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WO2025021218A1 - Forme cystal d'inhibiteur biologique contenant du propénone, son procédé de préparation et son utilisation - Google Patents

Forme cystal d'inhibiteur biologique contenant du propénone, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2025021218A1
WO2025021218A1 PCT/CN2024/108172 CN2024108172W WO2025021218A1 WO 2025021218 A1 WO2025021218 A1 WO 2025021218A1 CN 2024108172 W CN2024108172 W CN 2024108172W WO 2025021218 A1 WO2025021218 A1 WO 2025021218A1
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Prior art keywords
diffraction peak
diffraction
solvent
pyridin
ray powder
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Chinese (zh)
Inventor
许炜
张静涛
孙垚
何雷
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to a crystal form containing acrylone biological inhibitors, a preparation method and an application thereof.
  • FGFR Fibroblast Growth Factor Receptor
  • FGFR Fibroblast Growth Factor Receptor
  • FGFR tyrosine kinase, including four subtypes: FGFR1, FGFR2, FGFR3, and FGFR4.
  • FGFR dimerizes and autophosphorylates, thereby activating downstream signaling pathways: RAS-RAF-MAPK, PI3K-AKT, STAT, and PLC ⁇ .
  • FGFR-mediated signal transduction plays an important role in cell proliferation, migration, differentiation, and survival.
  • FGFR aberrations were present in approximately 7.1% of cancers.
  • FGFR1 amplification aberrations are present in approximately 20% of lung squamous cell carcinomas and approximately 20% of breast cancers.
  • FGFR2 rearrangement aberrations are present in approximately 15% of cholangiocarcinomas, FGFR2 point mutations are present in approximately 10% of endometrial carcinomas, and FGFR2b amplifications are present in approximately 10% of gastric cancers.
  • FGFR3 point mutations are present in approximately 20% of metastatic urothelial carcinomas.
  • FGFR inhibitors As a drug, FGFR inhibitors have good application prospects in the pharmaceutical industry. They are expected to become the first-line treatment for cholangiocarcinoma and a new choice for targeted cancer therapy regardless of cancer type. They are expected to be used for cancer patients with various FGFR aberrations.
  • the current standard treatment for cholangiocarcinoma is chemotherapy, which has a poor prognosis and no second-line treatment.
  • the main problems with FGFR inhibitors are that patients develop drug resistance about 7 months after taking the drug, and drugs related to the FGFR1 target have hyperphosphatemia toxicity.
  • Patent PCT/CN2023/073557 discloses a series of biological inhibitors containing propylene ketones.
  • suitable crystals that are easy to store, have long-term stability and high bioavailability are sought.
  • the present invention has conducted a comprehensive study on the crystal forms of the above-mentioned compounds.
  • the object of the present invention is to provide a crystalline form of a compound represented by general formula (I) or a stereoisomer thereof.
  • R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, aldehyde, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, C1-6 alkylcarbonyl , aminocarbonyl, 3-12 membered cycloalkyl-carbonyl, 3-12 membered heterocyclyl-carbonyl, preferably, R1 is selected from deuterium, halogen, amino, hydroxyl, cyano, aldehyde, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 haloalkoxy, C1-6 1-3
  • R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl or C1-6 alkylamino ;
  • R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 alkylamino or C3-12 cycloalkyl ;
  • R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy or C 3-12 cycloalkyl; preferably selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 haloalkoxy or C 3-6 cycloalkyl;
  • R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy or C 3-12 cycloalkyl; preferably selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 haloalkoxy or C 3-6 cycloalkyl;
  • R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy.
  • the compound is as follows:
  • the crystalline form is a hydrate or anhydrate; when it is a hydrate, the number of water is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 2.
  • the crystalline form of the compound or its stereoisomer is a crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one.
