WO2023093812A1 - Crystal form of triazolone compound and use thereof - Google Patents

Crystal form of triazolone compound and use thereof Download PDF

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Publication number
WO2023093812A1
WO2023093812A1 PCT/CN2022/134142 CN2022134142W WO2023093812A1 WO 2023093812 A1 WO2023093812 A1 WO 2023093812A1 CN 2022134142 W CN2022134142 W CN 2022134142W WO 2023093812 A1 WO2023093812 A1 WO 2023093812A1
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crystal form
compound
formula
present
ray powder
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PCT/CN2022/134142
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French (fr)
Chinese (zh)
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陈正霞
孙继奎
张杨
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南京明德新药研发有限公司
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Publication of WO2023093812A1 publication Critical patent/WO2023093812A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings

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  • the present invention relates to the crystal form of triazolone compounds and applications thereof, in particular to the crystal form of the compound of formula (I), the crystal form of the compound of formula (I), the compound of formula (II) and its crystal form, the compound of formula (III) Compound and crystal form thereof, compound of formula (IV) and crystal form thereof.
  • DHODH Dihydroorotate dehydrogenase
  • DHODH has been confirmed as a therapeutic target for various diseases, such as cancer, viral infection, autoimmune diseases (rheumatoid arthritis and multiple sclerosis), etc.
  • diseases such as cancer, viral infection, autoimmune diseases (rheumatoid arthritis and multiple sclerosis), etc.
  • the virus needs a large amount of nucleosides in the host cell to complete replication, so blocking the host's DHODH pyrimidine synthesis pathway can effectively inhibit virus replication.
  • the demand for pyrimidine nucleotides is far greater than that of normal cells, and it will rely on de novo synthesis. Blocking DHODH can effectively prevent tumor cell proliferation.
  • Studies have shown that DHODH is highly expressed in a variety of tumors and is positively correlated with the poor prognosis of clinical tumor patients. Inhibiting the expression of DHODH can inhibit tumor proliferation.
  • Inhibiting DHODH activity can effectively inhibit the proliferation of activated lymphocytes and the secretion of cytokines. Activated lymphocytes also require a large amount of nucleic acid for proliferation and metabolism, and are more sensitive to the inhibition of DHODH activity. DHODH inhibitors such as leflunomide and teriflunomide are also effective drugs for the treatment of autoimmune diseases, such as rheumatoid arthritis, intestinal inflammation and other diseases.
  • DHODH has not only become a potential target for anti-tumor therapy, but also an effective target for broad-spectrum anti-viral infection and treatment of autoimmune diseases.
  • the development and research of specific inhibitors for it is of great significance.
  • the present invention provides crystal form A of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 21.535 ⁇ 0.20°;
  • 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: 5.741 ⁇ 0.20° , 11.431 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A contains at least 6, 7, 8, 9, 10 or 11 characteristic diffraction peaks selected from the following: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20 °, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20°, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A contains at least 6, 7, 8, 9, 10 or 11 characteristic diffraction peaks selected from the following: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.2 0°, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20°, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 17.967 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20°, 25.175 ⁇ 0.20°, 28.055 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 16.717 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20°, 25.175 ⁇ 0.20°, 28.055 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.532 ⁇ 0.20°, 15.856 ⁇ 0.20°, 16.717 ⁇ 0.20°, 17.152 ⁇ 0.20°, 17.386 ⁇ 0.20°, 17.785 ⁇ 0.20°, 17.967 ⁇ 0.20°, 18.344 ⁇ 0.20°, 18.538 ⁇ 0.20 °, 18.845 ⁇ 0.20°, 19.114 ⁇ 0.20°, 20.728 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.580 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20°, 25.175 ⁇ 0.20°, 25.529 ⁇ 0.20 °, 28.055 ⁇ 0.20°, 32.907 ⁇ 0.20°, 33.735 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741°, 11.431°, 12.681°, 13.366°, 14.953°, 15.532°, 15.856°, 16.717 °, 17.152°, 17.386°, 17.785°, 17.967°, 18.344°, 18.538°, 18.845°, 19.114°, 20.728°, 20.923°, 21.535°, 22.580°, 22.916°, 24.311°, 25.175° , 25.529°, 28.055°, 32.907°, 33.735°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 8.685 ⁇ 0.20°, 9.257 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 13.956 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.532 ⁇ 0.20°, 15.856 ⁇ 0.20°, 16.717 ⁇ 0.20°, 17.152 ⁇ 0.20°, 17.386 ⁇ 0.20°, 17.785 ⁇ 0.20 °, 17.967 ⁇ 0.20°, 18.344 ⁇ 0.20°, 18.538 ⁇ 0.20°, 18.845 ⁇ 0.20°, 19.114 ⁇ 0.20°, 19.615 ⁇ 0.20°, 20.728 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.580 ⁇ 0.20 °, 22.916 ⁇ 0.20°, 23.721 ⁇ 0.20°, 24.311 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741°, 8.685°, 9.257°, 11.431°, 12.681°, 13.366°, 13.956°, 14.953 °, 15.532°, 15.856°, 16.717°, 17.152°, 17.386°, 17.785°, 17.967°, 18.344°, 18.538°, 18.845°, 19.114°, 19.615°, 20.728°, 20.923°, 21.535° , 22.580°, 22.916°, 23.721°, 24.311°, 25.175°, 25.529°, 26.282°, 26.496°, 26.806°, 26.983°, 27.191°, 27.625°, 28.055°, 28.682°, 29.338°, 29.862°, 3 0.168°, 30.567° , 30.821
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, and/or 11.431 ⁇ 0.20°, and/or 12.681 ⁇ 0.20°, and /or 13.366 ⁇ 0.20°, and/or 14.953 ⁇ 0.20°, and/or 15.532 ⁇ 0.20°, and/or 15.856 ⁇ 0.20°, and/or 16.717 ⁇ 0.20°, and/or 17.152 ⁇ 0.20°, and/or 17.386 ⁇ 0.20°, and/or 17.785 ⁇ 0.20°, and/or 17.967 ⁇ 0.20°, and/or 18.344 ⁇ 0.20°, and/or 18.538 ⁇ 0.20°, and/or 18.845 ⁇ 0.20°, and/or 19.114 ⁇ 0.20°, and/or 20.728 ⁇ 0.20°, and/or 20.923 ⁇ 0.20°, and/or 21.535 ⁇ 0.20°, and/or 22.580 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, and/or 11.431 ⁇ 0.20°, and/or 8.685 ⁇ 0.20°, and /or 9.257 ⁇ 0.20°, and/or 12.681 ⁇ 0.20°, and/or 13.366 ⁇ 0.20°, and/or 13.956 ⁇ 0.20°, and/or 14.953 ⁇ 0.20°, and/or 15.532 ⁇ 0.20°, and/or 15.856 ⁇ 0.20°, and/or 16.717 ⁇ 0.20°, and/or 17.152 ⁇ 0.20°, and/or 17.386 ⁇ 0.20°, and/or 17.785 ⁇ 0.20°, and/or 17.967 ⁇ 0.20°, and/or 18.344 ⁇ 0.20°, and/or 18.538 ⁇ 0.20°, and/or 18.845 ⁇ 0.20°, and/or 19.114 ⁇ 0.20°, and/or 19.615 ⁇ 0.20°
  • the XRPD pattern of the crystal form A of the compound of formula (I) is shown in FIG. 1 .
  • thermogravimetric analysis curve of the above-mentioned crystal form A reaches a weight loss of 0.66% at 130°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form A is shown in FIG. 2 .
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 152.4°C ⁇ 3°C.
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 152.4°C ⁇ 5°C.
  • the DSC spectrum of the above crystal form A is shown in FIG. 3 .
  • the present invention also provides crystal form B of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°;
  • the present invention also provides crystal form B of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, 16.079 ⁇ 0.20°, 19.654 ⁇ 0.20°, 25.131 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B contains at least 4, 5, 6 or 7 characteristic diffraction peaks selected from the following: 9.954 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B contains at least 4, 5, 6, 7, 8 or 9 characteristic diffraction peaks selected from the following: 9.954 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°, 21.151 ⁇ 0.20°, 22.376 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°, 21.151 ⁇ 0.20°, 22.376 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form, represented by 2 ⁇ angle at least includes 6, 7, 8, 9, 10, 11, 12, 13, 14 selected from the following , 15 or 16 feature diffraction peaks: 9.954 ⁇ 0.20 °, 14.658 ⁇ 0.20 °, 16.079 ⁇ 0.20 °, 16.727 ⁇ 0.20 °, 17.496 ⁇ 0.20 °, 19.189 ⁇ 0.20 °, 19.654 ⁇ 0.20 °, 20.722 ⁇ 0 0 .20 °, 21.151 ⁇ 0.20°, 22.376 ⁇ 0.20°, 22.923 ⁇ 0.20°, 24.212 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20°, 26.729 ⁇ 0.20°, 31.415 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, 14.658 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 17.496 ⁇ 0.20°, 19.189 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°, 21.151 ⁇ 0.20°, 22.376 ⁇ 0.20°, 22.923 ⁇ 0.20°, 24.212 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20 °, 26.729 ⁇ 0.20°, 31.415 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.022 ⁇ 0.20°, 9.954 ⁇ 0.20°, 11.191 ⁇ 0.20°, 12.474 ⁇ 0.20°, 14.658 ⁇ 0.20°, 15.040 ⁇ 0.20°, 15.335 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 16.996 ⁇ 0.20°, 17.266 ⁇ 0.20°, 17.496 ⁇ 0.20°, 19.189 ⁇ 0.20°, 19.654 ⁇ 0.20 °, 19.928 ⁇ 0.20°, 20.415 ⁇ 0.20°, 20.722 ⁇ 0.20°, 20.962 ⁇ 0.20°, 21.151 ⁇ 0.20°, 22.376 ⁇ 0.20°, 22.923 ⁇ 0.20°, 24.212 ⁇ 0.20°, 24.757 ⁇ 0.20°, 25.131 ⁇ 0.20 °, 26.196 ⁇ 0.20°, 26.024 ⁇ 0.20°, 26.729 ⁇ 0.20
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.022°, 9.954°, 11.191°, 12.474°, 14.658°, 15.040°, 15.335°, 16.079 °, 16.727°, 16.996°, 17.266°, 17.496°, 19.189°, 19.654°, 19.928°, 20.415°, 20.722°, 20.962°, 21.151°, 22.376°, 22.923°, 24.212°, 24.757° , 25.131°, 26.196°, 26.024°, 26.729°, 26.977°, 29.549°, 29.970°, 30.456°, 30.694°, 31.415°, 32.010°, 32.396°, 35.702°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 6.213 ⁇ 0.20°, 6.458 ⁇ 0.20°, 8.022 ⁇ 0.20°, 9.954 ⁇ 0.20°, 11.191 ⁇ 0.20°, 12.474 ⁇ 0.20°, 12.852 ⁇ 0.20°, 13.180 ⁇ 0.20°, 14.658 ⁇ 0.20°, 15.040 ⁇ 0.20°, 15.335 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 16.996 ⁇ 0.20 °, 17.266 ⁇ 0.20°, 17.496 ⁇ 0.20°, 18.389 ⁇ 0.20°, 18.693 ⁇ 0.20°, 19.189 ⁇ 0.20°, 19.654 ⁇ 0.20°, 19.928 ⁇ 0.20°, 20.415 ⁇ 0.20°, 20.722 ⁇ 0.20°, 20.962 ⁇ 0.20 °, 21.151 ⁇ 0.20°, 21.710 ⁇ 0.20°, 21.928 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 6.213°, 6.458°, 8.022°, 9.954°, 11.191°, 12.474°, 12.852°, 13.180 °, 14.658°, 15.040°, 15.335°, 16.079°, 16.727°, 16.996°, 17.266°, 17.496°, 18.389°, 18.693°, 19.189°, 19.654°, 19.928°, 20.415°, 20.722° , 20.962°, 21.151°, 21.710°, 21.928°, 22.376°, 22.923°, 24.212°, 24.757°, 25.131°, 25.447°, 26.024°, 26.196°, 26.729°, 26.977°, 27.649°, 28.899°, 2 9.549°, 29.970° , 30.456°
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.022 ⁇ 0.20°, and/or 9.954 ⁇ 0.20°, and/or 11.191 ⁇ 0.20°, and /or 12.474 ⁇ 0.20°, and/or 14.658 ⁇ 0.20°, and/or 15.040 ⁇ 0.20°, and/or 15.335 ⁇ 0.20°, and/or 16.079 ⁇ 0.20°, and/or 16.727 ⁇ 0.20°, and/or 16.996 ⁇ 0.20°, and/or 17.266 ⁇ 0.20°, and/or 17.496 ⁇ 0.20°, and/or 19.189 ⁇ 0.20°, and/or 19.654 ⁇ 0.20°, and/or 19.928 ⁇ 0.20°, and/or 20.415 ⁇ 0.20°, and/or 20.722 ⁇ 0.20°, and/or 20.962 ⁇ 0.20°, and/or 21.151 ⁇ 0.20°, and/or 22.376 ⁇ 0.20
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, and/or 19.654 ⁇ 0.20°, and/or 6.213 ⁇ 0.20°, and /or 6.458 ⁇ 0.20°, and/or 8.022 ⁇ 0.20°, and/or 11.191 ⁇ 0.20°, and/or 12.474 ⁇ 0.20°, and/or 12.852 ⁇ 0.20°, and/or 13.180 ⁇ 0.20°, and/or 14.658 ⁇ 0.20°, and/or 15.040 ⁇ 0.20°, and/or 15.335 ⁇ 0.20°, and/or 16.079 ⁇ 0.20°, and/or 16.727 ⁇ 0.20°, and/or 16.996 ⁇ 0.20°, and/or 17.266 ⁇ 0.20°, and/or 17.496 ⁇ 0.20°, and/or 18.389 ⁇ 0.20°, and/or 18.693 ⁇ 0.20°, and/or 19.189 ⁇ 0.20°
  • the XRPD spectrum of the crystal form B of the compound of formula (I) is shown in FIG. 4 .
  • thermogravimetric analysis curve of the above crystal form B reaches a weight loss of 1.06% at 130.0°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form B is shown in FIG. 5 .
  • the differential scanning calorimetry curve of the above-mentioned crystal form B has an onset value of an endothermic peak at 143.8°C ⁇ 3°C.
  • the differential scanning calorimetry curve of the above-mentioned crystal form B has an endothermic peak at 143.8°C ⁇ 5°C.
  • the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 6 .
  • the present invention provides a compound of formula (II),
  • the invention also provides crystal form C of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.117 ⁇ 0.20°, 16.434 ⁇ 0.20°, 24.235 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.117 ⁇ 0.20°, 13.942 ⁇ 0.20°, 14.871 ⁇ 0.20°, 16.434 ⁇ 0.20°, 17.670 ⁇ 0.20°, 21.270 ⁇ 0.20°, 24.235 ⁇ 0.20°, 27.099 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.117 ⁇ 0.20°, 13.942 ⁇ 0.20°, 14.871 ⁇ 0.20°, 16.434 ⁇ 0.20°, 17.670 ⁇ 0.20°, 21.270 ⁇ 0.20°, 24.235 ⁇ 0.20°, 24.992 ⁇ 0.20°, 27.099 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.117 ⁇ 0.20°, 13.051 ⁇ 0.20°, 13.942 ⁇ 0.20°, 14.871 ⁇ 0.20°, 16.434 ⁇ 0.20°, 17.670 ⁇ 0.20°, 18.979 ⁇ 0.20°, 21.270 ⁇ 0.20°, 23.636 ⁇ 0.20°, 24.235 ⁇ 0.20°, 24.992 ⁇ 0.20°, 25.851 ⁇ 0.20°, 27.099 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.117 ⁇ 0.20°, 13.051 ⁇ 0.20°, 13.942 ⁇ 0.20°, 14.871 ⁇ 0.20°, 16.434 ⁇ 0.20°, 17.670 ⁇ 0.20°, 18.979 ⁇ 0.20°, 21.270 ⁇ 0.20°, 23.636 ⁇ 0.20°, 24.235 ⁇ 0.20°, 24.992 ⁇ 0.20°, 25.851 ⁇ 0.20°, 27.099 ⁇ 0.20°, 28.565 ⁇ 0.20 °, 30.135 ⁇ 0.20°, 31.174 ⁇ 0.20°.
  • the XRPD spectrum of the crystal form C of the compound of formula (II) is shown in FIG. 7 .
  • the present invention also provides a compound of formula (III),
  • the invention also provides crystal form D of the compound of formula (III), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.549 ⁇ 0.20°, 16.867 ⁇ 0.20°, 22.037 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 8.549 ⁇ 0.20°, 16.867 ⁇ 0.20°, 17.461 ⁇ 0.20°, 18.061 ⁇ 0.20°, 20.239 ⁇ 0.20°, 22.037 ⁇ 0.20°.
  • the XRPD pattern of the crystal form D of the compound of formula (III) is shown in FIG. 8 .
  • the invention also provides crystal form E of the compound of formula (III), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.528 ⁇ 0.20°, 16.970 ⁇ 0.20°, 25.361 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 8.528 ⁇ 0.20°, 16.970 ⁇ 0.20°, 17.583 ⁇ 0.20°, 19.124 ⁇ 0.20°, 20.892 ⁇ 0.20°, 24.189 ⁇ 0.20°, 25.361 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 8.528 ⁇ 0.20°, 15.667 ⁇ 0.20°, 16.970 ⁇ 0.20°, 17.583 ⁇ 0.20°, 17.994 ⁇ 0.20°, 19.124 ⁇ 0.20°, 20.892 ⁇ 0.20°, 24.189 ⁇ 0.20°, 25.361 ⁇ 0.20°, 30.468 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 8.528 ⁇ 0.20°, 14.332 ⁇ 0.20°, 15.667 ⁇ 0.20°, 16.099 ⁇ 0.20°, 16.970 ⁇ 0.20°, 17.583 ⁇ 0.20°, 17.994 ⁇ 0.20°, 19.124 ⁇ 0.20°, 20.892 ⁇ 0.20°, 22.187 ⁇ 0.20°, 24.189 ⁇ 0.20°, 25.361 ⁇ 0.20°, 26.348 ⁇ 0.20°, 30.468 ⁇ 0.20 °.
  • the XRPD pattern of the crystal form E of the compound of formula (III) is shown in FIG. 9 .
  • the present invention provides a compound of formula (IV),
  • the present invention also provides the crystal form F of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.883 ⁇ 0.20°, 11.157 ⁇ 0.20°, 16.652 ⁇ 0.20°;
  • the present invention also provides the crystal form F of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.883 ⁇ 0.20°, 16.652 ⁇ 0.20°, 25.352 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 8.365 ⁇ 0.20°, 8.883 ⁇ 0.20°, 11.157 ⁇ 0.20°, 12.701 ⁇ 0.20°, 16.652 ⁇ 0.20°, 17.735 ⁇ 0.20°, 18.278 ⁇ 0.20°, 25.352 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 8.365 ⁇ 0.20°, 8.883 ⁇ 0.20°, 11.157 ⁇ 0.20°, 12.701 ⁇ 0.20°, 16.652 ⁇ 0.20°, 17.735 ⁇ 0.20°, 18.278 ⁇ 0.20°, 21.347 ⁇ 0.20°, 22.359 ⁇ 0.20°, 25.352 ⁇ 0.20°.
  • the XRPD pattern of the crystal form F of the compound of formula (IV) is shown in FIG. 10 .
  • the present invention also provides crystal form G of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.043 ⁇ 0.20°, 12.879 ⁇ 0.20°, 23.105 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 7.043 ⁇ 0.20°, 8.978 ⁇ 0.20°, 11.517 ⁇ 0.20°, 12.879 ⁇ 0.20°, 17.318 ⁇ 0.20°, 18.995 ⁇ 0.20°, 19.849 ⁇ 0.20°, 23.105 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 7.043 ⁇ 0.20°, 8.978 ⁇ 0.20°, 11.517 ⁇ 0.20°, 12.879 ⁇ 0.20°, 14.337 ⁇ 0.20°, 16.833 ⁇ 0.20°, 17.318 ⁇ 0.20°, 18.995 ⁇ 0.20°, 19.849 ⁇ 0.20°, 20.635 ⁇ 0.20°, 23.105 ⁇ 0.20°, 25.950 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 7.043 ⁇ 0.20°, 8.978 ⁇ 0.20°, 11.517 ⁇ 0.20°, 12.879 ⁇ 0.20°, 14.337 ⁇ 0.20°, 16.058 ⁇ 0.20°, 16.833 ⁇ 0.20°, 17.318 ⁇ 0.20°, 18.995 ⁇ 0.20°, 19.849 ⁇ 0.20°, 20.635 ⁇ 0.20°, 23.105 ⁇ 0.20°, 25.950 ⁇ 0.20°, 26.131 ⁇ 0.20 °.
