group. The cells were incubated at 37°C in a 5% CO2 incubator.

[0370] 3) Perform two solution changes on Day 3 and Day 7 respectively, and add the compound as in step 2);

[0371] 4) On Day 10, remove the cell culture plate and add an equal volume of CTG reagent (the CTG reagent needs to be brought back to temperature and premixed according to the reagent instructions). Gently mix for 10 minutes (speed 300) on a constant temperature mixer (Hangzhou Ausen Instrument Co., Ltd., MSC-100). Perform chemiluminescence detection using an ELISA reader (Thermo, Varioskan LUX).

[0372] 5) Perform data analysis on the measurement results: The CV% of the control group should be less than 20%, and the z' value should be greater than 0.5. For data meeting the above quality control results, calculate cell viability (inhibition rate (%) = 100 * (control group average - experimental group) / (control group average - culture medium control group average). Use GraphPad Prism8 to perform nonlinear regression fitting of the compound's inhibition rate curve and obtain the IC50 value.

[0373] Data list:

[0374] The specific data from the biochemical experiments and cell viability detection experiments are shown in the table below:

[0375] 3. Solubility Assay

[0376] 1) Prepare 0.1M Na2PO4 buffer (pH 7.4):

[0377] Add 11g Na2HPO4 (FW: 141.96) and 3.5g NaH2PO4·2H2O (FW: 156.03) to 1L of Mili-Q water, and adjust the pH to 7.4 with phosphoric acid or sodium hydroxide;

[0378] 2) Take 10 μL of the test compound (concentration: 10 mM in DMSO) and add it to 990 μL of the Na2PO4 buffer prepared in step 1 (final DMSO concentration: 1%).

[0379] 3) Shake the sample tube at room temperature for 2 hours (1000 rpm / min);

[0380] 4) Preparation of calibration curve:

[0381] a) Preparation of 300 μM spiking solution (SS):

[0382] Add 6 μL (10 mM in DMSO) of the test compound stock solution to 194 μL MeOH / ACN (4:1);

[0383] b) Plot the standard curve:

[0384] 5) Centrifuge the sample (10 minutes, 12,000 rpm) to precipitate undissolved particles. Filter the supernatant through a 0.22 μm filter membrane and then transfer the supernatant to a new centrifuge tube.

[0385] 6) Dilute the supernatant 10 times with 100mM buffer.

[0386] Add the supernatant (10 μL) to the buffer (100 mM, 90 μL) and dilute 10 times;

[0387] 7) Sample preparation for LC-MS / MS (API 4000) detection

[0388] Add 10 μL of sample (10-fold dilution) and standard curve sample to 400 μL of solution (MeOH:ACN = 1:1), perform instrument detection, and calculate the solubility value based on the standard curve.

[0389] The experimental results are shown in the table below:

[0390] 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 cyclic nitrogen-containing compound, characterized in that, It is a compound represented by Formula II or a compound represented by Formula IX; in, In the compound shown in Formula II, x' is water and q is 0.01-2.5; In the compounds shown in Formula IX, d is 1-2, g is water, tetrahydrofuran, isopropanol, 1,4-dioxane or methyl tert-butyl ether, and h is 0-3.

2. The cyclic nitrogen-containing compound as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In the compound shown in Formula II, q is 0.1, 0.5, 0.56, 0.6, 1, 1.5, 2 or 2.5; (2) In the compound shown in Formula IX, d is 1, 1.1, 1.2, 1.02 or 1.5; (3) In the compound represented by Formula IX, h is 0; or h is 0.1-3, for example, if g is water, h is 3; if g is tetrahydrofuran, h is 0.2, 0.1 or 0.16; if g is isopropanol, h is 0.9, 0.98 or 1; if g is 1,4-dioxane, h is 3, 2.96 or 2.9; if g is methyl tert-butyl ether, h is 0.4, 0.45 or 0.

5.

