WO2024041605A1 - Sel pharmaceutiquement acceptable d'inhibiteur de parp dérivé d'hétéroaryle et son utilisation - Google Patents

Sel pharmaceutiquement acceptable d'inhibiteur de parp dérivé d'hétéroaryle et son utilisation Download PDF

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WO2024041605A1
WO2024041605A1 PCT/CN2023/114679 CN2023114679W WO2024041605A1 WO 2024041605 A1 WO2024041605 A1 WO 2024041605A1 CN 2023114679 W CN2023114679 W CN 2023114679W WO 2024041605 A1 WO2024041605 A1 WO 2024041605A1
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crystal form
ray powder
powder diffraction
diffraction pattern
radiation
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PCT/CN2023/114679
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English (en)
Chinese (zh)
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宫正
马金翼
陈雷
范江
窦赢
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四川海思科制药有限公司
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Publication of WO2024041605A1 publication Critical patent/WO2024041605A1/fr

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and in particular relates to a pharmaceutically acceptable salt of a small molecule compound with PARP-1 inhibitory activity and its crystal form, as well as their use in preparing drugs for treating related diseases.
  • the BRCA1/2 gene is a tumor suppressor gene and plays an important role in DNA damage repair and normal cell growth. This gene mutation can inhibit the normal repair ability after DNA damage, causing homologous recombination deficiency (HRD), that is, loss of BRCA function or mutation or loss of function of other homologous recombination-related genes, making DNA repair of double-strand breaks impossible.
  • HRD homologous recombination deficiency
  • PARP Poly(ADP-ribose) polymerase
  • PARP is a DNA repair enzyme that plays a key role in the DNA repair pathway. PARP is activated when DNA is damaged and broken. As a molecular sensor of DNA damage, it has the function of identifying and binding to the location of DNA breaks, thereby activating and catalyzing the polyADP ribosylation of the receptor protein and participating in the DNA repair process. PARP plays a key role in the process of DNA single-strand base excision and repair.
  • PARP inhibitors In HRD tumor cells, the double-stranded DNA cannot be repaired, and PARP inhibitors block single-strand repair, resulting in a "synthetic lethal" effect, leading to tumor cell death.
  • PARP inhibitors have a "trapping" effect on the PARP protein, causing the PARP protein that binds to damaged DNA to be trapped on the DNA, directly causing other DNA repair proteins to be unable to bind, eventually leading to cell death.
  • Several PARP inhibitors have been successfully developed, such as olaparib, rucapali, and niraparib. However, adverse reactions limit their ability to be used in combination with chemotherapy drugs. This may be related to the lack of selectivity of marketed PARP inhibitors against the PARP family.
  • the present invention relates to the compound N-cyclopropyl-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) represented by formula (I) )Pharmaceutically acceptable salts and various crystal forms of methyl)piperazin-1-yl)pyridinecarboxamide, and their use in preparing drugs for treating related diseases.
  • the compound provided by the invention has high selectivity, good activity, and low toxic and side effects. Its salt crystal form has excellent characteristics such as high purity, good solubility, stable physical and chemical properties, resistance to high temperature, high humidity and strong light, and low hygroscopicity.
  • the present invention provides a pharmaceutically acceptable salt of the compound represented by formula (I),
  • pharmaceutically acceptable salts include but are not limited to hydrochloride, sulfate, maleate, phosphate, tartrate, fumarate, citrate, naphthalene disulfonate, and p-toluenesulfonate. , methanesulfonate, benzenesulfonate, oxalate, gentisate and hydrobromide.
  • the pharmaceutically acceptable salt is a hydrochloride, preferably hydrochloride Form A, using Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position: 10.39° ⁇ 0.2°, 11.13° ⁇ 0.2°, 11.64° ⁇ 0.2°, 17.70° ⁇ 0.2°, 24.72° ⁇ 0.2°, 26.26° ⁇ 0.2°, 28.32° ⁇ 0.2°.
  • the pharmaceutically acceptable salt is hydrochloride Form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 6.82° ⁇ 0.2°, 10.39° ⁇ 0.2°, 11.13° ⁇ 0.2°, 11.64° ⁇ 0.2°, 17.70° ⁇ 0.2°, 21.97° ⁇ 0.2°, 22.34° ⁇ 0.2°, 24.72° ⁇ 0.2°, 26.26° ⁇ 0.2°, 28.32° ⁇ 0.2°.
  • the pharmaceutically acceptable salt is hydrochloride Form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 6.82° ⁇ 0.2°, 10.39° ⁇ 0.2°, 11.13° ⁇ 0.2°, 11.64° ⁇ 0.2°, 15.96° ⁇ 0.2°, 17.70° ⁇ 0.2°, 18.83° ⁇ 0.2°, 20.04° ⁇ 0.2°, 21.97° ⁇ 0.2°, 22.34° ⁇ 0.2°, 22.84° ⁇ 0.2°, 24.72° ⁇ 0.2°, 26.26° ⁇ 0.2°, 28.32° ⁇ 0.2°, 26.88° ⁇ 0.2°, 29.62° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride crystalline form A of the present invention is shown in Figure 3 using Cu-K ⁇ radiation.
  • the hydrochloride crystal form A of the present invention has a differential scanning calorimetry analysis curve and a thermogravimetric analysis curve as shown in Figure 1 and Figure 2 respectively.
  • the pharmaceutically acceptable salt is hydrochloride crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 7.71° ⁇ 0.2°, 9.02° ⁇ 0.2°, 9.56° ⁇ 0.2°, 24.94° ⁇ 0.2°.
  • the pharmaceutically acceptable salt is hydrochloride crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 7.71° ⁇ 0.2°, 9.02° ⁇ 0.2°, 9.56° ⁇ 0.2°, 12.60° ⁇ 0.2°, 14.67° ⁇ 0.2°, 15.41° ⁇ 0.2°, 16.67° ⁇ 0.2°, 18.62° ⁇ 0.2°, 20.56° ⁇ 0.2°, 24.94° ⁇ 0.2°, 25.99° ⁇ 0.2°, 27.49° ⁇ 0.2°.
  • the pharmaceutically acceptable salt is hydrochloride crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 7.71° ⁇ 0.2°, 9.02° ⁇ 0.2°, 9.56° ⁇ 0.2°, 12.60° ⁇ 0.2°, 14.67° ⁇ 0.2°, 15.41° ⁇ 0.2°, 16.67° ⁇ 0.2°, 18.62° ⁇ 0.2°, 20.56° ⁇ 0.2°, 22.82° ⁇ 0.2°, 24.94° ⁇ 0.2°, 25.99° ⁇ 0.2°, 27.49° ⁇ 0.2°, 29.55° ⁇ 0.2°, 31.45° ⁇ 0.2°, 32.34° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride salt Form B of the present invention is shown in Figure 6 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the hydrochloride crystal form B of the present invention are shown in Figure 4 and Figure 5 respectively.
  • the pharmaceutically acceptable salt is a sulfate salt Form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 6.77° ⁇ 0.2°, 9.00 ° ⁇ 0.2°, 26.43° ⁇ 0.2°.
  • the pharmaceutically acceptable salt is sulfate salt Form A, which is an X-ray powder using Cu-K ⁇ radiation.
  • the diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.77° ⁇ 0.2°, 9.00° ⁇ 0.2°, 25.21° ⁇ 0.2°, and 26.43° ⁇ 0.2°.
  • the pharmaceutically acceptable salt is a sulfate salt Form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 6.77° ⁇ 0.2°, 9.00 ° ⁇ 0.2°, 13.13° ⁇ 0.2°, 15.37° ⁇ 0.2°, 16.67° ⁇ 0.2°, 18.20° ⁇ 0.2°, 19.22° ⁇ 0.2°, 21.51° ⁇ 0.2°, 25.21° ⁇ 0.2°, 26.43° ⁇ 0.2°, 30.47° ⁇ 0.2°, 31.88° ⁇ 0.2°, 34.42° ⁇ 0.2°, 36.45° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the sulfate crystalline form A of the present invention is shown in Figure 9 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the sulfate crystal form A of the present invention are shown in Figure 7 and Figure 8 respectively.
  • the pharmaceutically acceptable salt is maleate salt Form A, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.81 ⁇ 0.2°, 8.42 ⁇ 0.2°, 13.59 ⁇ 0.2°, 14.96 ⁇ 0.2°, 20.49 ⁇ 0.2°, 26.02 ⁇ 0.2°, 27.42 ⁇ 0.2°, 31.43 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is maleate salt Form A, wherein the ratio of Compound 1 to maleate salt is 1:1.
  • the pharmaceutically acceptable salt is maleate salt Form A, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.81 ⁇ 0.2°, 8.42 ⁇ 0.2°, 13.59 ⁇ 0.2°, 14.96 ⁇ 0.2°, 17.23 ⁇ 0.2°, 18.07 ⁇ 0.2°, 19.46 ⁇ 0.2°, 20.49 ⁇ 0.2°, 22.12 ⁇ 0.2°, 22.43 ⁇ 0.2°, 25.32 ⁇ 0.2°, 26.02 ⁇ 0.2°, 27.42 ⁇ 0.2°, 31.43 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is maleate salt Form A, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.81 ⁇ 0.2°, 8.42 ⁇ 0.2°, 9.89 ⁇ 0.2°, 13.59 ⁇ 0.2°, 14.96 ⁇ 0.2°, 17.23 ⁇ 0.2°, 18.07 ⁇ 0.2°, 19.46 ⁇ 0.2°, 20.49 ⁇ 0.2°, 22.12 ⁇ 0.2°, 22.43 ⁇ 0.2°, 23.88 ⁇ 0.2°, 24.53 ⁇ 0.2°, 25.32 ⁇ 0.2°, 26.02 ⁇ 0.2°, 27.42 ⁇ 0.2°, 31.43 ⁇ 0.2°, 32.27 ⁇ 0.2°.
  • the maleate crystal form A of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 12.
  • the maleate crystal form A of the present invention has a differential scanning calorimetry analysis curve and a thermogravimetric analysis curve as shown in Figure 10 and Figure 11 respectively.
  • the pharmaceutically acceptable salt is the maleate salt.
  • the maleate salt is Form B.
  • the ratio of Compound 1 to the maleate salt is is 1:1, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.25 ⁇ 0.2°, 7.44 ⁇ 0.2°, 17.95 ⁇ 0.2°, 18.80 ⁇ 0.2°, 20.12 ⁇ 0.2 °.