  • the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form I;
  • the X-ray powder diffraction spectrum of Form I has a diffraction peak at 2 ⁇ of 9.0 ⁇ 0.2°; or a diffraction peak at 9.6 ⁇ 0.2°; or a diffraction peak at 11.7 ⁇ 0.2°; or a diffraction peak at 13.4 ⁇ 0.2°; or a diffraction peak at 14.9 ⁇ 0.2°; or a diffraction peak at 20.6 ⁇ 0.2°; or a diffraction peak at 21.9 ⁇ 0.2° ; or having a diffraction peak at 24.2 ⁇ 0.2°; or having a diffraction peak at 24.9 ⁇ 0.2°; or having a diffraction peak at 26.9 ⁇ 0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9 or 10 thereof;
  • the X-ray powder diffraction pattern of Form I comprises at least one or more diffraction peaks located at 2 ⁇ of 13.4 ⁇ 0.2°, 14.9 ⁇ 0.2°, and 24.9 ⁇ 0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2 ⁇ of 9.0 ⁇ 0.2°, 9.6 ⁇ 0.2°, 11.7 ⁇ 0.2°, 21.9 ⁇ 0.2°, and 24.2 ⁇ 0.2°, preferably 2, 3, 4 or 5 of them;
  • the X-ray powder diffraction pattern of Form I optionally further comprises one or more diffraction peaks located at 2 ⁇ of 12.7 ⁇ 0.2°, 17.6 ⁇ 0.2°, 20.6 ⁇ 0.2°, 24.0 ⁇ 0.2°, and 26.9 ⁇ 0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included;
  • the X-ray powder diffraction pattern of Form I comprises one or more diffraction peaks located at 2 ⁇ of 8.2 ⁇ 0.2°, 9.9 ⁇ 0.2°, 13.6 ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.7 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.3 ⁇ 0.2°, and 19.9 ⁇ 0.2°; preferably, it comprises diffraction peaks at 4, 5, 6, or 8 of them;
  • the X-ray powder diffraction pattern of the crystalline form I has diffraction peaks at the following positions at 2 ⁇ :
  • Cu-K ⁇ radiation is used, and X-rays expressed in terms of 2 ⁇ angles and interplanar spacing d values are used.
  • the characteristic diffraction peaks are shown in Table 1.
  • the X-ray powder diffraction pattern of Form I is substantially as shown in FIG. 1
  • the DSC pattern is as shown in FIG. 2
  • the TGA pattern is as shown in FIG. 3
  • the IR pattern is as shown in FIG. 4 .
  • the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form II;
  • the X-ray powder diffraction pattern of Form II has a diffraction peak at 2 ⁇ of 5.3 ⁇ 0.2°; or a diffraction peak at 8.3 ⁇ 0.2°; or a diffraction peak at 10.6 ⁇ 0.2°; or a diffraction peak at 14.0 ⁇ 0.2°; or a diffraction peak at 16.0 ⁇ 0.2°; or a diffraction peak at 16.6 ⁇ 0.2°; or a diffraction peak at 19.2 ⁇ 0.2°; or A diffraction peak at 24.7 ⁇ 0.2°; or a diffraction peak at 26.2 ⁇ 0.2°; or a diffraction peak at 26.5 ⁇ 0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably comprising any 6, 7, 8, 9 or 10 thereof;
  • the X-ray powder diffraction pattern of Form II comprises at least one or more diffraction peaks located at 2 ⁇ of 5.3 ⁇ 0.2°, 10.6 ⁇ 0.2°, and 24.7 ⁇ 0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2 ⁇ of 8.3 ⁇ 0.2°, 16.0 ⁇ 0.2°, 16.6 ⁇ 0.2°, 26.2 ⁇ 0.2°, and 26.5 ⁇ 0.2°, preferably 2, 3, 4 or 5 of them;
  • the X-ray powder diffraction pattern of Form II optionally further comprises one or more diffraction peaks located at 2 ⁇ of 14.0 ⁇ 0.2°, 14.5 ⁇ 0.2°, 19.2 ⁇ 0.2°, 21.6 ⁇ 0.2°, and 25.6 ⁇ 0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them;
  • the X-ray powder diffraction pattern of Form II comprises one or more diffraction peaks located at 2 ⁇ of 5.3 ⁇ 0.2°, 8.3 ⁇ 0.2°, 10.6 ⁇ 0.2°, 14.0 ⁇ 0.2°, 16.0 ⁇ 0.2°, 16.6 ⁇ 0.2°, 19.2 ⁇ 0.2°, 24.7 ⁇ 0.2°, 26.2 ⁇ 0.2°, and 26.5 ⁇ 0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 selected from them;
  • the X-ray powder diffraction pattern of the crystalline form II has diffraction peaks at the following positions at 2 ⁇ :
  • Cu-K ⁇ radiation is used, and the X-ray characteristic diffraction peaks represented by 2 ⁇ angles and interplanar spacing d values are shown in Table 2.
  • the X-ray powder diffraction pattern of Form II is substantially as shown in FIG. 5
  • the DSC pattern is as shown in FIG. 6
  • the TGA pattern is as shown in FIG. 7 .
