WO2024061353A1 - Crystal form of quinazoline compound and preparation method therefor - Google Patents

Crystal form of quinazoline compound and preparation method therefor Download PDF

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WO2024061353A1
WO2024061353A1 PCT/CN2023/120754 CN2023120754W WO2024061353A1 WO 2024061353 A1 WO2024061353 A1 WO 2024061353A1 CN 2023120754 W CN2023120754 W CN 2023120754W WO 2024061353 A1 WO2024061353 A1 WO 2024061353A1
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crystal form
compound
present
ray powder
formula
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PCT/CN2023/120754
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French (fr)
Chinese (zh)
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代天资
姚婷
赵乐乐
李鹏
贺海鹰
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南京明德新药研发有限公司
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Publication of WO2024061353A1 publication Critical patent/WO2024061353A1/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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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

Definitions

  • the invention discloses a crystal form of a quinazoline compound and its preparation method, and specifically discloses the crystal form of the compound of formula (I) and its preparation method and application.
  • RAS protein is a guanine nucleoside-binding protein with guanosine triphosphohydrolase (GTPase) activity. It mainly contains three subtypes, KRAS, NRAS and HRAS. As a binary molecular switch controlled by the GDP/GTP cycle, the RAS protein can cycle between an active GTP-bound state (GTP-RAS) and an inactive GDP-bound state (GDP-RAS). This cycle has an important regulatory function in cells and is closely related to cell proliferation, survival, metabolism, migration, immunity and growth.
  • GTPase guanine nucleoside-binding protein with guanosine triphosphohydrolase
  • SOS1 (English full name Son of Sevenless 1) is a type of GEF that regulates the GDP/GTP cycle of RAS protein. After the cell surface receptor is activated and binds to intracellular Grb2, Grb2 recruits SOS1 to the cell membrane, and then SOS1 catalyzes RAS-GDP/GTP exchange, thereby activating downstream signaling pathways. Small molecule SOS1 inhibitors that bind to the catalytic site can block the binding of SOS1 to RAS proteins, thereby effectively reducing the abnormal activation of RAS downstream signaling pathways in cancer cells and playing a role in treating cancer.
  • SOS1 small molecule inhibitors BI-1701963 (WO2018115380, WO2019122129) developed by Boehringer Ingelheim have entered Phase I clinical trials.
  • the SOS1 inhibitors developed by Bayer (WO2018172250, WO2019201848) are still in the preclinical research stage.
  • some studies have suggested that drugs in the RAS pathway are prone to develop resistance in clinical applications.
  • inhibition of ERK phosphorylation will activate negative feedback to the upstream RAS pathway. This negative feedback regulatory mechanism is closely related to SOS1. Therefore, the development of SOS1 small molecule inhibitors has broad application prospects.
  • AMG-510 is a potent, orally bioavailable, selective covalent inhibitor of KRAS G12C developed by Amgen for the treatment of locally advanced or metastatic non-small cell lung cancer harboring KRAS G12C mutations. Its structure is as follows:
  • the present invention provides crystal form A of the compound of formula (I), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2 ⁇ angles: 15.492 ⁇ 0.200°, 16.458 ⁇ 0.200°, 18.657 ⁇ 0.200° and 20.638 ⁇ 0.200°;
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 14.223 ⁇ 0.200°, 14.589 ⁇ 0.200°, 14.894 ⁇ 0.200°, 15.492 ⁇ 0.200°, 16.061 ⁇ 0.200°, 16.458 ⁇ 0.200°, 18.657 ⁇ 0.200° and 20.638 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A contains at least 4, 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 14.223 ⁇ 0.200 °, 14.589 ⁇ 0.200°, 14.894 ⁇ 0.200°, 15.492 ⁇ 0.200°, 16.061 ⁇ 0.200°, 16.458 ⁇ 0.200°, 18.657 ⁇ 0.200° and 20.638 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 14.223 ⁇ 0.100°, 14.589 ⁇ 0.100°, 14.894 ⁇ 0.100°, 15.492 ⁇ 0.100°, 16.061 ⁇ 0.100°, 16.458 ⁇ 0.100°, 18.657 ⁇ 0.100° and 20.638 ⁇ 0.100°.
  • the above-mentioned A crystal form has an X-ray powder diffraction pattern, expressed by 2 ⁇ angle, and contains at least 4, 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 14.223 ⁇ 0.100°, 14.589 ⁇ 0.100°, 14.894 ⁇ 0.100°, 15.492 ⁇ 0.100°, 16.061 ⁇ 0.100°, 16.458 ⁇ 0.100°, 18.657 ⁇ 0.100° and 20.638 ⁇ 0.100°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.736 ⁇ 0.200°, 14.223 ⁇ 0.200°, 14.589 ⁇ 0.200°, 14.894 ⁇ 0.200°, 15.492 ⁇ 0.200°, 16.061 ⁇ 0.200°, 16.458 ⁇ 0.200°, 18.657 ⁇ 0.200°, 19.407 ⁇ 0.200°, 20.638 ⁇ 0.200°, 21.810 ⁇ 0.200° and 22.836 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A contains at least 8, 9, 10, 11 or 12 characteristic diffraction peaks selected from the following: 7.736 ⁇ 0.200 °, 14.223 ⁇ 0.200°, 14.589 ⁇ 0.200°, 14.894 ⁇ 0.200°, 15.492 ⁇ 0.200°, 16.061 ⁇ 0.200°, 16.458 ⁇ 0.200°, 18.657 ⁇ 0.200°, 19.407 ⁇ 0.200°, 20.638 ⁇ 0.2 00° ⁇ 21.810 ⁇ 0.200 ° and 22.836 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.736 ⁇ 0.100°, 14.223 ⁇ 0.100°, 14.589 ⁇ 0.100°, 14.894 ⁇ 0.100°, 15.492 ⁇ 0.100°, 16.061 ⁇ 0.100°, 16.458 ⁇ 0.100°, 18.657 ⁇ 0.100°, 19.407 ⁇ 0.100°, 20.638 ⁇ 0.100°, 21.810 ⁇ 0.100° and 22.836 ⁇ 0.100°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A contains at least 8, 9, 10, 11 or 12 characteristic diffraction peaks selected from the following: 7.736 ⁇ 0.100 °, 14.223 ⁇ 0.100°, 14.589 ⁇ 0.100°, 14.894 ⁇ 0.100°, 15.492 ⁇ 0.100°, 16.061 ⁇ 0.100°, 16.458 ⁇ 0.100°, 18.657 ⁇ 0.100°, 19.407 ⁇ 0.100°, 20.638 ⁇ 0.1 00° ⁇ 21.810 ⁇ 0.100 ° and 22.836 ⁇ 0.100°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.736 ⁇ 0.200°, 9.070 ⁇ 0.200°, 11.289 ⁇ 0.200°, 11.678 ⁇ 0.200°, 14.223 ⁇ 0.200° ⁇ 14.589 ⁇ 0.200° ⁇ 14.894 ⁇ 0.200° ⁇ 15.492 ⁇ 0.200° ⁇ 16.061 ⁇ 0.200° ⁇ 16.458 ⁇ 0.200° ⁇ 18.657 ⁇ 0.200° ⁇ 19.407 ⁇ 0.200° ⁇ 20.638 ⁇ 0.200° ⁇ 21.0 85 ⁇ 0.200°, 21.810 ⁇ 0.200° and 22.836 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.736 ⁇ 0.100°, 9.070 ⁇ 0.100°, 11.289 ⁇ 0.100°, 11.678 ⁇ 0.100°, 14.223 ⁇ 0.100° ⁇ 14.589 ⁇ 0.100° ⁇ 14.894 ⁇ 0.100° ⁇ 15.492 ⁇ 0.100° ⁇ 16.061 ⁇ 0.100° ⁇ 16.458 ⁇ 0.100° ⁇ 18.657 ⁇ 0.100° ⁇ 19.407 ⁇ 0.100° ⁇ 20.638 ⁇ 0.100° ⁇ 21.0 85 ⁇ 0.100°, 21.810 ⁇ 0.100° and 22.836 ⁇ 0.100°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.736 ⁇ 0.200°, 8.475 ⁇ 0.200°, 9.070 ⁇ 0.200°, 11.289 ⁇ 0.200°, 11.678 ⁇ 0.200° ⁇ 12.363 ⁇ 0.200° ⁇ 14.223 ⁇ 0.200° ⁇ 14.589 ⁇ 0.200° ⁇ 14.894 ⁇ 0.200° ⁇ 15.492 ⁇ 0.200° ⁇ 16.061 ⁇ 0.200° ⁇ 16.458 ⁇ 0.200° ⁇ 17.000 ⁇ 0.200° ⁇ 18.6 57 ⁇ 0.200°, 19.030 ⁇ 0.200° ⁇ 19.407 ⁇ 0.200° ⁇ 19.882 ⁇ 0.200° ⁇ 20.638 ⁇ 0.200° ⁇ 21.085 ⁇ 0.200° ⁇ 21.810 ⁇ 0.200° ⁇ 22.836 ⁇ 0.200° ⁇ 23.717 ⁇ 0.200° ⁇ 24.147 ⁇ 0.200° ⁇ 24.6 93 ⁇ 0.200°, 25.311 ⁇ 0.200°, 26.802
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.736 ⁇ 0.200°, 8.475 ⁇ 0.200°, 9.070 ⁇ 0.200°, 11.289 ⁇ 0.200°, 11.678 ⁇ 0.200° ⁇ 12.363 ⁇ 0.200° ⁇ 14.223 ⁇ 0.200° ⁇ 14.589 ⁇ 0.200° ⁇ 14.894 ⁇ 0.200° ⁇ 15.492 ⁇ 0.200° ⁇ 16.061 ⁇ 0.200° ⁇ 16.458 ⁇ 0.200° ⁇ 17.000 ⁇ 0.200° ⁇ 18.6 57 ⁇ 0.200°, 19.030 ⁇ 0.200° ⁇ 19.407 ⁇ 0.200° ⁇ 19.882 ⁇ 0.200° ⁇ 20.638 ⁇ 0.200° ⁇ 21.085 ⁇ 0.200° ⁇ 21.810 ⁇ 0.200° ⁇ 22.836 ⁇ 0.200° ⁇ 23.717 ⁇ 0.200° ⁇ 24.147 ⁇ 0.200° ⁇ 24.6 93 ⁇ 0.200°, 25.311 ⁇ 0.200° ⁇ 26.802
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.736 ⁇ 0.100°, 8.475 ⁇ 0.100°, 9.070 ⁇ 0.100°, 11.289 ⁇ 0.100°, 11.678 ⁇ 0.100° ⁇ 12.363 ⁇ 0.100° ⁇ 14.223 ⁇ 0.100° ⁇ 14.589 ⁇ 0.100° ⁇ 14.894 ⁇ 0.100° ⁇ 15.492 ⁇ 0.100° ⁇ 16.061 ⁇ 0.100° ⁇ 16.458 ⁇ 0.100° ⁇ 17.000 ⁇ 0.100° ⁇ 18.6 57 ⁇ 0.100°, 19.030 ⁇ 0.100° ⁇ 19.407 ⁇ 0.100° ⁇ 19.882 ⁇ 0.100° ⁇ 20.638 ⁇ 0.100° ⁇ 21.085 ⁇ 0.100° ⁇ 21.810 ⁇ 0.100° ⁇ 22.836 ⁇ 0.100° ⁇ 23.717 ⁇ 0.100° ⁇ 24.147 ⁇ 0.100° ⁇ 24.6 93 ⁇ 0.100°, 25.311 ⁇ 0.100°, 26.802
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.736 ⁇ 0.100°, 8.475 ⁇ 0.100°, 9.070 ⁇ 0.100°, 11.289 ⁇ 0.100°, 11.678 ⁇ 0.100° ⁇ 12.363 ⁇ 0.100° ⁇ 14.223 ⁇ 0.100° ⁇ 14.589 ⁇ 0.100° ⁇ 14.894 ⁇ 0.100° ⁇ 15.492 ⁇ 0.100° ⁇ 16.061 ⁇ 0.100° ⁇ 16.458 ⁇ 0.100° ⁇ 17.000 ⁇ 0.100° ⁇ 18.6 57 ⁇ 0.100°, 19.030 ⁇ 0.100° ⁇ 19.407 ⁇ 0.100° ⁇ 19.882 ⁇ 0.100° ⁇ 20.638 ⁇ 0.100° ⁇ 21.085 ⁇ 0.100° ⁇ 21.810 ⁇ 0.100° ⁇ 22.836 ⁇ 0.100° ⁇ 23.717 ⁇ 0.100° ⁇ 24.147 ⁇ 0.100° ⁇ 24.6 93 ⁇ 0.100°, 25.311 ⁇ 0.100° ⁇ 26.802
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 7.736°, 8.475° ⁇ 9.070° ⁇ 11.289° ⁇ 11.678° ⁇ 12.363° ⁇ 14.223° ⁇ 14.589° ⁇ 14.894° ⁇ 15.492° ⁇ 16.061° ⁇ 16.458° ⁇ 17.000° ⁇ 18.657° ⁇ 19.030° ⁇ 19.407° ⁇ 19.88 2°, 20.638° , 21.085°, 21.810°, 22.836°, 23.717°, 24.147°, 24.693°, 25.311°, 26.802°, 27.462°, 28.537° and 31.264°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.736°, 8.475°, 9.070°, 11.289°, 11.678°, 12.363°, 14.223°, 14.589 °, 14.894°, 15.492°, 16.061°, 16.458°, 17.000°, 18.657°, 19.030°, 19.407°, 19.882°, 20.638°, 21.085°, 21.810°, 22.836°, 23.717°, 24.147°, 24 .693° ⁇ 25.311°, 26.802°, 27.462°, 28.537°, 30.090°, 31.264°, 32.346°, 33.429°, 35.334° and 36.567°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 15.492 ⁇ 0.200°, 16.458 ⁇ 0.200°, 18.657 ⁇ 0.200°, and/or 7.736 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 15.492 ⁇ 0.100°, 16.458 ⁇ 0.100°, 18.657 ⁇ 0.100°, and/or 7.736 ⁇ 0.100°, and/or 8.475 ⁇ 0.100°, and/or 9.070 ⁇ 0.100°, and/or 11.289 ⁇ 0.100°, and/or 11.678 ⁇ 0.100°, and/or 12.363 ⁇ 0.100°, and/or 14.223 ⁇ 0.100°, and/or 14.589 ⁇ 0.100°, and/or 14.894 ⁇ 0.100°, and/or 16.061 ⁇ 0.100°, and/or 17.000 ⁇ 0.100°, and/or 19.030 ⁇ 0.100°, and/or 19.407 ⁇ 0.100°, and/or or 19.882 ⁇ 0.100°, and/or 20.638 ⁇ 0.100°, and/or 21.085 ⁇ 0.100°, and/or 21.810 ⁇ 0.100
  • the XRPD pattern of the above-mentioned Form A is basically as shown in Figure 1.
  • the differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak starting point at 169.0 ⁇ 5°C.
  • the differential scanning calorimetry curve of the above-mentioned crystal form A has the starting points of endothermic peaks at 31.6 ⁇ 5°C and 169.0 ⁇ 5°C.
  • the DSC pattern of the above-mentioned crystal form A is basically as shown in Figure 2.
  • thermogravimetric analysis curve of the above-mentioned crystal form A reaches a weight loss of 1.48% at 160.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form A is basically as shown in Figure 3.
  • the present invention also provides the B crystal form of the compound of formula (I), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2 ⁇ angles: 5.932 ⁇ 0.200°, 12.435 ⁇ 0.200°, 14.091 ⁇ 0.200° and 16.496 ⁇ 0.200°;
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.932 ⁇ 0.200°, 8.551 ⁇ 0.200°, 10.855 ⁇ 0.200°, 12.435 ⁇ 0.200°, 14.091 ⁇ 0.200°, 15.171 ⁇ 0.200°, 16.496 ⁇ 0.200° and 23.682 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form, expressed in 2 ⁇ angle, contains at least 4, 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 5.932 ⁇ 0.200 °, 8.551 ⁇ 0.200°, 10.855 ⁇ 0.200°, 12.435 ⁇ 0.200°, 14.091 ⁇ 0.200°, 15.171 ⁇ 0.200°, 16.496 ⁇ 0.200° and 23.682 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.932 ⁇ 0.200°, 6.751 ⁇ 0.200°, 8.551 ⁇ 0.200°, 9.098 ⁇ 0.200°, 10.855 ⁇ 0.200°, 12.435 ⁇ 0.200°, 14.091 ⁇ 0.200°, 15.171 ⁇ 0.200°, 16.496 ⁇ 0.200°, 19.193 ⁇ 0.200°, 20.501 ⁇ 0.200° and 23.682 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form, expressed in 2 ⁇ angle contains at least 8, 9, 10, 11 or 12 characteristic diffraction peaks selected from the following: 5.932 ⁇ 0.200 °, 6.751 ⁇ 0.200°, 8.551 ⁇ 0.200°, 9.098 ⁇ 0.200°, 10.855 ⁇ 0.200°, 12.435 ⁇ 0.200°, 14.091 ⁇ 0.200°, 15.171 ⁇ 0.200°, 16.496 ⁇ 0.200°, 19.193 ⁇ 0.200° ,20.501 ⁇ 0.200 ° and 23.682 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.932 ⁇ 0.200°, 6.751 ⁇ 0.200°, 8.551 ⁇ 0.200°, 9.098 ⁇ 0.200°, 10.186 ⁇ 0.200° ⁇ 10.855 ⁇ 0.200° ⁇ 11.710 ⁇ 0.200° ⁇ 12.435 ⁇ 0.200° ⁇ 14.091 ⁇ 0.200° ⁇ 15.171 ⁇ 0.200° ⁇ 16.049 ⁇ 0.200° ⁇ 16.496 ⁇ 0.200° ⁇ 17.438 ⁇ 0.200° ⁇ 18.6 58 ⁇ 0.200°, 19.193 ⁇ 0.200°, 20.501 ⁇ 0.200°, 21.241 ⁇ 0.200°, 21.977 ⁇ 0.200°, 23.682 ⁇ 0.200°, 26.127 ⁇ 0.200°, 26.981 ⁇ 0.200° and 29.033 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.932°, 6.751°, 8.551°, 9.098°, 10.186°, 10.855°, 11.710°, 12.435 °, 14.091°, 15.171°, 16.049°, 16.496°, 17.438°, 18.658°, 19.193°, 20.501°, 21.241°, 21.977°, 23.682°, 26.127°, 26.981° and 29.033°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.932 ⁇ 0.200°, 12.435 ⁇ 0.200°, 14.091 ⁇ 0.200°, and/or 6.751 ⁇ 0.200°.
  • the XRPD pattern of the above-mentioned B crystal form is basically as shown in Figure 4.
  • the XRPD spectrum analysis data of the above-mentioned Form B is shown in Table 2.
  • the differential scanning calorimetry curve of the above-mentioned B crystal form has the starting points of endothermic peaks at 64.5 ⁇ 5°C and 121.7 ⁇ 5°C.
  • the DSC pattern of the above-mentioned B crystal form is basically as shown in Figure 5.
  • thermogravimetric analysis curve of the above-mentioned B crystal form has a weight loss of 4.01% at 105.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned B crystal form is basically as shown in Figure 6.
  • the present invention also provides the C crystal form of the compound of formula (I), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2 ⁇ angles: 13.546 ⁇ 0.200°, 14.908 ⁇ 0.200°, 15.539 ⁇ 0.200°, 18.230 ⁇ 0.200° and 22.932 ⁇ 0.200°;
