WO2024041605A1 - Pharmaceutically acceptable salt of heteroaryl derivative parp inhibitor and use thereof - Google Patents

Pharmaceutically acceptable salt of heteroaryl derivative parp inhibitor and use thereof Download PDF

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Publication number
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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French (fr)
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/en

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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
    • 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.

Abstract

The present invention relates to multiple crystalline forms of a pharmaceutically acceptable salt of a compound N-cyclopropyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide, a preparation method therefor, and a use thereof in medicine.

Description

一种杂芳基衍生物PARP抑制剂药学上可接受的盐及其用途A pharmaceutically acceptable salt of a heteroaryl derivative PARP inhibitor and its use 技术领域Technical field
本发明属于药物领域，尤其涉及一种具有PARP-1抑制活性的小分子化合物的药学上可接受的盐及其晶型，以及它们在制备治疗相关疾病的药物中的用途。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.
背景技术Background technique
大约5％的乳腺癌患者与BRCA1/2基因胚系突变相关(BRCA1基因3％，BRCA2基因2％)。BRCA1突变导致的乳腺癌大部分为三阴性乳腺癌(70％)，而BRCA2突变更可能导致***受体阳性乳腺癌(70％)。BRCA1/2基因是抑癌基因，在DNA损伤修复、细胞正常生长等方面均具有重要作用。该基因突变可抑制DNA损伤后正常修复能力，引起同源重组缺陷(homologous recombination deficiency，HRD)，即BRCA功能缺失或其他同源重组相关基因发生突变或功能缺失，使双链断裂的DNA修复不能通过同源重组修复(homologous recombinant repair，HRR)，最终导致癌变。聚腺苷二磷酸核糖聚合酶(PARP)是一种DNA修复酶，在DNA修复通路中起关键作用。DNA损伤断裂时会激活PARP，它作为DNA损伤的一种分子感受器，具有识别、结合到DNA断裂位置的功能，进而激活、催化受体蛋白的聚ADP核糖基化作用，参与DNA的修复过程。PARP在DNA单链碱基切除、修复过程中发挥关键作用。在HRD肿瘤细胞中DNA双链无法修复，PARP抑制剂又阻断单链修复，从而形成“合成致死”效应，导致肿瘤细胞死亡。PARP抑制剂对PARP蛋白有“诱捕”作用，导致与受损DNA结合的PARP蛋白被困在DNA上下不来了，直接造成其他的DNA修复蛋白也结合不上来了，最终导致细胞死亡。目前已有多款PARP抑制剂被成功开发，如奥拉帕利，卢卡帕利和尼拉帕利等，然而不良反应限制了其与化疗药物联合使用的能力。这可能与上市的PARP抑制剂缺少对PARP家族的选择性有关，这些副作用包括端锚聚合酶抑制引起的肠道毒性和PARP-2抑制导致的血液毒性。因此开发高选择性的PARP-1抑制剂，降低非选择性的PARP抑制剂的相关毒副作用具有重要的临床意义。Approximately 5% of breast cancer patients are associated with germline mutations in the BRCA1/2 genes (3% in the BRCA1 gene and 2% in the BRCA2 gene). The majority of breast cancers caused by BRCA1 mutations are triple-negative breast cancers (70%), while BRCA2 mutations are more likely to cause estrogen receptor-positive breast cancers (70%). 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. Through homologous recombinant repair (HRR), it ultimately leads to cancer. 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. 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. These side effects include intestinal toxicity caused by tankyrase inhibition and hematological toxicity caused by PARP-2 inhibition. Therefore, it is of great clinical significance to develop highly selective PARP-1 inhibitors and reduce the toxic and side effects associated with non-selective PARP inhibitors.
当用于治疗人类时，重要的是一种治疗剂，像N-环丙基-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶甲酰胺的结晶形式随着时间的过去以及在该药剂的不同制造批次中保留其多晶型稳定性和化学稳定性、溶解度、以及其他物理化学特性。如果这些物理化学特性随着时间的过去并且在批次中变化，则治疗有效剂量的给药是个问题，并且可导致毒性副作用或治疗无效，尤其是在特定的多晶型物在使用之前分解为较低活性、无活性、或毒性化合物时。因此，选择稳定的、可重复制造的、并且具备有利于其作为治疗剂使用的物理化学特性的结晶剂形式是非常重要的。When used to treat humans, it is important to have a therapeutic agent like N-cyclopropyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5- The crystalline form of naphthyridin-3-yl)methyl)piperazin-1-yl)pyridinecarboxamide retains its polymorphic and chemical stability over time and across different manufacturing batches of the agent, solubility, and other physical and chemical properties. If these physicochemical properties vary over time and within batches, administration of therapeutically effective doses is problematic and can lead to toxic side effects or therapeutic ineffectiveness, especially if a specific polymorph breaks down into With less active, inactive, or toxic compounds. Therefore, it is important to select a crystallization form that is stable, reproducibly manufacturable, and possesses physicochemical properties that favor its use as a therapeutic agent.
发明内容Contents of the invention
本发明涉及式(I)所示化合物N-环丙基-5-(4-((7-乙基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶甲酰胺的药学上可接受的盐及多种晶型，以及在制备治疗相关疾病的药物中的用途。本发明提供的化合物选择性高，活性好，毒副作用低，其盐晶型具有纯度高、溶解性好、物理和化学性质稳定、能耐高温、高湿及强光照、引湿性低等优异特性。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.
本发明提供一种式(I)所示化合物的药学上可接受的盐，
The present invention provides a pharmaceutically acceptable salt of the compound represented by formula (I),
其中，药学上可接受的盐包括但不限于盐酸盐、硫酸盐、马来酸盐、磷酸盐、酒石酸盐、富马酸盐、柠檬酸盐、萘二磺酸盐、对甲苯磺酸盐、甲磺酸盐、苯磺酸盐、草酸盐、龙胆酸盐和氢溴酸盐。Among them, 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.
在一些实施方案中，所述药学上可接受的盐为盐酸盐，优选为盐酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a hydrochloride, preferably hydrochloride Form A, using Cu-Kα radiation, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为盐酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrochloride Form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，所述药学上可接受的盐为盐酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrochloride Form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，本发明的盐酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱如图3所示。In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystalline form A of the present invention is shown in Figure 3 using Cu-Kα radiation.
在一些实施方案中，本发明的盐酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图1、图2所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为盐酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：7.71°±0.2°、9.02°±0.2°、9.56°±0.2°、24.94°±0.2°。In some embodiments, the pharmaceutically acceptable salt is hydrochloride crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 7.71°±0.2°, 9.02°±0.2°, 9.56°±0.2°, 24.94°±0.2°.
在一些实施方案中，所述药学上可接受的盐为盐酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrochloride crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，所述药学上可接受的盐为盐酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrochloride crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，本发明的盐酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图6所示。In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt Form B of the present invention is shown in Figure 6 using Cu-Kα radiation.
在一些实施方案中，本发明的盐酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线分别如图4、图5所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为硫酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：6.77°±0.2°、9.00°±0.2°、26.43°±0.2°。In some embodiments, the pharmaceutically acceptable salt is a sulfate salt Form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ positions: 6.77°±0.2°, 9.00 °±0.2°, 26.43°±0.2°.
在一些实施方案中，所述药学上可接受的盐为硫酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末 衍射图谱在以下2θ位置具有特征衍射峰：6.77°±0.2°、9.00°±0.2°、25.21°±0.2°、26.43°±0.2°。In some embodiments, the pharmaceutically acceptable salt is sulfate salt Form A, which is an X-ray powder using Cu-Kα radiation. The diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.77°±0.2°, 9.00°±0.2°, 25.21°±0.2°, and 26.43°±0.2°.
在一些实施方案中，所述药学上可接受的盐为硫酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a sulfate salt Form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明的硫酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图9所示。In some embodiments, the X-ray powder diffraction pattern of the sulfate crystalline form A of the present invention is shown in Figure 9 using Cu-Kα radiation.
在一些实施方案中，本发明的硫酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图7、图8所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为马来酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is maleate salt Form A, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为马来酸盐晶型A，其中化合物I与马来酸盐的比例为1:1。In some embodiments, the pharmaceutically acceptable salt is maleate salt Form A, wherein the ratio of Compound 1 to maleate salt is 1:1.
在一些实施方案中，所述药学上可接受的盐为马来酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is maleate salt Form A, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为马来酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is maleate salt Form A, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的马来酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图12所示。In some embodiments, the maleate crystal form A of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 12.
在一些实施方案中，本发明所述的马来酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图10、图11所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为马来酸盐，在一些实施方案中，马来酸盐为晶型B，在一些实施方案中，化合物I与马来酸盐的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：6.25±0.2°、7.44±0.2°、17.95±0.2°、18.80±0.2°、20.12±0.2°。In some embodiments, the pharmaceutically acceptable salt is the maleate salt. In some embodiments, the maleate salt is Form B. In some embodiments, the ratio of Compound 1 to the maleate salt is is 1:1, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.25±0.2°, 7.44±0.2°, 17.95±0.2°, 18.80±0.2°, 20.12±0.2 °.
在一些实施方案中，所述药学上可接受的盐为马来酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is maleate salt Form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为马来酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is maleate salt Form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的马来酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图15所示。In some embodiments, the maleate crystal form B of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 15.
在一些实施方案中，本发明所述的马来酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线 分别如图13、图14所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为磷酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is phosphate Form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为磷酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is phosphate Form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为磷酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is phosphate Form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的磷酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图18所示。In some embodiments, the X-ray powder diffraction pattern of the phosphate crystalline form A of the present invention is shown in Figure 18 using Cu-Kα radiation.
在一些实施方案中，本发明所述的磷酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图16、图17所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为磷酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：4.44±0.2°、5.13±0.2°、10.58±0.2°、16.02±0.2°。In some embodiments, the pharmaceutically acceptable salt is a phosphate form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.44±0.2°, 5.13± 0.2°, 10.58±0.2°, 16.02±0.2°.
在一些实施方案中，所述药学上可接受的盐为磷酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a phosphate form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为磷酸盐晶型B，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a phosphate crystal Form B, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的磷酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图21所示。In some embodiments, the phosphate crystal form B of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 21.
在一些实施方案中，本发明所述的磷酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线分别如图19、图20所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为磷酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：4.76±0.2°、9.52±0.2°、10.40±0.2°、15.78±0.2°、19.69±0.2°、22.47±0.2°。In some embodiments, the pharmaceutically acceptable salt is a phosphate salt Form C, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为磷酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a phosphate salt Form C, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为磷酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。 In some embodiments, the pharmaceutically acceptable salt is a phosphate salt Form C, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述磷酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图如图24所示。In some embodiments, the phosphate crystal Form C of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 24.
在一些实施方案中，本发明所述磷酸盐晶型C，其差示扫描量热分析曲线、热重分析曲线分别如图22、图23所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为酒石酸盐，在一些实施方案中，化合物I与酒石酸的比例为1:1，在一些实施方案中，酒石酸盐为晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a tartrate salt. In some embodiments, the ratio of Compound I to tartaric acid is 1:1. In some embodiments, the tartrate salt is Form A, using Cu -Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为酒石酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is tartrate crystal form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的酒石酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图27所示。In some embodiments, the tartrate crystal form A of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 27.
在一些实施方案中，本发明所述的酒石酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图25、图26所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为酒石酸盐，在一些实施方案中，酒石酸盐为晶型B，在一些实施方案中，化合物I与酒石酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：4.31±0.2°、8.76±0.2°、24.85±0.2°、26.40±0.2°。In some embodiments, the pharmaceutically acceptable salt is a tartrate salt. In some embodiments, the tartrate salt is Form B. In some embodiments, the ratio of Compound I to tartaric acid is 1:1, using Cu -Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.31±0.2°, 8.76±0.2°, 24.85±0.2°, 26.40±0.2°.
在一些实施方案中，本发明所述的酒石酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图30所示。In some embodiments, the tartrate crystal form B of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 30.
在一些实施方案中，本发明所述的酒石酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线分别如图28、图29所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为酒石酸盐，在一些实施方案中，酒石酸盐为晶型C，在一些实施方案中，晶型C的化合物I与酒石酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：7.02±0.2°、7.74±0.2°、8.48±0.2°、9.47±0.2°、10.29±0.2°、16.22±0.2°、19.50±0.2°、20.66±0.2°、25.13±0.2°、27.15±0.2°。In some embodiments, the pharmaceutically acceptable salt is a tartrate salt. In some embodiments, the tartrate salt is Form C. In some embodiments, the ratio of Compound I to tartaric acid in Form C is 1: 1. Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.02±0.2°, 7.74±0.2°, 8.48±0.2°, 9.47±0.2°, 10.29±0.2°, 16.22 ±0.2°, 19.50±0.2°, 20.66±0.2°, 25.13±0.2°, 27.15±0.2°.
在一些实施方案中，所述药学上可接受的盐为酒石酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is tartrate crystal form C, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为酒石酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is tartrate crystal form C, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的酒石酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图如图33所示。In some embodiments, the tartrate crystal form C of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 33.
在一些实施方案中，本发明所述的酒石酸盐晶型C，其差示扫描量热分析曲线、热重分析曲线分别如图31、图32所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为富马酸盐，在一些实施方案中，富马酸盐为晶型A，在一些实施方案中，晶型A的化合物I与富马酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉 末衍射图谱在以下2θ位置具有特征衍射峰：5.72±0.2°、11.50±0.2°、18.93±0.2°、20.62±0.2°、27.75±0.2°。In some embodiments, the pharmaceutically acceptable salt is a fumarate salt. In some embodiments, the fumarate salt is Form A. In some embodiments, Compound I of Form A is a combination of fumarate and fumarate. Acid ratio is 1:1, using Cu-Kα radiation, its X-ray powder The final diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.72±0.2°, 11.50±0.2°, 18.93±0.2°, 20.62±0.2°, 27.75±0.2°.
在一些实施方案中，所述药学上可接受的盐为富马酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is fumarate salt Form A, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为富马酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is fumarate salt Form A, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的富马酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图36所示。In some embodiments, the fumarate crystalline Form A of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 36.
在一些实施方案中，本发明所述的富马酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图34、图35所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为柠檬酸盐，在一些实施方案中，柠檬酸盐为晶型A，在一些实施方案中，晶型A的化合物I与柠檬酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a citrate salt, in some embodiments, the citrate salt is Form A, and in some embodiments, the ratio of Compound I of Form A to citric acid is 1:1, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为柠檬酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is citrate Form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为柠檬酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is citrate Form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的柠檬酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图39所示。In some embodiments, the X-ray powder diffraction pattern of the citrate crystalline form A of the present invention is shown in Figure 39 using Cu-Kα radiation.
