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WO2025223483A1 - Composé azoté à cycle condensé, forme cristalline de celui-ci, procédé de préparation et utilisation de celui-ci - Google Patents

Composé azoté à cycle condensé, forme cristalline de celui-ci, procédé de préparation et utilisation de celui-ci

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Publication number
WO2025223483A1
WO2025223483A1 PCT/CN2025/090761 CN2025090761W WO2025223483A1 WO 2025223483 A1 WO2025223483 A1 WO 2025223483A1 CN 2025090761 W CN2025090761 W CN 2025090761W WO 2025223483 A1 WO2025223483 A1 WO 2025223483A1
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WO
WIPO (PCT)
Prior art keywords
formula
crystal form
compound shown
compound
radiation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/090761
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English (en)
Chinese (zh)
Inventor
贺虎
阚超
葛崇勋
刘颂
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Synrx Therapeutics Biomedical Technology Co Ltd
Original Assignee
Hangzhou Synrx Therapeutics Biomedical Technology Co Ltd
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Publication of WO2025223483A1 publication Critical patent/WO2025223483A1/fr
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Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to cyclic nitrogen-containing compounds, their crystal forms, preparation methods, and uses.
  • Double-strand breaks 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.
  • DNA double-strand breaks are typically repaired via 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).
  • NHEJ non-homologous end joining
  • HR homologous recombination
  • Alt-NHEJ alternative non-homologous recombination end joining
  • MMEJ microhomological end joining
  • TMEJ microhomological end joining
  • MMEJ DNA polymerase theta-mediated end-joining
  • DNA polymerase theta (Pol theta, or Pol ⁇ ) 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 Pol ⁇ to substrates. Pol ⁇ 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 Pol ⁇ is involved in DNA replication arrest; its loss of function leads to increased replication pressure in tumor cells, resulting in apoptosis.
  • Pol ⁇ 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 Pol ⁇ overexpression. These phenomena suggest that Pol ⁇ may play an important role in these cancers and is a potential tumor-specific target.
  • Pol ⁇ 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 Pol ⁇ and HR deficiency; its small-molecule inhibitors can kill HR-deficient tumor cells in vitro and in vivo.
  • HR-deficient reversion mutation-resistant tumors resistant to PARP inhibitors such as Olaparib
  • Pol ⁇ inhibitors can resensitize cells to PARP inhibitors, providing valuable therapeutic opportunities.
  • Pol ⁇ 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.
  • Pol ⁇ has been reported to participate in cGAS-STING-mediated immune activation; therefore, targeting Pol ⁇ also has the potential to enhance immunotherapy.
  • Pol ⁇ is a highly promising target for cancer treatment.
  • Designing ATPase activity inhibitors targeting the Pol ⁇ 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.
  • the technical problem to be solved by this invention is to overcome the limitation of the single solid form of polymerase theta inhibitor compounds in the prior art.
  • this invention provides cyclic nitrogen-containing compounds, their crystal forms, preparation methods, and uses.
  • the cyclic nitrogen-containing compounds and their crystal forms provided by this invention exhibit significantly improved ATPase activity and protein inhibitory effects compared to the prior art.
  • the present invention solves the above-mentioned technical problems through the following technical solutions.
  • This invention provides a compound represented by Formula II.
  • x’ (solvent) is water or acetone
  • q (molar equivalent of solvent) is 0.1, 0.5, 0.56, 0.6, 1, 1.5, 2 or 2.5.
  • the crystal form A of the compound represented by Formula II when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations: 5.98 ⁇ 0.2°, 11.94 ⁇ 0.2°, 18.36 ⁇ 0.2°, 21.30 ⁇ 0.2°, 23.29 ⁇ 0.2°, and 27.72 ⁇ 0.2°.
  • the crystal form A of the compound represented by Formula II has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 9.00 ⁇ 0.2°, 10.84 ⁇ 0.2°, 17.91 ⁇ 0.2°, 22.05 ⁇ 0.2°, 5.98 ⁇ 0.2°, 11.94 ⁇ 0.2°, 18.36 ⁇ 0.2°, 21.30 ⁇ 0.2°, and 23.29 ⁇ 0.2°.
  • the crystal form A of the compound represented by Formula II whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 13.46 ⁇ 0.2°, 14.16 ⁇ 0.2°, 14.72 ⁇ 0.2°, 19.99 ⁇ 0.2°, 20.65 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.62 ⁇ 0.2°, 28.96 ⁇ 0.2°, 29.68 ⁇ 0.2°, 30.29 ⁇ 0.2°, and 31.08 ⁇ 0.2°.
  • the crystal form A of the compound represented by Formula II has X-ray powder diffraction patterns, expressed in terms of 2 ⁇ angles, with the diffraction peaks shown in Table 1.
  • the crystal form A of the compound represented by Formula II has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 1.
  • the differential scanning calorimetry (DSC) curve of the compound represented by Formula II, in crystal form A has endothermic peaks at peak temperatures of 98.33 ⁇ 3°C and 206.94 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) curve of crystal form A of the compound represented by Formula II is basically as shown in Figure 2.
  • the crystal form A of the compound represented by Formula II exhibits a weight loss of approximately 0.48% in the temperature range of 34.7 ⁇ 3°C to 70.0 ⁇ 3°C, approximately 2.11% in the temperature range of 70.0 ⁇ 3°C to 95.0 ⁇ 3°C, approximately 1.38% in the temperature range of 95.0 ⁇ 3°C to 140.0 ⁇ 3°C, and approximately 0.34% in the temperature range of 140.0 ⁇ 3°C to 220.0 ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of crystal form A of the compound represented by Formula II is basically as shown in Figure 3.
  • x’ is water and q is 1.
  • the compound represented by Formula II is crystal form B of the compound represented by Formula II, and its X-ray powder diffraction pattern, expressed as an angle of 2 ⁇ , using Cu-K ⁇ radiation, shows diffraction peaks at 8.10 ⁇ 0.2°, 8.37 ⁇ 0.2°, 13.94 ⁇ 0.2°, 15.67 ⁇ 0.2°, 20.72 ⁇ 0.2°, 24.4 ⁇ 0.2°, and 24.83 ⁇ 0.2°.
  • the crystal form B of the compound represented by Formula II when subjected to Cu-K ⁇ radiation and expressed in 2 ⁇ angle X-ray powder diffraction pattern, also has diffraction peaks at one or more of the following locations: 13.33 ⁇ 0.2°, 14.79 ⁇ 0.2°, 17.63 ⁇ 0.2° and 21.15 ⁇ 0.2°.
  • the crystal form B of the compound represented by Formula II has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 8.10 ⁇ 0.2°, 8.37 ⁇ 0.2°, 13.94 ⁇ 0.2°, 15.67 ⁇ 0.2°, 20.72 ⁇ 0.2°, 14.26 ⁇ 0.2°, 16.61 ⁇ 0.2°, 17.91 ⁇ 0.2°, and 18.70 ⁇ 0.2°.
  • the crystal form B of the compound represented by Formula II whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 14.26 ⁇ 0.2°, 16.61 ⁇ 0.2°, 17.91 ⁇ 0.2°, 18.70 ⁇ 0.2°, 19.13 ⁇ 0.2°, 19.62 ⁇ 0.2°, 20.03 ⁇ 0.2°, 23.92 ⁇ 0.2°, 24.20 ⁇ 0.2°, and 25.42 ⁇ 0.2°.
  • the crystal form B of the compound represented by Formula II has X-ray powder diffraction patterns, expressed in 2 ⁇ angles, with the diffraction peaks shown in Table 2.
  • the crystal form B of the compound represented by Formula II has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 4.
  • x’ is acetone, and q is 0.56, 0.5, or 0.6, for example, q is 0.56.
  • the present invention provides a crystal form C of the compound shown in Formula I, which has diffraction peaks at 11.51 ⁇ 0.2°, 18.01 ⁇ 0.2°, 22.56 ⁇ 0.2° and 25.68 ⁇ 0.2° in its X-ray powder diffraction pattern expressed in 2 ⁇ angle using Cu-K ⁇ radiation.
  • the crystal form C of the compound represented by Formula I has an X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , which also has diffraction peaks at one or more of the following locations: 12.88 ⁇ 0.2°, 15.05 ⁇ 0.2°, 20.85 ⁇ 0.2°, 21.68 ⁇ 0.2°, 23.11 ⁇ 0.2°, and 24.79 ⁇ 0.2°.
  • the strongest diffraction peak is found at 11.51 ⁇ 0.2° in the X-ray powder diffraction pattern expressed as 2 ⁇ angle using Cu-K ⁇ radiation.
  • the crystal form C of the compound represented by Formula I has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 11.51 ⁇ 0.2°, 18.01 ⁇ 0.2°, 22.56 ⁇ 0.2°, 25.68 ⁇ 0.2°, 12.88 ⁇ 0.2°, 15.05 ⁇ 0.2°, 20.85 ⁇ 0.2°, 21.68 ⁇ 0.2°, and 23.11 ⁇ 0.2°.
  • the crystal form C of the compound represented by Formula I when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 9.022 ⁇ 0.2°, 10.212 ⁇ 0.2°, 16.163 ⁇ 0.2°, 16.96 ⁇ 0.2°, 17.22 ⁇ 0.2°, 26.937 ⁇ 0.2°, 29.445 ⁇ 0.2°, 30.137 ⁇ 0.2°, and 30.354 ⁇ 0.2°.
  • the crystal form C of the compound represented by Formula I has X-ray powder diffraction patterns, expressed in terms of 2 ⁇ angles, with the diffraction peaks shown in Table 3.
  • the differential scanning calorimetry (DSC) curve of the compound represented by Formula I, crystal form C has an endothermic peak at a peak temperature of 238.92 ⁇ 3 °C.
  • the differential scanning calorimetry (DSC) curve of crystal form C of the compound represented by Formula I is basically as shown in Figure 6.
  • thermogravimetric analysis (TGA) curve of crystal form C of the compound represented by Formula I is basically as shown in Figure 7.
  • the crystal form C of the compound represented by Formula I is solvent-free.
  • This invention provides a 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.
  • e is 0 (solvent-free) in the compound represented by Formula III.
  • e (molar equivalent of water) is 1-2, for example, e is 1.5.
  • 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 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 4.61 ⁇ 0.2°, 5.02 ⁇ 0.2°, 9.19 ⁇ 0.2° and 13.76 ⁇ 0.2°.
  • the crystal form A of the compound represented by Formula III when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form A of the compound represented by Formula III has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form A of the compound represented by Formula III whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form A of the compound represented by Formula III has X-ray powder diffraction patterns, expressed in terms of 2 ⁇ angles, with the diffraction peaks shown in Table 4.
  • the crystal form A of the compound represented by Formula III has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 8.
  • w is 1, 1.1, or 1.06 (molar equivalent of hydrochloric acid), for example, 1.06.
  • e in crystal form A of the compound represented by Formula III, e is 0 or 1.5. Preferably, e is 0.
  • 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 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form B of the compound represented by Formula III when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form B of the compound represented by Formula III has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form B of the compound represented by Formula III when subjected to Cu-K ⁇ radiation and exhibiting an X-ray powder diffraction pattern at an angle of 2 ⁇ , 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°.
