WO2021088987A1 - Forme saline servant d'inhibiteur sélectif de her2, et formes cristallines et utilisation de celle-ci - Google Patents

Forme saline servant d'inhibiteur sélectif de her2, et formes cristallines et utilisation de celle-ci Download PDF

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WO2021088987A1
WO2021088987A1 PCT/CN2020/127123 CN2020127123W WO2021088987A1 WO 2021088987 A1 WO2021088987 A1 WO 2021088987A1 CN 2020127123 W CN2020127123 W CN 2020127123W WO 2021088987 A1 WO2021088987 A1 WO 2021088987A1
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crystal form
compound
formula
angles
following
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PCT/CN2020/127123
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Chinese (zh)
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陈新海
姜奋
张丽
陈兆国
于衍新
陈曙辉
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南京明德新药研发有限公司
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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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

Definitions

  • the present invention relates to a salt form and its crystal forms as a HER2 inhibitor, and the application of the salt form and its crystal form in the preparation of medicines for treating HER2 related diseases.
  • HER Human epidermal growth factor receptor
  • EGFR Human epidermal growth factor receptor
  • HER2 is overexpressed in a variety of cancers, and HER2 overexpression indicates that tumors are more aggressive and easier to relapse and metastasize early.
  • Herceptin humanized anti-HER2 monoclonal antibody
  • HER2 has become a therapeutic target for breast cancer, gastric cancer, and esophageal cancer.
  • the HER2 small molecule kinase inhibitors currently on the market and under development usually also inhibit HER1 at the same time. Studies have shown that inhibiting HER1 will produce target-related side effects, such as skin rash and diarrhea.
  • the present invention provides crystal form A of the compound of formula (I), and its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.18 ⁇ 0.20°, 12.01 ⁇ 0.20° and 24.60 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 10.18 ⁇ 0.20°, 12.01 ⁇ 0.20°, 13.67 ⁇ 0.20°, 17.41 ⁇ 0.20°, 20.15 ⁇ 0.20 °, 20.59 ⁇ 0.20°, 22.64 ⁇ 0.20° and 24.60 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80°, 10.18°, 12.01°, 13.67°, 14.70°, 16.32°, 17.41°, 18.86° , 19.73°, 20.15°, 20.59°, 21.61°, 22.64°, 23.57°, 24.13°, 24.60°, 25.41°, 25.77°, 28.52° and 29.15°.
  • the XRPD pattern of the above-mentioned crystal form A is shown in FIG. 1.
  • the XRPD pattern analysis data of the above-mentioned crystal form A is shown in Table 1.
  • the present invention also provides the B crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.41 ⁇ 0.20°, 12.86 ⁇ 0.20° and 15.64 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 6.41 ⁇ 0.20°, 7.32 ⁇ 0.20°, 12.86 ⁇ 0.20°, 15.64 ⁇ 0.20°, 16.26 ⁇ 0.20 °, 20.00 ⁇ 0.20°, 21.09 ⁇ 0.20° and 21.70 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 6.41°, 7.32°, 10.52°, 12.86°, 15.64°, 16.26°, 17.44°, 19.34° , 20.00, 21.09°, 21.70°, 22.48°, 25.84°, 27.40° and 28.72°.
  • the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 2.
  • the XRPD pattern analysis data of the above-mentioned crystal form B is shown in Table 2.
  • the differential scanning calorimetry curve of the above-mentioned crystal form B has an endothermic peak at 202.5 ⁇ 3°C.
  • the DSC chart of the above-mentioned crystal form B is shown in FIG. 3.
  • the present invention also provides crystal form C of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.80 ⁇ 0.20°, 13.02 ⁇ 0.20° and 18.03 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 9.80 ⁇ 0.20°, 13.02 ⁇ 0.20°, 16.70 ⁇ 0.20°, 18.03 ⁇ 0.20°, 19.47 ⁇ 0.20 °, 21.00 ⁇ 0.20°, 23.67 ⁇ 0.20° and 25.15 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 9.80°, 13.02°, 16.70°, 18.03°, 19.47°, 21.00°, 22.74°, 23.67° And 25.15°.
  • the XRPD pattern of the above-mentioned crystal form C is shown in FIG. 4.
  • the XRPD pattern analysis data of the above-mentioned crystal form C is shown in Table 3.
  • the differential scanning calorimetry curve of the above-mentioned crystal form C has an endothermic peak at 175.4 ⁇ 3°C.
  • the DSC chart of the above-mentioned crystal form C is shown in FIG. 5.