在一些实施方案中，本发明所述的柠檬酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图37、图38所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为萘二磺酸盐，在一些实施方案中，萘二磺酸盐具有晶型A，在一些实施方案中，晶型A的化合物I和萘二磺酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a naphthalene disulfonate salt. In some embodiments, the naphthalene disulfonate salt has Form A. In some embodiments, Compound I of Form A and The ratio of naphthalenedisulfonic acid is 1:1, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为萘二磺酸盐晶型A，使用Cu-Kα辐射其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is naphthalene disulfonate crystal form A, and its X-ray powder diffraction pattern using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为萘二磺酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。 In some embodiments, 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 2θ position using Cu-Kα 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°.
在一些实施方案中，本发明所述的萘二磺酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图42所示。In some embodiments, the X-ray powder diffraction pattern of the naphthalenedisulfonate crystalline form A of the present invention is shown in Figure 42 using Cu-Kα radiation.
在一些实施方案中，本发明所述的萘二磺酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图40、图41所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为萘二磺酸盐，在一些实施方案中，萘二磺酸盐具有晶型B，在一些实施方案中，晶型B的化合物I和萘二磺酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a naphthalene disulfonate salt. In some embodiments, the naphthalene disulfonate salt has Form B. In some embodiments, Form B of Compound I and The ratio of naphthalenedisulfonic acid is 1:1, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为萘二磺酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is naphthalene disulfonate crystal form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ 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°.
在一些实施方案中，本发明所述的萘二磺酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图45所示。In some embodiments, the naphthalene disulfonate crystal Form B of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 45.
在一些实施方案中，本发明所述的萘二磺酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线分别如图43、图44所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为萘二磺酸盐，在一些实施方案中，萘二磺酸盐具有晶型C，在一些实施方案中，晶型C的化合物I和萘二磺酸的比例为1:1，萘二磺酸盐晶型C使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：6.04±0.2°、18.13±0.2°。In some embodiments, the pharmaceutically acceptable salt is a naphthalene disulfonate salt. In some embodiments, the naphthalene disulfonate salt has Form C. In some embodiments, Compound I of Form C and The ratio of naphthalene disulfonic acid is 1:1. The naphthalene disulfonate crystal form C uses Cu-Kα radiation. Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.04±0.2°, 18.13±0.2°. .
在一些实施方案中，本发明所述的萘二磺酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图如图48所示。In some embodiments, the naphthalene disulfonate crystal Form C of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 48.
在一些实施方案中，本发明所述的萘二磺酸盐晶型C，其差示扫描量热分析曲线、热重分析曲线分别如图46、图47所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为对甲苯磺酸盐，在一些实施方案中，对甲苯磺酸盐具有晶型A，在一些实施方案中，晶型A的化合物I和对甲苯磺酸盐的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：7.09±0.2°、10.74±0.2°、16.65±0.2°、21.21±0.2°、28.36±0.2°。In some embodiments, the pharmaceutically acceptable salt is a p-toluenesulfonate salt. In some embodiments, the p-toluenesulfonate salt has Form A. In some embodiments, Compound I of Form A and The ratio of p-toluenesulfonate is 1:1, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 7.09±0.2°, 10.74±0.2°, 16.65±0.2°, 21.21 ±0.2°, 28.36±0.2°.
在一些实施方案中，本发明所述的对甲苯磺酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图51所示。In some embodiments, the p-toluenesulfonate crystal form A of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 51.
在一些实施方案中，本发明所述的对甲苯磺酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图49、图50所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为对甲苯磺酸盐，在一些实施方案中，对甲苯磺酸盐具有晶型B，在一些实施方案中，晶型B的化合物I和对甲苯磺酸盐的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a p-toluenesulfonate salt, in some embodiments, 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-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的对甲苯磺酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图54所示。In some embodiments, the p-toluenesulfonate crystal Form B of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 54.
在一些实施方案中，本发明所述的对甲苯磺酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线分别如图52、图53所示。 In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为对甲苯磺酸盐，在一些实施方案中，对甲苯磺酸盐具有晶型C，在一些实施方案中，晶型C的化合物I和对甲苯磺酸盐的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：4.52±0.2°、7.66±0.2°、9.02±0.2°、24.58±0.2°。In some embodiments, the pharmaceutically acceptable salt is a p-toluenesulfonate salt, in some embodiments, 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-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.52±0.2°, 7.66±0.2°, 9.02±0.2°, 24.58 ±0.2°.
在一些实施方案中，所述药学上可接受的盐为对甲苯磺酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is p-toluenesulfonate Form C, which has an X-ray powder diffraction pattern using Cu-Kα radiation with a characteristic diffraction peak at the following 2θ 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°.
在一些实施方案中，所述的对甲苯磺酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图如图57所示。In some embodiments, the p-toluenesulfonate crystal Form C is irradiated using Cu-Kα, and its X-ray powder diffraction pattern is shown in Figure 57.
在一些实施方案中，所述的对甲苯磺酸盐晶型C，其差示扫描量热分析曲线、热重分析曲线分别如图55、图56所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为对甲苯磺酸盐，在一些实施方案中，对甲苯磺酸盐具有晶型D，在一些实施方案中，晶型D的化合物I和对甲苯磺酸盐的比例为1:1，晶型D，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is a p-toluenesulfonate salt. In some embodiments, the p-toluenesulfonate salt has Form D. In some embodiments, Compound I of Form D and The ratio of p-toluenesulfonate is 1:1, crystal form D, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为对甲苯磺酸盐晶型D，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, 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 2θ position using Cu-Kα 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°.
在一些实施方案中，所述药学上可接受的盐为对甲苯磺酸盐晶型D，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is p-toluenesulfonate Form D, which has an X-ray powder diffraction pattern using Cu-Kα radiation with a characteristic diffraction peak at the following 2θ 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°.
在一些实施方案中，本发明所述的对甲苯磺酸盐晶型D，使用Cu-Kα辐射，其X-射线粉末衍射图如图60所示。In some embodiments, the p-toluenesulfonate crystal Form D of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 60.
在一些实施方案中，本发明所述的对甲苯磺酸盐晶型D，其差示扫描量热分析曲线、热重分析曲线分别如图58、图59所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为甲磺酸盐晶型A，在一些实施方案中，化合物I与甲磺酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：8.15±0.2°、15.95±0.2°。In some embodiments, the pharmaceutically acceptable salt is methanesulfonate crystal form A. In some embodiments, the ratio of compound I to methanesulfonic acid is 1:1, using Cu-Kα radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.15±0.2°, 15.95±0.2°.
在一些实施方案中，本发明所述的甲磺酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图63所示。In some embodiments, the mesylate crystal form A of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 63.
在一些实施方案中，本发明所述的甲苯磺酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图61、图62所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为甲磺酸盐晶型B，在一些实施方案中，化合物I与甲磺酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is methanesulfonate crystal form B. In some embodiments, the ratio of compound I to methanesulfonic acid is 1:1, using Cu-Kα radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为甲磺酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is methanesulfonate crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，所述药学上可接受的盐为甲磺酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is methanesulfonate crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，本发明所述的甲磺酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图66所示。In some embodiments, the mesylate crystal Form B of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 66.
在一些实施方案中，本发明所述的对甲苯磺酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线分别如图64、图65所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为甲磺酸盐晶型C，在一些实施方案中，化合物I与甲磺酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：4.51±0.2°、6.38±0.2°、7.14±0.2°、8.99±0.2°、17.11±0.2°、21.76±0.2°。In some embodiments, the pharmaceutically acceptable salt is methanesulfonate crystal form C. In some embodiments, the ratio of compound I to methanesulfonic acid is 1:1, using Cu-Kα radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为甲磺酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is methanesulfonate crystalline form C, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，本发明所述的甲磺酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图如图69所示。In some embodiments, the mesylate crystal Form C of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 69.
在一些实施方案中，本发明所述的甲磺酸盐晶型C，其差示扫描量热分析曲线、热重分析曲线分别如图67、图68所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为甲磺酸盐晶型D，在一些实施方案中，化合物I与甲磺酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：9.15±0.2°、16.23±0.2°、19.98±0.2°、27.60±0.2°。In some embodiments, the pharmaceutically acceptable salt is methanesulfonate crystal form D. In some embodiments, the ratio of compound I to methanesulfonic acid is 1:1, using Cu-Kα radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.15±0.2°, 16.23±0.2°, 19.98±0.2°, 27.60±0.2°.
在一些实施方案中，所述药学上可接受的盐为甲磺酸盐晶型D，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is methanesulfonate crystal form D, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，所述药学上可接受的盐为甲磺酸盐晶型D，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is methanesulfonate crystal form D, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，本发明所述的甲磺酸盐晶型D，使用Cu-Kα辐射，其X-射线粉末衍射图如图72所示。In some embodiments, the methanesulfonate crystal form D of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 72.
在一些实施方案中，本发明所述的甲磺酸盐晶型D，其差示扫描量热分析曲线、热重分析曲线分别如图70、图71所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为苯磺酸盐晶型A，在一些实施方案中，化合物I与苯磺酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is benzenesulfonate crystal form A. In some embodiments, the ratio of compound I to benzenesulfonic acid is 1:1, using Cu-Kα radiation, and its -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为苯磺酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is benzenesulfonate crystal form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，本发明所述的苯磺酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图75所示。In some embodiments, the benzenesulfonate crystalline Form A of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 75.
在一些实施方案中，本发明所述的苯磺酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图73、图74所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为苯磺酸盐晶型B，在一些实施方案中，化合物I与苯磺酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is benzenesulfonate crystal form B. In some embodiments, the ratio of compound I to benzenesulfonic acid is 1:1, using Cu-Kα radiation, and its -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为苯磺酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is benzenesulfonate crystal form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，本发明所述的苯磺酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图78所示。In some embodiments, the benzene sulfonate crystal Form B of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 78.
在一些实施方案中，发明所述的苯磺酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线分别如图76、图77所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为苯磺酸盐晶型C，在一些实施方案中，化合物I与苯磺酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：5.63±0.2°、17.04±0.2°、18.50±0.2°、20.19±0.2°、23.77±0.2°。In some embodiments, the pharmaceutically acceptable salt is benzenesulfonate crystal form C. In some embodiments, the ratio of compound I to benzenesulfonic acid is 1:1, using Cu-Kα radiation, and its -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.63±0.2°, 17.04±0.2°, 18.50±0.2°, 20.19±0.2°, 23.77±0.2°.
在一些实施方案中，发明所述的苯磺酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图如图81所示。In some embodiments, the benzene sulfonate crystal Form C of the invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 81.
在一些实施方案中，发明所述的苯磺酸盐晶型C，其差示扫描量热分析曲线、热重分析曲线分别如图79、图80所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为草酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：4.89±0.2°、5.51±0.2°、9.80±0.2°、15.52±0.2°、17.10±0.2°、20.22±0.2°。In some embodiments, the pharmaceutically acceptable salt is oxalate form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为草酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is oxalate form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为草酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is oxalate form A, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的草酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图84所示。In some embodiments, the X-ray powder diffraction pattern of the oxalate crystalline form A of the present invention is shown in Figure 84 using Cu-Kα radiation.
在一些实施方案中，本发明所述的草酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图82、图83所示。 In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为草酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is oxalate form B, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为草酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is oxalate form B, which has an X-ray powder diffraction pattern using Cu-Kα radiation with characteristic diffraction peaks at the following 2θ 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°.
本在一些实施方案中，所述药学上可接受的盐为草酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is oxalate crystal form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述草酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图87所示。In some embodiments, the X-ray powder diffraction pattern of the oxalate crystalline Form B of the present invention is shown in Figure 87 using Cu-Kα radiation.
在一些实施方案中，本发明所述草酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线分别如图85、图86所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为龙胆酸盐晶型A，在一些实施方案中，化合物I与龙胆酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is gentisate Form A. In some embodiments, the ratio of Compound I to gentisic acid is 1:1, using Cu-Kα radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为龙胆酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is gentisate Form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，所述药学上可接受的盐为龙胆酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is gentisate Form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，本发明所述的龙胆酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图90所示。In some embodiments, the X-ray powder diffraction pattern of the gentisate crystalline form A of the present invention is shown in Figure 90 using Cu-Kα radiation.
在一些实施方案中，本发明所述的龙胆酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图88、图89所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为龙胆酸盐晶型B，在一些实施方案中，化合物I与龙胆酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°、。In some embodiments, the pharmaceutically acceptable salt is gentisate crystal Form B. In some embodiments, the ratio of Compound I to gentisic acid is 1:1, using Cu-Kα radiation, where -The ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°,.
在一些实施方案中，所述药学上可接受的盐为龙胆酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is gentisate Form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，前述的式(I)所示化合物的龙胆酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图93所示。 In some embodiments, 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-Kα radiation.
在一些实施方案中，前述的式(I)所示化合物的龙胆酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线如图91、图92所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为氢溴酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°、。In some embodiments, the pharmaceutically acceptable salt is hydrobromide salt Form A, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为氢溴酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrobromide salt Form A, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的氢溴酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图如图96所示。In some embodiments, the hydrobromide salt Form A of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 96.
在一些实施方案中，本发明所述的氢溴酸盐晶型A，其差示扫描量热分析曲线、热重分析曲线分别如图94、图95所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为氢溴酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°、。In some embodiments, the pharmaceutically acceptable salt is hydrobromide salt Form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°,.