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 13.546 ⁇ 0.200°, 14.908 ⁇ 0.200°, 15.539 ⁇ 0.200°, 16.401 ⁇ 0.200°, 18.230 ⁇ 0.200°, 18.699 ⁇ 0.200°, 20.226 ⁇ 0.200° and 22.932 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form, expressed in 2 ⁇ angle contains at least 4, 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 13.546 ⁇ 0.200 °, 14.908 ⁇ 0.200°, 15.539 ⁇ 0.200°, 16.401 ⁇ 0.200°, 18.230 ⁇ 0.200°, 18.699 ⁇ 0.200°, 20.226 ⁇ 0.200° and 22.932 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.410 ⁇ 0.200°, 8.474 ⁇ 0.200°, 13.546 ⁇ 0.200°, 14.122 ⁇ 0.200°, 14.908 ⁇ 0.200°, 15.539 ⁇ 0.200°, 16.401 ⁇ 0.200°, 18.230 ⁇ 0.200°, 18.699 ⁇ 0.200°, 19.665 ⁇ 0.200°, 20.226 ⁇ 0.200° and 22.932 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form, expressed by 2 ⁇ angle contains at least 8, 9, 10, 11 or 12 characteristic diffraction peaks selected from the following: 7.410 ⁇ 0.200°, 8.474 ⁇ 0.200°, 13.546 ⁇ 0.200°, 14.122 ⁇ 0.200°, 14.908 ⁇ 0.200°, 15.539 ⁇ 0.200°, 16.401 ⁇ 0.200°, 18.230 ⁇ 0.200°, 18.699 ⁇ 0.200°, 19.665 ⁇ 0.200°, 20.226 ⁇ 0.200° and 22.932 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.410 ⁇ 0.200°, 8.474 ⁇ 0.200°, 9.093 ⁇ 0.200°, 11.284 ⁇ 0.200°, 13.546 ⁇ 0.200° ⁇ 14.122 ⁇ 0.200° ⁇ 14.908 ⁇ 0.200° ⁇ 15.539 ⁇ 0.200° ⁇ 16.401 ⁇ 0.200° ⁇ 18.230 ⁇ 0.200° ⁇ 18.699 ⁇ 0.200° ⁇ 18.911 ⁇ 0.200° ⁇ 19.665 ⁇ 0.200° ⁇ 20.2 26 ⁇ 0.200°, 21.508 ⁇ 0.200° and 22.932 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.410 ⁇ 0.100°, 8.474 ⁇ 0.100°, 9.093 ⁇ 0.100°, 11.284 ⁇ 0.100°, 13.546 ⁇ 0.100° ⁇ 14.122 ⁇ 0.100° ⁇ 14.908 ⁇ 0.100° ⁇ 15.539 ⁇ 0.100° ⁇ 16.401 ⁇ 0.100° ⁇ 18.230 ⁇ 0.100° ⁇ 18.699 ⁇ 0.100° ⁇ 18.911 ⁇ 0.100° ⁇ 19.665 ⁇ 0.100° ⁇ 20.2 26 ⁇ 0.100°, 21.508 ⁇ 0.100° and 22.932 ⁇ 0.100°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.410 ⁇ 0.200°, 8.474 ⁇ 0.200°, 9.093 ⁇ 0.200°, 11.284 ⁇ 0.200°, 11.439 ⁇ 0.200° ⁇ 13.546 ⁇ 0.200° ⁇ 14.122 ⁇ 0.200° ⁇ 14.908 ⁇ 0.200° ⁇ 15.539 ⁇ 0.200° ⁇ 16.401 ⁇ 0.200° ⁇ 16.743 ⁇ 0.200° ⁇ 17.169 ⁇ 0.200° ⁇ 18.230 ⁇ 0.200° ⁇ 18.6 99 ⁇ 0.200°, 18.911 ⁇ 0.200° ⁇ 19.665 ⁇ 0.200° ⁇ 20.226 ⁇ 0.200° ⁇ 21.508 ⁇ 0.200° ⁇ 22.932 ⁇ 0.200° ⁇ 23.907 ⁇ 0.200° ⁇ 25.111 ⁇ 0.200° ⁇ 27.317 ⁇ 0.200° ⁇ 29.113 ⁇ 0.200° and 31.3 25 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.410 ⁇ 0.100°, 8.474 ⁇ 0.100°, 9.093 ⁇ 0.100°, 11.284 ⁇ 0.100°, 11.439 ⁇ 0.100° ⁇ 13.546 ⁇ 0.100° ⁇ 14.122 ⁇ 0.100° ⁇ 14.908 ⁇ 0.100° ⁇ 15.539 ⁇ 0.100° ⁇ 16.401 ⁇ 0.100° ⁇ 16.743 ⁇ 0.100° ⁇ 17.169 ⁇ 0.100° ⁇ 18.230 ⁇ 0.100° ⁇ 18.6 99 ⁇ 0.100°, 18.911 ⁇ 0.100° ⁇ 19.665 ⁇ 0.100° ⁇ 20.226 ⁇ 0.100° ⁇ 21.508 ⁇ 0.100° ⁇ 22.932 ⁇ 0.100° ⁇ 23.907 ⁇ 0.100° ⁇ 25.111 ⁇ 0.100° ⁇ 27.317 ⁇ 0.100° ⁇ 29.113 ⁇ 0.100° and 31.3 25 ⁇ 0.100°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.410°, 8.474°, 9.093°, 11.284°, 11.439°, 13.546°, 14.122°, 14.908 °, 15.539°, 16.401°, 16.743°, 17.169°, 18.230°, 18.699°, 18.911°, 19.665°, 20.226°, 21.508°, 22.932°, 23.907°, 25.111°, 27.317°, 29.113° and 31 .325°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.410 ⁇ 0.200°, 8.474 ⁇ 0.200°, 9.093 ⁇ 0.200°, 11.284 ⁇ 0.200°, 11.439 ⁇ 0.200° ⁇ 13.546 ⁇ 0.200° ⁇ 14.122 ⁇ 0.200° ⁇ 14.908 ⁇ 0.200° ⁇ 15.539 ⁇ 0.200° ⁇ 16.401 ⁇ 0.200° ⁇ 16.743 ⁇ 0.200° ⁇ 17.169 ⁇ 0.200° ⁇ 18.230 ⁇ 0.200° ⁇ 18.6 99 ⁇ 0.200°, 18.911 ⁇ 0.200° ⁇ 19.665 ⁇ 0.200° ⁇ 20.226 ⁇ 0.200° ⁇ 21.508 ⁇ 0.200° ⁇ 22.932 ⁇ 0.200° ⁇ 23.907 ⁇ 0.200° ⁇ 25.111 ⁇ 0.200° ⁇ 27.317 ⁇ 0.200° ⁇ 29.113 ⁇ 0.200° and 31.3 25 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.410 ⁇ 0.100°, 8.474 ⁇ 0.100°, 9.093 ⁇ 0.100°, 11.284 ⁇ 0.100°, 11.439 ⁇ 0.100° ⁇ 13.546 ⁇ 0.100° ⁇ 14.122 ⁇ 0.100° ⁇ 14.908 ⁇ 0.100° ⁇ 15.539 ⁇ 0.100° ⁇ 16.401 ⁇ 0.100° ⁇ 16.743 ⁇ 0.100° ⁇ 17.169 ⁇ 0.100° ⁇ 18.230 ⁇ 0.100° ⁇ 18.6 99 ⁇ 0.100°, 18.911 ⁇ 0.100° ⁇ 19.665 ⁇ 0.100° ⁇ 20.226 ⁇ 0.100° ⁇ 21.508 ⁇ 0.100° ⁇ 22.932 ⁇ 0.100° ⁇ 23.907 ⁇ 0.100° ⁇ 25.111 ⁇ 0.100° ⁇ 27.317 ⁇ 0.100° ⁇ 29.113 ⁇ 0.100° and 31.3 25 ⁇ 0.100°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 13.546 ⁇ 0.200°, 14.908 ⁇ 0.200°, 15.539 ⁇ 0.200°, and/or 7.410 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 13.546 ⁇ 0.100°, 14.908 ⁇ 0.100°, 15.539 ⁇ 0.100°, and/or 7.410 ⁇ 0.100°.
  • the XRPD pattern of the above-mentioned crystal form C is basically as shown in Figure 7.
  • the differential scanning calorimetry curve of the above-mentioned crystal form C has an endothermic peak starting point at 169.2 ⁇ 5°C.
  • the DSC pattern of the above-mentioned crystal form C is basically as shown in Figure 8.
  • the weight loss of the above-mentioned C crystal form in the thermogravimetric analysis curve reaches 2.00% at 130.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form C is basically as shown in Figure 9.
  • the present invention also provides the use of the crystalline form of the compound of formula (I) in the preparation of a drug for treating KRAS mutant solid tumor diseases.
  • the present invention also provides the use of crystal form A of the compound of formula (I) above in the preparation of drugs for treating KRAS mutant solid tumor diseases.
  • the present invention also provides the following biological testing method for the crystal form of the compound of formula (I) above:
  • Test method 1 In vivo efficacy evaluation of compounds in Miapaca2 nude mouse transplanted tumor model
  • Human pancreatic cancer cells (Miapaca2) were cultured in adherent monolayer in vitro. The culture conditions were DMEM medium plus 10% fetal calf serum at 37°C in a 5% CO 2 incubator. Passages were performed with routine digestion using trypsin–EDTA two to three times a week. When the cell saturation is 80%–90% and the number reaches the required number, collect the cells, count, and inoculate.
  • mice Female, 6-7 weeks old, were purchased from Shanghai Sipur-Bike Experimental Animal Co., Ltd.
  • Miapaca2 cells (added with matrix, volume ratio 1:1) were subcutaneously inoculated into the right back of each mouse. Administration in groups was started when the average tumor volume reached 118 mm 3 .
  • the tumor inhibitory efficacy of the test compounds was evaluated by using TGI (%).
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI (%) [1 – (average tumor volume at the end of treatment in a certain treatment group - average tumor volume at the beginning of treatment in the treatment group)/(average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group) Tumor volume)] ⁇ 100%.
  • the compound of the present invention can better inhibit the activity of SOS1; it also has obvious inhibitory activity on the proliferation of DLD-1 cell p-ERK, and has good pharmacokinetic properties (including good oral bioavailability, oral exposure, half-life and clearance rate, etc.); the compound has no significant inhibitory effect on the hERG potassium ion channel and is highly safe; the compound of the present invention has excellent tumor inhibitory effect on the human pancreatic cancer Miapaca-2 xenograft tumor model.
  • the crystal form of the compound of formula (I) of the present invention is easy to obtain, has good physical and chemical stability, and has high industrial application value and economic value.
  • Differential scanning calorimetry (DSC) of the crystalline forms described in this invention is subject to experimental error and is slightly affected by the degree of dryness of the sample, from one machine to another and from one sample to another.
  • the position and peak value of the endothermic peak may be slightly different, and the experimental error or difference may be less than or equal to 10°C, or less than or equal to 9°C, or less than or equal to 8°C, or less than or equal to 7°C, or less than or equal to 6°C.
  • the DSC absorbs
  • the peak position of a thermal peak or the numerical value of a peak cannot be considered absolute.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • the solvent used in the present invention is commercially available.
  • Boc represents tert-butoxycarbonyl
  • DCM dichloromethane
  • DMF represents N, N-dimethylformamide
  • THF represents tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • EtOH represents ethanol
  • MeOH represents methanol
  • ACN (MeCN) represents acetonitrile
  • EtOAc represents ethyl acetate
  • H 2 O represents water
  • Acetone represents acetone
  • IPAc represents isopropyl acetate
  • MTBE represents methyl tert-butyl ether
  • 1,4-Dioxane represents 1 , 4-dioxane
  • n-Heptane represents n-heptane
  • i-PrOAc represents isopropyl acetate
  • TEA represents triethylamine
  • DIPEA represents diisopropylethylamine
  • BID represents twice a day
  • QD represents once a day
  • X-ray powder diffraction (X-ray powder diffractometer, XRPD) method one of the present invention, the test parameters are shown in Table 4.
  • test parameters of the differential scanning calorimeter (DSC) method of the present invention are shown in Table 6.
  • thermogravimetric analyzer (TGA) method of the present invention are shown in Table 7.
  • test parameters of the dynamic vapor adsorption analysis (Dynamic Vapor Sorption, DVS) method of the present invention are shown in Table 8.
  • Figure 1 XRPD spectrum of Cu-K ⁇ radiation of crystal form A of compound of formula (I).
  • FIG. 8 DSC spectrum of crystal form C of compound of formula (I).
  • FIG 11 Single crystal X-ray diffraction (SXRD) three-dimensional structure ellipsoid diagram of the compound of formula (I).
  • the compound of formula (I) (150 mg, 261 ⁇ mol) was added to n-heptane (1.5 mL), the reaction solution was stirred at 50°C for 24 hours, then stirred at 25°C for 2 hours, filtered, the filter cake was washed with n-heptane (3 mL), and vacuum dried at 50°C to obtain the A crystal form of the compound of formula (I).
  • Hygroscopicity evaluation classification table Note: ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • the DVS spectrum of the crystal form A of compound of formula (I) is shown in Figure 10.
  • the DVS results show that the sample absorbs moisture and gains weight by 0.3815% under the conditions of 25°C/80% RH, and the sample is slightly hygroscopic. After completing the DVS test (0-95-0% RH), take out the sample and expose it to the air for XRPD testing. The results show that the crystal form has not changed before and after the DVS test.
  • the crystal form of compound A of formula (I) is slightly hygroscopic at 25 ⁇ 1°C and 80 ⁇ 2% RH, and the crystal form remains unchanged.
  • X-ray light source high-intensity micro-focus rotating anode light source, Cu target;
  • Tube voltage 50kV
  • Tube current 45mA
  • Goniometer four axes (Kappa, ⁇ , 2 ⁇ , ) goniometer;
  • Detector Large-area photon II detector, the effective area of the detector is 14cm ⁇ 10cm, and the distance between the detector and the sample is automatically adjustable by the motor.
  • the basic structural information of this compound is: molecular formula 2(C 29 H 36 F 3 N 5 O 4 ) ⁇ CH 3 CN, crystal system orthorhombic, space group P2 1 2 1 2 1 , wavelength
  • the single crystal data shows that the single crystal is the acetonitrile compound of the compound of formula (I).
  • the ellipsoid diagram of its single crystal SXRD three-dimensional structure is shown in Figure 11.
  • the results show that C12 and C18 in the figure are R, R configuration.
  • Small molecule compounds bind to the catalytic site of SOS1 and inhibit the binding of SOS1 to KRAS (G12C).
  • SOS1 small molecule compounds
  • G12C fluorescently labeled SOS1 protein to fluorescently labeled KRAS (G12C) protein
  • the fluorescence emitted changes.
  • a homogeneous time-resolved fluorescence (HTRF) binding assay was used to detect the ability of the compounds of the present invention to inhibit the binding of SOS1 and KRAS (G12C).
  • KRAS (G12C) protein was expressed and purified by Wuhan Pujian Biotechnology Co., Ltd., SOS1 exchange domin (564-1049) protein (H ⁇ man recombinant) was purchased from Cytoskeleton, Mab Anti 6HIS-XL665 and Mab Anti GST-E ⁇ cryptate were purchased from Cisbio.
  • the multifunctional microplate reader Nivo5 was purchased from PerkinElmer.
  • 1X buffer preparation (prepared and used immediately): Hepes: 5mM; NaCl: 150mM; EDTA: 10mM; Igepal: 0.0025%; KF: 100mM; DTT: 1mM; BSA: 005%;
  • DMSO dilute the compound to be tested 5 times to the 8th concentration, that is, from 1mM to 0.064 ⁇ M.
  • Example-Min Use the equation (Sample-Min)/(Max-Min) ⁇ 100% to convert the original data into an inhibition rate.
  • the value of IC 50 can be obtained by curve fitting with four parameters (log(inhibitor) vs. response in GraphPad Prism --Variable slope mode derived).
  • the test results of the inhibitory activity of the compounds of the present invention on the binding of KRAS (G12C) and SOS1 are shown in Table 12.
  • the compound of the present invention has a significant inhibitory effect on the binding of KRAS (G12C) and SOS1.
  • H358 cells with KRAS (G12C) mutation the KRAS signaling pathway is abnormally activated.
  • Small molecule SOS1 inhibitors reduce its GEF activity and reduce the ratio of activated RAS-GTP by inhibiting the binding of SOS1 to RAS protein. Further downregulating the phosphorylation level of the MEK/ERK pathway downstream of RAS, achieving the effect of inhibiting cell proliferation. Small molecules were co-cultured with H358 cells in a 3D space, and then cell readings were used to indirectly reflect the proliferation inhibitory activity of SOS1 inhibitors on H358 cells.
  • RPMI1640 medium fetal calf serum, penicillin/streptomycin antibiotics were purchased from Vicente, and low melting point agarose was purchased from Sigma.
  • Almar blue reagent was purchased from Invitrogen.
  • NCI-H358 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo multi-label analyzer (PerkinElmer).
  • H358 cells were seeded in a 96-well U-shaped plate.
  • the compound to be tested was diluted 3 times to the ninth concentration with a volley gun, that is, from 6mM to 0.9 ⁇ M, and a double well experiment was set up.
  • the concentration of compounds transferred into the cell plate ranged from 30 ⁇ M to 4.5 nM.
  • the cell plate was placed in a carbon dioxide incubator and cultured for another 7 days.
  • the compound and cells were incubated for 14 days. 20 ⁇ L of Almar blue detection reagent was added to each well of the cell plate. The dye-added plate was placed on a horizontal shaker for 15 minutes, and then the plate was incubated at room temperature for 5 hours to stabilize the luminescence signal. Take multi-label analyzer readings.
  • IC 50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • the compound of the present invention can inhibit the proliferation of H358 cells under 3D conditions.
  • DLD-1 cells were purchased from Nanjing Kebai; 1640 culture medium was purchased from Biological Industries; fetal calf serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio, and its ingredient list is shown in Table 13.
  • DLD-1 cells were seeded in a transparent 96-well cell culture plate, with 80 ⁇ L of cell suspension per well, each well containing 8,000 DLD-1 cells.
  • the cell plate was placed in a carbon dioxide incubator and incubated at 37°C overnight;
  • IC 50 can be obtained by curve fitting with four parameters (log(inhibitor) vs. response in GraphPad Prism --Variable slope mode derived).
  • Max well The reading value of the positive control well is 1X lysate
  • Negative control well reading value is 0.5% DMSO cell well cell lysate
  • the compound of the present invention has a significant inhibitory effect on the proliferation of p-ERK in DLD-1 cells.
  • mice Male, Beijing Weitonglihua Experimental Animal Technology Co., Ltd.
  • Standard protocols were used to test the pharmacokinetic characteristics of the compounds in rodents after intravenous injection and oral administration.
  • the candidate compounds were formulated into clear solutions and given to mice for a single intravenous injection and oral administration.
  • the vehicle for intravenous injection and oral administration is a mixed vehicle composed of 5% dimethyl sulfoxide, 5% solutol and 90% water.
  • This project uses four male Balb/c mice, and two mice are administered intravenously at a dose of 10 mg/kg. The data at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration are collected. Plasma samples; the other two mice were orally administered orally at a dose of 50 mg/kg.
  • Plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration. Blood samples were collected. Then place it on ice and centrifuge to separate the plasma within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis. Use LC-MS/MS analysis method to quantitatively analyze blood drug concentration and calculate pharmacokinetic parameters, such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), tissue distribution (Vdss), drug Area under the curve (AUC 0-last ), bioavailability (F), etc.
  • C max peak concentration
  • CL clearance rate
  • T 1/2 half-life
  • Vdss tissue distribution
  • AUC 0-last drug Area under the curve
  • bioavailability F
  • the compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.