  • the present invention also provides the D crystal form of the compound of formula (I), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.64 ⁇ 0.20°, 21.38 ⁇ 0.20° and 22.02 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 12.64 ⁇ 0.20°, 14.32 ⁇ 0.20°, 15.78 ⁇ 0.20°, 18.40 ⁇ 0.20°, 20.20 ⁇ 0.20 °, 21.38 ⁇ 0.20°, 22.02 ⁇ 0.20° and 26.93 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 9.16°, 10.68°, 12.64°, 13.34°, 14.32°, 14.79°, 15.78°, 16.75° , 18.40°, 20.20°, 21.38°, 22.02°, 23.98°, 25.48°, 26.93° and 28.21°.
  • the XRPD pattern of the above-mentioned crystal form D is shown in FIG. 6.
  • the XRPD pattern analysis data of the above-mentioned crystal form D is shown in Table 4.
  • the differential scanning calorimetry curve of the above-mentioned crystal form D has an endothermic peak starting point at 171.8 ⁇ 3°C.
  • the DSC chart of the above-mentioned crystal form D is shown in FIG. 7.
  • thermogravimetric analysis curve (TGA) of the above-mentioned crystal form D has a weight loss of 0.98% at 150 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form D is shown in FIG. 8.
  • the present invention also provides a compound of formula (II):
  • the present invention also provides the E crystal form of the compound of formula (II), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 19.76 ⁇ 0.20°, 22.83 ⁇ 0.20° and 25.59 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 10.26 ⁇ 0.20°, 11.49 ⁇ 0.20°, 13.25 ⁇ 0.20°, 13.95 ⁇ 0.20°, 15.41 ⁇ 0.20 °, 19.76 ⁇ 0.20°, 22.83 ⁇ 0.20° and 25.59 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 5.90°, 10.26°, 11.49°, 11.84°, 13.25°, 13.95°, 14.64°, 15.41° , 17.12°, 17.83°, 19.76°, 20.05°, 21.27°, 21.89°, 22.20°, 22.83°, 23.55°, 24.82°, 25.59°, 27.02°, 28.48°, 32.02° and 33.52°.
  • the XRPD pattern of the above-mentioned crystal form E is shown in FIG. 9.
  • the XRPD pattern analysis data of the above-mentioned crystal form E is shown in Table 5.
  • the differential scanning calorimetry curve of the above-mentioned crystal form E has an onset of an endothermic peak at 215.0 ⁇ 3°C.
  • the DSC chart of the above-mentioned crystal form E is shown in FIG. 10.
  • the present invention also provides a compound of formula (III):
  • the present invention also provides the F crystal form of the compound of formula (III), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 14.24 ⁇ 0.20°, 16.69 ⁇ 0.20° and 22.85 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 14.24 ⁇ 0.20°, 16.69 ⁇ 0.20°, 18.05 ⁇ 0.20°, 20.14 ⁇ 0.20°, and 22.85 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 14.24°, 16.69°, 18.05°, 20.14° and 22.85°.
  • the XRPD pattern of the above crystal form F is shown in FIG. 11.
  • the XRPD pattern analysis data of the above-mentioned crystal form F is shown in Table 6.
  • the present invention also provides a compound of formula (IV):
  • the present invention also provides the G crystal form of the compound of formula (IV), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 11.47 ⁇ 0.20°, 16.88 ⁇ 0.20° and 23.78 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 11.47 ⁇ 0.20°, 14.50 ⁇ 0.20°, 15.48 ⁇ 0.20°, 16.29 ⁇ 0.20°, 16.88 ⁇ 0.20 °, 21.70 ⁇ 0.20°, 22.65 ⁇ 0.20° and 23.78 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 11.47°, 14.50°, 15.48°, 16.29°, 16.88°, 18.90°, 20.10°, 21.70° , 21.99°, 22.65°, 23.78°, 24.19° and 24.98°.
  • the XRPD pattern of the above-mentioned crystal form G is shown in FIG. 12.
  • the XRPD pattern analysis data of the above-mentioned crystal form G is shown in Table 7.
  • the differential scanning calorimetry curve of the above-mentioned crystal form G has an endothermic peak at 215.0 ⁇ 3°C.
  • the DSC chart of the above-mentioned crystal form G is shown in FIG. 13.
  • the present invention also provides a compound of formula (V):
  • the present invention also provides the H crystal form of the compound of formula (V), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.23 ⁇ 0.20°, 10.95 ⁇ 0.20° and 21.10 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 9.23 ⁇ 0.20°, 10.95 ⁇ 0.20°, 13.61 ⁇ 0.20°, 21.10 ⁇ 0.20°, 21.60 ⁇ 0.20 °, 22.59 ⁇ 0.20°, 23.79 ⁇ 0.20° and 24.98 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 9.23°, 10.95°, 12.95°, 13.61°, 15.37°, 16.08°, 16.97°, 17.98° , 19.28°, 19.95°, 21.10°, 21.60°, 22.59°, 23.79°, 24.98°, 26.54° and 32.64°.
  • the crystal form of compound H of the above formula (V) has an XRPD pattern as shown in FIG. 14.