3. A crystal form C of the compound shown in Formula I or a cyclic nitrogen-containing compound as described in claim 1 or 2, characterized in that, It satisfies one or more of the following conditions: (1) The compound shown in Formula II is crystal form A of the compound shown in Formula II. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 9.00±0.2°, 10.84±0.2°, 17.91±0.2° and 22.05±0.2°. (2) The crystal form C of the compound shown in Formula I has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 11.51±0.2°, 18.01±0.2°, 22.56±0.2° and 25.68±0.2°. The structure of the compound shown in Formula I is as follows: (3) The compound shown in Formula IX is crystal form A of the compound shown in Formula IX. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, shows diffraction peaks at 5.96±0.2°, 16.71±0.2°, 17.79±0.2°, 20.33±0.2° and 24.66±0.2°. (4) The compound shown in Formula IX is crystal form B of the compound shown in Formula IX. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, shows diffraction peaks at 5.34±0.2°, 9.34±0.2°, 9.92±0.2°, 12.84±0.2° and 16.61±0.2°. (5) The compound shown in Formula IX is crystal form C of the compound shown in Formula IX. Its X-ray powder diffraction pattern, expressed in terms of 2θ angle using Cu-Kα radiation, shows diffraction peaks at 5.23±0.2° and 19.82±0.2°. (6) The compound shown in Formula IX is crystal form D of the compound shown in Formula IX. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 6.13±0.2°, 10.87±0.2° and 18.38±0.2°. (7) The compound shown in Formula IX is crystal form E of the compound shown in Formula IX. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, shows diffraction peaks at 5.66±0.2°, 11.50±0.2°, 17.97±0.2°, 19.83±0.2°, 23.95±0.2° and 26.58±0.2°. (8) The compound shown in Formula IX is crystal form F of the compound shown in Formula IX. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 6.15±0.2°, 16.55±0.2°, 17.30±0.2° and 21.48±0.2°. (9) The compound shown in Formula IX is the crystal form G of the compound shown in Formula IX. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 7.65±0.2°, 13.76±0.2°, 20.35±0.2°, 21.01±0.2° and 21.57±0.2°, and g is 1,4-dioxane; (10) The compound shown in Formula IX is the crystal form H of the compound shown in Formula IX. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.27±0.2°, 9.70±0.2°, 16.55±0.2° and 19.78±0.2°, and g is methyl tert-butyl ether; (11) The compound shown in Formula IX is crystal form I of the compound shown in Formula IX. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 6.01±0.2°, 10.63±0.2° and 12.79±0.2°. (12) The compound shown in Formula IX is crystal form J of the compound shown in Formula IX. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 5.27±0.2°, 8.18±0.2°, 9.72±0.2°, 10.54±0.2°, 11.06±0.2°, 12.44±0.2°, 18.79±0.2° and 20.21±0.2°.