Abstract

Disclosed are a crystal form of a quinazoline compound and a preparation method therefor. Particularly, disclosed are a crystal form of a compound of formula (I), a preparation method therefor, and use thereof.

Description

喹唑啉类化合物的晶型及其制备方法Crystal forms of quinazoline compounds and preparation methods thereof
本申请主张如下优先权：This application claims the following priority:
CN202211169562.X，2022年09月23日。CN202211169562.X, September 23, 2022.
技术领域Technical Field
本发明公开了一种喹唑啉类化合物的晶型及其制备方法，具体公开了式(I)化合物的晶型及其制备方法应用。The invention discloses a crystal form of a quinazoline compound and its preparation method, and specifically discloses the crystal form of the compound of formula (I) and its preparation method and application.
背景技术Background technique
RAS蛋白是一种拥有鸟苷三磷酸水解酶(GTPase)活性的鸟嘌呤核苷结合蛋白，主要包含三种亚型，KRAS，NRAS和HRAS。作为GDP/GTP循环控制的二进制分子开关，RAS蛋白可以在活性的GTP结合状态(GTP-RAS)和无活性的GDP结合状态(GDP-RAS)之间循环。这一循环在细胞中具有重要的调控功能，同细胞的增殖，存活，代谢，迁移，免疫和生长密切相关。RAS protein is a guanine nucleoside-binding protein with guanosine triphosphohydrolase (GTPase) activity. It mainly contains three subtypes, KRAS, NRAS and HRAS. As a binary molecular switch controlled by the GDP/GTP cycle, the RAS protein can cycle between an active GTP-bound state (GTP-RAS) and an inactive GDP-bound state (GDP-RAS). This cycle has an important regulatory function in cells and is closely related to cell proliferation, survival, metabolism, migration, immunity and growth.
SOS1(英文全称Son of Sevenless 1)是一类调控RAS蛋白GDP/GTP循环的GEF。细胞表面受体被激活并与胞内Grb2结合后，Grb2招募SOS1至细胞膜，随后SOS1催化RAS-GDP/GTP交换，进而激活下游信号通路。结合在催化位点的小分子SOS1抑制剂，可以阻断SOS1与RAS蛋白的结合，从而有效降低癌细胞中RAS下游信号通路的异常激活，起到治疗癌症的作用。目前SOS1小分子抑制剂只有勃林格殷格翰公司开发的BI-1701963(WO2018115380，WO2019122129)进入了I期临床实验。拜耳公司(WO2018172250，WO2019201848)开发的SOS1抑制剂仍处于临床前研究阶段。近年来有研究认为，RAS通路的药物在临床应用中很容易产生耐药，部分耐药产生的原因是ERK磷酸化被抑制后会负反馈激活上游RAS通路。而这一负反馈调节机制与SOS1密切相关。因此，开发SOS1小分子抑制剂具有广阔的应用前景。SOS1 (English full name Son of Sevenless 1) is a type of GEF that regulates the GDP/GTP cycle of RAS protein. After the cell surface receptor is activated and binds to intracellular Grb2, Grb2 recruits SOS1 to the cell membrane, and then SOS1 catalyzes RAS-GDP/GTP exchange, thereby activating downstream signaling pathways. Small molecule SOS1 inhibitors that bind to the catalytic site can block the binding of SOS1 to RAS proteins, thereby effectively reducing the abnormal activation of RAS downstream signaling pathways in cancer cells and playing a role in treating cancer. Currently, only SOS1 small molecule inhibitors BI-1701963 (WO2018115380, WO2019122129) developed by Boehringer Ingelheim have entered Phase I clinical trials. The SOS1 inhibitors developed by Bayer (WO2018172250, WO2019201848) are still in the preclinical research stage. In recent years, some studies have suggested that drugs in the RAS pathway are prone to develop resistance in clinical applications. Part of the reason for resistance is that inhibition of ERK phosphorylation will activate negative feedback to the upstream RAS pathway. This negative feedback regulatory mechanism is closely related to SOS1. Therefore, the development of SOS1 small molecule inhibitors has broad application prospects.
AMG-510是安进公司开发的一种有效的，口服生物可利用的，选择性的KRAS G12C共价抑制剂，用于治疗携带KRAS G12C突变的局部晚期或转移性非小细胞肺癌。其结构如下所示：
AMG-510 is a potent, orally bioavailable, selective covalent inhibitor of KRAS G12C developed by Amgen for the treatment of locally advanced or metastatic non-small cell lung cancer harboring KRAS G12C mutations. Its structure is as follows:
发明内容Contents of the invention
本发明提供式(I)化合物的A晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：15.492±0.200°、16.458±0.200°、18.657±0.200°和20.638±0.200°；
The present invention provides crystal form A of the compound of formula (I), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2θ angles: 15.492±0.200°, 16.458±0.200°, 18.657±0.200° and 20.638± 0.200°;
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、18.657±0.200°和20.638±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 14.223±0.200°, 14.589±0.200°, 14.894±0.200°, 15.492±0.200°, 16.061± 0.200°, 16.458±0.200°, 18.657±0.200° and 20.638±0.200°.
本发明的一些方案中，上述A晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的4、5、6、7或8个特征衍射峰：14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、18.657±0.200°和20.638±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A, expressed in 2θ angle, contains at least 4, 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 14.223±0.200 °, 14.589±0.200°, 14.894±0.200°, 15.492±0.200°, 16.061±0.200°, 16.458±0.200°, 18.657±0.200° and 20.638±0.200°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.223±0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、18.657±0.100°和20.638±0.100°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 14.223±0.100°, 14.589±0.100°, 14.894±0.100°, 15.492±0.100°, 16.061± 0.100°, 16.458±0.100°, 18.657±0.100° and 20.638±0.100°.
本发明的一些方案中，上述A晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的4、5、6、7或8个特征衍射峰：14.223±0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、18.657±0.100°和20.638±0.100°。In some embodiments of the present invention, the above-mentioned A crystal form has an X-ray powder diffraction pattern, expressed by 2θ angle, and contains at least 4, 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 14.223±0.100°, 14.589±0.100°, 14.894±0.100°, 15.492±0.100°, 16.061±0.100°, 16.458±0.100°, 18.657±0.100° and 20.638±0.100°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.200°、14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、18.657±0.200°、19.407±0.200°、20.638±0.200°、21.810±0.200°和22.836±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.736±0.200°, 14.223±0.200°, 14.589±0.200°, 14.894±0.200°, 15.492± 0.200°, 16.061±0.200°, 16.458±0.200°, 18.657±0.200°, 19.407±0.200°, 20.638±0.200°, 21.810±0.200° and 22.836±0.200°.
本发明的一些方案中，上述A晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的8、9、10、11或12个特征衍射峰：7.736±0.200°、14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、18.657±0.200°、19.407±0.200°、20.638±0.200°、21.810±0.200°和22.836±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A, expressed in 2θ angle, contains at least 8, 9, 10, 11 or 12 characteristic diffraction peaks selected from the following: 7.736±0.200 °, 14.223±0.200°, 14.589±0.200°, 14.894±0.200°, 15.492±0.200°, 16.061±0.200°, 16.458±0.200°, 18.657±0.200°, 19.407±0.200°, 20.638±0.2 00°、21.810±0.200 ° and 22.836±0.200°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.100°、14.223±0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、18.657±0.100°、19.407±0.100°、20.638±0.100°、21.810±0.100°和22.836±0.100°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.736±0.100°, 14.223±0.100°, 14.589±0.100°, 14.894±0.100°, 15.492± 0.100°, 16.061±0.100°, 16.458±0.100°, 18.657±0.100°, 19.407±0.100°, 20.638±0.100°, 21.810±0.100° and 22.836±0.100°.
本发明的一些方案中，上述A晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的8、9、10、11或12个特征衍射峰：7.736±0.100°、14.223±0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、18.657±0.100°、19.407±0.100°、20.638±0.100°、21.810±0.100°和22.836±0.100°。 In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A, expressed in 2θ angle, contains at least 8, 9, 10, 11 or 12 characteristic diffraction peaks selected from the following: 7.736±0.100 °, 14.223±0.100°, 14.589±0.100°, 14.894±0.100°, 15.492±0.100°, 16.061±0.100°, 16.458±0.100°, 18.657±0.100°, 19.407±0.100°, 20.638±0.1 00°、21.810±0.100 ° and 22.836±0.100°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.200°、9.070±0.200°、11.289±0.200°、11.678±0.200°、14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、18.657±0.200°、19.407±0.200°、20.638±0.200°、21.085±0.200°、21.810±0.200°和22.836±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.736±0.200°, 9.070±0.200°, 11.289±0.200°, 11.678±0.200°, 14.223± 0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、18.657±0.200°、19.407±0.200°、20.638±0.200°、21.0 85±0.200°, 21.810± 0.200° and 22.836±0.200°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.100°、9.070±0.100°、11.289±0.100°、11.678±0.100°、14.223±0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、18.657±0.100°、19.407±0.100°、20.638±0.100°、21.085±0.100°、21.810±0.100°和22.836±0.100°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.736±0.100°, 9.070±0.100°, 11.289±0.100°, 11.678±0.100°, 14.223± 0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、18.657±0.100°、19.407±0.100°、20.638±0.100°、21.0 85±0.100°, 21.810± 0.100° and 22.836±0.100°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.200°、8.475±0.200°、9.070±0.200°、11.289±0.200°、11.678±0.200°、12.363±0.200°、14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、17.000±0.200°、18.657±0.200°、19.030±0.200°、19.407±0.200°、19.882±0.200°、20.638±0.200°、21.085±0.200°、21.810±0.200°、22.836±0.200°、23.717±0.200°、24.147±0.200°、24.693±0.200°、25.311±0.200°、26.802±0.200°、27.462±0.200°、28.537±0.200°和31.264±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.736±0.200°, 8.475±0.200°, 9.070±0.200°, 11.289±0.200°, 11.678± 0.200°、12.363±0.200°、14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、17.000±0.200°、18.6 57±0.200°, 19.030± 0.200°、19.407±0.200°、19.882±0.200°、20.638±0.200°、21.085±0.200°、21.810±0.200°、22.836±0.200°、23.717±0.200°、24.147±0.200°、24.6 93±0.200°, 25.311± 0.200°, 26.802±0.200°, 27.462±0.200°, 28.537±0.200° and 31.264±0.200°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.200°、8.475±0.200°、9.070±0.200°、11.289±0.200°、11.678±0.200°、12.363±0.200°、14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、17.000±0.200°、18.657±0.200°、19.030±0.200°、19.407±0.200°、19.882±0.200°、20.638±0.200°、21.085±0.200°、21.810±0.200°、22.836±0.200°、23.717±0.200°、24.147±0.200°、24.693±0.200°、25.311±0.200°、26.802±0.200°、27.462±0.200°、28.537±0.200°、30.090±0.200°、31.264±0.200°、32.346±0.200°、33.429±0.200°、35.334±0.200°和36.567±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.736±0.200°, 8.475±0.200°, 9.070±0.200°, 11.289±0.200°, 11.678± 0.200°、12.363±0.200°、14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、17.000±0.200°、18.6 57±0.200°, 19.030± 0.200°、19.407±0.200°、19.882±0.200°、20.638±0.200°、21.085±0.200°、21.810±0.200°、22.836±0.200°、23.717±0.200°、24.147±0.200°、24.6 93±0.200°, 25.311± 0.200°、26.802±0.200°、27.462±0.200°、28.537±0.200°、30.090±0.200°、31.264±0.200°、32.346±0.200°、33.429±0.200°、35.334±0.200° and 36.5 67±0.200°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.100°、8.475±0.100°、9.070±0.100°、11.289±0.100°、11.678±0.100°、12.363±0.100°、14.223±0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、17.000±0.100°、18.657±0.100°、19.030±0.100°、19.407±0.100°、19.882±0.100°、20.638±0.100°、21.085±0.100°、21.810±0.100°、22.836±0.100°、23.717±0.100°、24.147±0.100°、24.693±0.100°、25.311±0.100°、26.802±0.100°、27.462±0.100°、28.537±0.100°和31.264±0.100°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.736±0.100°, 8.475±0.100°, 9.070±0.100°, 11.289±0.100°, 11.678± 0.100°、12.363±0.100°、14.223±0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、17.000±0.100°、18.6 57±0.100°, 19.030± 0.100°、19.407±0.100°、19.882±0.100°、20.638±0.100°、21.085±0.100°、21.810±0.100°、22.836±0.100°、23.717±0.100°、24.147±0.100°、24.6 93±0.100°, 25.311± 0.100°, 26.802±0.100°, 27.462±0.100°, 28.537±0.100° and 31.264±0.100°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.100°、8.475±0.100°、9.070±0.100°、11.289±0.100°、11.678±0.100°、12.363±0.100°、14.223±0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、17.000±0.100°、18.657±0.100°、19.030±0.100°、19.407±0.100°、19.882±0.100°、20.638±0.100°、21.085±0.100°、21.810±0.100°、22.836±0.100°、23.717±0.100°、24.147±0.100°、24.693±0.100°、25.311±0.100°、26.802±0.100°、27.462±0.100°、28.537±0.100°、30.090±0.100°、31.264±0.100°、32.346±0.100°、33.429±0.100°、35.334±0.100°和36.567±0.100°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.736±0.100°, 8.475±0.100°, 9.070±0.100°, 11.289±0.100°, 11.678± 0.100°、12.363±0.100°、14.223±0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、17.000±0.100°、18.6 57±0.100°, 19.030± 0.100°、19.407±0.100°、19.882±0.100°、20.638±0.100°、21.085±0.100°、21.810±0.100°、22.836±0.100°、23.717±0.100°、24.147±0.100°、24.6 93±0.100°, 25.311± 0.100°、26.802±0.100°、27.462±0.100°、28.537±0.100°、30.090±0.100°、31.264±0.100°、32.346±0.100°、33.429±0.100°、35.334±0.100° and 36.5 67±0.100°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736°、 8.475°、9.070°、11.289°、11.678°、12.363°、14.223°、14.589°、14.894°、15.492°、16.061°、16.458°、17.000°、18.657°、19.030°、19.407°、19.882°、20.638°、21.085°、21.810°、22.836°、23.717°、24.147°、24.693°、25.311°、26.802°、27.462°、28.537°和31.264°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 7.736°, 8.475°、9.070°、11.289°、11.678°、12.363°、14.223°、14.589°、14.894°、15.492°、16.061°、16.458°、17.000°、18.657°、19.030°、19.407°、19.88 2°, 20.638° , 21.085°, 21.810°, 22.836°, 23.717°, 24.147°, 24.693°, 25.311°, 26.802°, 27.462°, 28.537° and 31.264°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736°、8.475°、9.070°、11.289°、11.678°、12.363°、14.223°、14.589°、14.894°、15.492°、16.061°、16.458°、17.000°、18.657°、19.030°、19.407°、19.882°、20.638°、21.085°、21.810°、22.836°、23.717°、24.147°、24.693°、25.311°、26.802°、27.462°、28.537°、30.090°、31.264°、32.346°、33.429°、35.334°和36.567°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 7.736°, 8.475°, 9.070°, 11.289°, 11.678°, 12.363°, 14.223°, 14.589 °, 14.894°, 15.492°, 16.061°, 16.458°, 17.000°, 18.657°, 19.030°, 19.407°, 19.882°, 20.638°, 21.085°, 21.810°, 22.836°, 23.717°, 24.147°, 24 .693°、 25.311°, 26.802°, 27.462°, 28.537°, 30.090°, 31.264°, 32.346°, 33.429°, 35.334° and 36.567°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.492±0.200°、16.458±0.200°、18.657±0.200°、和/或7.736±0.200°、和/或8.475±0.200°、和/或9.070±0.200°、和/或11.289±0.200°、和/或11.678±0.200°、和/或12.363±0.200°、和/或14.223±0.200°、和/或14.589±0.200°、和/或14.894±0.200°、和/或16.061±0.200°、和/或17.000±0.200°、和/或19.030±0.200°、和/或19.407±0.200°、和/或19.882±0.200°、和/或20.638±0.200°、和/或21.085±0.200°、和/或21.810±0.200°、和/或22.836±0.200°、和/或23.717±0.200°、和/或24.147±0.200°、和/或24.693±0.200°、和/或25.311±0.200°、和/或26.802±0.200°、和/或27.462±0.200°、和/或28.537±0.200°、和/或30.090±0.200°、和/或31.264±0.200°、和/或32.346±0.200°、和/或33.429±0.200°、和/或35.334±0.200°、和/或36.567±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 15.492±0.200°, 16.458±0.200°, 18.657±0.200°, and/or 7.736±0.200°. , and/or 8.475±0.200°, and/or 9.070±0.200°, and/or 11.289±0.200°, and/or 11.678±0.200°, and/or 12.363±0.200°, and/or 14.223±0.200°, and /or 14.589±0.200°, and/or 14.894±0.200°, and/or 16.061±0.200°, and/or 17.000±0.200°, and/or 19.030±0.200°, and/or 19.407±0.200°, and/or 19.882±0.200°, and/or 20.638±0.200°, and/or 21.085±0.200°, and/or 21.810±0.200°, and/or 22.836±0.200°, and/or 23.717±0.200°, and/or 24.147± 0.200°, and/or 24.693±0.200°, and/or 25.311±0.200°, and/or 26.802±0.200°, and/or 27.462±0.200°, and/or 28.537±0.200°, and/or 30.090±0.200° , and/or 31.264±0.200°, and/or 32.346±0.200°, and/or 33.429±0.200°, and/or 35.334±0.200°, and/or 36.567±0.200°.
本发明的一些方案中，上述A晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.492±0.100°、16.458±0.100°、18.657±0.100°、和/或7.736±0.100°、和/或8.475±0.100°、和/或9.070±0.100°、和/或11.289±0.100°、和/或11.678±0.100°、和/或12.363±0.100°、和/或14.223±0.100°、和/或14.589±0.100°、和/或14.894±0.100°、和/或16.061±0.100°、和/或17.000±0.100°、和/或19.030±0.100°、和/或19.407±0.100°、和/或19.882±0.100°、和/或20.638±0.100°、和/或21.085±0.100°、和/或21.810±0.100°、和/或22.836±0.100°、和/或23.717±0.100°、和/或24.147±0.100°、和/或24.693±0.100°、和/或25.311±0.100°、和/或26.802±0.100°、和/或27.462±0.100°、和/或28.537±0.100°、和/或30.090±0.100°、和/或31.264±0.100°、和/或32.346±0.100°、和/或33.429±0.100°、和/或35.334±0.100°、和/或36.567±0.100°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2θ angles: 15.492±0.100°, 16.458±0.100°, 18.657±0.100°, and/or 7.736±0.100°, and/or 8.475±0.100°, and/or 9.070±0.100°, and/or 11.289±0.100°, and/or 11.678±0.100°, and/or 12.363±0.100°, and/or 14.223±0.100°, and/or 14.589±0.100°, and/or 14.894±0.100°, and/or 16.061±0.100°, and/or 17.000±0.100°, and/or 19.030±0.100°, and/or 19.407±0.100°, and/or or 19.882±0.100°, and/or 20.638±0.100°, and/or 21.085±0.100°, and/or 21.810±0.100°, and/or 22.836±0.100°, and/or 23.717±0.100°, and/or 24.147±0.100°, and/or 24.693±0.100°, and/or 25.311±0.100°, and /or 26.802±0.100°, and/or 27.462±0.100°, and/or 28.537±0.100°, and/or 30.090±0.100°, and/or 31.264±0.100°, and/or 32.346±0.100°, and/or 33.429±0.100°, and/or 35.334±0.100°, and/or 36.567±0.100°.
本发明的一些方案中，上述A晶型的XRPD图谱基本如图1所示。In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form A is basically as shown in Figure 1.
本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示。In some solutions of the present invention, the XRPD spectrum analysis data of the above-mentioned crystal form A is shown in Table 1.
表1式(I)化合物A晶型的XRPD图谱解析数据