在一些实施方案中，所述药学上可接受的盐为氢溴酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrobromide salt Form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为氢溴酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrobromide salt Form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，本发明所述的氢溴酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图如图99所示。In some embodiments, the hydrobromide crystal Form B of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 99.
在一些实施方案中，本发明所述的氢溴酸盐晶型B，其差示扫描量热分析曲线、热重分析曲线分别如图97、图98所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为氢溴酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrobromide salt Form C, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
在一些实施方案中，所述药学上可接受的盐为氢溴酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrobromide salt Form C, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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 °.
在一些实施方案中，本发明所述的氢溴酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图如图102所示。In some embodiments, the hydrobromide crystal Form C of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 102.
在一些实施方案中，本发明所述的氢溴酸盐晶型C，其差示扫描量热分析曲线、热重分析曲线分别如图100、图101所示。In some embodiments, 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.
在一些实施方案中，所述药学上可接受的盐为氢溴酸盐晶型D，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrobromide salt Form D, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，所述药学上可接受的盐为氢溴酸盐晶型D，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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°。In some embodiments, the pharmaceutically acceptable salt is hydrobromide salt Form D, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα 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°.
在一些实施方案中，本发明所述的氢溴酸盐晶型D，使用Cu-Kα辐射，其X-射线粉末衍射图如图105所示。In some embodiments, the hydrobromide crystal Form D of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern is shown in Figure 105.
在一些实施方案中，本发明所述的氢溴酸盐晶型C，其差示扫描量热分析曲线、热重分析曲线分别如图103、图104所示。In some embodiments, 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.
本发明还提供一种药物组合物，其中，所述药物组合物含有治疗有效量的前述任一盐晶型，以及药学上可接受的载体和/或赋形剂，优选所述治疗有效量为1-600mg。该药物组合物可以为单位制剂形式(单位制剂也被称为“制剂规格”)。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. Preferably, 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").
本发明还提供前述任意一项方案所述的盐晶型或组合物在制备治疗/预防PARP介导的疾病的药物中的用途。进一步地，所述PARP介导的疾病为肿瘤。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.
本发明还提供了一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的前述任意一项方案所示的盐晶型或其组合物，所述疾病优选为肿瘤，优选所述治疗有效量为1-600mg。一些实施方案中，本发明中所述哺乳动物包括人。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 For tumors, the therapeutically effective dose is preferably 1-600 mg. In some embodiments, mammals of the present invention include humans.
本申请中所述“有效量”或“治疗有效量”是指按游离碱计，给予足够量的本申请公开的盐晶型，其将在某种程度上缓解所治疗的疾病或病症的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物***的任何其它希望改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的盐晶型的组合物。治疗有效量的实例，以游离碱计，包括但不限于1-600mg、1-500mg、1-400mg、1-300mg、1-250mg、1-200mg、1-150mg、1-125mg、1-100mg、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；20-600mg、20-500mg、20-400mg、20-350mg、20-300mg、20-250mg、20-200mg、20-150mg、20-125mg、20-100mg、20-90mg、20-80mg、20-70mg、20-60mg、20-50mg、20-40mg、20-30mg；50-600mg、50-500mg、50-400mg、50-300mg、50-250mg、50-200mg、50-150mg、50-125mg、50-100mg；100-600mg、100-500mg、100-400mg、100-300mg、100-250mg、100-200mg；The "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. For example, 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. Examples of therapeutically effective amounts, based on free base, 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; 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg , 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg; 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50 -150mg, 50-125mg, 50-100mg; 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;
在一些实施方案中，本发明的药物组合物或制剂含有上述治疗有效量的本发明晶型；In some embodiments, 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;
本发明涉及一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含治疗有效量的本发明所述的晶型以及载体和/或赋形剂。该药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。在一些实施方案中，该药物组合物包括但不限于1mg、1.25mg、2.5mg、5mg、10mg、12.5mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、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的本发明晶型物中的游离碱。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"). In some embodiments, 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.
一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明晶型，以 及药学上可接受的载体和/或赋形剂，治疗有效量以游离碱计，优选1-600mg，所述的疾病优选肿瘤，特别是脑肿瘤。A method for treating a disease in a mammal, the method 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.
一种用于治疗哺乳动物的疾病的方法所述方法包括，将药物本发明晶型物，以及药学上可接受的载体和/或赋形剂，以游离碱计，以1-600mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-600mg/天、20-600mg/天、25-600mg/天、50-600mg/天、75-600mg/天、100-600mg/天、200-600mg/天、10-600mg/天、20-600mg/天、25-600mg/天、50-600mg/天、75-600mg/天、100-600mg/天、200-600mg/天、25-600mg/天、50-600mg/天、100-600mg/天、200-600mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于1mg/天、5mg/天、10mg/天、20mg/天、25mg/天、50mg/天、75mg/天、100mg/天、125mg/天、150mg/天、200mg/天、400mg/天、600mg/天。A method for treating diseases in mammals. The method 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. In some embodiments, 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/day, 200mg/day, 400mg/day, 600mg/day.
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的晶型物，该试剂盒包含本发明晶型物，本发明晶型物的量与上述药物组合物中其游离碱计量相同。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.
本发明中本发明晶型物的量在每种情况下以游离碱的形式换算。The amounts of the crystalline forms of the invention in the present invention are in each case converted into free base form.
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。"Preparation specification" refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
本发明所述的晶型物，以原料药的约5重量％至约100重量％存在；在某些实施方案中，以原料药的约10重量％至约100重量％存在；在某些实施方案中，以原料药的约15重量％至约100重量％存在；在某些实施方案中，以原料药的约20重量％至约100重量％存在；在某些实施方案中，以原料药的约25重量％至约100重量％存在；在某些实施方案中，以原料药的约30重量％至约100重量％存在；在某些实施方案中，以原料药的约35重量％至约100重量％存在；在某些实施方案中，以原料药的约40重量％至约100重量％存在；在某些实施方案中，以原料药的约45重量％至约100重量％存在；在某些实施方案中，以原料药的约50重量％至约100重量％存在；在某些实施方案中，以原料药的约55重量％至约100重量％存在；在某些实施方案中，以原料药的约60重量％至约100重量％存在；在某些实施方案中，以原料药的约65重量％至约100重量％存在；在某些实施方案中，以原料药的约70重量％至约100重量％存在；在某些实施方案中，以原料药的约75重量％至约100重量％存在；在某些实施方案中，以原料药的约80重量％至约100重量％存在；在某些实施方案中，以原料药的约85重量％至约100重量％存在；在某些实施方案中，以原料药的约90重量％至约100重量％存在；在某些实施方案中，以原料药的约95重量％至约100重量％存在；在某些实施方案中，以原料药的约98重量％至约100重量％存在；在某些实施方案中，以原料药的约99重量％至约100重量％存在；在某些实施方案中，基本上所有的原料药都是基本纯的晶体。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. present from about 25% to about 100% by weight of the drug substance; in certain embodiments, present from about 30% to about 100% by weight of the drug substance; in certain embodiments, from about 35% to about 100% by weight of the drug substance Present at about 100% by weight; in certain embodiments, present at about 40% by weight to about 100% by weight of the drug substance; in certain embodiments, present at about 45% by weight to about 100% by weight of the drug substance; In certain embodiments, present from about 50% to about 100% by weight of the drug substance; in certain embodiments, present from about 55% to about 100% by weight of the drug substance; , present at about 60% to about 100% by weight of the drug substance; in certain embodiments, present at about 65% to about 100% by weight of the drug substance; in certain embodiments, at about 60% by weight of the drug substance Present at 70% to about 100% by weight; in certain embodiments, present at about 75% to about 100% by weight of the drug substance; in certain embodiments, present at about 80% to about 100% by weight of the drug substance Present at % by weight; in certain embodiments, present at about 85% to about 100% by weight of the drug substance; in certain embodiments, present at about 90% by weight to about 100% by weight of the drug substance; In some embodiments, present at about 95% to about 100% by weight of the drug substance; in certain embodiments, present at about 98% to about 100% by weight of the drug substance; in certain embodiments, From about 99% to about 100% by weight of the drug substance is present; in certain embodiments, substantially all of the drug substance is substantially pure crystals.
本发明的晶型物可以经如下的制备方法制备：The crystalline form of the present invention can be prepared by the following preparation method:
1、挥发实验：将样品澄清溶液在不同温度下敞口挥发至溶剂干。1. Volatilization experiment: Volatilize the clear solution of the sample at different temperatures until the solvent is dry.
2、晶浆实验：将样品的过饱和溶液(有不溶固体存在)在不同溶剂体系中某个温度下进行搅拌。2. Crystal slurry experiment: Stir the supersaturated solution of the sample (with insoluble solids present) at a certain temperature in different solvent systems.
3、抗溶剂实验：取样品溶解在良溶剂中，加入抗溶剂(不良溶剂)，析出固体短时搅拌后立即过滤处理。3. 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.
4、冷却结晶实验：在高温下将一定量的样品溶解到相应溶剂中，然后直接在室温或低温搅拌析晶。4. 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.
5、高分子模板实验：在样品澄清溶液中加入不同种类的高分子材料，置于室温下敞口挥发至溶剂干。5. 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.
6、热方法实验：将样品按一定热方法结晶条件处理并冷却至室温。 6. Thermal method experiment: Treat the sample according to certain thermal crystallization conditions and cool it to room temperature.
7、水汽扩散实验：将样品在室温下一定湿度环境中放置。7. Water vapor diffusion experiment: Place the sample in a certain humidity environment at room temperature.
本发明所述的良溶剂和不良溶剂是相对而言的，在一对溶剂中，溶解度较高者为良溶剂，溶解度较低者为不良溶剂。上述制备方法所采用的溶剂，在未指明时，可采用单一溶剂，也可以采用两种或两种以上的组合。The good solvent and poor solvent described in the present invention are relative terms. Among a pair of solvents, the one with higher solubility is a good solvent, and 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.
本发明公开的X-射线粉末衍射或DSC图、TGA图，与其实质上相同的也属于本发明的范围。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.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。“IC 50 ” refers to the half inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
“醚类溶剂”是指含有醚键-O-且碳原子数为2至10个的链状化合物或环状化合物，具体实例包括但不限于：四氢呋喃、***、丙二醇甲醚、甲基叔丁基醚、异丙醚或1,4-二氧六环。"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.
“醇类溶剂”是指一个或多个“羟基”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。"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". The "hydroxyl group" and the "C 1-6 alkyl group""As defined above, specific examples include, but are not limited to: methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol or trifluoroethanol.
“酯类溶剂”是指含碳原子数为1至4个的低级有机酸与含碳原子数为1至6个的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。"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.
“酮类溶剂”是指羰基(-C(O)-)与两个烃基相连的化合物，根据分子中烃基的不同，酮可分为脂肪酮、脂环酮、芳香酮、饱和酮和不饱和酮，具体实例包括但不限于：丙酮、苯乙酮、4-甲基-2-戊酮。"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.
“腈类溶剂”是指一个或多个“氰基”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“氰基”和“C1-6烷基”如前文所定义，具体实例包括但不限于：乙腈或丙腈。"Nitrile 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.
“卤代烃类溶剂”是指一个或多个“卤素原子”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“C1-6烷基”如前文所定义，具体实例包括但不限于：二氯甲烷、1,2-二氯乙烷、氯仿或四氯化碳。"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.
如本发明所用，“本发明的晶体”、“本发明的晶型”、“本发明的晶型物”等可互换使用。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.
本发明所述“室温”一般指4-30℃，优选地指20±5℃。The "room temperature" mentioned in the present invention generally refers to 4-30°C, preferably 20±5°C.
本发明晶型结构可以使用本领域普通技术人员已知的各种分析技术分析，包括但不限于，X-射线粉末衍射(XRD)、示差扫描热法(DSC)和/或热重分析(Thermogravimetric Analysis，TGA)，又叫热重法(Thermogravimetry，TG)。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).
本发明所述的“2θ或2θ角度”是指基于X射线衍射实验中设置的以度数(°)表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶型的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)，所述2θ的误差范围可以是±0.3、±0.2或±0.1。The "2θ or 2θ 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 θ with a lattice plane, the experimental setup requires recording the reflected beam at an angle 2θ. It should be understood that reference herein to specific 2θ values for a particular crystalline form is intended to mean 2θ values (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein, and that the 2θ error range may be ±0.3, ±0.2 or ±0.1.
可以理解的是，本发明描述的和保护的数值为近似值。数值内的变化可能归因于设备的校准、设备误差、晶体的纯度、晶体大小、样本大小以及其他因素。It is understood that the numerical values described and claimed herein are approximations. Variations within values may be attributed to calibration of the equipment, equipment errors, purity of the crystals, crystal size, sample size, and other factors.
可以理解的是，本发明的晶型不限于与本发明公开的附图中描述的特征图谱完全相同的特征图谱，比如XRD、DSC、TGA，具有与附图中描述的哪些图谱基本上相同或本质上相同的特征图谱的任何晶型均落入本发明的范围内。It can be understood that the 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.
可以理解的是，差示扫描量热(DSC)领域中所熟知的，DSC曲线的熔融峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明的结晶化合物具有特征峰位置的DSC图，具有与本发明附图中提供的DSC图实质上相同的性质，测量值误差容限为±5℃内，一般要求在±3℃。 It can be understood that, as is well known in the field of differential scanning calorimetry (DSC), 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℃.
“载体”指的是：不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性，并能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系，非限制性的实例包括微囊与微球、纳米粒、脂质体等。"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.
“赋形剂”指的是：其本身并非治疗剂，用作稀释剂、辅料、粘合剂和/或媒介物，用于添加至药物组合物中以改善其处置或储存性质或允许或促进化合物或药物组合物形成用于给药的单位剂型。如本领域技术人员所已知的，药用赋形剂可提供各种功能且可描述为润湿剂、缓冲剂、助悬剂、润滑剂、乳化剂、崩解剂、吸收剂、防腐剂、表面活性剂、着色剂、矫味剂及甜味剂。药用赋形剂的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉及马铃薯淀粉；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素、乙酸纤维素、羟丙基甲基纤维素、羟丙基纤维素、微晶纤维素及交联羧甲基纤维素(例如交联羧甲基纤维素钠)；(4)黄蓍胶粉；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格溶液(Ringer’s solution)；(19)乙醇；(20)pH缓冲溶液；(21)聚酯、聚碳酸酯和/或聚酐；及(22)其他用于药物制剂中的无毒相容物质。"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. As is known to those skilled in the art, 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 ester and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Pyrogen-free water; (17) Isotonic saline; ( 18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyester, polycarbonate and/or polyanhydride; and (22) other non-toxic solutions used in pharmaceutical preparations Compatible substances.
附图说明Description of drawings
图1为式(I)所示化合物的盐酸盐晶型A的差示扫描量热分析曲线图谱。Figure 1 is a differential scanning calorimetry analysis curve chart of the hydrochloride crystal form A of the compound represented by formula (I).
图2为式(I)所示化合物的盐酸盐晶型A的热重分析图谱。Figure 2 is a thermogravimetric analysis chart of the hydrochloride crystal form A of the compound represented by formula (I).
图3为式(I)所示化合物的盐酸盐晶型A的X-射线粉末衍射图谱。Figure 3 is an X-ray powder diffraction pattern of the hydrochloride crystal form A of the compound represented by formula (I).
图4为式(I)所示化合物的盐酸盐晶型B的差示扫描量热分析曲线图谱。Figure 4 is a differential scanning calorimetry analysis curve chart of the hydrochloride crystal form B of the compound represented by formula (I).
图5为式(I)所示化合物的盐酸盐晶型B的热重分析图谱。Figure 5 is a thermogravimetric analysis chart of the hydrochloride crystal form B of the compound represented by formula (I).
图6为式(I)所示化合物的盐酸盐晶型B的X-射线粉末衍射图谱。Figure 6 is an X-ray powder diffraction pattern of the hydrochloride crystal form B of the compound represented by formula (I).
图7为式(I)所示化合物的硫酸盐晶型A的差示扫描量热分析曲线图谱。Figure 7 is a differential scanning calorimetry analysis curve chart of the sulfate crystal form A of the compound represented by formula (I).
图8为式(I)所示化合物的硫酸盐晶型A的热重分析图谱。Figure 8 is a thermogravimetric analysis chart of the sulfate crystal form A of the compound represented by formula (I).
图9为式(I)所示化合物的硫酸盐晶型A的X-射线粉末衍射图谱。Figure 9 is an X-ray powder diffraction pattern of the sulfate crystal form A of the compound represented by formula (I).
图10为式(I)所示化合物的马来酸盐晶型A的差示扫描量热分析曲线图谱。Figure 10 is a differential scanning calorimetry analysis curve chart of the maleate salt crystal form A of the compound represented by formula (I).
图11为式(I)所示化合物的马来酸盐晶型A的热重分析图谱。Figure 11 is a thermogravimetric analysis chart of the maleate salt form A of the compound represented by formula (I).
图12为式(I)所示化合物的马来酸盐晶型A的X-射线粉末衍射图谱。Figure 12 is an X-ray powder diffraction pattern of the maleate salt crystal form A of the compound represented by formula (I).
图13为式(I)所示化合物的马来酸盐晶型B的差示扫描量热分析曲线图谱。Figure 13 is a differential scanning calorimetry analysis curve chart of the maleate salt crystal form B of the compound represented by formula (I).
图14为式(I)所示化合物的马来酸盐晶型B的热重分析图谱。Figure 14 is a thermogravimetric analysis chart of the maleate salt crystal form B of the compound represented by formula (I).