  • the XRPD pattern of the crystal form G of the compound of formula (IV) above is shown in FIG. 11 .
  • the present invention also provides the crystal form H of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.303 ⁇ 0.20°, 14.560 ⁇ 0.20°, 23.443 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 7.303 ⁇ 0.20°, 14.560 ⁇ 0.20°, 15.502 ⁇ 0.20°, 18.330 ⁇ 0.20°, 21.690 ⁇ 0.20°, 23.443 ⁇ 0.20°, 24.600 ⁇ 0.20°, 25.793 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 7.303 ⁇ 0.20°, 14.560 ⁇ 0.20°, 15.502 ⁇ 0.20°, 18.330 ⁇ 0.20°, 18.981 ⁇ 0.20°, 21.690 ⁇ 0.20°, 23.443 ⁇ 0.20°, 24.600 ⁇ 0.20°, 25.793 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 7.303 ⁇ 0.20°, 9.362 ⁇ 0.20°, 14.560 ⁇ 0.20°, 15.502 ⁇ 0.20°, 17.858 ⁇ 0.20°, 18.330 ⁇ 0.20°, 18.981 ⁇ 0.20°, 19.721 ⁇ 0.20°, 21.690 ⁇ 0.20°, 22.373 ⁇ 0.20°, 23.443 ⁇ 0.20°, 24.600 ⁇ 0.20°, 25.793 ⁇ 0.20°.
  • the XRPD pattern of the crystal form H of the compound of formula (IV) is shown in FIG. 12 .
  • the present invention also provides the compound of formula (II), compound of formula (II), compound of formula (IV), crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, and crystal form G .
  • the above enteritis includes ulcerative enteritis and Crohn's disease.
  • the crystal form of the present invention has the characteristics of good stability and excellent PK properties, and has excellent therapeutic effect on enteritis.
  • the intermediate compound 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, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods 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, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • X-ray powder diffraction can detect information such as changes in crystal forms, crystallinity, and crystal structure state, and is a common method for identifying crystal forms.
  • the peak positions of an XRPD pattern mainly depend on the structure of the crystalline form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention.
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • 2-MeTHF 2-methyl Tetrahydrofuran
  • Dioxane represents dioxane
  • ACN represents acetonitrile
  • Toluene represents toluene
  • Acetone represents acetone
  • EtOAc represents ethyl acetate
  • THF represents tetrahydrofuran
  • H 2 O represents water
  • TosOH represents p-toluenesulfonic acid
  • Pd(dppf)Cl 2 Represents 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride.
  • Test method About 10-20 mg of sample is used for XRPD detection.
  • Phototube voltage 30kV
  • phototube current 10mA
  • Anti-scatter slit 2.50mm
  • Step size 0.5 seconds
  • the present invention 's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
  • Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under N2 conditions, heat the sample from 25°C (room temperature) to 300°C (or 350°C) at a heating rate of 10°C/min.
  • Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under N2 conditions, heat the sample from room temperature to 350°C at a heating rate of 10°C/min or lose 20% of its weight.
  • Figure 1 is the Cu-K ⁇ radiation XRPD spectrum of (I) compound crystal form A.
  • Fig. 2 is the TGA spectrogram of (I) compound crystal form A.
  • Fig. 3 is the DSC spectrogram of (I) compound crystal form A.
  • Fig. 4 is the Cu-K ⁇ radiation XRPD spectrum of (I) compound crystal form B.
  • Fig. 5 is the TGA spectrogram of (I) compound crystal form B.
  • Fig. 6 is the DSC spectrogram of (I) compound crystal form B.
  • Fig. 7 is the Cu-K ⁇ radiation XRPD spectrum of (II) compound crystal form C.
  • Fig. 8 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form D of compound (III).
  • Fig. 9 is the Cu-K ⁇ radiation XRPD spectrum of (III) compound crystal form E.
  • Fig. 10 is the Cu-K ⁇ radiation XRPD spectrum of (IV) compound crystal form F.
  • Fig. 11 is the Cu-K ⁇ radiation XRPD spectrum of (IV) compound crystal form G.
  • Fig. 12 is the Cu-K ⁇ radiation XRPD spectrum of Form H of compound (IV).
  • Figure 13 is the amorphous spectrum of compound (I).
  • Figure 14 is a graph of body weight changes.
  • Fig. 15 is a graph showing the evaluation results of DAI (Daily Illness Index).
  • Figure 16 is a graph of colon density at the end point of the experiment.
  • Embodiment 1 Preparation of formula (I) compound crystal form A
  • step 1
  • Acetonitrile (900mL), 2,4,5-trifluorobenzonitrile (50.39g, 320.78mmol, 1eq), compound 5 (90g, 320.78mmol, 1eq) were added to the reaction flask, and stirring was started; then anhydrous potassium phosphate (136.18g, 641.56mmol, 2eq) was added thereto, the temperature was raised to 70°C, and the reaction was carried out for 15 hours.
  • N-methylpyrrolidone (472mL), potassium tert-butylate (21.87g, 194.94mmol, 1.3eq) into the reaction flask and start stirring; , 1,1-trifluoropropan-2-ol (18.81g, 164.95mmol, 1.1eq) was added to it, raised to room temperature 10-15°C, reacted for 0.5 hours, and then lowered the temperature to 0-5°C, then Compound 6 (59g, 149.95mmol, 92.6% purity, 1eq) was dissolved in N-methylpyrrolidone (236mL), added dropwise thereto, and reacted for 1 hour.
  • the reaction solution was concentrated under reduced pressure at 45°C, and then extracted by adding 500 mL of methyl tert-butyl ether; adding hydrochloric acid (1M) to the obtained aqueous phase to adjust the pH value to 5-6 After that, add methyl tert-butyl ether for extraction (700mL/time x 3 times); the obtained organic phase was washed with saturated brine (1L/time x 1 time), dried by adding anhydrous sodium sulfate, filtered, and the filtrate was Concentrate under reduced pressure at °C to obtain a crude product.
  • 1,4-dioxane (580mL), compound 8 (29g, 57.71mmol), bisanalyl borate (48.36g, 190.44mmol) were added to the reaction flask, and stirring was started; then triethylamine (438.58mmol, 61.05mL,), palladium acetate (2.59g, 11.54mmol, 0.2eq), pivalic anhydride (26.87g, 144.27mmol,), 1,4-bis(diphenylphosphine)butane (4.92g , 11.54mmol) was added therein, under the protection of nitrogen, the reaction was carried out at 100°C for 12 hours.
  • Embodiment 2 the preparation of formula (I) compound amorphous
  • Embodiment 3 Preparation of formula (I) compound crystal form B
  • the crystal form B of the compound of formula (I) was obtained.
  • the amorphous compound (50 mg) of formula (I) was dissolved in ethyl acetate (0.3 mL), and stirred at 20-25°C for 12 hours. The reaction solution was directly filtered, and the obtained solid was concentrated under reduced pressure at 45°C. The crystal form B of the compound of formula (I) was obtained.
  • the amorphous compound (50 mg) of formula (I) was dissolved in ethanol (0.3 mL), and stirred at 20-25°C for 12 hours. The reaction solution was directly filtered, and the obtained solid was concentrated under reduced pressure at 45°C. The crystal form B of the compound of formula (I) was obtained.
  • the compound of formula (I) was amorphous (50mg), methanol (0.9mL), water (0.3mL), stirred at 50°C for 14hr, and then the system was filtered to collect the filter cake, which was decompressed at 45°C with an oil pump Concentration gives the compound of formula (I) in Form B.
  • Embodiment 4 Preparation of formula (II) compound crystal form C
  • Embodiment 5 the preparation of formula (III) compound crystal form D
  • Embodiment 6 the preparation of formula (III) compound crystal form E
  • Embodiment 7 Preparation of formula (IV) compound crystal form F
  • Embodiment 8 Preparation of formula (IV) compound crystal form G
  • Embodiment 9 Preparation of formula (IV) compound crystal form H
  • Embodiment 10 the solid stability test of formula (I) compound crystal form A
  • Embodiment 11 solid stability test of formula (I) compound crystal form B
  • Embodiment 1 enzymatic experiment
  • the DHODH inhibitory activity of the compounds was detected by the following experimental methods.
  • DHODH uses flavin mononucleotide (FMN) to catalyze the oxidation of dihydroorotic acid DHO to orotic acid, and the re-oxidation of FMN requires the participation of coenzyme CoQ.
  • FMN flavin mononucleotide
  • Resazurin dye replaces CoQ as the enzyme activity
  • Resazurin solution is blue, and the resorufin produced after reduction has red fluorescence, and its fluorescence signal can be detected under the conditions of excitation wavelength 535nm and emission wavelength 590nm.
  • the reaction buffer components used in the experiment were 100mM Hepes pH 7.0, 150mM NaCl, 0.3% CHAPS, 0.5mg/ml BSA, 0.1 ⁇ M FMN, 1% DMSO.
  • the final concentration of the DHODH enzyme in the reaction system was 5 nM
  • the final concentration of the substrate L-DHO was 15 ⁇ M
  • the final concentration of the indicator Resazurin was 80 ⁇ M.
  • the components of the reaction termination buffer were 100mM Hepes pH7.0 and 5mM Orotate.
  • the compound of the present invention has excellent DHODH enzyme inhibitory activity.
  • the compound of the present invention has excellent metabolic stability (Cl) in vivo, IV and PO all show longer half-life (T 1/2 ); formula (I) crystal form A and crystal form B all have excellent oral absorption Drug exposure (AUC), and high oral bioavailability (>60%).
  • mice were anesthetized with 0.25 mL of anesthetic (1.25% Avertin, Easycheck, M2910).
  • the mice in the vehicle group and the compound dosage administration group were perfused with 150 ⁇ L of 1.5% TNBS solution (final concentration 50% ethanol) in the rectum.
  • the mice in the negative group were perfused with an equal volume of 50% ethanol in their rectums.
  • the first group is the negative group, the animals are given vehicle, the second group is the vehicle group (i.e. the modeling group), the animals are given the vehicle, the 3rd, 4th and 5th groups are the compound dosage administration groups, the animals are given different Dosage of crystal form A of formula (I), the solvent is 5% DMSO/10% Solutol solution/0.2% Tween80/84.8% aqueous solution, once a day.
  • the recording frequency was once a day (QD), days -1-7.
  • DAI Disease Activity Index
  • the recording frequency is once a day, on days -1-7, and is graded into 4 levels according to the following criteria:
  • Bloody stool (0, negative; 1, weakly positive for occult blood; 2, positive for occult blood; 3, obvious blood in stool; 4, massive blood in stool);
  • Colon tissue was divided longitudinally into two parts, and one part was fixed in the form of "Swiss" roll immersed in 10% neutral paraformaldehyde.
  • the other part was quick-frozen in liquid nitrogen first, and then stored in a -80°C refrigerator for the detection and analysis to be selected.
  • the experimental data should be expressed as mean ⁇ standard error (mean ⁇ S.E.M.).
  • the data were analyzed by ANOVA statistical method using GraphPad Prism. Compared with the vehicle group, *p ⁇ 0.05**p ⁇ 0.01***p ⁇ 0.005****p ⁇ 0.0001, P ⁇ 0.05 was considered statistically different.
  • DAI Daily Illness Index
  • the crystalline form A of the compound of formula (I) exhibited significant anti-inflammatory effects. It can significantly slow down the weight loss of mice with enteritis, improve the disease score (DAI) associated with diarrhea and blood in the stool, and can improve the increase in colon density caused by inflammation, which is consistent with the results of the DAI score.
  • DAI disease score

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Abstract

Disclosed are a crystal form of a triazolone compound and the use thereof. Specifically disclosed are a crystal form of a compound of formula (I), a compound of formula (II) and a crystal form thereof, a compound of formula (III) and a crystal form thereof, and a compound of formula (IV) and a crystal form thereof.

Description

三氮唑酮类化合物的晶型及其应用Crystal forms and applications of triazolone compounds
本发明主张如下优先权：The present invention claims the following priority:
CN202111424603.0，2021年11月26日。CN202111424603.0, November 26, 2021.
技术领域technical field
本发明涉及三氮唑酮类化合物的晶型及其应用，具体涉及式(I)化合物的晶型、式(I)化合物的晶型、式(II)化合物及其晶型、式(III)化合物及其晶型、式(IV)化合物及其晶型。The present invention relates to the crystal form of triazolone compounds and applications thereof, in particular to the crystal form of the compound of formula (I), the crystal form of the compound of formula (I), the compound of formula (II) and its crystal form, the compound of formula (III) Compound and crystal form thereof, compound of formula (IV) and crystal form thereof.
背景技术Background technique
二氢乳清酸脱氢酶(dihydroorotate dehydrogenase,DHODH)存在于人类线粒体内膜，是一种含铁的黄素依赖酶，是嘧啶核苷酸合成的限速酶，抑制DHODH可以阻断新生嘧啶核苷酸的合成,致使DNA(含腺嘧啶和胞嘧啶)、RNA(含尿嘧啶和胞嘧啶)、糖蛋白和磷脂等生物合成产生障碍，从而引起细胞周期阻滞，抑制细胞的异常增殖。因此，DHODH酶对人体细胞的增殖及新陈代谢至关重要。Dihydroorotate dehydrogenase (DHODH) exists in the inner membrane of human mitochondria. It is an iron-containing flavin-dependent enzyme and a rate-limiting enzyme for pyrimidine nucleotide synthesis. Inhibition of DHODH can block nascent pyrimidine The synthesis of nucleotides leads to obstacles in the biosynthesis of DNA (including adenine and cytosine), RNA (including uracil and cytosine), glycoproteins and phospholipids, thereby causing cell cycle arrest and inhibiting abnormal cell proliferation. Therefore, the DHODH enzyme is crucial to the proliferation and metabolism of human cells.
DHODH已被确证是多种疾病的治疗靶点，如癌症、病毒性感染、自身免疫性疾病(类风湿关节炎和多发性硬化)等。当细胞被病毒感染后，病毒需要大量依赖宿主细胞内的核苷来完成复制，因此阻断宿主的DHODH嘧啶合成通路可有效抑制病毒复制。在肿瘤细胞中，其对嘧啶核苷酸需要量远远大于正常细胞需要量，将依赖从头合成途径，阻断DHODH可以有效抗肿瘤细胞增殖作用。研究显示，DHODH在多种肿瘤中高表达，而且与临床肿瘤患者不良预后正相关，抑制DHODH表达可以抑制肿瘤增殖。DHODH has been confirmed as a therapeutic target for various diseases, such as cancer, viral infection, autoimmune diseases (rheumatoid arthritis and multiple sclerosis), etc. When a cell is infected by a virus, the virus needs a large amount of nucleosides in the host cell to complete replication, so blocking the host's DHODH pyrimidine synthesis pathway can effectively inhibit virus replication. In tumor cells, the demand for pyrimidine nucleotides is far greater than that of normal cells, and it will rely on de novo synthesis. Blocking DHODH can effectively prevent tumor cell proliferation. Studies have shown that DHODH is highly expressed in a variety of tumors and is positively correlated with the poor prognosis of clinical tumor patients. Inhibiting the expression of DHODH can inhibit tumor proliferation.
抑制DHODH活性可有效抑制活化淋巴细胞的增殖和细胞因子的分泌，活化的淋巴细胞也需要大量的核酸来进行增殖和代谢，对DHODH的活性抑制较为敏感。DHODH抑制剂例如来氟米特及特立氟胺也是治疗自身免疫疾病，如类风湿性关节炎、肠道炎症等疾病的有效药物。Inhibiting DHODH activity can effectively inhibit the proliferation of activated lymphocytes and the secretion of cytokines. Activated lymphocytes also require a large amount of nucleic acid for proliferation and metabolism, and are more sensitive to the inhibition of DHODH activity. DHODH inhibitors such as leflunomide and teriflunomide are also effective drugs for the treatment of autoimmune diseases, such as rheumatoid arthritis, intestinal inflammation and other diseases.
综上，DHODH不仅已经成为潜在的抗肿瘤治疗靶点，同时也是广谱抗病毒感染以及治疗自身免疫疾病的有效靶点，针对其进行特异性抑制剂的开发和研究具有重要的意义。In summary, DHODH has not only become a potential target for anti-tumor therapy, but also an effective target for broad-spectrum anti-viral infection and treatment of autoimmune diseases. The development and research of specific inhibitors for it is of great significance.
发明内容Contents of the invention
本发明提供了式(I)化合物的晶型A，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，11.431±0.20°，21.535±0.20°；The present invention provides crystal form A of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 11.431±0.20°, 21.535±0.20°;
Figure PCTCN2022134142-appb-000001
Figure PCTCN2022134142-appb-000001
本发明的一些方案中，上述A晶型的X射线粉末衍射图谱中，用2θ角表示，至少包含选自下述中的4、5、6、7或8个特征衍射峰：5.741±0.20°，11.431±0.20°，14.953±0.20°，15.856±0.20°，17.386±0.20°，21.535±0.20°，22.916±0.20°，25.175±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A, represented by 2θ angle, contains at least 4, 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 5.741±0.20° , 11.431±0.20°, 14.953±0.20°, 15.856±0.20°, 17.386±0.20°, 21.535±0.20°, 22.916±0.20°, 25.175±0.20°.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，11.431±0.20°，14.953±0.20°，15.856±0.20°，17.386±0.20°，21.535±0.20°，22.916±0.20°，25.175±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 11.431±0.20°, 14.953±0.20°, 15.856±0.20°, 17.386± 0.20°, 21.535±0.20°, 22.916±0.20°, 25.175±0.20°.
本发明的一些方案中，上述A晶型的X射线粉末衍射图谱中，用2θ角表示，至少包含选自下述中的6、7、8、9、10或11个特征衍射峰：5.741±0.20°，11.431±0.20°，12.681±0.20°，14.953±0.20°，15.856±0.20°，17.386±0.20°，20.923±0.20°，21.535±0.20°，22.916±0.20°，24.311±0.20°，25.175±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A, represented by 2θ angle, contains at least 6, 7, 8, 9, 10 or 11 characteristic diffraction peaks selected from the following: 5.741± 0.20°, 11.431±0.20°, 12.681±0.20°, 14.953±0.20°, 15.856±0.20°, 17.386±0.20°, 20.923±0.20°, 21.535±0.20°, 22.916±0.20°, 24.311±0.20 °, 25.175± 0.20°.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，11.431±0.20°，12.681±0.20°，14.953±0.20°，15.856±0.20°，17.386±0.20°，20.923±0.20°，21.535±0.20°，22.916±0.20°，24.311±0.20°，25.175±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 11.431±0.20°, 12.681±0.20°, 14.953±0.20°, 15.856± 0.20°, 17.386±0.20°, 20.923±0.20°, 21.535±0.20°, 22.916±0.20°, 24.311±0.20°, 25.175±0.20°.