Table 1 XRPD spectrum analysis data of compound A crystal form of formula (I)

本发明的一些方案中，上述A晶型，其差示扫描量热曲线在169.0±5℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak starting point at 169.0±5°C.
本发明的一些方案中，上述A晶型，其差示扫描量热曲线在31.6±5℃和169.0±5℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form A has the starting points of endothermic peaks at 31.6±5°C and 169.0±5°C.
本发明的一些方案中，上述A晶型，其DSC图谱基本如图2所示。In some aspects of the present invention, the DSC pattern of the above-mentioned crystal form A is basically as shown in Figure 2.
本发明的一些方案中，上述A晶型，其热重分析曲线在160.0±3℃时失重达1.48％。In some solutions of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form A reaches a weight loss of 1.48% at 160.0±3°C.
本发明的一些方案中，上述A晶型，其TGA图谱基本如图3所示。In some aspects of the present invention, the TGA spectrum of the above-mentioned crystal form A is basically as shown in Figure 3.
本发明还提供式(I)化合物的B晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：5.932±0.200°、12.435±0.200°、14.091±0.200°和16.496±0.200°；
The present invention also provides the B crystal form of the compound of formula (I), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2θ angles: 5.932±0.200°, 12.435±0.200°, 14.091±0.200° and 16.496 ±0.200°;
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.932±0.200°、8.551±0.200°、10.855±0.200°、12.435±0.200°、14.091±0.200°、15.171±0.200°、16.496±0.200°和23.682±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.932±0.200°, 8.551±0.200°, 10.855±0.200°, 12.435±0.200°, 14.091± 0.200°, 15.171±0.200°, 16.496±0.200° and 23.682±0.200°.
本发明的一些方案中，上述B晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的4、5、6、7或8个特征衍射峰：5.932±0.200°、8.551±0.200°、10.855±0.200°、12.435±0.200°、14.091±0.200°、15.171±0.200°、16.496±0.200°和23.682±0.200°。 In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form, expressed in 2θ angle, contains at least 4, 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 5.932±0.200 °, 8.551±0.200°, 10.855±0.200°, 12.435±0.200°, 14.091±0.200°, 15.171±0.200°, 16.496±0.200° and 23.682±0.200°.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.932±0.200°、6.751±0.200°、8.551±0.200°、9.098±0.200°、10.855±0.200°、12.435±0.200°、14.091±0.200°、15.171±0.200°、16.496±0.200°、19.193±0.200°、20.501±0.200°和23.682±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.932±0.200°, 6.751±0.200°, 8.551±0.200°, 9.098±0.200°, 10.855± 0.200°, 12.435±0.200°, 14.091±0.200°, 15.171±0.200°, 16.496±0.200°, 19.193±0.200°, 20.501±0.200° and 23.682±0.200°.
本发明的一些方案中，上述B晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的8、9、10、11或12个特征衍射峰：5.932±0.200°、6.751±0.200°、8.551±0.200°、9.098±0.200°、10.855±0.200°、12.435±0.200°、14.091±0.200°、15.171±0.200°、16.496±0.200°、19.193±0.200°、20.501±0.200°和23.682±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form, expressed in 2θ angle, contains at least 8, 9, 10, 11 or 12 characteristic diffraction peaks selected from the following: 5.932±0.200 °, 6.751±0.200°, 8.551±0.200°, 9.098±0.200°, 10.855±0.200°, 12.435±0.200°, 14.091±0.200°, 15.171±0.200°, 16.496±0.200°, 19.193±0.200° ,20.501±0.200 ° and 23.682±0.200°.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.932±0.200°、6.751±0.200°、8.551±0.200°、9.098±0.200°、10.186±0.200°、10.855±0.200°、11.710±0.200°、12.435±0.200°、14.091±0.200°、15.171±0.200°、16.049±0.200°、16.496±0.200°、17.438±0.200°、18.658±0.200°、19.193±0.200°、20.501±0.200°、21.241±0.200°、21.977±0.200°、23.682±0.200°、26.127±0.200°、26.981±0.200°和29.033±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.932±0.200°, 6.751±0.200°, 8.551±0.200°, 9.098±0.200°, 10.186± 0.200°、10.855±0.200°、11.710±0.200°、12.435±0.200°、14.091±0.200°、15.171±0.200°、16.049±0.200°、16.496±0.200°、17.438±0.200°、18.6 58±0.200°, 19.193± 0.200°, 20.501±0.200°, 21.241±0.200°, 21.977±0.200°, 23.682±0.200°, 26.127±0.200°, 26.981±0.200° and 29.033±0.200°.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.932°、6.751°、8.551°、9.098°、10.186°、10.855°、11.710°、12.435°、14.091°、15.171°、16.049°、16.496°、17.438°、18.658°、19.193°、20.501°、21.241°、21.977°、23.682°、26.127°、26.981°和29.033°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.932°, 6.751°, 8.551°, 9.098°, 10.186°, 10.855°, 11.710°, 12.435 °, 14.091°, 15.171°, 16.049°, 16.496°, 17.438°, 18.658°, 19.193°, 20.501°, 21.241°, 21.977°, 23.682°, 26.127°, 26.981° and 29.033°.
本发明的一些方案中，上述B晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.932±0.200°、12.435±0.200°、14.091±0.200°、和/或6.751±0.200°、和/或8.551±0.200°、和/或9.098±0.200°、和/或10.186±0.200°、和/或10.855±0.200°、和/或11.710±0.200°、和/或12.435±0.200°、和/或14.091±0.200°、和/或15.171±0.200°、和/或16.049±0.200°、和/或16.496±0.200°、和/或17.438±0.200°、和/或18.658±0.200°、和/或19.193±0.200°、和/或20.501±0.200°、和/或21.241±0.200°、和/或21.977±0.200°、和/或23.682±0.200°、和/或26.127±0.200°、和/或26.981±0.200°、和/或29.033±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 5.932±0.200°, 12.435±0.200°, 14.091±0.200°, and/or 6.751±0.200°. , and/or 8.551±0.200°, and/or 9.098±0.200°, and/or 10.186±0.200°, and/or 10.855±0.200°, and/or 11.710±0.200°, and/or 12.435±0.200°, and /or 14.091±0.200°, and/or 15.171±0.200°, and/or 16.049±0.200°, and/or 16.496±0.200°, and/or 17.438±0.200°, and/or 18.658±0.200°, and/or 19.193±0.200°, and/or 20.501±0.200°, and/or 21.241±0.200°, and/or 21.977±0.200°, and/or 23.682±0.200°, and/or 26.127±0.200°, and/or 26.981± 0.200°, and/or 29.033±0.200°.
本发明的一些方案中，上述B晶型的XRPD图谱基本如图4所示。In some solutions of the present invention, the XRPD pattern of the above-mentioned B crystal form is basically as shown in Figure 4.
本发明的一些方案中，上述B晶型的XRPD图谱解析数据如表2所示。In some aspects of the present invention, the XRPD spectrum analysis data of the above-mentioned Form B is shown in Table 2.
表2式(I)化合物B晶型的XRPD图谱解析数据
Table 2 XRPD spectrum analysis data of compound B crystal form of formula (I)
本发明的一些方案中，上述B晶型，其差示扫描量热曲线在64.5±5℃和121.7±5℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned B crystal form has the starting points of endothermic peaks at 64.5±5°C and 121.7±5°C.
本发明的一些方案中，上述B晶型，其DSC图谱基本如图5所示。In some aspects of the present invention, the DSC pattern of the above-mentioned B crystal form is basically as shown in Figure 5.
本发明的一些方案中，上述B晶型，其热重分析曲线在105.0±3℃时失重达4.01％。In some solutions of the present invention, the thermogravimetric analysis curve of the above-mentioned B crystal form has a weight loss of 4.01% at 105.0±3°C.
本发明的一些方案中，上述B晶型，其TGA图谱基本如图6所示。In some solutions of the present invention, the TGA spectrum of the above-mentioned B crystal form is basically as shown in Figure 6.
本发明还提供式(I)化合物的C晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：13.546±0.200°、14.908±0.200°、15.539±0.200°、18.230±0.200°和22.932±0.200°；
The present invention also provides the C crystal form of the compound of formula (I), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2θ angles: 13.546±0.200°, 14.908±0.200°, 15.539±0.200°, 18.230 ±0.200° and 22.932±0.200°;
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.546±0.200°、14.908±0.200°、15.539±0.200°、16.401±0.200°、18.230±0.200°、18.699±0.200°、20.226±0.200°和22.932±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 13.546±0.200°, 14.908±0.200°, 15.539±0.200°, 16.401±0.200°, 18.230± 0.200°, 18.699±0.200°, 20.226±0.200° and 22.932±0.200°.
本发明的一些方案中，上述C晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的4、5、6、7或8个特征衍射峰：13.546±0.200°、14.908±0.200°、15.539±0.200°、16.401±0.200°、18.230±0.200°、18.699±0.200°、20.226±0.200°和22.932±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form, expressed in 2θ angle, contains at least 4, 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 13.546±0.200 °, 14.908±0.200°, 15.539±0.200°, 16.401±0.200°, 18.230±0.200°, 18.699±0.200°, 20.226±0.200° and 22.932±0.200°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.410±0.200°、8.474±0.200°、13.546±0.200°、14.122±0.200°、14.908±0.200°、15.539±0.200°、16.401±0.200°、18.230±0.200°、18.699±0.200°、19.665±0.200°、20.226±0.200°和22.932±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.410±0.200°, 8.474±0.200°, 13.546±0.200°, 14.122±0.200°, 14.908± 0.200°, 15.539±0.200°, 16.401±0.200°, 18.230±0.200°, 18.699±0.200°, 19.665±0.200°, 20.226±0.200° and 22.932±0.200°.
本发明的一些方案中，上述C晶型，其X-射线粉末衍射图谱中，用2θ角表示，至少包含选自下列中的8、9、10、11或12个特征衍射峰：7.410±0.200°、8.474±0.200°、13.546±0.200°、14.122±0.200°、14.908±0.200°、15.539±0.200°、16.401±0.200°、18.230±0.200°、18.699±0.200°、19.665±0.200°、20.226±0.200°和22.932±0.200°。In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form, expressed by 2θ angle, contains at least 8, 9, 10, 11 or 12 characteristic diffraction peaks selected from the following: 7.410±0.200°, 8.474±0.200°, 13.546±0.200°, 14.122±0.200°, 14.908±0.200°, 15.539±0.200°, 16.401±0.200°, 18.230±0.200°, 18.699±0.200°, 19.665±0.200°, 20.226±0.200° and 22.932±0.200°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.410±0.200°、8.474±0.200°、9.093±0.200°、11.284±0.200°、13.546±0.200°、14.122±0.200°、14.908±0.200°、15.539±0.200°、16.401±0.200°、18.230±0.200°、18.699±0.200°、18.911±0.200°、19.665±0.200°、20.226±0.200°、21.508±0.200°和22.932±0.200°。 In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.410±0.200°, 8.474±0.200°, 9.093±0.200°, 11.284±0.200°, 13.546± 0.200°、14.122±0.200°、14.908±0.200°、15.539±0.200°、16.401±0.200°、18.230±0.200°、18.699±0.200°、18.911±0.200°、19.665±0.200°、20.2 26±0.200°, 21.508± 0.200° and 22.932±0.200°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.410±0.100°、8.474±0.100°、9.093±0.100°、11.284±0.100°、13.546±0.100°、14.122±0.100°、14.908±0.100°、15.539±0.100°、16.401±0.100°、18.230±0.100°、18.699±0.100°、18.911±0.100°、19.665±0.100°、20.226±0.100°、21.508±0.100°和22.932±0.100°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.410±0.100°, 8.474±0.100°, 9.093±0.100°, 11.284±0.100°, 13.546± 0.100°、14.122±0.100°、14.908±0.100°、15.539±0.100°、16.401±0.100°、18.230±0.100°、18.699±0.100°、18.911±0.100°、19.665±0.100°、20.2 26±0.100°, 21.508± 0.100° and 22.932±0.100°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.410±0.200°、8.474±0.200°、9.093±0.200°、11.284±0.200°、11.439±0.200°、13.546±0.200°、14.122±0.200°、14.908±0.200°、15.539±0.200°、16.401±0.200°、16.743±0.200°、17.169±0.200°、18.230±0.200°、18.699±0.200°、18.911±0.200°、19.665±0.200°、20.226±0.200°、21.508±0.200°、22.932±0.200°、23.907±0.200°、25.111±0.200°、27.317±0.200°、29.113±0.200°和31.325±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.410±0.200°, 8.474±0.200°, 9.093±0.200°, 11.284±0.200°, 11.439± 0.200°、13.546±0.200°、14.122±0.200°、14.908±0.200°、15.539±0.200°、16.401±0.200°、16.743±0.200°、17.169±0.200°、18.230±0.200°、18.6 99±0.200°, 18.911± 0.200°、19.665±0.200°、20.226±0.200°、21.508±0.200°、22.932±0.200°、23.907±0.200°、25.111±0.200°、27.317±0.200°、29.113±0.200° and 31.3 25±0.200°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.410±0.100°、8.474±0.100°、9.093±0.100°、11.284±0.100°、11.439±0.100°、13.546±0.100°、14.122±0.100°、14.908±0.100°、15.539±0.100°、16.401±0.100°、16.743±0.100°、17.169±0.100°、18.230±0.100°、18.699±0.100°、18.911±0.100°、19.665±0.100°、20.226±0.100°、21.508±0.100°、22.932±0.100°、23.907±0.100°、25.111±0.100°、27.317±0.100°、29.113±0.100°和31.325±0.100°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.410±0.100°, 8.474±0.100°, 9.093±0.100°, 11.284±0.100°, 11.439± 0.100°、13.546±0.100°、14.122±0.100°、14.908±0.100°、15.539±0.100°、16.401±0.100°、16.743±0.100°、17.169±0.100°、18.230±0.100°、18.6 99±0.100°, 18.911± 0.100°、19.665±0.100°、20.226±0.100°、21.508±0.100°、22.932±0.100°、23.907±0.100°、25.111±0.100°、27.317±0.100°、29.113±0.100° and 31.3 25±0.100°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.410°、8.474°、9.093°、11.284°、11.439°、13.546°、14.122°、14.908°、15.539°、16.401°、16.743°、17.169°、18.230°、18.699°、18.911°、19.665°、20.226°、21.508°、22.932°、23.907°、25.111°、27.317°、29.113°和31.325°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.410°, 8.474°, 9.093°, 11.284°, 11.439°, 13.546°, 14.122°, 14.908 °, 15.539°, 16.401°, 16.743°, 17.169°, 18.230°, 18.699°, 18.911°, 19.665°, 20.226°, 21.508°, 22.932°, 23.907°, 25.111°, 27.317°, 29.113° and 31 .325°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.410±0.200°、8.474±0.200°、9.093±0.200°、11.284±0.200°、11.439±0.200°、13.546±0.200°、14.122±0.200°、14.908±0.200°、15.539±0.200°、16.401±0.200°、16.743±0.200°、17.169±0.200°、18.230±0.200°、18.699±0.200°、18.911±0.200°、19.665±0.200°、20.226±0.200°、21.508±0.200°、22.932±0.200°、23.907±0.200°、25.111±0.200°、27.317±0.200°、29.113±0.200°和31.325±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.410±0.200°, 8.474±0.200°, 9.093±0.200°, 11.284±0.200°, 11.439± 0.200°、13.546±0.200°、14.122±0.200°、14.908±0.200°、15.539±0.200°、16.401±0.200°、16.743±0.200°、17.169±0.200°、18.230±0.200°、18.6 99±0.200°, 18.911± 0.200°、19.665±0.200°、20.226±0.200°、21.508±0.200°、22.932±0.200°、23.907±0.200°、25.111±0.200°、27.317±0.200°、29.113±0.200° and 31.3 25±0.200°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.410±0.100°、8.474±0.100°、9.093±0.100°、11.284±0.100°、11.439±0.100°、13.546±0.100°、14.122±0.100°、14.908±0.100°、15.539±0.100°、16.401±0.100°、16.743±0.100°、17.169±0.100°、18.230±0.100°、18.699±0.100°、18.911±0.100°、19.665±0.100°、20.226±0.100°、21.508±0.100°、22.932±0.100°、23.907±0.100°、25.111±0.100°、27.317±0.100°、29.113±0.100°和31.325±0.100°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 7.410±0.100°, 8.474±0.100°, 9.093±0.100°, 11.284±0.100°, 11.439± 0.100°、13.546±0.100°、14.122±0.100°、14.908±0.100°、15.539±0.100°、16.401±0.100°、16.743±0.100°、17.169±0.100°、18.230±0.100°、18.6 99±0.100°, 18.911± 0.100°、19.665±0.100°、20.226±0.100°、21.508±0.100°、22.932±0.100°、23.907±0.100°、25.111±0.100°、27.317±0.100°、29.113±0.100° and 31.3 25±0.100°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.546±0.200°、14.908±0.200°、15.539±0.200°、和/或7.410±0.200°、和/或8.474±0.200°、和/或9.093±0.200°、和/或11.284±0.200°、和/或11.439±0.200°、和/或14.122±0.200°、和/或16.401±0.200°、和/或16.743±0.200°、和/或17.169±0.200°、和/或18.230±0.200°、和/或18.699±0.200°、和/或18.911±0.200°、和/或19.665±0.200°、 和/或20.226±0.200°、和/或21.508±0.200°、和/或22.932±0.200°、和/或23.907±0.200°、和/或25.111±0.200°、和/或27.317±0.200°、和/或29.113±0.200°、和/或31.325±0.200°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 13.546±0.200°, 14.908±0.200°, 15.539±0.200°, and/or 7.410±0.200°. , and/or 8.474±0.200°, and/or 9.093±0.200°, and/or 11.284±0.200°, and/or 11.439±0.200°, and/or 14.122±0.200°, and/or 16.401±0.200°, and /or 16.743±0.200°, and/or 17.169±0.200°, and/or 18.230±0.200°, and/or 18.699±0.200°, and/or 18.911±0.200°, and/or 19.665±0.200°, and/or 20.226±0.200°, and/or 21.508±0.200°, and/or 22.932±0.200°, and/or 23.907±0.200°, and/or 25.111±0.200°, and/or 27.317±0.200°, and/ Or 29.113±0.200°, and/or 31.325±0.200°.
本发明的一些方案中，上述C晶型的X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：13.546±0.100°、14.908±0.100°、15.539±0.100°、和/或7.410±0.100°、和/或8.474±0.100°、和/或9.093±0.100°、和/或11.284±0.100°、和/或11.439±0.100°、和/或14.122±0.100°、和/或16.401±0.100°、和/或16.743±0.100°、和/或17.169±0.100°、和/或18.230±0.100°、和/或18.699±0.100°、和/或18.911±0.100°、和/或19.665±0.100°、和/或20.226±0.100°、和/或21.508±0.100°、和/或22.932±0.100°、和/或23.907±0.100°、和/或25.111±0.100°、和/或27.317±0.100°、和/或29.113±0.100°、和/或31.325±0.100°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2θ angles: 13.546±0.100°, 14.908±0.100°, 15.539±0.100°, and/or 7.410±0.100°. , and/or 8.474±0.100°, and/or 9.093±0.100°, and/or 11.284±0.100°, and/or 11.439±0.100°, and/or 14.122±0.100°, and/or 16.401±0.100°, and /or 16.743±0.100°, and/or 17.169±0.100°, and/or 18.230±0.100°, and/or 18.699±0.100°, and/or 18.911±0.100°, and/or 19.665±0.100°, and/or 20.226±0.100°, and/or 21.508±0.100°, and/or 22.932±0.100°, and/or 23.907±0.100°, and/or 25.111±0.100°, and/or 27.317±0.100°, and/or 29.113± 0.100°, and/or 31.325±0.100°.
本发明的一些方案中，上述C晶型的XRPD图谱基本如图7所示。In some solutions of the present invention, the XRPD pattern of the above-mentioned crystal form C is basically as shown in Figure 7.
本发明的一些方案中，上述C晶型的XRPD图谱解析数据如表3所示。In some solutions of the present invention, the XRPD spectrum analysis data of the above-mentioned C crystal form is shown in Table 3.
表3式(I)化合物C晶型的XRPD图谱解析数据
Table 3 XRPD spectrum analysis data of the crystal form of compound C of formula (I)
本发明的一些方案中，上述C晶型，其差示扫描量热曲线在169.2±5℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form C has an endothermic peak starting point at 169.2±5°C.
本发明的一些方案中，上述C晶型，其DSC图谱基本如图8所示。In some aspects of the present invention, the DSC pattern of the above-mentioned crystal form C is basically as shown in Figure 8.
本发明的一些方案中，上述C晶型，其热重分析曲线在130.0±3℃时失重达2.00％。In some solutions of the present invention, the weight loss of the above-mentioned C crystal form in the thermogravimetric analysis curve reaches 2.00% at 130.0±3°C.
本发明的一些方案中，上述C晶型，其TGA图谱基本如图9所示。In some aspects of the present invention, the TGA spectrum of the above-mentioned crystal form C is basically as shown in Figure 9.
本发明还提供了上述式(I)化合物的晶型在制备治疗KRAS突变实体瘤疾病的药物中的应用。The present invention also provides the use of the crystalline form of the compound of formula (I) in the preparation of a drug for treating KRAS mutant solid tumor diseases.
本发明还提供了上述式(I)化合物的A晶型在制备治疗KRAS突变实体瘤疾病的药物中的应用。The present invention also provides the use of crystal form A of the compound of formula (I) above in the preparation of drugs for treating KRAS mutant solid tumor diseases.
本发明还提供了上述式(I)化合物的晶型的如下生物测试方法：The present invention also provides the following biological testing method for the crystal form of the compound of formula (I) above:
测试方法1：化合物在Miapaca2裸鼠移植瘤模型的体内药效评价Test method 1: In vivo efficacy evaluation of compounds in Miapaca2 nude mouse transplanted tumor model
细胞培养： Cell culture:
人胰腺癌细胞(Miapaca2),体外贴壁单层培养,培养条件为DMEM培养基中加10％胎牛血清,37℃,5％CO2孵箱培养。一周两到三次用胰酶–EDTA进行常规消化处理传代。当细胞饱和度为80％–90％,数量到达要求时,收取细胞,计数,接种。Human pancreatic cancer cells (Miapaca2) were cultured in adherent monolayer in vitro. The culture conditions were DMEM medium plus 10% fetal calf serum at 37°C in a 5% CO 2 incubator. Passages were performed with routine digestion using trypsin–EDTA two to three times a week. When the cell saturation is 80%–90% and the number reaches the required number, collect the cells, count, and inoculate.
实验动物：Experimental animals:
Balb/c裸小鼠,雌性,6-7周,购自上海西普尔-必凯实验动物有限公司。Balb/c nude mice, female, 6-7 weeks old, were purchased from Shanghai Sipur-Bike Experimental Animal Co., Ltd.
模型制备：Model preparation:
将0.2mL(5×106个)Miapaca2细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背,肿瘤平均体积达到118mm3时开始分组给药。0.2 mL (5 × 10 6 ) Miapaca2 cells (added with matrix, volume ratio 1:1) were subcutaneously inoculated into the right back of each mouse. Administration in groups was started when the average tumor volume reached 118 mm 3 .
肿瘤测量和实验指标：Tumor measurements and experimental parameters:
每周两次用游标卡尺测量肿瘤直径,肿瘤体积以立方毫米计量,通过以下的公式计算:V＝0.5a×b2,其中a和b分别是肿瘤的长径和短径。受试化合物的抑瘤疗效通过使用TGI(％)来评价。TGI(％),反映肿瘤生长抑制率。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％。Tumor diameter was measured twice a week with a vernier caliper, and tumor volume was measured in cubic millimeters and calculated by the following formula: V=0.5a×b 2 , where a and b are the major and minor diameters of the tumor, respectively. The tumor inhibitory efficacy of the test compounds was evaluated by using TGI (%). TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [1 – (average tumor volume at the end of treatment in a certain treatment group - average tumor volume at the beginning of treatment in the treatment group)/(average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group) Tumor volume)]×100%.
实验结论：本发明的化合物与AMG-510联用在Miapaca2裸鼠移植瘤模型中展现出优异的抑瘤效果。Experimental conclusion: The compound of the present invention combined with AMG-510 showed excellent tumor inhibitory effect in the Miapaca2 nude mouse transplanted tumor model.
技术效果Technical effect
本发明化合物能较好的抑制SOS1的活性；还对DLD-1细胞p-ERK增殖抑制活性明显，并且具有良好的药代动力学性质(包括良好的口服生物利用度,口服暴露量,半衰期和清除率等)；化合物对hERG钾离子通道无显著抑制作用，安全性高；本发明化合物对人胰腺癌Miapaca-2异种移植瘤模型具有优异的抑瘤效果。本发明式(I)化合物的晶型易于获得、物理稳定性和化学稳定性均较好，具有很高的工业应用价值和经济价值。The compound of the present invention can better inhibit the activity of SOS1; it also has obvious inhibitory activity on the proliferation of DLD-1 cell p-ERK, and has good pharmacokinetic properties (including good oral bioavailability, oral exposure, half-life and clearance rate, etc.); the compound has no significant inhibitory effect on the hERG potassium ion channel and is highly safe; the compound of the present invention has excellent tumor inhibitory effect on the human pancreatic cancer Miapaca-2 xenograft tumor model. The crystal form of the compound of formula (I) of the present invention is easy to obtain, has good physical and chemical stability, and has high industrial application value and economic value.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
必须注意的是，除非上下文另有明确说明或与本文明显相悖，否则如本文和所附权利要求所用的本发明的内容(尤其随附权利要求书的内容)中使用的单数形式“一”、“一个”、“所述”及类似术语应解释为包括单数和复数两者。因此，例如，提及“所述化合物”包括提及一种或多种化合物；等等。It must be noted that, as used herein and in the appended claims, the singular forms "a", "a", "A", "the" and similar terms shall be construed to include both the singular and the plural. Thus, for example, reference to "the compound" includes reference to one or more compounds; and so on.
本发明所述晶型的差示扫描量热测定(DSC)有实验误差，并受样品的干燥程度有轻微影响，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于10℃，或小于等于9℃，或小于等于8℃，或小于等于7℃，或小于等于6℃，或小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸 热峰的峰位置或峰值的数值不能视为绝对的。Differential scanning calorimetry (DSC) of the crystalline forms described in this invention is subject to experimental error and is slightly affected by the degree of dryness of the sample, from one machine to another and from one sample to another. , the position and peak value of the endothermic peak may be slightly different, and the experimental error or difference may be less than or equal to 10°C, or less than or equal to 9°C, or less than or equal to 8°C, or less than or equal to 7°C, or less than or equal to 6°C. Or less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C, so the DSC absorbs The peak position of a thermal peak or the numerical value of a peak cannot be considered absolute.
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art. Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present invention are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, those skilled in the art sometimes need to modify or select the synthesis steps or reaction procedures based on the existing embodiments.
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。The present invention will be described in detail through examples below. These examples do not mean any limitation to the present invention.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。All solvents used in the present invention are commercially available and used without further purification.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：Boc代表叔丁氧基羰基；DCM代表二氯甲烷；DMF代表N，N-二甲基甲酰胺；THF代表四氢呋喃；DMSO代表二甲亚砜；EtOH代表乙醇；MeOH代表甲醇；ACN(MeCN)代表乙腈；EtOAc代表乙酸乙酯；H2O代表水；Acetone代表丙酮；IPAc代表乙酸异丙酯；MTBE代表甲基叔丁基醚；1,4-Dioxane代表1,4-二氧六环；n-Heptane代表正庚烷；i-PrOAc代表醋酸异丙酯；TEA代表三乙胺；DIPEA代表二异丙基乙胺；BID代表每天两次；QD代表每天一次；p.o.代表口服。The present invention uses the following abbreviations: Boc represents tert-butoxycarbonyl; DCM represents dichloromethane; DMF represents N, N-dimethylformamide; THF represents tetrahydrofuran; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; MeOH represents methanol; ACN (MeCN) represents acetonitrile; EtOAc represents ethyl acetate; H 2 O represents water; Acetone represents acetone; IPAc represents isopropyl acetate; MTBE represents methyl tert-butyl ether; 1,4-Dioxane represents 1 , 4-dioxane; n-Heptane represents n-heptane; i-PrOAc represents isopropyl acetate; TEA represents triethylamine; DIPEA represents diisopropylethylamine; BID represents twice a day; QD represents once a day ;po stands for oral administration.
化合物经手工或者软件命名，市售化合物采用供应商目录名称。Compounds are prepared manually or For software naming, commercially available compounds adopt supplier catalog names.
本发明仪器及分析方法Instrument and analysis method of the present invention
本发明X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法一，测试参数见表4。X-ray powder diffraction (X-ray powder diffractometer, XRPD) method one of the present invention, the test parameters are shown in Table 4.
表4 XRPD测试参数