4. The crystal form C of the compound of formula I as described in claim 3, or the cyclic nitrogen-containing compound, characterized in that, It satisfies one or more of the following conditions: (1) The crystal form A of the compound shown in Formula II, when subjected to Cu-Kα radiation and expressed in 2θ angle X-ray powder diffraction pattern, also has diffraction peaks at one or more of the following locations: 5.98±0.2°, 11.94±0.2°, 18.36±0.2°, 21.30±0.2°, 23.29±0.2° and 27.72±0.2°; For example, the crystal form A of the compound shown in Formula II has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 9.00±0.2°, 10.84±0.2°, 17.91±0.2°, 22.05±0.2°, 5.98±0.2°, 11.94±0.2°, 18.36±0.2°, 21.30±0.2°, and 23.29±0.2°. Preferably, the crystal form A of the compound shown in Formula II, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further has diffraction peaks at one or more of the following locations: 13.46±0.2°, 14.16±0.2°, 14.72±0.2°, 19.99±0.2°, 20.65±0.2°, 24.6±0.2°, 25.62±0.2°, 28.96±0.2°, 29.68±0.2°, 30.29±0.2°, and 31.08±0.2°; (2) The crystal form C of the compound shown in Formula I has a Cu-Kα radiation X-ray powder diffraction pattern expressed in 2θ angles with one or more of the following diffraction peaks: 12.88±0.2°, 15.05±0.2°, 20.85±0.2°, 21.68±0.2°, 23.11±0.2°, 24.79±0.2°; For example, in crystal form C of the compound shown in Formula I, the strongest diffraction peak is found at 11.51 ± 0.2° in the X-ray powder diffraction pattern expressed as 2θ angle using Cu-Kα radiation. For example, the crystal form C of the compound shown in Formula I has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 11.51±0.2°, 18.01±0.2°, 22.56±0.2°, 25.68±0.2°, 12.88±0.2°, 15.05±0.2°, 20.85±0.2°, 21.68±0.2°, and 23.11±0.2°. Preferably, the crystal form C of the compound shown in Formula I, when subjected to Cu-Kα radiation and expressed in 2θ angle X-ray powder diffraction pattern, further exhibits diffraction peaks at one or more of the following locations: 9.022±0.2°, 10.212±0.2°, 16.163±0.2°, 16.96±0.2°, 17.22±0.2°, 26.937±0.2°, 29.445±0.2°, 30.137±0.2°, and 30.354±0.2°. (3) The crystal form A of the compound shown in Formula IX, when subjected to Cu-Kα radiation and expressed in 2θ angle X-ray powder diffraction pattern, also has diffraction peaks at one or more of the following locations: 10.57±0.2°, 12.34±0.2°, 12.77±0.2°, 14.06±0.2°, 14.40±0.2°, 14.97±0.2°, 19.88±0.2°, 22.64±0.2°, 23.18±0.2° and 24.22±0.2°; For example, the crystal form A of the compound pair shown in Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.96±0.2°, 16.71±0.2°, 17.79±0.2°, 20.33±0.2°, 24.66±0.2°, 10.57±0.2°, 12.34±0.2°, 12.77±0.2°, 14.06±0.2°, 14.40±0.2°, and 14.97±0.2°. Preferably, the crystal form A of the compound shown in Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further exhibits diffraction peaks at one or more of the following locations: 9.93±0.2°, 10.13±0.2°, 11.03±0.2°, 11.88±0.2°, 17.56±0.2°, 18.41±0.2°, 18.70±0.2°, 20.68±0.2°, 22.11±0.2°, 25.43±0.2°, 25.98±0.2°, 27.35±0.2°, 27.52±0.2°, 28.08±0.2°, and 29.17±0.2°; (4) The crystal form B of the compound shown in Formula IX, when subjected to Cu-Kα radiation and expressed in 2θ angle X-ray powder diffraction pattern, also has diffraction peaks at one or more of the following locations: 8.20±0.2°, 10.13±0.2°, 11.12±0.2°, 13.18±0.2°, 16.13±0.2°, 18.67±0.2°, 19.47±0.2° and 19.85±0.2°; For example, the crystal form B of the compound shown in Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.34±0.2°, 9.34±0.2°, 9.92±0.2°, 12.84±0.2°, 16.61±0.2°, 8.20±0.2°, 10.13±0.2°, 13.18±0.2°, and 16.13±0.2°. Preferably, the crystal form B of the compound shown in Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle further has diffraction peaks at one or more of the following locations: 11.47±0.2°, 16.36±0.2°, 18.60±0.2° and 21.53±0.2°; (5) The crystal form C of the compound shown in Formula IX, when subjected to Cu-Kα radiation and expressed in 2θ angle X-ray powder diffraction pattern, also has diffraction peaks at one or more of the following locations: 9.21±0.2°, 16.11±0.2°, 16.57±0.2°, 19.39±0.2° and 20.01±0.2°; For example, the crystal form C of the compound shown in Formula IX has a relative intensity of 60%-100% for its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation, with a diffraction peak at 19.82±0.2°, preferably 70%-80%, for example 71.2%. For example, the crystal form C of the compound shown in Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.23±0.2°, 19.82±0.2°, 9.21±0.2°, 16.11±0.2°, 16.57±0.2°, 19.39±0.2°, 9.80±0.2°, 11.12±0.2°, and 20.01±0.2°. Preferably, the crystal form C of the compound shown in Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further exhibits diffraction peaks at one or more of the following locations: 8.07±0.2°, 8.26±0.2°, 9.80±0.2°, 11.12±0.2°, 12.72±0.2°, 15.24±0.2°, 15.48±0.2°, 18.20±0.2°, 18.71±0.2°, 21.52±0.2°, 23.51±0.2°, and 23.83±0.2°; (6) The crystal form D of the compound shown in Formula IX, when subjected to Cu-Kα radiation and expressed in 2θ angle X-ray powder diffraction pattern, also has diffraction peaks at one or more of the following locations: 8.52±0.2°, 12.18±0.2°, 13.12±0.2°, 16.60±0.2°, 20.07±0.2° and 24.00±0.2°; For