  • the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form III;
  • the X-ray powder diffraction spectrum of Form III has a diffraction peak at 2 ⁇ of 5.9 ⁇ 0.2°; or a diffraction peak at 8.7 ⁇ 0.2°; or a diffraction peak at 11.5 ⁇ 0.2°; or a diffraction peak at 11.9 ⁇ 0.2°; or a diffraction peak at 13.4 ⁇ 0.2°; or a diffraction peak at 14.1 ⁇ 0.2°; or a diffraction peak at 14.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form III comprises at least one or more diffraction peaks located at 2 ⁇ of 5.9 ⁇ 0.2°, 11.5 ⁇ 0.2°, and 11.9 ⁇ 0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2 ⁇ of 8.7 ⁇ 0.2°, 13.4 ⁇ 0.2°, 14.6 ⁇ 0.2°, 20.0 ⁇ 0.2°, and 24.4 ⁇ 0.2°, preferably 2, 3, 4 or 5 of them;
  • the X-ray powder diffraction pattern of Form III optionally further comprises one or more diffraction peaks located at 2 ⁇ of 8.0 ⁇ 0.2°, 9.7 ⁇ 0.2°, 14.1 ⁇ 0.2°, 24.9 ⁇ 0.2°, and 26.3 ⁇ 0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them are included;
  • the X-ray powder diffraction pattern of Form III comprises one or more diffraction peaks located at 2 ⁇ of 5.9 ⁇ 0.2°, 8.7 ⁇ 0.2°, 11.5 ⁇ 0.2°, 11.9 ⁇ 0.2°, 13.4 ⁇ 0.2°, 14.1 ⁇ 0.2°, 14.6 ⁇ 0.2°, 20.0 ⁇ 0.2°, 24.4 ⁇ 0.2°, and 24.9 ⁇ 0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 selected therefrom;
  • the X-ray powder diffraction pattern of the crystalline form III has diffraction peaks at the following positions at 2 ⁇ :
  • Cu-K ⁇ radiation is used, and the X-ray characteristic diffraction peaks represented by 2 ⁇ angles and interplanar spacing d values are shown in Table 3.
  • the X-ray powder diffraction pattern of Form III is substantially as shown in FIG. 8 .
  • the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form IV;
  • the X-ray powder diffraction spectrum of Form IV has a diffraction peak at 2 ⁇ of 5.2 ⁇ 0.2°; or a diffraction peak at 7.4 ⁇ 0.2°; or a diffraction peak at 10.5 ⁇ 0.2°; or a diffraction peak at 14.5 ⁇ 0.2°; or a diffraction peak at 14.9 ⁇ 0.2°; or a diffraction peak at 17.9 ⁇ 0.2°; or a diffraction peak at 19.5 ⁇ 0.2° ; or having a diffraction peak at 24.4 ⁇ 0.2°; or having a diffraction peak at 25.0 ⁇ 0.2°; or having a diffraction peak at 26.2 ⁇ 0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9 or 10 thereof;
  • the X-ray powder diffraction pattern of Form IV comprises at least one or more diffraction peaks located at 2 ⁇ of 5.2 ⁇ 0.2°, 7.4 ⁇ 0.2°, and 10.5 ⁇ 0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2 ⁇ of 14.9 ⁇ 0.2°, 19.5 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.0 ⁇ 0.2°, and 26.2 ⁇ 0.2°, preferably 2, 3, 4 or 5 of them;
  • the X-ray powder diffraction pattern of Form IV optionally further comprises one or more diffraction peaks located at 2 ⁇ of 8.1 ⁇ 0.2°, 14.5 ⁇ 0.2°, and 17.9 ⁇ 0.2°; preferably, at least any 2-3 of them; further preferably, any 2 or 3 of them;
  • the X-ray powder diffraction pattern of Form IV comprises one or more diffraction peaks located at 2 ⁇ of 5.2 ⁇ 0.2°, 7.4 ⁇ 0.2°, 10.5 ⁇ 0.2°, 14.5 ⁇ 0.2°, 14.9 ⁇ 0.2°, 17.9 ⁇ 0.2°, 19.5 ⁇ 0.2°, 24.4 ⁇ 0.2°, 25.0 ⁇ 0.2°, and 26.2 ⁇ 0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 of them;
  • the X-ray powder diffraction pattern of the crystalline form IV has diffraction peaks at the following positions at 2 ⁇ :
  • Cu-K ⁇ radiation is used, and the X-ray characteristic diffraction peaks represented by 2 ⁇ angles and interplanar spacing d values are shown in Table 4.
  • the X-ray powder diffraction pattern of Form IV is substantially as shown in FIG. 9 .