Table 4 XRPD test parameters

本发明X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法二，测试参数见表5。X-ray powder diffraction (X-ray powder diffractometer, XRPD) method two of the present invention, the test parameters are shown in Table 5.
表5 XRPD测试参数
Table 5 XRPD test parameters
本发明差热分析(Differential Scanning Calorimeter,DSC)方法，测试参数见表6。The test parameters of the differential scanning calorimeter (DSC) method of the present invention are shown in Table 6.
表6 DSC测试参数
Table 6 DSC test parameters
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法，测试参数见表7。The test parameters of the thermogravimetric analyzer (TGA) method of the present invention are shown in Table 7.
表7 TGA测试参数

Table 7 TGA test parameters

本发明动态蒸汽吸附分析(Dynamic Vapor Sorption,DVS)方法，测试参数见表8。The test parameters of the dynamic vapor adsorption analysis (Dynamic Vapor Sorption, DVS) method of the present invention are shown in Table 8.
表8 DVS测试参数
Table 8 DVS test parameters
附图说明Description of the drawings
图1：式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图。Figure 1: XRPD spectrum of Cu-Kα radiation of crystal form A of compound of formula (I).
图2：式(I)化合物A晶型的DSC谱图。Figure 2: DSC spectrum of crystal form A of compound of formula (I).
图3：式(I)化合物A晶型的TGA谱图。Figure 3: TGA spectrum of crystalline form A of compound (I).
图4：式(I)化合物B晶型的Cu-Kα辐射的XRPD谱图。Figure 4: XRPD spectrum of Cu-Kα radiation of compound B crystal form of formula (I).
图5：式(I)化合物B晶型的DSC谱图。Figure 5: DSC spectrum of crystal form B of compound of formula (I).
图6：式(I)化合物B晶型的TGA谱图。Figure 6: TGA spectrum of crystal form B of compound of formula (I).
图7：式(I)化合物C晶型的Cu-Kα辐射的XRPD谱图。Figure 7: Cu-Kα radiation XRPD spectrum of compound C crystal form of formula (I).
图8：式(I)化合物C晶型的DSC谱图。Figure 8: DSC spectrum of crystal form C of compound of formula (I).
图9：式(I)化合物C晶型的TGA谱图。Figure 9: TGA spectrum of crystal form C of compound of formula (I).
图10：式(I)化合物A晶型的DVS谱图。 Figure 10: DVS spectrum of crystal form A of compound of formula (I).
图11：式(I)化合物的单晶X射线衍射(SXRD)立体结构椭球图。Figure 11: Single crystal X-ray diffraction (SXRD) three-dimensional structure ellipsoid diagram of the compound of formula (I).
具体实施方式Detailed ways
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。In order to better understand the content of the present invention, further description is given below with reference to specific embodiments, but the specific implementations do not limit the content of the present invention.
实施例1：式(I)化合物的盐酸盐的制备Example 1: Preparation of hydrochloride salt of compound of formula (I)
合成路线：
synthetic route:
第一步first step
将化合物1(10.0g,49.9mmol)溶于甲醇(100mL)中,加入甲醛水溶液(20.3g,250mmol,纯度：37％),氰基硼氢化钠(9.41g,150mmol)和乙酸(15.0g,250mmol),在25℃下搅拌反应12小时。向反应液中加入水(300mL),用乙酸乙酯(200mL×3)萃取,有机相用饱和食盐水(100mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,1/0～10/1,V/V),分离得到化合物2。1H NMR(400MHz,CDCl3)δ4.21-4.18(m,1H),3.82-3.79(m,1H),3.13-3.06(m,1H),2.74-2.70(m,1H),2.60-2.52(m,1H),2.24(s,3H),2.11-2.07(m,1H),1.93-1.86(m,1H),1.45(s,9H),1.29(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H]+215,实测值215。Compound 1 (10.0g, 49.9mmol) was dissolved in methanol (100mL), and formaldehyde aqueous solution (20.3g, 250mmol, purity: 37%), sodium cyanoborohydride (9.41g, 150mmol) and acetic acid (15.0g) were added. 250mmol), stir and react at 25°C for 12 hours. Water (300mL) was added to the reaction solution, extracted with ethyl acetate (200mL×3), the organic phase was washed with saturated brine (100mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was passed through silica gel Compound 2 was separated and purified by column chromatography (dichloromethane/methanol, 1/0~10/1, V/V). 1 H NMR (400MHz, CDCl 3 ) δ4.21-4.18(m,1H),3.82-3.79(m,1H),3.13-3.06(m,1H),2.74-2.70(m,1H),2.60-2.52 (m,1H),2.24(s,3H),2.11-2.07(m,1H),1.93-1.86(m,1H),1.45(s,9H),1.29(d,J=7.2Hz,3H). MS-ESI calculated value [M+H] + 215, measured value 215.
第二步Step 2
将化合物2(7.25g,33.8mmol)溶于二氧六环(50mL)中,滴加氯化氢/二氧六环溶液(4M,67.6mL),反应液于25℃搅拌12小时,将反应液减压浓缩得到粗品化合物3的盐酸盐。1H NMR(400MHz,CD3OD)δ3.82-3.73(m,3H),3.74-3.66(m,1H),3.66-3.31(m,3H),3.02(s,3H),1.47(d,J＝7.2Hz,3H)。Dissolve compound 2 (7.25g, 33.8mmol) in dioxane (50mL), add hydrogen chloride/dioxane solution (4M, 67.6mL) dropwise, and stir the reaction solution at 25°C for 12 hours. Reduce the reaction solution to Concentrate under pressure to obtain crude compound 3 hydrochloride. 1 H NMR (400MHz, CD 3 OD) δ3.82-3.73(m,3H),3.74-3.66(m,1H),3.66-3.31(m,3H),3.02(s,3H),1.47(d, J=7.2Hz,3H).
第三步third step
将化合物3的盐酸盐(811mg,5.39mmol)溶于N,N-二甲基甲酰胺(15mL)中,滴加三乙胺(1.64g,16.2mmol)和化合物4(1.00g,2.69mmol),在25℃下搅拌反应12小时。过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,20/1～1/1,V/V),得到化合物5。MS-ESI计算值[M+H]+347,实测值347。 Dissolve the hydrochloride of compound 3 (811mg, 5.39mmol) in N,N-dimethylformamide (15mL), and add triethylamine (1.64g, 16.2mmol) and compound 4 (1.00g, 2.69mmol) dropwise. ), stir the reaction at 25°C for 12 hours. Filter, concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (dichloromethane/methanol, 20/1~1/1, V/V) to obtain compound 5. MS-ESI calculated value [M+H] + 347, measured value 347.
第四步the fourth step
将化合物5(254mg,733μmol)溶于二氯甲烷(5mL)中,加入化合物6(333mg,1.10mmol),4-二甲基氨基吡啶(8.96mg,73.3μmol)和N,N-二异丙基乙胺(284mg,2.20mmol),在25℃下搅拌反应12小时。向反应液中加入水(50mL),用乙酸乙酯(40mL×5)萃取,有机相用饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,1/0～10/1,V/V),得到化合物7。MS-ESI计算值[M+H]+613,实测值613。Compound 5 (254 mg, 733 μmol) was dissolved in dichloromethane (5 mL), and compound 6 (333 mg, 1.10 mmol), 4-dimethylaminopyridine (8.96 mg, 73.3 μmol) and N, N-diisopropyl were added. Ethylamine (284 mg, 2.20 mmol) was stirred and reacted at 25°C for 12 hours. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (40 mL × 5), the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was passed through silica gel Separate and purify by column chromatography (dichloromethane/methanol, 1/0~10/1, V/V) to obtain compound 7. MS-ESI calculated value [M+H] + 613, measured value 613.
第五步the fifth step
将化合物7(154mg,251μmol)溶于二甲基亚砜(5mL)中,加入化合物8(93.2mg,377μmol)和三乙胺(76.3mg,754μmol),在90℃下搅拌反应12小时。向反应液中加入水(50mL),用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(50mL×5)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈5％-30％,10min)得到式(I)化合物的盐酸盐。1H NMR(400MHz,CD3OD)δ8.40(s,1H),7.61(t,J＝7.2Hz,1H),7.42(t,J＝6.8Hz,1H),7.23(t,J＝7.2Hz,1H),7.16(s,1H),6.01-5.99(m,1H),4.93-4.86(m,1H)4.68-4.22(m,1H),4.04(s,3H),3.62-3.55(m,4H),3.23-3.19(m,1H),2.99(s,3H),2.62(s,3H),1.74(d,J＝6.8Hz,3H),1.57-1.48(m,3H),1.29(s,6H)。MS-ESI计算值[M+H]+576,实测值576。Compound 7 (154 mg, 251 μmol) was dissolved in dimethyl sulfoxide (5 mL), compound 8 (93.2 mg, 377 μmol) and triethylamine (76.3 mg, 754 μmol) were added, and the reaction was stirred at 90°C for 12 hours. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated brine (50 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was prepared High performance liquid chromatography separation and purification (chromatographic column: Xtimate C18 150×40mm×5μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 5%-30%, 10min) to obtain the hydrochloride of the compound of formula (I) . 1 H NMR (400MHz, CD 3 OD) δ8.40 (s, 1H), 7.61 (t, J = 7.2Hz, 1H), 7.42 (t, J = 6.8Hz, 1H), 7.23 (t, J = 7.2 Hz,1H),7.16(s,1H),6.01-5.99(m,1H),4.93-4.86(m,1H)4.68-4.22(m,1H),4.04(s,3H),3.62-3.55(m ,4H),3.23-3.19(m,1H),2.99(s,3H),2.62(s,3H),1.74(d,J＝6.8Hz,3H),1.57-1.48(m,3H),1.29( s,6H). MS-ESI calculated value [M+H] + 576, measured value 576.
实施例2：式(I)化合物A晶型的制备Example 2: Preparation of crystal form A of compound of formula (I)
合成路线：
synthetic route:
第一步first step
将式(I)化合物的盐酸盐(2.50g，4.34mmol)溶于水(100mL)和乙酸乙酯(100mL)中,向溶液中加入饱和碳酸钠溶液至pH为10左右,用乙酸乙酯(100mL×3)萃取,合并有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,冻干得到式(I)化合物。MS-ESI计算值[M+H]+576,实测值576。Dissolve the hydrochloride of the compound of formula (I) (2.50g, 4.34mmol) in water (100mL) and ethyl acetate (100mL), add saturated sodium carbonate solution to the solution until the pH is about 10, and use ethyl acetate to (100 mL × 3) extraction, the combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and freeze-dried to obtain the compound of formula (I). MS-ESI calculated value [M+H] + 576, measured value 576.
第二步Step 2
将式(I)化合物(150mg，261μmol)加入正庚烷(1.5mL)中,反应液在50℃下搅拌24小时后,在25℃下搅拌2小时,过滤,滤饼用正庚烷(3mL)洗涤,真空50℃干燥得到式(I)化合物的A晶型。1H NMR(400MHz,CD3OD)δ8.05(s,1H),7.51(t,J＝6.8Hz,1H),7.35(t,J＝6.8Hz,1H),7.13(t,J＝7.6Hz,1H),7.09(s, 1H),5.88-5.78(m,1H),4.79-4.00(m,2H),3.94(s,3H),3.48-3.32(m,1H),2.95-2.76(m,2H),2.41(s,3H),2.32(s,3H),2.29-2.21(m,1H),2.14-2.00(m,1H),1.63(d,J＝6.8Hz,3H),1.42(s,3H),1.33-1.22(m,6H)。MS-ESI计算值[M+H]+576,实测值576。式(I)化合物A晶型的XRPD使用相应的方法一测试，其XRPD、DSC，TGA，DVS检测结果依次如图1、图2、图3和图10所示。The compound of formula (I) (150 mg, 261 μmol) was added to n-heptane (1.5 mL), the reaction solution was stirred at 50°C for 24 hours, then stirred at 25°C for 2 hours, filtered, the filter cake was washed with n-heptane (3 mL), and vacuum dried at 50°C to obtain the A crystal form of the compound of formula (I). 1 H NMR (400 MHz, CD 3 OD) δ8.05 (s, 1H), 7.51 (t, J = 6.8 Hz, 1H), 7.35 (t, J = 6.8 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.09 (s, 1H), 5.88-5.78 (m, 1H), 4.79-4.00 (m, 2H), 3.94 (s, 3H), 3.48-3.32 (m, 1H), 2.95-2.76 (m, 2H), 2.41 (s, 3H), 2.32 (s, 3H), 2.29-2.21 (m, 1H), 2.14-2.00 (m, 1H), 1.63 (d, J = 6.8 Hz, 3H), 1.42 (s, 3H), 1.33-1.22 (m, 6H). MS-ESI calculated value [M+H] + 576, found 576. The XRPD of the crystal form A of the compound of formula (I) was tested using the corresponding method 1, and the XRPD, DSC, TGA, and DVS test results are shown in Figures 1, 2, 3, and 10, respectively.
将上述第二步中的正庚烷溶剂替换为表9中的溶剂，均得到式(I)化合物的A晶型。实验结果如表9所示。The n-heptane solvent in the second step above was replaced with the solvent in Table 9, and crystal form A of the compound of formula (I) was obtained. The experimental results are shown in Table 9.
表9 50℃悬浮搅拌试验
Table 9 50℃ suspension stirring test
实施例3：式(I)化合物B晶型的制备Example 3: Preparation of crystal form B of compound of formula (I)
将式(I)化合物(150mg，261μmol)加入水(1.5mL)中,反应液在50℃下搅拌24小时后,在25℃下搅拌2小时,反应液中有固体析出,过滤,滤饼用水(3mL)洗涤,真空50℃干燥得到式(I)化合物的B晶型。1H NMR(400MHz,CD3OD)δ8.05(s,1H),7.50(t,J＝6.8Hz,1H),7.35(t,J＝6.8Hz,1H),7.13(t,J＝7.8Hz,1H),7.09(s,1H),5.87-5.79(m,1H),4.72-4.03(m,2H),3.94(s,3H),3.50-3.32(m,1H),2.92-2.76(m,2H),2.41(s,3H),2.32(s,3H),2.29-2.23(m,1H),2.13-2.01(m,1H),1.62(d,J＝7.2Hz,3H),1.43(s,3H),1.35-1.24(m,6H)。MS-ESI计算值[M+H]+576,实测值576。式(I)化合物B晶型的XRPD使用相应的方法二测试，其XRPD，DSC，TGA检测结果依次如图4、图5和图6所示。Add the compound of formula (I) (150 mg, 261 μmol) to water (1.5 mL). The reaction solution is stirred at 50°C for 24 hours and then at 25°C for 2 hours. If a solid precipitates in the reaction solution, filter it and use water for the filter cake. (3mL), and dried under vacuum at 50°C to obtain the B crystal form of the compound of formula (I). 1 H NMR (400MHz, CD 3 OD) δ8.05(s,1H),7.50(t,J＝6.8Hz,1H),7.35(t,J＝6.8Hz,1H),7.13(t,J＝7.8 Hz,1H),7.09(s,1H),5.87-5.79(m,1H),4.72-4.03(m,2H),3.94(s,3H),3.50-3.32(m,1H),2.92-2.76( m,2H),2.41(s,3H),2.32(s,3H),2.29-2.23(m,1H),2.13-2.01(m,1H),1.62(d,J＝7.2Hz,3H),1.43 (s,3H),1.35-1.24(m,6H). MS-ESI calculated value [M+H] + 576, measured value 576. The XRPD of the crystal form B of the compound of formula (I) was tested using the corresponding method 2. The XRPD, DSC, and TGA detection results are shown in Figure 4, Figure 5, and Figure 6 in sequence.
实施例4：式(I)化合物C晶型的制备Example 4: Preparation of crystal form C of compound of formula (I)
将式(I)化合物(300mg，521μmol)溶于醋酸异丙酯(1.5mL)中,反应液在25℃下搅拌12小时,反应液中有固体析出,过滤,滤饼用鼓风干燥器150℃干燥得到式(I)化合物的C晶型。1H NMR(400MHz,CD3OD)δ8.04(s,1H),7.49(t,J＝6.8Hz,1H),7.38-7.31(m,1H),7.12(t,J＝7.8Hz,1H),7.09(s,1H),5.86-5.78(m,1H),4.61-3.98(m,2H),3.94(s,3H),3.48-3.32(m,1H),2.92-2.85(m,1H),2.83-2.75(m,1H),2.41(s,3H),2.31(s,3H),·2.29-2.23(m,1H),2.12-2.01(m,1H),1.62(d,J＝7.2Hz,3H),1.43(s,3H),1.33-1.27(m,6H)。MS-ESI计算值[M+H]+576,实测值576。式(I)化合物C晶型的XRPD使用相应的方法二测试，其XRPD，DSC，TGA检测结果依次如图7、图8和图9所示。Dissolve the compound of formula (I) (300 mg, 521 μmol) in isopropyl acetate (1.5 mL). The reaction solution is stirred at 25°C for 12 hours. If a solid precipitates in the reaction solution, filter it and dry the filter cake with a blast dryer for 150 seconds. ℃ drying to obtain the C crystal form of the compound of formula (I). 1 H NMR (400MHz, CD 3 OD) δ8.04(s,1H),7.49(t,J＝6.8Hz,1H),7.38-7.31(m,1H),7.12(t,J＝7.8Hz,1H ),7.09(s,1H),5.86-5.78(m,1H),4.61-3.98(m,2H),3.94(s,3H),3.48-3.32(m,1H),2.92-2.85(m,1H ),2.83-2.75(m,1H),2.41(s,3H),2.31(s,3H),·2.29-2.23(m,1H),2.12-2.01(m,1H),1.62(d,J＝ 7.2Hz,3H),1.43(s,3H),1.33-1.27(m,6H). MS-ESI calculated value [M+H] + 576, measured value 576. The XRPD of the crystal form C of the compound of formula (I) was tested using the corresponding method 2. The XRPD, DSC, and TGA detection results are shown in Figure 7, Figure 8, and Figure 9 in sequence.
实施例5：式(I)化合物A晶型的固体预稳定性试验 Example 5: Solid pre-stability test of crystal form A of compound of formula (I)
依据《原料药与制剂稳定性试验指导原则》(中国药典2020版四部通则9001)，考察式(I)化合物A晶型在高温(60℃，敞口)，高湿(25℃/相对湿度92.5％，敞口)，强光照(5000lx与紫外强度90μw/cm2，敞口)以及高温高湿条件下(40℃/相对湿度75％以及60℃/相对湿度75％或30℃/相对湿度65％，敞口)的预稳定性。According to the "Guiding Principles for Stability Testing of Raw Materials and Preparations" (Chinese Pharmacopoeia 2020 Edition Four General Chapters 9001), the crystal form of compound A of formula (I) was investigated at high temperature (60°C, exposed) and high humidity (25°C/relative humidity 92.5 %, exposure), strong light (5000lx and UV intensity 90μw/cm 2 , exposure) and high temperature and high humidity conditions (40℃/relative humidity 75% and 60℃/relative humidity 75% or 30℃/relative humidity 65 %, exposure) prestability.
称取式(I)化合物A晶型每份约30mg，置于干燥洁净的玻璃瓶中，摊成薄薄一层，作为供试样品，放置于影响因素条件下和加速条件下，其样品为完全暴露放样。高温、高湿在5天、10天取样分析，加速条件在1个月、2个月和3个月取样分析。光照条件下放置的样品为室温完全暴露放样。不同条件下放置的样品检测XRPD，检测结果与0天的初始检测结果进行比较，结果见下表10，结果表明式(I)化合物A晶型为稳定晶型。Weigh about 30 mg of each crystal form of compound A of formula (I), place it in a dry and clean glass bottle, spread it into a thin layer, and use it as a test sample. Place it under the conditions of influencing factors and acceleration conditions. The sample is Completely exposed and staked out. High temperature and high humidity were sampled and analyzed at 5 and 10 days, and accelerated conditions were sampled and analyzed at 1 month, 2 months and 3 months. Samples placed under light conditions are fully exposed to room temperature. Samples placed under different conditions were tested by XRPD. The test results were compared with the initial test results on day 0. The results are shown in Table 10 below. The results show that the crystal form A of compound of formula (I) is a stable crystal form.
表10式(I)化合物A晶型预稳定性晶型结果
Table 10 Pre-stabilized crystal form results of compound A crystal form of formula (I)
实施例6：式(I)化合物A晶型的吸湿性研究Example 6: Study on hygroscopicity of crystal form A of compound of formula (I)
实验材料：Experimental Materials:
动态蒸汽吸附仪Dynamic vapor adsorption instrument
实验方法：experimental method:
称取约10-20mg式(I)化合物的A晶型置于DVS样品盘内进行测试。Weigh about 10-20 mg of Form A of the compound of formula (I) and place it in a DVS sample pan for testing.
引湿性评价分类如表11所示：The classification of moisture absorption evaluation is shown in Table 11:
表11引湿性评价分类表