本发明的一些方案中，上述A晶型的其X射线粉末衍射图谱中，用2θ角表示，至少包含选自下述中的6、7、8、9、10或11个特征衍射峰：5.741±0.20°，11.431±0.20°，12.681±0.20°，13.366±0.20°，14.953±0.20°，15.856±0.20°，17.386±0.20°，21.535±0.20°，22.916±0.20°，24.311±0.20°，25.175±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A, represented by 2θ angle, contains at least 6, 7, 8, 9, 10 or 11 characteristic diffraction peaks selected from the following: 5.741 ±0.20°, 11.431±0.20°, 12.681±0.20°, 13.366±0.20°, 14.953±0.20°, 15.856±0.20°, 17.386±0.20°, 21.535±0.20°, 22.916±0.20°, 24.311±0.2 0°, 25.175 ±0.20°.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，11.431±0.20°，12.681±0.20°，13.366±0.20°，14.953±0.20°，15.856±0.20°，17.386±0.20°，21.535±0.20°，22.916±0.20°，24.311±0.20°，25.175±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 11.431±0.20°, 12.681±0.20°, 13.366±0.20°, 14.953± 0.20°, 15.856±0.20°, 17.386±0.20°, 21.535±0.20°, 22.916±0.20°, 24.311±0.20°, 25.175±0.20°.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，11.431±0.20°，12.681±0.20°，13.366±0.20°，14.953±0.20°，15.856±0.20°，17.386±0.20°，17.967±0.20°，20.923±0.20°，21.535±0.20°，22.916±0.20°，24.311±0.20°，25.175±0.20°，28.055±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 11.431±0.20°, 12.681±0.20°, 13.366±0.20°, 14.953± 0.20°, 15.856±0.20°, 17.386±0.20°, 17.967±0.20°, 20.923±0.20°, 21.535±0.20°, 22.916±0.20°, 24.311±0.20°, 25.175±0.20°, 28.055±0.20 °.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，11.431±0.20°，12.681±0.20°，13.366±0.20°，14.953±0.20°，15.856±0.20°，17.386±0.20°，16.717±0.20°，20.923±0.20°，21.535±0.20°，22.916±0.20°，24.311±0.20°，25.175±0.20°，28.055±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 11.431±0.20°, 12.681±0.20°, 13.366±0.20°, 14.953± 0.20°, 15.856±0.20°, 17.386±0.20°, 16.717±0.20°, 20.923±0.20°, 21.535±0.20°, 22.916±0.20°, 24.311±0.20°, 25.175±0.20°, 28.055±0.20 °.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，11.431±0.20°，12.681±0.20°，13.366±0.20°，14.953±0.20°，15.532±0.20°，15.856±0.20°，16.717±0.20°，17.152±0.20°，17.386±0.20°，17.785±0.20°，17.967±0.20°，18.344±0.20°，18.538±0.20°，18.845±0.20°，19.114±0.20°，20.728±0.20°，20.923±0.20°，21.535±0.20°，22.580±0.20°，22.916±0.20°，24.311±0.20°，25.175±0.20°，25.529±0.20°，28.055±0.20°，32.907±0.20°，33.735±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 11.431±0.20°, 12.681±0.20°, 13.366±0.20°, 14.953± 0.20°, 15.532±0.20°, 15.856±0.20°, 16.717±0.20°, 17.152±0.20°, 17.386±0.20°, 17.785±0.20°, 17.967±0.20°, 18.344±0.20°, 18.538±0.20 °, 18.845± 0.20°, 19.114±0.20°, 20.728±0.20°, 20.923±0.20°, 21.535±0.20°, 22.580±0.20°, 22.916±0.20°, 24.311±0.20°, 25.175±0.20°, 25.529±0.20 °, 28.055± 0.20°, 32.907±0.20°, 33.735±0.20°.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741°，11.431°，12.681°，13.366°，14.953°，15.532°，15.856°，16.717°，17.152°，17.386°，17.785°，17.967°，18.344°，18.538°，18.845°，19.114°，20.728°，20.923°，21.535°，22.580°，22.916°，24.311°，25.175°，25.529°，28.055°，32.907°，33.735°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741°, 11.431°, 12.681°, 13.366°, 14.953°, 15.532°, 15.856°, 16.717 °, 17.152°, 17.386°, 17.785°, 17.967°, 18.344°, 18.538°, 18.845°, 19.114°, 20.728°, 20.923°, 21.535°, 22.580°, 22.916°, 24.311°, 25.175° , 25.529°, 28.055°, 32.907°, 33.735°.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，8.685±0.20°，9.257±0.20°，11.431±0.20°，12.681±0.20°，13.366±0.20°，13.956±0.20°，14.953±0.20°，15.532±0.20°，15.856±0.20°，16.717±0.20°，17.152±0.20°，17.386±0.20°，17.785±0.20°，17.967±0.20°，18.344±0.20°，18.538±0.20°，18.845±0.20°，19.114±0.20°，19.615±0.20°，20.728±0.20°，20.923±0.20°，21.535±0.20°，22.580±0.20°，22.916±0.20°，23.721±0.20°，24.311±0.20°，25.175±0.20°，25.529±0.20°，26.282±0.20°，26.496±0.20°，26.806±0.20°，26.983±0.20°，27.191±0.20°，27.625±0.20°，28.055±0.20°，28.682±0.20°，29.338±0.20°，29.862±0.20°，30.168±0.20°，30.567±0.20°，30.821±0.20°，31.638±0.20°，31.931±0.20°，32.597±0.20°，32.907±0.20°，33.735±0.20°，34.076±0.20°，34.458±0.20°，34.611±0.20°，35.136±0.20°，36.725±0.20°，37.101±0.20°，37.713±0.20°，38.141±0.20°，38.429±0.20°，39.321±0.20°，39.588±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 8.685±0.20°, 9.257±0.20°, 11.431±0.20°, 12.681± 0.20°, 13.366±0.20°, 13.956±0.20°, 14.953±0.20°, 15.532±0.20°, 15.856±0.20°, 16.717±0.20°, 17.152±0.20°, 17.386±0.20°, 17.785±0.20 °, 17.967± 0.20°, 18.344±0.20°, 18.538±0.20°, 18.845±0.20°, 19.114±0.20°, 19.615±0.20°, 20.728±0.20°, 20.923±0.20°, 21.535±0.20°, 22.580±0.20 °, 22.916± 0.20°, 23.721±0.20°, 24.311±0.20°, 25.175±0.20°, 25.529±0.20°, 26.282±0.20°, 26.496±0.20°, 26.806±0.20°, 26.983±0.20°, 27.191±0.20 °, 27.625± 0.20°, 28.055±0.20°, 28.682±0.20°, 29.338±0.20°, 29.862±0.20°, 30.168±0.20°, 30.567±0.20°, 30.821±0.20°, 31.638±0.20°, 31.931±0.20 °, 32.597± 0.20°, 32.907±0.20°, 33.735±0.20°, 34.076±0.20°, 34.458±0.20°, 34.611±0.20°, 35.136±0.20°, 36.725±0.20°, 37.101±0.20°, 37.713±0.20 °, 38.141± 0.20°, 38.429±0.20°, 39.321±0.20°, 39.588±0.20°.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741°，8.685°，9.257°，11.431°，12.681°，13.366°，13.956°，14.953°，15.532°，15.856°，16.717°，17.152°，17.386°，17.785°，17.967°，18.344°，18.538°，18.845°，19.114°，19.615°，20.728°，20.923°，21.535°，22.580°，22.916°，23.721°，24.311°，25.175°，25.529°，26.282°，26.496°，26.806°，26.983°，27.191°，27.625°，28.055°，28.682°，29.338°，29.862°，30.168°，30.567°，30.821°，31.638°，31.931°，32.597°，32.907°，33.735°，34.076°，34.458°，34.611°，35.136°，36.725°，37.101°，37.713°，38.141°，38.429°，39.321°，39.588°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741°, 8.685°, 9.257°, 11.431°, 12.681°, 13.366°, 13.956°, 14.953 °, 15.532°, 15.856°, 16.717°, 17.152°, 17.386°, 17.785°, 17.967°, 18.344°, 18.538°, 18.845°, 19.114°, 19.615°, 20.728°, 20.923°, 21.535° , 22.580°, 22.916°, 23.721°, 24.311°, 25.175°, 25.529°, 26.282°, 26.496°, 26.806°, 26.983°, 27.191°, 27.625°, 28.055°, 28.682°, 29.338°, 29.862°, 3 0.168°, 30.567° , 30.821°, 31.638°, 31.931°, 32.597°, 32.907°, 33.735°, 34.076°, 34.458°, 34.611°, 35.136°, 36.725°, 37.101°, 37.713°, 38.141°, 38.429°, 39.321°, 39.588 °.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，和/或11.431±0.20°，和/或12.681±0.20°，和/或13.366±0.20°，和/或14.953±0.20°，和/或15.532±0.20°，和/或15.856±0.20°，和/或16.717±0.20°，和/或17.152±0.20°，和/或17.386±0.20°，和/或17.785±0.20°，和/或17.967±0.20°，和/或18.344±0.20°，和/或18.538±0.20°，和/或18.845±0.20°，和/或19.114±0.20°，和/或20.728±0.20°，和/或20.923±0.20°，和/或21.535±0.20°，和/或22.580±0.20°，和/或22.916±0.20°，和/或24.311±0.20°，和/或25.175±0.20°，和/或25.529±0.20°，和/或28.055±0.20°，和/或32.907±0.20°，和/或33.735±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, and/or 11.431±0.20°, and/or 12.681±0.20°, and /or 13.366±0.20°, and/or 14.953±0.20°, and/or 15.532±0.20°, and/or 15.856±0.20°, and/or 16.717±0.20°, and/or 17.152±0.20°, and/or 17.386±0.20°, and/or 17.785±0.20°, and/or 17.967±0.20°, and/or 18.344±0.20°, and/or 18.538±0.20°, and/or 18.845±0.20°, and/or 19.114± 0.20°, and/or 20.728±0.20°, and/or 20.923±0.20°, and/or 21.535±0.20°, and/or 22.580±0.20°, and/or 22.916±0.20°, and/or 24.311±0.20° , and/or 25.175±0.20°, and/or 25.529±0.20°, and/or 28.055±0.20°, and/or 32.907±0.20°, and/or 33.735±0.20°.
在本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，和/或11.431±0.20°，和/或8.685±0.20°，和/或9.257±0.20°，和/或12.681±0.20°，和/或13.366±0.20°，和/或13.956±0.20°，和/或14.953±0.20°，和/或15.532±0.20°，和/或15.856±0.20°，和/或16.717±0.20°，和/或17.152±0.20°，和/或17.386±0.20°，和/或17.785±0.20°，和/或17.967±0.20°，和/或18.344±0.20°，和/或18.538±0.20°，和/或18.845±0.20°，和/或19.114±0.20°，和/或19.615±0.20°，和/或20.728±0.20°，和/或20.923±0.20°，和/或21.535±0.20°，和/或22.580±0.20°，和/或22.916±0.20°，和/或23.721±0.20°，和/或24.311±0.20°，和/或25.175±0.20°，和/或25.529±0.20°，和/或26.282±0.20°，和/或26.496±0.20°，和/或26.806±0.20°，和/或26.983±0.20°，和/或27.191±0.20°，和/或27.625±0.20°，和/或28.055±0.20°，和/或28.682±0.20°，和/或29.338±0.20°，和/或29.862±0.20°，和/或30.168±0.20°，和/或30.567±0.20°，和/或30.821±0.20°，和/或31.638±0.20°，和/或31.931±0.20°，和/或32.597±0.20°，和/或32.907±0.20°，和/或33.735±0.20°，和/或 34.076±0.20°，和/或34.458±0.20°，和/或34.611±0.20°，和/或35.136±0.20°，和/或36.725±0.20°，和/或37.101±0.20°，和/或37.713±0.20°，和/或38.141±0.20°，和/或38.429±0.20°，和/或39.321±0.20°，和/或39.588±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, and/or 11.431±0.20°, and/or 8.685±0.20°, and /or 9.257±0.20°, and/or 12.681±0.20°, and/or 13.366±0.20°, and/or 13.956±0.20°, and/or 14.953±0.20°, and/or 15.532±0.20°, and/or 15.856±0.20°, and/or 16.717±0.20°, and/or 17.152±0.20°, and/or 17.386±0.20°, and/or 17.785±0.20°, and/or 17.967±0.20°, and/or 18.344± 0.20°, and/or 18.538±0.20°, and/or 18.845±0.20°, and/or 19.114±0.20°, and/or 19.615±0.20°, and/or 20.728±0.20°, and/or 20.923±0.20° , and/or 21.535±0.20°, and/or 22.580±0.20°, and/or 22.916±0.20°, and/or 23.721±0.20°, and/or 24.311±0.20°, and/or 25.175±0.20°, and /or 25.529±0.20°, and/or 26.282±0.20°, and/or 26.496±0.20°, and/or 26.806±0.20°, and/or 26.983±0.20°, and/or 27.191±0.20°, and/or 27.625±0.20°, and/or 28.055±0.20°, and/or 28.682±0.20°, and/or 29.338±0.20°, and/or 29.862±0.20°, and/or 30.168±0.20°, and/or 30.567± 0.20°, and/or 30.821±0.20°, and/or 31.638±0.20°, and/or 31.931±0.20°, and/or 32.597±0.20°, and/or 32.907±0.20°, and/or 33.735±0.20° , and/or 34.076±0.20°, and/or 34.458±0.20°, and/or 34.611±0.20°, and/or 35.136±0.20°, and/or 36.725±0.20°, and/or 37.101±0.20°, and /or 37.713±0.20°, and/or 38.141±0.20°, and/or 38.429±0.20°, and/or 39.321±0.20°, and/or 39.588±0.20°.
在本发明的一些方案中，上述式(I)化合物的晶型A，其XRPD图谱如图1所示。In some aspects of the present invention, the XRPD pattern of the crystal form A of the compound of formula (I) is shown in FIG. 1 .
本发明的一些方案中，上述晶型A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 are shown in Table 1.
表1式(I)化合物的晶型A的XRPD图谱解析数据The XRPD pattern analysis data of the crystal form A of the compound of formula (I) in table 1
Figure PCTCN2022134142-appb-000002
Figure PCTCN2022134142-appb-000002
Figure PCTCN2022134142-appb-000003
Figure PCTCN2022134142-appb-000003
在本发明的一些方案中，上述晶型A的热重分析曲线在130℃±3℃时失重达0.66％。In some solutions of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form A reaches a weight loss of 0.66% at 130°C±3°C.
在本发明的一些方案中，上述晶型A的TGA图谱如图2所示。In some solutions of the present invention, the TGA spectrum of the above crystal form A is shown in FIG. 2 .
在本发明的一些方案中，上述晶型A的差示扫描量热曲线在152.4℃±3℃处具有吸热峰的起始值。In some aspects of the present invention, the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 152.4°C±3°C.
在本发明的一些方案中，上述晶型A的差示扫描量热曲线在152.4℃±5℃处具有吸热峰的起始值。In some aspects of the present invention, the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 152.4°C±5°C.
在本发明的一些方案中，上述晶型A的DSC图谱如图3所示。In some solutions of the present invention, the DSC spectrum of the above crystal form A is shown in FIG. 3 .
本发明还提供式(I)化合物的晶型B，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.954±0.20°，19.654±0.20°，20.722±0.20°；The present invention also provides crystal form B of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.954±0.20°, 19.654±0.20°, 20.722±0.20°;
Figure PCTCN2022134142-appb-000004
Figure PCTCN2022134142-appb-000004
本发明还提供式(I)化合物的晶型B，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.954±0.20°，16.079±0.20°，19.654±0.20°，25.131±0.20°。The present invention also provides crystal form B of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.954±0.20°, 16.079±0.20°, 19.654±0.20°, 25.131± 0.20°.
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱中，用2θ角表示，至少包含选自下述中的4、5、6或7个特征衍射峰：9.954±0.20°，16.079±0.20°，16.727±0.20°，19.654±0.20°，20.722±0.20°，25.131±0.20°，26.024±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B, represented by 2θ angle, contains at least 4, 5, 6 or 7 characteristic diffraction peaks selected from the following: 9.954±0.20°, 16.079 ±0.20°, 16.727±0.20°, 19.654±0.20°, 20.722±0.20°, 25.131±0.20°, 26.024±0.20°.
在本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.954±0.20°，16.079±0.20°，16.727±0.20°，19.654±0.20°，20.722±0.20°，25.131±0.20°，26.024±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.954±0.20°, 16.079±0.20°, 16.727±0.20°, 19.654±0.20°, 20.722± 0.20°, 25.131±0.20°, 26.024±0.20°.
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱中，用2θ角表示，至少包含选自下述中的4、5、6、7、8或9个特征衍射峰：9.954±0.20°，16.079±0.20°，16.727±0.20°，19.654±0.20°，20.722±0.20°，21.151±0.20°，22.376±0.20°，25.131±0.20°，26.024±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B, represented by 2θ angle, contains at least 4, 5, 6, 7, 8 or 9 characteristic diffraction peaks selected from the following: 9.954± 0.20°, 16.079±0.20°, 16.727±0.20°, 19.654±0.20°, 20.722±0.20°, 21.151±0.20°, 22.376±0.20°, 25.131±0.20°, 26.024±0.20°.
在本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.954±0.20°，16.079±0.20°，16.727±0.20°，19.654±0.20°，20.722±0.20°，21.151±0.20°，22.376±0.20°，25.131±0.20°，26.024±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.954±0.20°, 16.079±0.20°, 16.727±0.20°, 19.654±0.20°, 20.722± 0.20°, 21.151±0.20°, 22.376±0.20°, 25.131±0.20°, 26.024±0.20°.
在本发明的一些方案中，上述B晶型的X射线粉末衍射图谱中，用2θ角表示，至少包含选自下述中的6、7、8、9、10、11、12、13、14、15或16个特征衍射峰：9.954±0.20°，14.658±0.20°，16.079±0.20°，16.727±0.20°，17.496±0.20°，19.189±0.20°，19.654±0.20°，20.722±0.20°，21.151±0.20°，22.376±0.20°，22.923±0.20°，24.212±0.20°，25.131±0.20°，26.024±0.20°，26.729±0.20°，31.415±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form, represented by 2θ angle, at least includes 6, 7, 8, 9, 10, 11, 12, 13, 14 selected from the following , 15 or 16 feature diffraction peaks: 9.954 ± 0.20 °, 14.658 ± 0.20 °, 16.079 ± 0.20 °, 16.727 ± 0.20 °, 17.496 ± 0.20 °, 19.189 ± 0.20 °, 19.654 ± 0.20 °, 20.722 ± 0 0 .20 °, 21.151 ±0.20°, 22.376±0.20°, 22.923±0.20°, 24.212±0.20°, 25.131±0.20°, 26.024±0.20°, 26.729±0.20°, 31.415±0.20°.
在本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.954±0.20°，14.658±0.20°，16.079±0.20°，16.727±0.20°，17.496±0.20°，19.189±0.20°，19.654±0.20°，20.722±0.20°，21.151±0.20°，22.376±0.20°，22.923±0.20°，24.212±0.20°，25.131±0.20°，26.024±0.20°，26.729±0.20°，31.415±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.954±0.20°, 14.658±0.20°, 16.079±0.20°, 16.727±0.20°, 17.496± 0.20°, 19.189±0.20°, 19.654±0.20°, 20.722±0.20°, 21.151±0.20°, 22.376±0.20°, 22.923±0.20°, 24.212±0.20°, 25.131±0.20°, 26.024±0.20 °, 26.729± 0.20°, 31.415±0.20°.
在本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.022±0.20°，9.954±0.20°，11.191±0.20°，12.474±0.20°，14.658±0.20°，15.040±0.20°，15.335±0.20°，16.079±0.20°，16.727±0.20°，16.996±0.20°，17.266±0.20°，17.496±0.20°，19.189±0.20°，19.654±0.20°，19.928±0.20°，20.415±0.20°，20.722±0.20°，20.962±0.20°，21.151±0.20°，22.376±0.20°，22.923±0.20°，24.212±0.20°，24.757±0.20°，25.131±0.20°，26.196±0.20°，26.024±0.20°，26.729±0.20°，26.977±0.20°，29.549±0.20°，29.970±0.20°，30.456±0.20°，30.694±0.20°，31.415±0.20°，32.010±0.20°，32.396±0.20°，35.702±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.022±0.20°, 9.954±0.20°, 11.191±0.20°, 12.474±0.20°, 14.658± 0.20°, 15.040±0.20°, 15.335±0.20°, 16.079±0.20°, 16.727±0.20°, 16.996±0.20°, 17.266±0.20°, 17.496±0.20°, 19.189±0.20°, 19.654±0.20 °, 19.928± 0.20°, 20.415±0.20°, 20.722±0.20°, 20.962±0.20°, 21.151±0.20°, 22.376±0.20°, 22.923±0.20°, 24.212±0.20°, 24.757±0.20°, 25.131±0.20 °, 26.196± 0.20°, 26.024±0.20°, 26.729±0.20°, 26.977±0.20°, 29.549±0.20°, 29.970±0.20°, 30.456±0.20°, 30.694±0.20°, 31.415±0.20°, 32.010±0.20 °, 32.396± 0.20°, 35.702±0.20°.
