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

Abstract

Provided in the present invention are a fused ring nitrogen-containing compound, a crystal form thereof, and a preparation method therefor and the use thereof. Specifically provided are a fused ring nitrogen-containing compound containing a compound as shown in 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 drug activity and broad 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 III.

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

[0013] Where w is 0.5-2.5; e is 0-2.

[0014] In one embodiment, in the compound represented by Formula III, w (molar equivalent of hydrochloric acid) is 0.5, 1, 1.1, 1.6, 1.7, 1.8, 1.76, 1.06, 1.5, or 2.

[0015] In one embodiment, e is 0 (solvent-free) in the compound represented by Formula III.

[0016] In one embodiment, in the compound represented by Formula III, e (molar equivalent of water) is 1-2, for example, e is 1.5.

[0017] In one embodiment, the compound represented by Formula III is crystal form A of the compound represented by Formula III, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 4.61±0.2°, 5.02±0.2°, 9.19±0.2° and 13.76±0.2°.

[0018] In one embodiment, the crystal form A of the compound represented by Formula III, 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: 6.57±0.2°, 6.89±0.2°, 9.96±0.2°, 10.48±0.2°, 10.64±0.2°, 14.69±0.2°, and 14.90±0.2°.

[0019] In one embodiment, the crystal form A of the compound represented by Formula III has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 4.61±0.2°, 5.02±0.2°, 9.19±0.2°, 13.76±0.2°, 6.57±0.2°, 6.89±0.2°, 9.96±0.2°, 10.48±0.2°, and 10.64±0.2°.

[0020] In one embodiment, the crystal form A of the compound represented by Formula III, 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: 18.34±0.2°, 19.13±0.2°, 19.30±0.2°, 20.81±0.2°, 21.68±0.2°, 23.09±0.2°, 24.03±0.2°, 26.13±0.2°, and 28.17±0.2°.

[0021] In one embodiment, the crystal form A of the compound represented by Formula III has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 2.

[0022] In one embodiment, the crystal form A of the compound represented by Formula III has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 4.

[0023] In one embodiment, in crystal form A of the compound represented by Formula III, w is 1, 1.1, or 1.06 (molar equivalent of hydrochloric acid), for example, 1.06.

[0024] In one embodiment, in crystal form A of the compound represented by Formula III, e is 0 or 1.5. Preferably, e is 0.

[0025] In one embodiment, the compound represented by Formula III is crystal form B of the compound represented by Formula III, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 6.47±0.2°, 7.19±0.2°, 9.11±0.2°, 11.63±0.2°, and 14.45±0.2°.

[0026] In one embodiment, the crystal form B of the compound represented by Formula III, 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: 17.37±0.2°, 18.21±0.2°, 19.44±0.2°, 20.17±0.2°, 20.82±0.2°, 22.41±0.2°, and 24.58±0.2°.

[0027] In one embodiment, the crystal form B of the compound represented by Formula III has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.47±0.2°, 7.19±0.2°, 9.11±0.2°, 11.63±0.2°, 14.45±0.2°, 17.37±0.2°, 18.21±0.2°, 19.44±0.2°, 20.17±0.2°, and 20.82±0.2°.

[0028] In one embodiment, the crystal form B of the compound represented by Formula III, when subjected to Cu-Kα radiation and exhibiting an X-ray powder diffraction pattern at an angle of 2θ, further shows diffraction peaks at one or more of the following locations: 12.94±0.2°, 13.41±0.2°, 15.41±0.2°, 15.75±0.2°, 16.23±0.2°, 16.72±0.2°, 26.01±0.2°, 26.17±0.2°, 26.47±0.2°, 27.96±0.2°, 28.62±0.2°, 30.04±0.2°, and 30.37±0.2°.

[0029] In one embodiment, the crystal form B of the compound represented by Formula III has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 3.

[0030] In one embodiment, the crystal form B of the compound represented by Formula III has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 5.

[0031] In one embodiment, the differential scanning calorimetry (DSC) curve of the compound represented by Formula III, in crystal form B, has an endothermic peak at a peak temperature of 186.88 ± 3 °C.

[0032] In one embodiment, the differential scanning calorimetry (DSC) curve of crystal form B of the compound represented by Formula III is basically as shown in Figure 6.

[0033] In one embodiment, the crystal form B of the compound represented by Formula III exhibits a weight loss of approximately 1.42% in the temperature range of 24.07±3℃ to 120.0±3℃ and a weight loss of approximately 9.84% in the temperature range of 120.00±3℃ to 205.00±3℃.

[0034] In one embodiment, the thermogravimetric analysis (TGA) curve of crystal form B of the compound represented by Formula III is basically as shown in Figure 7.

[0035] In one embodiment, in crystal form B of the compound represented by Formula III, w (molar equivalent of hydrochloric acid) is 1.76, 1.7, or 1.8, for example, 1.76.

[0036] In one embodiment, in crystal form B of the compound represented by Formula III, e is 0.

[0037] In one embodiment, the compound represented by Formula III is crystal form C of the compound represented by Formula III, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 9.84±0.2°, 10.51±0.2°, 12.19±0.2°, 13.39±0.2° and 14.40±0.2°.

[0038] In one embodiment, the crystal form C of the compound represented by Formula III, 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: 18.16±0.2°, 18.29±0.2°, 19.39±0.2°, 20.81±0.2°, 21.75±0.2°, 26.41±0.2°, and 27.48±0.2°.

[0039] In one embodiment, the crystal form C of the compound represented by Formula III has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 9.84±0.2°, 10.51±0.2°, 12.19±0.2°, 13.39±0.2°, 14.40±0.2°, 18.16±0.2°, 18.29±0.2°, 19.39±0.2°, 20.81±0.2°, 21.75±0.2°, and 26.41±0.2°.

[0040] In one embodiment, the crystal form C of the compound represented by Formula III, 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: 11.61±0.2°, 20.02±0.2°, 22.51±0.2°, 22.90±0.2°, 23.25±0.2°, 23.49±0.2°, 24.46±0.2°, 25.11±0.2°, 26.94±0.2°, 28.37±0.2°, 28.97±0.2°, and 29.32±0.2°.

[0041] In one embodiment, the crystal form C of the compound represented by Formula III has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 4.

[0042] In one embodiment, the crystal form C of the compound represented by Formula III has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 8.

[0043] In one embodiment, in the crystal form C of the compound represented by Formula III, w is 1.7, 1.8, or 1.6, for example, 1.7.

[0044] In one embodiment, in the crystal form C of the compound represented by Formula III, e is 0.

[0045] This invention provides a compound represented by formula IV.

[0046] Where r is 0.5-2 and t is 0-2.

[0047] In one embodiment, in the compound represented by Formula IV, r is 0.5, 0.9, 1, 0.97, 0.96, or 1.5.

[0048] In one embodiment, t is 0 in the compound represented by formula IV.

[0049] In one embodiment, in the compound represented by Formula IV, t is 1-2, for example, t is 1.7.

[0050] In one embodiment, the compound represented by Formula IV is crystal form A of the compound represented by Formula IV, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 5.14±0.2°, 9.01±0.2°, and 15.03±0.2°.

[0051] In one embodiment, the crystal form A of the compound represented by Formula IV, 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: 11.45±0.2°, 17.44±0.2°, 21.45±0.2°, 21.78±0.2°, 24.82±0.2°, 25.95±0.2°, and 26.68±0.2°.

[0052] In one embodiment, the crystal form A of the compound represented by Formula IV has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.14±0.2°, 9.01±0.2°, 15.03±0.2°, 11.45±0.2°, 17.44±0.2°, 21.45±0.2°, 21.78±0.2°, 24.82±0.2°, and 25.95±0.2°.

[0053] In one embodiment, the crystal form A of the compound represented by Formula IV, 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: 6.11±0.2°, 6.60±0.2°, 7.35±0.2°, 8.63±0.2°, 14.62±0.2°, 16.45±0.2°, 20.40±0.2°, 23.81±0.2°, 25.47±0.2°, 27.96±0.2°, and 28.43±0.2°.

[0054] In one embodiment, the crystal form A of the compound represented by Formula IV has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 5.

[0055] In one embodiment, the crystal form A of the compound represented by Formula IV has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 9.

[0056] In one embodiment, the crystal form A of the compound represented by Formula IV has r of 1, 0.97, or 0.9, for example, 0.97.

[0057] In one embodiment, the crystal form A of the compound represented by Formula IV has a value of 0.

[0058] In one embodiment, the compound represented by Formula IV is crystal form B of the compound represented by Formula IV, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 7.11±0.2°, 7.57±0.2°, 7.72±0.2°, 8.10±0.2°, and 10.27±0.2°.

[0059] In one embodiment, the crystal form B of the compound represented by Formula IV, 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: 13.86±0.2°, 14.11±0.2°, 14.71±0.2°, 15.44±0.2°, 16.07±0.2°, 23.18±0.2°, 24.18±0.2°, and 25.17±0.2°.

[0060] In one embodiment, the crystal form B of the compound represented by Formula IV has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 7.11±0.2°, 7.57±0.2°, 7.72±0.2°, 8.10±0.2°, 13.86±0.2°, 14.11±0.2°, 14.71±0.2°, 23.18±0.2°, 24.18±0.2°, and 25.17±0.2°.

