WO2019206268A1 - 一种c-MET抑制剂的晶型及其盐型和制备方法 - Google Patents

一种c-MET抑制剂的晶型及其盐型和制备方法 Download PDF

Info

Publication number
WO2019206268A1
WO2019206268A1 PCT/CN2019/084515 CN2019084515W WO2019206268A1 WO 2019206268 A1 WO2019206268 A1 WO 2019206268A1 CN 2019084515 W CN2019084515 W CN 2019084515W WO 2019206268 A1 WO2019206268 A1 WO 2019206268A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
crystal form
formula
ray powder
diffraction pattern
Prior art date
Application number
PCT/CN2019/084515
Other languages
English (en)
French (fr)
Inventor
徐雄彬
李刚
姚婷
王坤
胡利红
丁照中
Original Assignee
福建广生堂药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 福建广生堂药业股份有限公司 filed Critical 福建广生堂药业股份有限公司
Priority to AU2019260240A priority Critical patent/AU2019260240B2/en
Priority to CA3098336A priority patent/CA3098336C/en
Priority to EA202092558A priority patent/EA039713B1/ru
Priority to EP19791723.0A priority patent/EP3786155B1/en
Priority to US17/049,579 priority patent/US11465986B2/en
Priority to ES19791723T priority patent/ES2962679T3/es
Priority to KR1020207033747A priority patent/KR102374933B1/ko
Priority to JP2020560239A priority patent/JP7118349B2/ja
Priority to CN201980027588.0A priority patent/CN112004801B/zh
Publication of WO2019206268A1 publication Critical patent/WO2019206268A1/zh
Priority to ZA2020/07037A priority patent/ZA202007037B/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a crystal form of a c-MET inhibitor, a salt form thereof, and a preparation method, and also includes the use of the crystal form and the salt form in the preparation of a medicament for treating tumors.
  • the proto-oncogene Met-encoded c-Met is a highly binding receptor tyrosine kinase belonging to the RON subfamily and the only known receptor for scattering factors or hepatocyte growth factor (HGF). Binding of HGF to the extracellular domain of c-Met induces phosphorylation of c-Met and recruits a variety of interstitial factors such as GAB1 (growth factor receptor binding protein-1) and GAB2 (growth factor) in the C-terminal multifunctional region.
  • GAB1 growth factor receptor binding protein-1
  • GAB2 growth factor
  • Receptor binding protein-2 further attracts SHP2, PI3K and other molecules to bind thereto, thereby activating RAS/MAPK, PI3K/AKT, JAK/STAT pathway, etc., thereby regulating cell growth, migration, proliferation and survival.
  • Abnormal c-Met pathway induces tumorigenesis and metastasis, and abnormally high levels of c-Met are found in various human malignancies such as bladder cancer, gastric cancer, lung cancer, and breast cancer.
  • c-Met is also associated with tumor resistance to multiple kinase inhibitors.
  • the interaction between c-Met and the adhesion receptor CD44 amplifies the response of the signal peptide; interaction with the brain protein receptor from the protein activates the non-dependent ligand HGF c-Met, enhancing the invasion;
  • the interaction between the pro-apoptotic receptor FAS accelerates apoptosis; interaction with various receptor tyrosine kinases such as EGFR, VEGFR, etc., causes activation between each other to be regulated, and the angiogenesis process is affected.
  • the interaction between c-Met and these membrane receptors promotes tumorigenesis and metastasis, and induces drug resistance.
  • Tepotinib has high selectivity, it still has the disadvantages of low metabolic stability and large clearance rate in vivo. Therefore, the clinical need for metabolically stable c-Met inhibitors to make up for this deficiency.
  • the present invention provides a crystalline form of the compound of formula (I) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 4.54° ⁇ 0.2°, 13.70° ⁇ 0.2°, 17.84 ⁇ 0.2°, 21.24°. ⁇ 0.2° and 26.62 ⁇ 0.2°.
  • the A crystalline form has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 4.54° ⁇ 0.2°, 13.70° ⁇ 0.2°, 15.14 ⁇ 0.2°, 17.84 ⁇ 0.2°. 18.40° ⁇ 0.2°, 21.24° ⁇ 0.2°, 24.06° ⁇ 0.2°, 26.62 ⁇ 0.2° and 27.44 ⁇ 0.2°.
  • the A crystalline form has an X-ray powder diffraction pattern as shown in FIG.
  • the A crystalline form has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 4.538°, 9.021°, 11.300°, 13.699°, 15.141°, 16.640°, 17.840°, 18.399, 19.039, 19.620, 20.441, 21.241, 22.598, 24.060, 24.962, 25.660, 26.621, 27.440, 28.258, 29.159, 31.081, 32.465, 34.780, 35.400 36.920° and 38.760°.
  • the XRPD pattern analysis data of the above A crystal form is shown in Table 1.
  • the above Form A can also be characterized by DSC with an onset temperature of 171.90 ° C and a peak temperature of 173.09 ° C.
  • the A crystalline form has a differential scanning calorimetry curve having an endothermic peak at 171.90 ° C ⁇ 3 ° C.
  • the above-described Form A crystal has a differential scanning calorimetry curve as shown in FIG.
  • the above A crystal form can also be characterized by TGA.
  • TGA TGA spectrum shows that when heated to 223.23 ° C, the weight is reduced by 0.1870%, and when heated to 306.06 ° C, the weight is reduced by 10.03% at 205.06 ° C. A large weight loss began to appear in the future.