在本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.022°，9.954°，11.191°，12.474°，14.658°，15.040°，15.335°，16.079°，16.727°，16.996°，17.266°，17.496°，19.189°，19.654°，19.928°，20.415°，20.722°，20.962°，21.151°，22.376°，22.923°，24.212°，24.757°，25.131°，26.196°，26.024°，26.729°，26.977°，29.549°，29.970°，30.456°，30.694°，31.415°，32.010°，32.396°，35.702°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.022°, 9.954°, 11.191°, 12.474°, 14.658°, 15.040°, 15.335°, 16.079 °, 16.727°, 16.996°, 17.266°, 17.496°, 19.189°, 19.654°, 19.928°, 20.415°, 20.722°, 20.962°, 21.151°, 22.376°, 22.923°, 24.212°, 24.757° , 25.131°, 26.196°, 26.024°, 26.729°, 26.977°, 29.549°, 29.970°, 30.456°, 30.694°, 31.415°, 32.010°, 32.396°, 35.702°.
在本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.213±0.20°，6.458±0.20°，8.022±0.20°，9.954±0.20°，11.191±0.20°，12.474±0.20°，12.852±0.20°，13.180±0.20°，14.658±0.20°，15.040±0.20°，15.335±0.20°，16.079±0.20°，16.727±0.20°，16.996±0.20°，17.266±0.20°，17.496±0.20°，18.389±0.20°，18.693±0.20°，19.189±0.20°，19.654±0.20°，19.928±0.20°，20.415±0.20°，20.722±0.20°，20.962±0.20°，21.151±0.20°，21.710±0.20°，21.928±0.20°，22.376±0.20°，22.923±0.20°，24.212±0.20°，24.757±0.20°，25.131±0.20°，25.447±0.20°，26.024±0.20°，26.196±0.20°，26.729±0.20°，26.977±0.20°，27.649±0.20°，28.899±0.20°，29.549±0.20°，29.970±0.20°，30.456±0.20°，30.694±0.20°，31.098±0.20°，31.415±0.20°，32.010±0.20°，32.396±0.20°，33.344±0.20°，33.584±0.20°，33.900±0.20°，34.431±0.20°，34.889±0.20°，35.193±0.20°，35.702±0.20°，36.670±0.20°，37.683±0.20°，38.047±0.20°，38.645±0.20°，39.701±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 6.213±0.20°, 6.458±0.20°, 8.022±0.20°, 9.954±0.20°, 11.191± 0.20°, 12.474±0.20°, 12.852±0.20°, 13.180±0.20°, 14.658±0.20°, 15.040±0.20°, 15.335±0.20°, 16.079±0.20°, 16.727±0.20°, 16.996±0.20 °, 17.266± 0.20°, 17.496±0.20°, 18.389±0.20°, 18.693±0.20°, 19.189±0.20°, 19.654±0.20°, 19.928±0.20°, 20.415±0.20°, 20.722±0.20°, 20.962±0.20 °, 21.151± 0.20°, 21.710±0.20°, 21.928±0.20°, 22.376±0.20°, 22.923±0.20°, 24.212±0.20°, 24.757±0.20°, 25.131±0.20°, 25.447±0.20°, 26.024±0.20 °, 26.196± 0.20°, 26.729±0.20°, 26.977±0.20°, 27.649±0.20°, 28.899±0.20°, 29.549±0.20°, 29.970±0.20°, 30.456±0.20°, 30.694±0.20°, 31.098±0.20 °, 31.415± 0.20°, 32.010±0.20°, 32.396±0.20°, 33.344±0.20°, 33.584±0.20°, 33.900±0.20°, 34.431±0.20°, 34.889±0.20°, 35.193±0.20°, 35.702±0.20 °, 36.670± 0.20°, 37.683±0.20°, 38.047±0.20°, 38.645±0.20°, 39.701±0.20°.
在本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.213°，6.458°，8.022°，9.954°，11.191°，12.474°，12.852°，13.180°，14.658°，15.040°，15.335°，16.079°，16.727°，16.996°，17.266°，17.496°，18.389°，18.693°，19.189°，19.654°，19.928°，20.415°，20.722°，20.962°，21.151°，21.710°，21.928°，22.376°，22.923°，24.212°，24.757°，25.131°，25.447°，26.024°，26.196°，26.729°，26.977°，27.649°，28.899°，29.549°，29.970°，30.456°，30.694°，31.098°，31.415°，32.010°，32.396°，33.344°，33.584°，33.900°，34.431°，34.889°，35.193°，35.702°，36.670°，37.683°，38.047°，38.645°，39.701°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 6.213°, 6.458°, 8.022°, 9.954°, 11.191°, 12.474°, 12.852°, 13.180 °, 14.658°, 15.040°, 15.335°, 16.079°, 16.727°, 16.996°, 17.266°, 17.496°, 18.389°, 18.693°, 19.189°, 19.654°, 19.928°, 20.415°, 20.722° , 20.962°, 21.151°, 21.710°, 21.928°, 22.376°, 22.923°, 24.212°, 24.757°, 25.131°, 25.447°, 26.024°, 26.196°, 26.729°, 26.977°, 27.649°, 28.899°, 2 9.549°, 29.970° , 30.456°, 30.694°, 31.098°, 31.415°, 32.010°, 32.396°, 33.344°, 33.584°, 33.900°, 34.431°, 34.889°, 35.193°, 35.702°, 36.670°, 37.683°, 38.047°, 38.645 °, 39.701°.
在本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.022±0.20°，和/或9.954±0.20°，和/或11.191±0.20°，和/或12.474±0.20°，和/或14.658±0.20°，和/或15.040±0.20°，和/或15.335±0.20°，和/或16.079±0.20°，和/或16.727±0.20°，和/或16.996±0.20°， 和/或17.266±0.20°，和/或17.496±0.20°，和/或19.189±0.20°，和/或19.654±0.20°，和/或19.928±0.20°，和/或20.415±0.20°，和/或20.722±0.20°，和/或20.962±0.20°，和/或21.151±0.20°，和/或22.376±0.20°，和/或22.923±0.20°，和/或24.212±0.20°，和/或24.757±0.20°，和/或25.131±0.20°，和/或26.196±0.20°，和/或26.024±0.20°，和/或26.729±0.20°，和/或26.977±0.20°，和/或29.549±0.20°，和/或29.970±0.20°，和/或30.456±0.20°，和/或30.694±0.20°，和/或31.415±0.20°，和/或32.010±0.20°，和/或32.396±0.20°，和/或35.702±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.022±0.20°, and/or 9.954±0.20°, and/or 11.191±0.20°, and /or 12.474±0.20°, and/or 14.658±0.20°, and/or 15.040±0.20°, and/or 15.335±0.20°, and/or 16.079±0.20°, and/or 16.727±0.20°, and/or 16.996±0.20°, and/or 17.266±0.20°, and/or 17.496±0.20°, and/or 19.189±0.20°, and/or 19.654±0.20°, and/or 19.928±0.20°, and/or 20.415± 0.20°, and/or 20.722±0.20°, and/or 20.962±0.20°, and/or 21.151±0.20°, and/or 22.376±0.20°, and/or 22.923±0.20°, and/or 24.212±0.20° , and/or 24.757±0.20°, and/or 25.131±0.20°, and/or 26.196±0.20°, and/or 26.024±0.20°, and/or 26.729±0.20°, and/or 26.977±0.20°, and /or 29.549±0.20°, and/or 29.970±0.20°, and/or 30.456±0.20°, and/or 30.694±0.20°, and/or 31.415±0.20°, and/or 32.010±0.20°, and/or 32.396±0.20°, and/or 35.702±0.20°.
在本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.954±0.20°，和/或19.654±0.20°，和/或6.213±0.20°，和/或6.458±0.20°，和/或8.022±0.20°，和/或11.191±0.20°，和/或12.474±0.20°，和/或12.852±0.20°，和/或13.180±0.20°，和/或14.658±0.20°，和/或15.040±0.20°，和/或15.335±0.20°，和/或16.079±0.20°，和/或16.727±0.20°，和/或16.996±0.20°，和/或17.266±0.20°，和/或17.496±0.20°，和/或18.389±0.20°，和/或18.693±0.20°，和/或19.189±0.20°，和/或19.928±0.20°，和/或20.415±0.20°，和/或20.722±0.20°，和/或20.962±0.20°，和/或21.151±0.20°，和/或21.710±0.20°，和/或21.928±0.20°，和/或22.376±0.20°，和/或22.923±0.20°，和/或24.212±0.20°，和/或24.757±0.20°，和/或25.131±0.20°，和/或25.447±0.20°，和/或26.196±0.20°，和/或26.024±0.20°，和/或26.729±0.20°，和/或26.977±0.20°，和/或27.649±0.20°，和/或28.899±0.20°，和/或29.549±0.20°，和/或29.970±0.20°，和/或30.456±0.20°，和/或30.694±0.20°，和/或31.098±0.20°，和/或31.415±0.20°，和/或32.010±0.20°，和/或32.396±0.20°，和/或33.344±0.20°，和/或33.584±0.20°，和/或33.900±0.20°，和/或34.431±0.20°，和/或34.889±0.20°，和/或35.193±0.20°，和/或35.702±0.20°，和/或36.670±0.20°，和/或37.683±0.20°，和/或38.047±0.20°，和/或38.645±0.20°，和/或39.701±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.954±0.20°, and/or 19.654±0.20°, and/or 6.213±0.20°, and /or 6.458±0.20°, and/or 8.022±0.20°, and/or 11.191±0.20°, and/or 12.474±0.20°, and/or 12.852±0.20°, and/or 13.180±0.20°, and/or 14.658±0.20°, and/or 15.040±0.20°, and/or 15.335±0.20°, and/or 16.079±0.20°, and/or 16.727±0.20°, and/or 16.996±0.20°, and/or 17.266± 0.20°, and/or 17.496±0.20°, and/or 18.389±0.20°, and/or 18.693±0.20°, and/or 19.189±0.20°, and/or 19.928±0.20°, and/or 20.415±0.20° , and/or 20.722±0.20°, and/or 20.962±0.20°, and/or 21.151±0.20°, and/or 21.710±0.20°, and/or 21.928±0.20°, and/or 22.376±0.20°, and /or 22.923±0.20°, and/or 24.212±0.20°, and/or 24.757±0.20°, and/or 25.131±0.20°, and/or 25.447±0.20°, and/or 26.196±0.20°, and/or 26.024±0.20°, and/or 26.729±0.20°, and/or 26.977±0.20°, and/or 27.649±0.20°, and/or 28.899±0.20°, and/or 29.549±0.20°, and/or 29.970± 0.20°, and/or 30.456±0.20°, and/or 30.694±0.20°, and/or 31.098±0.20°, and/or 31.415±0.20°, and/or 32.010±0.20°, and/or 32.396±0.20° , and/or 33.344±0.20°, and/or 33.584±0.20°, and/or 33.900±0.20°, and/or 34.431±0.20°, and/or 34.889±0.20°, and/or 35.193±0.20°, and /or 35.702±0.20°, and/or 36.670±0.20°, and/or 37.683±0.20°, and/or 38.047±0.20°, and/or 38.645±0.20°, and/or 39.701±0.20°.
在本发明的一些方案中，上述式(I)化合物的晶型B，其XRPD图谱如图4所示。In some aspects of the present invention, the XRPD spectrum of the crystal form B of the compound of formula (I) is shown in FIG. 4 .
本发明的一些方案中，上述晶型B的XRPD图谱解析数据如表2所示。In some solutions of the present invention, the analysis data of the XRPD spectrum of the above-mentioned crystal form B is shown in Table 2.
表2式(I)化合物的晶型B的XRPD图谱解析数据The XRPD pattern analysis data of the crystal form B of the compound of formula (I) in table 2
Figure PCTCN2022134142-appb-000005
Figure PCTCN2022134142-appb-000005
Figure PCTCN2022134142-appb-000006
Figure PCTCN2022134142-appb-000006
在本发明的一些方案中，上述晶型B的热重分析曲线在130.0℃±3℃时失重达1.06％。In some solutions of the present invention, the thermogravimetric analysis curve of the above crystal form B reaches a weight loss of 1.06% at 130.0°C±3°C.
在本发明的一些方案中，上述晶型B的TGA图谱如图5所示。In some solutions of the present invention, the TGA spectrum of the above crystal form B is shown in FIG. 5 .
在本发明的一些方案中，上述晶型B的差示扫描量热曲线在143.8℃±3℃处具有吸热峰的起始值。In some solutions of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form B has an onset value of an endothermic peak at 143.8°C±3°C.
在本发明的一些方案中，上述晶型B的差示扫描量热曲线在143.8℃±5℃处具有吸热峰的起始值。在本发明的一些方案中，上述晶型B的DSC图谱如图6所示。In some solutions of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form B has an endothermic peak at 143.8°C±5°C. In some solutions of the present invention, the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 6 .
本发明提供了式(II)化合物，The present invention provides a compound of formula (II),
Figure PCTCN2022134142-appb-000007
Figure PCTCN2022134142-appb-000007
发明还提供了式(II)化合物的晶型C，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.117±0.20°，16.434±0.20°，24.235±0.20°。The invention also provides crystal form C of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.117±0.20°, 16.434±0.20°, 24.235±0.20°.
在本发明的一些方案中，上述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.117±0.20°，13.942±0.20°，14.871±0.20°，16.434±0.20°，17.670±0.20°，21.270±0.20°，24.235±0.20°，27.099±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2θ angles: 8.117±0.20°, 13.942±0.20°, 14.871±0.20°, 16.434±0.20°, 17.670± 0.20°, 21.270±0.20°, 24.235±0.20°, 27.099±0.20°.
在本发明的一些方案中，上述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.117±0.20°，13.942±0.20°，14.871±0.20°，16.434±0.20°，17.670±0.20°，21.270±0.20°，24.235±0.20°，24.992±0.20°，27.099±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2θ angles: 8.117±0.20°, 13.942±0.20°, 14.871±0.20°, 16.434±0.20°, 17.670± 0.20°, 21.270±0.20°, 24.235±0.20°, 24.992±0.20°, 27.099±0.20°.
在本发明的一些方案中，上述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.117±0.20°，13.051±0.20°，13.942±0.20°，14.871±0.20°，16.434±0.20°，17.670±0.20°，18.979±0.20°，21.270±0.20°，23.636±0.20°，24.235±0.20°，24.992±0.20°，25.851±0.20°，27.099±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2θ angles: 8.117±0.20°, 13.051±0.20°, 13.942±0.20°, 14.871±0.20°, 16.434± 0.20°, 17.670±0.20°, 18.979±0.20°, 21.270±0.20°, 23.636±0.20°, 24.235±0.20°, 24.992±0.20°, 25.851±0.20°, 27.099±0.20°.
在本发明的一些方案中，上述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.117±0.20°，13.051±0.20°，13.942±0.20°，14.871±0.20°，16.434±0.20°，17.670±0.20°，18.979±0.20°，21.270±0.20°，23.636±0.20°，24.235±0.20°，24.992±0.20°，25.851±0.20°，27.099±0.20°，28.565±0.20°，30.135±0.20°，31.174±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2θ angles: 8.117±0.20°, 13.051±0.20°, 13.942±0.20°, 14.871±0.20°, 16.434± 0.20°, 17.670±0.20°, 18.979±0.20°, 21.270±0.20°, 23.636±0.20°, 24.235±0.20°, 24.992±0.20°, 25.851±0.20°, 27.099±0.20°, 28.565±0.20 °, 30.135± 0.20°, 31.174±0.20°.
在本发明的一些方案中，上述式(II)化合物的晶型C，其XRPD图谱如图7所示。In some aspects of the present invention, the XRPD spectrum of the crystal form C of the compound of formula (II) is shown in FIG. 7 .
本发明的一些方案中，上述晶型C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 crystal form C are shown in Table 3.
表3式(II)化合物的晶型C的XRPD图谱解析数据Table 3 XRPD spectrum analysis data of the crystal form C of the compound of formula (II)
Figure PCTCN2022134142-appb-000008
Figure PCTCN2022134142-appb-000008
Figure PCTCN2022134142-appb-000009
Figure PCTCN2022134142-appb-000009
本发明还提供了式(III)化合物，The present invention also provides a compound of formula (III),
Figure PCTCN2022134142-appb-000010
Figure PCTCN2022134142-appb-000010
发明还提供式(III)化合物的晶型D，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.549±0.20°，16.867±0.20°，22.037±0.20°。The invention also provides crystal form D of the compound of formula (III), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.549±0.20°, 16.867±0.20°, 22.037±0.20°.
在本发明的一些方案中，上述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.549±0.20°，16.867±0.20°，17.461±0.20°，18.061±0.20°，20.239±0.20°，22.037±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form D has characteristic diffraction peaks at the following 2θ angles: 8.549±0.20°, 16.867±0.20°, 17.461±0.20°, 18.061±0.20°, 20.239± 0.20°, 22.037±0.20°.
在本发明的一些方案中，上述式(III)化合物的晶型D，其XRPD图谱如图8所示。In some aspects of the present invention, the XRPD pattern of the crystal form D of the compound of formula (III) is shown in FIG. 8 .
本发明的一些方案中，上述晶型D的XRPD图谱解析数据如表4所示。In some solutions of the present invention, the analytical data of the XRPD spectrum of the above crystal form D is shown in Table 4.
表4式(III)化合物的晶型D的XRPD图谱解析数据The XRPD pattern analysis data of the crystal form D of the compound of the formula (III) of table 4
Figure PCTCN2022134142-appb-000011
Figure PCTCN2022134142-appb-000011
Figure PCTCN2022134142-appb-000012
Figure PCTCN2022134142-appb-000012
发明还提供式(III)化合物的晶型E，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.528±0.20°，16.970±0.20°，25.361±0.20°；The invention also provides crystal form E of the compound of formula (III), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.528±0.20°, 16.970±0.20°, 25.361±0.20°;
Figure PCTCN2022134142-appb-000013
Figure PCTCN2022134142-appb-000013
在本发明的一些方案中，上述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.528±0.20°，16.970±0.20°，17.583±0.20°，19.124±0.20°，20.892±0.20°，24.189±0.20°，25.361±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2θ angles: 8.528±0.20°, 16.970±0.20°, 17.583±0.20°, 19.124±0.20°, 20.892± 0.20°, 24.189±0.20°, 25.361±0.20°.
在本发明的一些方案中，上述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.528±0.20°，15.667±0.20°，16.970±0.20°，17.583±0.20°，17.994±0.20°，19.124±0.20°，20.892±0.20°，24.189±0.20°，25.361±0.20°，30.468±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2θ angles: 8.528±0.20°, 15.667±0.20°, 16.970±0.20°, 17.583±0.20°, 17.994± 0.20°, 19.124±0.20°, 20.892±0.20°, 24.189±0.20°, 25.361±0.20°, 30.468±0.20°.
在本发明的一些方案中，上述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.528±0.20°，14.332±0.20°，15.667±0.20°，16.099±0.20°，16.970±0.20°，17.583±0.20°，17.994±0.20°，19.124±0.20°，20.892±0.20°，22.187±0.20°，24.189±0.20°，25.361±0.20°，26.348±0.20°，30.468±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2θ angles: 8.528±0.20°, 14.332±0.20°, 15.667±0.20°, 16.099±0.20°, 16.970± 0.20°, 17.583±0.20°, 17.994±0.20°, 19.124±0.20°, 20.892±0.20°, 22.187±0.20°, 24.189±0.20°, 25.361±0.20°, 26.348±0.20°, 30.468±0.20 °.
在本发明的一些方案中，上述式(III)化合物的晶型E，其XRPD图谱如图9所示。In some aspects of the present invention, the XRPD pattern of the crystal form E of the compound of formula (III) is shown in FIG. 9 .
本发明的一些方案中，上述晶型E的XRPD图谱解析数据如表5所示。In some solutions of the present invention, the analysis data of the XRPD spectrum of the above-mentioned crystal form E is shown in Table 5.
表5式(III)化合物的晶型E的XRPD图谱解析数据The XRPD spectrum analysis data of the crystal form E of the compound of the formula (III) in table 5
Figure PCTCN2022134142-appb-000014
Figure PCTCN2022134142-appb-000014
Figure PCTCN2022134142-appb-000015
Figure PCTCN2022134142-appb-000015
本发明提供式(IV)化合物，The present invention provides a compound of formula (IV),
Figure PCTCN2022134142-appb-000016
Figure PCTCN2022134142-appb-000016
本发明还提供式(IV)化合物的晶型F，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.883±0.20°，11.157±0.20°，16.652±0.20°；The present invention also provides the crystal form F of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.883±0.20°, 11.157±0.20°, 16.652±0.20°;
Figure PCTCN2022134142-appb-000017
Figure PCTCN2022134142-appb-000017
本发明还提供式(IV)化合物的晶型F，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.883±0.20°，16.652±0.20°，25.352±0.20°。The present invention also provides the crystal form F of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.883±0.20°, 16.652±0.20°, 25.352±0.20°.