图15为式(I)所示化合物的来酸盐晶型B的X-射线粉末衍射图谱。Figure 15 is an X-ray powder diffraction pattern of the salt form B of the compound represented by formula (I).
图16为式(I)所示化合物的磷酸盐晶型A的差示扫描量热分析曲线图谱。Figure 16 is a differential scanning calorimetry analysis curve chart of the phosphate crystal form A of the compound represented by formula (I).
图17为式(I)所示化合物的磷酸盐晶型A的热重分析图谱。Figure 17 is a thermogravimetric analysis chart of the phosphate crystal form A of the compound represented by formula (I).
图18为式(I)所示化合物的磷酸盐晶型A的X-射线粉末衍射图谱。Figure 18 is an X-ray powder diffraction pattern of the phosphate crystal form A of the compound represented by formula (I).
图19为式(I)所示化合物的磷酸盐晶型B的差示扫描量热分析曲线图谱。Figure 19 is a differential scanning calorimetry analysis curve chart of the phosphate crystal form B of the compound represented by formula (I).
图20为式(I)所示化合物的磷酸盐晶型B的热重分析图谱。Figure 20 is a thermogravimetric analysis chart of the phosphate crystal form B of the compound represented by formula (I).
图21为式(I)所示化合物的磷酸盐晶型B的X-射线粉末衍射图谱。Figure 21 is an X-ray powder diffraction pattern of the phosphate crystal form B of the compound represented by formula (I).
图22为式(I)所示化合物的磷酸盐晶型C的差示扫描量热分析曲线图谱。 Figure 22 is a differential scanning calorimetry analysis curve chart of the phosphate crystal form C of the compound represented by formula (I).
图23为式(I)所示化合物的磷酸盐晶型C的热重分析图谱。Figure 23 is a thermogravimetric analysis chart of the phosphate crystal form C of the compound represented by formula (I).
图24为式(I)所示化合物的磷酸盐晶型C的X-射线粉末衍射图谱。Figure 24 is an X-ray powder diffraction pattern of the phosphate crystal form C of the compound represented by formula (I).
图25为式(I)所示化合物的酒石酸盐晶型A的差示扫描量热分析曲线图谱。Figure 25 is a differential scanning calorimetry analysis curve chart of the tartrate crystal form A of the compound represented by formula (I).
图26为式(I)所示化合物的酒石酸盐晶型A的热重分析图谱。Figure 26 is a thermogravimetric analysis chart of the tartrate crystal form A of the compound represented by formula (I).
图27为式(I)所示化合物的酒石酸盐晶型A的X-射线粉末衍射图谱。Figure 27 is an X-ray powder diffraction pattern of the tartrate crystal form A of the compound represented by formula (I).
图28为式(I)所示化合物的酒石酸盐晶型B的差示扫描量热分析曲线图谱。Figure 28 is a differential scanning calorimetry analysis curve chart of the tartrate crystal form B of the compound represented by formula (I).
图29为式(I)所示化合物的酒石酸盐晶型B的热重分析图谱。Figure 29 is a thermogravimetric analysis chart of the tartrate crystal form B of the compound represented by formula (I).
图30为式(I)所示化合物的酒石酸盐晶型B的X-射线粉末衍射图谱。Figure 30 is an X-ray powder diffraction pattern of the tartrate crystal form B of the compound represented by formula (I).
图31为式(I)所示化合物的酒石酸盐晶型C的差示扫描量热分析曲线图谱。Figure 31 is a differential scanning calorimetry analysis curve chart of the tartrate crystal form C of the compound represented by formula (I).
图32为式(I)所示化合物的酒石酸盐晶型C的热重分析图谱。Figure 32 is a thermogravimetric analysis chart of the tartrate crystal form C of the compound represented by formula (I).
图33为式(I)所示化合物的酒石酸盐晶型C的X-射线粉末衍射图谱。Figure 33 is an X-ray powder diffraction pattern of the tartrate crystal form C of the compound represented by formula (I).
图34为式(I)所示化合物的富马酸盐晶型A的差示扫描量热分析曲线图谱。Figure 34 is a differential scanning calorimetry analysis curve chart of the fumarate crystal form A of the compound represented by formula (I).
图35为式(I)所示化合物的富马酸盐晶型A的热重分析图谱。Figure 35 is a thermogravimetric analysis chart of fumarate crystal form A of the compound represented by formula (I).
图36为式(I)所示化合物的富马酸盐晶型A的X-射线粉末衍射图谱。Figure 36 is an X-ray powder diffraction pattern of the fumarate salt form A of the compound represented by formula (I).
图37为式(I)所示化合物的柠檬酸盐晶型A的差示扫描量热分析曲线图谱。Figure 37 is a differential scanning calorimetry analysis curve chart of the citrate crystal form A of the compound represented by formula (I).
图38为式(I)所示化合物的柠檬酸盐晶型A的热重分析图谱。Figure 38 is a thermogravimetric analysis chart of the citrate crystal form A of the compound represented by formula (I).
图39为式(I)所示化合物的柠檬酸盐晶型A的X-射线粉末衍射图谱。Figure 39 is an X-ray powder diffraction pattern of the citrate crystal form A of the compound represented by formula (I).
图40为式(I)所示化合物的萘二磺酸盐晶型A的差示扫描量热分析曲线图谱。Figure 40 is a differential scanning calorimetry analysis curve chart of the naphthalene disulfonate crystal form A of the compound represented by formula (I).
图41为式(I)所示化合物的萘二磺酸盐晶型A的热重分析图谱。Figure 41 is a thermogravimetric analysis chart of the naphthalene disulfonate crystal form A of the compound represented by formula (I).
图42为式(I)所示化合物的萘二磺酸盐晶型A的X-射线粉末衍射图谱。Figure 42 is an X-ray powder diffraction pattern of the naphthalene disulfonate crystal form A of the compound represented by formula (I).
图43为式(I)所示化合物的萘二磺酸盐晶型B的差示扫描量热分析曲线图谱。Figure 43 is a differential scanning calorimetry analysis curve chart of the naphthalene disulfonate crystal form B of the compound represented by formula (I).
图44为式(I)所示化合物的萘二磺酸盐晶型B的热重分析图谱。Figure 44 is a thermogravimetric analysis chart of the naphthalene disulfonate crystal form B of the compound represented by formula (I).
图45为式(I)所示化合物的萘二磺酸盐晶型B的X-射线粉末衍射图谱。Figure 45 is an X-ray powder diffraction pattern of the naphthalene disulfonate crystal form B of the compound represented by formula (I).
图46为式(I)所示化合物的萘二磺酸盐晶型C的差示扫描量热分析曲线图谱。Figure 46 is a differential scanning calorimetry analysis curve diagram of the naphthalene disulfonate crystal form C of the compound represented by formula (I).
图47为式(I)所示化合物的萘二磺酸盐晶型C的热重分析图谱。Figure 47 is a thermogravimetric analysis chart of the naphthalene disulfonate crystal form C of the compound represented by formula (I).
图48为式(I)所示化合物的萘二磺酸盐晶型C的X-射线粉末衍射图谱。Figure 48 is an X-ray powder diffraction pattern of the naphthalene disulfonate crystal form C of the compound represented by formula (I).
图49为式(I)所示化合物的对甲苯磺酸盐晶型A的差示扫描量热分析曲线图谱。Figure 49 is a differential scanning calorimetry analysis curve chart of the p-toluenesulfonate crystal form A of the compound represented by formula (I).
图50为式(I)所示化合物的对甲苯磺酸盐晶型A的热重分析图谱。Figure 50 is a thermogravimetric analysis chart of the p-toluenesulfonate crystal form A of the compound represented by formula (I).
图51为式(I)所示化合物的对甲苯磺酸盐晶型A的X-射线粉末衍射图谱。Figure 51 is an X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A of the compound represented by formula (I).
图52为式(I)所示化合物的对甲苯磺酸盐晶型B的差示扫描量热分析曲线图谱。Figure 52 is a differential scanning calorimetry analysis curve chart of the p-toluenesulfonate crystal form B of the compound represented by formula (I).
图53为式(I)所示化合物的对甲苯磺酸盐晶型B的热重分析图谱。Figure 53 is a thermogravimetric analysis chart of the p-toluenesulfonate crystal form B of the compound represented by formula (I).
图54为式(I)所示化合物的对甲苯磺酸盐晶型B的X-射线粉末衍射图谱。Figure 54 is an X-ray powder diffraction pattern of the p-toluenesulfonate crystal form B of the compound represented by formula (I).
图55为式(I)所示化合物的对甲苯磺酸盐晶型C的差示扫描量热分析曲线图谱。Figure 55 is a differential scanning calorimetry analysis curve chart of the p-toluenesulfonate crystal form C of the compound represented by formula (I).
图56为式(I)所示化合物的对甲苯磺酸盐晶型C的热重分析图谱。Figure 56 is a thermogravimetric analysis chart of the p-toluenesulfonate crystal form C of the compound represented by formula (I).
图57为式(I)所示化合物的对甲苯磺酸盐晶型C的X-射线粉末衍射图谱。Figure 57 is an X-ray powder diffraction pattern of the p-toluenesulfonate crystal form C of the compound represented by formula (I).
图58为式(I)所示化合物的对甲苯磺酸盐晶型D的差示扫描量热分析曲线图谱。Figure 58 is a differential scanning calorimetry curve chart of the p-toluenesulfonate crystal form D of the compound represented by formula (I).
图59为式(I)所示化合物的对甲苯磺酸盐晶型D的热重分析图谱。Figure 59 is a thermogravimetric analysis chart of the p-toluenesulfonate crystal form D of the compound represented by formula (I).
图60为式(I)所示化合物的对甲苯磺酸盐晶型D的X-射线粉末衍射图谱。Figure 60 is an X-ray powder diffraction pattern of the p-toluenesulfonate crystal form D of the compound represented by formula (I).
图61为式(I)所示化合物的甲磺酸盐晶型A的差示扫描量热分析曲线图谱。 Figure 61 is a differential scanning calorimetry analysis curve chart of the mesylate crystal form A of the compound represented by formula (I).
图62为式(I)所示化合物的甲磺酸盐晶型A的热重分析图谱。Figure 62 is a thermogravimetric analysis chart of the mesylate crystal form A of the compound represented by formula (I).
图63为式(I)所示化合物的甲磺酸盐晶型A的X-射线粉末衍射图谱。Figure 63 is an X-ray powder diffraction pattern of the mesylate crystal form A of the compound represented by formula (I).
图64为式(I)所示化合物的甲磺酸盐晶型B的差示扫描量热分析曲线图谱。Figure 64 is a differential scanning calorimetry analysis curve chart of the mesylate crystal form B of the compound represented by formula (I).
图65为式(I)所示化合物的甲磺酸盐晶型B的热重分析图谱。Figure 65 is a thermogravimetric analysis chart of the mesylate crystal form B of the compound represented by formula (I).
图66为式(I)所示化合物的甲磺酸盐晶型B的X-射线粉末衍射图谱。Figure 66 is an X-ray powder diffraction pattern of the mesylate crystal form B of the compound represented by formula (I).
图67为式(I)所示化合物的甲磺酸盐晶型C的差示扫描量热分析曲线图谱。Figure 67 is a differential scanning calorimetry analysis curve chart of the mesylate crystal form C of the compound represented by formula (I).
图68为式(I)所示化合物的甲磺酸盐晶型C的热重分析图谱。Figure 68 is a thermogravimetric analysis chart of the mesylate crystal form C of the compound represented by formula (I).
图69为式(I)所示化合物的甲磺酸盐晶型C的X-射线粉末衍射图谱。Figure 69 is an X-ray powder diffraction pattern of the mesylate crystal form C of the compound represented by formula (I).
图70为式(I)所示化合物的甲磺酸盐晶型D的差示扫描量热分析曲线图谱。Figure 70 is a differential scanning calorimetry analysis curve chart of the mesylate crystal form D of the compound represented by formula (I).
图71为式(I)所示化合物的甲磺酸盐晶型D的热重分析图谱。Figure 71 is a thermogravimetric analysis chart of the mesylate crystal form D of the compound represented by formula (I).
图72为式(I)所示化合物的甲磺酸盐晶型D的X-射线粉末衍射图谱。Figure 72 is an X-ray powder diffraction pattern of the mesylate crystal form D of the compound represented by formula (I).
图73为式(I)所示化合物的苯磺酸盐晶型A的差示扫描量热分析曲线图谱。Figure 73 is a differential scanning calorimetry analysis curve chart of the benzene sulfonate crystal form A of the compound represented by formula (I).
图74为式(I)所示化合物的苯磺酸盐晶型A的热重分析图谱。Figure 74 is a thermogravimetric analysis chart of the benzene sulfonate crystal form A of the compound represented by formula (I).
图75为式(I)所示化合物的苯磺酸盐晶型A的X-射线粉末衍射图谱。Figure 75 is an X-ray powder diffraction pattern of the benzene sulfonate crystal form A of the compound represented by formula (I).
图76为式(I)所示化合物的苯磺酸晶型B的差示扫描量热分析曲线图谱。Figure 76 is a differential scanning calorimetry analysis curve chart of benzene sulfonic acid crystal form B of the compound represented by formula (I).
图77为式(I)所示化合物的苯磺酸晶型B的热重分析图谱。Figure 77 is a thermogravimetric analysis spectrum of benzene sulfonic acid crystal form B of the compound represented by formula (I).
图78为式(I)所示化合物的苯磺酸晶型B的X-射线粉末衍射图谱。Figure 78 is an X-ray powder diffraction pattern of benzene sulfonic acid crystal form B of the compound represented by formula (I).
图79为式(I)所示化合物的苯磺酸晶型C的差示扫描量热分析曲线图谱。Figure 79 is a differential scanning calorimetry analysis curve chart of benzene sulfonic acid crystal form C of the compound represented by formula (I).
图80为式(I)所示化合物的苯磺酸晶型C的热重分析图谱。Figure 80 is a thermogravimetric analysis chart of benzene sulfonic acid crystal form C of the compound represented by formula (I).
图81为式(I)所示化合物的苯磺酸晶型C的X-射线粉末衍射图谱。Figure 81 is an X-ray powder diffraction pattern of benzene sulfonic acid crystal form C of the compound represented by formula (I).
图82为式(I)所示化合物的草酸盐晶型A的差示扫描量热分析曲线图谱。Figure 82 is a differential scanning calorimetry analysis curve chart of the oxalate crystal form A of the compound represented by formula (I).
图83为式(I)所示化合物的草酸盐晶型A的热重分析图谱。Figure 83 is a thermogravimetric analysis chart of the oxalate crystal form A of the compound represented by formula (I).
图84为式(I)所示化合物的草酸盐晶型A的X-射线粉末衍射图谱。Figure 84 is an X-ray powder diffraction pattern of the oxalate crystal form A of the compound represented by formula (I).
图85为式(I)所示化合物的草酸盐晶型B的差示扫描量热分析曲线图谱。Figure 85 is a differential scanning calorimetry analysis curve chart of the oxalate crystal form B of the compound represented by formula (I).
图86为式(I)所示化合物的草酸盐晶型B的热重分析图谱。Figure 86 is a thermogravimetric analysis chart of the oxalate crystal form B of the compound represented by formula (I).
图87为式(I)所示化合物的草酸盐晶型B的X-射线粉末衍射图谱。Figure 87 is an X-ray powder diffraction pattern of the oxalate crystal form B of the compound represented by formula (I).
图88为式(I)所示化合物的龙胆酸盐晶型A的差示扫描量热分析曲线图谱。Figure 88 is a differential scanning calorimetry analysis curve chart of the gentisate crystal form A of the compound represented by formula (I).
图89为式(I)所示化合物的龙胆酸盐晶型A的热重分析图谱。Figure 89 is a thermogravimetric analysis chart of gentisate crystal form A of the compound represented by formula (I).
图90为式(I)所示化合物的龙胆酸盐晶型A的X-射线粉末衍射图谱。Figure 90 is an X-ray powder diffraction pattern of the gentisate crystal form A of the compound represented by formula (I).
图91为式(I)所示化合物的龙胆酸盐晶型B的差示扫描量热分析曲线图谱。Figure 91 is a differential scanning calorimetry analysis curve chart of the gentisate crystal form B of the compound represented by formula (I).
图92为式(I)所示化合物的龙胆酸盐晶型B的热重分析图谱。Figure 92 is a thermogravimetric analysis chart of gentisate crystal form B of the compound represented by formula (I).
图93为式(I)所示化合物的龙胆酸盐晶型B的X-射线粉末衍射图谱。Figure 93 is an X-ray powder diffraction pattern of the gentisate crystal form B of the compound represented by formula (I).
图94为式(I)所示化合物的氢溴酸盐晶型A的差示扫描量热分析曲线图谱。Figure 94 is a differential scanning calorimetry analysis curve chart of the hydrobromide salt form A of the compound represented by formula (I).
图95为式(I)所示化合物的氢溴酸盐晶型A的热重分析图谱。Figure 95 is a thermogravimetric analysis chart of the hydrobromide crystal form A of the compound represented by formula (I).
图96为式(I)所示化合物的氢溴酸盐晶型A的X-射线粉末衍射图谱。Figure 96 is an X-ray powder diffraction pattern of the hydrobromide crystal form A of the compound represented by formula (I).
图97为式(I)所示化合物的氢溴酸盐晶型B的差示扫描量热分析曲线图谱。Figure 97 is a differential scanning calorimetry analysis curve chart of the hydrobromide crystal form B of the compound represented by formula (I).
图98为式(I)所示化合物的氢溴酸盐晶型B的热重分析图谱。Figure 98 is a thermogravimetric analysis chart of the hydrobromide crystal form B of the compound represented by formula (I).
图99为式(I)所示化合物的氢溴酸盐晶型B的X-射线粉末衍射图谱。Figure 99 is an X-ray powder diffraction pattern of the hydrobromide salt form B of the compound represented by formula (I).
图100为式(I)所示化合物的氢溴酸盐晶型C的差示扫描量热分析曲线图谱。 Figure 100 is a differential scanning calorimetry analysis curve chart of the hydrobromide salt crystal form C of the compound represented by formula (I).
图101为式(I)所示化合物的氢溴酸盐晶型C的热重分析图谱。Figure 101 is a thermogravimetric analysis chart of the hydrobromide crystal form C of the compound represented by formula (I).
图102为式(I)所示化合物的氢溴酸盐晶型C的X-射线粉末衍射图谱。Figure 102 is an X-ray powder diffraction pattern of the hydrobromide salt form C of the compound represented by formula (I).
图103为式(I)所示化合物的氢溴酸盐晶型D的差示扫描量热分析曲线图谱。Figure 103 is a differential scanning calorimetry analysis curve chart of the hydrobromide crystal form D of the compound represented by formula (I).
图104为式(I)所示化合物的氢溴酸盐晶型D的热重分析图谱。Figure 104 is a thermogravimetric analysis chart of the hydrobromide crystal form D of the compound represented by formula (I).
图105为式(I)所示化合物的氢溴酸盐晶型D的X-射线粉末衍射图谱。Figure 105 is an X-ray powder diffraction pattern of the hydrobromide crystal form D of the compound represented by formula (I).
图106为小鼠MDA-MB-436皮下体内移植瘤模型的肿瘤生长曲线。Figure 106 shows the tumor growth curve of the mouse MDA-MB-436 subcutaneous in vivo transplanted tumor model.
图107为小鼠MDA-MB-436皮下体内移植瘤模型的动物体重变化曲线。Figure 107 is the animal body weight change curve of the mouse MDA-MB-436 subcutaneous in vivo transplanted tumor model.
具体实施方式Detailed ways
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The technical solution of the present invention will be described in detail below with reference to the accompanying drawings and examples, but the protection scope of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) 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).
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的测定使用LC-20AT(岛津)高压液相色谱仪(Kromasil 100-5-C18,4.6mm×250mm)。HPLC measurement used LC-20AT (Shimadzu) high-pressure liquid chromatograph (Kromasil 100-5-C18, 4.6mm×250mm).
XRD的测定使用X射线粉末衍射仪Bruker D8Advance Diffractometer进行分析。按照如下表方法进行X-射线粉末衍射测试。XRD was measured using an X-ray powder diffractometer Bruker D8Advance Diffractometer. Carry out X-ray powder diffraction test according to the method in the table below.
表1 XRD测试参数
Table 1 XRD test parameters
TGA和DSC图分别在TA 5500热重分析仪和TA 2500差示扫描量热仪上采集，测试参数如下表所示。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.
表2 DSC和TGA测试参数