  • the crystal form B of the compound represented by Formula III has X-ray powder diffraction patterns, expressed in terms of 2 ⁇ angles, with the diffraction peaks shown in Table 5.
  • the crystal form B of the compound represented by Formula III has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 9.
  • 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.
  • the differential scanning calorimetry (DSC) curve of crystal form B of the compound represented by Formula III is basically as shown in Figure 10.
  • 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°C to 120.0 ⁇ 3°C and a weight loss of approximately 9.84% in the temperature range of 120.00 ⁇ 3°C to 205.00 ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of crystal form B of the compound represented by Formula III is basically as shown in Figure 11.
  • w (molar equivalent of hydrochloric acid) is 1.76, 1.7, or 1.8, for example, 1.76.
  • 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 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form C of the compound represented by Formula III when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form C of the compound represented by Formula III has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form C of the compound represented by Formula III when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form C of the compound represented by Formula III has X-ray powder diffraction patterns, expressed in terms of 2 ⁇ angles, with the diffraction peaks shown in Table 6.
  • the crystal form C of the compound represented by Formula III has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 12.
  • w is 1.7, 1.8, or 1.6, for example, 1.7.
  • e 0.
  • This invention provides a compound represented by formula IV.
  • r is 0.5, 0.9, 1, 0.97, 0.96, or 1.5.
  • t is 0 in the compound represented by formula IV.
  • t is 1-2, for example, t is 1.7.
  • the crystal form A of the compound represented by Formula IV when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form A of the compound represented by Formula IV has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form A of the compound represented by Formula IV has X-ray powder diffraction patterns, expressed in terms of 2 ⁇ angles, with the diffraction peaks shown in Table 7.
  • the crystal form A of the compound represented by Formula IV has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 13.
  • the crystal form A of the compound represented by Formula IV has r of 1, 0.97, or 0.9, for example, 0.97.
  • the crystal form A of the compound represented by Formula IV has a value of 0.
  • 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 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form B of the compound represented by Formula IV when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form B of the compound represented by Formula IV has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form B of the compound represented by Formula IV whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form B of the compound represented by Formula IV has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 14.
  • the differential scanning calorimetry (DSC) curve of crystal form B of the compound represented by Formula IV is basically as shown in Figure 15.
  • thermogravimetric analysis (TGA) curve of crystal form B of the compound represented by formula IV is basically as shown in Figure 16.
  • t is 0 or 1.7.
  • t is 0.
  • 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.
  • This invention provides a compound represented by formula V.
  • y is 1.1, 1.2, 1.14, 1, 1.09, or 1.05.
  • i is 0, and u is 0.1, 0.91, 0.9, or 1, for example, 0.91.
  • u is 0, and i is 0.1, 0.18, 0.2, or 0.5, for example, 0.18 or 0.1.
  • the compound represented by formula V is crystal form A of the compound represented by formula V, and its X-ray powder diffraction pattern, expressed in 2 ⁇ angle using Cu-K ⁇ radiation, shows diffraction peaks at 5.15 ⁇ 0.2°, 8.34 ⁇ 0.2°, 15.51 ⁇ 0.2° and 15.88 ⁇ 0.2°.
  • the crystal form A of the compound represented by formula V when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations: 7.97 ⁇ 0.2°, 8.96 ⁇ 0.2°, 17.93 ⁇ 0.2°, 18.39 ⁇ 0.2°, 21.99 ⁇ 0.2°, and 27.73 ⁇ 0.2°.
  • the crystal form A of the compound represented by formula V has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 5.15 ⁇ 0.2°, 8.34 ⁇ 0.2°, 15.51 ⁇ 0.2°, 15.88 ⁇ 0.2°, 8.96 ⁇ 0.2°, 17.93 ⁇ 0.2°, 18.39 ⁇ 0.2°, 21.99 ⁇ 0.2°, and 27.73 ⁇ 0.2°.
  • the crystal form A of the compound represented by formula V whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 5.98 ⁇ 0.2°, 8.96 ⁇ 0.2°, 10.49 ⁇ 0.2°, 10.80 ⁇ 0.2°, 11.34 ⁇ 0.2°, 11.66 ⁇ 0.2°, 11.99 ⁇ 0.2°, 12.73 ⁇ 0.2°, 13.15 ⁇ 0.2°, 18.68 ⁇ 0.2°, 19.73 ⁇ 0.2°, 20.14 ⁇ 0.2°, 22.76 ⁇ 0.2°, and 23.24 ⁇ 0.2°.
  • the crystal form A of the compound represented by formula V has X-ray powder diffraction patterns, expressed in terms of 2 ⁇ angles, with the diffraction peaks shown in Table 9.
  • the crystal form A of the compound represented by formula V has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 17.
  • the differential scanning calorimetry (DSC) curve of the compound represented by formula V has endothermic peaks at peak temperatures of 88.96 ⁇ 3°C and 192.67 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) curve of crystal form A of the compound represented by formula V is basically as shown in Figure 18.
  • the crystal form A of the compound represented by Formula V exhibits a weight loss of approximately 0.92% in the temperature range of 32.34 ⁇ 3°C to 70.0 ⁇ 3°C and a weight loss of approximately 2.1% in the temperature range of 70.0 ⁇ 3°C to 180.0 ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of crystal form A of the compound represented by formula V is basically as shown in Figure 19.
  • y is 1.1, 1.2, or 1.14, for example, 1.14.
  • i is 0, y is 1.1, and u is 0.9; or, i is 0, y is 1.14, and u is 0.91.
  • 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 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form B of the compound represented by formula V when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form B of the compound represented by formula V has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form B of the compound represented by formula V whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form B of the compound represented by formula V has X-ray powder diffraction patterns, expressed in 2 ⁇ angles, with the diffraction peaks shown in Table 10.
  • y is 1.1, 1, or 1.09, for example, 1.09.
  • the compound represented by formula V is crystal form C of the compound represented by formula V, and its X-ray powder diffraction pattern, expressed in 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 5.19 ⁇ 0.2°, 8.39 ⁇ 0.2°, 10.47 ⁇ 0.2° and 11.51 ⁇ 0.2°.
  • the crystal form C of the compound represented by formula V when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations: 15.68 ⁇ 0.2°, 15.87 ⁇ 0.2°, 18.01 ⁇ 0.2°, 22.55 ⁇ 0.2°, and 25.67 ⁇ 0.2°.
  • the relative intensity of the diffraction peak at 11.51 ⁇ 0.2° is 80%-100% when the X-ray powder diffraction pattern is expressed as an angle of 2 ⁇ using Cu-K ⁇ radiation, and is preferably the strongest peak is at 11.51 ⁇ 0.2°.
  • the crystal form C of the compound represented by formula V whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 11.67 ⁇ 0.2°, 12.73 ⁇ 0.2°, 12.89 ⁇ 0.2°, 14.59 ⁇ 0.2°, 15.05 ⁇ 0.2°, 18.76 ⁇ 0.2°, 19.81 ⁇ 0.2°, 20.48 ⁇ 0.2°, 20.84 ⁇ 0.2°, 21.68 ⁇ 0.2°, 22.10 ⁇ 0.2°, 24.80 ⁇ 0.2°, and 25.27 ⁇ 0.2°.
  • the crystal form C of the compound represented by formula V has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 5.19 ⁇ 0.2°, 8.39 ⁇ 0.2°, 10.47 ⁇ 0.2°, 11.51 ⁇ 0.2°, 11.67 ⁇ 0.2°, 15.68 ⁇ 0.2°, 15.87 ⁇ 0.2°, 18.01 ⁇ 0.2°, and 22.55 ⁇ 0.2°.
  • the crystal form C of the compound represented by formula V has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed at 2 ⁇ angles, which show the diffraction peaks as shown in Table 11.
  • the crystal form C of the compound represented by formula V has endothermic peaks in its differential scanning calorimetry (DSC) curve at peak temperatures of 188.32 ⁇ 3°C and 221.66 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) curve of crystal form C of the compound represented by formula V is basically as shown in Figure 22.
  • the crystal form C of the compound represented by formula V exhibits a weight loss of approximately 0.71% in the temperature range of 29.55 ⁇ 3°C to 180.0 ⁇ 3°C and a weight loss of approximately 0.85% in the temperature range of 180.0 ⁇ 3°C to 220.0 ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of crystal form C of the compound represented by formula V is basically as shown in Figure 23.
  • u and i are 0, and y is 1; or, u is 0, i is 0.1, and y is 1.05.
  • This invention provides a compound represented by formula VI.
  • o in the compound represented by formula VI is 1, 1.01, 1.05, or 1.1.
  • the crystal form A of the compound represented by Formula VI when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form A of the compound represented by Formula VI has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form A of the compound represented by Formula VI has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed at 2 ⁇ angles, which show the diffraction peaks as shown in Table 12.
  • the crystal form A of the compound represented by formula VI has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 24.
  • This invention provides a compound represented by formula VII.
  • CH3SO3H is methanesulfonic acid
  • p (molar equivalent of mesylate) is 1-1.1.
  • p is 1:1, 1:1.03, 1:1.05, or 1:1.1.
  • p is 1, 1.03, 1.05 or 1.1 in the compound represented by formula VII.
  • 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-K ⁇ and expressed in 2 ⁇ angle, shows diffraction peaks at 9.00 ⁇ 0.2°, 17.44 ⁇ 0.2°, and 21.74 ⁇ 0.2°.
  • the crystal form A of the compound represented by Formula VII when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form A of the compound represented by Formula VII has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form A of the compound represented by Formula VII whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form A of the compound represented by Formula VII has X-ray powder diffraction patterns, expressed in 2 ⁇ angles, with the diffraction peaks shown in Table 13.
  • the crystal form A of the compound represented by Formula VII has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 25.
  • p is 1, 1.1, or 1.03, for example, 1.03.
  • This invention provides a compound represented by formula VIII.
  • C6H6O3S is benzenesulfonic acid ;
  • a (molar equivalent of ethyl acetate) is 0-1.
  • a is 0 (solvent-free).
  • a in the compound represented by formula VIII, a is 0-0.1, for example 0.07, 0.1 or 0.
  • the compound represented by Formula VIII is crystal form A of the compound represented by Formula VIII, and its X-ray powder diffraction pattern, expressed in 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 7.66 ⁇ 0.2°, 10.09 ⁇ 0.2°, 11.92 ⁇ 0.2° and 13.91 ⁇ 0.2°.
  • the compound crystal form A shown in Formula VIII when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , has one or more diffraction peaks at the following locations: 9.06 ⁇ 0.2°, 9.72 ⁇ 0.2°, 11.10 ⁇ 0.2°, 15.91 ⁇ 0.2°, 16.55 ⁇ 0.2°, 18.00 ⁇ 0.2°, 18.27 ⁇ 0.2°, and 19.16 ⁇ 0.2°.
  • the compound crystal form A shown in Formula VIII has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 7.66 ⁇ 0.2°, 10.09 ⁇ 0.2°, 11.92 ⁇ 0.2°, 13.91 ⁇ 0.2°, 9.06 ⁇ 0.2°, 9.72 ⁇ 0.2°, 11.10 ⁇ 0.2°, 15.91 ⁇ 0.2°, and 16.55 ⁇ 0.2°.