在本发明的一些方案中，上述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.365±0.20°，8.883±0.20°，11.157±0.20°，12.701±0.20°，16.652±0.20°，17.735±0.20°，18.278±0.20°，25.352±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form F has characteristic diffraction peaks at the following 2θ angles: 8.365±0.20°, 8.883±0.20°, 11.157±0.20°, 12.701±0.20°, 16.652± 0.20°, 17.735±0.20°, 18.278±0.20°, 25.352±0.20°.
在本发明的一些方案中，上述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.365±0.20°，8.883±0.20°，11.157±0.20°，12.701±0.20°，16.652±0.20°，17.735±0.20°，18.278±0.20°，21.347±0.20°，22.359±0.20°，25.352±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form F has characteristic diffraction peaks at the following 2θ angles: 8.365±0.20°, 8.883±0.20°, 11.157±0.20°, 12.701±0.20°, 16.652± 0.20°, 17.735±0.20°, 18.278±0.20°, 21.347±0.20°, 22.359±0.20°, 25.352±0.20°.
在本发明的一些方案中，上述式(IV)化合物的晶型F，其XRPD图谱如图10所示。In some aspects of the present invention, the XRPD pattern of the crystal form F of the compound of formula (IV) is shown in FIG. 10 .
本发明的一些方案中，上述晶型F的XRPD图谱解析数据如表6所示。In some solutions of the present invention, the XRPD spectrum analysis data of the above crystal form F are shown in Table 6.
表6式(IV)化合物的晶型F的XRPD图谱解析数据The XRPD pattern analysis data of the crystal form F of the compound of the formula (IV) of table 6
Figure PCTCN2022134142-appb-000018
Figure PCTCN2022134142-appb-000018
Figure PCTCN2022134142-appb-000019
Figure PCTCN2022134142-appb-000019
本发明还提供式(IV)化合物的G晶型，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.043±0.20°，12.879±0.20°，23.105±0.20°。The present invention also provides crystal form G of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.043±0.20°, 12.879±0.20°, 23.105±0.20°.
在本发明的一些方案中，上述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.043±0.20°，8.978±0.20°，11.517±0.20°，12.879±0.20°，17.318±0.20°，18.995±0.20°，19.849±0.20°，23.105±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form G has characteristic diffraction peaks at the following 2θ angles: 7.043±0.20°, 8.978±0.20°, 11.517±0.20°, 12.879±0.20°, 17.318± 0.20°, 18.995±0.20°, 19.849±0.20°, 23.105±0.20°.
在本发明的一些方案中，上述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.043±0.20°，8.978±0.20°，11.517±0.20°，12.879±0.20°，14.337±0.20°，16.833±0.20°，17.318±0.20°，18.995±0.20°，19.849±0.20°，20.635±0.20°，23.105±0.20°，25.950±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form G has characteristic diffraction peaks at the following 2θ angles: 7.043±0.20°, 8.978±0.20°, 11.517±0.20°, 12.879±0.20°, 14.337± 0.20°, 16.833±0.20°, 17.318±0.20°, 18.995±0.20°, 19.849±0.20°, 20.635±0.20°, 23.105±0.20°, 25.950±0.20°.
在本发明的一些方案中，上述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.043±0.20°，8.978±0.20°，11.517±0.20°，12.879±0.20°，14.337±0.20°，16.058±0.20°，16.833±0.20°，17.318±0.20°，18.995±0.20°，19.849±0.20°，20.635±0.20°，23.105±0.20°，25.950±0.20°，26.131±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form G has characteristic diffraction peaks at the following 2θ angles: 7.043±0.20°, 8.978±0.20°, 11.517±0.20°, 12.879±0.20°, 14.337± 0.20°, 16.058±0.20°, 16.833±0.20°, 17.318±0.20°, 18.995±0.20°, 19.849±0.20°, 20.635±0.20°, 23.105±0.20°, 25.950±0.20°, 26.131±0.20 °.
在本发明的一些方案中，上述式(IV)化合物的晶型G，其XRPD图谱如图11所示。In some aspects of the present invention, the XRPD pattern of the crystal form G of the compound of formula (IV) above is shown in FIG. 11 .
本发明的一些方案中，上述晶型G的XRPD图谱解析数据如表7所示。In some solutions of the present invention, the analytical data of the XRPD pattern of the above-mentioned crystal form G is shown in Table 7.
表7式(IV)化合物的晶型G的XRPD图谱解析数据The XRPD pattern analysis data of the crystal form G of the compound of formula (IV) in table 7
Figure PCTCN2022134142-appb-000020
Figure PCTCN2022134142-appb-000020
Figure PCTCN2022134142-appb-000021
Figure PCTCN2022134142-appb-000021
本发明还提供式(IV)化合物的晶型H，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.303±0.20°，14.560±0.20°，23.443±0.20°；The present invention also provides the crystal form H of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.303±0.20°, 14.560±0.20°, 23.443±0.20°;
Figure PCTCN2022134142-appb-000022
Figure PCTCN2022134142-appb-000022
在本发明的一些方案中，上述晶型H的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.303±0.20°，14.560±0.20°，15.502±0.20°，18.330±0.20°，21.690±0.20°，23.443±0.20°，24.600±0.20°，25.793±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2θ angles: 7.303±0.20°, 14.560±0.20°, 15.502±0.20°, 18.330±0.20°, 21.690± 0.20°, 23.443±0.20°, 24.600±0.20°, 25.793±0.20°.
在本发明的一些方案中，上述晶型H的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.303±0.20°，14.560±0.20°，15.502±0.20°，18.330±0.20°，18.981±0.20°，21.690±0.20°，23.443±0.20°，24.600±0.20°，25.793±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2θ angles: 7.303±0.20°, 14.560±0.20°, 15.502±0.20°, 18.330±0.20°, 18.981± 0.20°, 21.690±0.20°, 23.443±0.20°, 24.600±0.20°, 25.793±0.20°.
在本发明的一些方案中，上述晶型H的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.303±0.20°，9.362±0.20°，14.560±0.20°，15.502±0.20°，17.858±0.20°，18.330±0.20°，18.981±0.20°，19.721±0.20°，21.690±0.20°，22.373±0.20°，23.443±0.20°，24.600±0.20°，25.793±0.20°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2θ angles: 7.303±0.20°, 9.362±0.20°, 14.560±0.20°, 15.502±0.20°, 17.858± 0.20°, 18.330±0.20°, 18.981±0.20°, 19.721±0.20°, 21.690±0.20°, 22.373±0.20°, 23.443±0.20°, 24.600±0.20°, 25.793±0.20°.
在本发明的一些方案中，上述式(IV)化合物的晶型H，其XRPD图谱如图12所示。In some aspects of the present invention, the XRPD pattern of the crystal form H of the compound of formula (IV) is shown in FIG. 12 .
本发明的一些方案中，上述晶型H的XRPD图谱解析数据如表8所示。In some solutions of the present invention, the analytical data of the XRPD spectrum of the above crystal form H is shown in Table 8.
表8式(IV)化合物的晶型H的XRPD图谱解析数据The XRPD spectrum analysis data of the crystal form H of the compound of the formula (IV) in table 8
Figure PCTCN2022134142-appb-000023
Figure PCTCN2022134142-appb-000023
Figure PCTCN2022134142-appb-000024
Figure PCTCN2022134142-appb-000024
本发明还提供了式(II)化合物、式(II)化合物、式(IV)化合物、晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H在制备治疗与肠炎相关药物中的应用。The present invention also provides the compound of formula (II), compound of formula (II), compound of formula (IV), crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, and crystal form G . Application of the crystal form H in the preparation of medicines related to the treatment of enteritis.
在本发明的一些方案中，上述肠炎包括溃疡性肠炎和克罗恩病。In some aspects of the present invention, the above enteritis includes ulcerative enteritis and Crohn's disease.
技术效果technical effect
本发明晶型具有良好的稳定性，PK性质优的特点，具有优异的肠炎治疗作用。The crystal form of the present invention has the characteristics of good stability and excellent PK properties, and has excellent therapeutic effect on enteritis.
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，旨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 specific phrase or term should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
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 compound 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, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
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, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes on the basis of existing embodiments.
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：
Figure PCTCN2022134142-appb-000025
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 compounds of the present invention can be confirmed by conventional methods 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, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuKα radiation, and the scanning method is:
Figure PCTCN2022134142-appb-000025
After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
除非另有说明，X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施方案中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本试验所用仪器状况，衍射峰可能存在±0.20°的误差容限，也可能存在±0.10°的误差容限，因此所述衍射峰的误差容限不能视为绝对的。Unless otherwise specified, X-ray powder diffraction (XRPD) can detect information such as changes in crystal forms, crystallinity, and crystal structure state, and is a common method for identifying crystal forms. The peak positions of an XRPD pattern mainly depend on the structure of the crystalline form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention. At the same time, there may be experimental errors in the measurement of 2θ in the XRPD pattern, and there may be slight differences in the measurement of 2θ in the XRPD pattern between different instruments and different samples, so the value of 2θ in the XRPD pattern cannot be regarded as absolute. According to the condition of the instrument used in this test, there may be an error tolerance of ±0.20° or ±0.10° for the diffraction peak, so the error tolerance of the diffraction peak cannot be regarded as absolute.
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 specifically described by examples below, and these examples do not imply 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.
本发明采用下述缩略词：DCM代表二氯甲烷；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOH代表乙醇；MeOH代表甲醇；2-MeTHF代表2-甲基四氢呋喃；Dioxane代表二氧六环；ACN代表乙腈；Toluene代表甲苯；Acetone代表丙酮；EtOAc代表乙酸乙酯；THF代表四氢呋喃；H 2O代表水；TosOH代表对甲苯磺酸；Pd(dppf)Cl 2代表1,1'-双二苯基膦二茂铁二氯化钯。 The present invention adopts the following abbreviations: DCM stands for dichloromethane; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOH stands for ethanol; MeOH stands for methanol; 2-MeTHF stands for 2-methyl Tetrahydrofuran; Dioxane represents dioxane; ACN represents acetonitrile; Toluene represents toluene; Acetone represents acetone; EtOAc represents ethyl acetate; THF represents tetrahydrofuran; H 2 O represents water; TosOH represents p-toluenesulfonic acid; Pd(dppf)Cl 2 Represents 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022134142-appb-000026
软件命名，市售化合物采用供应商目录名称。 Compounds are named according to the conventional naming principles in this field or using
Figure PCTCN2022134142-appb-000026
The software is named, and the commercially available compounds adopt the supplier catalog name.
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法Powder X-ray diffraction (X-ray powder diffractometer, XRPD) method of the present invention
仪器型号：布鲁克D2PHASER射线衍射仪Instrument model: Bruker D2PHASER ray diffractometer
测试方法：大约10～20mg样品用于XRPD检测。Test method: About 10-20 mg of sample is used for XRPD detection.
详细的XRPD参数如下：The detailed XRPD parameters are as follows:
光管：Cu,kα,
Figure PCTCN2022134142-appb-000027
Light pipe: Cu, kα,
Figure PCTCN2022134142-appb-000027
光管电压：30kV，光管电流：10mAPhototube voltage: 30kV, phototube current: 10mA
发散狭缝：0.60mmDivergence slit: 0.60mm
探测器狭缝：5.827°Detector slit: 5.827°
防散射狭缝：2.50mmAnti-scatter slit: 2.50mm
扫描范围：3-40degScanning range: 3-40deg
步径：0.02degStep: 0.02deg
步长：0.5秒Step size: 0.5 seconds
样品盘转速：15rpmSample disk speed: 15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法The present invention's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
仪器型号：TA Discovery DSC 2500差示扫描量热仪Instrument Model: TA Discovery DSC 2500 Differential Scanning Calorimeter
测试方法：取样品(～1mg)置于DSC铝锅内进行测试，在N 2条件下，以10℃/min的升温速率，加热样品从25℃(室温)到300℃(或350℃)。 Test method: Take a sample (~1mg) and place it in a DSC aluminum pot for testing. Under N2 conditions, heat the sample from 25°C (room temperature) to 300°C (or 350°C) at a heating rate of 10°C/min.
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
仪器型号：TA Discovery TGA 5500热重分析仪Instrument Model: TA Discovery TGA 5500 Thermogravimetric Analyzer
测试方法：取样品(2～5mg)置于TGA铂金锅内进行测试，在N 2条件下，以10℃/min的升温速率，加热样品从室温到350℃或失重20％。 Test method: Take a sample (2~5mg) and place it in a TGA platinum pot for testing. Under N2 conditions, heat the sample from room temperature to 350°C at a heating rate of 10°C/min or lose 20% of its weight.
附图说明Description of drawings
图1为(I)化合物晶型A的Cu-Kα辐射的XRPD谱图。Figure 1 is the Cu-Kα radiation XRPD spectrum of (I) compound crystal form A.
图2为(I)化合物晶型A的TGA谱图。Fig. 2 is the TGA spectrogram of (I) compound crystal form A.
图3为(I)化合物晶型A的DSC谱图。Fig. 3 is the DSC spectrogram of (I) compound crystal form A.
图4为(I)化合物晶型B的Cu-Kα辐射的XRPD谱图。Fig. 4 is the Cu-Kα radiation XRPD spectrum of (I) compound crystal form B.
图5为(I)化合物晶型B的TGA谱图。Fig. 5 is the TGA spectrogram of (I) compound crystal form B.
图6为(I)化合物晶型B的DSC谱图。Fig. 6 is the DSC spectrogram of (I) compound crystal form B.
图7为(II)化合物晶型C的Cu-Kα辐射的XRPD谱图。Fig. 7 is the Cu-Kα radiation XRPD spectrum of (II) compound crystal form C.
图8为(III)化合物晶型D的Cu-Kα辐射的XRPD谱图。Fig. 8 is the Cu-Kα radiation XRPD spectrum of the crystal form D of compound (III).
图9为(III)化合物晶型E的Cu-Kα辐射的XRPD谱图。Fig. 9 is the Cu-Kα radiation XRPD spectrum of (III) compound crystal form E.
图10为(IV)化合物晶型F的Cu-Kα辐射的XRPD谱图。Fig. 10 is the Cu-Kα radiation XRPD spectrum of (IV) compound crystal form F.
图11为(IV)化合物晶型G的Cu-Kα辐射的XRPD谱图。Fig. 11 is the Cu-Kα radiation XRPD spectrum of (IV) compound crystal form G.
图12为(IV)化合物晶型H的Cu-Kα辐射的XRPD谱图。Fig. 12 is the Cu-Kα radiation XRPD spectrum of Form H of compound (IV).
图13为(I)化合物的无定形谱图。Figure 13 is the amorphous spectrum of compound (I).
图14为体重变化图。Figure 14 is a graph of body weight changes.
图15为DAI(日常疾病指数)评价结果图。Fig. 15 is a graph showing the evaluation results of DAI (Daily Illness Index).
图16为实验终点结肠密度图。Figure 16 is a graph of colon density at the end point of the experiment.
具体实施方法Specific implementation method
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail through examples below, but it does not imply any unfavorable limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
实施例1：式(I)化合物晶型A的制备Embodiment 1: Preparation of formula (I) compound crystal form A
Figure PCTCN2022134142-appb-000028
Figure PCTCN2022134142-appb-000028
步骤1：step 1:
在反应瓶中加入化合物1A(35g,247.25mmol,1eq)，乙醇(350mL)，水合肼(13.26g,259.62mmol,12.88mL,98％含量,1.05eq)氮气置换三次，25℃搅拌2hr。反应液进行减压浓缩得到粗品，得到化合物2A，直接用于用于下一步反应。 1H NMR(400MHz,CDCl 3)δ＝8.54(dd,J＝4.6Hz,1.2Hz,1H),8.20(s,1H),7.67(dd,J＝8.2Hz,1.4Hz,1H),7.16(dd,J＝8.2Hz,4.6Hz,1H),6.09(s,2H)；LCMS(ESI):156.1[M+H]。 Add compound 1A (35g, 247.25mmol, 1eq), ethanol (350mL), hydrazine hydrate (13.26g, 259.62mmol, 12.88mL, 98% content, 1.05eq) into the reaction flask for nitrogen replacement three times, and stir at 25°C for 2hr. The reaction solution was concentrated under reduced pressure to obtain a crude product, and compound 2A was obtained, which was directly used in the next reaction. 1 H NMR (400MHz, CDCl 3 ) δ=8.54(dd, J=4.6Hz, 1.2Hz, 1H), 8.20(s, 1H), 7.67(dd, J=8.2Hz, 1.4Hz, 1H), 7.16( dd, J = 8.2Hz, 4.6Hz, 1H), 6.09(s, 2H); LCMS (ESI): 156.1 [M+H].
步骤2：Step 2:
在反应瓶中加入化合物2A(38.5g,247.45mmol,1eq)，乙醇(800mL)氮气置换三次加入氯化亚铜(1.22g,12.37mmol,295.87μL,0.05eq)，加入无水乙二胺(44.62g,742.36mmol,49.68mL,3eq)搅拌10min，降温至0℃滴加三溴氟甲烷(133.98g,494.91mmol,2eq)氮气置换三次自然升温至25℃搅拌4hr。反应完成后加入水(400mL)淬灭，用甲基叔丁基醚(400mL×3)萃取，收集有机相，有机相用饱和食盐水洗涤(200mL/次×5次)，有机相用无水硫酸钠干燥，过滤，减压浓缩得到3A粗品，直接用于下一步反应。 1H NMR(400MHz,CDCl 3)δ＝8.49-8.61(m,1H),7.66-7.74(m,1H),7.15-7.22(m,1H),6.48-6.62(m,1H)；LCMS(ESI):235.9/237.9[M+H,M+2+H]。 Compound 2A (38.5g, 247.45mmol, 1eq) was added to the reaction flask, and cuprous chloride (1.22g, 12.37mmol, 295.87μL, 0.05eq) was added for nitrogen replacement with ethanol (800mL) three times, and anhydrous ethylenediamine ( 44.62g, 742.36mmol, 49.68mL, 3eq) and stirred for 10min, cooled to 0°C and added dropwise tribromofluoromethane (133.98g, 494.91mmol, 2eq) nitrogen replacement three times and naturally warmed to 25°C and stirred for 4hr. After the reaction was completed, add water (400mL) to quench, extract with methyl tert-butyl ether (400mL×3), collect the organic phase, wash the organic phase with saturated brine (200mL/time×5 times), wash the organic phase with anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product 3A, which is directly used in the next reaction. 1 H NMR (400MHz, CDCl 3 ) δ=8.49-8.61 (m, 1H), 7.66-7.74 (m, 1H), 7.15-7.22 (m, 1H), 6.48-6.62 (m, 1H); LCMS (ESI ):235.9/237.9[M+H,M+2+H].
Figure PCTCN2022134142-appb-000029
Figure PCTCN2022134142-appb-000029
步骤3：Step 3:
将二氯甲烷(1330mL)，化合物1(190g,1.44mol,186.27mL,1eq)加入反应瓶中，开始搅拌；然后将一水合对甲苯磺酸(16.41g,86.26mmol,0.06eq)加入其中后，将2,3-二氢吡喃(169.31g,2.01mol,184.04mL,1.4eq)滴加入其中(有放热现象，需要控温)，在20℃反应16小时。向反应液中加入饱和碳酸氢钠溶液(800mL)，搅拌10min，分离有机相，水相用二氯甲烷(300mL×2)进行萃取；合并所有有机相用饱和食盐水洗(800mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩。得到化合物2，直接用于下一步。 1H NMR(400MHz,CDCl 3)δ＝4.75-4.73(m,1H),4.23-4.20(m,2H),4.18-4.14(m,2H),3.90-3.84(m,1H),3.55-3.51(m,1H),1.88-1.70(m,2H),1.67-1.51(m,6H),1.44-1.34(m,2H),0.97-0.92(m,3H)。 Dichloromethane (1330mL), compound 1 (190g, 1.44mol, 186.27mL, 1eq) were added to the reaction flask, and stirring was started; then p-toluenesulfonic acid monohydrate (16.41g, 86.26mmol, 0.06eq) was added , 2,3-dihydropyran (169.31g, 2.01mol, 184.04mL, 1.4eq) was added dropwise (exothermic phenomenon, temperature control is required), and reacted at 20°C for 16 hours. Add saturated sodium bicarbonate solution (800mL) to the reaction solution, stir for 10min, separate the organic phase, and extract the aqueous phase with dichloromethane (300mL×2); combine all the organic phases and wash with saturated brine (800mL×3). Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Compound 2 was obtained and used directly in the next step. 1 H NMR (400MHz, CDCl 3 )δ=4.75-4.73(m,1H),4.23-4.20(m,2H),4.18-4.14(m,2H),3.90-3.84(m,1H),3.55-3.51 (m,1H), 1.88-1.70(m,2H), 1.67-1.51(m,6H), 1.44-1.34(m,2H), 0.97-0.92(m,3H).