  • the XRPD pattern analysis data of the above-mentioned compound H crystal form of formula (V) is shown in Table 8.
  • the present invention also provides compounds of formula (VI):
  • the present invention also provides the I crystal form of the compound of formula (VI), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.38 ⁇ 0.20°, 10.32 ⁇ 0.20° and 16.17 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form I has characteristic diffraction peaks at the following 2 ⁇ angles: 4.38 ⁇ 0.20°, 7.60 ⁇ 0.20°, 10.32 ⁇ 0.20°, 14.83 ⁇ 0.20°, 16.17 ⁇ 0.20 °, 20.13 ⁇ 0.20°, 23.45 ⁇ 0.20° and 24.99 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form I has characteristic diffraction peaks at the following 2 ⁇ angles: 4.38°, 4.97°, 6.13°, 7.60°, 10.32°, 11.85°, 12.88°, 14.30° , 14.83°, 16.17°, 17.48°, 18.63°, 19.81°, 20.13°, 21.86°, 22.62°, 23.45°, 24.99°, 25.75°, 27.66° and 29.88°.
  • the XRPD pattern of the above-mentioned crystal form I is shown in FIG. 15.
  • the XRPD pattern analysis data of the above-mentioned crystal form I are shown in Table 9.
  • the present invention also provides the J crystal form of the compound of formula (VI), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.74 ⁇ 0.20°, 16.59 ⁇ 0.20° and 23.29 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form J has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.20°, 7.74 ⁇ 0.20°, 16.59 ⁇ 0.20°, 17.26 ⁇ 0.20°, 21.31 ⁇ 0.20 °, 22.82 ⁇ 0.20° and 23.29 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form J has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80°, 7.74°, 11.56°, 13.29°, 13.88°, 14.73°, 15.51°, 16.59°, 17.26°, 18.37°, 18.87°, 20.13°, 21.31°, 21.58°, 22.35°, 22.82°, 23.29°, 24.56°, 24.95°, 26.09°, 26.68°, 27.94°, 31.23°, 33.36°, 34.90° , And 36.80°.
  • the XRPD pattern of the above-mentioned crystal form J is shown in FIG. 16.
  • the XRPD pattern analysis data of the above-mentioned crystal form J is shown in Table 10.
  • the crystalline form of compound J of the above formula (VI) has a differential scanning calorimetry curve having an endothermic peak starting point at 189.8 ⁇ 3°C.
  • the crystal form of compound J of the above formula (VI) has a DSC chart shown in FIG. 17.
  • the present invention also provides a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IV), a compound of formula (V), a compound of formula (VI) and A, B, C, D, E , F, G, H, I and J crystal forms in the preparation of drugs for the treatment of HER2 related diseases.
  • the salt form and each crystal form of the compound of the present invention are stable, are less affected by light, heat and humidity, have very high solubility, and have broad prospects for preparing medicines.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses 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; TFA stands for trifluoroacetic acid; TsOH stands for P-toluenesulfonic acid; mp represents melting point; EtSO 3 H represents ethanesulfonic acid; MeSO 3 H represents methanesulfonic acid; ATP represents adenosine triphosphate; HEPES represents 4-hydroxyethylpiperazine ethanesulfonic acid; EGTA represents ethylene glycol bis(2 -Aminoethyl ether) tetraacetic acid; MgCl 2 stands for magnesium dichloride; MnCl 2 stands for manganese dichloride; DTT stands for dithiothreitol; DCC stands for dicycl
  • Test method Approximately 10 mg sample is used for XRPD detection.
  • Light tube voltage 45kV
  • light tube current 40mA
  • the first solar slit 0.04rad
  • the second solar slit 0.04rad
  • Test method Take a sample ( ⁇ 1-5mg) and place it in a DSC aluminum pan for testing. Under the condition of 50mL/min N 2 and at a heating rate of 10°C/min, heat the sample from 25°C (room temperature) to before the sample is decomposed .
  • Figure 1 XRPD pattern of crystal form A.
  • Figure 2 XRPD pattern of Form B.
  • Figure 11 XRPD pattern of Form F.
  • Figure 12 XRPD pattern of Form G.
  • Figure 15 XRPD pattern of crystalline form I.
  • the synthetic route is as follows:
  • reaction solution was cooled to room temperature, slowly poured into 2.5L of water with stirring, filtered, the filter cake was washed with water (200mL*3), concentrated and dried under reduced pressure, the resulting crude product was mixed with petroleum ether (100mL) and ethyl acetate (100mL) as a mixed solvent