Table 2 DSC and TGA test parameters

本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。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.
实施例中无特殊说明，溶液是指水溶液。There is no special explanation in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，室温为20℃～30℃。There are no special instructions in the examples, and the room temperature is 20°C to 30°C.
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。The implementation process and beneficial effects of the present invention are described in detail below through specific examples, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the implementable scope of the present invention.
实施例1：化合物I的制备
Example 1: Preparation of Compound I
第一步：first step:
将6-甲基-5-硝基烟酸乙酯(10g，47.6mmol)和二氧化硒(21.14g，190.5mmol)溶于1,4-二氧六环(100ml)中，100℃回流过夜，反应结束后用垫有硅藻土的漏斗过滤，用乙酸乙酯洗涤硅藻土，滤液浓缩，所得残留物硅胶柱色谱分离纯化(洗脱剂比例：乙酸乙酯:石油醚(v/v)＝0％～40％)，得化合物1A(10.104g，94.7％)，黄色油状物。Dissolve 6-methyl-5-nitronicotinate ethyl ester (10g, 47.6mmol) and selenium dioxide (21.14g, 190.5mmol) in 1,4-dioxane (100ml), reflux at 100°C overnight , after the reaction is completed, filter with a funnel padded with diatomaceous earth, wash the diatomaceous earth with ethyl acetate, the filtrate is concentrated, and the obtained residue is separated and purified by silica gel column chromatography (eluent ratio: ethyl acetate:petroleum ether (v/v) )=0%~40%), compound 1A (10.104g, 94.7%) was obtained as a yellow oil.
LCMS(ESI)m/z＝225.1[M+1]+ LCMS(ESI)m/z＝225.1[M+1] +
第二步：Step two:
将氢化钠(2.695g，112.3mmol)溶于无水四氢呋喃(100ml)中，0℃搅拌，滴加三乙基2-丁基丙烯酯(28.3g，112.3mmol)，滴加完成后保持0℃搅拌20min，升温至40℃搅拌10min，转移至干冰乙醇浴中，将化合物1A(10.48g，46.8mmol)溶于无水四氢呋喃(100ml)中，滴加入反应瓶中，保持干冰乙醇浴，搅拌1h，反应完成后加入饱和氯化铵溶液(100ml)淬灭，加入乙酸乙酯(200ml)萃取，分离有机相，水相用乙酸乙酯(200ml×2)萃取，合并有机相，无水硫酸钠干燥，浓缩，所得残留物硅胶柱色 谱纯化(洗脱剂比例：乙酸乙酯:石油醚(v/v)＝0～10％)，得化合物1B(11.57g，76.8％)，两种异构体的混合物，黄色油状物。Dissolve sodium hydride (2.695g, 112.3mmol) in anhydrous tetrahydrofuran (100ml), stir at 0°C, add triethyl 2-butylpropenyl ester (28.3g, 112.3mmol) dropwise, and keep at 0°C after the dropwise addition is completed. Stir for 20 minutes, raise the temperature to 40°C, stir for 10 minutes, transfer to a dry ice ethanol bath, dissolve compound 1A (10.48g, 46.8mmol) in anhydrous tetrahydrofuran (100ml), add dropwise to the reaction bottle, keep the dry ice ethanol bath, and stir for 1 hour , after the reaction is completed, add saturated ammonium chloride solution (100ml) to quench, add ethyl acetate (200ml) for extraction, separate the organic phase, extract the aqueous phase with ethyl acetate (200ml×2), combine the organic phases, and add anhydrous sodium sulfate Dry, concentrate and color the residue on silica gel. After spectral purification (eluent ratio: ethyl acetate: petroleum ether (v/v) = 0-10%), compound 1B (11.57g, 76.8%) was obtained, a mixture of two isomers, as a yellow oil.
LC-MS(ESI)m/z＝323.1[M+1]+ LC-MS(ESI)m/z＝323.1[M+1] +
第三步：third step:
将化合物1B(11.57g，35.9mmol)溶于乙醇(50ml)中，加入10％钯碳催化剂(1g)，氢气置换三次，室温搅拌过夜，用垫有硅藻土的漏斗过滤，用无水乙醇洗涤硅藻土，滤液浓缩，所得残留物中加入4M盐酸-二氧六环溶液(60ml)，室温搅拌1h，浓缩，所得残留物中加入乙酸乙酯(50ml)，搅拌，过滤，滤饼用乙酸乙酯洗涤，干燥，得化合物1C(4.28g，42.0％)，白色固体。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.
1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.62(d,1H),7.75(s,1H),4.38–4.29(m,2H),3.24(dd,1H),2.97(dd,1H),2.62–2.53(m,1H),1.83–1.64(m,1H),1.55–1.35(m,1H),1.33(dd,3H),0.94(t,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.39(s,1H),8.62(d,1H),7.75(s,1H),4.38–4.29(m,2H),3.24(dd,1H), 2.97(dd,1H),2.62–2.53(m,1H),1.83–1.64(m,1H),1.55–1.35(m,1H),1.33(dd,3H),0.94(t,3H).
第四步：the fourth step:
将化合物1C(4.28g，17.3mmol)和2,3-二氯-5,6-二氰基苯醌(4.309g，19.0mmol)溶于二氧六环(86ml)中，100℃回流反应3.5h，反应结束后加入饱和碳酸氢钠溶液(40ml)和乙酸乙酯(120ml)，分离有机相，水相用乙酸乙酯(120ml×2)萃取，合并有机相，无水硫酸钠干燥，浓缩，所得残留物硅胶柱色谱纯化(洗脱剂比例：乙酸乙酯:石油醚＝0～50％)，得化合物1D(3.375g，79.5％)，淡黄色固体。Compound 1C (4.28g, 17.3mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (4.309g, 19.0mmol) were dissolved in dioxane (86ml), and the reaction was refluxed at 100°C for 3.5 h, after the reaction is completed, add saturated sodium bicarbonate solution (40ml) and ethyl acetate (120ml), separate the organic phase, extract the aqueous phase with ethyl acetate (120ml×2), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate The obtained residue was purified by silica gel column chromatography (eluent ratio: ethyl acetate: petroleum ether = 0-50%) to obtain compound 1D (3.375g, 79.5%), a light yellow solid.
LC-MS(ESI)m/z＝247.1[M+1]+ LC-MS(ESI)m/z＝247.1[M+1] +
第五步：the fifth step:
将化合物1D(3.375g，13.72mmol)溶于无水四氢呋喃(150ml)中，-78℃搅拌。分批加入氢化锂铝(1.564g，41.16mmol)，-78℃搅拌20min，升温至-40℃，搅拌20min，反应结束后，加入1M盐酸，调节体系pH至中性，减压蒸馏除去溶剂，所得残留物中加入甲醇/二氯甲烷(1:10)100ml，溶解残留物，超声震荡10min，过滤，收集滤液，滤饼重新用甲醇/二氯甲烷(1:10)100ml溶解，重复这一过程8次，合并滤液，浓缩，得化合物1E(2.8g，100％)，淡黄色固体。Compound 1D (3.375g, 13.72mmol) was dissolved in anhydrous tetrahydrofuran (150ml) and stirred at -78°C. Add lithium aluminum hydride (1.564g, 41.16mmol) in batches, stir at -78°C for 20 minutes, raise the temperature to -40°C, and stir for 20 minutes. After the reaction is completed, add 1M hydrochloric acid to adjust the pH of the system to neutral, and distill the solvent under reduced pressure. Add 100ml of methanol/dichloromethane (1:10) to the obtained residue to dissolve the residue, shake with ultrasonic for 10 minutes, filter, collect the filtrate, and dissolve the filter cake again with 100ml of methanol/dichloromethane (1:10), repeat this process The process was repeated 8 times, the filtrate was combined and concentrated to obtain compound 1E (2.8g, 100%) as a light yellow solid.
1H NMR(400MHz,DMSO)δ11.86(s,1H),8.37(d,1H),7.72(d,1H),7.62(d,1H),5.44(t,1H),4.61(d,2H),2.57–2.51(m,2H),1.18(t,3H). 1 H NMR (400MHz, DMSO) δ11.86(s,1H),8.37(d,1H),7.72(d,1H),7.62(d,1H),5.44(t,1H),4.61(d,2H ),2.57–2.51(m,2H),1.18(t,3H).
第六步：Step 6:
将1E(100mg,0.49mmol)加入到二氯甲烷(2.5mL)中，加入DMF(1mL)助溶，在0℃下滴加氯化亚砜(350mg,2.94mmol)，室温下反应1小时，LCMS检测原料反应完全，有产物生成，直接旋干得化合物1F(109mg,粗品)用于下一步反应Add 1E (100mg, 0.49mmol) to dichloromethane (2.5mL), add DMF (1mL) to help dissolve, add thionyl chloride (350mg, 2.94mmol) dropwise at 0°C, and react at room temperature for 1 hour. LCMS detects that the reaction of the raw materials is complete and product is generated. Compound 1F (109 mg, crude product) is directly spin-dried and used for the next reaction.
LC-MS(ESI):m/z＝223.1、225.1[M+H]+ LC-MS(ESI):m/z＝223.1, 225.1[M+H] +
第七步：Step 7:
将5-溴吡啶-2-羧酸甲酯(2.16g,10mmol),N-Boc-哌嗪(2.03g,11mmol)溶解到1,4-二氧六环(100mL)中,加入Cs2CO3(6.5g,20mmol)和RuPhos-Pd-G3(253mg,0.3mmol),氮气保护下100℃反应过夜，LCMS检测反应完全后停止反应，冷却至室温，过滤收集滤液，滤渣用乙酸乙酯洗涤(20mL×3)，浓缩滤液，加入少量无水乙醇，加热溶解，再加入大量石油醚，冷却后收集析出的晶体，得到化合物2(2.37g，73.4％)为淡黄色固体。Dissolve 5-bromopyridine-2-carboxylic acid methyl ester (2.16g, 10mmol) and N-Boc-piperazine (2.03g, 11mmol) into 1,4-dioxane (100mL), add Cs2CO3 (6.5 g, 20mmol) and RuPhos-Pd-G3 (253mg, 0.3mmol), react overnight at 100°C under nitrogen protection. Stop the reaction after LCMS detects that the reaction is complete, cool to room temperature, collect the filtrate by filtration, and wash the filter residue with ethyl acetate (20mL× 3) Concentrate the filtrate, add a small amount of absolute ethanol, heat to dissolve, then add a large amount of petroleum ether, collect the precipitated crystals after cooling, and obtain compound 2 (2.37g, 73.4%) as a light yellow solid.
LC-MS(ESI):m/z＝321.1[M+H]+.LC-MS(ESI): m/z=321.1[M+H] + .
第八步：Step 8:
将化合物2(400mg,1.24mmol)溶解到THF(10mL)和H2O(1mL)中，加入LiOH(30mg,1.24 mmol)，室温下搅拌反应2h，减压蒸馏除去溶剂，加水稀释，用乙酸乙酯(20mL×3)萃取,合并有机相，使用无水Na2SO4干燥,过滤旋干,向所得固体中加入DMF(10mL),搅拌下加入HATU(565mg,1.49mmol),室温搅拌，待固体完全溶解，加入DIEPA(2mL)，最后加入过量环丙胺，室温下搅拌过夜，LCMS监测反应完全后向体系中加入50mL乙酸乙酯，水洗(50mL×4)，收集有机相，无水硫酸钠干燥，过滤蒸干，使用硅胶色谱柱分离(PE:EA(v/v)＝1:0～1:1)得到化合物3(309mg，71.5％)为淡黄色固体。Compound 2 (400 mg, 1.24 mmol) was dissolved in THF (10 mL) and H2O (1 mL), and LiOH (30 mg, 1.24 mmol), stir the reaction at room temperature for 2 hours, evaporate the solvent under reduced pressure, dilute with water, extract with ethyl acetate (20mL×3), combine the organic phases, dry over anhydrous Na2SO4, filter and spin dry, add DMF ( 10mL), add HATU (565mg, 1.49mmol) under stirring, stir at room temperature, until the solid is completely dissolved, add DIEPA (2mL), finally add excess cyclopropylamine, stir at room temperature overnight, LCMS monitors that the reaction is complete, then add 50mL acetic acid to the system ethyl ester, washed with water (50 mL (309 mg, 71.5%) was a light yellow solid.
LC-MS(ESI):m/z＝347.2[M+H]+.LC-MS(ESI): m/z=347.2[M+H] + .
第九步：Step 9:
将3(309mg,0.89mmol)溶解于甲醇(5mL)中，加入盐酸二氧六环(5mL,4M)溶液，室温下反应两个小时，旋干得到化合物4(200mg,粗品).Dissolve 3 (309 mg, 0.89 mmol) in methanol (5 mL), add dioxane hydrochloride (5 mL, 4M) solution, react at room temperature for two hours, and spin to dryness to obtain compound 4 (200 mg, crude product).
LC-MS(ESI):m/z＝247.1[M+H]+.LC-MS(ESI): m/z=247.1[M+H] + .
第十步：Step 10:
将1F(100mg，0.44mmol)、化合物4(200mg,0.81mmol)溶解于无水乙腈(10mL)中，加入碘化钾(8mg,0.05mmol)和DIPEA(0.5mL)，经氮气置换后，于80℃下反应8小时，LCMS检测原料反应完全，有产物生成，将体系浓缩，加入碳酸氢钠饱和溶液(20mL)，使用DCM:MeOH(v/v)＝10:1的混合溶液(10mL×3)萃取，合并有机相，使用无水硫酸钠干燥，浓缩后过柱(DCM:MeOH(v/v)＝1:0～10:1)得到化合物I(76mg，38.1％)。Dissolve 1F (100 mg, 0.44 mmol) and compound 4 (200 mg, 0.81 mmol) in anhydrous acetonitrile (10 mL), add potassium iodide (8 mg, 0.05 mmol) and DIPEA (0.5 mL), and replace with nitrogen at 80°C. The reaction was carried out for 8 hours. LCMS detected that the reaction of the raw materials was complete and product was generated. The system was concentrated, saturated sodium bicarbonate solution (20 mL) was added, and a mixed solution of DCM:MeOH (v/v) = 10:1 (10 mL × 3) was used. Extract, combine the organic phases, dry with anhydrous sodium sulfate, concentrate and pass through column (DCM:MeOH (v/v) = 1:0 to 10:1) to obtain compound I (76 mg, 38.1%).
1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.40(d,1H),8.32(d,1H),8.23(d,1H),7.83(d,1H),7.75(s,1H),7.63(d,1H),7.39(dd,1H),3.65(s,2H),3.35–3.31(m,4H,overlapped with solvent DMSO peak),2.90–2.80(m,1H),2.59–2.52(m,6H,overlapped with solvent DMSO peak),1.19(t,3H),0.66(dd,2H),0.63(q,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.84(s,1H),8.40(d,1H),8.32(d,1H),8.23(d,1H),7.83(d,1H),7.75( s,1H),7.63(d,1H),7.39(dd,1H),3.65(s,2H),3.35–3.31(m,4H,overlapped with solvent DMSO peak),2.90–2.80(m,1H), 2.59–2.52(m,6H,overlapped with solvent DMSO peak),1.19(t,3H),0.66(dd,2H),0.63(q,2H).
LC-MS(ESI):m/z＝433.2[M+H]+.
LC-MS(ESI): m/z=433.2[M+H] + .
晶型制备Crystal preparation
实施例2：盐酸盐晶型A制备Example 2: Preparation of hydrochloride crystal form A
取50mg游离碱起始样品与等摩尔比的盐酸在1mL MeOH中室温下搅拌2天过滤烘干得到固体。化合物I的盐酸盐晶型A的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图1-3所示。Take 50 mg free base starting sample and hydrochloric acid in an equal molar ratio in 1 mL MeOH and stir at room temperature for 2 days. Filter and dry to obtain a solid. The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of compound I hydrochloride crystal form A are shown in Figures 1-3.
实施例3：盐酸盐晶型B制备Example 3: Preparation of Hydrochloride Crystal Form B
取50mg游离碱起始样品与等摩尔比的盐酸在1mL CHCl3中室温下搅拌2天过滤烘干得到固体。 化合物I的盐酸盐晶型B的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图4-6所示。Take 50 mg free base starting sample and hydrochloric acid in an equal molar ratio in 1 mL CHCl 3 and stir at room temperature for 2 days. Filter and dry to obtain a solid. The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of compound I hydrochloride crystal form B are shown in Figures 4-6.
实施例4：硫酸盐晶型A制备Example 4: Preparation of sulfate crystal form A
取50mg游离碱起始样品与等摩尔比的硫酸在1mL MeOH中室温下搅拌2天过滤烘干得到固体。化合物I的硫酸盐晶型A的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图7-9所示。Take 50 mg free base starting sample and sulfuric acid in an equal molar ratio in 1 mL MeOH and stir at room temperature for 2 days. Filter and dry to obtain a solid. The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of the sulfate crystal form A of Compound I are shown in Figures 7-9.
实施例5：马来酸盐晶型A制备Example 5: Preparation of Maleate Crystal Form A
游离碱起始样品与等摩尔比的马来酸在1mL MeOH室温下搅拌2天过滤烘干得到固体。The starting sample of free base and maleic acid in an equal molar ratio were stirred with 1 mL MeOH at room temperature for 2 days, filtered and dried to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,MeOD)δ8.54(s,1H),8.29(s,1H),7.94(s,1H),7.86(s,1H),7.82(s,1H),7.40(s,1H),6.28(s,2H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, MeOD) δ8.54(s,1H),8.29(s,1H),7.94(s,1H),7.86(s,1H),7.82 (s,1H),7.40(s,1H),6.28(s,2H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,MeOD)的峰位移解析，化合物I的化学位移7.40(s,1H)为26号位置的-CH峰，6.28(s,2H)的峰为马来酸的-CH峰，其比例为1:2，故可解析得到化合物I与马来酸的比例为1:1。More specifically, through the peak shift analysis of 1 H NMR (400MHz, MeOD), 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.
化合物I的马来酸盐晶型A的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图10-12所示。The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of the maleate crystal form A of Compound I are shown in Figures 10-12.
实施例6：马来酸盐晶型B制备Example 6: Preparation of Maleate Crystal Form B
取50mg游离碱起始样品与等摩尔比的马来酸在1mL THF中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and equal molar ratio of maleic acid in 1 mL THF and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,MeOD)δ8.55(s,1H),8.30(s,1H),7.95(s,1H),7.86(s,2H),7.41(s,1H),6.28(s,2H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, MeOD) δ8.55 (s, 1H), 8.30 (s, 1H), 7.95 (s, 1H), 7.86 (s, 2H), 7.41 (s,1H),6.28(s,2H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,MeOD)的峰位移解析，化合物I的化学位移7.41(s,1H)为26号位置的-CH峰，6.28(s,2H)的峰为马来酸的-CH峰，其比例为1:2，故可解析得到化合物I与马来酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, MeOD), 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.
化合物I的马来酸盐晶型B的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图13-15所示。具体峰值如表3所示。The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of the maleate crystal form B of Compound I are shown in Figures 13-15. The specific peak values are shown in Table 3.
表3

table 3

实施例7：磷酸盐晶型A制备Example 7: Preparation of Phosphate Crystal Form A
取50mg游离碱起始样品与等摩尔比的磷酸在1mL MeOH中室温下搅拌2天过滤烘干得到固体。化合物I的磷酸盐晶型A的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图16-18所示。Take 50 mg free base starting sample and equimolar ratio of phosphoric acid in 1 mL MeOH and stir at room temperature for 2 days. Filter and dry to obtain a solid. The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of the phosphate crystal form A of Compound I are shown in Figures 16-18.
实施例8：磷酸盐晶型B制备Example 8: Preparation of Phosphate Crystal Form B
取50mg游离碱起始样品与等摩尔比的磷酸在1mL Acetone/H2O(9:1,v/v)中室温下搅拌2天过滤烘干得到固体。化合物I的磷酸盐晶型B的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图19-21所示。Take 50 mg free base starting sample and equimolar ratio of phosphoric acid in 1 mL Acetone/H 2 O (9:1, v/v) and stir at room temperature for 2 days. Filter and dry to obtain a solid. The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of the phosphate crystal form B of Compound I are shown in Figures 19-21.
实施例9：磷酸盐晶型C制备Example 9: Preparation of Phosphate Crystal Form C
取50mg游离碱起始样品与等摩尔比的磷酸在1mL THF中室温下搅拌2天过滤烘干得到固体。化合物I的磷酸盐晶型C的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图22-24所示。具体峰值如表4所示。Take 50 mg free base starting sample and equimolar ratio of phosphoric acid in 1 mL THF and stir at room temperature for 2 days. Filter and dry to obtain a solid. The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of the phosphate crystal form C of Compound I are shown in Figures 22-24. The specific peak values are shown in Table 4.
表4