  • the compound crystal form A shown in Formula VIII whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 20.35 ⁇ 0.2°, 20.89 ⁇ 0.2°, 21.10 ⁇ 0.2°, 21.68 ⁇ 0.2°, 22.27 ⁇ 0.2°, 22.49 ⁇ 0.2°, 22.97 ⁇ 0.2°, 23.50 ⁇ 0.2°, 24.84 ⁇ 0.2°, 25.52 ⁇ 0.2°, and 29.36 ⁇ 0.2°.
  • the compound crystal form A shown in Formula VIII has X-ray powder diffraction patterns, expressed in 2 ⁇ angles, with the diffraction peaks shown in Table 14, obtained by Cu-K ⁇ radiation.
  • the crystal form A of the compound represented by Formula VIII has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 26.
  • a in the crystal form A of the compound represented by formula VIII, a is 0, 0.1, or 0.07, for example, 0.07.
  • This invention provides a compound represented by formula IX.
  • d (molar equivalent of p-toluenesulfonic acid) is 1-2;
  • g (solvent) is water, tetrahydrofuran, isopropanol, 1,4-dioxane or methyl tert-butyl ether;
  • h (solvent molar equivalent) 0-3.
  • d is 1, 1.1, 1.2, 1.02, or 1.5.
  • h is 0 (solvent-free) in the compound represented by formula IX.
  • h is 0.1-3.
  • h is water, h is 3; if g is tetrahydrofuran, h is 0.2, 0.1, or 0.16; if g is isopropanol, h is 0.9, 0.98, or 1; if g is 1,4-dioxane, h is 3, 2.96, or 2.9; if g is methyl tert-butyl ether, h is 0.4, 0.45, or 0.5.
  • the compound represented by Formula IX is crystal form A of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 5.96 ⁇ 0.2°, 16.71 ⁇ 0.2°, 17.79 ⁇ 0.2°, 20.33 ⁇ 0.2°, and 24.66 ⁇ 0.2°.
  • the crystal form A of the compound represented by Formula IX when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern: 10.57 ⁇ 0.2°, 12.34 ⁇ 0.2°, 12.77 ⁇ 0.2°, 14.06 ⁇ 0.2°, 14.40 ⁇ 0.2°, 14.97 ⁇ 0.2°, 19.88 ⁇ 0.2°, 22.64 ⁇ 0.2°, 23.18 ⁇ 0.2°, and 24.22 ⁇ 0.2°.
  • the crystal form A of the compound pair represented by Formula IX has X-ray powder diffraction patterns using Cu-K ⁇ radiation, expressed in 2 ⁇ angles, with diffraction peaks at 5.96 ⁇ 0.2°, 16.71 ⁇ 0.2°, 17.79 ⁇ 0.2°, 20.33 ⁇ 0.2°, 24.66 ⁇ 0.2°, 10.57 ⁇ 0.2°, 12.34 ⁇ 0.2°, 12.77 ⁇ 0.2°, 14.06 ⁇ 0.2°, 14.40 ⁇ 0.2°, and 14.97 ⁇ 0.2°.
  • the crystal form A of the compound represented by Formula IX whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 9.93 ⁇ 0.2°, 10.13 ⁇ 0.2°, 11.03 ⁇ 0.2°, 11.88 ⁇ 0.2°, 17.56 ⁇ 0.2°, 18.41 ⁇ 0.2°, 18.70 ⁇ 0.2°, 20.68 ⁇ 0.2°, 22.11 ⁇ 0.2°, 25.43 ⁇ 0.2°, 25.98 ⁇ 0.2°, 27.35 ⁇ 0.2°, 27.52 ⁇ 0.2°, 28.08 ⁇ 0.2°, and 29.17 ⁇ 0.2°.
  • the crystal form A of the compound represented by Formula IX has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed at 2 ⁇ angles, which show the diffraction peaks as shown in Table 15.
  • the crystal form A of the compound represented by Formula IX has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 27.
  • the differential scanning calorimetry (DSC) curve of the compound represented by Formula IX, in crystal form A has endothermic peaks at peak temperatures of 95.83 ⁇ 3°C and 194.7 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) curve of crystal form A of the compound represented by formula IX is basically as shown in Figure 28.
  • the crystal form A of the compound represented by Formula IX exhibits a weight loss of approximately 2.03% in the temperature range of 30.52 ⁇ 3°C to 60.0 ⁇ 3°C, approximately 5.13% in the temperature range of 60.0 ⁇ 3°C to 100.0 ⁇ 3°C, and approximately 0.5% in the temperature range of 100.0 ⁇ 3°C to 190.0 ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of crystal form A of the compound represented by formula IX is basically as shown in Figure 29.
  • crystal form A of the compound represented by formula IX g is water, d is 1, and h is 3.
  • the compound represented by formula IX is a single crystal of the compound represented by formula IX, wherein...
  • the compound represented by Formula IX is crystal form B of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 5.34 ⁇ 0.2°, 9.34 ⁇ 0.2°, 9.92 ⁇ 0.2°, 12.84 ⁇ 0.2°, and 16.61 ⁇ 0.2°.
  • the crystal form B of the compound represented by Formula IX when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations: 8.20 ⁇ 0.2°, 10.13 ⁇ 0.2°, 11.12 ⁇ 0.2°, 13.18 ⁇ 0.2°, 16.13 ⁇ 0.2°, 18.67 ⁇ 0.2°, 19.47 ⁇ 0.2°, and 19.85 ⁇ 0.2°.
  • the crystal form B of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 5.34 ⁇ 0.2°, 9.34 ⁇ 0.2°, 9.92 ⁇ 0.2°, 12.84 ⁇ 0.2°, 16.61 ⁇ 0.2°, 8.20 ⁇ 0.2°, 10.13 ⁇ 0.2°, 13.18 ⁇ 0.2°, and 16.13 ⁇ 0.2°.
  • the crystal form B of the compound represented by Formula IX whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed in 2 ⁇ angles further exhibits diffraction peaks at one or more of the following locations: 11.47 ⁇ 0.2°, 16.36 ⁇ 0.2°, 18.60 ⁇ 0.2°, and 21.53 ⁇ 0.2°.
  • the crystal form B of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in 2 ⁇ angles, with the diffraction peaks shown in Table 16.
  • the crystal form B of the compound represented by Formula IX has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 30.
  • crystal form B of the compound represented by formula IX d is 1.
  • This invention provides a compound represented by formula X.
  • C10H8O6S2 is 1,5 - naphthalenedisulfonic acid ;
  • j (molar equivalent of 1,5-naphthalenedisulfonic acid) is 0.5-1.5;
  • z (solvent) is water or acetonitrile
  • k is between 0 and 5.
  • j is 1, 0.9, 1.1, 1.02, or 0.93.
  • k is 0 (solvent-free) in the compound represented by formula X.
  • k is 0.01-5.
  • k is 5 or 4.8; or if z is acetonitrile, k is 0.07.
  • 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-K ⁇ radiation and expressed in 2 ⁇ angle, shows diffraction peaks at 7.46 ⁇ 0.2°, 12.01 ⁇ 0.2°, and 21.70 ⁇ 0.2°.
  • the crystal form A of the compound represented by formula X when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form A of the compound represented by formula X has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form A of the compound represented by formula X whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form A of the compound represented by formula X has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed at 2 ⁇ angles, which show the diffraction peaks as shown in Table 17.
  • the crystal form A of the compound represented by formula X has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 31.
  • k is 0, and j is 1, 1.1, or 1.02, for example, 1.02.
  • 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 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 8.96 ⁇ 0.2°, 10.81 ⁇ 0.2°, 17.92 ⁇ 0.2° and 22.07 ⁇ 0.2°.
  • the crystal form B of the compound represented by formula X when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form B of the compound represented by formula X whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • the crystal form B of the compound represented by formula X has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form B of the compound represented by formula X has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 32.
  • 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 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form C of the compound represented by formula X when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , 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°.
  • 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 2 ⁇ angle using Cu-K ⁇ radiation, with the diffraction peak at 22.61 ⁇ 0.2° being the strongest peak.
  • the crystal form C of the compound represented by formula X has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form C of the compound represented by formula X has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed at 2 ⁇ angles, which show the diffraction peaks as shown in Table 19.
  • the crystal form C,j of the compound represented by formula X is 1.
  • k is 0 and j is 1, or z is acetonitrile and k is 0.07.
  • the compound represented by formula X is crystal form D of the compound represented by formula X, and its X-ray powder diffraction pattern, expressed in terms of 2 ⁇ angle using Cu-K ⁇ radiation, shows diffraction peaks at 10.68 ⁇ 0.2° and 21.44 ⁇ 0.2°.
  • the crystal form D of the compound represented by formula X when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations: 15.77 ⁇ 0.2°, 16.88 ⁇ 0.2°, 19.82 ⁇ 0.2°, 21.76 ⁇ 0.2°, 23.62 ⁇ 0.2°, 24.95 ⁇ 0.2°, and 27.32 ⁇ 0.2°.
  • the crystal form D of the compound represented by formula X has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 10.68 ⁇ 0.2°, 21.44 ⁇ 0.2°, 15.77 ⁇ 0.2°, 16.88 ⁇ 0.2°, 19.82 ⁇ 0.2°, 21.76 ⁇ 0.2°, 23.62 ⁇ 0.2°, and 24.95 ⁇ 0.2°.
  • the crystal form D of the compound represented by formula X whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 7.27 ⁇ 0.2°, 7.87 ⁇ 0.2°, 13.59 ⁇ 0.2°, 14.54 ⁇ 0.2°, 16.25 ⁇ 0.2°, 17.29 ⁇ 0.2°, 17.66 ⁇ 0.2°, 19.63 ⁇ 0.2°, 20.27 ⁇ 0.2°, 22.62 ⁇ 0.2°, 23.09 ⁇ 0.2°, 24.33 ⁇ 0.2°, 24.64 ⁇ 0.2°, 26.37 ⁇ 0.2°, and 28.88 ⁇ 0.2°.
  • the crystal form D of the compound represented by formula X has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed at 2 ⁇ angles, which show the diffraction peaks as shown in Table 20.
  • the crystal form D of the compound represented by formula X is shown in Figure 34 using Cu-K ⁇ radiation and X-ray powder diffraction patterns.
  • the differential scanning calorimetry (DSC) curve of the compound represented by formula X, in crystal form D exhibits endothermic peaks at peak temperatures of 62.55 ⁇ 3°C, 86.97 ⁇ 3°C, and 267.15 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) curve of crystal form D of the compound represented by formula X is basically as shown in Figure 35.
  • the crystal form D of the compound represented by formula X exhibits a weight loss of approximately 4.49% in the temperature range of 32.27 ⁇ 3°C to 60.0 ⁇ 3°C, approximately 2.41% in the temperature range of 60.0 ⁇ 3°C to 120.0 ⁇ 3°C, and approximately 0.6% in the temperature range of 120.0 ⁇ 3°C to 240.0 ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of crystal form D of the compound represented by formula X is basically as shown in Figure 36.
  • j is 1 or 1.02, for example, 1.02.
  • k is 5, 4.8, or 4, for example, 4.8.
  • z is water, j is 1, and k is 5; or j is 1.02 and k is 4.8.
  • This invention provides a compound represented by formula XI.
  • n is 0.6, 1.1, 1.13, or 1.2 in the compound represented by formula XI.
  • m is 0 (solvent-free) in the compound represented by formula XI.