[0061] In one embodiment, the crystal form B of the compound represented by Formula IV, 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: 10.27±0.2°, 12.55±0.2°, 12.67±0.2°, 13.19±0.2°, 16.73±0.2°, 17.92±0.2°, 18.38±0.2°, 18.58±0.2°, 20.18±0.2°, 21.2±0.2°, 22.2±0.2°, 25.58±0.2°, and 27.82±0.2°.

[0062] In one embodiment, the crystal form B of the compound represented by Formula IV has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 6.

[0063] In one embodiment, the crystal form B of the compound represented by Formula IV has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 10.

[0064] In one embodiment, the differential scanning calorimetry (DSC) curve of the compound represented by Formula IV, in crystal form B, exhibits endothermic peaks at peak temperatures of 34.85±3℃, 90.79±3℃, and 204.38±3℃.

[0065] In one embodiment, the differential scanning calorimetry (DSC) curve of crystal form B of the compound represented by Formula IV is basically as shown in Figure 11.

[0066] In one embodiment, the crystal form B of the compound represented by Formula IV exhibits a weight loss of approximately 2.06% in the temperature range of 33.44±3℃ to 50.0±3℃, approximately 0.56% in the temperature range of 50.0±3℃ to 100.0±3℃, approximately 0.39% in the temperature range of 100.00±3℃ to 180.00±3℃, and approximately 1.0% in the temperature range of 180.00±3℃ to 230.00±3℃.

[0067] In one embodiment, the thermogravimetric analysis (TGA) curve of crystal form B of the compound represented by formula IV is basically as shown in Figure 12.

[0068] In one embodiment, in crystal form B of the compound represented by Formula IV, r is 1, 0.9, or 0.96, for example, 0.96.

[0069] In one embodiment, in crystal form B of the compound represented by formula IV, t is 0 or 1.7. Preferably, t is 0.

[0070] In one embodiment, in crystal form B of the compound represented by formula IV, r is 1 and t is 0; or, r is 0.96 and t is 0.

[0071] This invention provides a compound of formula V.

[0072] The structure of the compound shown in formula V is as follows:

[0073] y is 0.5-1.5; u is 0-2; i is 0-2. Preferably, i and u are 0.

[0074] In one embodiment, in the compound represented by formula V, y is 1.1, 1.2, 1.14, 1, 1.09, or 1.05.

[0075] In one embodiment, in the compound represented by formula V, y and u are both 0.

[0076] In one embodiment, in the compound represented by formula V, i is 0, and u is 0.1, 0.91, 0.9, or 1, for example, 0.91.

[0077] In one embodiment, in the compound represented by formula V, u is 0, and i is 0.1, 0.18, 0.2, or 0.5, for example, 0.18 or 0.1.

[0078] In one embodiment, the compound represented by formula V is crystal form B of the compound represented by formula V, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 6.83±0.2°, 12.89±0.2°, 14.44±0.2°, 15.91±0.2°, 25.08±0.2°, and 25.50±0.2°.

[0079] In one embodiment, the crystal form B of the compound represented by formula V, 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: 8.32±0.2°, 10.26±0.2°, 13.93±0.2°, 14.67±0.2°, 20.35±0.2°, 20.49±0.2°, 21.15±0.2°, and 21.65±0.2°.

[0080] In one embodiment, the crystal form B of the compound represented by formula V has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.83±0.2°, 12.89±0.2°, 14.44±0.2°, 15.91±0.2°, 25.08±0.2°, 25.50±0.2°, 8.32±0.2°, 20.35±0.2°, and 20.49±0.2°.

[0081] In one embodiment, the crystal form B of the compound represented by formula V, 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: 8.52±0.2°, 9.17±0.2°, 13.46±0.2°, 16.25±0.2°, and 17.94±0.2°.

[0082] In one embodiment, the crystal form B of the compound represented by formula V has X-ray powder diffraction patterns, expressed in 2θ angles, with the diffraction peaks shown in Table 7.

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

[0084] In one embodiment, in the crystal form B of the compound represented by formula V, y is 1.1, 1, or 1.09, for example, 1.09.

[0085] In one embodiment, in the crystal form B of the compound represented by formula V, u and i are 0.

[0086] This invention provides a compound represented by formula VI.

[0087] C4H4O4 is fumaric acid;

[0088] o (molar equivalent of fumaric acid) is 1-1.1.

[0089] In one embodiment, o in the compound represented by formula VI is 1, 1.01, 1.05, or 1.1.

[0090] In one embodiment, the compound represented by Formula VI is crystal form A of the compound represented by Formula VI, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 10.58±0.2°, 12.16±0.2° and 13.98±0.2°.

[0091] In one embodiment, the crystal form A of the compound represented by Formula VI, 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: 6.96±0.2°, 8.60±0.2°, 14.84±0.2°, 15.39±0.2°, 16.63±0.2°, and 17.08±0.2°.

[0092] In one embodiment, the crystal form A of the compound represented by Formula VI has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 10.58±0.2°, 12.16±0.2°, 13.98±0.2°, 6.96±0.2°, 8.60±0.2°, 14.84±0.2°, 15.39±0.2°, 16.63±0.2°, and 17.08±0.2°.

[0093] In one embodiment, the crystal form A of the compound represented by Formula VI, 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: 6.73±0.2°, 9.38±0.2°, 10.28±0.2°, 13.45±0.2°, 19.28±0.2°, and 18.67±0.2°.

[0094] In one embodiment, the crystal form A of the compound represented by Formula VI has X-ray powder diffraction patterns, expressed in terms of 2θ angles, with the diffraction peaks shown in Table 8.

[0095] In one embodiment, the crystal form A of the compound represented by Formula VI has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 14.

[0096] In one embodiment, in the crystal form A of the compound represented by Formula VI, o is 1, 1.1, or 1.01, for example, 1.01.

[0097] This invention provides a compound represented by formula VII.

[0098] CH3SO3H is methanesulfonic acid;

[0099] p (molar equivalent of mesylate) is 1-1.1.

[0100] In one embodiment, p is 1, 1.03, 1.05 or 1.1 in the compound represented by formula VII.

[0101] In one embodiment, the compound represented by Formula VII is crystal form A of the compound represented by Formula VII, and its X-ray powder diffraction pattern, irradiated with Cu-Kα and expressed in 2θ angle, shows diffraction peaks at 9.00±0.2°, 17.44±0.2°, and 21.74±0.2°.

[0102] In one embodiment, the crystal form A of the compound represented by Formula VII, 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: 5.13±0.2°, 6.73±0.2°, 8.61±0.2°, 17.74±0.2°, 24.43±0.2°, and 25.32±0.2°.

[0103] In one embodiment, the crystal form A of the compound represented by Formula VII has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 9.00±0.2°, 17.44±0.2°, 21.74±0.2°, 5.13±0.2°, 6.73±0.2°, 8.61±0.2°, 17.74±0.2°, 24.43±0.2°, and 25.32±0.2°.

[0104] In one embodiment, the crystal form A of the compound represented by Formula VII, 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: 15.55±0.2°, 10.05±0.2°, 11.57±0.2°, 22.37±0.2°, and 26.36±0.2°.

[0105] In one embodiment, the crystal form A of the compound represented by Formula VII has X-ray powder diffraction patterns, expressed in 2θ angles, with the diffraction peaks shown in Table 9.

[0106] In one embodiment, the crystal form A of the compound represented by Formula VII has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 15.

[0107] In one embodiment, in crystal form A of the compound represented by formula VII, p is 1, 1.1, or 1.03, for example, 1.03.

[0108] This invention provides a compound represented by formula X.

[0109] Among them, C 10 H8O6S2 is 1,5-naphthalenedisulfonic acid;

[0110] j (molar equivalent of 1,5-naphthalenedisulfonic acid) is 0.5-1.5;

[0111] z (solvent) is water or acetonitrile;

[0112] k is between 0 and 5.

[0113] In one embodiment, in the compound represented by formula X, j is 1, 0.9, 1.1, 1.02, or 0.93.

[0114] In one embodiment, k is 0 (solvent-free) in the compound represented by formula X.

[0115] In one embodiment, in the compound represented by formula X, k is 0.01-5. For example, if z is water, k is 5 or 4.8; or if z is acetonitrile, k is 0.07.

[0116] In one embodiment, the compound represented by formula X is crystal form A of the compound represented by formula X, and its X-ray powder diffraction pattern, radiated by Cu-Kα radiation and expressed in 2θ angle, shows diffraction peaks at 7.46±0.2°, 12.01±0.2°, and 21.70±0.2°.

[0117] In one embodiment, the crystal form A of the compound represented by formula X, 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: 11.43±0.2°, 13.53±0.2°, 17.24±0.2°, 18.49±0.2°, 18.77±0.2°, 21.08±0.2°, 24.57±0.2°, and 28.44±0.2°.

[0118] In one embodiment, the crystal form A of the compound represented by formula X has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 7.46±0.2°, 12.01±0.2°, 21.70±0.2°, 11.43±0.2°, 13.53±0.2°, 17.24±0.2°, 18.49±0.2°, 18.77±0.2°, and 21.08±0.2°.