  • the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form V;
  • the X-ray powder diffraction pattern of Form V has a diffraction peak at 2 ⁇ of 7.3 ⁇ 0.2°; or has a diffraction peak at 8.1 ⁇ 0.2°; or 9.0 ⁇ 0.2° has a diffraction peak; or 9.6 ⁇ 0.2° has a diffraction peak; or 10.6 ⁇ 0.2° has a diffraction peak; or 11.6 ⁇ 0.2° has a diffraction peak; or 12.7 ⁇ 0.2° has a diffraction peak; or 13.4 ⁇ 0.2° has a diffraction peak; or 14.2 ⁇ 0.2° has a diffraction peak;
  • the X-ray powder diffraction pattern of Form V comprises at least one or more diffraction peaks located at 2 ⁇ of 9.0 ⁇ 0.2°, 10.6 ⁇ 0.2°, and 14.2 ⁇ 0.2°, preferably 2 of them, and more preferably 3 of them; optionally, it may further comprise at least one of 2 ⁇ of 7.3 ⁇ 0.2°, 8.1 ⁇ 0.2°, 11.6 ⁇ 0.2°, 12.7 ⁇ 0.2°, and 13.4 ⁇ 0.2°, preferably 2, 3, 4 or 5 of them;
  • the X-ray powder diffraction pattern of Form V optionally further comprises one or more diffraction peaks located at 2 ⁇ of 9.6 ⁇ 0.2°, 25.0 ⁇ 0.2°, and 26.2 ⁇ 0.2°; preferably, at least any 2-3 of them; further preferably, any 2 or 3 of them;
  • the X-ray powder diffraction pattern of Form V comprises one or more diffraction peaks located at 2 ⁇ of 7.3 ⁇ 0.2°, 8.1 ⁇ 0.2°, 9.0 ⁇ 0.2°, 9.6 ⁇ 0.2°, 10.6 ⁇ 0.2°, 11.6 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.4 ⁇ 0.2°, 14.2 ⁇ 0.2°, and 26.2 ⁇ 0.2°; preferably, there are diffraction peaks at 4, 5, 6, 8 or 10 of them;
  • the X-ray powder diffraction pattern of the crystalline form V has diffraction peaks at the following positions at 2 ⁇ :
  • the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form VII;
  • the X-ray powder diffraction spectrum of Form VII has a diffraction peak at 2 ⁇ of 7.2 ⁇ 0.2°; or a diffraction peak at 8.6 ⁇ 0.2°; or a diffraction peak at 10.1 ⁇ 0.2°; or a diffraction peak at 10.7 ⁇ 0.2°; or a diffraction peak at 11.7 ⁇ 0.2°; or a diffraction peak at 14.4 ⁇ 0.2°; or a diffraction peak at 14.8 ⁇ 0.2°; or a diffraction peak at 16.7 ⁇ 0.
  • the X-ray powder diffraction pattern of Form VII is substantially as shown in FIG. 14 , and the DSC The spectrum is shown in Figure 15, and the TGA spectrum is shown in Figure 16.
  • the crystalline form of (S)-1-(3-(7-acetyl-4-amino-3-(pyrazolo[1,5-a]pyridin-6-ylidenealkynyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-methyl)prop-2-en-1-one is Form VIII;
  • the X-ray powder diffraction spectrum of Form VIII has a diffraction peak at 2 ⁇ of 5.3 ⁇ 0.2°; or a diffraction peak at 8.1 ⁇ 0.2°; or a diffraction peak at 8.3 ⁇ 0.2°; or a diffraction peak at 10.6 ⁇ 0.2°; or a diffraction peak at 13.4 ⁇ 0.2°; or a diffraction peak at 14.1 ⁇ 0.2°; or a diffraction peak at 14.8 ⁇ 0.2°; or a diffraction peak at 15.4 ⁇ 0.2°; or a diffraction peak at 16.0
  • the invention relates to a method for preparing the diffraction peaks of the present invention.
  • the method comprises: first, a diffraction peak at 14.5 ⁇ 0.2°, second, a diffraction peak at 24.5 ⁇ 0.2°, third, a diffraction peak at 25.1 ⁇ 0.2°, fourth, a diffraction peak at 25.1 ⁇ 0.2°, fifth, a diffraction peak at 30.1 ⁇ 0.2°, fifth, a diffraction peak at 19.5 ⁇ 0.2°, fifth, a diffraction peak at 24.5 ⁇ 0.2°, fifth, a diffraction peak at 25.1 ⁇ 0.2°, and fifth, a diffraction peak at 25.1 ⁇ 0.2°.