  • m is 0.5-1.5, for example 1, 1.07 or 1.1.
  • the crystal form A of the compound represented by formula XI when subjected to Cu-K ⁇ radiation and expressed in 2 ⁇ 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°.
  • the crystal form A of the compound represented by formula XI has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ 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°.
  • the crystal form A of the compound represented by formula XI has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed at 2 ⁇ angles, which show the diffraction peaks as shown in Table 21.
  • the compound represented by formula XI is crystal form B of the compound represented by formula XI, and its X-ray powder diffraction pattern, expressed in 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 8.22 ⁇ 0.2°, 19.38 ⁇ 0.2°, 20.38 ⁇ 0.2°, 23.43 ⁇ 0.2°, and 24.74 ⁇ 0.2°.
  • the crystal form B of the compound represented by formula XI has X-ray powder diffraction patterns using Cu-K ⁇ radiation, expressed in 2 ⁇ angles, with diffraction peaks at 8.22 ⁇ 0.2°, 19.38 ⁇ 0.2°, 20.38 ⁇ 0.2°, 23.43 ⁇ 0.2°, 24.74 ⁇ 0.2°, 9.31 ⁇ 0.2°, 12.92 ⁇ 0.2°, and 24.17 ⁇ 0.2°.
  • the crystal form B of the compound represented by formula XI whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 15.13 ⁇ 0.2°, 16.29 ⁇ 0.2°, 17.63 ⁇ 0.2°, 17.77 ⁇ 0.2°, 18.12 ⁇ 0.2°, 18.63 ⁇ 0.2°, 21.04 ⁇ 0.2°, 21.28 ⁇ 0.2°, and 26.46 ⁇ 0.2°.
  • the crystal form B of the compound represented by formula XI has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed at 2 ⁇ angles, which show the diffraction peaks as shown in Table 22.
  • the crystal form B of the compound represented by formula XI has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 38.
  • the crystal form B of the compound represented by formula XI is 1.1, 1.2, or 1.13, for example, 1.13.
  • the compound represented by Formula IX is crystal form C of the compound represented by Formula IX, and its X-ray powder diffraction pattern, radiated by Cu-K ⁇ radiation and expressed in 2 ⁇ angle, shows diffraction peaks at 5.23 ⁇ 0.2° and 19.82 ⁇ 0.2°.
  • the crystal form C of the compound represented by Formula IX when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations: 9.21 ⁇ 0.2°, 16.11 ⁇ 0.2°, 16.57 ⁇ 0.2°, 19.39 ⁇ 0.2°, and 20.01 ⁇ 0.2°.
  • the crystal form C of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 5.23 ⁇ 0.2°, 19.82 ⁇ 0.2°, 9.21 ⁇ 0.2°, 16.11 ⁇ 0.2°, 16.57 ⁇ 0.2°, 19.39 ⁇ 0.2°, 9.80 ⁇ 0.2°, 11.12 ⁇ 0.2°, and 20.01 ⁇ 0.2°.
  • the crystal form C of the compound represented by Formula IX whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 8.07 ⁇ 0.2°, 8.26 ⁇ 0.2°, 9.80 ⁇ 0.2°, 11.12 ⁇ 0.2°, 12.72 ⁇ 0.2°, 15.24 ⁇ 0.2°, 15.48 ⁇ 0.2°, 18.20 ⁇ 0.2°, 18.71 ⁇ 0.2°, 21.52 ⁇ 0.2°, 23.51 ⁇ 0.2°, and 23.83 ⁇ 0.2°.
  • the crystal form C of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in terms of 2 ⁇ angles, with the diffraction peaks shown in Table 23.
  • the crystal form C of the compound represented by Formula IX has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 39.
  • the crystal form C and d of the compound represented by Formula IX is 1, 1.1, or 1.02, for example, 1.02.
  • the crystal form C of the compound represented by Formula IX is tetrahydrofuran, g is 1, and h is 0.2; or g is tetrahydrofuran, d is 1.02, and h is 0.16; or d is 1 and h is 0.
  • the compound represented by Formula IX is crystal form D of the compound represented by Formula IX, and its X-ray powder diffraction pattern, radiated by Cu-K ⁇ radiation and expressed in 2 ⁇ angle, shows diffraction peaks at 6.13 ⁇ 0.2°, 10.87 ⁇ 0.2°, and 18.38 ⁇ 0.2°.
  • the crystal form D of the compound represented by Formula IX when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations: 8.52 ⁇ 0.2°, 12.18 ⁇ 0.2°, 13.12 ⁇ 0.2°, 16.60 ⁇ 0.2°, 20.07 ⁇ 0.2°, and 24.00 ⁇ 0.2°.
  • the crystal form D of the compound shown in Formula IX has a relative intensity of 80%-100% for its X-ray powder diffraction pattern expressed in 2 ⁇ angle using Cu-K ⁇ radiation, with the diffraction peak at 6.13 ⁇ 0.2°, and preferably the diffraction peak at 6.13 ⁇ 0.2° is the strongest peak.
  • the crystal form D of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 6.13 ⁇ 0.2°, 10.87 ⁇ 0.2°, 18.38 ⁇ 0.2°, 8.52 ⁇ 0.2°, 12.18 ⁇ 0.2°, 13.12 ⁇ 0.2°, 16.60 ⁇ 0.2°, 20.07 ⁇ 0.2°, and 24.00 ⁇ 0.2°.
  • the crystal form D of the compound represented by Formula IX whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 14.25 ⁇ 0.2°, 14.42 ⁇ 0.2°, 17.00 ⁇ 0.2°, 19.09 ⁇ 0.2°, 19.34 ⁇ 0.2°, 21.12 ⁇ 0.2°, 21.28 ⁇ 0.2°, 21.59 ⁇ 0.2°, 21.72 ⁇ 0.2°, 23.14 ⁇ 0.2°, and 24.27 ⁇ 0.2°.
  • the crystal form D of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in 2 ⁇ angles, with the diffraction peaks shown in Table 24.
  • the crystal form D of the compound represented by Formula IX has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 40.
  • the crystal form D of the compound represented by Formula IX is 1/3.
  • the crystal form D of the compound represented by Formula IX is D, g is water, d is 1, and h is 0, 1, or 3.
  • the compound represented by Formula IX is crystal form E of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 5.66 ⁇ 0.2°, 11.50 ⁇ 0.2°, 17.97 ⁇ 0.2°, 19.83 ⁇ 0.2°, 23.95 ⁇ 0.2°, and 26.58 ⁇ 0.2°.
  • the crystal form E of the compound represented by Formula IX when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations: 13.85 ⁇ 0.2°, 14.30 ⁇ 0.2°, 17.74 ⁇ 0.2°, 19.04 ⁇ 0.2°, 21.93 ⁇ 0.2°, 22.25 ⁇ 0.2°, 23.08 ⁇ 0.2°, and 23.43 ⁇ 0.2°.
  • the crystal form E of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 5.66 ⁇ 0.2°, 11.50 ⁇ 0.2°, 17.97 ⁇ 0.2°, 19.83 ⁇ 0.2°, 23.95 ⁇ 0.2°, 13.85 ⁇ 0.2°, 14.30 ⁇ 0.2°, 17.74 ⁇ 0.2°, 19.04 ⁇ 0.2°, and 21.93 ⁇ 0.2°.
  • the crystal form E of the compound represented by Formula IX whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , further exhibits diffraction peaks at one or more of the following locations: 8.45 ⁇ 0.2°, 9.02 ⁇ 0.2°, 9.84 ⁇ 0.2°, 11.19 ⁇ 0.2°, 12.70 ⁇ 0.2°, 15.59 ⁇ 0.2°, 16.56 ⁇ 0.2°, 16.93 ⁇ 0.2°, 18.75 ⁇ 0.2°, 20.55 ⁇ 0.2°, 25.05 ⁇ 0.2°, and 26.98 ⁇ 0.2°.
  • the crystal form E of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in 2 ⁇ angles, with the diffraction peaks shown in Table 25, obtained by Cu-K ⁇ radiation.
  • the crystal form E of the compound represented by formula IX has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 41.
  • the crystal form E of the compound represented by Formula IX has endothermic peaks in its differential scanning calorimetry (DSC) curve at peak temperatures of 102.94 ⁇ 3°C and 183.71 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) curve of crystal form E of the compound represented by formula IX is basically as shown in Figure 42.
  • the crystal form E of the compound represented by Formula IX exhibits a weight loss of approximately 3.11% in the temperature range of 33.06 ⁇ 3°C to 55.0 ⁇ 3°C, approximately 3.82% in the temperature range of 55.0 ⁇ 3°C to 120.0 ⁇ 3°C, and approximately 1.21% in the temperature range of 120.0 ⁇ 3°C to 190.0 ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of crystal form E of the compound represented by formula IX is basically as shown in Figure 43.
  • the crystal form E, d of the compound represented by Formula IX is 1, 1.1, or 1.02, for example, 1.02.
  • the crystal form F of the compound represented by Formula IX has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed at 2 ⁇ angles, which show the diffraction peaks as shown in Table 26.
  • the crystal form F of the compound represented by formula IX has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 44.
  • the differential scanning calorimetry (DSC) curve of the compound represented by formula IX, in crystal form F has an endothermic peak at a peak temperature of 266.84 ⁇ 3 °C.
  • the crystal form F of the compound represented by Formula IX exhibits a weight loss of approximately 2.2% in the temperature range of 34.19 ⁇ 3°C to 260.0 ⁇ 3°C according to thermogravimetric analysis (TGA).
  • thermogravimetric analysis (TGA) curve of crystal form F of the compound represented by formula IX is basically as shown in Figure 46.
  • d is 1, 1.1, or 1.02, for example, 1.02.
  • the compound represented by Formula IX is crystal form G of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 7.65 ⁇ 0.2°, 13.76 ⁇ 0.2°, 20.35 ⁇ 0.2°, 21.01 ⁇ 0.2°, and 21.57 ⁇ 0.2°.
  • g is 1,4-dioxane.
  • the crystal form G of the compound shown in Formula IX has a Cu-K ⁇ radiation X-ray powder diffraction pattern expressed in 2 ⁇ angles with one or more diffraction peaks at the following locations: 23.83 ⁇ 0.2°, 25.37 ⁇ 0.2°, 25.63 ⁇ 0.2° and 27.60 ⁇ 0.2°.
  • the crystal form G of the compound shown in Formula IX has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 7.65 ⁇ 0.2°, 13.76 ⁇ 0.2°, 20.35 ⁇ 0.2°, 21.01 ⁇ 0.2°, 21.57 ⁇ 0.2°, 23.83 ⁇ 0.2°, 25.37 ⁇ 0.2°, 25.63 ⁇ 0.2°, and 27.60 ⁇ 0.2°.
  • the crystal form G of the compound shown in Formula IX whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed in 2 ⁇ angles further exhibits diffraction peaks at one or more of the following locations: 11.87 ⁇ 0.2°, 12.60 ⁇ 0.2°, 12.76 ⁇ 0.2°, 16.07 ⁇ 0.2°, 20.05 ⁇ 0.2°, 22.75 ⁇ 0.2°, and 23.83 ⁇ 0.2°.
  • the crystal form G of the compound represented by Formula IX has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed in 2 ⁇ angles, which show the diffraction peaks as shown in Table 27.
