WO2024061353A1 - Forme cristalline de composé de quinazoline et son procédé de préparation - Google Patents

Forme cristalline de composé de quinazoline et son procédé de préparation Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
compound
present
ray powder
formula
Prior art date
Application number
PCT/CN2023/120754
Other languages
English (en)
Chinese (zh)
Inventor
代天资
姚婷
赵乐乐
李鹏
贺海鹰
Original Assignee
南京明德新药研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京明德新药研发有限公司 filed Critical 南京明德新药研发有限公司
Publication of WO2024061353A1 publication Critical patent/WO2024061353A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Battery Electrode And Active Subsutance (AREA)
  • Analysing Materials By The Use Of Radiation (AREA)
  • Developing Agents For Electrophotography (AREA)

Abstract

L'invention concerne une forme cristalline d'un composé de quinazoline et son procédé de préparation. En particulier, l'invention concerne une forme cristalline d'un composé de formule (I), son procédé de préparation et son utilisation.
PCT/CN2023/120754 2022-09-23 2023-09-22 Forme cristalline de composé de quinazoline et son procédé de préparation WO2024061353A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211169562.X 2022-09-23
CN202211169562 2022-09-23

Publications (1)

Publication Number Publication Date
WO2024061353A1 true WO2024061353A1 (fr) 2024-03-28

Family

ID=90453890

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/120754 WO2024061353A1 (fr) 2022-09-23 2023-09-22 Forme cristalline de composé de quinazoline et son procédé de préparation

Country Status (1)

Country Link
WO (1) WO2024061353A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2019201848A1 (fr) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
CN112805281A (zh) * 2018-10-15 2021-05-14 伊莱利利公司 Kras g12c抑制剂
WO2022068921A1 (fr) * 2020-09-30 2022-04-07 上海医药集团股份有限公司 Composé quinazoline et son application
CN114437084A (zh) * 2022-04-07 2022-05-06 苏州亚盛药业有限公司 杂环类化合物及其制备方法和应用
WO2022199670A1 (fr) * 2021-03-26 2022-09-29 南京明德新药研发有限公司 Dérivés cycliques hétéroaryle substitués par un groupe 6-carbamate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2019201848A1 (fr) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
CN112805281A (zh) * 2018-10-15 2021-05-14 伊莱利利公司 Kras g12c抑制剂
WO2022068921A1 (fr) * 2020-09-30 2022-04-07 上海医药集团股份有限公司 Composé quinazoline et son application
WO2022199670A1 (fr) * 2021-03-26 2022-09-29 南京明德新药研发有限公司 Dérivés cycliques hétéroaryle substitués par un groupe 6-carbamate
CN114437084A (zh) * 2022-04-07 2022-05-06 苏州亚盛药业有限公司 杂环类化合物及其制备方法和应用

Similar Documents

Publication Publication Date Title
EA027012B1 (ru) Ингибиторы cdc7
US11680061B2 (en) Crystal forms C and E of pyrazin-2(1H)-one compound and preparation method therefor
WO2020052647A1 (fr) Composé spiro-hétérocyclique agissant en tant qu'inhibiteur de lsd1 et son utilisation
KR20210034058A (ko) Lsd1억제제의 염 및 이의 결정형
CN116768861A (zh) Sos1蛋白降解靶向嵌合体及其组合物、制剂和用途
CN114685531A (zh) 四并环化合物及其药物组合物和应用
WO2022267495A1 (fr) Composé oxa-spirocyclique contenant de l'azote et son utilisation
US11603366B2 (en) Crystalline form and B crystalline form of pyrazine-2(1H)-ketone compound and preparation method thereof
WO2024061353A1 (fr) Forme cristalline de composé de quinazoline et son procédé de préparation
WO2022199591A1 (fr) Forme cristalline d'un composé pyridopyrazole substitué par du fluor et son procédé de préparation
WO2022022687A1 (fr) Formes salines et cristallines d'un composé tricyclique contenant un groupe pyrimidine et leur procédé de préparation
CA3098336C (fr) Forme cristalline d'un inhibiteur de c-met, forme de sel de celui-ci et son procede de preparation
US10067136B1 (en) Photoactivatable probes and uses thereof
WO2022048545A1 (fr) Forme cristalline de composé de pyridopyrimidine
WO2019101039A1 (fr) Dérivé de pyrimidine sulfamide, son procédé de préparation et son utilisation médicale
WO2020192637A1 (fr) Composé inhibiteur de brd4 sous forme solide, son procédé de préparation et son application
RU2794977C2 (ru) Соль ингибитора lsd1 и её полиморфная форма
WO2020224585A1 (fr) Sel et forme cristalline d'un inhibiteur d'activité de double kinase mtorc1/2 et son procédé de préparation
CN114945576B (zh) 氘代噻吩并吡啶类化合物
WO2023185869A1 (fr) Forme cristalline de fumarate de dérivé pyrrolohétérocyclique et son procédé de préparation
CN113646313B (zh) 一种a2a受体拮抗剂的盐型、晶型及其制备方法
US20230365596A1 (en) Crystal forms of pyridopyrazole compounds and preparation method therefor
WO2023088493A1 (fr) Composé furopyridone et utilisation associée
WO2021139794A1 (fr) Forme cristalline de dérivé de pyrrolidinyl-urée et son application
JP2024516885A (ja) ピロロトリアジン系化合物の塩形、その結晶形及びその製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23867638

Country of ref document: EP

Kind code of ref document: A1