  • the method comprises: first, a diffraction peak at 14.5 ⁇ 0.2°, third, a diffraction peak at 24.5 ⁇ 0.2°, fourth, a diffraction peak at 25.1 ⁇ 0.2°, fifth, a diffraction peak at 30.1 ⁇ 0.2°, fifth, a diffraction peak at 25.1 ⁇ 0.2°, and fifth, a diffraction peak at 30.1 ⁇ 0.2°.
  • the method comprises: first, a diffraction peak at 14.5 ⁇ 0.2°, third, a diffraction peak at 24.5 ⁇ 0.2°, fourth, a diffraction peak at 25.1 ⁇ 0.2°, fifth, a diffraction peak at 25.1 ⁇ 0.2°, fifth, a diffraction peak at 30 ...
  • the X-ray powder diffraction pattern of Form VII is substantially as shown in FIG. 17
  • the DSC pattern is as shown in FIG. 18
  • the TGA pattern is as shown in FIG. 19 .
  • the 2 ⁇ errors of the top ten diffraction peak positions with relative peak intensity in the X-ray powder diffraction patterns of the crystalline form I, form II, form III, form IV, form V, form VI, form VII, and form VIII and the diffraction peaks at the corresponding positions in Figures 1, 5, 8, 9, 10, 11, 14, and 17 are respectively ⁇ 0.2° to ⁇ 0.5°, preferably ⁇ 0.2° to ⁇ 0.3°, and most preferably ⁇ 0.2°.
  • the present invention also provides a method for preparing the above compound or a crystalline form of its stereoisomer, which is method one, two or three;
  • Method 1 dissolving the compound in a poor solvent, stirring or beating to obtain the corresponding crystal form
  • Method 2 heating the crystal form to obtain the corresponding crystal form
  • Method 3 dissolving the compound or crystal form in a positive solvent, adding an anti-solvent and stirring until a solid precipitates or cooling and crystallizing to obtain the corresponding crystal form;
  • the poor solvent is selected from one or more of acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone, methyl tert-butyl ether or water; preferably one or more of acetone, acetonitrile or toluene.
  • the positive solvent is selected from one or more of dimethyl sulfoxide, acetic acid, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone or N-methylpyrrolidone;
  • the anti-solvent is selected from one or more of alcohol solvents, heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, toluene or isopropyl ether; preferably one or more of methanol, ethyl acetate, water, heptane, methyl tert-butyl ether or isopropyl ether.
  • the present invention also provides a method for preparing the above compound or a crystalline form of its stereoisomer.
  • the preparation of Form I comprises the following steps: dissolving the compound in solvent A, beating the mixture to obtain the corresponding form I;
  • the preparation of Form I comprises the following steps: mixing the compound with solvent J, and then mixing with solvent K to obtain the corresponding Form I;
  • the preparation of Form II comprises the following steps: dissolving the compound in solvent B, and beating to obtain the corresponding Form II;
  • the preparation of Form II comprises the following steps: mixing the compound with a solvent L, and then mixing with a solvent M to obtain the corresponding Form II;
  • the preparation of the crystal form III comprises the following steps: heating the crystal form II to obtain the corresponding crystal form II;
  • the preparation of Form IV comprises the following steps: mixing the compound or the form with solvent C, and then mixing with solvent D to obtain the corresponding Form IV;
  • the preparation of Form V comprises the following steps: mixing the compound or the form with solvent E, and then mixing with solvent F to obtain the corresponding Form V;
  • the preparation of the crystal form VI comprises the following steps: dissolving the compound in a solvent G and stirring to obtain the corresponding crystal form VI;
  • the preparation of Form VII comprises the following steps: heating the Form VI to obtain the corresponding Form VII;
  • the preparation of the crystal form VIII comprises the following steps: mixing the compound with a solvent H, and then mixing with a solvent I to obtain the corresponding crystal form VIII;
  • the solvent A is preferably DMSO, ethyl acetate, dichloromethane, isopropyl acetate, methyl tert-butyl ether, MTBE, acetone, tetrahydrofuran, toluene, 2-butanone, 2-methyl-tetrahydrofuran, water or acetonitrile;
  • the solvent B is preferably an alcohol solvent, more preferably methanol, ethanol or isopropanol;
  • the solvent C is preferably a mixed solvent (1:5) of an alcohol solvent and a halogenated alkane solvent, more preferably a mixed solution of methanol and dichloromethane (1:5) or a mixed solution of ethanol and dichloromethane (1:5);
  • the solvent D is preferably an ether solvent, more preferably MTBE;
  • the solvent E is preferably an amide solvent, more preferably N-methylpyrrolidone or 1,4-dioxane;
  • the solvent F is
  • the heating temperature is preferably 50 to 70°C;
  • the solvent H is preferably a mixed solvent of a halogenated alkane solvent and an alcohol solvent (3:1), preferably a mixed solution of dichloromethane and ethanol (3:1);
  • the solvent I is preferably an ether solvent, more preferably MTBE;
  • the solvent J is preferably DMSO, acetic acid or DMF, and the solvent K is preferably water, acetone, ethyl acetate, acetonitrile, toluene, methyl tert-butyl ether, and n-heptane;
  • the solvent J is preferably NMP or 1,4-dioxane, and the solvent K is preferably an ether solvent, and more preferably methyl tert-butyl ether and isopropyl ether;
  • the solvent J is preferably a mixed solvent of an alcohol solvent and a halogenated alkane solvent (1:5), and preferably methanol:dichloromethane (1:5) or ethanol:dichloromethane (1:5), and the solvent K is preferably n-heptane, isopropyl ether, and n-hexane;
  • the solvent L is preferably DMSO, and the solvent M is preferably an alcohol solvent, and preferably isopropan
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above compound or a crystalline form of its stereoisomer, and one or more pharmaceutically acceptable carriers or excipients.