  • the crystal form G of the compound represented by formula IX is basically shown in Figure 47 using Cu-K ⁇ radiation and X-ray powder diffraction patterns.
  • d is 1, 1.1, or 1.2, for example, 1.1.
  • d is 1, g is 1,4-dioxane, and h is 3, or d is 1.1, g is 1,4-dioxane, and h is 2.96.
  • the compound represented by Formula IX is crystal form H of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 8.27 ⁇ 0.2°, 9.70 ⁇ 0.2°, 16.55 ⁇ 0.2° and 19.78 ⁇ 0.2°.
  • g represents methyl tert-butyl ether.
  • the crystal form H of the compound represented by Formula IX when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern: 10.39 ⁇ 0.2°, 11.07 ⁇ 0.2°, 11.60 ⁇ 0.2°, 12.56 ⁇ 0.2°, 17.07 ⁇ 0.2°, 19.09 ⁇ 0.2°, 21.12 ⁇ 0.2°, 21.46 ⁇ 0.2°, 25.23 ⁇ 0.2°, and 27.27 ⁇ 0.2°.
  • the crystal form H of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 8.27 ⁇ 0.2°, 9.70 ⁇ 0.2°, 16.55 ⁇ 0.2°, 19.78 ⁇ 0.2°, 11.07 ⁇ 0.2°, 12.56 ⁇ 0.2°, 17.07 ⁇ 0.2°, 19.09 ⁇ 0.2°, and 21.46 ⁇ 0.2°.
  • the crystal form H of the compound represented by Formula IX whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed in 2 ⁇ angles further exhibits diffraction peaks at one or more of the following locations: 5.21 ⁇ 0.2°, 11.60 ⁇ 0.2°, 15.29 ⁇ 0.2°, 18.79 ⁇ 0.2°, and 23.36 ⁇ 0.2°.
  • the crystal form H of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in 2 ⁇ angles, with the diffraction peaks shown in Table 28.
  • the crystal form H of the compound represented by formula IX has a Cu-K ⁇ radiation and X-ray powder diffraction pattern that is basically shown in Figure 48.
  • the differential scanning calorimetry (DSC) curve of the compound represented by Formula IX, in crystal form H exhibits endothermic peaks at peak temperatures of 45.53 ⁇ 3°C, 155.23 ⁇ 3°C, and 191.45 ⁇ 3°C.
  • the differential scanning calorimetry (DSC) curve of crystal form H of the compound represented by formula IX is basically as shown in Figure 49.
  • the crystal form H of the compound represented by Formula IX exhibits a weight loss of approximately 1.74% in the temperature range of 32.99 ⁇ 3°C to 100.0 ⁇ 3°C and a weight loss of approximately 5.38% in the temperature range of 100.0 ⁇ 3°C to 180.0 ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of crystal form H of the compound represented by formula IX is basically as shown in Figure 50.
  • the crystal form H of the compound represented by Formula IX, g is methyl tert-butyl ether, and h is 0.5, 0.4, or 0.45, for example, 0.45.
  • the crystal form H and d of the compound represented by Formula IX is 1:1 (i.e., 1).
  • the crystal form H of the compound represented by Formula IX g is methyl tert-butyl ether, h is 0.5, and d is 1.
  • the compound represented by Formula IX is crystal form I of the compound represented by Formula IX, and its X-ray powder diffraction pattern, radiated by Cu-K ⁇ radiation and expressed in 2 ⁇ angle, shows diffraction peaks at 6.01 ⁇ 0.2°, 10.63 ⁇ 0.2°, and 12.79 ⁇ 0.2°.
  • the crystal form I of the compound represented by Formula IX when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations: 14.20 ⁇ 0.2°, 16.67 ⁇ 0.2°, 18.00 ⁇ 0.2°, 18.74 ⁇ 0.2°, 20.07 ⁇ 0.2°, and 24.06 ⁇ 0.2°.
  • the crystal form I of the compound represented by Formula IX has a relative intensity of 80%-100% for its X-ray powder diffraction pattern expressed in 2 ⁇ angle using Cu-K ⁇ radiation, with the diffraction peak at 6.01 ⁇ 0.2° being the strongest peak.
  • the crystal form I of the compound represented by Formula IX has X-ray powder diffraction patterns expressed in 2 ⁇ angles using Cu-K ⁇ radiation, with diffraction peaks at 6.01 ⁇ 0.2°, 10.63 ⁇ 0.2°, 12.79 ⁇ 0.2°, 14.20 ⁇ 0.2°, 16.67 ⁇ 0.2°, 18.00 ⁇ 0.2°, 20.07 ⁇ 0.2°, and 24.06 ⁇ 0.2°.
  • the crystal form I of the compound represented by Formula IX whose X-ray powder diffraction pattern using Cu-K ⁇ radiation and expressed in 2 ⁇ angles further exhibits diffraction peaks at one or more of the following locations: 11.99 ⁇ 0.2°, 17.84 ⁇ 0.2°, and 23.22 ⁇ 0.2°.
  • the crystal form I of the compound represented by Formula IX has X-ray powder diffraction patterns using Cu-K ⁇ radiation and expressed at 2 ⁇ angles, which show the diffraction peaks as shown in Table 29.
  • the crystal form I of the compound represented by formula IX is shown in Figure 51 using Cu-K ⁇ radiation and X-ray powder diffraction patterns.
  • the crystal form I of the compound represented by formula IX has a d of 1.
  • crystal form I of the compound represented by formula IX d is 1 and h is 0.
  • the compound represented by Formula IX is crystal form J of the compound represented by Formula IX, and its X-ray powder diffraction pattern, expressed in 2 ⁇ angles using Cu-K ⁇ radiation, shows diffraction peaks at 5.27 ⁇ 0.2°, 8.18 ⁇ 0.2°, 9.72 ⁇ 0.2°, 10.54 ⁇ 0.2°, 11.06 ⁇ 0.2°, 12.44 ⁇ 0.2°, 18.79 ⁇ 0.2°, and 20.21 ⁇ 0.2°.
  • the crystal form J of the compound represented by Formula IX when subjected to Cu-K ⁇ radiation and expressed at an angle of 2 ⁇ , also exhibits diffraction peaks at one or more of the following locations: 15.30 ⁇ 0.2°, 16.41 ⁇ 0.2°, 18.79 ⁇ 0.2°, 19.07 ⁇ 0.2°, 19.66 ⁇ 0.2°, and 21.25 ⁇ 0.2°.
  • the crystal form J of the compound represented by Formula IX has X-ray powder diffraction patterns, expressed in 2 ⁇ angles, with the diffraction peaks shown in Table 30.
  • the crystal form J of the compound represented by formula IX is shown in Figure 52 using Cu-K ⁇ radiation and X-ray powder diffraction patterns.
  • the crystal form J of the compound represented by formula IX is 1.
  • the present invention provides a method for preparing the compound shown in Formula II, comprising the following steps: reacting the compound shown in Formula II (e.g., crystal form A of the compound shown in Formula II) with a mixed solvent of a ketone solvent (e.g., acetone) and water to obtain the compound shown in Formula II.
  • a mixed solvent of the ketone solvent e.g., acetone
  • the mixed solvent of the ketone solvent (e.g., acetone) and water is a mixed solution of acetone and water with a volume ratio of 19:1 (acetone/water).
  • 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.
  • an ester solvent e.g., ethyl acetate
  • a nitrile solvent e.g., acetonitrile
  • 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.
  • an ester solvent e.g., ethyl acetate
  • a nitrile solvent e.g., acetonitrile
  • 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.
  • an ester solvent e.g., ethyl acetate
  • a nitrile solvent e.g., acetonitrile
  • 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.
  • a nitrile solvent e.g., acetonitrile
  • the present invention provides a method for preparing the compound shown in Formula VIII, comprising the following steps: in an ester solvent (e.g., ethyl acetate), the compound shown in Formula I and benzenesulfonic acid are subjected to a salt-forming reaction to obtain the compound shown in Formula VIII.
  • an ester solvent e.g., ethyl acetate
  • the present invention provides a method for preparing the compound shown in Formula IX, comprising the following steps: in a ketone solvent (e.g., acetone) and water, and a nitrile solvent (e.g., acetonitrile), the compound shown in Formula I and p-toluenesulfonic acid are subjected to a salt-forming reaction to obtain the compound shown in Formula IX.
  • a ketone solvent e.g., acetone
  • a nitrile solvent e.g., acetonitrile
  • 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).
  • the compound of Formula IX can be mixed with a solvent and dried to obtain the compound of Formula IX;
  • the solvent is one or more of the following: ether solvents (e.g., tetrahydrofuran, 1,4-dioxane or methyl tert-butyl ether), alcohol solvents (e.g., isopropanol), and nitrile solvents (e.g., acetonitrile).
  • This invention provides a method for preparing crystal form B of the compound shown in Formula II, crystal form C of the compound shown in Formula I, 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 A of the compound shown in Formula V, crystal form B of the compound shown in Formula V, crystal form C 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 VIII, crystal form A of the compound shown in Formula IX, crystal form B of the compound shown in Formula IX, 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, crystal form D of the compound shown in Formula X, crystal form A of the compound shown in Formula XI, or crystal form B of the compound shown in Formula XI, comprising the
  • the compound is the compound shown in Formula II, and the solvent is a mixture of acetone and water, to obtain crystal form B of the compound shown in Formula II;
  • 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 ethyl acetate, to obtain crystal form A of the compound shown in Formula V;
  • 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 V, the solvent is acetonitrile, and the crystal form B of the compound shown in Formula V is added to the mixture to obtain the crystal form C 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 VIII, and the solution is ethyl acetate, to obtain crystal form A of the compound shown in Formula VIII;
  • the compound is the compound shown in Formula IX, and the solution is a mixture of acetone and water to obtain crystal form A of the compound shown in Formula IX;
  • the compound is the compound shown in Formula IX, and the solution is acetonitrile, to obtain crystal form B of the compound shown in Formula IX;
  • 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 X, and the solvent is a mixed solution of acetone and water, to obtain the crystal form D 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;
  • the compound is the compound shown in Formula XI, and the solvent is acetonitrile, to obtain crystal form B of the compound shown in Formula XI.
  • the present invention provides a method for preparing crystal forms C, E, F, G and H of the compound shown in Formula IX, which includes the following steps: drying and crystallizing a mixture of the compound and a solvent to obtain the crystal forms;
  • the compound is the compound shown in Formula IX (preferably crystal form A of the compound shown in Formula IX), and the solution is tetrahydrofuran to obtain crystal form C of the compound shown in Formula IX.
  • the compound is the compound shown in Formula IX (preferably crystal form A of the compound shown in Formula IX), and the solution is isopropanol, to obtain crystal form E of the compound shown in Formula IX;
  • the compound is the compound shown in Formula IX (preferably crystal form A of the compound shown in Formula IX), and the solution is acetonitrile and n-heptane to obtain crystal form F of the compound shown in Formula IX;
  • the compound is the compound shown in Formula IX (preferably crystal form A of the compound shown in Formula IX), and the solution is 1,4-dioxane to obtain crystal form G of the compound shown in Formula IX;
  • the compound is the compound shown in Formula IX (preferably crystal form A of the compound shown in Formula IX), and the solution is a mixed solution of acetonitrile and methyl tert-butyl ether to obtain crystal form H of the compound shown in Formula IX.