步骤4：Step 4:
将化合物2(327g,982.78mmol,65％纯度,1eq)，加入反应瓶中，开始搅拌；然后将水合肼(86.82g,1.47mol,84.29mL,85％含量,1.5eq)加入其中，将温度升至60℃，反应12小时。将反应液冷却至室温，加入水(185mL)后，分液；得到的水相用甲基叔丁基醚(100mL/次×2次)，合并有机相，用水(80mL/次×2次)萃取；合并水相，得到水溶液化合物3产率按照理论产量计算，直接用于下一步。 1H NMR(400MHz,D 2O-d 2)δ＝4.23-4.18(m,1H),4.12-4.08(m,2H),3.86-3.81(m,1H),3.58-3.54(m,1H),1.78-1.75(m,2H),1.61-1.45(m,4H)；LCMS(ESI):175.0[M+H]。 Compound 2 (327g, 982.78mmol, 65% purity, 1eq) was added to the reaction flask, and stirring was started; Rise to 60°C and react for 12 hours. Cool the reaction solution to room temperature, add water (185mL), and separate the liquids; the obtained aqueous phase is treated with methyl tert-butyl ether (100mL/time x 2 times), the organic phases are combined, and water (80mL/time x 2 times) Extraction; the aqueous phase was combined to obtain an aqueous solution. The yield of compound 3 was calculated according to the theoretical yield and used directly for the next step. 1 H NMR (400MHz, D 2 Od 2 )δ=4.23-4.18(m,1H),4.12-4.08(m,2H),3.86-3.81(m,1H),3.58-3.54(m,1H),1.78 -1.75 (m, 2H), 1.61-1.45 (m, 4H); LCMS (ESI): 175.0 [M+H].
步骤5：Step 5:
将化合物3(164g,941.46mmol,380mL,1eq)(上一步水溶液)，降温至0～5℃，然后将异氰酸乙酯(100.38g,1.41mol,111.78mL,1.5eq)滴加到其中，反应3小时，有大量白色固体生成。得到浅黄色悬浊水溶液化合物4，直接用于下一步。Compound 3 (164g, 941.46mmol, 380mL, 1eq) (aqueous solution of the previous step) was cooled to 0-5°C, and ethyl isocyanate (100.38g, 1.41mol, 111.78mL, 1.5eq) was added dropwise to it , reacted for 3 hours, a large amount of white solid was formed. A light yellow suspension aqueous solution compound 4 was obtained, which was directly used in the next step.
步骤6：Step 6:
将化合物4(230.9g,941.39mmol,1eq)(上一步反应液，质量按照理论产量计算)与水(100mL)混合后，加入氢氧化钠(18.83g,235.35mmol,50％含量,0.25eq)水溶液，升温至80～85℃，反应15小时。向反应体系中加入1M盐酸，将pH值调至7～8后，加入300mL二氯甲烷，过滤，滤液直接进行分液，水相用二氯甲烷(100mL/次×2次)萃取；合并有机相，用300mL饱和食盐水洗涤一次后，加入无水硫酸钠干燥，过滤，滤液在45℃下进行减压浓缩，得到固体化合物5。 1H NMR(400MHz,DMSO-d 6)δ＝11.64(s,1H),4.70-4.69(m,1H),4.53-4.50(m,1H),4.35-4.32(m,1H),3.76-3.70(m,1H),3.65-3.60(m,2H),3.51-3.47(m,1H),1.71-1.60(m,2H),1.53-1.47(m,4H),1.18(t,J＝6.4Hz,3H)；LCMS(ESI):228.1[M+H]。 Compound 4 (230.9g, 941.39mmol, 1eq) (the reaction solution in the previous step, the mass is calculated according to the theoretical yield) was mixed with water (100mL), and sodium hydroxide (18.83g, 235.35mmol, 50% content, 0.25eq) was added Aqueous solution, heated up to 80-85°C, reacted for 15 hours. Add 1M hydrochloric acid to the reaction system, adjust the pH value to 7-8, add 300mL dichloromethane, filter, the filtrate is directly separated, and the aqueous phase is extracted with dichloromethane (100mL/time × 2 times); phase, washed once with 300 mL of saturated brine, dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C to obtain compound 5 as a solid. 1 H NMR (400MHz,DMSO-d 6 )δ=11.64(s,1H),4.70-4.69(m,1H),4.53-4.50(m,1H),4.35-4.32(m,1H),3.76-3.70 (m,1H),3.65-3.60(m,2H),3.51-3.47(m,1H),1.71-1.60(m,2H),1.53-1.47(m,4H),1.18(t,J＝6.4Hz , 3H); LCMS (ESI): 228.1 [M+H].
步骤7：Step 7:
将乙腈(900mL)，2,4,5-三氟苯腈(50.39g,320.78mmol,1eq)，化合物5(90g,320.78mmol,1eq)加入反应瓶中，开始搅拌；然后将无水磷酸钾(136.18g,641.56mmol,2eq)加入其中，升温至70℃，反应15小时。向反应体系中加入1.5L饱和氯化铵溶液后，分液；得到的水相用500mL甲基叔丁基醚洗涤一次；合并有机相，用饱和食盐水洗涤(750mL/次×2次)，加入无水硫酸钠干燥后，过滤，滤液在45℃下进行减压浓缩；得到粗品，将粗品用乙醇(150mL)溶清后，将200mL水滴加到其中，室温20℃，搅拌12小时；过滤，收集滤饼，并在乙醇/水(200mL，3:4)混合搅拌1小时后，过滤，重复操作3次，得到类白色固体化合物6。 1H NMR(400MHz,CDCl 3)δ＝7.67(dd,J＝8.8Hz,5.6Hz,1H),7.47(dd,J＝9.6Hz,5.6Hz,1H),4.76-4.69(m,2H),4.49-4.46(m,1H),3.91-3.83(m,3H),3.63-3.58(m,1H),1.85-1.75(m,2H),1.66-1.56(m,4H),1.40(t,J＝7.2Hz,3H)。 Acetonitrile (900mL), 2,4,5-trifluorobenzonitrile (50.39g, 320.78mmol, 1eq), compound 5 (90g, 320.78mmol, 1eq) were added to the reaction flask, and stirring was started; then anhydrous potassium phosphate (136.18g, 641.56mmol, 2eq) was added thereto, the temperature was raised to 70°C, and the reaction was carried out for 15 hours. After adding 1.5L saturated ammonium chloride solution to the reaction system, separate the liquids; the obtained aqueous phase was washed once with 500 mL methyl tert-butyl ether; the combined organic phases were washed with saturated brine (750 mL/time × 2 times), After adding anhydrous sodium sulfate to dry, filter, and concentrate the filtrate under reduced pressure at 45°C; to obtain the crude product, dissolve the crude product with ethanol (150mL), add 200mL of water dropwise, stir at room temperature 20°C for 12 hours; filter , collect the filter cake, and after mixing and stirring in ethanol/water (200mL, 3:4) for 1 hour, filter and repeat the operation 3 times to obtain compound 6 as an off-white solid. 1 H NMR (400MHz, CDCl 3 ) δ=7.67(dd, J=8.8Hz, 5.6Hz, 1H), 7.47(dd, J=9.6Hz, 5.6Hz, 1H), 4.76-4.69(m, 2H), 4.49-4.46(m,1H),3.91-3.83(m,3H),3.63-3.58(m,1H),1.85-1.75(m,2H),1.66-1.56(m,4H),1.40(t,J =7.2Hz, 3H).
步骤8：Step 8:
将N-甲基吡咯烷酮(472mL)，叔丁基醇钾(21.87g,194.94mmol,1.3eq)加入反应瓶中开始搅拌；然后将温度降至0～-5℃后，将(2S)-1,1,1-三氟丙烷-2-醇(18.81g,164.95mmol,1.1eq)加入其中，升至室温10～15℃，反应0.5小时，然后将温度降至0～-5℃后，将化合物6(59g,149.95mmol,92.6％纯度,1eq)溶于N-甲基吡咯烷酮(236mL)后，滴加到其中，反应1小时。与其他批次合并后，将反应液倒入2.5L饱和氯化铵溶液将其淬灭，加入甲基叔丁基醚(1.5L/次×2次)进行萃取，合并有机相，用饱和食盐水洗(1.5L/次×3次)洗涤后，加入无水硫酸钠干燥，过滤，滤液进行减压浓缩。得到化合物7。 1H NMR(400MHz,CDCl 3)δ＝7.47-7.44(m,2H),4.76-4.71(m,3H),4.50-4.47(m,1H),3.92-3.84(m,3H),3.63-3.58(m,1H),1.86-1.76(m,2H),1.66-1.56(m,7H),1.41(t,J＝7.2Hz,3H)；LCMS(ESI):459.1[M+H]。 Add N-methylpyrrolidone (472mL), potassium tert-butylate (21.87g, 194.94mmol, 1.3eq) into the reaction flask and start stirring; , 1,1-trifluoropropan-2-ol (18.81g, 164.95mmol, 1.1eq) was added to it, raised to room temperature 10-15°C, reacted for 0.5 hours, and then lowered the temperature to 0-5°C, then Compound 6 (59g, 149.95mmol, 92.6% purity, 1eq) was dissolved in N-methylpyrrolidone (236mL), added dropwise thereto, and reacted for 1 hour. After merging with other batches, pour the reaction solution into 2.5L saturated ammonium chloride solution to quench it, add methyl tert-butyl ether (1.5L/time×2 times) for extraction, combine the organic phases, and wash with saturated salt After washing with water (1.5 L/time x 3 times), add anhydrous sodium sulfate to dry, filter, and concentrate the filtrate under reduced pressure. Compound 7 was obtained. 1 H NMR (400MHz, CDCl 3 )δ=7.47-7.44(m,2H),4.76-4.71(m,3H),4.50-4.47(m,1H),3.92-3.84(m,3H),3.63-3.58 (m, 1H), 1.86-1.76 (m, 2H), 1.66-1.56 (m, 7H), 1.41 (t, J = 7.2Hz, 3H); LCMS (ESI): 459.1 [M+H].
步骤9：Step 9:
将乙醇(740mL)，化合物7(74g,142.35mmol)加入反应瓶中，开始搅拌；然后将氢氧化钠(2M,320.28mL)加入其中，升温至70℃，反应25小时。向反应液中加入1.5L水后，反应液在45℃下进行减压浓缩，然后加入500mL甲基叔丁基醚萃取；得到的水相加入盐酸(1M)，将pH值调至5～6后，加入甲基叔丁基醚萃取(700mL/次×3次)；得到的有机相用饱和食盐水(1L/次×1次)洗涤后，加入无水硫酸钠干燥，过滤，滤液在45℃下进行减压浓缩，得到粗品。向上述粗品中加入200mL异丙醚，将温度升温至60℃，完全溶清后，搅拌10min；然后将温度自然降至20℃，继续搅拌12小时后，加入10mL四氢呋喃，然后将温度降至0～5℃后，继续搅拌0.5小时；低温快速过滤，滤饼用异丙醚/四氢呋喃(20:1,20mL×2次) 淋洗后，在45℃下进行减压浓缩。得到类白色固体化合物8。 1H NMR(400MHz,CDCl 3)δ＝7.97(dd,J＝10.8Hz,1H),7.52(dd,J＝5.6Hz,1H),4.90-4.84(m,1H),4.76-4.72(m,2H),4.51-4.82(m,2H),3.93-3.85(m,3H),3.64-3.59(m,1H),1.86-1.76(m,2H),1.66-1.56(m,7H),1.42(t,J＝7.2Hz,3H)；LCMS(ESI):478.1[M+H]。 Add ethanol (740mL) and compound 7 (74g, 142.35mmol) into the reaction flask, start stirring; then add sodium hydroxide (2M, 320.28mL) into it, heat up to 70°C, and react for 25 hours. After adding 1.5 L of water to the reaction solution, the reaction solution was concentrated under reduced pressure at 45°C, and then extracted by adding 500 mL of methyl tert-butyl ether; adding hydrochloric acid (1M) to the obtained aqueous phase to adjust the pH value to 5-6 After that, add methyl tert-butyl ether for extraction (700mL/time x 3 times); the obtained organic phase was washed with saturated brine (1L/time x 1 time), dried by adding anhydrous sodium sulfate, filtered, and the filtrate was Concentrate under reduced pressure at °C to obtain a crude product. Add 200mL of isopropyl ether to the above crude product, raise the temperature to 60°C, and stir for 10 minutes after completely dissolving; then lower the temperature to 20°C naturally, continue stirring for 12 hours, add 10mL of tetrahydrofuran, and then lower the temperature to 0 After ~5°C, continue to stir for 0.5 hours; filter quickly at low temperature, rinse the filter cake with isopropyl ether/tetrahydrofuran (20:1, 20mL×2 times), and concentrate under reduced pressure at 45°C. Compound 8 was obtained as an off-white solid. 1 H NMR (400MHz, CDCl 3 ) δ=7.97(dd, J=10.8Hz, 1H), 7.52(dd, J=5.6Hz, 1H), 4.90-4.84(m, 1H), 4.76-4.72(m, 2H),4.51-4.82(m,2H),3.93-3.85(m,3H),3.64-3.59(m,1H),1.86-1.76(m,2H),1.66-1.56(m,7H),1.42( t, J = 7.2 Hz, 3H); LCMS (ESI): 478.1 [M+H].
步骤10：Step 10:
将1,4-二氧六环(580mL)，化合物8(29g,57.71mmol)，双联嚬哪醇硼酸酯(48.36g,190.44mmol)加入反应瓶中，开始搅拌；然后将三乙胺(438.58mmol,61.05mL,)，醋酸钯(2.59g,11.54mmol,0.2eq)，特戊酸酐(26.87g,144.27mmol,)，1,4-双(二苯基膦)丁烷(4.92g,11.54mmol)加入其中，氮气保护下，100℃反应12小时。向反应体系中加入1L饱和氯化铵以及500mL甲基叔丁基醚，过滤，滤液直接分液；得到的有机相依次用饱和氯化铵溶液(1L/次×1次)，饱和碳酸氢钠溶液(1L/次×2次)，饱和食盐水(1L/次×1次)洗涤后，加入无水硫酸钠干燥，过滤。滤液在45℃下进行减压浓缩，得到的粗品经柱层析纯化(梯度洗脱：石油醚:乙酸乙酯＝5:1～2:1)，得到化合物9。 1H NMR(400MHz,CDCl 3)δ＝7.50(d,J＝10.8Hz,1H),7.20(d,J＝5.6Hz,1H),4.76-4.70(m,2H),4.62-4.55(m,1H),4.47(d,J＝12.8Hz,1H),3.90-3.84(m,3H),3.63-3.59(m,1H),1.86-1.74(m,2H),1.65-1.56(m,4H),1.51(d,J＝6.4Hz,3H),1.42-1.38(m,3H),1.35(s,12H)；LCMS(ESI):478.3,560.2[M-82+H,M+H]。 1,4-dioxane (580mL), compound 8 (29g, 57.71mmol), bisanalyl borate (48.36g, 190.44mmol) were added to the reaction flask, and stirring was started; then triethylamine (438.58mmol, 61.05mL,), palladium acetate (2.59g, 11.54mmol, 0.2eq), pivalic anhydride (26.87g, 144.27mmol,), 1,4-bis(diphenylphosphine)butane (4.92g , 11.54mmol) was added therein, under the protection of nitrogen, the reaction was carried out at 100°C for 12 hours. Add 1L saturated ammonium chloride and 500mL methyl tert-butyl ether to the reaction system, filter, and separate the filtrate directly; The solution (1 L/time x 2 times) was washed with saturated brine (1 L/time x 1 time), dried by adding anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 45°C, and the obtained crude product was purified by column chromatography (gradient elution: petroleum ether: ethyl acetate = 5:1-2:1) to obtain compound 9. 1 H NMR (400MHz, CDCl 3 ) δ=7.50(d, J=10.8Hz, 1H), 7.20(d, J=5.6Hz, 1H), 4.76-4.70(m, 2H), 4.62-4.55(m, 1H), 4.47(d, J=12.8Hz, 1H), 3.90-3.84(m, 3H), 3.63-3.59(m, 1H), 1.86-1.74(m, 2H), 1.65-1.56(m, 4H) , 1.51 (d, J=6.4Hz, 3H), 1.42-1.38 (m, 3H), 1.35 (s, 12H); LCMS (ESI): 478.3, 560.2 [M-82+H, M+H].
步骤11：Step 11:
在反应瓶中加入1,4-二氧六环(200mL)，水(40mL)，化合物9(20g,35.76mmol)，化合物3A(10.57g,44.69mmol)，三乙胺(10.85g,107.27mmol)氮气置换三次开始搅拌，加入Pd(dppf)Cl 2(5.23g,7.15mmol)，氮气置换三次85-90℃下搅拌8hr。反应液冷却至25℃后加入水(200mL)使用乙酸乙酯萃取(300mL×3)，收集有机相。有机相使用无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗品经柱层析纯化(石油醚：乙酸乙酯＝100:0～50:50)，得到化合物10。 1H NMR(400MHz,CDCl 3)δ＝8.62(d,J＝4.8Hz,1H),7.73(dd,J＝8.0Hz,1.2Hz,1H),7.62(d,J＝11.6Hz,1H),7.43-7.34(m,2H),7.17(dd,J＝8.0Hz,4.8Hz,1H),4.88-4.82(m,1H),4.77-4.72(m,2H),4.49(d,J＝6.4Hz,1H),3.93-3.85(m,3H),3.64-3.60(m,1H),1.87-1.76(m,2H),1.65-1.57(m,7H),1.42(t,J＝7.2Hz,3H)；LCMS(ESI):589.1[M+H]。 In the reaction flask, add 1,4-dioxane (200mL), water (40mL), compound 9 (20g, 35.76mmol), compound 3A (10.57g, 44.69mmol), triethylamine (10.85g, 107.27mmol ) was replaced with nitrogen three times and started to stir, and Pd(dppf)Cl 2 (5.23 g, 7.15 mmol) was added, replaced with nitrogen three times and stirred at 85-90° C. for 8 hr. After the reaction solution was cooled to 25°C, water (200 mL) was added and extracted with ethyl acetate (300 mL×3), and the organic phase was collected. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to obtain compound 10. 1 H NMR (400MHz, CDCl 3 ) δ=8.62(d, J=4.8Hz, 1H), 7.73(dd, J=8.0Hz, 1.2Hz, 1H), 7.62(d, J=11.6Hz, 1H), 7.43-7.34(m,2H),7.17(dd,J＝8.0Hz,4.8Hz,1H),4.88-4.82(m,1H),4.77-4.72(m,2H),4.49(d,J＝6.4Hz ,1H),3.93-3.85(m,3H),3.64-3.60(m,1H),1.87-1.76(m,2H),1.65-1.57(m,7H),1.42(t,J＝7.2Hz,3H ); LCMS (ESI): 589.1 [M+H].