[0119] In one embodiment, the crystal form A of the compound represented by formula X, 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: 5.71±0.2°, 13.93±0.2°, 14.91±0.2°, 15.34±0.2°, 22.12±0.2°, 22.80±0.2°, 22.95±0.2°, 24.99±0.2°, and 26.08±0.2°.

[0120] In one embodiment, the crystal form A of the compound represented by formula X has X-ray powder diffraction patterns using Cu-Kα radiation and expressed at 2θ angles, which show the diffraction peaks as shown in Table 10.

[0121] In one embodiment, the crystal form A of the compound represented by formula X has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 16.

[0122] In one embodiment, in the crystal form A of the compound represented by formula X, k is 0, and j is 1, 1.1, or 1.02, for example, 1.02.

[0123] In one embodiment, the compound represented by formula X is crystal form B of the compound represented by formula X, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 8.96±0.2°, 10.81±0.2°, 17.92±0.2° and 22.07±0.2°.

[0124] In one embodiment, the crystal form B of the compound represented by formula X, 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: 11.98±0.2°, 18.4±0.2°, 21.27±0.2°, 23.27±0.2°, 27.26±0.2°, and 27.77±0.2°.

[0125] In one embodiment, the crystal form B of the compound represented by formula X, 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: 5.95±0.2°, 14.09±0.2°, 15.80±0.2°, 16.97±0.2°, 20.03±0.2°, 22.42±0.2°, and 23.79±0.2°.

[0126] In one embodiment, the crystal form B of the compound represented by formula X has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 8.96±0.2°, 10.81±0.2°, 17.92±0.2°, 22.07±0.2°, 11.98±0.2°, 18.4±0.2°, 21.27±0.2°, and 23.27±0.2°.

[0127] In one embodiment, the crystal form B of the compound represented by formula X 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.

[0128] In one embodiment, the crystal form B of the compound represented by formula X has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 17.

[0129] In one embodiment, the crystal form B of the compound represented by formula X has k = 0 and j = 0.9, 1, or 0.93, for example, 0.93.

[0130] In one embodiment, the compound represented by formula X is crystal form C of the compound represented by formula X, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 11.30±0.2°, 22.61±0.2°, 24.69±0.2°, 26.16±0.2°, and 28.57±0.2°.

[0131] In one embodiment, the crystal form C of the compound represented by formula X, 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: 6.36±0.2°, 12.82±0.2°, 17.07±0.2°, 17.48±0.2°, 18.61±0.2°, 20.24±0.2°, and 20.94±0.2°.

[0132] Preferably, the crystal form C of the compound represented by formula X has a relative intensity of 50%-100% for its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation, with the diffraction peak at 22.61±0.2° being the strongest peak.

[0133] In one embodiment, the crystal form C of the compound represented by formula X has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 11.30±0.2°, 22.61±0.2°, 24.69±0.2°, 26.16±0.2°, 28.57±0.2°, 6.36±0.2°, 18.61±0.2°, 12.82±0.2°, and 17.07±0.2°.

[0134] In one embodiment, the crystal form C of the compound represented by formula X, 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: 12.11±0.2° and 15.12±0.2°.

[0135] In one embodiment, the crystal form C of the compound represented by formula X 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.

[0136] In one embodiment, the crystal form C of the compound represented by formula X has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 18.

[0137] In one embodiment, the crystal form C,j of the compound represented by formula X is 1.

[0138] In one embodiment, in the crystal form C of the compound represented by formula X, k is 0 and j is 1, or z is acetonitrile and k is 0.07.

[0139] This invention provides a compound represented by formula XI.

[0140] Wherein, n (the molar equivalent of sodium ions) is 0-1.5.

[0141] In one embodiment, n is 0.6, 1.1, 1.13, or 1.2 in the compound represented by formula XI.

[0142] In one embodiment, m is 0 (solvent-free) in the compound represented by formula XI.

[0143] In one embodiment, in the compound represented by formula XI, m is 0.5-1.5, for example 1, 1.07 or 1.1.

[0144] In one embodiment, the compound represented by formula XI is crystal form A of the compound represented by formula XI, and its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles shows diffraction peaks at 12.78±0.2°, 14.09±0.2° and 14.98±0.2°.

[0145] In one embodiment, the crystal form A of the compound represented by formula XI, 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: 10.67±0.2°, 18.82±0.2°, 19.49±0.2° and 23.58±0.2°.

[0146] In one embodiment, the crystal form A of the compound represented by formula XI, 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: 6.9±0.2°, 9.39±0.2°, 17.22±0.2°, 19.35±0.2°, 21.80±0.2°, 22.45±0.2°, 24.15±0.2°, and 27.926±0.2°.

[0147] In one embodiment, the crystal form A of the compound represented by formula XI has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 12.78±0.2°, 14.09±0.2°, 14.98±0.2°, 10.67±0.2°, 18.82±0.2°, 19.49±0.2°, 23.58±0.2°, and 21.80±0.2°.

[0148] In one embodiment, the crystal form A of the compound represented by formula XI has X-ray powder diffraction patterns using Cu-Kα radiation and expressed at 2θ angles, which show the diffraction peaks as shown in Table 13.

[0149] In one embodiment, the crystal form A of the compound represented by formula XI has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically shown in Figure 19.

[0150] In one embodiment, the crystal form A of the compound represented by formula XI has m = 0 and n = 0.6, 0.7, or 0.62, for example, 0.62.

[0151] The present invention provides a method for preparing the compound shown in Formula III, comprising the following steps: in an ester solvent (e.g., ethyl acetate) or a nitrile solvent (e.g., acetonitrile), the compound shown in Formula I and hydrochloric acid are subjected to a salt-forming reaction to obtain the compound shown in Formula III.

[0152] The present invention provides a method for preparing the compound shown in Formula IV, comprising the following steps: in an ester solvent (e.g., ethyl acetate) or a nitrile solvent (e.g., acetonitrile), the compound shown in Formula I and sulfuric acid are subjected to a salt-forming reaction to obtain the compound shown in Formula IV.

[0153] The present invention provides a method for preparing the compound shown in Formula V, comprising the following steps: in an ester solvent (e.g., ethyl acetate) or a nitrile solvent (e.g., acetonitrile), the compound shown in Formula I and phosphoric acid are subjected to a salt-forming reaction to obtain the compound shown in Formula V.

[0154] The present invention provides a method for preparing the compound shown in Formula VI or Formula VII, comprising the following steps: in a nitrile solvent (e.g., acetonitrile), the compound shown in Formula I, methanesulfonic acid, or fumaric acid are subjected to a salt-forming reaction to obtain the compound shown in Formula VI or Formula VII.

[0155] The present invention provides a method for preparing the compound shown in Formula X, comprising the following steps: subjecting the compound shown in Formula I and 1,5-naphthalenedisulfonic acid to a salt formation reaction in a ketone solvent (e.g., acetone) and water, an ester solvent (e.g., ethyl acetate) or a nitrile solvent (e.g., acetonitrile) to obtain the compound shown in Formula X. Preferably, the mixed solvent of the ketone solvent and water is a mixed solution of acetone and water with a volume ratio of 19:1 (acetone / water).

[0156] The present invention provides a method for preparing the compound shown in Formula XI, comprising the following steps: in an ester solvent (e.g., ethyl acetate), the compound shown in Formula I and NaOH are subjected to a salt-forming reaction to obtain the compound shown in Formula XI.

[0157] The present invention provides a method for preparing crystal form A, crystal form B, crystal form C of the compound shown in Formula III, crystal form A, crystal form B of the compound shown in Formula IV, crystal form B of the compound shown in Formula IV, crystal form A of the compound shown in Formula V, crystal form A of the compound shown in Formula VI, crystal form A of the compound shown in Formula VII, crystal form A of the compound shown in Formula X, crystal form B of the compound shown in Formula X, crystal form C of the compound shown in Formula X, and crystal form A of the compound shown in Formula XI, comprising the following steps: cooling a mixture of the compound and a solvent to crystallize, drying, and obtaining the crystal form.

[0158] The compound is the compound shown in Formula III, and the solvent is ethyl acetate, to obtain crystal form A or crystal form B of the compound shown in Formula III;

[0159] The compound is the compound shown in Formula III, and the solvent is acetonitrile, to obtain crystal form C of the compound shown in Formula III;

[0160] The compound is the compound shown in Formula IV, and the solvent is ethyl acetate, to obtain crystal form A of the compound shown in Formula IV;

[0161] The compound is the compound shown in Formula IV, and the solvent is acetonitrile, to obtain crystal form B of the compound shown in Formula IV;

[0162] The compound is the compound shown in Formula V, and the solvent is acetonitrile, to obtain crystal form B of the compound shown in Formula V;

[0163] The compound is the compound shown in Formula VI, and the solvent is acetonitrile, to obtain crystal form A of the compound shown in Formula VI;

[0164] The compound is the compound shown in Formula VII, and the solvent is acetonitrile, to obtain crystal form A of the compound shown in Formula VII;

[0165] The compound is the compound shown in Formula X, and the solvent is a mixed solution of acetone and water, to obtain crystal form A of the compound shown in Formula X;

[0166] The compound is the compound shown in Formula X, and the solvent is ethyl acetate, to obtain crystal form B of the compound shown in Formula X;

[0167] The compound is the compound shown in Formula X, and the solvent is acetonitrile, to obtain crystal form C of the compound shown in Formula X;

[0168] The compound is the compound shown in Formula XI, and the solvent is ethyl acetate, to obtain crystal form A of the compound shown in Formula XI.