  • the slurry was beaten twice, filtered, and the filter cake was rinsed with the same volume ratio of the above-mentioned mixed solvent (50 mL*3), and concentrated and dried under reduced pressure to obtain compound 10.
  • reaction solution was cooled to room temperature, the precipitated solid was removed by filtration and the filter cake was rinsed with chlorobenzene (110 mL), the resulting filtrate was collected, and triethylamine (99.62g, 984.51mmol, 137mL, 1.65eq) was slowly added to it and the internal temperature was controlled Below 30°C, the reaction solution was stirred at 25°C for 16 hours. The reaction solution was directly concentrated to dryness under reduced pressure to obtain compound 12.
  • the compound represented by formula (I) (56.5g) was added to a mixed solution of n-heptane and ethyl acetate (753mL:377mL), and the resulting suspension was heated and stirred at 50°C for 40 hours, slowly cooled, filtered, and solid After drying under reduced pressure, the crystal form D of the compound of formula (I) was obtained by XRPD detection.
  • the influencing factors high temperature, high humidity and light
  • the stability of acceleration conditions and the stability of intermediate conditions were investigated for the crystal form D.
  • the purpose of this test is to detect the in vitro inhibitory activity of the compound against HER1 (ErbB1), HER2 (ErbB2), and HER4 (ErbB4).
  • the enzymes used in this test are human ErbB1, ErbB2 and ErbB4.
  • Eurofins Pharma Discovery Service provides an activity detection method.
  • the results of the inhibitory activity of the test compounds against HER1, HER2, and HER4 are shown in Table 15.
  • test compound buffer 5 ⁇ L
  • peptide substrate poly(Glu, Tyr) 4:1) (2.5 ⁇ L)
  • ErbB 4-20ng, 2.5 ⁇ L
  • MnCl 2 50mM, 1.25 ⁇ L
  • DH 2 O 3.75 ⁇ L
  • [ ⁇ - 33 P]ATP 10 ⁇ L
  • Luciferase in Cell-Titer-Glo reagent uses luciferin, oxygen and ATP as reaction substrates to produce oxyluciferin and release energy in the form of light. Since the luciferase reaction requires ATP, the total amount of light produced by the reaction is directly proportional to the total amount of ATP that reflects cell viability.
  • NCI-N87 cell line ATCC-CRL-5822
  • BT-474 cell line ATCC-HTB-20
  • Cell culture medium (RPMI 1640 medium (Invitrogen#22400-105; 10% serum Invitrogen#10090148; L-glutamine 1 ⁇ , Gibco#25030-081; double antibody Hyclone#SV30010)
  • the compound concentration is 10 mM, and the compound is diluted with DMSO to make the initial concentration 4 mM. Add compound to the plate, 9 ⁇ L per well.
  • Test result The test result is shown in Table 16.
  • the crystal form of compound D of formula (I) of the present invention has significant proliferation inhibitory activity on NCI-N87 cells and BT-474 cells.
  • mice Female BALB/c nude mice, 6-8 weeks old, weighing 18-22 grams; Supplier: Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.
  • Human gastric cancer NCI-N87 cells were cultured in a monolayer in vitro.
  • the culture conditions were RPMI-1640 medium with 10% fetal bovine serum, 100U/mL penicillin, 100 ⁇ g/mL streptomycin, 37°C, and 5% CO 2 culture.
  • Tumor cell inoculation (tumor inoculation)
  • test compound is formulated into a solution of appropriate concentration, and the solvent is 10% NMP+10% ethylene glycol stearate+80% water 4.
  • the experimental index is to investigate whether the tumor growth is inhibited, delayed or cured.
  • the tumor diameter was measured with vernier calipers twice a week.
  • TGI (%) [1- (Average tumor volume at the end of a certain treatment group-the average tumor volume at the start of the treatment group) / (Average tumor volume at the end of the solvent control group- The average tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • the statistical analysis is based on the RTV data at the end of the experiment using SPSS software for analysis.
  • the comparison between two groups is analyzed by T test, and the comparison between three or more groups is analyzed by one-way ANOVA. If the variance is uniform (the F value is not significantly different), the analysis should be performed by Tukey's method. If the variance is not uniform ( There is a significant difference in the F value), and the Games-Howell method is used for testing. p ⁇ 0.05 considered a significant difference.
  • the crystal form D of the compound of formula (I) of the present invention has an excellent effect of inhibiting tumor growth.