example, the crystal form D of the compound shown in Formula IX has an X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation, with a relative intensity of the diffraction peak at 6.13±0.2° of 80%-100%, preferably with the strongest diffraction peak at 6.13±0.2°. For example, the crystal form D of the compound shown in Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.13±0.2°, 10.87±0.2°, 18.38±0.2°, 8.52±0.2°, 12.18±0.2°, 13.12±0.2°, 16.60±0.2°, 20.07±0.2°, and 24.00±0.2°. Preferably, the crystal form D of the compound shown in Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further exhibits diffraction peaks at one or more of the following locations: 14.25±0.2°, 14.42±0.2°, 17.00±0.2°, 19.09±0.2°, 19.34±0.2°, 21.12±0.2°, 21.28±0.2°, 21.59±0.2°, 21.72±0.2°, 23.14±0.2°, and 24.27±0.2°; (7) The crystal form E of the compound shown in Formula IX, when subjected to Cu-Kα radiation and expressed in 2θ angle X-ray powder diffraction pattern, also has diffraction peaks at one or more of the following locations: 13.85±0.2°, 14.30±0.2°, 17.74±0.2°, 19.04±0.2°, 21.93±0.2°, 22.25±0.2°, 23.08±0.2° and 23.43±0.2°; For example, the crystal form E of the compound shown in Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.66±0.2°, 11.50±0.2°, 17.97±0.2°, 19.83±0.2°, 23.95±0.2°, 13.85±0.2°, 14.30±0.2°, 17.74±0.2°, 19.04±0.2°, and 21.93±0.2°. Preferably, the crystal form E of the compound shown in Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further has diffraction peaks at one or more of the following locations: 8.45±0.2°, 9.02±0.2°, 9.84±0.2°, 11.19±0.2°, 12.70±0.2°, 15.59±0.2°, 16.56±0.2°, 16.93±0.2°, 18.75±0.2°, 20.55±0.2°, 25.05±0.2°, and 26.98±0.2°; (8) The crystal form F of the compound shown in Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles also has diffraction peaks at one or more of the following locations: 10.34±0.2°, 15.73±0.2°, 16.34±0.2°, 20.42±0.2°, 20.72±0.2°, 24.34±0.2° and 25.74±0.2°; For example, the crystal form F of the compound shown in Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.15±0.2°, 16.55±0.2°, 17.30±0.2°, 21.48±0.2°, 10.34±0.2°, 15.73±0.2°, 16.34±0.2°, 20.42±0.2°, and 20.72±0.2°. Preferably, the crystal form F of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further exhibits diffraction peaks at one or more of the following locations: 6.99±0.2°, 11.85±0.2°, 12.27±0.2°, 12.57±0.2°, 13.97±0.2°, 18.42±0.2°, 20.98±0.2°, 21.22±0.2°, 21.83±0.2°, 21.97±0.2°, 26.02±0.2°, and 26.83±0.2°; (9) The crystal form G of the compound shown in Formula IX has a diffraction peak at one or more of the following locations when its X-ray powder diffraction pattern is expressed in 2θ angle using Cu-Kα radiation: 23.83±0.2°, 25.37±0.2°, 25.63±0.2° and 27.60±0.2°. For example, the crystal form G of the compound shown in Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 7.65±0.2°, 13.76±0.2°, 20.35±0.2°, 21.01±0.2°, 21.57±0.2°, 23.83±0.2°, 25.37±0.2°, 25.63±0.2°, and 27.60±0.2°. Preferably, the crystal form G of the compound shown in Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further has diffraction peaks at one or more of the following locations: 11.87±0.2°, 12.60±0.2°, 12.76±0.2°, 16.07±0.2°, 20.05±0.2°, 22.75±0.2° and 23.83±0.2°; (10) The crystal form H of the compound shown in Formula IX, when subjected to Cu-Kα radiation and expressed in 2θ angle X-ray powder diffraction pattern, also has diffraction peaks at one or more of the following locations: 10.39±0.2°, 11.07±0.2°, 11.60±0.2°, 12.56±0.2°, 17.07±0.2°, 19.09±0.2°, 21.12±0.2°, 21.46±0.2°, 25.23±0.2° and 27.27±0.2°; For example, the crystal form H of the compound shown in Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 8.27±0.2°, 9.70±0.2°, 16.55±0.2°, 19.78±0.2°, 11.07±0.2°, 12.56±0.2°, 17.07±0.2°, 19.09±0.2°, and 21.46±0.2°. Preferably, the crystal form H of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles further has diffraction peaks at one or more of the following locations: 5.21±0.2°, 11.60±0.2°, 15.29±0.2°, 18.79±0.2° and 23.36±0.2°; (11) The crystal form I of the compound shown in Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles also has diffraction peaks at one or more of the following locations: 14.20±0.2°, 16.67±0.2°, 18.00±0.2°, 18.74±0.2°, 20.07±0.2° and 24.06±0.2°; For example, the crystal form I of the compound shown in Formula IX has an X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation, with a relative intensity of 80%-100% at 6.01±0.2°, preferably with the strongest diffraction peak at 6.01±0.2°. For example, the crystal form I of the compound shown in Formula IX has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.01±0.2°, 10.63±0.2°, 12.79±0.2°, 14.20±0.2°, 16.67±0.2°, 18.00±0.2°, 20.07±0.2°, and 24.06±0.2°. Preferably, the crystal form I of the compound represented by Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle further has diffraction peaks at one or more of the following locations: 11.99±0.2°, 17.84±0.2° and 23.22±0.2°; (12) The crystal form J of the compound shown in Formula IX, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle also has diffraction peaks at one or more of the following locations: 15.30±0.2°, 16.41±0.2°, 18.79±0.2°, 19.07±0.2°, 19.66±0.2° and 21.25±0.2°.