[0169] In the preparation method, the cooling crystallization is, for example, cooling from 50°C to 25°C.

[0170] In the preparation method, the drying is, for example, centrifugal drying and / or vacuum drying.

[0171] Preferably, the method for preparing crystal form A, crystal form B, crystal form C of the compound shown in Formula III, crystal form A of the compound shown in Formula IV, crystal form B of the compound shown in Formula IV, crystal form B of the compound shown in Formula V, crystal form A of the compound shown in Formula VI, crystal form A of the compound shown in Formula VII, crystal form A of the compound shown in Formula X, crystal form B of the compound shown in Formula X, or crystal form C of the compound shown in Formula X includes the following steps: crystallizing a mixture of the compound shown in Formula I, a solvent, and an acid to obtain the crystal form.

[0172] The solution is ethyl acetate and the acid is hydrochloric acid, yielding crystal form A of the compound shown in Formula III;

[0173] The solution is ethyl acetate and the acid is hydrochloric acid, yielding crystal form B of the compound shown in Formula III;

[0174] The solution is acetonitrile and the acid is hydrochloric acid, yielding crystal form C of the compound shown in Formula III;

[0175] The solution is ethyl acetate and the acid is sulfuric acid, yielding crystal form A of the compound shown in Formula IV;

[0176] The solution is acetonitrile and the acid is sulfuric acid, yielding crystal form B of the compound shown in Formula IV;

[0177] The solution is acetonitrile and the acid is phosphoric acid, yielding crystal form B of the compound shown in formula V;

[0178] The solution is acetonitrile and the acid is fumaric acid, yielding crystal form A of the compound shown in formula VI;

[0179] The solution is acetonitrile and the acid is methanesulfonic acid, yielding crystal form A of the compound shown in formula VII;

[0180] The solution is a mixture of acetone and water, and the acid is 1,5-naphthalenedisulfonic acid, to obtain crystal form A of the compound shown in formula X;

[0181] The solution is ethyl acetate and the acid is 1,5-naphthalenedisulfonic acid, yielding crystal form B of the compound shown in formula X;

[0182] The solution is acetonitrile, and the acid is 1,5-naphthalenedisulfonic acid, yielding crystal form C of the compound shown in formula X.

[0183] 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).

[0184] Preferably, in the preparation method, the molar ratio of hydrochloric acid to the compound of formula I can be (0.8-1.2):1 (preferably 1:1) to obtain the crystal form A of the compound shown in formula III.

[0185] Preferably, in the preparation method, the molar ratio of hydrochloric acid to the compound of formula I can be (1.6-2.2):1 (preferably 2:1) to obtain the crystal form B of the compound shown in formula III.

[0186] Preferably, in the preparation method, the acetone and water mixture is a volume ratio of 19:1 (acetone / water) of acetone and water.

[0187] Preferably, in the preparation method, the compound represented by Formula I is in a conventional form in the art (e.g., the amorphous form of the compound represented by Formula I or the crystal form A of the compound represented by Formula II). Preferably, when the crystal form A of the compound represented by Formula III, the crystal form B of the compound represented by Formula III, the crystal form C of the compound represented by Formula III, and the crystal form A of the compound represented by Formula IV are obtained, the compound represented by Formula I is the crystal form A of the compound represented by Formula II.

[0188] Preferably, in the preparation method, when the acid is hydrochloric acid, sulfuric acid, or phosphoric acid, the acid is an ethyl acetate solution of the acid, for example, a concentrated acid aqueous solution with a volume ratio of 1:9 (acid / ethyl acetate) is mixed with ethyl acetate to obtain a mixed solution.

[0189] In one embodiment, the crystallization in the preparation method is dry crystallization (e.g., vacuum drying at 50°C).

[0190] Preferably, the method for preparing crystal form A of the compound shown in Formula XI includes the following steps: crystallizing a mixture of the compound shown in Formula I, a solvent, and a sodium salt (e.g., NaOH) to obtain the crystal form of the sodium salt of the compound shown in Formula I or its solvate.

[0191] The solvent is ethyl acetate, which yields crystal form A of the compound shown in formula XI.

[0192] In one embodiment, the crystallization of the compound represented by formula XI in the preparation method of crystal form A is performed by cooling crystallization (e.g., cooling from 50°C to 25°C after suspension) and drying (e.g., vacuum drying).

[0193] The present invention provides a pharmaceutical composition comprising substance X and pharmaceutical excipients, wherein substance X is a compound shown in III, IV, V, VI, VII, X, XI above (e.g., a crystal form of the above compound) or a crystal form C of a compound shown in Formula I above.

[0194] This invention provides the use of substance X or the above-described pharmaceutical composition in the preparation of a medicament, wherein the medicament 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 the compound shown in III, IV, V, VI, VII, X, XI above or crystal form C of the compound shown in formula I above.

[0195] Preferably, the substance X is crystal form A of the compound shown in Formula III, crystal form B of the compound shown in Formula III, crystal form C of the compound shown in Formula III, crystal form A of the compound shown in Formula IV, crystal form B of the compound shown in Formula IV, crystal form B of the compound shown in Formula V, crystal form A of the compound shown in Formula VI, crystal form A of the compound shown in Formula VII, crystal form A of the compound shown in Formula X, crystal form B of the compound shown in Formula X, crystal form C of the compound shown in Formula X, or crystal form A of the compound shown in Formula XI.

[0196] Terminology Explanation:

[0197] 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.

[0198] 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”.

[0199] 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.

[0200] 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.

[0201] As used herein, the structure of the compound represented by Formula I is as follows:

[0202] 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.

[0203] 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.

[0204] The reagents and raw materials used in this invention are all commercially available.

[0205] 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

[0206] Figure 1 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula II.

[0207] Figure 2 shows the differential scanning calorimeter of crystal form A of the compound represented by formula II.

[0208] Figure 3 shows the thermogravimetric analysis spectrum of crystal form A of the compound represented by formula II.

[0209] Figure 4 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by Formula III.

[0210] Figure 5 shows the X-ray powder diffraction pattern of crystal form B of the compound represented by Formula III.

[0211] Figure 6 shows the differential scanning calorimeter of crystal form B of the compound represented by formula III.

[0212] Figure 7 shows the thermogravimetric analysis (TGA) spectrum of crystal form B of the compound represented by Formula III.

[0213] Figure 8 shows the X-ray powder diffraction pattern of crystal form C of the compound represented by Formula III.

[0214] Figure 9 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula IV.

[0215] Figure 10 shows the X-ray powder diffraction pattern of crystal form B of the compound shown in Formula IV.

[0216] Figure 11 shows the differential scanning calorimeter of crystal form B of the compound represented by formula IV.

[0217] Figure 12 shows the thermogravimetric analysis (TGA) spectrum of crystal form B of the compound represented by formula IV.

[0218] Figure 13 shows the X-ray powder diffraction pattern of crystal form B of the compound represented by formula V.

[0219] Figure 14 is an X-ray powder diffraction pattern of crystal form A of the compound shown in Formula VI.

[0220] Figure 15 shows the X-ray powder diffraction pattern of crystal form A of the compound shown in Formula VII.

[0221] Figure 16 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula X.

[0222] Figure 17 shows the X-ray powder diffraction pattern of crystal form B of the compound represented by formula X.

[0223] Figure 18 shows the X-ray powder diffraction pattern of crystal form C of the compound represented by formula X.

[0224] Figure 19 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula XI. Detailed Implementation

[0225] 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.

[0226] The X-ray powder diffraction (XRPD) testing method involved in this invention is shown in the table below:

[0227] The single-crystal testing method involved in this invention is as follows:

[0228] Model: Bruker A8 Advance X-ray Diffractometer

[0229] 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.

[0230] Micro-focal spot light source, with a spot size no larger than 100mm.

[0231] X-ray optical system, multilayer film micro-focusing optical system.

[0232] Angle measuring instrument: Kappa (Kappa, ω, 2θ, φ) quadriaxial angle measuring instrument, equipped with an automatic angle measuring head.

[0233] 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.

[0234] Low-temperature cooling system: Supports testing in the temperature range of 80K to 500K.

[0235] The test methods for thermogravimetric analysis (TGA) curves and differential scanning calorimetry (DSC) curves involved in this invention are shown in the table below:

[0236] 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):

[0237] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0238] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0239] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0240] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0241] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0242] The method for testing moisture content is as follows: Fischer titration (KF).