注：ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重。Table 11 Hygroscopicity evaluation classification table


Note: ΔW% represents the moisture absorption weight gain of the test product at 25±1℃ and 80±2%RH.
实验结果：Experimental results:
式(I)化合物A晶型的DVS谱图如图10所示。DVS结果显示，样品在25℃/80％RH条件下吸湿增重0.3815％，样品略有吸湿性。完成DVS测试(0-95-0％RH)后，取出样品暴露在空气中测试XRPD，结果显示DVS测试前、后晶型未变。The DVS spectrum of the crystal form A of compound of formula (I) is shown in Figure 10. The DVS results show that the sample absorbs moisture and gains weight by 0.3815% under the conditions of 25°C/80% RH, and the sample is slightly hygroscopic. After completing the DVS test (0-95-0% RH), take out the sample and expose it to the air for XRPD testing. The results show that the crystal form has not changed before and after the DVS test.
实验结论：Experimental results:
式(I)化合物A晶型在25±1℃和80±2％RH下略有吸湿性，且晶型前后不变。The crystal form of compound A of formula (I) is slightly hygroscopic at 25±1°C and 80±2% RH, and the crystal form remains unchanged.
实施例:7：式(I)化合物的单晶X-射线衍射检测分析Example: 7: Single crystal X-ray diffraction detection and analysis of the compound of formula (I)
1.仪器参数和数据收集1. Instrument parameters and data collection
生产厂家：布鲁克公司；Manufacturer: Bruker Company;
仪器型号：Bruker D8 VENTUREInstrument model: Bruker D8 VENTURE
X-射线光源：采用高强度微聚焦旋转阳极光源，Cu靶；X-ray light source: high-intensity micro-focus rotating anode light source, Cu target;
功率：2.5kW；Power: 2.5kW;
管电压：50kV；Tube voltage: 50kV;
管电流：45mA；Tube current: 45mA;
测角仪：四轴(Kappa，ω，2θ，)测角仪；Goniometer: four axes (Kappa, ω, 2θ, ) goniometer;
探测器：大面积光子II型探测器，探测器有效面积14cm×10cm，探测器到样品的距离马达自动可调。Detector: Large-area photon II detector, the effective area of the detector is 14cm × 10cm, and the distance between the detector and the sample is automatically adjustable by the motor.
2.晶体培养2.Crystal culture
取10mg式(I)化合物的A晶型加入2mL乙腈中搅拌，样品全部溶解，将样品清液置于4mL半密封样品瓶中，在室温下缓慢挥发。两周后得到无色片状晶体。Add 10 mg of Form A of the compound of formula (I) to 2 mL of acetonitrile and stir until all the sample is dissolved. Place the sample clear liquid in a 4 mL semi-sealed sample bottle and slowly evaporate at room temperature. Colorless flaky crystals were obtained after two weeks.
3.检测结果3.Test results
该化合物的基本结构信息为：分子式2(C29H36F3N5O4)·CH3CN，晶系正交晶系，空间群P212121，波长晶胞参数为α＝β＝γ＝90°，晶胞体积 The basic structural information of this compound is: molecular formula 2(C 29 H 36 F 3 N 5 O 4 )·CH 3 CN, crystal system orthorhombic, space group P2 1 2 1 2 1 , wavelength The unit cell parameters are α=β=γ=90°, unit cell volume
4.结论4 Conclusion
单晶数据显示，单晶为式(I)化合物的乙腈合物。其单晶SXRD立体结构椭球图见附图11。结果显示，图中C12、C18为R，R构型。The single crystal data shows that the single crystal is the acetonitrile compound of the compound of formula (I). The ellipsoid diagram of its single crystal SXRD three-dimensional structure is shown in Figure 11. The results show that C12 and C18 in the figure are R, R configuration.
生物学活性：Biological activity:
实验例1：KRAS(G12C)和SOS1结合实验 Experimental example 1: KRAS(G12C) and SOS1 binding experiment
实验原理：Experimental principle:
小分子化合物结合在SOS1的催化位点,而抑制SOS1与KRAS(G12C)的结合。荧光标记的SOS1蛋白与荧光标记的KRAS(G12C)蛋白的结合被抑制时,发出的荧光发生改变。通过检测荧光改变,可以测试小分子阻止SOS1与KRAS(G12C)结合的能力。采用均相时间分辨荧光(HTRF)结合试验来检测本发明的化合物抑制SOS1与KRAS(G12C)相互结合的能力。Small molecule compounds bind to the catalytic site of SOS1 and inhibit the binding of SOS1 to KRAS (G12C). When the binding of fluorescently labeled SOS1 protein to fluorescently labeled KRAS (G12C) protein is inhibited, the fluorescence emitted changes. By detecting changes in fluorescence, the ability of small molecules to prevent the binding of SOS1 to KRAS (G12C) can be tested. A homogeneous time-resolved fluorescence (HTRF) binding assay was used to detect the ability of the compounds of the present invention to inhibit the binding of SOS1 and KRAS (G12C).
实验材料：Experimental Materials:
KRAS(G12C)蛋白由武汉普健生物科技有限公司表达纯化,SOS1 exchange domin(564-1049)protein(Hμman recombinant)购自Cytoskeleton,Mab Anti 6HIS-XL665和Mab Anti GST-Eμcryptate购自Cisbio。多功能酶标仪Nivo5购自于PerkinElmer。KRAS (G12C) protein was expressed and purified by Wuhan Pujian Biotechnology Co., Ltd., SOS1 exchange domin (564-1049) protein (Hμman recombinant) was purchased from Cytoskeleton, Mab Anti 6HIS-XL665 and Mab Anti GST-Eμcryptate were purchased from Cisbio. The multifunctional microplate reader Nivo5 was purchased from PerkinElmer.
实验方法：experimental method:
1X buffer配制(现配现用):Hepes:5mM；NaCl:150mM；EDTA:10mM；Igepal:0.0025％；KF:100mM；DTT:1mM；BSA:005％；1X buffer preparation (prepared and used immediately): Hepes: 5mM; NaCl: 150mM; EDTA: 10mM; Igepal: 0.0025%; KF: 100mM; DTT: 1mM; BSA: 005%;
用DMSO将待测化合物用排枪进行5倍稀释至第8个浓度,即从1mM稀释至0.064μM。Use DMSO to dilute the compound to be tested 5 times to the 8th concentration, that is, from 1mM to 0.064μM.
用1X buffer将待测化合物各梯度稀释成DMSO为2％的工作液,5μL/孔加到对应孔中,对应浓度梯度为20μM至0.00128nM,置双复孔实验。1000转,离心1分钟。Use 1X buffer to dilute each gradient of the compound to be tested into a working solution of 2% DMSO. Add 5 μL/well to the corresponding wells. The corresponding concentration gradient is from 20 μM to 0.00128 nM. Set up a double well experiment. Centrifuge at 1000 rpm for 1 minute.
用1X buffer配制KRAS(G12C)(200nM)和Mab Anti GST-Eμcryptate(1ng/μL)的混和工作液,将该混合工作液放置25℃中孵育5分钟,2.5μL/孔加入到对应孔。Use 1X buffer to prepare a mixed working solution of KRAS (G12C) (200nM) and Mab Anti GST-Eμcryptate (1ng/μL). Place the mixed working solution at 25°C and incubate for 5 minutes. Add 2.5μL/well to the corresponding well.
用1X buffer配制SOS1(80nM)和Mab Anti 6HIS-XL665(8g/μL)的混和工作液,2.5μL/孔加入到对应孔中,Blank孔中加入2.5μL Mab Anti 6HIS-XL665(8g/μL)稀释液,此时化合物终浓度梯度为10μM稀释至0.64nM,KRAS(G12C)(500nM),MAb Anti GST-Eu cryptate(0.25ng/μL),SOS1(20nM),Mab Anti 6HIS-XL665(2g/μL),反应体系置于25℃反应60分钟。反应结束后采用多标记分析仪读取HTRF。Use 1X buffer to prepare a mixed working solution of SOS1 (80nM) and Mab Anti 6HIS-XL665 (8g/μL). Add 2.5μL/well to the corresponding well, and add 2.5μL Mab Anti 6HIS-XL665 (8g/μL) to the blank well. Dilution, at this time the final concentration gradient of the compound is 10μM diluted to 0.64nM, KRAS (G12C) (500nM), MAb Anti GST-Eu cryptate (0.25ng/μL), SOS1 (20nM), Mab Anti 6HIS-XL665 (2g/ μL), the reaction system was placed at 25°C for 60 minutes. After the reaction, a multi-label analyzer is used to read the HTRF.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)×100％将原始数据换算成抑制率,IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。本发明的化合物对KRAS(G12C)和SOS1结合的抑制活性测试结果见表12。Use the equation (Sample-Min)/(Max-Min) × 100% to convert the original data into an inhibition rate. The value of IC 50 can be obtained by curve fitting with four parameters (log(inhibitor) vs. response in GraphPad Prism --Variable slope mode derived). The test results of the inhibitory activity of the compounds of the present invention on the binding of KRAS (G12C) and SOS1 are shown in Table 12.
表12本发明化合物对KRAS(G12C)和SOS1结合的IC50值测试结果
Table 12 IC 50 value test results of the compounds of the present invention binding to KRAS (G12C) and SOS1
实验结论：本发明化合物对KRAS(G12C)和SOS1结合有显著的抑制效果。Experimental conclusion: The compound of the present invention has a significant inhibitory effect on the binding of KRAS (G12C) and SOS1.
实验例2：H358细胞3D增殖抑制活性测试Experimental Example 2: H358 cell 3D proliferation inhibitory activity test
实验原理： Experimental principle:
KRAS(G12C)突变的H358细胞中,KRAS信号通路异常激活。小分子SOS1抑制剂通过抑制SOS1与RAS蛋白的结合,降低其GEF活性,减少激活状态RAS-GTP的比例。进一步下调RAS下游的MEK/ERK通路的磷酸化水平,达到抑制细胞增殖的效果。将小分子与H358细胞在3D空间内共培养,然后通过细胞读数,间接反映SOS1抑制剂对H358细胞的增殖抑制活性。In H358 cells with KRAS (G12C) mutation, the KRAS signaling pathway is abnormally activated. Small molecule SOS1 inhibitors reduce its GEF activity and reduce the ratio of activated RAS-GTP by inhibiting the binding of SOS1 to RAS protein. Further downregulating the phosphorylation level of the MEK/ERK pathway downstream of RAS, achieving the effect of inhibiting cell proliferation. Small molecules were co-cultured with H358 cells in a 3D space, and then cell readings were used to indirectly reflect the proliferation inhibitory activity of SOS1 inhibitors on H358 cells.
实验材料：Experimental Materials:
RPMI1640培养基,胎牛血清,盘尼西林/链霉素抗生素购自维森特,低熔点琼脂糖购自Sigma。Almar blue试剂购自Invitrogen。NCI-H358细胞系购自南京科佰生物科技有限公司。Nivo多标记分析仪(PerkinElmer)。RPMI1640 medium, fetal calf serum, penicillin/streptomycin antibiotics were purchased from Vicente, and low melting point agarose was purchased from Sigma. Almar blue reagent was purchased from Invitrogen. NCI-H358 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo multi-label analyzer (PerkinElmer).
实验方法：experimental method:
将H358细胞种于96孔U型板中,先将低熔点琼脂糖配成2％的母液,使用时先将琼脂糖母液在微波炉中加热使其完全融化,之后至于42℃水浴锅中使琼脂糖保持液体状态。将凝胶加入含血清的培养基中配成凝胶浓度为0.6％作为底层胶,按照每孔50μL铺到96孔U型板中。待底层胶凝固后,再将2％凝胶加入到含细胞的培养基中,配成凝胶浓度为0.4％的含细胞的上层胶,细胞密度为4×104细胞/毫升,按照每孔75μL加到铺有底层胶的96孔U型板中,细胞密度为3000个每孔。待上层胶凝固后细胞板置于二氧化碳培养箱中过夜培养。H358 cells were seeded in a 96-well U-shaped plate. First, prepare the low melting point agarose into a 2% stock solution. When using, first heat the agarose stock solution in a microwave oven to completely melt it, and then place the agar in a 42°C water bath. The sugar remains in a liquid state. Add the gel to the serum-containing culture medium to prepare a gel concentration of 0.6% as the bottom gel, and spread it into a 96-well U-shaped plate at 50 μL per well. After the bottom gel is solidified, add 2% gel to the cell-containing culture medium to form a cell-containing upper gel with a gel concentration of 0.4% and a cell density of 4×10 4 cells/ml. Add 75 μL to a 96-well U-shaped plate covered with bottom glue, and the cell density is 3000 cells per well. After the upper gel has solidified, the cell plate is placed in a carbon dioxide incubator and cultured overnight.
加化合物当天,在铺好细胞的96孔U型板中加入85μL液体培养基。将待测化合物用排枪进行3倍稀释至第9个浓度,即从6mM稀释至0.9μM，设置双复孔实验。向中间板中加入97μL培养基,再按照对应位置,转移2.5μL每孔的梯度稀释化合物至中间板,混匀后转移40μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是30μM至4.5nM。细胞板置于二氧化碳培养箱中培养7天,第8天,将待测化合物用排枪进行3倍稀释至第九个浓度,即从6mM稀释至0.9μM,设置双复孔实验。像中间板中加入198μL培养基,再按照对应位置,转移2μL每孔的梯度稀释化合物至第一块中间板中,再向第二块中间板中加入100μL培养基,取第一块中间板中的混匀化合物100μL加入,混匀后转移40μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是30μM至4.5nM。细胞板置于二氧化碳培养箱中再培养7天。化合物与细胞共孵育14天,向细胞板中加入每孔20μL的Almar blue检测试剂,将加染料的板子置于水平摇床上震荡15分钟,再将板子至于室温孵育至5小时使发光信号稳定。采用多标记分析仪读数。On the day when the compound is added, add 85 μL of liquid culture medium to the 96-well U-shaped plate with cells. Use a volley gun to dilute the compound to be tested 3 times to the ninth concentration, that is, dilute it from 6mM to 0.9μM, and set up a double well experiment. Add 97 μL of culture medium to the middle plate, then transfer 2.5 μL of the gradient dilution compound per well to the middle plate according to the corresponding position, mix well, and transfer 40 μL of each well to the cell plate. The concentration of compounds transferred into the cell plate ranged from 30 μM to 4.5 nM. The cell plate was cultured in a carbon dioxide incubator for 7 days. On the 8th day, the compound to be tested was diluted 3 times to the ninth concentration with a volley gun, that is, from 6mM to 0.9μM, and a double well experiment was set up. Add 198 μL culture medium to the middle plate, and then transfer 2 μL of the gradient dilution compound per well to the first middle plate according to the corresponding position, then add 100 μL culture medium to the second middle plate, and take the medium from the first middle plate. Add 100 μL of mixed compound, mix well, and transfer 40 μL per well to the cell plate. The concentration of compounds transferred into the cell plate ranged from 30 μM to 4.5 nM. The cell plate was placed in a carbon dioxide incubator and cultured for another 7 days. The compound and cells were incubated for 14 days. 20 μL of Almar blue detection reagent was added to each well of the cell plate. The dye-added plate was placed on a horizontal shaker for 15 minutes, and then the plate was incubated at room temperature for 5 hours to stabilize the luminescence signal. Take multi-label analyzer readings.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)×100％将原始数据换算成抑制率,IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。Use the equation (Sample-Min)/(Max-Min) × 100% to convert the original data into an inhibition rate. The value of IC 50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
实验结论：本发明化合物能在3D条件下抑制H358细胞的增殖。Experimental conclusion: The compound of the present invention can inhibit the proliferation of H358 cells under 3D conditions.
实验例3：DLD-1细胞p-ERK增殖抑制活性测试Experimental Example 3: DLD-1 cell p-ERK proliferation inhibitory activity test
实验材料： Experimental Materials:
DLD-1细胞购自南京科佰；1640培养基购自Biological Industries；胎牛血清购自Biosera；Advanced Phospho-ERK1/2(THR202/TYR204)KIT购自Cisbio，其成分表见表13。DLD-1 cells were purchased from Nanjing Kebai; 1640 culture medium was purchased from Biological Industries; fetal calf serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio, and its ingredient list is shown in Table 13.
表13 Advanced Phospho-ERK1/2(THR202/TYR204)KIT成分表
Table 13 Advanced Phospho-ERK1/2 (THR202/TYR204) KIT ingredients
实验方法：experimental method:
DLD-1细胞种于透明96孔细胞培养板中，80μL细胞悬液每孔，每孔包含8000个DLD-1细胞，细胞板放入二氧化碳培养箱，37℃过夜孵育；DLD-1 cells were seeded in a transparent 96-well cell culture plate, with 80 μL of cell suspension per well, each well containing 8,000 DLD-1 cells. The cell plate was placed in a carbon dioxide incubator and incubated at 37°C overnight;
将待测化合物用100％DMSO稀释到2mM作为第一个浓度，然后再用移液器进行5倍稀释至第8个浓度，即从2mM稀释至0.026μM。取2μL化合物加入78μL细胞饥饿培养基，混匀后，取20μL化合物溶液加入到对应细胞板孔中，细胞板放回二氧化碳培养箱继续孵育1小时，此时化合物浓度为10μM至0.128nM，DMSO浓度为0.5％；Dilute the compound to be tested with 100% DMSO to 2mM as the first concentration, and then use a pipette to dilute 5 times to the 8th concentration, that is, dilute from 2mM to 0.026μM. Add 2 μL of the compound to 78 μL of cell starvation medium. After mixing, add 20 μL of the compound solution into the corresponding cell plate well. Return the cell plate to the carbon dioxide incubator and continue incubating for 1 hour. At this time, the compound concentration is 10 μM to 0.128 nM, and the DMSO concentration is is 0.5%;
结束孵育后，弃掉细胞上清加入50μL细胞裂解液每孔，室温摇晃孵育30分钟；After the incubation, discard the cell supernatant and add 50 μL of cell lysis solution to each well, shake at room temperature and incubate for 30 minutes;
使用Detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍；Use Detection buffer to dilute Phospho-ERK1/2 Eu Cryptate antibody and Phospho-ERK1/2 d2 antibody 20 times;
取16μL细胞裂解物上清每孔到新的384白色微孔板中，再加入2μL Phospho-ERK1/2 Eu Cryptate antibody稀释液和2μL Phospho-ERK1/2 d2 antibody稀释液，常温孵育4小时；Take 16 μL of cell lysate supernatant from each well into a new 384 white microwell plate, then add 2 μL of Phospho-ERK1/2 Eu Cryptate antibody diluent and 2 μL of Phospho-ERK1/2 d2 antibody diluent, and incubate at room temperature for 4 hours;
孵育结束后使用多标记分析仪读取HTRF excitation:320nm,emission:615nm,665nm。After the incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。Use the equation (Sample-Min)/(Max-Min)*100% to convert the original data into an inhibition rate. The value of IC 50 can be obtained by curve fitting with four parameters (log(inhibitor) vs. response in GraphPad Prism --Variable slope mode derived).
Max孔：阳性对照孔读值为1X裂解液Max well: The reading value of the positive control well is 1X lysate
Min孔：阴性对照孔读值为0.5％DMSO细胞孔细胞裂解液Min well: Negative control well reading value is 0.5% DMSO cell well cell lysate
本发明的化合物对DLD-1细胞p-ERK的抑制活性测试结果件表14。The test results of the inhibitory activity of the compounds of the present invention on p-ERK of DLD-1 cells are shown in Table 14.
表14本发明化合物对DLD-1细胞p-ERK增殖的IC50值测试结果