步骤12：Step 12:
在反应瓶中加入化合物10(24g,40.75mmol)，无水乙醇(300mL)，磷酸(75.88g,774.26mmol)，然后氮气置换三次，在50℃搅拌1小时。反应完成后反应液加入到饱和碳酸氢钠水溶液中淬灭，调节pH值至7-8。使用乙酸乙酯萃取(800mL/次×2次)，收集有机相，使用饱和食盐水(400mL/次×3次)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物粗品。粗品中加入乙酸乙酯(50mL)，正庚烷(150mL)搅拌10min后过滤，收集滤饼；滤饼继续加入乙酸乙酯(50mL)，正庚烷(15 0mL)搅拌10min后过滤，收集滤饼真空干燥得到式(I)化合物晶型A。 1H NMR(400MHz,CDCl 3)δ＝8.62(d,J＝4.6Hz,1H),7.73(dd,J＝8.2,1.38Hz,1H),7.62(d,J＝11.6Hz,1H),7.33-7.46(m,2H),7.17(dd,J＝8.2,4.63Hz,1H),4.79-4.91(m,1H),4.69(d,J＝6.2Hz,2H),3.92(q,J＝7.2Hz,2H),2.27(s,1H),1.62(d,J＝6.4Hz,3H),1.43(t,J＝7.2Hz,3H)。晶型A的XRPD谱图如图1所示，TGA图如图2所示，DSC图如图3所示。 Compound 10 (24g, 40.75mmol), absolute ethanol (300mL), phosphoric acid (75.88g, 774.26mmol) were added to the reaction flask, and nitrogen was replaced three times, and stirred at 50°C for 1 hour. After the reaction was completed, the reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution, and the pH value was adjusted to 7-8. Extract with ethyl acetate (800 mL/time x 2 times), collect the organic phase, wash with saturated brine (400 mL/time x 3 times), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Ethyl acetate (50mL) was added to the crude product, n-heptane (150mL) was stirred for 10min and then filtered, and the filter cake was collected; The cake was dried in vacuo to obtain Form A of the compound of formula (I). 1 H NMR (400MHz, CDCl 3 ) δ=8.62(d,J=4.6Hz,1H),7.73(dd,J=8.2,1.38Hz,1H),7.62(d,J=11.6Hz,1H),7.33 -7.46(m,2H),7.17(dd,J=8.2,4.63Hz,1H),4.79-4.91(m,1H),4.69(d,J=6.2Hz,2H),3.92(q,J=7.2 Hz, 2H), 2.27 (s, 1H), 1.62 (d, J=6.4Hz, 3H), 1.43 (t, J=7.2Hz, 3H). The XRPD spectrum of Form A is shown in Figure 1 , the TGA chart is shown in Figure 2 , and the DSC chart is shown in Figure 3 .
实施例2：式(I)化合物无定形的制备Embodiment 2: the preparation of formula (I) compound amorphous
在拇指瓶中将式(I)化合物晶型A(300mg)溶于丙酮(4mL)后，20℃搅拌0.5小时，过滤，得到滤液在45℃下进行减压浓缩。得到式(I)化合物的无定形。无定形谱图如图13所示。Dissolve the compound of formula (I) Form A (300 mg) in acetone (4 mL) in a thumb bottle, stir at 20°C for 0.5 hour, filter, and concentrate the filtrate under reduced pressure at 45°C. An amorphous form of the compound of formula (I) is obtained. The amorphous spectrum is shown in Figure 13.
实施例3：式(I)化合物晶型B的制备Embodiment 3: Preparation of formula (I) compound crystal form B
在拇指瓶中将式(I)化合物晶型A(50mg)溶于水(200μL)，甲醇(600μL)，50℃搅拌12小时，过滤，得到固体在45℃下进行减压浓缩。得到式(I)化合物晶型B。Dissolve formula (I) compound Form A (50mg) in water (200μL), methanol (600μL) in a thumb bottle, stir at 50°C for 12 hours, filter, and concentrate the solid under reduced pressure at 45°C. The crystal form B of the compound of formula (I) was obtained.
将式(I)化合物晶型A(48.2mg)，水(4mL)加入反应瓶中，50℃搅拌16小时。过滤，得到固体在45℃下进行减压浓缩。得到式(I)化合物晶型B。Add the crystal form A (48.2 mg) of the compound of formula (I) and water (4 mL) into the reaction flask, and stir at 50° C. for 16 hours. After filtration, the obtained solid was concentrated under reduced pressure at 45 °C. The crystal form B of the compound of formula (I) was obtained.
将式(I)化合物无定形(50mg)溶于乙酸乙酯(0.3mL)后，20～25℃搅拌12小时。反应液直接过滤，得到的固体在45℃下进行减压浓缩。得到式(I)化合物晶型B。The amorphous compound (50 mg) of formula (I) was dissolved in ethyl acetate (0.3 mL), and stirred at 20-25°C for 12 hours. The reaction solution was directly filtered, and the obtained solid was concentrated under reduced pressure at 45°C. The crystal form B of the compound of formula (I) was obtained.
将式(I)化合物无定形(50mg)溶于乙醇(0.3mL)后，20～25℃搅拌12小时。反应液直接过滤，得到的固体在45℃下进行减压浓缩。得到式(I)化合物晶型B。The amorphous compound (50 mg) of formula (I) was dissolved in ethanol (0.3 mL), and stirred at 20-25°C for 12 hours. The reaction solution was directly filtered, and the obtained solid was concentrated under reduced pressure at 45°C. The crystal form B of the compound of formula (I) was obtained.
在反应瓶中式(I)化合物无定形(50mg)，甲醇(0.9mL)，水(0.3mL)，50℃搅拌14hr后将体系进行过滤，收集滤饼，滤饼用油泵在45℃下减压浓缩得到式(I)化合物晶型B。In the reaction flask, the compound of formula (I) was amorphous (50mg), methanol (0.9mL), water (0.3mL), stirred at 50°C for 14hr, and then the system was filtered to collect the filter cake, which was decompressed at 45°C with an oil pump Concentration gives the compound of formula (I) in Form B.
将甲基叔丁基醚(25mL)，式(I)化合物晶型A(1.8g,3.57mmol,1eq)加入反应瓶中，开始搅拌，升温至50℃，搅拌15小时。过滤，得到固体在45℃下进行减压浓缩，得到式(I)化合物的晶型B。 1H NMR(400MHz,CDCl 3)δ＝8.65(d,J＝4.8Hz,1H),7.75-7.73(m,1H),7.61(d,J＝11.6Hz,1H),7.43-7.34(m,2H),7.19-7.16(m,1H),4.88-4.82(m,1H),4.69(s,2H),3.95-3.89(m,2H),2.22-2.18(m,1H),1.62(d,J＝6.4Hz,3H),1.43(t,J＝7.2Hz,3H)；LCMS(ESI):505.0[M+H]。晶型B的XRPD谱图如图4所示，TGA图如图5所示，DSC图如图6所示。 Add methyl tert-butyl ether (25mL), compound of formula (I) Form A (1.8g, 3.57mmol, 1eq) into the reaction flask, start stirring, raise the temperature to 50°C, and stir for 15 hours. After filtration, the obtained solid was concentrated under reduced pressure at 45° C. to obtain the crystal form B of the compound of formula (I). 1 H NMR (400MHz, CDCl 3 ) δ=8.65(d, J=4.8Hz, 1H), 7.75-7.73(m, 1H), 7.61(d, J=11.6Hz, 1H), 7.43-7.34(m, 2H),7.19-7.16(m,1H),4.88-4.82(m,1H),4.69(s,2H),3.95-3.89(m,2H),2.22-2.18(m,1H),1.62(d, J=6.4Hz, 3H), 1.43(t, J=7.2Hz, 3H); LCMS (ESI): 505.0 [M+H]. The XRPD spectrum of Form B is shown in Figure 4, the TGA chart is shown in Figure 5, and the DSC chart is shown in Figure 6.
实施例4：式(II)化合物晶型C的制备Embodiment 4: Preparation of formula (II) compound crystal form C
Figure PCTCN2022134142-appb-000030
Figure PCTCN2022134142-appb-000030
15℃下，在反应瓶中加入式(I)化合物晶型A(150mg,297.13μmol,1eq)，乙酸乙酯(3mL)，降温至0℃加入盐酸/乙酸乙酯(4M,445.69μL,6eq)，自然升温至15℃搅拌0.5小时。有大量固体生成，反应体系进行过滤，滤饼减压浓缩得到式(II)化合物的晶型C。 1H NMR(400MHz,CD 3OD)δ＝8.75(d,J＝4.50Hz,1H),8.54(dd,J＝8.38,1.25Hz,1H),7.83(dd,J＝8.25,5.50Hz,1H),7.76(d,J＝11.13Hz,1H),7.63(d,J＝5.63Hz,1H),7.40-7.53(m,1H),5.32-5.44(m,1H),4.62(s,2H),3.93(q,J＝7.13Hz,2H),1.64(d,J＝6.38Hz,3H),1.40(t,J＝7.19Hz,3H)。晶型C的XRPD谱图如图7所示。 At 15°C, add formula (I) compound crystal form A (150mg, 297.13μmol, 1eq), ethyl acetate (3mL) into the reaction flask, cool down to 0°C and add hydrochloric acid/ethyl acetate (4M, 445.69μL, 6eq ), naturally warming up to 15°C and stirring for 0.5 hours. A large amount of solids were formed, the reaction system was filtered, and the filter cake was concentrated under reduced pressure to obtain the crystal form C of the compound of formula (II). 1 H NMR (400MHz, CD 3 OD) δ = 8.75 (d, J = 4.50Hz, 1H), 8.54 (dd, J = 8.38, 1.25Hz, 1H), 7.83 (dd, J = 8.25, 5.50Hz, 1H ),7.76(d,J=11.13Hz,1H),7.63(d,J=5.63Hz,1H),7.40-7.53(m,1H),5.32-5.44(m,1H),4.62(s,2H) , 3.93 (q, J=7.13Hz, 2H), 1.64 (d, J=6.38Hz, 3H), 1.40 (t, J=7.19Hz, 3H). The XRPD spectrum of Form C is shown in FIG. 7 .
实施例5:式(III)化合物晶型D的制备Embodiment 5: the preparation of formula (III) compound crystal form D
Figure PCTCN2022134142-appb-000031
Figure PCTCN2022134142-appb-000031
15℃下，在反应瓶中加入式(I)化合物晶型A(200mg,396.17μmol,1eq)，乙酸乙酯(4mL)，降温至0℃加入甲磺酸(39.98mg,415.98μmol,29.61μL,1.05eq)，自然升温至15℃搅拌0.5小时。有大量固体生成，反应体系进行过滤，滤饼真空干燥得到式(III)化合物的晶型D。 1H NMR(400MHz,CD 3OD)δppm8.76(d,J＝5.50Hz,1H),8.59(dd,J＝8.32,1.19Hz,1H),7.86(dd,J＝8.38,5.63Hz,1H),7.76(d,J＝11.01Hz,1H),7.63(d,J＝5.75Hz,1H),7.41-7.53(m,1H),5.32-5.48(m,1H),4.61(s,2H),3.92(q,J＝7.17Hz,2H),2.70(s,3H),1.63(d,J＝6.38Hz,3H),1.39(t,J＝7.19Hz,3H)。晶型D的XRPD谱图如图8所示。 At 15°C, add formula (I) compound crystal form A (200mg, 396.17μmol, 1eq), ethyl acetate (4mL) into the reaction flask, cool down to 0°C and add methanesulfonic acid (39.98mg, 415.98μmol, 29.61μL , 1.05eq), naturally heated to 15°C and stirred for 0.5 hours. A large amount of solids were formed, the reaction system was filtered, and the filter cake was vacuum-dried to obtain the crystal form D of the compound of formula (III). 1 H NMR (400MHz, CD 3 OD) δppm8.76 (d, J = 5.50Hz, 1H), 8.59 (dd, J = 8.32, 1.19Hz, 1H), 7.86 (dd, J = 8.38, 5.63Hz, 1H ),7.76(d,J=11.01Hz,1H),7.63(d,J=5.75Hz,1H),7.41-7.53(m,1H),5.32-5.48(m,1H),4.61(s,2H) , 3.92 (q, J=7.17Hz, 2H), 2.70 (s, 3H), 1.63 (d, J=6.38Hz, 3H), 1.39 (t, J=7.19Hz, 3H). The XRPD spectrum of Form D is shown in FIG. 8 .
实施例6:式(III)化合物晶型E的制备Embodiment 6: the preparation of formula (III) compound crystal form E
15℃下，在反应瓶中加入式(III)化合物的晶型D(80mg)，乙醇(1mL)，50℃搅拌16小时后降温至15℃搅拌0.5小时，有固体生成，将反应体系进行过滤，滤饼减压浓缩得到式(III)化合物的晶型E。晶型E的XRPD谱图如图9所示。At 15°C, add the crystal form D (80mg) of the compound of formula (III) and ethanol (1mL) into the reaction bottle, stir at 50°C for 16 hours, then cool down to 15°C and stir for 0.5 hours, a solid is formed, and the reaction system is filtered , and the filter cake was concentrated under reduced pressure to obtain the crystal form E of the compound of formula (III). The XRPD spectrum of Form E is shown in FIG. 9 .
实施例7：式(IV)化合物晶型F的制备Embodiment 7: Preparation of formula (IV) compound crystal form F
Figure PCTCN2022134142-appb-000032
Figure PCTCN2022134142-appb-000032
15℃下，在反应瓶中加入式(I)化合物晶型A(1.2g,2.38mmol,1eq)，乙酸乙酯(30mL)，降温至0℃加入对甲苯磺酸(429.79mg,2.50mmol,1.05eq)，自然升温至15℃搅拌0.5小时。有大量固体生成，反应体系进行过滤，滤饼减压浓缩得到式(IV)化合物的晶型F。 1H NMR(400MHz,CD 3OD)δppm 8.71(dd,J＝5.38,1.25Hz,1H),8.45(dd,J＝8.25,1.38Hz,1H),7.69-7.80(m,4H),7.61(d,J＝5.75Hz,1H),7.37-7.52(m,1H),7.24(d,J＝8.00Hz,2H),5.32-5.41(m,1H),4.62(s,2H),3.93(q,J＝7.17Hz,2H),2.38(s,3H),1.63(d,J＝6.38Hz,3H),1.40(t,J＝7.19Hz,3H)。晶型F的XRPD谱图如图10所示。 At 15°C, add formula (I) compound crystal form A (1.2g, 2.38mmol, 1eq), ethyl acetate (30mL) into the reaction flask, cool down to 0°C and add p-toluenesulfonic acid (429.79mg, 2.50mmol, 1.05eq), naturally heated to 15°C and stirred for 0.5 hours. A large amount of solids are formed, the reaction system is filtered, and the filter cake is concentrated under reduced pressure to obtain the crystal form F of the compound of formula (IV). 1 H NMR (400MHz, CD 3 OD) δppm 8.71 (dd, J = 5.38, 1.25Hz, 1H), 8.45 (dd, J = 8.25, 1.38Hz, 1H), 7.69-7.80 (m, 4H), 7.61 ( d,J=5.75Hz,1H),7.37-7.52(m,1H),7.24(d,J=8.00Hz,2H),5.32-5.41(m,1H),4.62(s,2H),3.93(q , J=7.17Hz, 2H), 2.38(s, 3H), 1.63(d, J=6.38Hz, 3H), 1.40(t, J=7.19Hz, 3H). The XRPD spectrum of Form F is shown in FIG. 10 .
实施例8：式(IV)化合物晶型G的制备Embodiment 8: Preparation of formula (IV) compound crystal form G
在反应瓶中加入式(IV)化合物的晶型F(80mg)，乙醇(1mL)，在50℃下搅拌16小时后，降温至 15℃，继续搅拌0.5小时，有固体生成，将反应体系进行过滤，滤饼减压浓缩得到式(IV)化合物的晶型G。晶型G的XRPD谱图如图11所示。Add the crystal form F (80mg) of the compound of formula (IV) and ethanol (1mL) into the reaction flask, stir at 50°C for 16 hours, then cool down to 15°C, and continue to stir for 0.5 hours, a solid is formed, and the reaction system is carried out After filtration, the filter cake was concentrated under reduced pressure to obtain the crystal form G of the compound of formula (IV). The XRPD spectrum of Form G is shown in FIG. 11 .
实施例9：式(IV)化合物晶型H的制备Embodiment 9: Preparation of formula (IV) compound crystal form H
在反应瓶中加入式(IV)化合物晶型F(80mg)，甲基叔丁基醚(1mL)，在50℃下搅拌16小时，然后将反应体系进行过滤，滤饼减压浓缩得到式(IV)化合物的晶型H。晶型H的XRPD谱图如图12所示。Add formula (IV) compound crystal form F (80 mg) and methyl tert-butyl ether (1 mL) into the reaction flask, stir at 50 ° C for 16 hours, then filter the reaction system, and concentrate the filter cake under reduced pressure to obtain the formula ( IV) Form H of the compound. The XRPD spectrum of Form H is shown in FIG. 12 .
实施例10：式(I)化合物晶型A的固体稳定性试验Embodiment 10: the solid stability test of formula (I) compound crystal form A
分别精密称取化合物约20mg置于干燥洁净的玻璃瓶中，摊成薄薄一层，作为供试样品，加速条件下(40℃/75％RH和60℃/75％RH)，其样品为完全暴露放样。加速条件在10天、1个月、2个月、3个月取样分析。在考察时间点，将相应的供试样品取出，用瓶盖盖好，0天的样品从冰箱中取出，待样品恢复至室温后进行分析，实验结果如表9所示。Accurately weigh about 20 mg of the compound and place it in a dry and clean glass bottle, and spread it into a thin layer as the test sample. Under accelerated conditions (40°C/75%RH and 60°C/75%RH), the sample is Fully exposed stakeout. Accelerated conditions were sampled and analyzed at 10 days, 1 month, 2 months, and 3 months. At the time point of investigation, the corresponding test samples were taken out and covered with bottle caps. The 0-day samples were taken out of the refrigerator and analyzed after the samples returned to room temperature. The experimental results are shown in Table 9.
表9.式(I)化合物晶型A的固体稳定性试验结果Table 9. Solid stability test results of formula (I) compound crystal form A
Figure PCTCN2022134142-appb-000033
Figure PCTCN2022134142-appb-000033
结论：式(I)化合物晶型A具有良好的稳定性。Conclusion: The crystal form A of the compound of formula (I) has good stability.
实施例11：式(I)化合物晶型B的固体稳定性试验Embodiment 11: solid stability test of formula (I) compound crystal form B
分别精密称取化合物约20mg置于干燥洁净的玻璃瓶中，摊成薄薄一层，作为供试样品，放置于加速条件下(40℃/75％RH和60℃/75％RH)，其样品为完全暴露放样。加速条件在10天、1个月、2个月、3个月取样分析。在考察时间点，将相应的供试样品取出，用瓶盖盖好，0天的样品从冰箱中取出，待样品恢复至室温后进行分析，实验结果如表10所示。Accurately weigh about 20 mg of the compound respectively and place it in a dry and clean glass bottle, spread it into a thin layer, and place it under accelerated conditions (40°C/75%RH and 60°C/75%RH) as the test sample. The samples are set out for full exposure. Accelerated conditions were sampled and analyzed at 10 days, 1 month, 2 months, and 3 months. At the time of investigation, the corresponding test samples were taken out and covered with bottle caps. The 0-day samples were taken out of the refrigerator and analyzed after the samples returned to room temperature. The experimental results are shown in Table 10.
表10.式(I)化合物晶型B的固体稳定性试验结果Table 10. Solid stability test results of formula (I) compound crystal form B
Figure PCTCN2022134142-appb-000034
Figure PCTCN2022134142-appb-000034
结论：式(I)化合物晶型B具有良好的稳定性。Conclusion: The crystal form B of the compound of formula (I) has good stability.
生物学部分biology part
实施例1：酶学实验Embodiment 1: enzymatic experiment
化合物的DHODH抑制活性通过以下实验方法检测。The DHODH inhibitory activity of the compounds was detected by the following experimental methods.