Table 4

实施例10：酒石酸盐晶型A制备Example 10: Preparation of Tartrate Crystal Form A
取50mg游离碱起始样品与等摩尔比的酒石酸在1mL MeOH中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and equal molar ratio of tartaric acid in 1 mL MeOH and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.41(s,1H),8.36(s,1H),8.23(s,1H),7.84(s,1H),7.81(s,1H),7.76(s,1H),7.62(s,1H),7.39(s,1H),4.29(s,2H),3.66(s,2H),1.18(s,3H),0.67(s,1H),0.62(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ11.88(s,1H),8.41(s,1H),8.36(s,1H),8.23(s,1H) ),7.84(s,1H),7.81(s,1H),7.76(s,1H),7.62(s,1H),7.39(s,1H),4.29(s,2H),3.66(s,2H) ,1.18(s,3H),0.67(s,1H),0.62(s,1H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.39(s,1H)为26号位置的-CH峰，4.29(s,2H)的峰为酒石酸的-CH峰，其比例为1:2，故可解析得到化合物I与酒石酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.39 (s, 1H), which is the -CH peak at position 26, and the peak at 4.29 (s, 2H) is The -CH peak of tartaric acid has a ratio of 1:2, so it can be analyzed that the ratio of compound I to tartaric acid is 1:1.
化合物I的酒石酸盐晶型A的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图25-27所示。The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of the tartrate crystal form A of Compound I are shown in Figures 25-27.
实施例11：酒石酸盐晶型B制备Example 11: Preparation of Tartrate Crystal Form B
由游离碱起始样品与等摩尔比的酒石酸在1mL Acetone/H2O(9:1,v/v)中室温下搅拌2天过滤烘干得到固体。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.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.41(s,1H),8.36(s,1H),8.23(s,1H),7.84(s,1H),7.81(s,1H),7.76(s,1H),7.62(s,1H),7.41(s,1H),4.28(s,2H),3.66(s,2H),1.18(s,3H),0.61(s,4H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ11.88(s,1H),8.41(s,1H),8.36(s,1H),8.23(s,1H) ),7.84(s,1H),7.81(s,1H),7.76(s,1H),7.62(s,1H),7.41(s,1H),4.28(s,2H),3.66(s,2H) ,1.18(s,3H),0.61(s,4H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.41(s,1H)为26号位置的-CH峰，4.28(s,2H)的峰为酒石酸的-CH峰，其比例为1:2，故可解析得到化合物I与酒石酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.41 (s, 1H), which is the -CH peak at position 26, and the peak at 4.28 (s, 2H) is The -CH peak of tartaric acid has a ratio of 1:2, so it can be analyzed that the ratio of compound I to tartaric acid is 1:1.
化合物I的酒石酸盐晶型B的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图28-30所示。The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of compound I tartrate crystal form B are shown in Figures 28-30.
实施例12：酒石酸盐晶型C制备Example 12: Preparation of Tartrate Crystal Form C
由游离碱起始样品与等摩尔比的酒石酸在1mL THF中室温下搅拌2天过滤烘干得到固体。 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.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.41(s,1H),8.36(s,1H),8.24(s,1H),7.81(s,1H),7.76(s,1H),7.62(s,1H),7.38(s,1H),4.27(s,2H),3.66(s,2H),1.76(s,1H),1.16(s,3H),0.62(s,4H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ11.88(s,1H),8.41(s,1H),8.36(s,1H),8.24(s,1H) ),7.81(s,1H),7.76(s,1H),7.62(s,1H),7.38(s,1H),4.27(s,2H),3.66(s,2H),1.76(s,1H) ,1.16(s,3H),0.62(s,4H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.38(s,1H)为26号位置的-CH峰，4.27(s,2H)的峰为酒石酸的-CH峰，其比例为1:2，故可解析得到化合物I与酒石酸的比例为1:1。More specifically, through the peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.38 (s, 1H), which is the -CH peak at position 26, and the peak at 4.27 (s, 2H) is The -CH peak of tartaric acid has a ratio of 1:2, so it can be analyzed that the ratio of compound I to tartaric acid is 1:1.
化合物I的酒石酸盐晶型C的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图31-33所示。The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of compound I tartrate crystal form C are shown in Figures 31-33.
实施例13：富马酸盐晶型A制备Example 13: Preparation of fumarate crystal form A
取50mg游离碱起始样品与等摩尔比的富马酸在1mL MeOH中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and an equal molar ratio of fumaric acid in 1 mL MeOH and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.41(s,1H),8.37(s,1H),8.24(s,1H),7.84(s,1H),7.76(s,1H),7.41(s,1H),6.61(s,2H),1.18(s,3H),0.62(s,4H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ11.88(s,1H),8.41(s,1H),8.37(s,1H),8.24(s,1H) ),7.84(s,1H),7.76(s,1H),7.41(s,1H),6.61(s,2H),1.18(s,3H),0.62(s,4H) show that the salt formation ratio is 1: 1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.41(s,1H)为26号位置的-CH峰，6.61(s,2H)的峰为富马酸的-CH峰，其比例为1:2，故可解析得到化合物I与富马酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.41 (s, 1H), which is the -CH peak at position 26, and the peak at 6.61 (s, 2H) is The -CH peak of fumaric acid has a ratio of 1:2, so it can be analyzed that the ratio of compound I to fumaric acid is 1:1.
化合物I的富马酸盐晶型A的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图34-36所示。具体峰值如表5所示。The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of the fumarate crystal form A of Compound I are shown in Figures 34-36. The specific peak values are shown in Table 5.
表5