  • the present invention also provides the above compound or its crystalline form of stereoisomers, the above pharmaceutical composition is used in the preparation of treatment and
  • the invention relates to a method for preparing a drug for treating and/or preventing FGFR1-4 related diseases, and particularly a method for preparing a drug for treating and/or preventing FGFR1-4 related diseases.
  • the present invention also provides the crystalline form of the above-mentioned compound or its stereoisomer, and the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating and/or preventing cancer and achondroplasia-related diseases; preferably, the cancer is selected from colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervical cancer, urothelial carcinoma, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.
  • the cancer is selected from colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, myelom
  • the present invention also provides a method for treating and/or preventing FGFR-related diseases, comprising administering a therapeutically effective amount of the compound as described above or a crystalline form of its stereoisomer, or the pharmaceutical composition as described above to a subject in need thereof, preferably the FGFR is FGFR1-4.
  • the present invention also provides a method for treating and/or preventing cancer and achondroplasia-related diseases, comprising administering a therapeutically effective amount of the compound as described above or a crystalline form of its stereoisomer, or the pharmaceutical composition as described above to a subject in need; preferably, the cancer is selected from colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervical cancer, urothelial carcinoma, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.
  • the cancer is selected from colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma
  • the compounds of the present invention add non-hydrogen substituents at specific positions of the parent nucleus, which can greatly improve the enzyme activity of FGFR2 V564F and the inhibitory activity of cell resistance mutations, thereby solving the problem that there is no drug that can treat V564F resistance with currently marketed drugs.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 8 carbon atoms, further preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spiro rings, fused rings and bridged rings, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.
  • FIG1 is an XRPD diagram of Form I.
  • FIG2 is a DSC diagram of Form I.
  • FIG3 is a TGA diagram of Form I.
  • FIG5 is an XRPD diagram of Form II.
  • FIG6 is a DSC diagram of Form II.
  • FIG. 7 is a TGA diagram of Form II.
  • FIG8 is an XRPD diagram of Form III.
  • FIG. 9 is an XRPD diagram of Form IV.
  • FIG. 10 is an XRPD diagram of Form V.
  • FIG. 11 is an XRPD diagram of Form VI.
  • FIG. 12 is a DSC diagram of Form VI.
  • FIG. 13 is a TGA diagram of Form VI.
  • FIG. 14 is an XRPD diagram of Form VII.
  • FIG. 15 is a DSC diagram of Form VII.
  • FIG. 16 is a TGA diagram of Form VII.
  • FIG. 17 is an XRPD diagram of Form VIII.
  • FIG. 18 is a DSC diagram of Form VIII.
  • FIG. 19 is a TGA diagram of Form VIII.
  • the CellTiter-Glo method was used to detect the inhibitory effect of compounds on the proliferation of NCI-H716, SNU-16 and BaF3 FGFR2-BICC1 V564F cells.
  • the highest concentration of the compound tested was 1000nM, 3-fold dilution, a total of 9 concentrations (1000nM-0.15nM).
  • the compounds were added on the second day, and the cells were incubated for 72 hours before detection using the CellTiter-Glo Luminescebt detection kit.
  • Inhibition rate (%) [(average value of positive control wells - value of sample wells) / (average value of positive control wells - average value of negative control wells)] ⁇ 100, where the positive control wells are reaction wells without compound enzyme, and the negative control wells are reaction wells without enzyme.