DHODH以黄素单核苷酸(FMN)催化二氢乳清酸DHO氧化生成乳清酸，而FMN的重新氧化则需要辅酶CoQ的参与，在检测DHODH酶活的实验中，Resazurin染料代替CoQ作为酶活反应中最终的电子受体。Resazurin溶液呈蓝色，还原后生成的resorufin有红色荧光，激发波长535nm，发射波长590nm条件下可检测其荧光信号。实验所用的反应缓冲液组分为100mM Hepes pH 7.0,150mM NaCl,0.3％CHAPS,0.5mg/ml BSA,0.1μM FMN,1％DMSO。反应体系内DHODH酶的终浓度为5nM，底物L-DHO终浓度为15μM，指示剂Resazurin终浓度为80μM。反应终止缓冲液组分为100mM Hepes pH7.0及5mM Orotate。具体方法如下：将2倍终浓度的DHODH酶溶液与化合物进行混合，室温孵育20min，加入2倍终浓度的底物混合溶液L-DHO及resazurin以开始反应，避光室温孵育45min。然后向反应体系内加入2倍终浓度的反应终止缓冲液以终止反应，室温孵育10min，在Ex/Em＝535/590nm条件下EnVision检测反应体系的荧光信号。DHODH uses flavin mononucleotide (FMN) to catalyze the oxidation of dihydroorotic acid DHO to orotic acid, and the re-oxidation of FMN requires the participation of coenzyme CoQ. In the experiment of detecting DHODH enzyme activity, Resazurin dye replaces CoQ as the enzyme activity The final electron acceptor in the reaction. Resazurin solution is blue, and the resorufin produced after reduction has red fluorescence, and its fluorescence signal can be detected under the conditions of excitation wavelength 535nm and emission wavelength 590nm. The reaction buffer components used in the experiment were 100mM Hepes pH 7.0, 150mM NaCl, 0.3% CHAPS, 0.5mg/ml BSA, 0.1μM FMN, 1% DMSO. The final concentration of the DHODH enzyme in the reaction system was 5 nM, the final concentration of the substrate L-DHO was 15 μM, and the final concentration of the indicator Resazurin was 80 μM. The components of the reaction termination buffer were 100mM Hepes pH7.0 and 5mM Orotate. The specific method is as follows: mix 2 times the final concentration of DHODH enzyme solution with the compound, incubate at room temperature for 20 minutes, add 2 times the final concentration of the substrate mixed solution L-DHO and resasurin to start the reaction, and incubate at room temperature for 45 minutes in the dark. Then, 2-fold final concentration of reaction termination buffer was added to the reaction system to terminate the reaction, incubated at room temperature for 10 min, and EnVision detected the fluorescence signal of the reaction system under the condition of Ex/Em=535/590nm.
结论：本发明化合物具有优异的DHODH酶抑制活性。Conclusion: the compound of the present invention has excellent DHODH enzyme inhibitory activity.
实验例2：药代动力学评价Experimental Example 2: Pharmacokinetic Evaluation
实验过程：将0.04mg/mL 5％DMSO/10％Solutol溶液/85％水试验化合物的澄清溶液经尾静脉注射到雄性SD大鼠体内(过夜禁食，7-9周龄)，给药剂量为0.2mg/kg。将30mg/mL在30％PEG400/10％Solutol 溶液/60％水试验化合物的澄清溶液灌胃给予到雄性SD大鼠(过夜禁食，7-9周龄)，给药剂量为300mg/kg。两组动物分别于给药后0.0833、0.25、0.5、1.0、2.0、4.0、8.0、24h从颈静脉和0.25、0.5、1.0、2.0、4.0、8.0、10、24h从尾静脉采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。 Experimental process: 0.04mg/mL 5% DMSO/10% Solutol solution/85% water clear solution of the test compound was injected into male SD rats (overnight fasting, 7-9 weeks old) through the tail vein, and the dosage 0.2mg/kg. Male SD rats (overnight fasted, 7-9 weeks old) were intragastrically administered 30 mg/mL of a clear solution of test compound in 30% PEG400/10% Solutol solution/60% water at a dose of 300 mg/kg. About 30 μL blood was collected from the jugular vein at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration, and about 30 μL was collected from the tail vein at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 10, and 24 hours after administration. Plasma was centrifuged in an anticoagulant tube added with EDTA-K2. Plasma drug concentration was determined by LC-MS/MS method, and relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software.
实验数据分析：Experimental data analysis:
表11药代动力学数据汇总表Table 11 Pharmacokinetic data summary table
 the 式(I)化合物的无定形Amorphous form of compound of formula (I) 晶型AForm A 晶型BForm B
给药方式Method of administration IVIV POPO POPO
C 0(nM) C 0 (nM) 16831683 ---- ----
C max(nM) C max (nM) ---- 4432044320 5520655206
T max(h) T max (h) ---- 8.08.0 8.08.0
T 1/2(h) T 1/2 (h) 4.24.2 4343 2626
Vd ss(L/kg) Vd ss (L/kg) 0.90.9 ---- ----
Cl(mL/min/kg)Cl(mL/min/kg) 2.92.9 ---- ----
T last(h) T last (h) 24twenty four 24twenty four 24twenty four
AUC 0-last(nM.h) AUC 0-last (nM.h) 22222222 880327880327 944294944294
AUC 0-inf(nM.h) AUC 0-inf (nM.h) 22642264 29651632965163 22604272260427
MRT 0-last(h) MRT 0-last (h) 4.74.7 1212 1313
F(％)F(%) ---- 87％87% 67％67%
注：--表示未测；Note: -- means untested;
结论：本发明化合物具有优异的体内的代谢稳定性(Cl)，IV和PO均表现较长的半衰期(T 1/2)；式(I)晶型A和晶型B均有优异的口服吸收药物暴露量(AUC)，和较高的口服吸收生物利用度(>60％)。 Conclusion: the compound of the present invention has excellent metabolic stability (Cl) in vivo, IV and PO all show longer half-life (T 1/2 ); formula (I) crystal form A and crystal form B all have excellent oral absorption Drug exposure (AUC), and high oral bioavailability (>60%).
实验例3：体内药效学评价Experimental example 3: In vivo pharmacodynamic evaluation
1研究目的：为验证受试物在三硝基苯磺酸(2,4,6-trinitrobenzene sulfonic acid，TNBS)诱导的Balb/C小鼠结肠炎模型上的效果。1 Research purpose: To verify the effect of the test substance on the colitis model of Balb/C mice induced by trinitrobenzenesulfonic acid (2,4,6-trinitrobenzene sulfonic acid, TNBS).
2肠炎诱导实验设计：实验第0天，小鼠用0.25mL的麻醉剂(1.25％阿佛丁，Easycheck易核，M2910)进行麻醉。溶媒组及化合物剂量给药组小鼠直肠灌注150μL 1.5％TNBS溶液(终浓度50％乙醇)。阴性组小 鼠直肠灌注等体积的50％乙醇。2 Experimental design of enteritis induction: On the 0th day of the experiment, mice were anesthetized with 0.25 mL of anesthetic (1.25% Avertin, Easycheck, M2910). The mice in the vehicle group and the compound dosage administration group were perfused with 150 μL of 1.5% TNBS solution (final concentration 50% ethanol) in the rectum. The mice in the negative group were perfused with an equal volume of 50% ethanol in their rectums.
3给药：第1组为阴性组，动物给予溶媒，第2组为溶媒组(即造模组)，动物给与溶媒，第3、4和5组为化合物剂量给药组，动物给予不同剂量的式(I)晶型A，溶媒采用5％DMSO/10％Solutol溶液/0.2％Tween80/84.8％水溶液，一天一次。3 Administration: the first group is the negative group, the animals are given vehicle, the second group is the vehicle group (i.e. the modeling group), the animals are given the vehicle, the 3rd, 4th and 5th groups are the compound dosage administration groups, the animals are given different Dosage of crystal form A of formula (I), the solvent is 5% DMSO/10% Solutol solution/0.2% Tween80/84.8% aqueous solution, once a day.
4测量4 measurements
4.1体重4.1 Weight
记录频率为一天一次(QD)，第-1-7天。The recording frequency was once a day (QD), days -1-7.
4.2疾病活动指数(DAI)4.2 Disease Activity Index (DAI)
记录频率为一天一次，第-1-7天，按照以下标准评为4个等级：The recording frequency is once a day, on days -1-7, and is graded into 4 levels according to the following criteria:
体重变化(0，≤1％；1，1-5％；2，6-10％；3，11-20％；4，>20％)；Body weight change (0, ≤1%; 1, 1-5%; 2, 6-10%; 3, 11-20%; 4, >20%);
血便(0，阴性；1，隐血弱阳性；2，隐血阳性；3，明显便血；4，大量便血)；Bloody stool (0, negative; 1, weakly positive for occult blood; 2, positive for occult blood; 3, obvious blood in stool; 4, massive blood in stool);
粪便评分(0，正常；1，软便；2，松散便；3，稀便；4，腹泻)Stool score (0, normal; 1, soft stool; 2, loose stool; 3, loose stool; 4, diarrhea)
以上3部分的分数相加得到日常疾病指数值。The scores of the above three parts are added to obtain the daily disease index value.
4.3结肠采集4.3 Colon collection
第8天，所有动物接受过量CO 2后脱颈处死。剪开腹腔，取小鼠结肠，去除结肠周围的组织，测量从回盲肠到***的纵向长度，剖开结肠，清洗肠内物，分别称重，计算结肠密度。 On day 8, all animals were sacrificed by decapitation after receiving excessive CO 2 . The abdominal cavity was cut open, the mouse colon was taken, the tissues around the colon were removed, the longitudinal length from the ileocecum to the anus was measured, the colon was cut open, the intestinal contents were cleaned, weighed separately, and the density of the colon was calculated.
4.4样本处理4.4 Sample processing
结肠组织纵切一分为二，一份以“Swiss”卷的形式浸入10％中性多聚甲醛固定。Colon tissue was divided longitudinally into two parts, and one part was fixed in the form of "Swiss" roll immersed in 10% neutral paraformaldehyde.
另一份先液氮速冻，后保存于-80℃冰箱，用于待选的检测分析。The other part was quick-frozen in liquid nitrogen first, and then stored in a -80°C refrigerator for the detection and analysis to be selected.
5统计分析5 Statistical Analysis
实验数据应用均数±标准误表示(mean±S.E.M.)。数据由GraphPad Prism采用数据进行ANOVA统计方法分析。与溶媒组相比，*p<0.05**p<0.01***p<0.005****p<0.0001，P<0.05认为有统计学差异。The experimental data should be expressed as mean ± standard error (mean ± S.E.M.). The data were analyzed by ANOVA statistical method using GraphPad Prism. Compared with the vehicle group, *p<0.05**p<0.01***p<0.005****p<0.0001, P<0.05 was considered statistically different.
6实验结果6 Experimental results
6.1动物体重结果6.1 Animal body weight results
第-1至7天，每天一次称量体重，动物体重变化如图14所示。与造模组相比，式(I)化合物晶型A5mpk和10mpk剂量均能够显著减缓小鼠体重的下降，且在第7天具有统计学显著性差异(p<0.0001)，对小鼠的体重保护效果显著。On days -1 to 7, body weight was measured once a day, and the body weight changes of the animals are shown in FIG. 14 . Compared with the model group, the formula (I) compound crystal form A5mpk and 10mpk doses can significantly slow down the decline of the body weight of the mice, and there is a statistically significant difference on the 7th day (p<0.0001), and the body weight of the mice The protective effect is remarkable.
6.2日常疾病指数(DAI)6.2 Daily Illness Index (DAI)
第-1至7天，综合体重，血便和粪便评分，DAI(日常疾病指数)评价结果如图15所示。与造模组相 比，式(I)化合物晶型A 5mpk和10mpk给药可明显改善小鼠疾病评分，DAI评分效果与造模组相比呈现高显著性差异，p<0.0001。On days -1 to 7, the combined body weight, bloody stool and stool scores, and DAI (Daily Illness Index) evaluation results are shown in Figure 15 . Compared with the modeling group, the administration of formula (I) compound crystal form A 5mpk and 10mpk can significantly improve the disease score of the mice, and the DAI score effect shows a highly significant difference compared with the modeling group, p<0.0001.
6.3结肠密度分析结果6.3 Results of colon density analysis
与造模组相比，化合物晶型A 5mpk和10mpk剂量下可在实验终点显著改善炎症导致的结肠密度增加，且具有显著性差异，p<0.0001，实验结果如图16所示(注：*p<0.05**p<0.01***p<0.005****p<0.0001,与溶媒组相比，ANOVA)。Compared with the model group, compound crystal form A at doses of 5mpk and 10mpk can significantly improve the colon density increase caused by inflammation at the experimental end point, and there is a significant difference, p<0.0001, the experimental results are shown in Figure 16 (Note: * p<0.05**p<0.01***p<0.005****p<0.0001, compared with vehicle group, ANOVA).
综上所述，TNBS诱导的小鼠结肠炎(IBD)模型上，式(I)化合物的晶型A展示了显著的抗炎效果。能够明显减缓肠炎小鼠体重下降，改善腹泻和便血相关的疾病评分(DAI)，能够改善炎症导致的结肠密度增加，与DAI评分结果一致。To sum up, on the TNBS-induced colitis (IBD) model in mice, the crystalline form A of the compound of formula (I) exhibited significant anti-inflammatory effects. It can significantly slow down the weight loss of mice with enteritis, improve the disease score (DAI) associated with diarrhea and blood in the stool, and can improve the increase in colon density caused by inflammation, which is consistent with the results of the DAI score.

Claims (19)

  1. 式(I)化合物的晶型A，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，11.431±0.20°，21.535±0.20°；The crystal form A of the compound of formula (I) is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 11.431±0.20°, 21.535±0.20°;
    Figure PCTCN2022134142-appb-100001
    Figure PCTCN2022134142-appb-100001
  2. 根据权利要求1所述的晶型A，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，11.431±0.20°，14.953±0.20°，15.856±0.20°，17.386±0.20°，21.535±0.20°，22.916±0.20°，25.175±0.20°。According to claim 1, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 11.431±0.20°, 14.953±0.20°, 15.856±0.20°, 17.386±0.20 °, 21.535±0.20°, 22.916±0.20°, 25.175±0.20°.
  3. 根据权利要求1所述的晶型A，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741±0.20°，11.431±0.20°，12.681±0.20°，14.953±0.20°，15.856±0.20°，17.386±0.20°，20.923±0.20°，21.535±0.20°，22.916±0.20°，24.311±0.20°，25.175±0.20°。According to claim 1, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.741±0.20°, 11.431±0.20°, 12.681±0.20°, 14.953±0.20°, 15.856±0.20 °, 17.386±0.20°, 20.923±0.20°, 21.535±0.20°, 22.916±0.20°, 24.311±0.20°, 25.175±0.20°.
  4. 根据权利要求1所述的晶型A，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.741°，11.431°，12.681°，13.366°，14.953°，15.532°，15.856°，16.717°，17.152°，17.386°，17.785°，17.967°，18.344°，18.538°，18.845°，19.114°，20.728°，20.923°，21.535°，22.580°，22.916°，24.311°，25.175°，25.529°，28.055°，32.907°，33.735°。According to the crystal form A according to claim 1, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.741°, 11.431°, 12.681°, 13.366°, 14.953°, 15.532°, 15.856°, 16.717° , 17.152°, 17.386°, 17.785°, 17.967°, 18.344°, 18.538°, 18.845°, 19.114°, 20.728°, 20.923°, 21.535°, 22.580°, 22.916°, 24.311°, 25.175°, 25.529°, 28.055 °, 32.907°, 33.735°.
  5. 根据权利要求1～4任意一项所述的晶型A，上述式(I)化合物的晶型A，其XRPD图谱如图1所示。According to the crystal form A described in any one of claims 1-4, the crystal form A of the compound of formula (I) above has an XRPD spectrum as shown in FIG. 1 .
  6. 根据权利要求1～4任意一项所述的晶型A，其热重分析曲线在130℃±3℃时失重达0.66％。According to any one of claims 1 to 4, the crystal form A has a weight loss of 0.66% at a thermogravimetric analysis curve at 130°C±3°C.
  7. 根据权利要求6所述的晶型A，其TGA图谱如图2所示。According to the crystal form A described in claim 6, its TGA spectrum is as shown in Figure 2.
  8. 根据权利要求1～4任意一项所述的晶型A，其差示扫描量热曲线在152.4℃±3℃处具有吸热峰的起始值。The crystal form A according to any one of claims 1-4, its differential scanning calorimetry curve has an endothermic peak start value at 152.4°C±3°C.
  9. 根据权利要求8所述的晶型A，其DSC图谱如图3所示。The crystal form A according to claim 8, its DSC spectrum is as shown in Figure 3.
  10. 式(I)化合物的晶型B，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.954±0.20°，19.654±0.20°，20.722±0.20°；The crystal form B of the compound of formula (I) is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.954±0.20°, 19.654±0.20°, 20.722±0.20°;
    Figure PCTCN2022134142-appb-100002
    Figure PCTCN2022134142-appb-100002
  11. 根据权利要求10所述的晶型B，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.954±0.20°，16.079±0.20°，16.727±0.20°，19.654±0.20°，20.722±0.20°，25.131±0.20°，26.024±0.20°。The crystal form B according to claim 10, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.954±0.20°, 16.079±0.20°, 16.727±0.20°, 19.654±0.20°, 20.722±0.20 °, 25.131±0.20°, 26.024±0.20°.
  12. 根据权利要求11所述的晶型B，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.954±0.20°，16.079±0.20°，16.727±0.20°，19.654±0.20°，20.722±0.20°，21.151±0.20°，22.376±0.20°，25.131±0.20°，26.024±0.20°。According to the crystal form B according to claim 11, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 9.954±0.20°, 16.079±0.20°, 16.727±0.20°, 19.654±0.20°, 20.722±0.20 °, 21.151±0.20°, 22.376±0.20°, 25.131±0.20°, 26.024±0.20°.
  13. 根据权利要求12所述的晶型B，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.022°，9.954°，11.191°，12.474°，14.658°，15.040°，15.335°，16.079°，16.727°，16.996°，17.266°，17.496°，19.189°，19.654°，19.928°，20.415°，20.722°，20.962°，21.151°，22.376°，22.923°，24.212°，24.757°，25.131°，26.196°，26.024°，26.729°，26.977°，29.549°，29.970°，30.456°，30.694°，31.415°，32.010°，32.396°，35.702°。According to claim 12, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.022°, 9.954°, 11.191°, 12.474°, 14.658°, 15.040°, 15.335°, 16.079° , 16.727°, 16.996°, 17.266°, 17.496°, 19.189°, 19.654°, 19.928°, 20.415°, 20.722°, 20.962°, 21.151°, 22.376°, 22.923°, 24.212°, 24.757°, 25.131°, 26.196 °, 26.024°, 26.729°, 26.977°, 29.549°, 29.970°, 30.456°, 30.694°, 31.415°, 32.010°, 32.396°, 35.702°.
  14. 根据权利要求10～13任意一项所述的晶型B，其热重分析曲线在130.0℃±3℃时失重达1.06％。According to any one of claims 10-13, the crystal form B has a weight loss of 1.06% at 130.0°C±3°C in its thermogravimetric analysis curve.
  15. 根据权利要求14所述的晶型B，其TGA图谱如图5所示。The crystal form B according to claim 14, whose TGA spectrum is as shown in FIG. 5 .
  16. 根据权利要求10～13任意一项所述的晶型B，其差示扫描量热曲线在143.8℃±3℃处具有吸热峰的起始值。The crystal form B according to any one of claims 10-13, whose differential scanning calorimetry curve has an endothermic peak start value at 143.8°C±3°C.
  17. 根据权利要求16所述的晶型B，其DSC图谱如图6所示。The crystal form B according to claim 16, its DSC spectrum is as shown in Figure 6.
  18. 根据权利要求1～17任意一项所述的晶型A、晶型B在制备治疗与肠炎相关药物中的应用。Use of the crystal form A and crystal form B according to any one of claims 1-17 in the preparation of medicines for treating enteritis-related diseases.
  19. 根据权利要求18所述的应用，其中肠炎包括溃疡性肠炎和克罗恩病。The use according to claim 18, wherein enteritis includes ulcerative enteritis and Crohn's disease.
PCT/CN2022/134142 2021-11-26 2022-11-24 Crystal form of triazolone compound and use thereof WO2023093812A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110023302A (en) * 2016-10-27 2019-07-16 拜耳股份有限公司 2,4,5- trisubstituted 1,2,4-triazoles ketone as DHODH inhibitor
CN110248937A (en) * 2016-10-27 2019-09-17 拜耳股份有限公司 4,5- ring-type 1,2,4- triazolone
WO2021238881A1 (en) * 2020-05-29 2021-12-02 南京明德新药研发有限公司 Triazolone compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110023302A (en) * 2016-10-27 2019-07-16 拜耳股份有限公司 2,4,5- trisubstituted 1,2,4-triazoles ketone as DHODH inhibitor
CN110248937A (en) * 2016-10-27 2019-09-17 拜耳股份有限公司 4,5- ring-type 1,2,4- triazolone
WO2021238881A1 (en) * 2020-05-29 2021-12-02 南京明德新药研发有限公司 Triazolone compound

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