  • the pharmaceutically acceptable salt is maleate salt Form B, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.25 ⁇ 0.2°, 7.44 ⁇ 0.2°, 10.51 ⁇ 0.2°, 17.24 ⁇ 0.2°, 17.95 ⁇ 0.2°, 18.80 ⁇ 0.2°, 19.91 ⁇ 0.2°, 20.12 ⁇ 0.2°, 25.57 ⁇ 0.2°, 26.65 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is maleate salt Form B, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.25 ⁇ 0.2°, 7.44 ⁇ 0.2°, 10.51 ⁇ 0.2°, 14.90 ⁇ 0.2°, 15.78 ⁇ 0.2°, 16.44 ⁇ 0.2°, 16.77 ⁇ 0.2°, 17.24 ⁇ 0.2°, 17.95 ⁇ 0.2°, 18.80 ⁇ 0.2°, 19.91 ⁇ 0.2°, 20.12 ⁇ 0.2°, 21.81 ⁇ 0.2°, 23.11 ⁇ 0.2°, 25.57 ⁇ 0.2°, 26.65 ⁇ 0.2°.
  • the maleate crystal form B of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 15.
  • the maleate crystal form B of the present invention has a differential scanning calorimetry analysis curve and a thermogravimetric analysis curve. As shown in Figure 13 and Figure 14 respectively.
  • the pharmaceutically acceptable salt is phosphate Form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 4.68 ⁇ 0.2°, 9.34 ⁇ 0.2°, 15.48 ⁇ 0.2°, 17.67 ⁇ 0.2°, 18.20 ⁇ 0.2°, 18.46 ⁇ 0.2°, 19.91 ⁇ 0.2°, 22.40 ⁇ 0.2°, 25.48 ⁇ 0.2°, 28.13 ⁇ 0.2°, 29.61 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is phosphate Form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 4.68 ⁇ 0.2°, 9.34 ⁇ 0.2°, 15.48 ⁇ 0.2°, 17.67 ⁇ 0.2°, 18.20 ⁇ 0.2°, 18.46 ⁇ 0.2°, 19.91 ⁇ 0.2°, 21.76 ⁇ 0.2°, 22.40 ⁇ 0.2°, 24.81 ⁇ 0.2°, 25.48 ⁇ 0.2°, 26.28 ⁇ 0.2°, 28.13 ⁇ 0.2°, 29.61 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is phosphate Form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 4.68 ⁇ 0.2°, 9.34 ⁇ 0.2°, 12.03 ⁇ 0.2°, 14.03 ⁇ 0.2°, 15.48 ⁇ 0.2°, 17.67 ⁇ 0.2°, 18.20 ⁇ 0.2°, 18.46 ⁇ 0.2°, 19.47 ⁇ 0.2°, 19.91 ⁇ 0.2°, 21.76 ⁇ 0.2°, 22.40 ⁇ 0.2°, 24.81 ⁇ 0.2°, 25.48 ⁇ 0.2°, 26.28 ⁇ 0.2°, 28.13 ⁇ 0.2°, 29.61 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the phosphate crystalline form A of the present invention is shown in Figure 18 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the phosphate crystal form A of the present invention are shown in Figure 16 and Figure 17 respectively.
  • the pharmaceutically acceptable salt is a phosphate form B, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.44 ⁇ 0.2°, 5.13 ⁇ 0.2°, 10.58 ⁇ 0.2°, 16.02 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is a phosphate form B, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.44 ⁇ 0.2°, 5.13 ⁇ 0.2°, 8.86 ⁇ 0.2°, 10.58 ⁇ 0.2°, 12.22 ⁇ 0.2°, 16.02 ⁇ 0.2°, 17.37 ⁇ 0.2°, 17.60 ⁇ 0.2°, 20.57 ⁇ 0.2°, 23.70 ⁇ 0.2°, 26.56 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is a phosphate crystal Form B, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.44 ⁇ 0.2°, 5.13 ⁇ 0.2°, 8.86 ⁇ 0.2 °, 9.42 ⁇ 0.2°, 10.58 ⁇ 0.2°, 12.22 ⁇ 0.2°, 13.26 ⁇ 0.2°, 16.02 ⁇ 0.2°, 16.42 ⁇ 0.2°, 17.37 ⁇ 0.2°, 17.60 ⁇ 0.2°, 19.56 ⁇ 0.2°, 20.32 ⁇ 0.2 °, 20.57 ⁇ 0.2°, 21.07 ⁇ 0.2°, 21.48 ⁇ 0.2°, 22.46 ⁇ 0.2°, 23.70 ⁇ 0.2°, 24.53 ⁇ 0.2°, 25.35 ⁇ 0.2°, 26.56 ⁇ 0.2°.
  • the phosphate crystal form B of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 21.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the phosphate crystal form B of the present invention are shown in Figure 19 and Figure 20 respectively.
  • the pharmaceutically acceptable salt is a phosphate salt Form C, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 4.76 ⁇ 0.2°, 9.52 ⁇ 0.2°, 10.40 ⁇ 0.2°, 15.78 ⁇ 0.2°, 19.69 ⁇ 0.2°, 22.47 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is a phosphate salt Form C, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 4.76 ⁇ 0.2°, 9.52 ⁇ 0.2°, 10.40 ⁇ 0.2°, 15.78 ⁇ 0.2°, 19.69 ⁇ 0.2°, 20.42 ⁇ 0.2°, 21.19 ⁇ 0.2°, 22.47 ⁇ 0.2°, 25.07 ⁇ 0.2°, 26.97 ⁇ 0.2°, 28.59 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is a phosphate salt Form C, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 4.76 ⁇ 0.2°, 9.52 ⁇ 0.2°, 10.40 ⁇ 0.2°, 15.78 ⁇ 0.2°, 17.01 ⁇ 0.2°, 19.69 ⁇ 0.2°, 20.42 ⁇ 0.2°, 21.19 ⁇ 0.2°, 22.47 ⁇ 0.2°, 24.06 ⁇ 0.2°, 25.07 ⁇ 0.2°, 26.97 ⁇ 0.2°, 28.59 ⁇ 0.2°, 29.07 ⁇ 0.2°.
  • the phosphate crystal Form C of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 24.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the phosphate crystal Form C of the present invention are shown in Figure 22 and Figure 23 respectively.
  • the pharmaceutically acceptable salt is a tartrate salt.
  • the ratio of Compound I to tartaric acid is 1:1.
  • the tartrate salt is Form A, using Cu -K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.14 ⁇ 0.2°, 8.23 ⁇ 0.2°, 10.31 ⁇ 0.2°, 19.42 ⁇ 0.2°, 20.66 ⁇ 0.2°, 24.81 ⁇ 0.2°, 26.30 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is tartrate crystal form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 4.14 ⁇ 0.2°, 8.23 ⁇ 0.2°, 10.31 ⁇ 0.2°, 19.42 ⁇ 0.2°, 20.66 ⁇ 0.2°, 22.48 ⁇ 0.2°, 24.81 ⁇ 0.2°, 26.30 ⁇ 0.2°, 29.53 ⁇ 0.2°.
  • the tartrate crystal form A of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 27.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the tartrate crystal form A of the present invention are shown in Figure 25 and Figure 26 respectively.
  • the pharmaceutically acceptable salt is a tartrate salt.
  • the tartrate salt is Form B.
  • the ratio of Compound I to tartaric acid is 1:1, using Cu -K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.31 ⁇ 0.2°, 8.76 ⁇ 0.2°, 24.85 ⁇ 0.2°, 26.40 ⁇ 0.2°.
  • the tartrate crystal form B of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 30.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the tartrate crystal form B of the present invention are shown in Figure 28 and Figure 29 respectively.
  • the pharmaceutically acceptable salt is a tartrate salt.
  • the tartrate salt is Form C.
  • the ratio of Compound I to tartaric acid in Form C is 1: 1.
  • the pharmaceutically acceptable salt is tartrate crystal form C, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.02 ⁇ 0.2°, 7.74 ⁇ 0.2°, 8.48 ⁇ 0.2°, 9.47 ⁇ 0.2°, 10.29 ⁇ 0.2°, 12.25 ⁇ 0.2°, 16.22 ⁇ 0.2°, 18.50 ⁇ 0.2°, 19.50 ⁇ 0.2°, 20.66 ⁇ 0.2°, 24.20 ⁇ 0.2°, 25.13 ⁇ 0.2°, 27.15 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is tartrate crystal form C, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.02 ⁇ 0.2°, 7.74 ⁇ 0.2°, 8.48 ⁇ 0.2°, 9.47 ⁇ 0.2°, 10.29 ⁇ 0.2°, 12.25 ⁇ 0.2°, 16.22 ⁇ 0.2°, 18.50 ⁇ 0.2°, 19.50 ⁇ 0.2°, 20.66 ⁇ 0.2°, 24.20 ⁇ 0.2°, 25.13 ⁇ 0.2°, 27.15 ⁇ 0.2°, 29.93 ⁇ 0.2°, 31.42 ⁇ 0.2°.
  • the tartrate crystal form C of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 33.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the tartrate crystal form C of the present invention are shown in Figure 31 and Figure 32 respectively.
  • the pharmaceutically acceptable salt is a fumarate salt.
  • the fumarate salt is Form A.
  • Compound I of Form A is a combination of fumarate and fumarate. Acid ratio is 1:1, using Cu-K ⁇ radiation, its X-ray powder The final diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.72 ⁇ 0.2°, 11.50 ⁇ 0.2°, 18.93 ⁇ 0.2°, 20.62 ⁇ 0.2°, 27.75 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is fumarate salt Form A, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.72 ⁇ 0.2°, 7.77 ⁇ 0.2°, 10.34 ⁇ 0.2°, 11.50 ⁇ 0.2°, 13.45 ⁇ 0.2°, 15.46 ⁇ 0.2°, 17.68 ⁇ 0.2°, 18.93 ⁇ 0.2°, 19.39 ⁇ 0.2°, 20.62 ⁇ 0.2°, 27.75 ⁇ 0.2°, 28.19 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is fumarate salt Form A, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.72 ⁇ 0.2°, 7.77 ⁇ 0.2°, 8.56 ⁇ 0.2°, 10.34 ⁇ 0.2°, 11.50 ⁇ 0.2°, 13.45 ⁇ 0.2°, 15.46 ⁇ 0.2°, 17.68 ⁇ 0.2°, 18.93 ⁇ 0.2°, 19.39 ⁇ 0.2°, 20.62 ⁇ 0.2°, 23.72 ⁇ 0.2°, 27.75 ⁇ 0.2°, 28.19 ⁇ 0.2°.
  • the fumarate crystalline Form A of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 36.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the fumarate crystalline Form A of the present invention are shown in Figure 34 and Figure 35 respectively.