5. The crystal form C of the compound of formula I as described in claim 3, or the cyclic nitrogen-containing compound, characterized in that, It satisfies one or more of the following conditions: (1) The crystal form A of the compound shown in Formula II has the diffraction peaks shown in Table 1 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 1 Preferably, the crystal form A of the compound represented by Formula II has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 1. (2) The differential scanning calorimetry curve of the compound shown in Formula II has endothermic peaks at peak temperatures of 98.33±3℃ and 206.94±3℃. Preferably, the differential scanning calorimetry curve of crystal form A of the compound represented by Formula II is basically as shown in Figure 2; (3) The thermogravimetric analysis curve of the compound shown in Formula II, crystal form A, shows a weight loss of about 0.48% in the temperature range of 34.7±3℃ to 70.0±3℃, a weight loss of about 2.11% in the temperature range of 70.0±3℃ to 95.0±3℃, a weight loss of about 1.38% in the temperature range of 95.0±3℃ to 140.0±3℃, and a weight loss of about 0.34% in the temperature range of 140.0±3℃ to 220.0±3℃; Preferably, the thermogravimetric analysis curve of crystal form A of the compound represented by Formula II is basically as shown in Figure 3; (4) In the crystal form A of the compound shown in Formula II, x' is water and q is 1; (5) The crystal form C of the compound shown in Formula I has the diffraction peaks shown in Table 2 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 2 Preferably, the crystal form C of the compound shown in Formula I has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 4. (6) The differential scanning calorimetry curve of the compound shown in Formula I has an endothermic peak at a peak temperature of 238.92±3℃. Preferably, the differential scanning calorimetry curve of crystal form C of the compound shown in Formula I is basically as shown in Figure 5; (7) The crystal form C of the compound shown in Formula I has a thermogravimetric analysis curve showing a weight loss of about 0.81% in the temperature range of 35.56±3℃ to 230.00±3℃; Preferably, the thermogravimetric analysis curve of crystal form C of the compound shown in Formula I is basically as shown in Figure 6; (8) The crystal form C of the compound shown in Formula I is solvent-free; (9) The crystal form A of the compound shown in Formula IX has the diffraction peaks shown in Table 3 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 3 Preferably, the crystal form A of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 7. (10) The differential scanning calorimetry curve of the compound shown in Formula IX, crystal form A, has endothermic peaks at peak temperatures of 95.83±3℃ and 194.7±3℃. Preferably, the differential scanning calorimetry curve of crystal form A of the compound represented by formula IX is basically as shown in Figure 8; (11) The thermogravimetric analysis curve of the compound shown in Formula IX, crystal form A, shows a weight loss of about 2.03% in the temperature range of 30.52±3℃ to 60.0±3℃, a weight loss of about 5.13% in the temperature range of 60.0±3℃ to 100.0±3℃, and a weight loss of about 0.5% in the temperature range of 100.0±3℃ to 190.0±3℃; Preferably, the thermogravimetric analysis curve of crystal form A of the compound represented by formula IX is basically as shown in Figure 9; (12) In the crystal form A of the compound shown in Formula IX, g is water, d is 1, and h is 3; (13) The crystal form B of the compound shown in Formula IX has the diffraction peaks shown in Table 4 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 4 Preferably, the crystal form B of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 11. (14) In the crystal form B of the compound shown in Formula IX, d is 1; (15) In the crystal form B of the compound shown in Formula IX, h is 0; (16) The crystal form C of the compound shown in Formula IX has the diffraction peaks shown in Table 5 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 5 Preferably, the crystal form C of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 12. (17) The crystal form C of the compound shown in Formula IX is 1, 1.1 or 1.02, for example 1.02; Preferably, in the crystal form C of the compound represented by Formula IX, g is tetrahydrofuran, d is 1, and h is 0.2; or, g is tetrahydrofuran, d is 1.02, and h is 0.16; or, d is 1, and h is 0. (18) The crystal form D of the compound shown in Formula IX has the diffraction peaks shown in Table 6 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 6 Preferably, the crystal form D of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 13. (19) The crystal form D of the compound represented by Formula IX is 1; Preferably, in the compound represented by Formula IX, crystal form D, g is water, d is 1, and h is 0, 1, or 3; (20) The crystal form E of the compound shown in Formula IX has the diffraction peaks shown in Table 7 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 7 Preferably, the crystal form