  • the cooling crystallization is, for example, cooling from 50°C to 25°C.
  • the acetone and water mixture can be a volume ratio of 19:1 (acetone/water) acetone and water mixture.
  • the drying is, for example, centrifugal drying and/or vacuum drying.
  • the method for preparing crystal form B of the compound represented by Formula II includes the following steps: crystallizing crystal form A of the compound represented by Formula II with a mixture of acetone and water (e.g., a suspension) to obtain crystal form B of the compound represented by Formula II.
  • the crystallization is performed by, for example, cooling crystallization (e.g., cooling from 50°C to 25°C) and drying (e.g., centrifugation and/or vacuum drying) to obtain crystal form B of the compound shown in Formula II.
  • cooling crystallization e.g., cooling from 50°C to 25°C
  • drying e.g., centrifugation and/or vacuum drying
  • the acetone and water mixture can be a volume ratio of 19:1 (acetone/water) of acetone and water.
  • the method for preparing crystal form C of the compound shown in Formula I includes the following steps: crystallizing crystal form A of the compound shown in Formula II with a mixture of ethyl acetate or acetonitrile (e.g., a suspension) to obtain crystal form C of the compound shown in Formula I.
  • a mixture of ethyl acetate or acetonitrile e.g., a suspension
  • the crystallization of the compound represented by Formula I in the preparation method of crystal form C is performed by cooling crystallization (e.g., cooling from 50°C to 25°C) and drying (e.g., centrifugation and/or vacuum drying).
  • cooling crystallization e.g., cooling from 50°C to 25°C
  • drying e.g., centrifugation and/or vacuum drying
  • the 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 A, crystal form B of the compound shown in Formula IV, crystal form A, 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 VIII, crystal form A, crystal form B of the compound shown in Formula IX, crystal form A, crystal form B of the compound shown in Formula X, or crystal form C of the compound shown in Formula X comprises the following steps: crystallizing a mixture of the compound shown in Formula I, a solvent, and an acid to obtain the crystal form.
  • the solution is ethyl acetate and the acid is hydrochloric acid, yielding crystal form A of the compound shown in Formula III;
  • the solution is ethyl acetate and the acid is hydrochloric acid, yielding crystal form B of the compound shown in Formula III;
  • the solution is acetonitrile and the acid is hydrochloric acid, yielding crystal form C of the compound shown in Formula III;
  • the solution is a mixture of acetone and water, and the acid is p-toluenesulfonic acid, to obtain crystal form A of the compound shown in Formula IX;
  • 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;
  • the solution is acetonitrile, and the acid is 1,5-naphthalenedisulfonic acid, yielding crystal form C of the compound shown in formula X.
  • the crystallization is performed by cooling crystallization (e.g., cooling from 50°C to 25°C) and drying (e.g., vacuum drying).
  • cooling crystallization e.g., cooling from 50°C to 25°C
  • drying e.g., vacuum drying
  • 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.
  • 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.
  • the acetone and water mixture is a volume ratio of 19:1 (acetone/water) of acetone and water.
  • 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).
  • 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.
  • the compound represented by Formula I is the crystal form A of the compound represented by Formula II.
  • the acid 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.
  • the method for preparing crystal form C of the compound shown in Formula V includes the following steps: mixing a mixture of the compound shown in Formula I, acetonitrile, and phosphoric acid with crystal form B of the compound shown in Formula V, and crystallizing to obtain crystal form C of the compound shown in Formula V;
  • the crystallization is performed by cooling crystallization (e.g., cooling from 50°C to 25°C) and drying (e.g., vacuum drying).
  • cooling crystallization e.g., cooling from 50°C to 25°C
  • drying e.g., vacuum drying
  • the method for preparing crystal forms C, E, F, G, and H of the compound represented by Formula IX includes the following steps: crystallizing a mixture of crystal form A of the compound represented by Formula IX and a solvent;
  • the solution is a mixture of acetonitrile and methyl tert-butyl ether (e.g., a mixture of acetonitrile and methyl tert-butyl ether in a volume ratio of 1:4), yielding the crystal form H of the compound shown in Formula IX.
  • a mixture of acetonitrile and methyl tert-butyl ether e.g., a mixture of acetonitrile and methyl tert-butyl ether in a volume ratio of 1:4
  • the crystallization in the preparation method is dry crystallization (e.g., vacuum drying at 50°C).
  • the crystallization is performed by filtration.
  • the preparation method when obtaining crystal form F of the compound represented by Formula IX, comprises the following steps: adding n-heptane to a mixed solvent of crystal form A of the compound represented by Formula IX and acetonitrile, and crystallizing.
  • the preparation method when obtaining crystal form H of the compound represented by Formula IX, comprises the following steps: adding methyl tert-butyl ether to a mixed solvent of crystal form A of the compound represented by Formula IX and acetonitrile, and crystallizing.
  • the present invention provides a method for preparing crystal form I of the compound shown in Formula IX, which includes the following steps: heating crystal form A of the compound shown in Formula IX at 25°C (preferably under nitrogen protection) to obtain crystal form I of the compound shown in Formula IX.
  • the method for preparing crystal form D of the compound shown in Formula IX includes the following steps: heating crystal form A of the compound shown in Formula IX at 55°C (preferably under nitrogen protection) to obtain crystal form D of the compound shown in Formula IX.
  • the method for preparing crystal form J of the compound shown in Formula IX includes the following steps: heating crystal form H of the compound shown in Formula IX at 170°C (preferably under nitrogen protection) to obtain crystal form J of the compound shown in Formula IX.
  • This invention provides a method for preparing a single crystal of the compound shown in Formula IX, comprising the following steps:
  • Step (1) Mix the mixture of the compound shown in Formula I, acetone and water with crystal form A of the compound shown in Formula IX;
  • Step (2) Add a mixture of toluene-4-sulfonic acid, acetone and water, and crystallize to obtain a single crystal of the compound shown in Formula IX.
  • the mass ratio of the compound represented by Formula I to acetone can be (0.5-2):(8-12), for example 1.63:10.3.
  • the mass ratio of acetone to water can be (9-11):(0.5-1.5), for example, 10.3:1.3.
  • step (1) the mixing can be performed at 45-55°C.
  • the mass ratio of crystal form A of the compound represented by Formula IX to the compound represented by Formula I can be 1:100 to 1:10, for example 8:163.
  • the mass ratio of toluene-4-sulfonic acid, acetone and water can be (1-2.5):(5-10):(0.5-1.5), for example 0.58:2.57:0.32.
  • the toluene-4-sulfonic acid in step (2), can be toluene-4-sulfonic acid monohydrate.
  • the mixture in step (2), can be added in two parts.
  • the first addition is made at 45-55°C, and the mass ratio of toluene-4-sulfonic acid to the compound represented by Formula I is 1:(2-4), for example, 0.58:1.63.
  • the second addition is made at 20-30°C, and the mass ratio of toluene-4-sulfonic acid to the compound represented by Formula I is 1:(4-8), for example, 0.29:1.63.
  • the method for preparing a single crystal of the compound represented by Formula IX involves filtering after crystallization to obtain a single crystal of the compound represented by Formula IX.
  • the method for preparing crystal form D of the compound shown in Formula X includes the following steps: crystallizing a mixture of crystal form A of the compound shown in Formula X, a mixed solution of acetone and water, and a mixture of 1,5-naphthalenedisulfonic acid to obtain crystal form D of the compound shown in Formula X.
  • the crystallization of the compound represented by formula X in the preparation method of crystal form D is performed by cooling crystallization (e.g., cooling from 50°C to 25°C after suspension) and drying (e.g., vacuum drying).
  • the method for preparing crystal form D of the compound represented by formula X uses a acetone-water mixture with a volume ratio of 19:1 (acetone/water).
  • the method for preparing crystal form A or crystal form B 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.
  • a sodium salt e.g., NaOH
  • the solvent is ethyl acetate, which yields crystal form A of the compound shown in formula XI;
  • the solvent is acetonitrile, and the crystal form B of the compound shown in formula XI is obtained.
  • the crystallization of the compound represented by formula XI is performed by cooling crystallization (e.g., cooling from 50°C to 25°C after suspension) or drying (e.g., vacuum drying).
  • cooling crystallization e.g., cooling from 50°C to 25°C after suspension
  • drying e.g., vacuum drying
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising substance X and pharmaceutical excipients, wherein substance X is a compound represented by formulas II, III, IV, V, VI, VII, VIII, IX, X, XI or a crystal form C of a compound represented by formula I.
  • 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 a compound represented by formulas II, III, IV, V, VI, VII, VIII, IX, X, XI or a crystalline form C of a compound represented by formula I.
  • substance X is crystal form A of the compound shown in Formula II, crystal form B of the compound shown in Formula II, 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 A of the compound shown in Formula V, crystal form B of the compound shown in Formula V, crystal form C 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 VIII, and crystal form A of the compound shown in Formula X.
  • solvent refers to a crystal form of a substance whose crystal structure contains a solvent.
  • hydrate refers to a solvate whose crystal structure contains water as the solvent.
  • 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.
  • 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”.
  • 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.
  • the peak positions may have errors, for example, a 2 ⁇ 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.
  • salt, composition, or excipient 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.
  • 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.
  • the reagents and raw materials used in this invention are all commercially available.
  • 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.
  • Figure 1 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula II.
  • Figure 2 shows the differential scanning calorimeter of crystal form A of the compound represented by formula II.
  • Figure 3 shows the thermogravimetric analysis spectrum of crystal form A of the compound represented by formula II.
  • Figure 4 shows the X-ray powder diffraction pattern of crystal form B of the compound represented by formula II.
  • Figure 5 shows the X-ray powder diffraction pattern of crystal form C of the compound shown in Formula I.
  • Figure 6 shows the differential scanning calorimeter of the crystal form of the compound represented by Formula I.
  • FIG. 7 shows the thermogravimetric analysis (TGA) spectrum of the crystal form of the compound represented by Formula I.
  • Figure 8 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by Formula III.
  • Figure 9 shows the X-ray powder diffraction pattern of crystal form B of the compound represented by Formula III.
  • Figure 10 shows the differential scanning calorimeter of crystal form B of the compound represented by Formula III.
  • FIG. 11 shows the thermogravimetric analysis (TGA) spectrum of crystal form B of the compound represented by Formula III.
  • Figure 12 shows the X-ray powder diffraction pattern of crystal form C of the compound shown in Formula III.
  • Figure 13 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula IV.
  • Figure 14 shows the X-ray powder diffraction pattern of crystal form B of the compound shown in Formula IV.
  • Figure 15 shows the differential scanning calorimeter of crystal form B of the compound represented by formula IV.
  • FIG 16 shows the thermogravimetric analysis (TGA) spectrum of crystal form B of the compound represented by formula IV.
  • Figure 17 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula V.
  • Figure 18 shows the differential scanning calorimeter of crystal form A of the compound represented by formula V.
  • FIG 19 shows the thermogravimetric analysis (TGA) spectrum of crystal form A of the compound represented by formula V.
  • Figure 20 shows the X-ray powder diffraction pattern of crystal form B of the compound represented by formula V.
  • Figure 21 shows the X-ray powder diffraction pattern of crystal form C of the compound represented by formula V.