  • the pharmaceutically acceptable salt is a citrate salt
  • the citrate salt is Form A
  • the ratio of Compound I of Form A to citric acid is 1:1, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.11 ⁇ 0.2°, 8.67 ⁇ 0.2°, 10.62 ⁇ 0.2°, 12.24 ⁇ 0.2°, 18.39 ⁇ 0.2 °, 18.90 ⁇ 0.2°, 22.59 ⁇ 0.2°, 26.10 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is citrate Form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 6.11 ⁇ 0.2°, 8.67 ⁇ 0.2°, 10.62 ⁇ 0.2°, 12.24 ⁇ 0.2°, 18.39 ⁇ 0.2°, 18.90 ⁇ 0.2°, 22.59 ⁇ 0.2°, 24.56 ⁇ 0.2°, 24.99 ⁇ 0.2°, 26.10 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is citrate Form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 6.11 ⁇ 0.2°, 8.67 ⁇ 0.2°, 10.62 ⁇ 0.2°, 12.24 ⁇ 0.2°, 18.39 ⁇ 0.2°, 18.90 ⁇ 0.2°, 22.59 ⁇ 0.2°, 24.56 ⁇ 0.2°, 24.99 ⁇ 0.2°, 25.40 ⁇ 0.2°, 26.10 ⁇ 0.2°, 28.06 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the citrate crystalline form A of the present invention is shown in Figure 39 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the citrate crystal form A of the present invention are shown in Figure 37 and Figure 38 respectively.
  • the pharmaceutically acceptable salt is a naphthalene disulfonate salt.
  • the naphthalene disulfonate salt has Form A.
  • Compound I of Form A and The ratio of naphthalenedisulfonic acid is 1:1, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.33 ⁇ 0.2°, 8.17 ⁇ 0.2°, 10.06 ⁇ 0.2°, 11.84 ⁇ 0.2°, 12.23 ⁇ 0.2°, 14.62 ⁇ 0.2°, 16.77 ⁇ 0.2°, 17.60 ⁇ 0.2°, 19.49 ⁇ 0.2°, 21.99 ⁇ 0.2°, 23.83 ⁇ 0.2°, 24.22 ⁇ 0.2°, 25.97 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is naphthalene disulfonate crystal form A, and its X-ray powder diffraction pattern using Cu-K ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ positions: 7.33 ⁇ 0.2°, 8.17 ⁇ 0.2°, 10.06 ⁇ 0.2°, 10.87 ⁇ 0.2°, 11.84 ⁇ 0.2°, 12.23 ⁇ 0.2°, 13.13 ⁇ 0.2°, 14.62 ⁇ 0.2°, 16.78 ⁇ 0.2°, 17.60 ⁇ 0.2°, 18.26 ⁇ 0.2°, 19.49 ⁇ 0.2°, 20.18 ⁇ 0.2°, 21.99 ⁇ 0.2°, 23.83 ⁇ 0.2°, 24.22 ⁇ 0.2°, 25.97 ⁇ 0.2°, 26.43 ⁇ 0.2°, 28.19 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is naphthalene disulfonate crystal form A, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position using Cu-K ⁇ radiation: 7.33 ⁇ 0.2° , 8.17 ⁇ 0.2°, 10.06 ⁇ 0.2°, 10.88 ⁇ 0.2°, 11.84 ⁇ 0.2°, 12.23 ⁇ 0.2°, 13.13 ⁇ 0.2°, 14.62 ⁇ 0.2°, 16.78 ⁇ 0.2°, 17.60 ⁇ 0.2°, 19.49 ⁇ 0.2° , 20.18 ⁇ 0.2°, 21.99 ⁇ 0.2°, 23.83 ⁇ 0.2°, 24.22 ⁇ 0.2°, 25.97 ⁇ 0.2°, 26.43 ⁇ 0.2°, 28.19 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the naphthalenedisulfonate crystalline form A of the present invention is shown in Figure 42 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the naphthalenedisulfonate crystal form A of the present invention are shown in Figure 40 and Figure 41 respectively.
  • the pharmaceutically acceptable salt is a naphthalene disulfonate salt.
  • the naphthalene disulfonate salt has Form B.
  • Form B of Compound I and The ratio of naphthalenedisulfonic acid is 1:1, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.68 ⁇ 0.2°, 7.90 ⁇ 0.2°, 12.80 ⁇ 0.2°, 13.20 ⁇ 0.2°, 13.72 ⁇ 0.2°, 14.90 ⁇ 0.2°, 15.80 ⁇ 0.2°, 17.55 ⁇ 0.2°, 22.67 ⁇ 0.2°, 23.70 ⁇ 0.2°, 24.72 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is naphthalene disulfonate crystal form B, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position: 6.68 ⁇ 0.2° , 7.90 ⁇ 0.2°, 12.80 ⁇ 0.2°, 13.20 ⁇ 0.2°, 13.72 ⁇ 0.2°, 14.90 ⁇ 0.2°, 15.80 ⁇ 0.2°, 17.55 ⁇ 0.2°, 22.67 ⁇ 0.2°, 23.70 ⁇ 0.2°, 24.72 ⁇ 0.2° , 26.36 ⁇ 0.2°, 29.42 ⁇ 0.2°.
  • the naphthalene disulfonate crystal Form B of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 45.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the naphthalene disulfonate crystal Form B of the present invention are shown in Figure 43 and Figure 44 respectively.
  • the pharmaceutically acceptable salt is a naphthalene disulfonate salt.
  • the naphthalene disulfonate salt has Form C.
  • Compound I of Form C and The ratio of naphthalene disulfonic acid is 1:1.
  • the naphthalene disulfonate crystal form C uses Cu-K ⁇ radiation. Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.04 ⁇ 0.2°, 18.13 ⁇ 0.2°. .
  • the naphthalene disulfonate crystal Form C of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 48.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the naphthalene disulfonate crystal Form C of the present invention are shown in Figure 46 and Figure 47 respectively.
  • the pharmaceutically acceptable salt is a p-toluenesulfonate salt.
  • the p-toluenesulfonate salt has Form A.
  • Compound I of Form A and The ratio of p-toluenesulfonate is 1:1, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.09 ⁇ 0.2°, 10.74 ⁇ 0.2°, 16.65 ⁇ 0.2°, 21.21 ⁇ 0.2°, 28.36 ⁇ 0.2°.
  • the p-toluenesulfonate crystal form A of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 51.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the p-toluenesulfonate crystal form A of the present invention are shown in Figure 49 and Figure 50 respectively.
  • the pharmaceutically acceptable salt is a p-toluenesulfonate salt
  • the p-toluenesulfonate salt has Form B, and in some embodiments, Form B of Compound I and The ratio of p-toluenesulfonate is 1:1, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.48 ⁇ 0.2°, 4.92 ⁇ 0.2°, 6.72 ⁇ 0.2°, 7.32 ⁇ 0.2°, 13.25 ⁇ 0.2°, 15.75 ⁇ 0.2°, 17.09 ⁇ 0.2°, 26.31 ⁇ 0.2°.
  • the p-toluenesulfonate crystal Form B of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 54.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the p-toluenesulfonate crystal Form B of the present invention are shown in Figure 52 and Figure 53 respectively.
  • the pharmaceutically acceptable salt is a p-toluenesulfonate salt
  • the p-toluenesulfonate salt has Form C, and in some embodiments, Form C of Compound I and The ratio of p-toluenesulfonate is 1:1, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.52 ⁇ 0.2°, 7.66 ⁇ 0.2°, 9.02 ⁇ 0.2°, 24.58 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is p-toluenesulfonate Form C, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with a characteristic diffraction peak at the following 2 ⁇ position: 4.52 ⁇ 0.2°. , 6.05 ⁇ 0.2°, 7.66 ⁇ 0.2°, 9.02 ⁇ 0.2°, 15.43 ⁇ 0.2°, 16.95 ⁇ 0.2°, 19.23 ⁇ 0.2°, 24.58 ⁇ 0.2°.
  • the p-toluenesulfonate crystal Form C is irradiated using Cu-K ⁇ , and its X-ray powder diffraction pattern is shown in Figure 57.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the p-toluenesulfonate crystal form C are shown in Figure 55 and Figure 56 respectively.
  • the pharmaceutically acceptable salt is a p-toluenesulfonate salt.
  • the p-toluenesulfonate salt has Form D.
  • Compound I of Form D and The ratio of p-toluenesulfonate is 1:1, crystal form D, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.62 ⁇ 0.2°, 8.31 ⁇ 0.2°, 11.21 ⁇ 0.2°, 14.30 ⁇ 0.2°, 16.23 ⁇ 0.2°, 16.63 ⁇ 0.2°, 16.95 ⁇ 0.2°, 17.61 ⁇ 0.2°, 18.79 ⁇ 0.2°, 25.63 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is p-toluenesulfonate crystal form D, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position using Cu-K ⁇ radiation: 5.62 ⁇ 0.2°. , 8.31 ⁇ 0.2°, 11.21 ⁇ 0.2°, 14.30 ⁇ 0.2°, 15.48 ⁇ 0.2°, 16.23 ⁇ 0.2°, 16.63 ⁇ 0.2°, 16.95 ⁇ 0.2°, 17.61 ⁇ 0.2°, 18.79 ⁇ 0.2°, 20.06 ⁇ 0.2° , 21.53 ⁇ 0.2°, 23.14 ⁇ 0.2°, 25.63 ⁇ 0.2°, 26.55 ⁇ 0.2°, 28.83 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is p-toluenesulfonate Form D, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with a characteristic diffraction peak at the following 2 ⁇ position: 5.62 ⁇ 0.2°. , 8.31 ⁇ 0.2°, 11.21 ⁇ 0.2°, 14.30 ⁇ 0.2°, 15.48 ⁇ 0.2°, 16.23 ⁇ 0.2°, 16.63 ⁇ 0.2°, 16.95 ⁇ 0.2°, 17.61 ⁇ 0.2°, 18.79 ⁇ 0.2°, 20.06 ⁇ 0.2° , 21.53 ⁇ 0.2°, 22.49 ⁇ 0.2°, 23.14 ⁇ 0.2°, 25.63 ⁇ 0.2°, 26.55 ⁇ 0.2°, 28.83 ⁇ 0.2°.
  • the p-toluenesulfonate crystal Form D of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 60.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the p-toluenesulfonate crystal Form D of the present invention are shown in Figure 58 and Figure 59 respectively.
  • the pharmaceutically acceptable salt is methanesulfonate crystal form A.
  • the ratio of compound I to methanesulfonic acid is 1:1, using Cu-K ⁇ radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 8.15 ⁇ 0.2°, 15.95 ⁇ 0.2°.