  • mice were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in rats (plasma) at a dose of 5 mg/kg orally.
  • Test drug Example of the present invention, homemade.
  • LC/MS/MS analysis instrument AB Sciex API 4000Qtrap.
  • Constant temperature water bath HWS-12, Shanghai Yiheng Science
  • CO2 incubator Thermo-311, Thermo
  • a Take out a strain of Ba/F 3 FGFR2-BICC-V564F cells from the cell bank, resuscitate the cells with RPMI-1640 medium (RPMI-1640 + 10% FBS), place the resuscitated cells in a cell culture bottle (label the cell type, date, name of the culturer, etc. on the bottle wall) and culture them in a CO 2 incubator (the incubator temperature is 37°C and the CO 2 concentration is 5%).
  • RPMI-1640 medium RPMI-1640 + 10% FBS
  • the cells were subcultured every three days, and then continued to be cultured in a CO2 incubator. This process was repeated until the cell number met the in vivo efficacy requirements.
  • mice were marked with disposable universal ear tags for mice and rats before inoculation;
  • mice were inoculated sequentially (0.1 mL of cell suspension was inoculated per mouse).
  • Tumor volume (mm 3 ) length (mm) ⁇ width (mm) ⁇ width (mm)/2
  • mice bearing tumors were randomly divided into groups according to their weight and tumor size;
  • test drug was started to be administered (administration method: oral administration; administration volume: 10 mL/kg; administration frequency: once a day; administration cycle: 14 days; solvent: 10% Solutol HS15/0.5% CMC-Na).
  • Tumors were measured and weighed twice a week after the start of the test drug administration.
  • TGI (%) [1-(average tumor volume at the end of a treatment group administration - average tumor volume at the beginning of administration of the treatment group)/(average tumor volume at the end of treatment of the solvent control group - average tumor volume at the beginning of treatment of the solvent control group)] ⁇ 100%.
  • TGI (%) [1-(average tumor volume at the end of administration of a treatment group - average tumor volume at the beginning of administration of the treatment group)/average tumor volume at the beginning of administration of the treatment group] ⁇ 100%.
  • Method (1) Take the compound of Example 1 and pass it through a column, then rotary evaporate or freeze-dry to obtain an amorphous solid. Weigh 20 mg of the free base amorphous solid, add 100 ⁇ L of ethyl acetate (or any one of MTBE, acetone, and acetonitrile), and stir at room temperature. The slurry was centrifuged for 2 weeks and vacuum dried at 40° C. to obtain a solid. The obtained solid was detected by XRPD to be Form I, with an XRPD pattern as shown in FIG1 , a DSC pattern as shown in FIG2 , a TGA pattern as shown in FIG3 , and an IR pattern as shown in FIG4 .
  • Method (2) Weigh 0.5 g of amorphous solid free base, add 7.5 mL of DMSO, heat to 50°C, cool to room temperature, add 2.5 mL of water, stir at room temperature for 16 hours, filter, and obtain Form I with a yield of 63%.
  • Method (5) Weigh 500 mg of the free base amorphous solid, add 20 mL of dioxane, slurry at room temperature for 2 days, filter, and heat the sample at 150°C for 5 minutes to obtain Form I.
  • Form II Preparation of Form II: Weigh 20 mg of the free base amorphous solid, add 100 ⁇ L of methanol (or ethanol or isopropanol), slurry at room temperature for 2 weeks, centrifuge, and vacuum dry at 40°C to obtain a solid.
  • the obtained solid is Form II by XRPD detection, with the XRPD diagram shown in Figure 5, the DSC diagram shown in Figure 6, and the TGA diagram shown in Figure 7.
  • Form III Preparation of Form III: Weigh 20 mg of free base Form II solid, heat to 100° C., and maintain for 2 h. The obtained solid is Form III by XRPD detection, and has an XRPD pattern as shown in FIG8 .
  • Form V Weigh 20 mg of free base amorphous (or any crystalline form), add 0.5 mL of N-methylpyrrolidone, dissolve in a 40°C water bath, and filter. Add 2 ml of isopropanol, and solid precipitates overnight. Centrifuge and vacuum dry at 40°C to obtain a solid. The obtained solid is detected by XRPD to be Form V, which has an XRPD pattern as shown in Figure 10.
  • Form VI Preparation of Form VI: Weigh 50 mg of free base amorphous solid into a glass vial, add 1,4-dioxane/2 ml, stir at room temperature for 48 hours, filter, and obtain a solid.
  • the obtained solid is Form VI when XRPD is detected, and has an XRPD pattern as shown in FIG11 , a DSC pattern as shown in FIG12 , and a TGA pattern as shown in FIG13 .