  • Figure 22 shows the differential scanning calorimeter of the crystal form C of the compound represented by formula V.
  • FIG. 23 shows the thermogravimetric analysis (TGA) spectrum of the crystal form C of the compound represented by formula V.
  • Figure 24 is an X-ray powder diffraction pattern of crystal form A of the compound shown in formula VI.
  • Figure 25 shows the X-ray powder diffraction pattern of crystal form A of the compound shown in Formula VII.
  • Figure 26 shows the X-ray powder diffraction pattern of crystal form A of the compound shown in formula VIII.
  • Figure 27 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula IX.
  • Figure 28 shows the differential scanning calorimeter of crystal form A of the compound represented by formula IX.
  • FIG. 29 shows the thermogravimetric analysis (TGA) spectrum of crystal form A of the compound represented by formula IX.
  • Figure 30 shows the X-ray powder diffraction pattern of crystal form B of the compound represented by formula IX.
  • Figure 31 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula X.
  • Figure 32 shows the X-ray powder diffraction pattern of crystal form B of the compound represented by formula X.
  • Figure 33 shows the X-ray powder diffraction pattern of crystal form C of the compound represented by formula X.
  • Figure 34 is an X-ray powder diffraction pattern of crystal form D of the compound represented by formula X.
  • Figure 35 shows the differential scanning calorimeter of the crystal form D of the compound represented by formula X.
  • Figure 36 shows the thermogravimetric analysis (TGA) spectrum of crystal form D of the compound represented by formula X.
  • Figure 37 shows the X-ray powder diffraction pattern of crystal form A of the compound represented by formula XI.
  • Figure 38 shows the X-ray powder diffraction pattern of crystal form B of the compound represented by formula XI.
  • Figure 39 shows the X-ray powder diffraction pattern of crystal form C of the compound represented by formula IX.
  • Figure 40 shows the X-ray powder diffraction pattern of crystal form D of the compound represented by formula IX.
  • Figure 41 is an X-ray powder diffraction pattern of crystal form E of the compound represented by formula IX.
  • Figure 42 shows the differential scanning calorimeter of the crystal form E of the compound represented by formula IX.
  • FIG 43 shows the thermogravimetric analysis (TGA) spectrum of crystal form E of the compound represented by formula IX.
  • Figure 44 is an X-ray powder diffraction pattern of crystal form F of the compound represented by formula IX.
  • Figure 45 shows the differential scanning calorimeter of the crystal form of the compound represented by formula IX.
  • FIG 46 shows the thermogravimetric analysis (TGA) spectrum of crystal form F of the compound represented by formula IX.
  • Figure 47 shows the X-ray powder diffraction pattern of crystal form G of the compound represented by formula IX.
  • Figure 48 shows the X-ray powder diffraction pattern of crystal form H of the compound represented by formula IX.
  • Figure 49 shows the differential scanning calorimeter of the crystal form H of the compound represented by formula IX.
  • FIG 50 shows the thermogravimetric analysis (TGA) spectrum of crystal form H of the compound represented by formula IX.
  • Figure 51 is an X-ray powder diffraction pattern of crystal form I of the compound shown in formula IX.
  • Figure 52 shows the X-ray powder diffraction pattern of crystal form J of the compound represented by formula IX.
  • Figure 53 shows the XRPD images of crystal form C of the compound shown in Formula I after being placed under open and closed conditions at 25°C/60%RH.
  • Figure 54 shows the XRPD images of crystal form C of the compound shown in formula V after being placed under open and closed conditions at 25°C/60%RH.
  • Figure 55 shows the XRPD images of crystal form A of the compound shown in Formula IX after being placed under open and closed conditions at 25°C/60%RH.
  • Figure 56 shows the XRPD images of crystal form F of the compound represented by formula IX after being placed under open and closed conditions at 25°C/60%RH.
  • Figure 57 shows the molecular structure of a single crystal of the compound represented by Formula IX.
  • XRPD X-ray powder diffraction
  • the single-crystal testing method involved in this invention is as follows:
  • 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.
  • Micro-focal spot light source with a spot size no larger than 100mm.
  • Angle measuring instrument Kappa (Kappa, ⁇ , 2 ⁇ , ⁇ ) quadriaxial angle measuring instrument, equipped with an automatic angle measuring head.
  • Detector A brand-new semiconductor two-dimensional imaging technology detector with both photon counting and integration functions; detection area 208 ⁇ 128mm2 ; pixel size: ⁇ 135 ⁇ m ⁇ 135 ⁇ m, 1:1 coupling with the chip, and no beam taper ratio.
  • Low-temperature cooling system Supports testing in the temperature range of 80K to 500K.
  • thermogravimetric analysis (TGA) curves and differential scanning calorimetry (DSC) curves involved in this invention are shown in the table below:
  • 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):
  • Deliquescence Absorbs sufficient moisture to form a liquid
  • the weight gain due to hygroscopic absorption is not less than 15%;
  • the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;
  • the weight gain due to moisture absorption is less than 2% but not less than 0.2%;
  • the weight gain due to moisture absorption is less than 0.2%.
  • the method for testing moisture content is as follows: Fischer titration (KF).
  • PLM polarizing microscopes
  • HPLC high-performance liquid chromatography
  • 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.
  • 2 mol/L lithium diisopropylamino 70 mL was slowly added dropwise while maintaining the temperature below -60 °C.
  • the reaction was continued at this low temperature for 2 hours.
  • 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 by adding 100 mL of water in an ice-water bath.
  • Step 5 (9H-fluorene-9-yl)methyl(6-chloro-7-fluorothiazo[4,5-c]pyridin-2-yl)carbamate hydrobromic acid Salt
  • Step 7 6-Chloro-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-7-fluorothiazo[4,5-c]pyridine
  • Step 8 6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-2-(2,5-dimethyl-1H-pyrrolo-1-yl)-7-fluorothiazolyl Azo[4,5-c]pyridine
  • 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
  • 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 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.
  • 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°C (enthalpy 121.36 J/g) and 206.94°C (enthalpy 66.798 J/g), with onset x values of 72.55°C and 200.15°C, respectively.
  • the TGA spectrum is shown in Figure 3. The sample lost 0.48% weight when heated from 34.69°C to 70.0°C, 2.11% weight when heated from 70.0°C to 95.0°C, 1.38% weight when heated from 95.0°C to 140.0°C, and approximately 0.34% weight in the temperature range of 140.0°C to 220.0°C. DSC and TGA analyses indicate that crystal form A is a monohydrate.
  • the resulting white solid is crystalline form C of the compound shown in Formula I, and its XRPD pattern is shown in Figure 5. It exhibits the diffraction peaks shown in Table 3 below.
  • the DSC pattern of crystalline form C of the compound shown in Formula I is shown in Figure 6. An endothermic peak was observed at the peak temperature of 238.92°C (enthalpy of 106.67 J/g) in the DSC curve.
  • the TGA pattern is shown in Figure 7. The sample lost 0.81% of its weight when heated from 35.56°C to 230.0°C. DSC and TGA analyses indicate that the free basal crystalline form C of the compound shown in Formula I is an anhydrous hydrate.
  • Example 2 The compound shown in Formula III has crystal form A.
  • Example 3 shows the crystal form B of the compound represented by Formula III.
  • the DSC spectrum of compound B (formula III) is shown in Figure 10. An endothermic peak was observed at the peak temperature of 186.88°C (enthalpy of 164.82 J/g), with an onset point (Onset x) of 172.09°C.
  • the TGA spectrum is shown in Figure 11. The sample lost 1.42% of its weight when heated from 24.07°C to 120.0°C and 9.84% of its weight when heated from 120.0°C to 205.0°C. DSC and TGA analyses indicate that compound B (formula III) is an anhydrous hydrate.
  • Example 6 Crystal form B of the compound shown in Formula IV
  • the DSC spectrum of crystal form B of the compound shown in Formula IV is shown in Figure 15. 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 16.
  • the molar ratio of the compound shown in Formula I to phosphoric acid was 1:1.14, and crystal form A of the compound shown in Formula V was a hydrate.
  • the XRPD pattern of crystal form A of the phosphate of the compound shown in Formula I is shown in Figure 17, and it exhibits the diffraction peaks shown in Table 9 below.
  • the DSC spectrum of compound A (formula V) is shown in Figure 18. Two endothermic peaks were observed at peak temperatures of 88.96°C (enthalpy 42.827 J/g) and 192.67°C (enthalpy 52.713 J/g), with onset x values of 66.74°C and 183.41°C, respectively.
  • the TGA spectrum is shown in Figure 19. The sample lost 0.92% of its weight when heated from 32.34°C to 70.0°C and 2.10% when heated from 70.0°C to 180.0°C. DSC and TGA analyses indicate that phosphate form A (formula V) of compound I is a hydrate, with a water content of 0.91 parts based on TGA calculations.
  • Crystal form C of the compound shown in Formula V was an anhydrous hydrate. NMR showed that the phosphate crystal form C of the compound shown in Formula I (crystal form C of the compound shown in Formula V) contained 0.1 equivalents of acetonitrile.
  • the XRPD pattern of crystal form C of the compound shown in Formula I is shown in Figure 21, and it exhibits the diffraction peaks shown in Table 11 below.
  • the DSC spectrum of compound C (formula V) is shown in Figure 22. Endothermic peaks were observed at peak temperatures of 188.32°C (enthalpy 41.702 J/g) and 221.66°C (enthalpy 32.668 J/g), with onset x values of 175.87°C and 32.668°C, respectively.
  • the TGA spectrum is shown in Figure 23. The sample lost 0.71% of its weight when heated from 29.55°C to 180.0°C and 0.85% of its weight when heated from 180.0°C to 220.0°C.
  • the DSC spectrum of crystal form A of the compound represented by Formula IX is shown in Figure 28. Two endothermic peaks were observed in the DSC curve at peak temperatures of 95.83°C (enthalpy 244.34 J/g) and 194.7°C (enthalpy 34.862 J/g), with onset x values of 57.37°C and 181.84°C, respectively.
  • the TGA spectrum is shown in Figure 29. The sample lost 2.03% weight when heated from 30.52°C to 60.0°C, 5.13% weight when heated from 60.0°C to 100.0°C, and 0.50% weight when heated from 100.0°C to 190.0°C.
  • NMR data show that the molar ratio of water to the compound represented by Formula I and p-toluenesulfonic acid in crystal form A of the compound represented by Formula IX is 3:1:1.
  • the compound shown in Formula I (1.63 kg, 3.11 mol) was added to a mixed solution of 10.3 kg acetone and 1.30 kg water, and the temperature was controlled at 45-55 °C. Then, 80 g of crystal form A of the compound shown in Formula IX was added to obtain a mixture. 0.58 kg of toluene-4-sulfonic acid monohydrate was dissolved in 2.57 kg acetone and 0.32 kg water, and added dropwise to the above mixture. The mixture was stirred at 45-55 °C for 2 hours. The temperature was then lowered to 20-30 °C, and the mixture was stirred for 2 hours.
  • the DSC spectrum of compound D (formula X) is shown in Figure 35. Three endothermic peaks were observed at peak temperatures of 62.55°C (enthalpy 111.00 J/g), 86.97°C (enthalpy 39.972 J/g), and 267.15°C (enthalpy 55.716 J/g), with onset x values of 39.64°C, 70.37°C, and 256.54°C, respectively.