table 5

实施例14：柠檬酸盐晶型A制备Example 14: Preparation of Citrate Crystal Form A
取50mg游离碱起始样品与等摩尔比的柠檬酸在1mL MeOH中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and citric acid in an equal molar ratio in 1 mL MeOH and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,MeOD)δ8.50(s,1H),8.26(s,1H),7.92(s,1H),7.90(s,1H),7.84(s,1H),7.79(s,1H),7.36(s,1H),3.34(s,1H),2.91(s,1H),2.87(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, MeOD) δ8.50 (s, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.84 (s,1H),7.79(s,1H),7.36(s,1H),3.34(s,1H),2.91(s,1H),2.87(s,1H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,MeOD)的峰位移解析，化合物I的化学位移7.36(s,1H)为26号位置的-CH峰，2.91(s,1H)的峰为柠檬酸的-CH峰，其比例为1:1，故可解析得到化合物I与柠檬酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, MeOD), the chemical shift of compound I is 7.36 (s, 1H), which is the -CH peak at position 26, and the peak at 2.91 (s, 1H) is that of citric acid. -CH peak, the ratio is 1:1, so it can be analyzed that the ratio of compound I to citric acid is 1:1.
化合物I的柠檬酸盐晶型A的差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图37-39所示。具体峰值如表6所示。The differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) of the citrate salt crystal form A of Compound I are shown in Figures 37-39. The specific peak values are shown in Table 6.
表6
Table 6
实施例15：萘二磺酸盐晶型A制备Example 15: Preparation of Naphthalene Disulfonate Crystal Form A
取50mg游离碱起始样品与等摩尔比的1,5-萘二磺酸在1mlMeOH中室温下搅拌2天过滤烘干得到固体。Take 50 mg of the starting free base sample and 1,5-naphthalenedisulfonic acid in an equal molar ratio in 1 ml of MeOH and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.84(s,1H),8.54(s,1H),7.93(s,1H),7.91(s,1H),7.77(s,1H),7.50(s,1H),7.40(s,2H),3.14(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.24(s,1H),8.84(s,1H),8.54(s,1H),7.93(s,1H) ),7.91(s,1H),7.77(s,1H),7.50(s,1H),7.40(s,2H),3.14(s,1H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.40(s,2H)其中一个H为26号位置的-CH峰，另一个H为1,5-萘二磺酸的-CH峰，其比例为1:1，故可解析得 到化合物I与1,5-萘二磺酸的比例为1:1。More specifically, through the peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.40 (s, 2H). One H is the -CH peak at position 26, and the other H is 1. The -CH peak of 5-naphthalenedisulfonic acid has a ratio of 1:1, so it can be analyzed The ratio of compound I to 1,5-naphthalenedisulfonic acid is 1:1.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图40-42所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 40-42.
实施例16：萘二磺酸盐晶型B制备Example 16: Preparation of Naphthalene Disulfonate Crystal Form B
取50mg游离碱起始样品与等摩尔比的1,5-萘二磺酸在1mL Acetone/H2O(9:1,v/v)中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and 1,5-naphthalene disulfonic acid in an equal molar ratio in 1 mL Acetone/H 2 O (9:1, v/v) and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.86(s,2H),8.54(s,1H),8.43(s,1H),8.30(s,1H),7.93(s,1H),7.91(s,1H),7.88(s,1H),7.82(s,1H),7.51(s,1H),7.40(s,2H),2.09(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.24(s,1H),8.86(s,2H),8.54(s,1H),8.43(s,1H) ),8.30(s,1H),7.93(s,1H),7.91(s,1H),7.88(s,1H),7.82(s,1H),7.51(s,1H),7.40(s,2H) ,2.09(s,1H) shows that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.40(s,2H)其中一个H为26号位置的-CH峰，另一个H为1,5-萘二磺酸的-CH峰，其比例为1:1，故可解析得到化合物I与1,5-萘二磺酸的比例为1:1。More specifically, through the peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.40 (s, 2H). One H is the -CH peak at position 26, and the other H is 1. The -CH peak of 5-naphthalenedisulfonic acid has a ratio of 1:1, so it can be analyzed that the ratio of compound I to 1,5-naphthalenedisulfonic acid is 1:1.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图43-45所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 43-45.
实施例17：萘二磺酸盐晶型C制备Example 17: Preparation of Naphthalene Disulfonate Crystal Form C
取50mg游离碱起始样品与等摩尔比的1,5-萘二磺酸在1mL THF中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and 1,5-naphthalenedisulfonic acid in an equal molar ratio in 1 mL THF and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.86(s,2H),8.54(s,1H),8.45(s,1H),8.31(s,1H),7.93(s,1H),7.91(s,1H),7.82(s,1H),7.40(s,2H),1.76(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.24(s,1H),8.86(s,2H),8.54(s,1H),8.45(s,1H) ),8.31(s,1H),7.93(s,1H),7.91(s,1H),7.82(s,1H),7.40(s,2H),1.76(s,1H) show that the salt formation ratio is 1: 1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.40(s,2H)其中一个H为26号位置的-CH峰，另一个H为1,5-萘二磺酸的-CH峰，其比例为1:1，故可解析得到化合物I与1,5-萘二磺酸的比例为1:1。More specifically, through the peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.40 (s, 2H). One H is the -CH peak at position 26, and the other H is 1. The -CH peak of 5-naphthalenedisulfonic acid has a ratio of 1:1, so it can be analyzed that the ratio of compound I to 1,5-naphthalenedisulfonic acid is 1:1.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图46-48所示。Its differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 46-48.
实施例18：对甲苯磺酸盐晶型A制备Example 18: Preparation of p-toluenesulfonate crystal form A
取50mg游离碱起始样品与等摩尔比的对甲苯磺酸在1mL CHCl3中室温下搅拌2天过滤烘干得到固体。Take 50 mg of the starting free base sample and an equal molar ratio of p-toluenesulfonic acid in 1 mL of CHCl 3 and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),9.96(s,1H),8.54(s,1H),8.41(s,2H),8.30(s,1H),7.81(s,3H),7.48(s,3H),7.10(s,2H),2.29(s,3H),1.21(s,4H),0.68(s,5H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.23(s,1H),9.96(s,1H),8.54(s,1H),8.41(s,2H) ),8.30(s,1H),7.81(s,3H),7.48(s,3H),7.10(s,2H),2.29(s,3H),1.21(s,4H),0.68(s,5H) The salt-to-salt ratio is shown to be 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.48(s,3H)其中一个H为26号位置的-CH峰，另外2个H为对甲苯磺酸的-CH峰，其比例为1:2，故可解析得到化合物I与对甲苯磺酸的比例为1:1。More specifically, through the peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.48 (s, 3H). One H is the -CH peak at position 26, and the other two H are opposite. The -CH peak of toluenesulfonic 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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图49-51所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 49-51.
实施例19：对甲苯磺酸盐晶型B制备Example 19: Preparation of p-toluenesulfonate crystal form B
取50mg游离碱起始样品与等摩尔比的对甲苯磺酸在1mL Acetone/H2O(9:1,v/v)中室温下搅拌2天过滤烘干得到固体。Take 50 mg of the starting free base sample and an equal molar ratio of p-toluenesulfonic acid in 1 mL of Acetone/H 2 O (9:1, v/v) and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),9.98(s,1H),8.54(s,1H),8.42(s,1H),8.30(s,1H),7.90(s,1H),7.87(s,1H),7.82(s,1H),7.46(s,3H),7.10(s,2H),2.29(s,3H),2.09(s,2H),1.22(s,4H),0.61(s,5H)显示成盐比为1:1。 According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.23(s,1H),9.98(s,1H),8.54(s,1H),8.42(s,1H) ),8.30(s,1H),7.90(s,1H),7.87(s,1H),7.82(s,1H),7.46(s,3H),7.10(s,2H),2.29(s,3H) ,2.09(s,2H),1.22(s,4H),0.61(s,5H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.46(s,3H)其中一个H为26号位置的-CH峰，另外2个H为对甲苯磺酸的-CH峰，其比例为1:2，故可解析得到化合物I与对甲苯磺酸的比例为1:1。More specifically, through the peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.46 (s, 3H). One H is the -CH peak at position 26, and the other two H are opposite. The -CH peak of toluenesulfonic 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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图52-54所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 52-54.
实施例20：对甲苯磺酸盐晶型C制备Example 20: Preparation of p-toluenesulfonate crystal form C
取50mg游离碱起始样品与等摩尔比的对甲苯磺酸在1mL THF中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and equimolar ratio of p-toluenesulfonic acid in 1 mL THF and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.53(s,1H),8.42(s,1H),8.30(s,1H),7.87(s,1H),7.82(s,1H),7.77(s,1H),7.46(s,3H),7.10(s,2H),2.29(s,4H),1.76(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.24(s,1H),8.53(s,1H),8.42(s,1H),8.30(s,1H) ),7.87(s,1H),7.82(s,1H),7.77(s,1H),7.46(s,3H),7.10(s,2H),2.29(s,4H),1.76(s,1H) The salt-to-salt ratio is shown to be 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.46(s,3H)其中一个H为26号位置的-CH峰，另外2个H为对甲苯磺酸的-CH峰，其比例为1:2，故可解析得到化合物I与对甲苯磺酸的比例为1:1。More specifically, through the peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.46 (s, 3H). One H is the -CH peak at position 26, and the other two H are opposite. The -CH peak of toluenesulfonic 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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图55-57所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 55-57.
实施例21：对甲苯磺酸盐晶型D制备Example 21: Preparation of p-toluenesulfonate crystal form D
取50mg游离碱起始样品与等摩尔比的对甲苯磺酸在1mL MeOH中得到。样品在室温下搅拌2天澄清，转至5℃搅拌1天后澄清，转至-20℃搅拌5天析出固体。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.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.54(s,1H),8.41(s,1H),8.30(s,1H),7.88(s,1H),7.82(s,2H),7.48(s,2H),7.46(s,1H),7.10(s,2H),3.16(s,1H),2.28(s,3H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.21(s,1H),8.54(s,1H),8.41(s,1H),8.30(s,1H) ),7.88(s,1H),7.82(s,2H),7.48(s,2H),7.46(s,1H),7.10(s,2H),3.16(s,1H),2.28(s,3H) The salt-to-salt ratio is shown to be 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.46(s,1H)为26号位置的-CH峰，7.48(s,2H)为对甲苯磺酸的-CH峰，其比例为1:2，故可解析得到化合物I与对甲苯磺酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), 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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图58-60所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 58-60.
实施例22：甲磺酸盐晶型A制备Example 22: Preparation of Methanesulfonate Crystal Form A
取50mg游离碱起始样品与等摩尔比的甲磺酸在1mL CHCl3中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and equimolar ratio of methanesulfonic acid in 1 mL CHCl 3 and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.02(s,1H),8.54(s,1H),8.42(s,1H),8.30(s,1H),7.89(s,2H),7.81(s,1H),7.46(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.24(s,1H),10.02(s,1H),8.54(s,1H),8.42(s,1H) ), 8.30(s,1H),7.89(s,2H),7.81(s,1H),7.46(s,1H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.46(s,1H)为26号位置的-CH峰，10.02(s,1H)为甲磺酸的-OH峰，其比例为1:1，故可解析得到化合物I与甲磺酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.46 (s, 1H), which is the -CH peak at position 26, and 10.02 (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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图61-63所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 61-63.
实施例23：甲磺酸盐晶型B制备Example 23: Preparation of Methanesulfonate Crystal Form B
取50mg游离碱起始样品与等摩尔比的甲磺酸在1mL Acetone/H2O(9:1,v/v)中室温下搅拌2天过滤烘干得到固体。Take 50 mg of the starting sample of free base and an equal molar ratio of methanesulfonic acid in 1 mL of Acetone/H 2 O (9:1, v/v), stir at room temperature for 2 days, filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.24(s,1H),9.95(s,1H),8.54(s,1H),8.42(s,1H),8.30(s,1H),7.87(s,1H),7.81(s,1H),7.47(s,1H),2.29(s, 4H),2.09(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.24(s,1H),12.24(s,1H),9.95(s,1H),8.54(s,1H) ),8.42(s,1H),8.30(s,1H),7.87(s,1H),7.81(s,1H),7.47(s,1H),2.29(s, 4H), 2.09(s,1H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.47(s,1H)为26号位置的-CH峰，9.95(s,1H)为甲磺酸的-OH峰，其比例为1:1，故可解析得到化合物I与甲磺酸的比例为1:1。More specifically, through the peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.47 (s, 1H) for the -CH peak at position 26, and 9.95 (s, 1H) is for 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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图64-66所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 64-66.
实施例24：甲磺酸盐晶型C制备Example 24: Preparation of Methanesulfonate Crystal Form C
取50mg游离碱起始样品与等摩尔比的甲磺酸在1mL THF中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and equimolar ratio of methanesulfonic acid in 1 mL THF and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.54(s,1H),8.42(s,1H),8.31(s,1H),7.87(s,1H),7.82(s,1H),7.47(s,1H),2.30(s,3H),1.91(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.24(s,1H),8.54(s,1H),8.42(s,1H),8.31(s,1H) ),7.87(s,1H),7.82(s,1H),7.47(s,1H),2.30(s,3H),1.91(s,1H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.47(s,1H)为26号位置的-CH峰，10.00(s,1H)为甲磺酸的-OH峰，其比例为1:1，故可解析得到化合物I与甲磺酸的比例为1:1。More specifically, through the peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), 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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图67-69所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 67-69.
实施例25：甲磺酸盐晶型D制备Example 25: Preparation of Methanesulfonate Crystal Form D
取50mg游离碱起始样品与等摩尔比的甲磺酸在1mL MeOH中得到。样品在室温下搅拌2天澄清，转至5℃搅拌1天后澄清，转至-20℃搅拌5天析出固体。Take 50 mg free base starting sample and equal molar ratio of methanesulfonic acid in 1 mL 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.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO)δ12.21(s,1H),8.54(s,1H),8.40(s,1H),8.30(s,1H),7.89(s,1H),7.81(s,2H),7.77(s,1H),7.47(s,1H),2.31(s,3H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO) δ12.21(s,1H),8.54(s,1H),8.40(s,1H),8.30(s,1H),7.89 (s,1H),7.81(s,2H),7.77(s,1H),7.47(s,1H),2.31(s,3H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.47(s,1H)为26号位置的-CH峰，10.01(s,1H)为甲磺酸的-OH峰，其比例为1:1，故可解析得到化合物I与甲磺酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.47 (s, 1H), which is the -CH peak at position 26, and 10.01 (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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图70-72所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 70-72.
实施例26：苯磺酸盐晶型A制备Example 26: Preparation of benzenesulfonate crystal form A
取50mg游离碱起始样品与等摩尔比的苯磺酸在1mL CHCl3中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and equimolar ratio of benzenesulfonic acid in 1 mL CHCl 3 and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),9.95(s,1H),8.54(d,J＝1.3Hz,1H),8.32(s,1H),8.30(s,1H),7.82(s,1H),7.60(s,2H),7.30(s,1H),7.29(d,J＝5.1Hz,3H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.24 (s, 1H), 9.95 (s, 1H), 8.54 (d, J = 1.3Hz, 1H), 8.32(s,1H),8.30(s,1H),7.82(s,1H),7.60(s,2H),7.30(s,1H),7.29(d,J＝5.1Hz,3H) show the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.30(s,1H)为26号位置的-CH峰，7.60(s,2H)为苯磺酸的-CH峰，其比例为1:2，故可解析得到化合物I与苯磺酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), 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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图73-75所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 73-75.
实施例27：苯磺酸盐晶型B制备Example 27: Preparation of benzenesulfonate crystal form B
取50mg游离碱起始样品与等摩尔比的苯磺酸在1mL Acetone/H2O(9:1,v/v)中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and equimolar ratio of benzenesulfonic acid in 1 mL Acetone/H 2 O (9:1, v/v) and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.53(s, 1H),8.42(s,1H),8.30(s,1H),7.82(s,1H),7.60(s,2H),7.49(s,1H),7.29(s,3H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.24(s,1H),8.53(s, 1H),8.42(s,1H),8.30(s,1H),7.82(s,1H),7.60(s,2H),7.49(s,1H),7.29(s,3H) show that the salt formation ratio is 1 :1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.49(s,1H)为26号位置的-CH峰，7.60(s,2H)为苯磺酸的-CH峰，其比例为1:2，故可解析得到化合物I与苯磺酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.49 (s, 1H), which is the -CH peak at position 26, and 7.60 (s, 2H), which is 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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图76-78所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 76-78.
实施例28：苯磺酸盐晶型C制备Example 28: Preparation of benzenesulfonate crystal form C
取50mg游离碱起始样品与等摩尔比的苯磺酸在1mL THF中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and equimolar ratio of benzenesulfonic acid in 1 mL THF and stir at room temperature for 2 days. Filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.53(s,1H),8.41(s,1H),8.30(s,1H),7.82(s,3H),7.58(s,2H),7.47(s,1H),7.29(s,3H),1.76(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ12.24(s,1H),8.53(s,1H),8.41(s,1H),8.30(s,1H) ),7.82(s,3H),7.58(s,2H),7.47(s,1H),7.29(s,3H),1.76(s,1H) show that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.47(s,1H)为26号位置的-CH峰，7.58(s,2H)为苯磺酸的-CH峰，其比例为1:2，故可解析得到化合物I与苯磺酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.47 (s, 1H) for the -CH peak at position 26, and 7.58 (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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图79-81所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 79-81.
实施例29：草酸盐晶型A制备Example 29: Preparation of Oxalate Crystal Form A
取50mg游离碱起始样品与等摩尔比的草酸在1mL CHCl3中室温下搅拌2天过滤烘干得到固体。其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图82-84所示。Take 50 mg of the free base starting sample and oxalic acid in an equal molar ratio in 1 mL of CHCl 3 and stir at room temperature for 2 days. Filter and dry to obtain a solid. Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 82-84.
实施例30：草酸盐晶型B制备Example 30: Preparation of Oxalate Crystal Form B
取50mg游离碱起始样品与等摩尔比的草酸在1mL Acetone/H2O(9:1,v/v)中室温下搅拌2天过滤烘干得到固体。其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图85-87所示。Take 50 mg of the starting free base sample and oxalic acid in an equal molar ratio, stir in 1 mL of Acetone/H 2 O (9:1, v/v) at room temperature for 2 days, filter and dry to obtain a solid. Its differential scanning calorimetry curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 85-87.
实施例31：龙胆酸盐晶型A制备Example 31: Preparation of gentisate crystal form A
取50mg游离碱起始样品与等摩尔比的龙胆酸在1mL MeOH中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and gentisic acid in an equal molar ratio, stir in 1 mL MeOH at room temperature for 2 days, filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),9.10(s,1H),8.41(s,1H),8.35(s,1H),8.23(s,1H),7.84(s,1H),7.76(s,1H),7.63(s,1H),7.41(s,1H),7.14(s,1H),6.91(s,1H),6.74(s,1H)显示成盐比为1:1。According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ11.88(s,1H),9.10(s,1H),8.41(s,1H),8.35(s,1H) ),8.23(s,1H),7.84(s,1H),7.76(s,1H),7.63(s,1H),7.41(s,1H),7.14(s,1H),6.91(s,1H) ,6.74(s,1H) shows that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.41(s,1H)为26号位置的-CH峰，6.91(s,1H)为龙胆酸的-OH峰，其比例为1:1，故可解析得到化合物I与龙胆酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), the chemical shift of compound I is 7.41 (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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图88-90所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 88-90.
实施例32：龙胆酸盐晶型B制备Example 32: Preparation of gentisate crystal form B
取50mg游离碱起始样品与等摩尔比的龙胆酸在1mL CHCl3中室温下搅拌2天过滤烘干得到固体。Take 50 mg free base starting sample and gentisic acid in an equal molar ratio, stir in 1 mL CHCl 3 at room temperature for 2 days, filter and dry to obtain a solid.
根据谱图中重点关注的部分峰位移例如1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),9.06(s,1H),8.41(s,1H),8.35(s,1H),8.32(s,1H),8.23(s,1H),7.40(s,1H),7.14(s,1H),6.91(s,1H),6.90(d,J＝3.2Hz,1H),6.75(s,1H),6.73(s,1H)显示成盐比为1:1。 According to the partial peak shifts of focus in the spectrum, such as 1 H NMR (400MHz, DMSO-d 6 ) δ11.88(s,1H),9.06(s,1H),8.41(s,1H),8.35(s,1H) ),8.32(s,1H),8.23(s,1H),7.40(s,1H),7.14(s,1H),6.91(s,1H),6.90(d,J＝3.2Hz,1H),6.75 (s,1H),6.73(s,1H) shows that the salt formation ratio is 1:1.
更具体的，通过1H NMR(400MHz,DMSO-d6)的峰位移解析，化合物I的化学位移7.40(s,1H)为26号位置的-CH峰，6.91(s,1H)为龙胆酸的-OH峰，其比例为1:1，故可解析得到化合物I与龙胆酸的比例为1:1。More specifically, through peak shift analysis of 1 H NMR (400MHz, DMSO-d 6 ), 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.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图91-93所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 91-93.
实施例33：氢溴酸盐晶型A制备Example 33: Preparation of Hydrobromide Crystal Form A
取50mg游离碱起始样品与等摩尔比的氢溴酸在1mL MeOH中室温下搅拌2天过滤烘干得到固体。Take 50 mg of the starting free base sample and an equal molar ratio of hydrobromic acid in 1 mL of MeOH and stir at room temperature for 2 days. Filter and dry to obtain a solid.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图94-96所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 94-96.
实施例34：氢溴酸盐晶型B制备Example 34: Preparation of Hydrobromide Crystal Form B
取50mg游离碱起始样品与等摩尔比的氢溴酸在1mL CHCl3中室温下搅拌2天过滤烘干得到固体。Take 50 mg of the starting free base sample and an equal molar ratio of hydrobromic acid in 1 mL of CHCl 3 and stir at room temperature for 2 days. Filter and dry to obtain a solid.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图97-99所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 97-99.
实施例35：氢溴酸盐晶型C制备Example 35: Preparation of Hydrobromide Crystal Form C
取50mg游离碱起始样品与等摩尔比的氢溴酸在1mL Acetone/H2O(9:1)中室温下搅拌2天过滤烘干得到固体。Take 50 mg of the starting free base sample and hydrobromic acid in an equal molar ratio, stir in 1 mL of Acetone/H 2 O (9:1) at room temperature for 2 days, filter and dry to obtain a solid.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图100-102所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 100-102.
实施例36：氢溴酸盐晶型D制备Example 36: Preparation of hydrobromide crystal form D
取50mg游离碱起始样品与等摩尔比的氢溴酸在1mL THF中室温下搅拌2天过滤烘干得到固体。Take 50 mg of the free base starting sample and an equal molar ratio of hydrobromic acid in 1 mL of THF and stir at room temperature for 2 days. Filter and dry to obtain a solid.
其差示扫描量热分析曲线图谱、热重分析图谱、X-射线粉末衍射图谱(XRD)图103-105所示。Its differential scanning calorimetry analysis curve pattern, thermogravimetric analysis pattern, and X-ray powder diffraction pattern (XRD) are shown in Figures 103-105.
生物测试例Biological test examples
1、PARP1酶活性测试实验1. PARP1 enzyme activity test experiment
PARP1化学荧光检测试剂盒购自BPS Bioscience。将试剂盒中的组蛋白溶液用1X PBS稀释5倍，取25μL组蛋白稀释液至微孔板中，于4℃孵育过夜。孵育结束后，PBST(0.05％Tween-20)洗板3次，取100μL封闭液至微孔板中，于25℃孵育90分钟；孵育结束后，PBST洗板3次。取测试缓冲液稀释的不同浓度的化合物2.5μL和12.5μL底物混合溶液(1.25μL10X PARP测试缓冲液；1.25μL10X PARP测试混合液；2.5μL Activated DNA，7.5μL双蒸水)至微孔板。将PARP1酶稀释到2ng/μL，取10μL至微孔板，反应体系于25℃孵育60分钟；PARP1 chemical fluorescence detection kit was purchased from BPS Bioscience. Dilute the histone solution in the kit 5 times with 1X PBS, add 25 μL 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 μL blocking solution to the microplate, and incubate at 25°C for 90 minutes; after the incubation, wash the plate three times with PBST. Take 2.5 μL of compounds of different concentrations diluted in test buffer and 12.5 μL substrate mixed solution (1.25 μL 10X PARP test buffer; 1.25 μL 10X PARP test mix; 2.5 μL Activated DNA, 7.5 μL double-distilled water) to the microplate. Dilute the PARP1 enzyme to 2ng/μL, take 10μL into the microwell plate, and incubate the reaction system at 25°C for 60 minutes;
孵育结束后，PBST洗板3次。将Streptavidin-HRP用封闭液稀释50倍，然后取25μL至微孔板，于25℃孵育30分钟。孵育结束后，PBST洗板3次，按照1:1(v/v)混匀ELISA ECL底物A和底物B，取50μL至微孔板，读取化学发光值。After the incubation, wash the plate three times with PBST. Dilute Streptavidin-HRP 50 times with blocking solution, then transfer 25 μL to the microplate and incubate at 25°C for 30 minutes. After the incubation, wash the plate three times with PBST, mix ELISA ECL substrate A and substrate B at a ratio of 1:1 (v/v), take 50 μL into the microplate, and read the chemiluminescence value.
根据公式[(1-(RLUsample-RLUmin)/(RLUmax-RLUmin))×100％]计算抑制率，其中RLUsample为化合物孔读值，RLUmax为溶剂对照孔读值，RLUmin为不含PARP1酶对照孔读值，使用GraphPad Prism软件通过四参数(log(inhibitor)vs.response--Variable slope)进行曲线拟合并计算IC50值。Calculate the inhibition rate according to the formula [(1-(RLU sample -RLU min )/(RLU max -RLU min ))×100%], where RLUsample is the reading value of the compound well, RLUmax is the reading value of the solvent control well, and RLUmin is the reading value of the solvent control well. PARP1 enzyme control well reading value, use GraphPad Prism software to perform curve fitting through four parameters (log (inhibitor) vs. response--Variable slope) and calculate IC 50 value.
表7
Table 7
2、PARP2、PARP5A、PARP5B、PARP6、PARP7、PARP14与PARP15酶活性测试实验 2. PARP2, PARP5A, PARP5B, PARP6, PARP7, PARP14 and PARP15 enzyme activity test experiments
PARP2、PARP5A、PARP5B、PARP6、PARP7、PARP14与PARP15化学荧光检测试剂盒均购自BPS Bioscience。将试剂盒中的组蛋白溶液用1X PBS稀释5倍，取25μL组蛋白稀释液至微孔板中，于4℃孵育过夜。孵育结束后，PBST(0.05％Tween-20)洗板3次，取100μL封闭液至微孔板中，于25℃孵育90分钟；孵育结束后，PBST洗板3次。取2.5μL测试缓冲液稀释的化合物I和5μL底物混合溶液至微孔板。取5μL稀释后的PARP酶至微孔板，反应体系于25℃孵育60分钟。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 μL 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 μL 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 μL of compound I diluted in test buffer and 5 μL of substrate mixed solution to the microwell plate. Add 5 μL of diluted PARP enzyme to the microwell plate, and incubate the reaction system at 25°C for 60 minutes.
孵育结束后，PBST洗板3次。将Streptavidin-HRP用封闭液稀释50倍，然后取25μL至微孔板，于25℃孵育30分钟。孵育结束后，PBST洗板3次，按照1:1(v/v)混匀ELISA ECL底物A和底物B，取25μL至微孔板，读取化学发光值。After the incubation, wash the plate three times with PBST. Dilute Streptavidin-HRP 50 times with blocking solution, then transfer 25 μL to the microplate and incubate at 25°C for 30 minutes. After the incubation, wash the plate three times with PBST, mix ELISA ECL substrate A and substrate B at a ratio of 1:1 (v/v), take 25 μL into the microwell plate, and read the chemiluminescence value.
根据公式[(1-(RLUsample-RLUmin)/(RLUmax-RLUmin))×100％]计算抑制率，其中RLUsample为化合物孔读值，RLUmax为溶剂对照孔读值，RLUmin为不含PARP1酶对照孔读值，使用GraphPad Prism软件通过四参数(log(inhibitor)vs.response--Variable slope)进行曲线拟合并计算IC50值。Calculate the inhibition rate according to the formula [(1-(RLU sample -RLU min )/(RLU max -RLU min ))×100%], where RLU sample is the reading value of the compound well, RLU max is the reading value of the solvent control well, and RLU min For readings from control wells without PARP1 enzyme, use GraphPad Prism software to perform curve fitting and calculate IC 50 values through four parameters (log(inhibitor) vs. response--Variable slope).
测试结果：本发明的化合物在体外对PARP2酶活性的抑制作用较弱，其对应的IC50值为27.47nM；化合物在体外对PARP5A、PARP5B、PARP6、PARP7、PARP14与PARP15酶活性的抑制作用很弱，对应的IC50值均大于500nM。具体的测试结果如表8所示。Test results: 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. The specific test results are shown in Table 8.
表8
Table 8
本发明的化合物具有良好的PARP1抑制选择性。The compounds of the present invention have good PARP1 inhibition selectivity.
3、MDA-MB-436细胞活性测试实验3. MDA-MB-436 cell activity test experiment
人乳腺瘤细胞MDA-MB-436，购置于ATCC，培养基为Leibovitz's L-15(添加10μg/mL胰岛素、16μg/mL谷胱甘肽、10％胎牛血清和1％双抗)，培养于37℃、无CO2孵箱中。第一天收集处于指数生长期的细胞，用培养基将细胞悬液调整到4000个/135μL。每孔加135μL细胞悬液于96-孔细胞培养板，孵育过夜。第二天，加入不同浓度的化合物，置于孵箱中培养孵育7天。培养结束后，按照CellTiter-Glo试剂盒(Promega，G7573)操作说明，每孔加入75μL预先融化并平衡到室温的CTG溶液，用微孔板震荡器混匀2分钟，于室温放置10分钟后用Envision2104读板仪(PerkinElmer)测定萤光信号值。抑制率使用公式[(1–(RLUcompound–RLUblank)/(RLUcontrol–RLUblank))×100％]计算获得，其中RLUcompound为药物处理组的读数，RLUcontrol为溶剂对照组的平均值，RLUblank为无细胞孔平均值。应用GraphPad Prism软件，计算IC50值。Human breast tumor cells MDA-MB-436 were purchased from ATCC, the culture medium was Leibovitz's L-15 (added with 10 μg/mL insulin, 16 μg/mL glutathione, 10% fetal bovine serum and 1% double antibody), and cultured in In a 37℃, 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 μL. Add 135 μL 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. After the culture, according to the instructions of CellTiter-Glo kit (Promega, G7573), add 75 μL of CTG solution that has been melted and equilibrated to room temperature in each well, mix with a microplate shaker for 2 minutes, and leave it at room temperature for 10 minutes before using. The fluorescence signal value was measured using Envision2104 plate reader (PerkinElmer). The inhibition rate is calculated using the formula [(1–(RLU compound –RLU blank )/(RLU control –RLU blank ))×100%], where RLU compound is the reading of the drug treatment group, and RLU control is the average value of the solvent control group. , RLU blank is the average value of cell-free wells. Use GraphPad Prism software to calculate IC 50 values.
测试结果:本发明化合物对乳腺瘤细胞MDA-MB-436具有显著抑制作用。Test results: The compound of the present invention has a significant inhibitory effect on breast tumor cells MDA-MB-436.
表9