  • Form VII Preparation of Form VII: Weigh 10 mg of Form VI sample, place in a vacuum drying oven at 60°C and dry for 12 h to convert into Form VII, which has an XRPD pattern as shown in Figure 14, a DSC pattern as shown in Figure 15, and a TGA pattern as shown in Figure 16.
  • Form I is relatively stable under high temperature, high humidity, high temperature and high humidity, and light conditions.
  • the impurities are significantly increased, which can well meet the requirements of later long-term storage and preparation process.
  • Crystal form I absorbs moisture and increases weight by about 1.84% under RH80%, and is slightly hygroscopic. After two cycles of moisture absorption and desorption under 0-95% relative humidity, the XRPD spectrum of crystal form I has an additional peak, which means that the crystal form has not changed.
  • Form I was prepared into suspensions with an aqueous solution containing 0.5% HPMC K4M and an aqueous solution containing 1.0% SDS. The suspensions were all gavaged and administered to rats, with three rats in each group in parallel, and the dosage was 30 mg/kg. Form I was dissolved in a solution containing 5% DMSO + 10% Solutol + 85% PBS, filtered through a filter membrane, and the filtrate was used as an animal intravenous preparation for intravenous injection. It was administered to rats, with three rats in parallel, and the dosage was 2 mg/kg.

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Abstract

L'invention concerne une forme cristalline d'un inhibiteur biologique contenant du propénone, son procédé de préparation et son utilisation. En particulier, la présente invention concerne une forme cristalline d'un composé représenté par la formule générale (I), un procédé de préparation, une composition pharmaceutique contenant une quantité thérapeutiquement efficace du sel et/ou de la forme cristalline, et son utilisation en tant qu'inhibiteur dans le traitement du cancer.
PCT/CN2024/108172 2023-07-27 2024-07-29 Forme cystal d'inhibiteur biologique contenant du propénone, son procédé de préparation et son utilisation Pending WO2025021218A1 (fr)

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CN112939982A (zh) * 2021-01-21 2021-06-11 药雅科技(上海)有限公司 一种炔类杂环btk抑制剂及其制备方法和用途
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CN114853740A (zh) * 2021-02-03 2022-08-05 药雅科技(上海)有限公司 炔类嘧啶化合物作为fgfr抑制剂的制备方法和用途
WO2022166469A1 (fr) * 2021-02-03 2022-08-11 药雅科技(上海)有限公司 Inhibiteur de kinase fgfr et son utilisation
CN116096707A (zh) * 2020-06-05 2023-05-09 金耐特生物制药公司 成纤维细胞生长因子受体激酶的抑制剂
WO2023143514A1 (fr) * 2022-01-28 2023-08-03 上海翰森生物医药科技有限公司 Bioinhibiteur contenant de la propylène cétone, son procédé de préparation et son utilisation
WO2024125532A1 (fr) * 2022-12-12 2024-06-20 杭州德睿智药科技有限公司 Nouveau composé hétérocyclique agissant en tant qu'inhibiteur des cdk, et utilisation associée

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160136168A1 (en) * 2013-07-18 2016-05-19 Taiho Pharmaceutical Co., Ltd. Therapeutic agent for fgfr inhibitor-resistant cancer
CN116096707A (zh) * 2020-06-05 2023-05-09 金耐特生物制药公司 成纤维细胞生长因子受体激酶的抑制剂
WO2022033532A1 (fr) * 2020-08-13 2022-02-17 上海和誉生物医药科技有限公司 Fgfr et inhibiteur de mutation de celui-ci, procédé de préparation correspondant et utilisation associée
CN112939982A (zh) * 2021-01-21 2021-06-11 药雅科技(上海)有限公司 一种炔类杂环btk抑制剂及其制备方法和用途
CN114853740A (zh) * 2021-02-03 2022-08-05 药雅科技(上海)有限公司 炔类嘧啶化合物作为fgfr抑制剂的制备方法和用途
WO2022166469A1 (fr) * 2021-02-03 2022-08-11 药雅科技(上海)有限公司 Inhibiteur de kinase fgfr et son utilisation
WO2023143514A1 (fr) * 2022-01-28 2023-08-03 上海翰森生物医药科技有限公司 Bioinhibiteur contenant de la propylène cétone, son procédé de préparation et son utilisation
WO2024125532A1 (fr) * 2022-12-12 2024-06-20 杭州德睿智药科技有限公司 Nouveau composé hétérocyclique agissant en tant qu'inhibiteur des cdk, et utilisation associée

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