[0243] The ion chromatograph testing conditions involved in this application are as follows:

[0244] The nuclear magnetic resonance (NMR) testing conditions involved in this application are as follows:

[0245] The testing conditions for polarizing microscopes (PLM) involved in this application are as follows:

[0246] The high-performance liquid chromatography (HPLC) testing conditions involved in this application are as follows:

[0247] Example 1. Preparation method of the compound shown in Formula II

[0248] Intermediate 1: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0249] Step 1: (2-chloro-5-methoxypyridin-4-yl)boronic acid

[0250] 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] + .

[0251] Step 2: Methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0252] 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] + .

[0253] Step 3: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0254] 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] + .

[0255] 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

[0256] Step 1: O-((9H-fluorene-9-yl)methyl)carbonate isothiocyanate

[0257] 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).

[0258] Step 2: (6-chloro-5-fluoropyridin-3-yl)tert-butyl carbamate

[0259] 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] + .

[0260] Step 3: (4-bromo-6-chloro-5-fluoropyridine)-3-carbamate tert-butyl ester

[0261] (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] + .

[0262] Step 4: 4-Bromo-6-chloro-5-fluoropyridine-3-amine

[0263] (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] + .

[0264] Step 5: (9H-fluorene-9-yl)methyl(6-chloro-7-fluorothiazo[4,5-c]pyridin-2-yl)carbamate hydrobromide

[0265] 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] + .

[0266] Step 6: 6-Chloro-7-fluorothiazo[4,5-c]pyridine-2-amine

[0267] 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] + .

[0268] Step 7: 6-Chloro-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-7-fluorothiazo[4,5-c]pyridine

[0269] 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] + .

[0270] 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

[0271] 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] + .

[0272] Step 9: 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-fluorothiazo[4,5-c]pyridine-2-amine hydrochloride

[0273] 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] + .

[0274] 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

[0275] 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] + .

[0276] 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.

[0277] Table 1

[0278] 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.

[0279] Example 2: The compound shown in Formula III has crystal form A.

[0280] 30 mg of the compound of formula II (crystal form A) was added to 0.5 mL of ethyl acetate and heated to 50 °C. 0.05 mL of dilute hydrochloric acid solution was added to the system (dilute hydrochloric acid preparation method: 0.1 mL of concentrated hydrochloric acid (37% wt) dissolved in 0.9 mL of ethyl acetate). 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 the compound of formula III (crystal form A). Ion chromatography showed that the molar ratio of the compound of formula I to hydrochloric acid was 1:1.06. The XRPD pattern of the compound of formula III (crystal form A) is shown in Figure 4, and it exhibits the diffraction peaks shown in Table 2 below.

[0281] Table 2

[0282] Example 3 shows the crystal form B of the compound represented by Formula III.

[0283] 30 mg of the compound of formula II (crystal form A) was added to 0.5 mL of ethyl acetate and heated to 50 °C. 0.096 mL of dilute hydrochloric acid solution was added to the system (dilute hydrochloric acid preparation method: 0.1 mL of concentrated hydrochloric acid dissolved in 0.9 mL of ethyl acetate). 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 the compound of formula III (crystal form B). Ion chromatography showed that the molar ratio of the compound of formula I to hydrochloric acid was 1:1.76. The XRPD pattern of the compound of formula III (crystal form B) is shown in Figure 5, and it exhibits the diffraction peaks shown in Table 3 below.

[0284] Table 3

[0285] The DSC spectrum of compound B (formula III) is shown in Figure 6. An endothermic peak was observed at the peak temperature of 186.88℃ (enthalpy of 164.82 J / g), with an onset point (Onset x) of 172.09℃. The TGA spectrum is shown in Figure 7. The sample lost 1.42% of its weight when heated from 24.07℃ to 120.0℃ and 9.84% of its weight when heated from 120.0℃ to 205.0℃. DSC and TGA analyses confirm that compound B (formula III) is an anhydrous hydrate.

[0286] Example 4: Crystal form C of the compound shown in Formula III

[0287] 30 mg of the compound of crystal form A shown in Formula II was added to 0.5 mL of acetonitrile and heated to 50 °C. 0.096 mL of dilute hydrochloric acid solution was added to the system (dilute hydrochloric acid preparation method: 0.1 mL of concentrated hydrochloric acid dissolved in 0.9 mL of ethyl acetate). 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 the compound of crystal form C shown in Formula III. The molar ratio of the compound of Formula I to hydrochloric acid was 1:1.7. The XRPD pattern of the compound of crystal form C shown in Formula III is shown in Figure 8, and it exhibits the diffraction peaks shown in Table 4 below.

[0288] Table 4

[0289] Crystal form A of the compound shown in Formula IV in Example 5

[0290] 30 mg of the compound of formula II (crystal form A) was added to 0.5 mL of ethyl acetate and heated to 50 °C. 0.033 mL of dilute sulfuric acid solution was added to the system (dilute sulfuric acid preparation method: 0.1 mL of sulfuric acid dissolved in 0.9 mL of ethyl acetate). 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 the compound of formula IV (crystal form A). The molar ratio of the compound of formula I to sulfuric acid was 1:0.97. The XRPD pattern of the compound of formula IV (crystal form A) is shown in Figure 9, and it exhibits the diffraction peaks shown in Table 5 below.

[0291] Table 5

[0292] Example 6: Crystal form B of the compound shown in Formula IV

[0293] 30 mg of the compound shown in Formula I was added to 0.5 mL of acetonitrile, and the mixture was heated to 50 °C. 0.033 mL of dilute sulfuric acid solution was added to the system (dilute sulfuric acid preparation method: 0.1 mL of sulfuric acid dissolved in 0.9 mL of ethyl acetate). The entire system was stirred at 50 °C for 2 hours, then cooled to 25 °C and stirred again. The mixture was filtered, and 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 IV. The molar ratio of the compound shown in Formula I to sulfuric acid was 1:0.96. The XRPD pattern of crystal form B of the compound shown in Formula IV is shown in Figure 10, and it exhibits the diffraction peaks shown in Table 6 below.

[0294] Table 6

[0295] The DSC spectrum of crystal form B of the compound shown in Formula IV is shown in Figure 11. Endothermic peaks were observed at peak temperatures of 34.85 °C (enthalpy 56.75 J / g), 90.79 °C (enthalpy 28.413 J / g), and 204.38 °C (enthalpy 70.95 J / g), with onset x values ​​of 11.47 °C, 67.49 °C, and 196.17 °C, respectively. The TGA spectrum is shown in Figure 12. The sample lost 2.06% of its weight when heated from 33.44 °C to 50.0 °C, 0.56% from 50.0 °C to 100.0 °C, 0.39% from 100.0 °C to 180.0 °C, and 1% from 180.0 °C to 230.0 °C.

[0296] Example 7 Crystal form B of the compound shown in formula V

[0297] 30 mg of the compound shown in Formula I was added to 0.5 mL of acetonitrile and heated to 50 °C. 0.041 mL of dilute phosphoric acid solution was added to the system (dilute phosphoric acid preparation method: 0.1 mL of phosphoric acid dissolved in 0.9 mL of ethyl acetate). 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 the phosphate crystal form B of the compound shown in Formula I (crystal form B of the compound shown in Formula V). The molar ratio of the compound shown in Formula I to phosphoric acid was 1:1.09. The XRPD pattern of the phosphate crystal form B of the compound shown in Formula I (crystal form B of the compound shown in Formula V) is shown in Figure 13, and it exhibits the diffraction peaks shown in Table 7 below.

[0298] Table 7

[0299] Crystal form A of the compound shown in Formula VI in Example 8

[0300] 30 mg of the compound shown in Formula I and 7.04 mg of fumaric 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 A of the compound shown in Formula VI. The molar ratio of the compound shown in Formula I to fumaric acid was 1:1.01. The XRPD pattern of crystal form A of the fumarate of the compound shown in Formula I (crystal form A of the compound shown in Formula VI) is shown in Figure 14, and it exhibits the diffraction peaks shown in Table 8 below.

[0301] MRI: 1H NMR (400MHz, DMSO-d6) δ13.65(s,1H),13.11(s,2H),9.16(d,J=2.0Hz,1H),8.92(s,1H),8.19( s,1H),7.63(s,1H),7.53(s,1H),6.63(s,2H),4.03(s,3H),3.61(s,3H),2.26(d,J=1.6Hz,3H).

[0302] Table 8

[0303] Crystal form A of the compound shown in Formula VII in Example 9

[0304] 30 mg of the compound shown in Formula I was added to 0.5 mL of acetonitrile, and the mixture was heated to 50 °C. 0.039 mL of methanesulfonic acid solution (0.1 mL of methanesulfonic acid dissolved in 0.9 mL of ethyl acetate) was added. The entire system was stirred at 50 °C for 2 hours, then cooled to 25 °C and stirred again. The mixture was filtered, and 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 VII. The molar ratio of the compound shown in Formula I to methanesulfonic acid was 1:1.03. The XRPD pattern of crystal form A of the compound shown in Formula VII is shown in Figure 15, and it exhibits the diffraction peaks shown in Table 9 below.

[0305] MRI: 1 H NMR (400MHz, DMSO-d6) δ13.64(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),4.03(s,3H),3.62(s,3H),2.63(s,3H),2.29(s,3H),2.26(d,J=1.6Hz,3H).