Table 9

4、小鼠MDA-MB-436皮下体内移植瘤模型4. Mouse MDA-MB-436 subcutaneous in vivo transplanted tumor model
人乳腺癌MDA-MB-436细胞置于Leibovitz's L-15培养基(添加10μg/mL胰岛素、16μg/mL谷胱甘肽、10％胎牛血清和1％双抗)，在37℃条件下培养。一周两次用胰酶进行常规消化处理传代。当细胞饱和度为80％-90％，数量达到要求时，收取细胞，计数后接种。将0.2mL(10×106个)MDA-MB-436细胞(加基质胶，体积比为1:1)皮下接种于BALB/c裸小鼠(来源于北京维通利华实验动物技术有限公司)的右后背，肿瘤平均体积达到约180mm3时开始分组给药(记为Day0)。溶媒组给予5％DMSO、30％PEG400与65％的20％磺丁基-β-环糊精溶液，给药组给予化合物(Day0-Day10:1mg/kg；Day11-Day28:0.1mg/kg)，给药频率为每天一次，给药周期为29天，设置停药观察期14天。分组后开始每周两次用游标卡尺测量肿瘤直径，肿瘤体积的计算公式为：V＝0.5×a×b2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用TGI(％)＝[1–(某处理组给药结束时平均瘤体积–该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积–溶剂对照组开始治疗时平均瘤体积)]×100％进行评价。肿瘤生长曲线与动物体重变化曲线分别如图106与图107所示。Human breast cancer MDA-MB-436 cells were placed in Leibovitz's L-15 medium (added with 10 μg/mL insulin, 16 μg/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-β-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. After grouping, the tumor diameter was measured twice a week with a vernier caliper. The calculation formula of tumor volume was: V=0.5×a×b 2 , where a and b represent the long and short diameters of the tumors respectively. The tumor inhibitory effect of the compound is calculated by 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.
测试结果：给药28天后，给予化合物的TGI为119％；停药后给予化合物的动物肿瘤未再次生长。给予化合物的动物体重无明显降低。合说明化合物具有良好的肿瘤生长抑制以及诱导肿瘤消退的药效，且耐受性良好。Test results: After 28 days of administration, the TGI of the compound administered was 119%; the tumors of animals administered the compound did not grow again after drug withdrawal. There was no significant decrease in body weight of animals administered the compound. The combination shows that the compound has good efficacy in inhibiting tumor growth and inducing tumor regression, and is well tolerated.
5、大鼠药代动力学测试5. Rat pharmacokinetic test
1.1试验动物：雄性SD大鼠，220g左右，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。1.1 Test animals: male SD rats, about 220g, 6 to 8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
1.2试验设计：试验当天，6只SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。1.2 Experimental design: On the day of the experiment, 6 SD rats were randomly divided into groups according to body weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.
表10

注：静脉给药溶媒:10％DMA+10％Solutol+80％Saline；灌胃给药溶媒：
5％DMSO+30％PEG400+65％(20％SBE-CD)
(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；DMSO：二
甲基亚砜；SBE-CD：β环糊精)Table 10

Note: 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: β-cyclodextrin)
于给药前及给药后异氟烷麻醉经眼眶取血0.15mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为：0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。其中，部分实施例测试结果如下所示。Before and after administration, 0.15 mL of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, and 24h. Before analysis and detection, all samples were stored at -80°C and quantitatively analyzed using LC-MS/MS. Among them, the test results of some examples are as follows.
表11


-：不适用。Table 11


-:not applicable.
结论：化合物具有良好的大鼠体内药代动力特征。Conclusion: The compound has good pharmacokinetic characteristics in rats.
晶型测试例Crystal form test example
1、化合物I的药用盐稳定性数据1. Stability data of pharmaceutical salts of Compound I
取样品分别在25℃/60％RH、40℃/75％RH条件下进行试验，HPLC检测纯度。Samples were taken and tested under the conditions of 25°C/60%RH and 40°C/75%RH respectively, and the purity was detected by HPLC.
供试品溶液制备方法及HPLC检测纯度条件依次见下表；The test solution preparation method and HPLC purity testing conditions are shown in the table below;
表12供试品溶液制备方法
Table 12 Preparation method of test solution
表13 HPLC检测纯度条件
Table 13 HPLC purity detection conditions
表14化合物I游离碱及其盐晶型在不同条件下的化学稳定性(采用HPLC测定纯度)

Table 14 Chemical stability of compound I free base and its salt crystal forms under different conditions (purity determined by HPLC)

结论：化合物I的马来酸盐晶型B、磷酸盐晶型C、富马酸盐晶型A、柠檬酸盐晶型A具有较好的化学稳定性和晶型稳定性。Conclusion: 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.
2、化合物I的药用盐溶解度数据2. Solubility data of pharmaceutical salts of Compound I
称取约20mg物料(以游离碱计算)于4mL离心管中，加入4mL溶剂，在37℃下旋转混合1、2、4和24小时(25rpm)，取样约0.9mL离心过滤，滤液测试HPLC浓度和pH。溶解度试验结果总结于下表。结果显示所有样品在pH 1.0缓冲液中均溶清，在pH 4.5缓冲液中马来酸盐晶型B、柠檬酸盐晶型A和磷酸盐晶型C的溶解度相对较高，在pH 6.8缓冲液中柠檬酸盐晶型A的溶解度相对较高。Weigh about 20 mg of material (calculated as free base) into a 4 mL centrifuge tube, add 4 mL of solvent, rotate and mix at 37°C for 1, 2, 4 and 24 hours (25 rpm), take a sample of about 0.9 mL and centrifuge for filtration, and test the HPLC concentration of the filtrate and pH. The solubility test results are summarized in the table below. The results show that all samples are soluble in pH 1.0 buffer. The solubilities of maleate crystal form B, citrate crystal form A and phosphate crystal form C are relatively high in pH 4.5 buffer. The solubility of citrate crystal form A in liquid is relatively high.
表15

Table 15

化合物I的马来酸盐晶型B、磷酸盐晶型C、富马酸盐晶型A、柠檬酸盐晶型A具有较好的溶解性。 Maleate crystal form B, phosphate crystal form C, fumarate crystal form A, and citrate crystal form A of compound I have good solubility.

Claims (16)

  1. 本发明提供一种式(I)所示化合物的药学上可接受的盐，
    The present invention provides a pharmaceutically acceptable salt of the compound represented by formula (I),
    其中，所述药学上可接受的盐选自盐酸盐、硫酸盐、马来酸盐、磷酸盐、酒石酸盐、富马酸盐、柠檬酸盐、萘二磺酸盐、对甲苯磺酸盐、甲磺酸盐、苯磺酸盐、草酸盐、龙胆酸盐和氢溴酸盐。Wherein, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, maleate, phosphate, tartrate, fumarate, citrate, naphthalenedisulfonate, p-toluenesulfonate , methanesulfonate, benzenesulfonate, oxalate, gentisate and hydrobromide.
  2. 根据权利要求1所述的盐，其中，所述药学上可接受的盐为马来酸盐，优选为马来酸盐晶型B，优选式I化合物与马来酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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 salt according to claim 1, wherein the pharmaceutically acceptable salt is maleate, preferably maleate crystal form B, preferably the ratio of the compound of formula I to maleic acid is 1:1, Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
  3. 根据权利要求1所述的盐，其中，所述药学上可接受的盐为马来酸盐晶型B，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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 salt according to claim 1, wherein the pharmaceutically acceptable salt is maleate crystal form B, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
  4. 根据权利要求2或3所述的盐，其X-射线粉末衍射图基本如图15所示。The salt according to claim 2 or 3 has an X-ray powder diffraction pattern substantially as shown in Figure 15.
  5. 根据权利要求1所述的盐，其中，所述药学上可接受的盐为磷酸盐，优选为磷酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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 salt according to claim 1, wherein the pharmaceutically acceptable salt is a phosphate, preferably a phosphate crystal form C, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristics at the following 2θ position Diffraction peaks: 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°.
  6. 根据权利要求5所述的盐，其中，所述药学上可接受的盐为磷酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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 salt according to claim 5, wherein the pharmaceutically acceptable salt is phosphate crystal form C, using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 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°.
  7. 根据权利要求5或6所述的盐，其中，所述药学上可接受的盐为磷酸盐晶型C，使用Cu-Kα辐射，其X-射线粉末衍射图基本如图24所示。The salt according to claim 5 or 6, wherein the pharmaceutically acceptable salt is phosphate crystal form C, using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 24.
  8. 根据权利要求1所述的盐，其中，所述药学上可接受的盐为富马酸盐，优选为富马酸盐晶型A，优选化合物I与富马酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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 salt according to claim 1, wherein the pharmaceutically acceptable salt is fumarate, preferably fumarate crystal form A, preferably the ratio of compound I to fumaric acid is 1:1, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
  9. 根据权利要求8所述的盐，其中，所述药学上可接受的盐为富马酸盐晶型A，使用Cu-Kα辐 射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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 salt according to claim 8, wherein the pharmaceutically acceptable salt is fumarate crystal form A, using Cu-Kα radiation. The X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
  10. 根据权利要求8或9所述的盐，使用Cu-Kα辐射，其X-射线粉末衍射图基本如图36所示。According to the salt according to claim 8 or 9, using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 36.
  11. 根据权利要求1所述的盐，其中，所述药学上可接受的盐为柠檬酸盐，优选为柠檬酸盐晶型A，优选化合物I与柠檬酸的比例为1:1，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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 salt according to claim 1, wherein the pharmaceutically acceptable salt is citrate, preferably citrate crystal form A, preferably the ratio of compound I to citric acid is 1:1, using Cu-Kα Radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ 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°.
  12. 根据权利要求11所述的盐，其中，所述药学上可接受的盐为柠檬酸盐晶型A，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：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 salt according to claim 11, wherein the pharmaceutically acceptable salt is citrate crystal form A, using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 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°.
  13. 根据权利要求11或12所述的盐，使用Cu-Kα辐射，其X-射线粉末衍射图基本如图39所示。According to the salt according to claim 11 or 12, using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 39.
  14. 一种药物组合物，其中，所述药物组合物含有治疗有效量的权利要求1-13任意一项所述的盐，以及药学上可接受的载体和/或赋形剂，优选所述治疗有效量以游离碱计为1-600mg。A pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of the salt according to any one of claims 1-13, and a pharmaceutically acceptable carrier and/or excipient, preferably the therapeutically effective amount The amount is 1-600 mg based on free base.
  15. 权利要求1-13任意一项所述的盐在制备治疗/预防PARP介导的疾病的药物中的用途，优选所述PARP介导的疾病为肿瘤。The use of the salt according to any one of claims 1 to 13 in the preparation of medicaments for the treatment/prevention of PARP-mediated diseases, preferably the PARP-mediated diseases are tumors.
  16. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-13任意一项方案所述的盐，所述疾病优选为肿瘤，优选所述治疗有效量以游离碱计为1-600mg。 A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the salt described in any one of claims 1-13, the disease is preferably a tumor, preferably the therapeutically effective amount The amount is 1-600 mg based on free base.
PCT/CN2023/114679 2022-08-24 2023-08-24 Pharmaceutically acceptable salt of heteroaryl derivative parp inhibitor and use thereof WO2024041605A1 (en)

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