  • the mesylate crystal form A of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 63.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the tosylate crystal form A of the present invention are shown in Figure 61 and Figure 62 respectively.
  • the pharmaceutically acceptable salt is methanesulfonate crystal form B.
  • the ratio of compound I to methanesulfonic acid is 1:1, using Cu-K ⁇ radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 8.44 ⁇ 0.2°, 9.29 ⁇ 0.2°, 14.17 ⁇ 0.2°, 16.99 ⁇ 0.2°, 18.38 ⁇ 0.2°, 21.00 ⁇ 0.2°, 24.77 ⁇ 0.2°, 28.01 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is methanesulfonate crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 8.44 ⁇ 0.2°, 9.29 ⁇ 0.2°, 12.14 ⁇ 0.2°, 14.17 ⁇ 0.2°, 16.99 ⁇ 0.2°, 18.38 ⁇ 0.2°, 20.34 ⁇ 0.2°, 21.00 ⁇ 0.2°, 21.74 ⁇ 0.2°, 23.62 ⁇ 0.2°, 24.77 ⁇ 0.2°, 26.85 ⁇ 0.2°, 28.01 ⁇ 0.2°, 32.97 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is methanesulfonate crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 8.44 ⁇ 0.2°, 9.29 ⁇ 0.2°, 12.14 ⁇ 0.2°, 14.17 ⁇ 0.2°, 16.99 ⁇ 0.2°, 18.38 ⁇ 0.2°, 20.34 ⁇ 0.2°, 21.00 ⁇ 0.2°, 21.74 ⁇ 0.2°, 23.62 ⁇ 0.2°, 24.77 ⁇ 0.2°, 26.85 ⁇ 0.2°, 28.01 ⁇ 0.2°, 29.77 ⁇ 0.2°, 32.97 ⁇ 0.2°, 36.77 ⁇ 0.2°.
  • the mesylate crystal Form B of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 66.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the p-toluenesulfonate crystal Form B of the present invention are shown in Figure 64 and Figure 65 respectively.
  • the pharmaceutically acceptable salt is methanesulfonate crystal form C.
  • the ratio of compound I to methanesulfonic acid is 1:1, using Cu-K ⁇ radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.51 ⁇ 0.2°, 6.38 ⁇ 0.2°, 7.14 ⁇ 0.2°, 8.99 ⁇ 0.2°, 17.11 ⁇ 0.2°, 21.76 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is methanesulfonate crystalline form C, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 4.51 ⁇ 0.2°, 6.38 ⁇ 0.2°, 7.14 ⁇ 0.2°, 8.99 ⁇ 0.2°, 11.57 ⁇ 0.2°, 13.26 ⁇ 0.2°, 17.11 ⁇ 0.2°, 20.55 ⁇ 0.2°, 21.76 ⁇ 0.2°.
  • the mesylate crystal Form C of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 69.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the mesylate crystal Form C of the present invention are shown in Figure 67 and Figure 68 respectively.
  • the pharmaceutically acceptable salt is methanesulfonate crystal form D.
  • the ratio of compound I to methanesulfonic acid is 1:1, using Cu-K ⁇ radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 9.15 ⁇ 0.2°, 16.23 ⁇ 0.2°, 19.98 ⁇ 0.2°, 27.60 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is methanesulfonate crystal form D, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 9.15 ⁇ 0.2°, 9.97 ⁇ 0.2°, 15.17 ⁇ 0.2°, 16.23 ⁇ 0.2°, 18.88 ⁇ 0.2°, 19.44 ⁇ 0.2°, 19.98 ⁇ 0.2°, 21.53 ⁇ 0.2°, 22.49 ⁇ 0.2°, 26.01 ⁇ 0.2°, 26.42 ⁇ 0.2°, 27.60 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is methanesulfonate crystal form D, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 7.93 ⁇ 0.2°, 9.15 ⁇ 0.2°, 9.97 ⁇ 0.2°, 12.59 ⁇ 0.2°, 16.23 ⁇ 0.2°, 18.09 ⁇ 0.2°, 18.88 ⁇ 0.2°, 19.44 ⁇ 0.2°, 19.98 ⁇ 0.2°, 21.53 ⁇ 0.2°, 22.11 ⁇ 0.2°, 22.49 ⁇ 0.2°, 26.01 ⁇ 0.2°, 26.42 ⁇ 0.2°, 27.60 ⁇ 0.2°, 28.96 ⁇ 0.2°.
  • the methanesulfonate crystal form D of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 72.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the mesylate crystal form D of the present invention are shown in Figure 70 and Figure 71 respectively.
  • the pharmaceutically acceptable salt is benzenesulfonate crystal form A.
  • the ratio of compound I to benzenesulfonic acid is 1:1, using Cu-K ⁇ radiation, and its -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.93 ⁇ 0.2°, 6.65 ⁇ 0.2°, 7.88 ⁇ 0.2°, 11.27 ⁇ 0.2°, 16.93 ⁇ 0.2°, 19.98 ⁇ 0.2°, 24.57 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is benzenesulfonate crystal form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 4.93 ⁇ 0.2°, 6.65 ⁇ 0.2°, 7.88 ⁇ 0.2°, 11.27 ⁇ 0.2°, 16.93 ⁇ 0.2°, 19.98 ⁇ 0.2°, 24.57 ⁇ 0.2°, 27.06 ⁇ 0.2°, 30.39 ⁇ 0.2°.
  • the benzenesulfonate crystalline Form A of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 75.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the benzene sulfonate crystal Form A of the present invention are shown in Figure 73 and Figure 74 respectively.
  • the pharmaceutically acceptable salt is benzenesulfonate crystal form B.
  • the ratio of compound I to benzenesulfonic acid is 1:1, using Cu-K ⁇ radiation, and its -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.60 ⁇ 0.2°, 6.83 ⁇ 0.2°, 7.79 ⁇ 0.2°, 10.40 ⁇ 0.2°, 11.69 ⁇ 0.2°, 12.80 ⁇ 0.2°, 13.68 ⁇ 0.2°, 15.58 ⁇ 0.2°, 18.16 ⁇ 0.2°, 20.04 ⁇ 0.2°, 22.41 ⁇ 0.2°, 24.01 ⁇ 0.2°, 24.89 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is benzenesulfonate crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 5.60 ⁇ 0.2°, 6.83 ⁇ 0.2°, 7.79 ⁇ 0.2°, 10..40 ⁇ 0.2°, 11.69 ⁇ 0.2°, 12.80 ⁇ 0.2°, 13.68 ⁇ 0.2°, 15.58 ⁇ 0.2°, 18.16 ⁇ 0.2°, 20.04 ⁇ 0.2°, 22.41 ⁇ 0.2°, 24.01 ⁇ 0.2°, 24.89 ⁇ 0.2°, 28.10 ⁇ 0.2°.
  • the benzene sulfonate crystal Form B of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 78.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the benzene sulfonate crystal Form B according to the invention are shown in Figure 76 and Figure 77 respectively.
  • the pharmaceutically acceptable salt is benzenesulfonate crystal form C.
  • the ratio of compound I to benzenesulfonic acid is 1:1, using Cu-K ⁇ radiation, and its -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.63 ⁇ 0.2°, 17.04 ⁇ 0.2°, 18.50 ⁇ 0.2°, 20.19 ⁇ 0.2°, 23.77 ⁇ 0.2°.
  • the benzene sulfonate crystal Form C of the invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 81.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the benzene sulfonate crystal Form C according to the invention are shown in Figure 79 and Figure 80 respectively.
  • the pharmaceutically acceptable salt is oxalate form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 4.89 ⁇ 0.2°, 5.51 ⁇ 0.2°, 9.80 ⁇ 0.2°, 15.52 ⁇ 0.2°, 17.10 ⁇ 0.2°, 20.22 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is oxalate form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 4.89 ⁇ 0.2°, 5.51 ⁇ 0.2°, 9.80 ⁇ 0.2°, 12.62 ⁇ 0.2°, 15.52 ⁇ 0.2°, 17.10 ⁇ 0.2°, 18.35 ⁇ 0.2°, 19.74 ⁇ 0.2°, 20.22 ⁇ 0.2°, 21.69 ⁇ 0.2°, 24.96 ⁇ 0.2°, 25.45 ⁇ 0.2°, 26.35 ⁇ 0.2°, 29.28 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is oxalate form A, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 4.89 ⁇ 0.2°, 5.51 ⁇ 0.2°, 9.80 ⁇ 0.2°, 12.62 ⁇ 0.2°, 15.52 ⁇ 0.2°, 17.10 ⁇ 0.2°, 18.35 ⁇ 0.2°, 19.74 ⁇ 0.2°, 20.22 ⁇ 0.2°, 21.69 ⁇ 0.2°, 24.96 ⁇ 0.2°, 25.45 ⁇ 0.2°, 26.35 ⁇ 0.2°, 28.00 ⁇ 0.2°, 29.28 ⁇ 0.2°, 31.01 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the oxalate crystalline form A of the present invention is shown in Figure 84 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the oxalate crystal form A of the present invention are shown in Figure 82 and Figure 83 respectively.
  • the pharmaceutically acceptable salt is oxalate form B, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 6.85 ⁇ 0.2°, 9.05 ⁇ 0.2°, 10.27 ⁇ 0.2°, 14.79 ⁇ 0.2°, 19.04 ⁇ 0.2°, 19.42 ⁇ 0.2°, 20.63 ⁇ 0.2°, 24.67 ⁇ 0.2°, 25.03 ⁇ 0.2°, 27.62 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is oxalate form B, which has an X-ray powder diffraction pattern using Cu-K ⁇ radiation with characteristic diffraction peaks at the following 2 ⁇ positions: 6.85 ⁇ 0.2°, 7.77 ⁇ 0.2°, 9.05 ⁇ 0.2°, 9.46 ⁇ 0.2°, 10.27 ⁇ 0.2°, 12.34 ⁇ 0.2°, 14.79 ⁇ 0.2°, 18.59 ⁇ 0.2°, 19.04 ⁇ 0.2°, 19.42 ⁇ 0.2°, 20.63 ⁇ 0.2°, 21.33 ⁇ 0.2°, 22.47 ⁇ 0.2°, 24.67 ⁇ 0.2°, 25.03 ⁇ 0.2°, 25.69 ⁇ 0.2°, 27.62 ⁇ 0.2°, 31.58 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is oxalate crystal form B, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.85 ⁇ 0.2°, 7.77 ⁇ 0.2°, 9.05 ⁇ 0.2°, 9.46 ⁇ 0.2°, 10.27 ⁇ 0.2°, 12.34 ⁇ 0.2°, 13.49 ⁇ 0.2°, 14.79 ⁇ 0.2°, 18.13 ⁇ 0.2°, 18.59 ⁇ 0.2°, 19.04 ⁇ 0.2°, 19.42 ⁇ 0.2°, 20.63 ⁇ 0.2°, 21.33 ⁇ 0.2°, 22.47 ⁇ 0.2°, 24.67 ⁇ 0.2°, 25.03 ⁇ 0.2°, 25.69 ⁇ 0.2°, 27.62 ⁇ 0.2°, 29.00 ⁇ 0.2°, 29.77 ⁇ 0.2°, 31.58 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the oxalate crystalline Form B of the present invention is shown in Figure 87 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the oxalate crystal form B of the present invention are shown in Figure 85 and Figure 86 respectively.