[0306] Table 9

[0307] Crystal form A of the compound shown in Formula X in Example 10

[0308] 30 mg of the compound shown in Formula I and 22.06 mg of 1,5-naphthalenedisulfonic 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 X. The molar ratio of the compound shown in Formula I to 1,5-naphthalenedisulfonic acid was 1:1.02. The XRPD pattern of crystal form A of the compound shown in Formula X is shown in Figure 16, and it exhibits the diffraction peaks shown in Table 10 below.

[0309] MRI: 1H NMR (400MHz, DMSO-d6) δ13.64(s,1H),9.15(d,J=2.0Hz,1H),8.91(s,1H),8.85(d,J=8.4Hz,2H),8.18(s,1H),7.92(d,J=7.2 Hz,2H),7.63(s,1H),7.53(s,1H),7.40(dd,J=8.4,7.6Hz,2H),4.03(s,3H),3.61(s,3H),2.63(s,3H),2.26(d,J=1.6Hz,3H).

[0310] Table 10

[0311] Example 11 Crystal form B of the compound shown in formula X

[0312] 30 mg of the compound shown in Formula I and 22.06 mg of 1,5-naphthalenedisulfonic acid were added to 0.5 mL of ethyl acetate, 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 X. The molar ratio of the compound shown in Formula I to 1,5-naphthalenedisulfonic acid was 1:0.93. The XRPD pattern of crystal form B of the compound shown in Formula X is shown in Figure 17, and it exhibits the diffraction peaks shown in Table 11 below.

[0313] MRI: 1 H NMR (400MHz, DMSO-d6) δ13.64(s,1H),9.15(d,J=2.0Hz,1H),8.91(s,1H),8.86(d,J=8.4Hz,2H),8.18(s,1H),7.92(d,J=7.2 Hz,2H),7.63(s,1H),7.53(s,1H),7.40(dd,J=8.4,7.6Hz,2H),4.03(s,3H),3.61(s,3H),2.63(s,3H),2.26(d,J=1.6Hz,3H).

[0314] Table 11

[0315] Example 12 Crystal form C of the compound shown by formula X

[0316] 30 mg of the compound shown in Formula X and 22.06 mg of 1,5-naphthalenedisulfonic 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 C of the compound shown in Formula X. The molar ratio of the compound shown in Formula I to 1,5-naphthalenedisulfonic acid was 1:1.00. The XRPD pattern of crystal form C of the compound shown in Formula X is shown in Figure 18, and it exhibits the diffraction peaks shown in Table 12 below.

[0317] MRI: 1 H NMR (400MHz, DMSO-d6) δ13.65(s,1H),9.16(d,J=2.0Hz,1H),8.92(s,1H),8.86(d,J=8.4Hz,2H),8.19(s,1H),7.92(d,J=7.2 Hz,2H),7.63(s,1H),7.53(s,1H),7.40(dd,J=8.4,7.6Hz,2H),4.03(s,3H),3.61(s,3H),2.63(s,3H),2.26(d,J=1.6Hz,3H).

[0318] Table 12

[0319] Crystal form A of the compound shown in Formula XI in Example 13

[0320] 30 mg of the compound shown in Formula I and 2.50 mg of sodium hydroxide were added to 0.5 mL of ethyl acetate, 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 XI. The molar ratio of the compound shown in Formula I to sodium was 1:0.62. The XRPD pattern of crystal form A of the compound shown in Formula XI is shown in Figure 19, and it exhibits the diffraction peaks shown in Table 13 below.

[0321] Table 13

[0322] Test Example 2

[0323] 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℃.

[0324] Test results show that the compound A shown in Formula III has moderate hygroscopicity, absorbing 4.8% of water.

[0325] Test Example 3

[0326] The solubility of compound A, represented by Formula III obtained in the above examples, was tested using the following method:

[0327] Weigh 9 mg of compound A (crystal form) as shown in Formula III into a 20 mL glass bottle, add 4 mL of solvent, and stir the resulting suspension or clear solution at 37°C and 400 rpm. Take samples at 0.5 hours and 2 hours, 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.

[0328] The results show that the crystal form obtained in this application has good solubility, as shown in the table below:

[0329] A represents a solubility of 0.01-0.1 mg / mL, and B represents a solubility of 0.1-1 mg / L.

[0330] Test Example 4

[0331] 1. Biochemical activity assay of Polθ inhibitors (ADP Glo assay)

[0332] The N-terminus of the Polθ protein contains a helicase domain with ATPase activity, capable of hydrolyzing ATP to ADP. The ATPase activity of the Polθ protein and the inhibitory effect of small molecule compounds on the protein can be analyzed using the ADP-Glo ​​assay kit (ADP-Glo™ Kinase Assay, Promega, V9102). The specific detection method is as follows:

[0333] 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.

[0334] 2) Prepare 2x ssDNA-Pol θ 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.

[0335] 3) Prepare a 2x ATP solution. Add an equal volume of 2x ATP solution to all wells and let stand at room temperature for 60 min.

[0336] 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;

[0337] 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.

[0338] 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.

[0339] 2. Cell viability assay for Pol θ inhibitors

[0340] 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:

[0341] 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.

[0342] 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, Multidrop 8). 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.

[0343] 3) Perform two solution changes on Day 3 and Day 7 respectively, and add the compound as in step 2);

[0344] 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).

[0345] 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.

[0346] Data list:

[0347] The specific data from the biochemical experiments and cell viability detection experiments are shown in the table below:

[0348] 3. Solubility Assay

[0349] 1) Prepare 0.1M Na2PO4 buffer (pH 7.4):

[0350] 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;

[0351] 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%).

[0352] 3) Shake the sample tube at room temperature for 2 hours (1000 rpm / min);

[0353] 4) Preparation of calibration curve:

[0354] a) Preparation of 300 μM spiking solution (SS):

[0355] Add 6 μL (10 mM in DMSO) of the test compound stock solution to 194 μL MeOH / ACN (4:1);

[0356] b) Plot the standard curve:

[0357] 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.

[0358] 6) Dilute the supernatant 10 times with 100mM buffer.

[0359] Add the supernatant (10 μL) to the buffer (100 mM, 90 μL) and dilute 10 times;

[0360] 7) Sample preparation for LC-MS / MS (API 4000) detection

[0361] 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.

[0362] The experimental results are shown in the table below:

[0363] 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 the compound shown in Formula III, the compound shown in Formula IV, the compound shown in Formula V, the compound shown in Formula VI, the compound shown in Formula VII, the compound shown in Formula X, or the compound shown in Formula XI; in, In the compound shown in Formula III, w is 0.5-2.5 and e is 0; In the compound shown in Formula IV, r is 0.5-2 and t is 0; In the compound shown in Formula V, y is 0.5-1.5, u is 0, and i is 0; In the compound shown in Formula VI, C4H4O4 is fumaric acid, and o is 1-1.1; In the compound shown in Formula VII, CH3SO3H is methanesulfonic acid, and p is 1-1.1; In the compound shown by formula X, C 10 H8O6S2 represents 1,5-naphthalenedisulfonic acid, j represents 0.5-1.5, z represents water or acetonitrile, and k represents 0; In the compound shown in Formula XI, n is 0-1.5 and m is 0.

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 III, w is 0.5, 1, 1.1, 1.6, 1.7, 1.8, 1.76, 1.06, 1.5 or 2; (4) In the compound shown in Formula IV, r is 0.5, 0.9, 1, 0.97, 0.96 or 1.5; (2) In the compound shown in formula V, y is 1.1, 1.2, 1.14, 1, 1.09 or 1.05; (3) In the compound shown in Formula VI, o is 1, 1.01, 1.05 or 1.1; (4) In the compound shown in Formula VII, p is 1, 1.03, 1.05 or 1.1; (5) In the compound represented by formula X, j is 1, 0.9, 1.1, 1.02 or 0.93; (6) In the compound shown in formula XI, n is 0.6, 1.1, 1.13 or 1.

2.