E of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 14. (21) The differential scanning calorimetry curve of the compound shown in Formula IX has endothermic peaks at peak temperatures of 102.94±3℃ and 183.71±3℃. Preferably, the differential scanning calorimetry curve of crystal form E of the compound represented by formula IX is basically as shown in Figure 15; (22) The thermogravimetric analysis curve of the compound shown in Formula IX, crystal form E, shows a weight loss of about 3.11% in the temperature range of 33.06±3℃ to 55.0±3℃, a weight loss of about 3.82% in the temperature range of 55±3℃ to 120.0±3℃, and a weight loss of about 1.21% in the temperature range of 120.0±3℃ to 190.0±3℃; Preferably, the thermogravimetric analysis curve of the crystal form E of the compound represented by Formula IX is basically as shown in Figure 16; (23) The crystal form E of the compound shown in Formula IX is 1, 1.1 or 1.02, for example 1.02; Preferably, in the crystal form E of the compound represented by Formula IX, d is 1, g is isopropanol, and h is 1; Alternatively, d is 1.02, g is isopropanol, and h is 0.98; (24) The crystal form F of the compound shown in Formula IX has the diffraction peaks shown in Table 8 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 8 Preferably, the crystal form F of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 17. (25) The differential scanning calorimetry curve of the compound shown in Formula IX has an endothermic peak at a peak temperature of 266.84±3℃. Preferably, the differential scanning calorimetry curve of crystal form F of the compound represented by formula IX is basically as shown in Figure 18; (26) The crystal form F of the compound shown in Formula IX has a thermogravimetric analysis curve showing a weight loss of about 2.2% in the temperature range of 34.19±3℃ to 260.0±3℃; Preferably, the thermogravimetric analysis curve of crystal form F of the compound represented by formula IX is basically as shown in Figure 19; (27) In the crystal form F of the compound shown in Formula IX, d is 1, 1.1 or 1.02, for example 1.02; Preferably, in the crystal form F of the compound represented by Formula IX, d is 1 and h is 0; (28) The crystal form G of the compound shown in Formula IX has the diffraction peaks shown in Table 9 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 9 Preferably, the crystal form G of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 20. (29) In the crystal form G of the compound shown in Formula IX, d is 1, 1.1 or 1.2, for example 1.1; Preferably, in the crystal form G of the compound represented by Formula IX, d is 1, g is 1,4-dioxane, and h is 3, or d is 1.1, g is 1,4-dioxane, and h is 2.96; (30) The crystal form H of the compound shown in Formula IX has the diffraction peaks shown in Table 10 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 10 Preferably, the crystal form H of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 21. (31) The differential scanning calorimetry curve of the compound shown in Formula IX has endothermic peaks at peak temperatures of 45.53±3℃, 155.23±3℃ and 191.45±3℃. Preferably, the differential scanning calorimetry curve of crystal form H of the compound represented by formula IX is basically as shown in Figure 22; (32) The thermogravimetric analysis curve of the compound shown in Formula IX, crystal form H, shows a weight loss of about 1.74% in the temperature range of 32.99±3℃ to 100.0±3℃ and a weight loss of about 5.38% in the temperature range of 100±3℃ to 180.0±3℃. Preferably, the thermogravimetric analysis curve of crystal form H of the compound represented by formula IX is basically as shown in Figure 23; (33) The crystal form H of the compound shown in Formula IX, g is methyl tert-butyl ether, and h is 0.5, 0.4 or 0.45, for example 0.45; (34) The crystal form of the compound represented by formula IX is H, and d is 1; Preferably, in the compound represented by Formula IX, the crystal form H, g is methyl tert-butyl ether, h is 0.5, and d is 1; (35) The crystal form I of the compound shown in Formula IX has the diffraction peaks shown in Table 11 in the X-ray powder diffraction pattern of Cu-Kα radiation and expressed in 2θ angle. Table 11 Preferably, the crystal form I of the compound represented by Formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 24. (36) The crystal form of the compound represented by formula IX is I, and d is 1; (37) In the crystal form I of the compound represented by formula IX, h is 0; Preferably, in the crystal form I of the compound represented by formula IX, d is 1 and h is 0; (38) The crystal form J of the compound shown in Formula IX has the diffraction peaks shown in Table 12 in the X-ray powder diffraction pattern of Cu-Kα radiation and expressed in 2θ angle. Table 12 Preferably, the crystal form J of the compound represented by formula IX has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 25. (39) The crystal form J of the compound represented by formula IX is 1; Preferably, the crystal form J of the compound represented by Formula IX has d = 1 and h = 0.