  • the pharmaceutically acceptable salt is gentisate Form A.
  • the ratio of Compound I to gentisic acid is 1:1, using Cu-K ⁇ radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.09 ⁇ 0.2°, 7.62 ⁇ 0.2°, 8.08 ⁇ 0.2°, 16.16 ⁇ 0.2°, 19.26 ⁇ 0.2°, 21.28 ⁇ 0.2°, 24.72 ⁇ 0.2°, 25.26 ⁇ 0.2°, 26.25 ⁇ 0.2°, 26.76 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is gentisate Form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 7.09 ⁇ 0.2°, 7.62 ⁇ 0.2°, 8.08 ⁇ 0.2°, 13.96 ⁇ 0.2°, 16.16 ⁇ 0.2°, 19.26 ⁇ 0.2°, 21.28 ⁇ 0.2°, 21.84 ⁇ 0.2°, 22.93 ⁇ 0.2°, 24.72 ⁇ 0.2°, 25.26 ⁇ 0.2°, 26.25 ⁇ 0.2°, 26.76 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is gentisate Form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 7.09 ⁇ 0.2°, 7.62 ⁇ 0.2°, 8.08 ⁇ 0.2°, 13.96 ⁇ 0.2°, 15.21 ⁇ 0.2°, 16.16 ⁇ 0.2°, 19.26 ⁇ 0.2°, 21.28 ⁇ 0.2°, 21.84 ⁇ 0.2°, 22.93 ⁇ 0.2°, 24.72 ⁇ 0.2°, 25.26 ⁇ 0.2°, 26.25 ⁇ 0.2°, 26.76 ⁇ 0.2°, 29.05 ⁇ 0.2°, 30.79 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the gentisate crystalline form A of the present invention is shown in Figure 90 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the gentisate crystal form A of the present invention are shown in Figure 88 and Figure 89 respectively.
  • the pharmaceutically acceptable salt is gentisate crystal Form B.
  • the ratio of Compound I to gentisic acid is 1:1, using Cu-K ⁇ radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.27 ⁇ 0.2°, 9.27 ⁇ 0.2°, 14.66 ⁇ 0.2°, 15.65 ⁇ 0.2°, 19.85 ⁇ 0.2°, 20.76 ⁇ 0.2°, 23.65 ⁇ 0.2°, 25.29 ⁇ 0.2°,.
  • the pharmaceutically acceptable salt is gentisate Form B, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.27 ⁇ 0.2°, 9.27 ⁇ 0.2°, 11.68 ⁇ 0.2°, 14.66 ⁇ 0.2°, 15.65 ⁇ 0.2°, 19.85 ⁇ 0.2°, 20.76 ⁇ 0.2°, 22.42 ⁇ 0.2°, 23.65 ⁇ 0.2°, 25.29 ⁇ 0.2°, 27.08 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the gentisate crystal form B of the compound represented by formula (I) is shown in Figure 93 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry and thermogravimetric analysis curves of the gentisate crystal form B of the compound represented by formula (I) are shown in Figure 91 and Figure 92.
  • the pharmaceutically acceptable salt is hydrobromide salt Form A, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.71 ⁇ 0.2°, 8.78 ⁇ 0.2°, 10.39 ⁇ 0.2°, 17.69 ⁇ 0.2°, 18.75 ⁇ 0.2°, 24.73 ⁇ 0.2°, 26.31 ⁇ 0.2°, 26.73 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is hydrobromide salt Form A, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.71 ⁇ 0.2°, 8.78 ⁇ 0.2°, 10.39 ⁇ 0.2°, 17.69 ⁇ 0.2°, 18.75 ⁇ 0.2°, 20.19 ⁇ 0.2°, 21.48 ⁇ 0.2°, 24.73 ⁇ 0.2°, 26.31 ⁇ 0.2°, 26.73 ⁇ 0.2°, 29.34 ⁇ 0.2°.
  • the hydrobromide salt Form A of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 96.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the hydrobromide salt crystal Form A of the present invention are shown in Figure 94 and Figure 95 respectively.
  • the pharmaceutically acceptable salt is hydrobromide salt Form B, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 8.80 ⁇ 0.2°, 9.54 ⁇ 0.2°, 13.40 ⁇ 0.2°, 20.89 ⁇ 0.2°, 22.09 ⁇ 0.2°, 22.51 ⁇ 0.2°, 25.25 ⁇ 0.2°, 27.01 ⁇ 0.2°,.
  • the pharmaceutically acceptable salt is hydrobromide salt Form B, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 8.80 ⁇ 0.2°, 9.54 ⁇ 0.2°, 11.99 ⁇ 0.2°, 13.40 ⁇ 0.2°, 14.19 ⁇ 0.2°, 19.01 ⁇ 0.2°, 20.24 ⁇ 0.2°, 20.89 ⁇ 0.2°, 22.09 ⁇ 0.2°, 22.51 ⁇ 0.2°, 23.23 ⁇ 0.2°, 25.25 ⁇ 0.2°, 27.01 ⁇ 0.2°, 28.40 ⁇ 0.2°, 29.85 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is hydrobromide salt Form B, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 8.80 ⁇ 0.2°, 9.54 ⁇ 0.2°, 11.99 ⁇ 0.2°, 13.40 ⁇ 0.2°, 14.19 ⁇ 0.2°, 16.06 ⁇ 0.2°, 19.01 ⁇ 0.2°, 20.24 ⁇ 0.2°, 20.89 ⁇ 0.2°, 22.09 ⁇ 0.2°, 22.51 ⁇ 0.2°, 23.23 ⁇ 0.2°, 25.25 ⁇ 0.2°, 26.10 ⁇ 0.2°, 27.01 ⁇ 0.2°, 27.41 ⁇ 0.2°, 28.40 ⁇ 0.2°, 29.85 ⁇ 0.2°, 32.36 ⁇ 0.2°.
  • the hydrobromide crystal Form B of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 99.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the hydrobromide salt crystal Form B of the present invention are shown in Figure 97 and Figure 98 respectively.
  • the pharmaceutically acceptable salt is hydrobromide salt Form C, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.71 ⁇ 0.2°, 7.47 ⁇ 0.2°, 11.13 ⁇ 0.2°, 15.05 ⁇ 0.2°, 17.93 ⁇ 0.2°, 19.00 ⁇ 0.2°, 20.13 ⁇ 0.2°, 21.23 ⁇ 0.2°, 22.06, 23.89 ⁇ 0.2°, 26.23 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is hydrobromide salt Form C, using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.71 ⁇ 0.2°, 7.47 ⁇ 0.2°, 9.59 ⁇ 0.2°, 11.13 ⁇ 0.2°, 15.05 ⁇ 0.2°, 17.93 ⁇ 0.2°, 19.00 ⁇ 0.2°, 20.13 ⁇ 0.2°, 21.23 ⁇ 0.2°, 22.06, 23.89 ⁇ 0.2°, 26.23 ⁇ 0.2 °.
  • the hydrobromide crystal Form C of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 102.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the hydrobromide salt crystal Form C of the present invention are shown in Figure 100 and Figure 101 respectively.
  • the pharmaceutically acceptable salt is hydrobromide salt Form D, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 11.33 ⁇ 0.2°, 14.51 ⁇ 0.2°, 18.08 ⁇ 0.2°, 20.91 ⁇ 0.2°, 22.01 ⁇ 0.2°, 24.04 ⁇ 0.2°, 25.30 ⁇ 0.2°.
  • the pharmaceutically acceptable salt is hydrobromide salt Form D, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions using Cu-K ⁇ radiation: 11.33 ⁇ 0.2°, 13.16 ⁇ 0.2°, 13.94 ⁇ 0.2°, 14.51 ⁇ 0.2°, 18.08 ⁇ 0.2°, 19.15 ⁇ 0.2°, 20.91 ⁇ 0.2°, 22.01 ⁇ 0.2°, 22.77 ⁇ 0.2°, 24.04 ⁇ 0.2°, 25.30 ⁇ 0.2°, 28.93 ⁇ 0.2°.
  • the hydrobromide crystal Form D of the present invention uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern is shown in Figure 105.
  • the differential scanning calorimetry analysis curve and the thermogravimetric analysis curve of the hydrobromide salt crystal Form C of the present invention are shown in Figure 103 and Figure 104 respectively.
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of any of the aforementioned salt crystal forms, and a pharmaceutically acceptable carrier and/or excipient.
  • the therapeutically effective amount is 1-600mg.
  • the pharmaceutical composition may be in the form of a unit dosage form (a unit dosage form is also referred to as a "formulation strength").
  • the present invention also provides the use of the salt crystal form or composition described in any of the preceding solutions in the preparation of drugs for the treatment/prevention of PARP-mediated diseases. Further, the PARP-mediated disease is tumor.
  • the present invention also provides a method for treating a disease in a mammal, which method includes administering to a subject a therapeutically effective amount of the salt crystal form or a composition thereof shown in any of the foregoing schemes.
  • the disease is preferably
  • the therapeutically effective dose is preferably 1-600 mg.
  • mammals of the present invention include humans.
  • an "effective amount” or “therapeutically effective amount” mentioned in this application refers to the administration of a sufficient amount of the salt crystal form disclosed in this application on a free base basis, which will alleviate the disease or condition being treated to a certain extent. one or more symptoms. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system.
  • an "effective amount” for therapeutic use is a composition containing a salt form disclosed herein that is required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include but are not limited to 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg , 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5 -90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg , 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10 -30mg, 10-20mg;
  • the pharmaceutical composition or preparation of the present invention contains a therapeutically effective amount of the crystalline form of the present invention as described above;
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which contains a therapeutically effective amount of the crystalline form of the present invention and a carrier and/or excipient.
  • the pharmaceutical composition may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation specification").