  • the TGA spectrum is shown in Figure 36.
  • the sample lost 4.49% weight when heated from 32.27°C to 60.0°C, 2.41% weight when heated from 60.0°C to 120.0°C, and 0.60% weight when heated from 120.0°C to 240.0°C.
  • NMR data show that the crystal form D of the compound shown in formula X contains only 0.1% acetone, and the KF moisture test result shows that it contains 9.1% water, indicating that the water content of crystal form D is 4.8 equivalents.
  • crystal form A of the compound shown in Formula I (crystal form A of the compound shown in Formula IX) was added to 5.2 mL of tetrahydrofuran. After stirring at 25 °C, the mixture was filtered and dried under vacuum at 50 °C for 2 hours to obtain crystal form C of the compound shown in Formula IX, which is a solvate of tetrahydrofuran.
  • the molar ratio of the compound shown in Formula I to p-toluenesulfonic acid and tetrahydrofuran was 1:1.02:0.16.
  • the XRPD pattern of crystal form C of the compound shown in Formula IX is shown in Figure 39, and it exhibits the diffraction peaks shown in Table 23 below.
  • the crystal form A of the compound shown in Formula IX was heated at 55 °C under a nitrogen atmosphere to obtain the crystal form D of the compound shown in Formula IX.
  • the molar ratio of the compound shown in Formula I to p-toluenesulfonic acid was 1:1.
  • the XRPD pattern of the p-toluenesulfonate salt of the compound shown in Formula I is shown in Figure 40, and it has the diffraction peaks shown in Table 24 below.
  • crystal form A of the compound shown in Formula IX was added to 0.2 mL of isopropanol, heated to 50 °C and shaken, filtered, and dried under vacuum at 50 °C for 2 hours to obtain crystal form E of the p-toluenesulfonate isopropanol solvate of the compound shown in Formula I (crystal form E of the compound shown in Formula IX). Its 1H NMR spectrum showed that this crystal form contained 0.98 equivalents of isopropanol.
  • the molar ratio of the compound shown in Formula I, p-toluenesulfonic acid, and isopropanol was 1:1.02:0.98.
  • the XRPD pattern of crystal form E of the compound shown in Formula IX is shown in Figure 41, and it exhibits the diffraction peaks shown in Table 25 below.
  • the DSC spectrum of crystal form E of the compound shown in Formula IX is shown in Figure 42. Two endothermic peaks were observed in the DSC curve at peak temperatures of 102.94 °C (enthalpy 207.35 J/g) and 183.71 °C (enthalpy 34.855 J/g), with onset x values of 65.61 °C and 176.33 °C, respectively.
  • the TGA spectrum is shown in Figure 43. The sample lost 3.11% weight when heated from 33.06 °C to 55.0 °C, 3.82% weight when heated from 55.0 °C to 120.00 °C, and 1.21% weight when heated from 120.0 °C to 190.0 °C.
  • the DSC spectrum of crystal form F of compound IX is shown in Figure 45.
  • An endothermic peak was observed at the peak temperature of 266.84°C (enthalpy of 70.167 J/g) in the DSC curve, and the onset point (onset x) of the endothermic peak was 263.55°C.
  • the TGA spectrum is shown in Figure 46. The sample lost 2.2% of its weight when heated from 34.19°C to 260.0°C.
  • Example 25 Crystal form G of the compound shown in Formula IX
  • the DSC spectrum of crystal form H of compound IX is shown in Figure 49. Endothermic peaks were observed at peak temperatures of 45.53°C (enthalpy 10.478 J/g), 155.23°C (enthalpy 29.331 J/g), and 191.45°C (enthalpy 23.665 J/g), with onset x values of 29.17°C, 134.74°C, and 184.26°C, respectively.
  • the TGA spectrum is shown in Figure 50. The sample lost 1.74% weight when heated from 32.99°C to 100.0°C and 5.38% weight when heated from 100.0°C to 180.0°C.
  • the crystal form A of the compound shown in Formula IX was heated at 25°C under a nitrogen atmosphere to obtain the crystal form I of the compound shown in Formula IX.
  • the molar ratio of the compound shown in Formula I to p-toluenesulfonic acid was 1:1.
  • the XRPD pattern of crystal form I of the compound shown in Formula I is shown in Figure 51, and it exhibits the diffraction peaks shown in Table 29 below.
  • the crystal form H of the compound shown in Formula IX was heated at 170 °C under a nitrogen atmosphere to remove the solvent, yielding the crystal form J of the compound shown in Formula IX.
  • the molar ratio of the compound shown in Formula I to p-toluenesulfonic acid was 1:1.01.
  • the XRPD pattern of crystal form J of the compound shown in Formula IX is shown in Figure 52, and it exhibits the diffraction peaks shown in Table 30 below.
  • the crystal form C of the compound of formula I in Examples 1-2, the crystal form C of the compound of formula V obtained in Example 9, the crystal form A of the compound of formula IX obtained in Example 13, and the crystal form F of the compound of formula IX obtained in Example 24 were placed under open and closed conditions at 25°C/60%RH for two weeks, as shown in Figures 53, 54, 55, and 56.
  • the crystal form stability was good.
  • 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°C.
  • Test results show that: the crystal form C of the compound shown in Formula I is non-hygroscopic and its crystal form remains unchanged before and after the test; the crystal form A of the compound shown in Formula III has moderate hygroscopicity, absorbing 4.8% water; the crystal form A of the compound shown in Formula IX absorbs 0.2% water; and the crystal form C of the compound shown in Formula V absorbs 1.7% water.
  • crystal form C (8 mg) of compound I, crystal form A (9 mg) of compound III, crystal form A (11.7 mg) of compound IX, and crystal form C (10 mg) of compound V into 20 mL glass bottles. Add 4 mL of solvent. Stir the resulting suspension or clear solution at 37 °C at 400 rpm. Take samples at 0.5 h and 2 h, 0.5 mL each time, and centrifuge at 37 °C at 14,000 rpm for 5 min. Finally, perform content testing on the resulting filtrate.
  • A represents a solubility of 0.01-0.1 mg/mL
  • B represents a solubility of 0.1-1 mg/L.
  • the N-terminus of the Pol ⁇ protein contains a helicase domain with ATPase activity, capable of hydrolyzing ATP to ADP.
  • the ATPase activity of the Pol ⁇ protein and the inhibitory effect of small molecule compounds on the protein can be analyzed using the ADP-Glo assay kit (ADP-GloTM Kinase Assay, Promega, V9102).
  • the specific detection method is as follows:
  • ssDNA SEQ ID NO.1:5'-CCAGTGAATTGTTGCTCGGTACCTGCTAAC-3', Hangzhou Youkang Biotechnology Co., Ltd.
  • a reaction buffer containing 10 mM DTT (dithiothreitol), 20 mM MgCl2 , Tris-HCl, and pH 7.5 was prepared.
  • the CV% of the control group's test results should be less than 10%, and the z' value should be greater than 0.5.
  • a nonlinear regression was used to fit the inhibition rate curve of the compound and the IC50 value was obtained.
  • the in vitro efficacy of the inhibitor was assessed using a cell viability assay, specifically the commonly used CTG assay, employing CellTiter Glo reagent (Promega, G7573).
  • the specific assay method is as follows:
  • Drug treatment was performed 24 hours after cell seeding, which was recorded as Day 0.
  • the compound was added using an automated pipette (Thermo, Multidrop8).
  • the plate was set as a 96-well plate with an initial concentration of 30 ⁇ M.
  • 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.

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Abstract

La présente invention concerne un composé azoté à cycle condensé, une forme cristalline de celui-ci, un procédé de préparation et l'utilisation de celui-ci. L'invention concerne en particulier un solvate d'un composé représenté par la formule (I), un sel du composé représenté par la formule (I), ou un solvate du sel du composé représenté par la formule (I). Le composé azoté à cycle condensé et sa forme cristalline selon la présente invention présentent une bonne activité pharmaceutique et de larges perspectives médicinales.
PCT/CN2025/090761 2024-04-24 2025-04-23 Composé azoté à cycle condensé, forme cristalline de celui-ci, procédé de préparation et utilisation de celui-ci Pending WO2025223483A1 (fr)

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PCT/CN2025/090735 Pending WO2025223477A1 (fr) 2024-04-24 2025-04-23 Composé azoté à cycles fusionnés, forme cristalline de celui-ci, son procédé de préparation et son utilisation
PCT/CN2025/090736 Pending WO2025223478A1 (fr) 2024-04-24 2025-04-23 Composé contenant de l'azote à cycle condensé, forme cristalline associée, procédé de préparation s'y rapportant et utilisation associée

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PCT/CN2025/090736 Pending WO2025223478A1 (fr) 2024-04-24 2025-04-23 Composé contenant de l'azote à cycle condensé, forme cristalline associée, procédé de préparation s'y rapportant et utilisation associée

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020243459A1 (fr) * 2019-05-31 2020-12-03 Ideaya Biosciences, Inc. Dérivés de thiadiazolyle comme inhibiteurs de l'adn polymérase thêta
WO2022118210A1 (fr) * 2020-12-02 2022-06-09 Ideaya Biosciences, Inc. Dérivés substitués de thiadiazolyle comme inhibiteurs de l'adn polymérase thêta
WO2022259204A1 (fr) * 2021-06-11 2022-12-15 Ideaya Biosciences, Inc. Composés thiadiazolyle liés à o utilisés en tant qu'inhibiteurs de l'adn polymérase thêta
WO2023134739A1 (fr) * 2022-01-13 2023-07-20 南京再明医药有限公司 Composé cyclothiazole à six chaînons et son utilisation
WO2023134708A1 (fr) * 2022-01-12 2023-07-20 Beigene , Ltd. Dérivés de thiazolopyridyl amide en tant qu'inhibiteurs d'adn polymérase thêta
WO2024088407A1 (fr) * 2022-10-28 2024-05-02 杭州圣域生物医药科技有限公司 Composé cyclique fusionné contenant de l'azote, son intermédiaire, son procédé de préparation et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020243459A1 (fr) * 2019-05-31 2020-12-03 Ideaya Biosciences, Inc. Dérivés de thiadiazolyle comme inhibiteurs de l'adn polymérase thêta
WO2022118210A1 (fr) * 2020-12-02 2022-06-09 Ideaya Biosciences, Inc. Dérivés substitués de thiadiazolyle comme inhibiteurs de l'adn polymérase thêta
WO2022259204A1 (fr) * 2021-06-11 2022-12-15 Ideaya Biosciences, Inc. Composés thiadiazolyle liés à o utilisés en tant qu'inhibiteurs de l'adn polymérase thêta
WO2023134708A1 (fr) * 2022-01-12 2023-07-20 Beigene , Ltd. Dérivés de thiazolopyridyl amide en tant qu'inhibiteurs d'adn polymérase thêta
WO2023134739A1 (fr) * 2022-01-13 2023-07-20 南京再明医药有限公司 Composé cyclothiazole à six chaînons et son utilisation
WO2024088407A1 (fr) * 2022-10-28 2024-05-02 杭州圣域生物医药科技有限公司 Composé cyclique fusionné contenant de l'azote, son intermédiaire, son procédé de préparation et son utilisation

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