6. The cyclic nitrogen-containing compound as described in claim 1, characterized in that, The compound represented by Formula IX is a single crystal of the compound represented by Formula IX, where g is water, h is 3, and d is 1. It has the following unit cell parameters: triclinic crystal system, space group p-1; α＝89.299(7)°， β＝86.519(6)°， γ=84.364(6)°, The number of asymmetric units within the unit cell is Z = 2, and the crystal density is 1.46 mg / m³. 3 .

7. A method for preparing crystal form C of the compound of formula I as described in any one of claims 3-6 or the cyclic nitrogen-containing compound, characterized in that, It is any of the following schemes: Option 1: Option 1 includes the following steps: cooling the mixture of the compound and the solvent to crystallize, drying, and obtaining the crystal form; The compound is the compound shown in Formula II, and the solvent is ethyl acetate or acetonitrile, to obtain the crystal form C of the compound shown in Formula I; The compound is the compound shown in Formula IX, and the solution is a mixture of acetone and water to obtain crystal form A of the compound shown in Formula IX; The compound is the compound shown in Formula IX, and the solution is acetonitrile, to obtain crystal form B of the compound shown in Formula IX; Option 2 Scheme 2 includes the following steps: Precipitating and drying a mixture of the compound and solvent to obtain the crystal form; The compound is crystal form A of the compound shown in Formula IX, and the solution is tetrahydrofuran, to obtain crystal form C of the compound shown in Formula IX; The compound is crystal form A of the compound shown in Formula IX, and the solution is isopropanol, to obtain crystal form E of the compound shown in Formula IX; The compound is crystal form A of the compound shown in Formula IX, and the solution is acetonitrile and n-heptane to obtain crystal form F of the compound shown in Formula IX; The compound is crystal form A of the compound shown in Formula IX, and the solution is 1,4-dioxane, to obtain crystal form G of the compound shown in Formula IX; The compound is crystal form A of the compound shown in Formula IX, and the solution is a mixed solution of acetonitrile and methyl tert-butyl ether to obtain crystal form H of the compound shown in Formula IX; Option 3: Scheme 3 includes the following steps: Under nitrogen protection, the crystal form A of the compound shown in Formula IX is heated at 55°C to obtain the crystal form D of the compound shown in Formula IX; Alternatively, under nitrogen protection, the crystal form A of the compound shown in Formula IX is heated at 25°C to obtain the crystal form I of the compound shown in Formula IX; Alternatively, under nitrogen protection, the crystal form H of the compound shown in Formula IX is heated at 170°C to obtain the crystal form J of the compound shown in Formula IX. Option 4: Option 4 includes the following steps: Step (1): Mix the mixture of the compound shown in Formula I, acetone and water with crystal form A of the compound shown in Formula IX; Step (2): Add a mixture of toluene-4-sulfonic acid, acetone and water, crystallize to obtain a single crystal of the compound shown in Formula IX.