Table 14 IC 50 value test results of compounds of the present invention on DLD-1 cell p-ERK proliferation

实验结论：本发明化合物对DLD-1细胞p-ERK增殖有显著的抑制效果。Experimental conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation of p-ERK in DLD-1 cells.
实验例4：化合物药代动力学评价Experimental Example 4: Evaluation of Compound Pharmacokinetics
实验材料：Experimental Materials:
Balb/c小鼠(雄性,北京维通利华实验动物技术有限公司)Balb/c mice (male, Beijing Weitonglihua Experimental Animal Technology Co., Ltd.)
实验操作：Experimental operation:
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征,实验中候选化合物配成澄清溶液,给予小鼠单次静脉注射及口服给药。静注及口服溶媒为5％二甲基亚砜、5％solutol与90％水配成的混合溶媒。该项目使用四只雄性Balb/c小鼠,两只小鼠进行静脉注射给药,给药剂量为10mg/kg,收集给药后0.083,0.25,0.5,1,2,4,8,24h的血浆样品；另外两只小鼠口服灌胃给药,给药剂量为50mg/kg,收集给药后0.25、0.5,1,2,4,6,8,12,24h的血浆样品,血液样本采集后置于冰上，并于1小时之内离心分离血浆(离心条件：6000g，3分钟，2-8℃)。血浆样本在分析前存放时则放于-80℃冰箱内。以LC-MS/MS分析方法定量分析血药浓度,并计算药代参数,如达峰浓度(Cmax),清除率(CL),半衰期(T1/2),组织分布(Vdss),药时曲线下面积(AUC0-last),生物利用度(F)等。Standard protocols were used to test the pharmacokinetic characteristics of the compounds in rodents after intravenous injection and oral administration. In the experiment, the candidate compounds were formulated into clear solutions and given to mice for a single intravenous injection and oral administration. The vehicle for intravenous injection and oral administration is a mixed vehicle composed of 5% dimethyl sulfoxide, 5% solutol and 90% water. This project uses four male Balb/c mice, and two mice are administered intravenously at a dose of 10 mg/kg. The data at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration are collected. Plasma samples; the other two mice were orally administered orally at a dose of 50 mg/kg. Plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration. Blood samples were collected. Then place it on ice and centrifuge to separate the plasma within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis. Use LC-MS/MS analysis method to quantitatively analyze blood drug concentration and calculate pharmacokinetic parameters, such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), tissue distribution (Vdss), drug Area under the curve (AUC 0-last ), bioavailability (F), etc.
实验结果如表15所示：The experimental results are shown in Table 15:
表15本发明化合物的药代动力学测试结果
Table 15 Pharmacokinetic test results of compounds of the present invention
实验结论：本发明化合物具有良好的药代动力学性质,包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。 Experimental conclusion: The compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.

Claims (12)

  1. 式(I)化合物的A晶型，其X-射线粉末衍射图谱(XRPD)在下列2θ角处具有特征衍射峰：15.492±0.200°、16.458±0.200°、18.657±0.200°和20.638±0.200°；
    The X-ray powder diffraction pattern (XRPD) of the A crystal form of the compound of formula (I) has characteristic diffraction peaks at the following 2θ angles: 15.492±0.200°, 16.458±0.200°, 18.657±0.200° and 20.638±0.200°;
  2. 根据权利要求1所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、18.657±0.200°和20.638±0.200°。According to the A crystal form of claim 1, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 14.223±0.200°, 14.589±0.200°, 14.894±0.200°, 15.492±0.200°, 16.061± 0.200°, 16.458±0.200°, 18.657±0.200° and 20.638±0.200°.
  3. 根据权利要求2所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.200°、14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、18.657±0.200°、19.407±0.200°、20.638±0.200°、21.810±0.200°和22.836±0.200°。According to the A crystal form of claim 2, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.736±0.200°, 14.223±0.200°, 14.589±0.200°, 14.894±0.200°, 15.492± 0.200°, 16.061±0.200°, 16.458±0.200°, 18.657±0.200°, 19.407±0.200°, 20.638±0.200°, 21.810±0.200° and 22.836±0.200°.
  4. 根据权利要求3所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.100°、9.070±0.100°、11.289±0.100°、11.678±0.100°、14.223±0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、18.657±0.100°、19.407±0.100°、20.638±0.100°、21.085±0.100°、21.810±0.100°和22.836±0.100°。According to the A crystal form of claim 3, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.736±0.100°, 9.070±0.100°, 11.289±0.100°, 11.678±0.100°, 14.223± 0.100°、14.589±0.100°、14.894±0.100°、15.492±0.100°、16.061±0.100°、16.458±0.100°、18.657±0.100°、19.407±0.100°、20.638±0.100°、21.0 85±0.100°, 21.810± 0.100° and 22.836±0.100°.
  5. 根据权利要求4所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736±0.200°、8.475±0.200°、9.070±0.200°、11.289±0.200°、11.678±0.200°、12.363±0.200°、14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、17.000±0.200°、18.657±0.200°、19.030±0.200°、19.407±0.200°、19.882±0.200°、20.638±0.200°、21.085±0.200°、21.810±0.200°、22.836±0.200°、23.717±0.200°、24.147±0.200°、24.693±0.200°、25.311±0.200°、26.802±0.200°、27.462±0.200°、28.537±0.200°和31.264±0.200°。According to the A crystal form of claim 4, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.736±0.200°, 8.475±0.200°, 9.070±0.200°, 11.289±0.200°, 11.678± 0.200°、12.363±0.200°、14.223±0.200°、14.589±0.200°、14.894±0.200°、15.492±0.200°、16.061±0.200°、16.458±0.200°、17.000±0.200°、18.6 57±0.200°, 19.030± 0.200°、19.407±0.200°、19.882±0.200°、20.638±0.200°、21.085±0.200°、21.810±0.200°、22.836±0.200°、23.717±0.200°、24.147±0.200°、24.6 93±0.200°, 25.311± 0.200°, 26.802±0.200°, 27.462±0.200°, 28.537±0.200° and 31.264±0.200°.
  6. 根据权利要求5所述的A晶型，其X-射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.736°、8.475°、9.070°、11.289°、11.678°、12.363°、14.223°、14.589°、14.894°、15.492°、16.061°、16.458°、17.000°、18.657°、19.030°、19.407°、19.882°、20.638°、21.085°、21.810°、22.836°、23.717°、24.147°、24.693°、25.311°、26.802°、27.462°、28.537°和31.264°。According to the A crystal form of claim 5, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.736°, 8.475°, 9.070°, 11.289°, 11.678°, 12.363°, 14.223°, 14.589 °, 14.894°, 15.492°, 16.061°, 16.458°, 17.000°, 18.657°, 19.030°, 19.407°, 19.882°, 20.638°, 21.085°, 21.810°, 22.836°, 23.717°, 24.147°, 24 .693°、 25.311°, 26.802°, 27.462°, 28.537° and 31.264°.
  7. 式(I)化合物的A晶型，其XRPD图谱基本如图1所示。 The XRPD pattern of crystal form A of the compound of formula (I) is basically as shown in Figure 1.
  8. 根据权利要求1～7任意一项所述的A晶型，其差示扫描量热(DSC)曲线在169.0±5℃处具有吸热峰的起始点。According to the A crystal form according to any one of claims 1 to 7, its differential scanning calorimetry (DSC) curve has the starting point of the endothermic peak at 169.0±5°C.
  9. 根据权利要求8所述的A晶型，其DSC图谱基本如图2所示。The A crystal form according to claim 8 has a DSC spectrum substantially as shown in Figure 2.
  10. 根据权利要求1～7任意一项所述的A晶型，其热重分析(TGA)曲线在160.0±3℃时失重达1.48％。According to the A crystal form according to any one of claims 1 to 7, its thermogravimetric analysis (TGA) curve has a weight loss of 1.48% at 160.0±3°C.
  11. 根据权利要求10所述的A晶型，其TGA图谱基本如图3所示。According to the A crystal form of claim 10, its TGA pattern is basically as shown in Figure 3.
  12. 根据权利要求1～11任意一项所述式(I)化合物的A晶型在制备治疗KRAS突变实体瘤疾病的药物中的应用。 The application of crystal form A of the compound of formula (I) according to any one of claims 1 to 11 in the preparation of a drug for treating KRAS mutant solid tumor diseases.
PCT/CN2023/120754 2022-09-23 2023-09-22 Crystal form of quinazoline compound and preparation method therefor WO2024061353A1 (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167928A (en) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 The quinazoline and derivative that Novel warp benzylamino as SOS1 inhibitor replaces
WO2019201848A1 (en) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-methyl-aza-quinazolines
CN112805281A (en) * 2018-10-15 2021-05-14 伊莱利利公司 KRAS G12C inhibitors
WO2022068921A1 (en) * 2020-09-30 2022-04-07 上海医药集团股份有限公司 Quinazoline compound and application thereof
CN114437084A (en) * 2022-04-07 2022-05-06 苏州亚盛药业有限公司 Heterocyclic compound and preparation method and application thereof
WO2022199670A1 (en) * 2021-03-26 2022-09-29 南京明德新药研发有限公司 6-carbamate substituted heteroaryl ring derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167928A (en) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 The quinazoline and derivative that Novel warp benzylamino as SOS1 inhibitor replaces
WO2019201848A1 (en) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-methyl-aza-quinazolines
CN112805281A (en) * 2018-10-15 2021-05-14 伊莱利利公司 KRAS G12C inhibitors
WO2022068921A1 (en) * 2020-09-30 2022-04-07 上海医药集团股份有限公司 Quinazoline compound and application thereof
WO2022199670A1 (en) * 2021-03-26 2022-09-29 南京明德新药研发有限公司 6-carbamate substituted heteroaryl ring derivatives
CN114437084A (en) * 2022-04-07 2022-05-06 苏州亚盛药业有限公司 Heterocyclic compound and preparation method and application thereof

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