  • the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg , 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 275mg, 300mg , 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg of the free base in the crystal form of the present invention.
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a crystalline form of the present invention, to and pharmaceutically acceptable carriers and/or excipients.
  • the therapeutically effective amount is based on free base, preferably 1-600 mg.
  • the disease is preferably tumor, especially brain tumor.
  • a method for treating diseases in mammals includes: combining the crystalline form of the present invention and pharmaceutically acceptable carriers and/or excipients at 1-600 mg/day on a free base basis.
  • a daily dose is administered to the subject, which may be a single dose or divided doses.
  • the daily dose includes, but is not limited to, 10-600 mg/day, 20-600 mg/day, 25-600 mg/day, 50 -600mg/day, 75-600mg/day, 100-600mg/day, 200-600mg/day, 10-600mg/day, 20-600mg/day, 25-600mg/day, 50-600mg/day, 75-600mg /day, 100-600mg/day, 200-600mg/day, 25-600mg/day, 50-600mg/day, 100-600mg/day, 200-600mg/day, 25-400mg/day, 50-400mg/day , 100-400 mg/day, 200-400 mg/day, in some embodiments, the daily dosage includes but is not limited to 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 75 mg /day, 100mg/day, 125mg/day, 150mg/
  • the present invention relates to a kit, which may include a crystalline form in the form of a single dose or multiple doses.
  • the kit contains the crystalline form of the present invention, and the amount of the crystalline form of the present invention is equal to its free base in the above pharmaceutical composition. The measurements are the same.
  • Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
  • the crystalline form described in the present invention is present in about 5% to about 100% by weight of the bulk drug; in some embodiments, it is present in about 10% to about 100% by weight of the bulk drug; in some embodiments In some embodiments, it is present at about 15% to about 100% by weight of the bulk drug; in certain embodiments, it is present at about 20% to about 100% by weight of the bulk drug; in certain embodiments, it is present at about 15% to about 100% by weight of the bulk drug.
  • the crystalline form of the present invention can be prepared by the following preparation method:
  • Crystal slurry experiment Stir the supersaturated solution of the sample (with insoluble solids present) at a certain temperature in different solvent systems.
  • Antisolvent experiment Dissolve the sample in a good solvent, add an antisolvent (poor solvent), stir the precipitated solid for a short time and then filter it immediately.
  • Cooling crystallization experiment Dissolve a certain amount of sample into the corresponding solvent at high temperature, and then stir and crystallize directly at room temperature or low temperature.
  • Polymer template experiment Add different types of polymer materials to the sample clarification solution, and leave it at room temperature to evaporate until the solvent dries.
  • the good solvent and poor solvent described in the present invention are relative terms.
  • the one with higher solubility is a good solvent
  • the one with lower solubility is a poor solvent.
  • the solvent used in the above preparation method when not specified, can be a single solvent or a combination of two or more solvents.
  • the X-ray powder diffraction, DSC diagram, and TGA diagram disclosed in the present invention which are substantially the same, also belong to the scope of the present invention.
  • IC 50 refers to the half inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
  • Ether solvent refers to a chain or cyclic compound containing an ether bond -O- and having 2 to 10 carbon atoms. Specific examples include but are not limited to: tetrahydrofuran, diethyl ether, propylene glycol methyl ether, and methyl tert-butyl ether. ether, isopropyl ether or 1,4-dioxane.
  • Alcoholic solvent refers to a group derived from one or more "hydroxyl groups” replacing one or more hydrogen atoms on a "C 1-6 alkyl group”.
  • Ester solvent refers to a combination of a lower organic acid containing 1 to 4 carbon atoms and a lower alcohol containing 1 to 6 carbon atoms. Specific examples include but are not limited to: ethyl acetate, isoacetate Propyl or butyl acetate.
  • Ketone solvent refers to a compound in which a carbonyl group (-C(O)-) is connected to two hydrocarbon groups. According to the different hydrocarbon groups in the molecule, ketones can be divided into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones and unsaturated ketones. Specific examples of ketones include, but are not limited to: acetone, acetophenone, and 4-methyl-2-pentanone.
  • Nirile solvent refers to a group derived from one or more "cyano groups” replacing one or more hydrogen atoms on a "C 1-6 alkyl group”.
  • the "cyano group” and “C 1-6 alkyl group”"Alkyl” is as defined above, and specific examples include but are not limited to: acetonitrile or propionitrile.
  • Halogenated hydrocarbon solvent refers to a group derived from one or more "halogen atoms” replacing one or more hydrogen atoms on the "C 1-6 alkyl group”.
  • the "halogen atom” and “C 1 "-6 alkyl” is as defined above. Specific examples include but are not limited to: methylene chloride, 1,2-dichloroethane, chloroform or carbon tetrachloride.
  • crystals of the present invention As used herein, “crystals of the present invention”, “crystalline forms of the present invention”, “crystalline forms of the present invention”, etc. may be used interchangeably.
  • room temperature generally refers to 4-30°C, preferably 20 ⁇ 5°C.
  • the crystal structure of the present invention can be analyzed using various analytical techniques known to those of ordinary skill in the art, including but not limited to, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC) and/or thermogravimetric analysis (Thermogravimetric Analysis (TGA), also called thermogravimetry (TG).
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric Analysis
  • TG thermogravimetry
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present invention refers to the peak position expressed in degrees (°) based on the setting in the X-ray diffraction experiment, and is usually the abscissa unit in the diffraction pattern. If the reflection is diffracted when the incident beam forms an angle ⁇ with a lattice plane, the experimental setup requires recording the reflected beam at an angle 2 ⁇ . It should be understood that reference herein to specific 2 ⁇ values for a particular crystalline form is intended to mean 2 ⁇ values (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein, and that the 2 ⁇ error range may be ⁇ 0.3, ⁇ 0.2 or ⁇ 0.1.
  • crystal form of the present invention is not limited to the characteristic patterns that are exactly the same as those described in the drawings disclosed in the present invention, such as XRD, DSC, TGA, which patterns are basically the same as those described in the drawings or Any crystalline form with essentially the same characteristic pattern falls within the scope of the invention.
  • the melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compound of the present invention has a DSC chart with a characteristic peak position, has substantially the same properties as the DSC chart provided in the drawings of the present invention, and the error tolerance of the measurement value is within ⁇ 5°C, generally Required to be within ⁇ 3°C.
  • Carrier refers to a vehicle that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound. It can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and transfer the drug to the body.
  • Non-limiting examples of delivery systems to targeted organs include microcapsules and microspheres, nanoparticles, liposomes, etc.
  • Excipient means an excipient that is not itself a therapeutic agent and is used as a diluent, excipient, binder and/or vehicle and is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate The compounds or pharmaceutical compositions are formed into unit dosage forms for administration.
  • pharmaceutical excipients may serve various functions and may be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives , surfactants, colorants, flavoring agents and sweeteners.
  • Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (such as croscarmellose sodium) ; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, red Flower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as oils Ethyl acid este
  • Figure 1 is a differential scanning calorimetry analysis curve chart of the hydrochloride crystal form A of the compound represented by formula (I).
  • Figure 2 is a thermogravimetric analysis chart of the hydrochloride crystal form A of the compound represented by formula (I).
  • Figure 3 is an X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound represented by formula (I).
  • Figure 4 is a differential scanning calorimetry analysis curve chart of the hydrochloride crystal form B of the compound represented by formula (I).
  • Figure 5 is a thermogravimetric analysis chart of the hydrochloride crystal form B of the compound represented by formula (I).
  • Figure 6 is an X-ray powder diffraction pattern of the hydrochloride crystal form B of the compound represented by formula (I).
  • Figure 7 is a differential scanning calorimetry analysis curve chart of the sulfate crystal form A of the compound represented by formula (I).
  • Figure 8 is a thermogravimetric analysis chart of the sulfate crystal form A of the compound represented by formula (I).
  • Figure 9 is an X-ray powder diffraction pattern of the sulfate crystal form A of the compound represented by formula (I).
  • Figure 10 is a differential scanning calorimetry analysis curve chart of the maleate salt crystal form A of the compound represented by formula (I).
  • Figure 11 is a thermogravimetric analysis chart of the maleate salt form A of the compound represented by formula (I).
  • Figure 12 is an X-ray powder diffraction pattern of the maleate salt crystal form A of the compound represented by formula (I).
  • Figure 13 is a differential scanning calorimetry analysis curve chart of the maleate salt crystal form B of the compound represented by formula (I).
  • Figure 14 is a thermogravimetric analysis chart of the maleate salt crystal form B of the compound represented by formula (I).
  • Figure 15 is an X-ray powder diffraction pattern of the salt form B of the compound represented by formula (I).
  • Figure 16 is a differential scanning calorimetry analysis curve chart of the phosphate crystal form A of the compound represented by formula (I).
  • Figure 17 is a thermogravimetric analysis chart of the phosphate crystal form A of the compound represented by formula (I).
  • Figure 18 is an X-ray powder diffraction pattern of the phosphate crystal form A of the compound represented by formula (I).
  • Figure 19 is a differential scanning calorimetry analysis curve chart of the phosphate crystal form B of the compound represented by formula (I).
  • Figure 20 is a thermogravimetric analysis chart of the phosphate crystal form B of the compound represented by formula (I).
  • Figure 21 is an X-ray powder diffraction pattern of the phosphate crystal form B of the compound represented by formula (I).
  • Figure 22 is a differential scanning calorimetry analysis curve chart of the phosphate crystal form C of the compound represented by formula (I).
  • Figure 23 is a thermogravimetric analysis chart of the phosphate crystal form C of the compound represented by formula (I).
  • Figure 24 is an X-ray powder diffraction pattern of the phosphate crystal form C of the compound represented by formula (I).
  • Figure 25 is a differential scanning calorimetry analysis curve chart of the tartrate crystal form A of the compound represented by formula (I).
  • Figure 26 is a thermogravimetric analysis chart of the tartrate crystal form A of the compound represented by formula (I).
  • Figure 27 is an X-ray powder diffraction pattern of the tartrate crystal form A of the compound represented by formula (I).
  • Figure 28 is a differential scanning calorimetry analysis curve chart of the tartrate crystal form B of the compound represented by formula (I).
  • Figure 29 is a thermogravimetric analysis chart of the tartrate crystal form B of the compound represented by formula (I).
  • Figure 30 is an X-ray powder diffraction pattern of the tartrate crystal form B of the compound represented by formula (I).
  • Figure 31 is a differential scanning calorimetry analysis curve chart of the tartrate crystal form C of the compound represented by formula (I).
  • Figure 32 is a thermogravimetric analysis chart of the tartrate crystal form C of the compound represented by formula (I).