3. 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 III is crystal form A of the compound shown in Formula III. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 4.61±0.2°, 5.02±0.2°, 9.19±0.2° and 13.76±0.2°. (2) The compound shown in Formula III is crystal form B of the compound shown in Formula III. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, shows diffraction peaks at 6.47±0.2°, 7.19±0.2°, 9.11±0.2°, 11.63±0.2° and 14.45±0.2°. (3) The compound shown in Formula III is crystal form C of the compound shown in Formula III. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, shows diffraction peaks at 9.84±0.2°, 10.51±0.2°, 12.19±0.2°, 13.39±0.2° and 14.40±0.2°. (4) The compound shown in Formula IV is crystal form A of the compound shown in Formula IV. Its X-ray powder diffraction pattern, expressed in terms of 2θ angle using Cu-Kα radiation, shows diffraction peaks at 5.14±0.2°, 9.01±0.2° and 15.03±0.2°. (5) The compound shown in Formula IV is crystal form B of the compound shown in Formula IV. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, shows diffraction peaks at 7.11±0.2°, 7.57±0.2°, 7.72±0.2°, 8.10±0.2° and 10.27±0.2°. (6) The compound shown in Formula V is crystal form B of the compound shown in Formula V. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, shows diffraction peaks at 6.83±0.2°, 12.89±0.2°, 14.44±0.2°, 15.91±0.2°, 25.08±0.2° and 25.50±0.2°. (7) The compound shown in Formula VI is crystal form A of the compound shown in Formula VI. Its X-ray powder diffraction pattern, expressed in terms of 2θ angle using Cu-Kα radiation, has diffraction peaks at 10.58±0.2°, 12.16±0.2° and 13.98±0.2°. (8) The compound shown in Formula VII is crystal form A of the compound shown in Formula VII. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 9.00±0.2°, 17.44±0.2° and 21.74±0.2°. (9) The compound shown in Formula X is crystal form A of the compound shown in Formula X. Its X-ray powder diffraction pattern, expressed in terms of 2θ angle using Cu-Kα radiation, has diffraction peaks at 7.46±0.2°, 12.01±0.2° and 21.70±0.2°. (10) The compound shown in Formula X is crystal form B of the compound shown in Formula X. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 8.96±0.2°, 10.81±0.2°, 17.92±0.2° and 22.07±0.2°. (11) The compound shown in Formula X is crystal form C of the compound shown in Formula X. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, shows diffraction peaks at 11.30±0.2°, 22.61±0.2°, 24.69±0.2°, 26.16±0.2° and 28.57±0.2°. (12) The compound shown in Formula XI is the crystal form A of the compound shown in Formula XI. Its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 12.78±0.2°, 14.09±0.2° and 14.98±0.2°.

4. The cyclic nitrogen-containing compound as described in claim 3, characterized in that, It satisfies one or more of the following conditions: (1) The crystal form A of the compound shown in Formula III, 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: 6.57±0.2°, 6.89±0.2°, 9.96±0.2°, 10.48±0.2°, 10.64±0.2°, 14.69±0.2° and 14.90±0.2°; For example, the crystal form A of the compound shown in Formula III has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 4.61±0.2°, 5.02±0.2°, 9.19±0.2°, 13.76±0.2°, 6.57±0.2°, 6.89±0.2°, 9.96±0.2°, 10.48±0.2°, and 10.64±0.2°. Preferably, the crystal form A of the compound shown in Formula III, 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: 18.34±0.2°, 19.13±0.2°, 19.30±0.2°, 20.81±0.2°, 21.68±0.2°, 23.09±0.2°, 24.03±0.2°, 26.13±0.2°, and 28.17±0.2°; (2) The crystal form B of the compound shown in Formula III, 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: 17.37±0.2°, 18.21±0.2°, 19.44±0.2°, 20.17±0.2°, 20.82±0.2°, 22.41±0.2° and 24.58±0.2°; For example, the crystal form B of the compound shown in Formula III has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.47±0.2°, 7.19±0.2°, 9.11±0.2°, 11.63±0.2°, 14.45±0.2°, 17.37±0.2°, 18.21±0.2°, 19.44±0.2°, 20.17±0.2°, and 20.82±0.2°. Preferably, the crystal form B of the compound shown in Formula III, when analyzed by Cu-Kα radiation and expressed in 2θ angles, further exhibits diffraction peaks at one or more of the following locations: 12.94±0.2°, 13.41±0.2°, 15.41±0.2°, 15.75±0.2°, 16.23±0.2°, 16.72±0.2°, 26.01±0.2°, 26.17±0.2°, 26.47±0.2°, 27.96±0.2°, 28.62±0.2°, 30.04±0.2°, and 30.37±0.2°. (3) The crystal form C of the compound shown in Formula III, 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: 18.16±0.2°, 18.29±0.2°, 19.39±0.2°, 20.81±0.2°, 21.75±0.2°, 26.41±0.2° and 27.48±0.2°; For example, the crystal form C of the compound shown in Formula III has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 9.84±0.2°, 10.51±0.2°, 12.19±0.2°, 13.39±0.2°, 14.40±0.2°, 18.16±0.2°, 18.29±0.2°, 19.39±0.2°, 20.81±0.2°, 21.75±0.2°, and 26.41±0.2°. Preferably, the crystal form C of the compound shown in Formula III, 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: 11.61±0.2°, 20.02±0.2°, 22.51±0.2°, 22.90±0.2°, 23.25±0.2°, 23.49±0.2°, 24.46±0.2°, 25.11±0.2°, 26.94±0.2°, 28.37±0.2°, 28.97±0.2°, and 29.32±0.2°; (4) The crystal form A of the compound shown in Formula IV, 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: 11.45±0.2°, 17.44±0.2°, 21.45±0.2°, 21.78±0.2°, 24.82±0.2°, 25.95±0.2° and 26.68±0.2°; For example, the crystal form A of the compound shown in Formula IV has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 5.14±0.2°, 9.01±0.2°, 15.03±0.2°, 11.45±0.2°, 17.44±0.2°, 21.45±0.2°, 21.78±0.2°, 24.82±0.2°, and 25.95±0.2°. Preferably, the crystal form A of the compound shown in Formula IV, 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: 6.11±0.2°, 6.60±0.2°, 7.35±0.2°, 8.63±0.2°, 14.62±0.2°, 16.45±0.2°, 20.40±0.2°, 23.81±0.2°, 25.47±0.2°, 27.96±0.2°, and 28.43±0.2°; (5) The crystal form B of the compound shown in Formula IV, 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: 13.86±0.2°, 14.11±0.2°, 14.71±0.2°, 15.44±0.2°, 16.07±0.2°, 23.18±0.2°, 24.18±0.2° and 25.17±0.2°; For example, the crystal form B of the compound shown in Formula IV has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 7.11±0.2°, 7.57±0.2°, 7.72±0.2°, 8.10±0.2°, 13.86±0.2°, 14.11±0.2°, 14.71±0.2°, 23.18±0.2°, 24.18±0.2°, and 25.17±0.2°. Preferably, the crystal form B of the compound shown in Formula IV, 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: 10.27±0.2°, 12.55±0.2°, 12.67±0.2°, 13.19±0.2°, 16.73±0.2°, 17.92±0.2°, 18.38±0.2°, 18.58±0.2°, 20.18±0.2°, 21.2±0.2°, 22.2±0.2°, 25.58±0.2°, and 27.82±0.2°; (6) The crystal form B of the compound shown in Formula V, 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: 8.32±0.2°, 10.26±0.2°, 13.93±0.2°, 14.67±0.2°, 20.35±0.2°, 20.49±0.2°, 21.15±0.2° and 21.65±0.2°; For example, the crystal form B of the compound shown in Formula V has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.83±0.2°, 12.89±0.2°, 14.44±0.2°, 15.91±0.2°, 25.08±0.2°, 25.50±0.2°, 8.32±0.2°, 20.35±0.2°, and 20.49±0.2°. Preferably, the crystal form B of the compound shown in Formula V, 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: 8.52±0.2°, 9.17±0.2°, 13.46±0.2°, 16.25±0.2° and 17.94±0.2°; (7) The crystal form A of the compound shown in Formula VI, 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: 6.96±0.2°, 8.60±0.2°, 14.84±0.2°, 15.39±0.2°, 16.63±0.2° and 17.08±0.2°; For example, the crystal form A of the compound shown in Formula VI has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 10.58±0.2°, 12.16±0.2°, 13.98±0.2°, 6.96±0.2°, 8.60±0.2°, 14.84±0.2°, 15.39±0.2°, 16.63±0.2°, and 17.08±0.2°. Preferably, the crystal form A of the compound shown in Formula VI, 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: 6.73±0.2°, 9.38±0.2°, 10.28±0.2°, 13.45±0.2°, 19.28±0.2° and 18.67±0.2°; (8) The crystal form A of the compound shown in Formula VII, 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: 5.13±0.2°, 6.73±0.2°, 8.61±0.2°, 17.74±0.2°, 24.43±0.2° and 25.32±0.2°; For example, the crystal form A of the compound shown in Formula VII has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 9.00±0.2°, 17.44±0.2°, 21.74±0.2°, 5.13±0.2°, 6.73±0.2°, 8.61±0.2°, 17.74±0.2°, 24.43±0.2°, and 25.32±0.2°. Preferably, the crystal form A of the compound shown in Formula VII, 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: 15.55±0.2°, 10.05±0.2°, 11.57±0.2°, 22.37±0.2° and 26.36±0.2°; (9) The crystal form A of the compound shown in Formula X, 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: 11.43±0.2°, 13.53±0.2°, 17.24±0.2°, 18.49±0.2°, 18.77±0.2°, 21.08±0.2°, 24.57±0.2° and 28.44±0.2°; For example, the crystal form A of the compound represented by formula X has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 7.46±0.2°, 12.01±0.2°, 21.70±0.2°, 11.43±0.2°, 13.53±0.2°, 17.24±0.2°, 18.49±0.2°, 18.77±0.2°, and 21.08±0.2°. Preferably, the crystal form A of the compound represented by formula X, 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: 5.71±0.2°, 13.93±0.2°, 14.91±0.2°, 15.34±0.2°, 22.12±0.2°, 22.80±0.2°, 22.95±0.2°, 24.99±0.2°, and 26.08±0.2°; (10) The crystal form B of the compound shown in Formula X, 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: 11.98±0.2°, 18.4±0.2°, 21.27±0.2°, 23.27±0.2°, 27.26±0.2° and 27.77±0.2°; For example, the crystal form B of the compound represented by formula X has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, showing diffraction peaks at 8.96±0.2°, 10.81±0.2°, 17.92±0.2°, 22.07±0.2°, 11.98±0.2°, 18.4±0.2°, 21.27±0.2°, and 23.27±0.2°. Preferably, the crystal form B of the compound represented by formula X, 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: 5.95±0.2°, 14.09±0.2°, 15.80±0.2°, 16.97±0.2°, 20.03±0.2°, 22.42±0.2° and 23.79±0.2°; (11) The crystal form C of the compound shown in formula X, 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: 6.36±0.2°, 12.82±0.2°, 17.07±0.2°, 17.48±0.2°, 18.61±0.2°, 20.24±0.2° and 20.94±0.2°; For example, the crystal form C of the compound represented by formula X has a relative intensity of 50%-100% for its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation, with the diffraction peak at 22.61±0.2° being the strongest peak. For example, the crystal form C of the compound represented by formula X has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, showing diffraction peaks at 11.30±0.2°, 22.61±0.2°, 24.69±0.2°, 26.16±0.2°, 28.57±0.2°, 6.36±0.2°, 18.61±0.2°, 12.82±0.2°, and 17.07±0.2°. Preferably, the crystal form C of the compound represented by formula X, 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: 12.11±0.2° and 15.12±0.2°; (12) The crystal form A of the compound shown in Formula XI, 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: 10.67±0.2°, 18.82±0.2°, 19.49±0.2° and 23.58±0.2°; For example, the crystal form A of the compound shown in Formula XI has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 12.78±0.2°, 14.09±0.2°, 14.98±0.2°, 10.67±0.2°, 18.82±0.2°, 19.49±0.2°, 23.58±0.2°, and 21.80±0.2°. Preferably, the crystal form A of the compound shown in Formula XI, 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: 6.9±0.2°, 9.39±0.2°, 17.22±0.2°, 19.35±0.2°, 21.80±0.2°, 22.45±0.2°, 24.15±0.2°, and 27.926±0.2°.