Abstract

L'invention concerne une forme saline servant d'inhibiteur de HER2 et des formes cristallines de celle-ci, et une utilisation de la forme saline et des formes cristallines de celle-ci dans la préparation de médicaments pour le traitement de maladies associées à HER2.
PCT/CN2020/127123 2019-11-08 2020-11-06 Forme saline servant d'inhibiteur sélectif de her2, et formes cristallines et utilisation de celle-ci WO2021088987A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024044570A1 (fr) * 2022-08-22 2024-02-29 Iambic Therapeutics, Inc. Composés et procédés de modulation de her2

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WO2005065266A2 (fr) * 2003-12-29 2005-07-21 Bristol-Myers Squibb Company Composes de pyrrolotriazine disubstituee
CN1922182A (zh) * 2003-12-29 2007-02-28 布里斯托尔-迈尔斯·斯奎布公司 作为激酶抑制剂的吡咯并三嗪化合物
WO2007059257A2 (fr) * 2005-11-15 2007-05-24 Array Biopharma Inc. Inhibiteurs erbb
CN101326171A (zh) * 2005-11-16 2008-12-17 Imtm股份有限公司 用作治疗炎症及其它疾病的前药的新型双用途肽酶抑制剂
CN101611041A (zh) * 2006-12-12 2009-12-23 武田药品工业株式会社 稠合杂环化合物
WO2019214651A1 (fr) * 2018-05-08 2019-11-14 南京明德新药研发有限公司 Dérivés de pyrrolo[2,1-f][1,2,4]triazine servant d'inhibiteurs sélectifs de her2 et leur application

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005065266A2 (fr) * 2003-12-29 2005-07-21 Bristol-Myers Squibb Company Composes de pyrrolotriazine disubstituee
CN1922182A (zh) * 2003-12-29 2007-02-28 布里斯托尔-迈尔斯·斯奎布公司 作为激酶抑制剂的吡咯并三嗪化合物
WO2007059257A2 (fr) * 2005-11-15 2007-05-24 Array Biopharma Inc. Inhibiteurs erbb
CN101326171A (zh) * 2005-11-16 2008-12-17 Imtm股份有限公司 用作治疗炎症及其它疾病的前药的新型双用途肽酶抑制剂
CN101611041A (zh) * 2006-12-12 2009-12-23 武田药品工业株式会社 稠合杂环化合物
WO2019214651A1 (fr) * 2018-05-08 2019-11-14 南京明德新药研发有限公司 Dérivés de pyrrolo[2,1-f][1,2,4]triazine servant d'inhibiteurs sélectifs de her2 et leur application

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024044570A1 (fr) * 2022-08-22 2024-02-29 Iambic Therapeutics, Inc. Composés et procédés de modulation de her2

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