  • Figure 33 is an X-ray powder diffraction pattern of the tartrate crystal form C of the compound represented by formula (I).
  • Figure 34 is a differential scanning calorimetry analysis curve chart of the fumarate crystal form A of the compound represented by formula (I).
  • Figure 35 is a thermogravimetric analysis chart of fumarate crystal form A of the compound represented by formula (I).
  • Figure 36 is an X-ray powder diffraction pattern of the fumarate salt form A of the compound represented by formula (I).
  • Figure 37 is a differential scanning calorimetry analysis curve chart of the citrate crystal form A of the compound represented by formula (I).
  • Figure 38 is a thermogravimetric analysis chart of the citrate crystal form A of the compound represented by formula (I).
  • Figure 39 is an X-ray powder diffraction pattern of the citrate crystal form A of the compound represented by formula (I).
  • Figure 40 is a differential scanning calorimetry analysis curve chart of the naphthalene disulfonate crystal form A of the compound represented by formula (I).
  • Figure 41 is a thermogravimetric analysis chart of the naphthalene disulfonate crystal form A of the compound represented by formula (I).
  • Figure 42 is an X-ray powder diffraction pattern of the naphthalene disulfonate crystal form A of the compound represented by formula (I).
  • Figure 43 is a differential scanning calorimetry analysis curve chart of the naphthalene disulfonate crystal form B of the compound represented by formula (I).
  • Figure 44 is a thermogravimetric analysis chart of the naphthalene disulfonate crystal form B of the compound represented by formula (I).
  • Figure 45 is an X-ray powder diffraction pattern of the naphthalene disulfonate crystal form B of the compound represented by formula (I).
  • Figure 46 is a differential scanning calorimetry analysis curve diagram of the naphthalene disulfonate crystal form C of the compound represented by formula (I).
  • Figure 47 is a thermogravimetric analysis chart of the naphthalene disulfonate crystal form C of the compound represented by formula (I).
  • Figure 48 is an X-ray powder diffraction pattern of the naphthalene disulfonate crystal form C of the compound represented by formula (I).
  • Figure 49 is a differential scanning calorimetry analysis curve chart of the p-toluenesulfonate crystal form A of the compound represented by formula (I).
  • Figure 50 is a thermogravimetric analysis chart of the p-toluenesulfonate crystal form A of the compound represented by formula (I).
  • Figure 51 is an X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A of the compound represented by formula (I).
  • Figure 52 is a differential scanning calorimetry analysis curve chart of the p-toluenesulfonate crystal form B of the compound represented by formula (I).
  • Figure 53 is a thermogravimetric analysis chart of the p-toluenesulfonate crystal form B of the compound represented by formula (I).
  • Figure 54 is an X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B of the compound represented by formula (I).
  • Figure 55 is a differential scanning calorimetry analysis curve chart of the p-toluenesulfonate crystal form C of the compound represented by formula (I).
  • Figure 56 is a thermogravimetric analysis chart of the p-toluenesulfonate crystal form C of the compound represented by formula (I).
  • Figure 57 is an X-ray powder diffraction pattern of the p-toluenesulfonate crystal form C of the compound represented by formula (I).
  • Figure 58 is a differential scanning calorimetry curve chart of the p-toluenesulfonate crystal form D of the compound represented by formula (I).
  • Figure 59 is a thermogravimetric analysis chart of the p-toluenesulfonate crystal form D of the compound represented by formula (I).
  • Figure 60 is an X-ray powder diffraction pattern of the p-toluenesulfonate crystal form D of the compound represented by formula (I).
  • Figure 61 is a differential scanning calorimetry analysis curve chart of the mesylate crystal form A of the compound represented by formula (I).
  • Figure 62 is a thermogravimetric analysis chart of the mesylate crystal form A of the compound represented by formula (I).
  • Figure 63 is an X-ray powder diffraction pattern of the mesylate crystal form A of the compound represented by formula (I).
  • Figure 64 is a differential scanning calorimetry analysis curve chart of the mesylate crystal form B of the compound represented by formula (I).
  • Figure 65 is a thermogravimetric analysis chart of the mesylate crystal form B of the compound represented by formula (I).
  • Figure 66 is an X-ray powder diffraction pattern of the mesylate crystal form B of the compound represented by formula (I).
  • Figure 67 is a differential scanning calorimetry analysis curve chart of the mesylate crystal form C of the compound represented by formula (I).
  • Figure 68 is a thermogravimetric analysis chart of the mesylate crystal form C of the compound represented by formula (I).
  • Figure 69 is an X-ray powder diffraction pattern of the mesylate crystal form C of the compound represented by formula (I).
  • Figure 70 is a differential scanning calorimetry analysis curve chart of the mesylate crystal form D of the compound represented by formula (I).
  • Figure 71 is a thermogravimetric analysis chart of the mesylate crystal form D of the compound represented by formula (I).
  • Figure 72 is an X-ray powder diffraction pattern of the mesylate crystal form D of the compound represented by formula (I).
  • Figure 73 is a differential scanning calorimetry analysis curve chart of the benzene sulfonate crystal form A of the compound represented by formula (I).
  • Figure 74 is a thermogravimetric analysis chart of the benzene sulfonate crystal form A of the compound represented by formula (I).
  • Figure 75 is an X-ray powder diffraction pattern of the benzene sulfonate crystal form A of the compound represented by formula (I).
  • Figure 76 is a differential scanning calorimetry analysis curve chart of benzene sulfonic acid crystal form B of the compound represented by formula (I).
  • Figure 77 is a thermogravimetric analysis spectrum of benzene sulfonic acid crystal form B of the compound represented by formula (I).
  • Figure 78 is an X-ray powder diffraction pattern of benzene sulfonic acid crystal form B of the compound represented by formula (I).
  • Figure 79 is a differential scanning calorimetry analysis curve chart of benzene sulfonic acid crystal form C of the compound represented by formula (I).
  • Figure 80 is a thermogravimetric analysis chart of benzene sulfonic acid crystal form C of the compound represented by formula (I).
  • Figure 81 is an X-ray powder diffraction pattern of benzene sulfonic acid crystal form C of the compound represented by formula (I).
  • Figure 82 is a differential scanning calorimetry analysis curve chart of the oxalate crystal form A of the compound represented by formula (I).
  • Figure 83 is a thermogravimetric analysis chart of the oxalate crystal form A of the compound represented by formula (I).
  • Figure 84 is an X-ray powder diffraction pattern of the oxalate crystal form A of the compound represented by formula (I).
  • Figure 85 is a differential scanning calorimetry analysis curve chart of the oxalate crystal form B of the compound represented by formula (I).
  • Figure 86 is a thermogravimetric analysis chart of the oxalate crystal form B of the compound represented by formula (I).
  • Figure 87 is an X-ray powder diffraction pattern of the oxalate crystal form B of the compound represented by formula (I).
  • Figure 88 is a differential scanning calorimetry analysis curve chart of the gentisate crystal form A of the compound represented by formula (I).
  • Figure 89 is a thermogravimetric analysis chart of gentisate crystal form A of the compound represented by formula (I).
  • Figure 90 is an X-ray powder diffraction pattern of the gentisate crystal form A of the compound represented by formula (I).
  • Figure 91 is a differential scanning calorimetry analysis curve chart of the gentisate crystal form B of the compound represented by formula (I).
  • Figure 92 is a thermogravimetric analysis chart of gentisate crystal form B of the compound represented by formula (I).
  • Figure 93 is an X-ray powder diffraction pattern of the gentisate crystal form B of the compound represented by formula (I).
  • Figure 94 is a differential scanning calorimetry analysis curve chart of the hydrobromide salt form A of the compound represented by formula (I).
  • Figure 95 is a thermogravimetric analysis chart of the hydrobromide crystal form A of the compound represented by formula (I).
  • Figure 96 is an X-ray powder diffraction pattern of the hydrobromide crystal form A of the compound represented by formula (I).
  • Figure 97 is a differential scanning calorimetry analysis curve chart of the hydrobromide crystal form B of the compound represented by formula (I).
  • Figure 98 is a thermogravimetric analysis chart of the hydrobromide crystal form B of the compound represented by formula (I).
  • Figure 99 is an X-ray powder diffraction pattern of the hydrobromide salt form B of the compound represented by formula (I).
  • Figure 100 is a differential scanning calorimetry analysis curve chart of the hydrobromide salt crystal form C of the compound represented by formula (I).
  • Figure 101 is a thermogravimetric analysis chart of the hydrobromide crystal form C of the compound represented by formula (I).
  • Figure 102 is an X-ray powder diffraction pattern of the hydrobromide salt form C of the compound represented by formula (I).
  • Figure 103 is a differential scanning calorimetry analysis curve chart of the hydrobromide crystal form D of the compound represented by formula (I).
  • Figure 104 is a thermogravimetric analysis chart of the hydrobromide crystal form D of the compound represented by formula (I).
  • Figure 105 is an X-ray powder diffraction pattern of the hydrobromide crystal form D of the compound represented by formula (I).
  • Figure 106 shows the tumor growth curve of the mouse MDA-MB-436 subcutaneous in vivo transplanted tumor model.
  • Figure 107 is the animal body weight change curve of the mouse MDA-MB-436 subcutaneous in vivo transplanted tumor model.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), the internal standard is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • HPLC measurement used LC-20AT (Shimadzu) high-pressure liquid chromatograph (Kromasil 100-5-C18, 4.6mm ⁇ 250mm).
  • XRD X-ray powder diffractometer Bruker D8Advance Diffractometer. Carry out X-ray powder diffraction test according to the method in the table below.
  • TGA and DSC images were collected on TA 5500 thermogravimetric analyzer and TA 2500 differential scanning calorimeter respectively. The test parameters are shown in the table below.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology. Waiting for the company.
  • the solution refers to an aqueous solution.
  • the room temperature is 20°C to 30°C.
  • Dissolve compound 1B (11.57g, 35.9mmol) in ethanol (50ml), add 10% palladium carbon catalyst (1g), replace with hydrogen three times, stir at room temperature overnight, filter with a funnel lined with diatomaceous earth, and use absolute ethanol Wash the diatomaceous earth, and concentrate the filtrate.
  • Add 4M hydrochloric acid-dioxane solution (60 ml) to the residue, stir at room temperature for 1 hour, and concentrate.
  • Add ethyl acetate (50 ml) to the residue, stir, filter, and use for filter cake. Washed with ethyl acetate and dried to obtain compound 1C (4.28g, 42.0%) as a white solid.
  • the chemical shift of compound I is 7.40 (s, 1H), which is the -CH peak at position 26, and the peak at 6.28 (s, 2H) is maleic acid.