5. The cyclic nitrogen-containing compound as described in claim 3, characterized in that, It satisfies one or more of the following conditions: (1) The crystal form A of the compound shown in Formula III 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 A of the compound represented by Formula III has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 4. (2) In the crystal form A of the compound shown in Formula III, w is 1, 1.1 or 1.06, for example 1.06; (3) The crystal form B of the compound shown in Formula III 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 B of the compound represented by Formula III has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 5. (4) The differential scanning calorimetry curve of the compound shown in Formula III has an endothermic peak at a peak temperature of 186.88±3℃. Preferably, the differential scanning calorimetry curve of crystal form B of the compound represented by Formula III is basically as shown in Figure 6; (5) The thermogravimetric analysis curve of the compound shown in Formula III, crystal form B, shows a weight loss of about 1.42% in the temperature range of 24.07±3℃ to 120.0±3℃ and a weight loss of about 9.84% in the temperature range of 120.00±3℃ to 205.00±3℃. Preferably, the thermogravimetric analysis curve of crystal form B of the compound represented by Formula III is basically as shown in Figure 7; (6) In the crystal form B of the compound shown in Formula III, w is 1.76, 1.7 or 1.8, for example 1.76; (7) The crystal form C of the compound shown in Formula III 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 C of the compound represented by Formula III has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 8. (8) In the crystal form C of the compound shown in Formula III, w is 1.7, 1.8 or 1.6, for example 1.7; (9) The crystal form A of the compound shown in Formula IV 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 A of the compound represented by Formula IV has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 9. (10) The crystal form A of the compound shown in Formula IV, r is 1, 0.97 or 0.9, for example 0.97; (11) The crystal form B of the compound shown in Formula IV 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 B of the compound shown in Formula IV has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 10. (12) The differential scanning calorimetry curve of the compound shown in Formula IV, crystal form B, has endothermic peaks at peak temperatures of 34.85±3℃, 90.79±3℃ and 204.38±3℃. Preferably, the differential scanning calorimetry curve of crystal form B of the compound represented by Formula IV is basically as shown in Figure 11; (13) The crystal form B of the compound shown in Formula IV has a thermogravimetric analysis curve showing a weight loss of about 2.06% in the temperature range of 33.44±3℃ to 50.0±3℃, a weight loss of about 0.56% in the temperature range of 50.0±3℃ to 100.0±3℃, a weight loss of about 0.39% in the temperature range of 100.00±3℃ to 180.00±3℃, and a weight loss of about 1% in the temperature range of 180.00±3℃ to 230.00±3℃; Preferably, the thermogravimetric analysis curve of crystal form B of the compound represented by Formula IV is basically as shown in Figure 12; (14) In the crystal form B of the compound shown in Formula IV, r is 1, 0.9 or 0.96, for example 0.96; (15) The crystal form B of the compound shown in Formula V 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 B of the compound shown in Formula V has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 13. (16) In the crystal form B of the compound shown in formula V, y is 1.1, 1 or 1.09, for example 1.09; (17) The crystal form A of the compound shown in Formula VI 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 A of the compound shown in Formula VI has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 14. (18) In the crystal form A of the compound shown in Formula VI, o is 1, 1.1 or 1.01, for example 1.01; (19) The crystal form A of the compound shown in Formula VII 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 A of the compound represented by Formula VII has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 15. (20) In the crystal form A of the compound shown in Formula VII, p is 1:1, 1:1.1 or 1:1.03, for example 1:1.03; (21) The crystal form A of the compound represented by formula X has the diffraction peaks shown in Table 10 as shown in the X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle. Table 10 Preferably, the crystal form A of the compound represented by formula X has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 16. (22) In the crystal form A of the compound shown by formula X, k is 0, and j is 1, 1.1 or 1.02, for example 1.02; (23) The crystal form B of the compound represented by formula X has the diffraction peaks shown in Table 11 in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Table 11 Preferably, the crystal form B of the compound represented by formula X has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 17. (24) The crystal form B of the compound shown in formula X, where k is 0 and j is 0.9, 1 or 0.93, for example 0.93; (25) The crystal form C of the compound represented by formula X 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 C of the compound represented by formula X has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 18. (26) The crystal form C of the compound represented by formula X is 1; (27) The crystal form A of the compound shown in Formula XI has the diffraction peaks shown in Table 13 in the X-ray powder diffraction pattern of Cu-Kα radiation and expressed in 2θ angle. Table 13 Preferably, the crystal form A of the compound represented by formula XI has a Cu-Kα radiation and X-ray powder diffraction pattern that is basically as shown in Figure 19; (28) The crystal form A of the compound shown in Formula XI, where m is 0 and n is 0.6, 0.7 or 0.62, for example 0.

62.

6. A method for preparing a cyclic nitrogen-containing compound as described in any one of claims 3-5, 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 III, and the solvent is ethyl acetate, to obtain crystal form A or crystal form B of the compound shown in Formula III; The compound is the compound shown in Formula III, and the solvent is acetonitrile, to obtain crystal form C of the compound shown in Formula III; The compound is the compound shown in Formula IV, and the solvent is ethyl acetate, to obtain crystal form A of the compound shown in Formula IV; The compound is the compound shown in Formula IV, and the solvent is acetonitrile, to obtain crystal form B of the compound shown in Formula IV; The compound is the compound shown in Formula V, and the solvent is acetonitrile, to obtain crystal form B of the compound shown in Formula V; The compound is the compound shown in Formula VI, and the solvent is acetonitrile, to obtain crystal form A of the compound shown in Formula VI; The compound is the compound shown in Formula VII, and the solvent is acetonitrile, to obtain crystal form A of the compound shown in Formula VII; The compound is the compound shown in Formula X, and the solvent is a mixed solution of acetone and water, to obtain crystal form A of the compound shown in Formula X; The compound is the compound shown in Formula X, and the solvent is ethyl acetate, to obtain crystal form B of the compound shown in Formula X; The compound is the compound shown in Formula X, and the solvent is acetonitrile, to obtain crystal form C of the compound shown in Formula X; The compound is the compound shown in Formula XI, and the solvent is ethyl acetate, to obtain crystal form A of the compound shown in Formula XI.

7. The preparation method according to claim 6, 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 drying is centrifugal and / or vacuum drying.

8. A pharmaceutical composition comprising a compound of Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula X, or Formula XI as described in claim 1 or 2, and a pharmaceutical excipient. Preferably, the pharmaceutical composition comprises the compound of formula III, formula IV, formula V, formula VI, formula VII, formula X, or formula XI as described in any one of claims 3-5, and a pharmaceutical excipient.

9. The use of a pharmaceutical composition as claimed in claim 8 or a compound of formula III, IV, V, VI, VII, X, or XI as claimed in claim 1 or 2 in the preparation of a medicament, wherein the medicament is used to treat lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, or colon cancer.

10. The use of a compound of formula III, formula IV, formula V, formula VI, formula VII, formula X, or formula XI as described in any one of claims 3-5 in the preparation of a medicament, wherein the medicament is used to treat lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, or colon cancer.

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