8. The preparation method according to claim 7, characterized in that, It satisfies one or more of the following conditions: (1) The cooling crystallization is achieved by cooling from 50°C to 25°C; (2) The acetone and water mixture is a mixture of acetone and water with a volume ratio of 19:1; (3) The drying is centrifugal and / or vacuum drying; (4) In step (1), the mass ratio of the compound shown in Formula I to acetone is (0.5-2):(8-12), for example 1.63:10.3; (5) In step (1), the mass ratio of acetone to water is (9-11):(0.5-1.5), for example, 10.3:1.3; (6) In step (1), the mass ratio of crystal form A of the compound shown in Formula IX to the compound shown in Formula I is 1:100 to 1:10, for example 8:

163. (7) In step (2), the mass ratio of toluene-4-sulfonic acid, acetone and water is (1-2.5):(5-10):(0.5-1.5), for example 0.58:2.57:0.32; (8) In step (2), the toluene-4-sulfonic acid is toluene-4-sulfonic acid monohydrate; (9) In step (2), the mixture is added in two parts. Preferably, the first addition is made at 45-55°C, and the mass ratio of toluene-4-sulfonic acid to the compound shown in Formula I is 1:(2-4), for example, 0.58:1.

63. The second addition is made at 20-30°C, and the mass ratio of toluene-4-sulfonic acid to the compound shown in Formula I is 1:(4-8), for example, 0.29:1.

63.

9. A pharmaceutical composition comprising crystal form C of a compound of formula II as claimed in claim 1 or 2, a compound of formula IX as claimed in claim 1 or 2, or a compound of formula I as claimed in claim 3, and pharmaceutical excipients; Preferably, the pharmaceutical composition comprises the compound of Formula II or the compound of Formula IX as described in any one of claims 3-6.

10. The use of a crystal form C of the pharmaceutical composition of claim 9, the compound of formula II of claim 1 or 2, the compound of formula IX of claim 1 or 2, or the compound of formula I of claim 3 in the preparation of a medicament, wherein the medicament is used for the prevention or treatment of lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, or colon cancer. Preferably, the application is the use of the compound of Formula II or the compound of Formula IX according to any one of claims 3-6 in the preparation of the drug.

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