  • the -CH peak has a ratio of 1:2, so it can be analyzed that the ratio of compound I to maleic acid is 1:1.
  • the chemical shift of compound I is 7.41 (s, 1H), which is the -CH peak at position 26, and the peak at 6.28 (s, 2H) is maleic acid.
  • the -CH peak has a ratio of 1:2, so it can be analyzed that the ratio of compound I to maleic acid is 1:1.
  • the starting sample of free base was mixed with tartaric acid in an equal molar ratio in 1 mL Acetone/H 2 O (9:1, v/v) at room temperature for 2 days, and the mixture was filtered and dried to obtain a solid.
  • the starting sample of free base was mixed with an equal molar ratio of tartaric acid in 1 mL of THF and stirred at room temperature for 2 days.
  • the solid was obtained by filtering and drying.
  • a starting sample of 50 mg of free base was prepared with an equal molar ratio of p-toluenesulfonic acid in 1 mL of MeOH.
  • the sample was clarified after stirring at room temperature for 2 days, then stirred at 5°C for 1 day and then clarified, and solid was precipitated after stirring at -20°C for 5 days.
  • the chemical shift of compound I is 7.46 (s, 1H) for the -CH peak at position 26, and 7.48 (s, 2H) for p-toluene.
  • the -CH peak of sulfonic acid has a ratio of 1:2, so it can be analyzed that the ratio of compound I to p-toluenesulfonic acid is 1:1.
  • thermogravimetric analysis pattern thermogravimetric analysis pattern
  • XRD X-ray powder diffraction pattern
  • the chemical shift of compound I is 7.47 (s, 1H), which is the -CH peak at position 26, and 10.00 (s, 1H), which is methanesulfonate.
  • the -OH peak of acid has a ratio of 1:1, so it can be analyzed that the ratio of compound I to methanesulfonic acid is 1:1.
  • the chemical shift of compound I is 7.30 (s, 1H) for the -CH peak at position 26, and 7.60 (s, 2H) for benzene sulfonate.
  • the -CH peak of acid has a ratio of 1:2, so it can be analyzed that the ratio of compound I to benzenesulfonic acid is 1:1.
  • the chemical shift of compound I is 7.40 (s, 1H) for the -CH peak at position 26, and 6.91 (s, 1H) for gentian.
  • the -OH peak of acid has a ratio of 1:1, so it can be analyzed that the ratio of compound I to gentisic acid is 1:1.
  • PARP1 chemical fluorescence detection kit was purchased from BPS Bioscience. Dilute the histone solution in the kit 5 times with 1X PBS, add 25 ⁇ L of the histone dilution solution to the microplate, and incubate at 4°C overnight. After the incubation, wash the plate three times with PBST (0.05% Tween-20), add 100 ⁇ L blocking solution to the microplate, and incubate at 25°C for 90 minutes; after the incubation, wash the plate three times with PBST.
  • PBST 0.05% Tween-20
  • PARP2, PARP5A, PARP5B, PARP6, PARP7, PARP14 and PARP15 chemical fluorescence detection kits were purchased from BPS Bioscience. Dilute the histone solution in the kit 5 times with 1X PBS, add 25 ⁇ L of the histone dilution solution to the microplate, and incubate at 4°C overnight. After the incubation, wash the plate three times with PBST (0.05% Tween-20), add 100 ⁇ L of blocking solution to the microwell plate, and incubate at 25°C for 90 minutes; after the incubation, wash the plate three times with PBST. Take 2.5 ⁇ L of compound I diluted in test buffer and 5 ⁇ L of substrate mixed solution to the microwell plate. Add 5 ⁇ L of diluted PARP enzyme to the microwell plate, and incubate the reaction system at 25°C for 60 minutes.
  • the compound of the present invention has a weak inhibitory effect on PARP2 enzyme activity in vitro, and its corresponding IC 50 value is 27.47nM; the compound has a strong inhibitory effect on PARP5A, PARP5B, PARP6, PARP7, PARP14 and PARP15 enzyme activity in vitro. Weak, the corresponding IC 50 values are greater than 500nM.
  • Table 8 The specific test results are shown in Table 8.
  • the compounds of the present invention have good PARP1 inhibition selectivity.
  • Human breast tumor cells MDA-MB-436 were purchased from ATCC, the culture medium was Leibovitz's L-15 (added with 10 ⁇ g/mL insulin, 16 ⁇ g/mL glutathione, 10% fetal bovine serum and 1% double antibody), and cultured in In a 37°C, CO2 -free incubator. Collect cells in the exponential growth phase on the first day, and use culture medium to adjust the cell suspension to 4000 cells/135 ⁇ L. Add 135 ⁇ L of cell suspension to each well of a 96-well cell culture plate and incubate overnight. The next day, compounds of different concentrations were added and placed in an incubator for 7 days.
  • Human breast cancer MDA-MB-436 cells were placed in Leibovitz's L-15 medium (added with 10 ⁇ g/mL insulin, 16 ⁇ g/mL glutathione, 10% fetal bovine serum and 1% double antibody) and cultured at 37°C. . Passage was performed twice a week with routine digestion treatment with trypsin. When the cell saturation is 80%-90% and the number reaches the required number, collect the cells, count them and inoculate them. 0.2 mL (10 ⁇ 10 6 cells) MDA-MB-436 cells (plus Matrigel, volume ratio 1:1) were subcutaneously inoculated into BALB/c nude mice (sourced from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd.
  • group administration was started when the average tumor volume reached approximately 180 mm 3 (recorded as Day 0).
  • the vehicle group was given 5% DMSO, 30% PEG400 and 65% 20% sulfobutyl- ⁇ -cyclodextrin solution, and the drug group was given compound (Day0-Day10: 1mg/kg; Day11-Day28: 0.1mg/kg) , the dosing frequency is once a day, the dosing cycle is 29 days, and the drug withdrawal observation period is set to 14 days.
  • the tumor diameter was measured twice a week with a vernier caliper.
  • TGI (%) [1 – (average tumor volume at the end of administration in a certain treatment group – average tumor volume at the beginning of administration in this treatment group)/(average tumor volume at the end of treatment in the solvent control group – solvent
  • the average tumor volume in the control group at the beginning of treatment was evaluated by ⁇ 100%.
  • the tumor growth curve and animal weight change curve are shown in Figure 106 and Figure 107 respectively.
  • Test animals male SD rats, about 220g, 6 to 8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Intravenous administration vehicle 10% DMA+10% Solutol+80% Saline; intragastric administration vehicle: 5%DMSO+30%PEG400+65%(20%SBE-CD) (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; DMSO: dimethyl sulfoxide; SBE-CD: ⁇ -cyclodextrin)
  • the compound has good pharmacokinetic characteristics in rats.
  • test solution preparation method and HPLC purity testing conditions are shown in the table below;
  • the maleate crystal form B, phosphate crystal form C, fumarate crystal form A, and citrate crystal form A of compound I have good chemical stability and crystal form stability.
  • Maleate crystal form B, phosphate crystal form C, fumarate crystal form A, and citrate crystal form A of compound I have good solubility.

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Abstract

La présente invention concerne de multiples formes cristallines d'un sel pharmaceutiquement acceptable d'un composé N-cyclopropyl-5-(4-((7-éthyl-6-oxo-5,6-dihydro-1,5-naphtyridin-3-yl)méthyl)pipérazin-1-yl)picolinamide, son procédé de préparation et son utilisation en médecine.
PCT/CN2023/114679 2022-08-24 2023-08-24 Sel pharmaceutiquement acceptable d'inhibiteur de parp dérivé d'hétéroaryle et son utilisation WO2024041605A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
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WO2009053373A1 (fr) * 2007-10-26 2009-04-30 Janssen Pharmaceutica Nv Dérivés de quinolinone en tant qu'inhibiteurs de parp
WO2010111626A2 (fr) * 2009-03-27 2010-09-30 Takeda Pharmaceutical Company Limited Inhibiteurs de la poly(adp-ribose)polymérase (parp)
CN107849040A (zh) * 2015-06-09 2018-03-27 第药品株式会社 三环衍生化合物、其制备方法、和含有其的药物组合物
CN114144413A (zh) * 2019-07-19 2022-03-04 阿斯利康(瑞典)有限公司 Parp1抑制剂
CN115232154A (zh) * 2021-04-23 2022-10-25 上海翰森生物医药科技有限公司 杂环类衍生物抑制剂、其制备方法和应用
WO2022225934A1 (fr) * 2021-04-19 2022-10-27 Xinthera, Inc. Inhibiteurs de parp1 et leurs utilisations
WO2022222921A1 (fr) * 2021-04-22 2022-10-27 微境生物医药科技(上海)有限公司 Inhibiteur de parp contenant une structure de pipérazine, son procédé de préparation et son utilisation pharmaceutique
WO2023046034A1 (fr) * 2021-09-22 2023-03-30 明慧医药（杭州）有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et application de celui-ci
WO2023051716A1 (fr) * 2021-09-30 2023-04-06 海思科医药集团股份有限公司 Inhibiteur de parp dérivé d'hétéroaryle et son utilisation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009053373A1 (fr) * 2007-10-26 2009-04-30 Janssen Pharmaceutica Nv Dérivés de quinolinone en tant qu'inhibiteurs de parp
WO2010111626A2 (fr) * 2009-03-27 2010-09-30 Takeda Pharmaceutical Company Limited Inhibiteurs de la poly(adp-ribose)polymérase (parp)
CN107849040A (zh) * 2015-06-09 2018-03-27 第药品株式会社 三环衍生化合物、其制备方法、和含有其的药物组合物
CN114144413A (zh) * 2019-07-19 2022-03-04 阿斯利康(瑞典)有限公司 Parp1抑制剂
WO2022225934A1 (fr) * 2021-04-19 2022-10-27 Xinthera, Inc. Inhibiteurs de parp1 et leurs utilisations
WO2022222921A1 (fr) * 2021-04-22 2022-10-27 微境生物医药科技(上海)有限公司 Inhibiteur de parp contenant une structure de pipérazine, son procédé de préparation et son utilisation pharmaceutique
CN115232154A (zh) * 2021-04-23 2022-10-25 上海翰森生物医药科技有限公司 杂环类衍生物抑制剂、其制备方法和应用
WO2023046034A1 (fr) * 2021-09-22 2023-03-30 明慧医药（杭州）有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et application de celui-ci
WO2023051716A1 (fr) * 2021-09-30 2023-04-06 海思科医药集团股份有限公司 Inhibiteur de parp dérivé d'hétéroaryle et son utilisation

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