  • the above A crystal form has a thermogravimetric analysis curve having a weight loss of 0.1870% at 223.23 ° C ⁇ 3 ° C and a weight loss of 10.22% at 306.06 ° C ⁇ 3 ° C.
  • thermogravimetric analysis curve of the above A crystal form is shown in FIG.
  • the above-described infrared spectrum of Form A contained in 3046cm -1 ⁇ 5cm -1, 2938cm - 1 ⁇ 5cm -1, 2914cm -1 ⁇ 5cm -1, 2884cm -1 ⁇ 5cm -1, 2849cm -1 ⁇ 5cm -1, 2780cm -1 ⁇ 5cm -1, 2734cm - 1 ⁇ 5cm -1, 2679cm -1 ⁇ 5cm -1, 2242cm -1 ⁇ 5cm -1, 1732cm -1 ⁇ 2cm -1, 1716cm -1 ⁇ 2cm -1 , 1671cm - 1 ⁇ 2cm -1 , 1631cm -1 ⁇ 2cm -1 , 1595cm -1 ⁇ 2cm -1 , 1556cm -1 ⁇ 2cm -1 , 1547cm -1 ⁇ 2cm -1 ,
  • the invention also provides a compound of formula (II).
  • the present invention also provides a crystalline form B of the compound of formula (II), the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 4.34 ° ⁇ 0.2 °, 12.99 ° ⁇ 0.2 °, 15.35 ° ⁇ 0.2 ° and 25.50 ° ⁇ 0.2 °.
  • the B crystal form has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 4.34° ⁇ 0.2°, 6.50° ⁇ 0.2°, 8.65° ⁇ 0.2°, 10.82° ⁇ 0.2°, 12.99° ⁇ 0.2°, 15.35° ⁇ 0.2°, 17.96° ⁇ 0.2°, and 25.50° ⁇ 0.2°.
  • the above-described Form B crystal has an X-ray powder diffraction pattern as shown in FIG.
  • the B crystal form has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 4.335°, 6.502°, 8.645°, 10.816°, 12.986°, 15.349°, 15.782°, 16.109°, 17.955°, 18.447°, 19.057°, 19.534°, 19.816°, 20.531°, 21.16°, 22.265°, 22.752°, 23.907°, 24.407°, 25.499°, 26.248°, 26.886°, 27.725°, 28.004° , 28.653°, 29.127°, 29.779°, 30.432°, 31.064°, 33.734°, and 37.02°.
  • the XRPD pattern analysis data of the above B crystal form is shown in Table 2.
  • the B crystal form has a differential scanning calorimetry curve having an endothermic peak at 43.98 ° C ⁇ 3 ° C and 219.64 ° C ⁇ 3 ° C.
  • the B-form, the differential scanning calorimetry curve is shown in FIG.
  • the above B crystal form has a thermogravimetric analysis curve having a weight loss of 0.5270% at 73.64 ° C ⁇ 3 ° C and a loss of 1.542% at 230.90 ° C ⁇ 3 ° C.
  • thermogravimetric analysis curve of the above B crystal form is shown in FIG.
  • the invention also provides a compound of formula (III).
  • the present invention also provides a crystalline form C of the compound of formula (III), the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 6.94 ° ⁇ 0.2 °, 19.08 ° ⁇ 0.2 °, 21.05 ° ⁇ 0.2 ° and 24.73 ° ⁇ 0.2 °.
  • the C crystal form has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 6.94° ⁇ 0.2°, 9.94° ⁇ 0.2°, 17.29° ⁇ 0.2°, 18.04° ⁇ 0.2°, 19.08° ⁇ 0.2°, 21.05° ⁇ 0.2°, 24.12° ⁇ 0.2°, and 24.73° ⁇ 0.2°.
  • the C crystal form has an X-ray powder diffraction pattern as shown in FIG.
  • the C crystal form has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 6.94°, 9.94°, 13.36°, 15.271°, 16.83°, 17.286°, 18.038°, 18.767, 19.082, 20.605, 21.054, 21.884, 22.615, 23.228, 24.118, 24.728, 25.182, 25.813, 28.182, 30.757, 31.498, 33.318, 33.77 and 34.595 .
  • the XRPD pattern analysis data of the above C crystal form is shown in Table 3.
  • the above C crystal form has a differential scanning calorimetry curve having an endothermic peak at 198.16 °C ⁇ 3 °C.
  • the C-form, the differential scanning calorimetry curve is shown in FIG.
  • the above C crystal form has a thermogravimetric analysis curve having a weight loss of 0.4541% at 204.73 ° C ⁇ 3 ° C.
  • thermogravimetric analysis curve of the above C crystal form is shown in FIG.
  • the present invention also provides the use of the above compound or crystal form for the preparation of a medicament for treating cancer.
  • the invention also provides a compound or crystal form as described above for use in the treatment of cancer.
  • the present invention also provides a method of treating cancer by administering the above compound or crystal form.
  • cancer is preferably liver cancer.
  • the preparation method of the salt form and the crystal form of the compound represented by the formula (I) of the present invention is simple, and the crystal form is relatively stable, high temperature and high humidity, and is convenient for preparation.
  • 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, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the present invention uses the following abbreviations:
  • DIEA N,N-diisopropylethylamine
  • Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • Pd(PPh3)2Cl2 bis(triphenylphosphine)palladium dichloride.
  • Test method Approximately 10-20 mg samples were used for XRPD detection.
  • DSC Differential Scanning Calorimeter
  • Test method A sample (0.5 to 1 mg) was placed in a DSC aluminum pan for testing, and the sample was heated from room temperature (25 ° C) to 300 ° C or 350 ° C at a heating rate of 10 ° C / min under 50 mL / min N 2 .
  • TGA Thermal Gravimetric Analyzer
  • Test method take the sample (2 ⁇ 5mg) in a TGA platinum pot for testing, at 25mL / min N2, at a heating rate of 10 ° C / min, heat the sample from room temperature (25 ° C) to 300 ° C, 350 ° C or Lose weight 20%.
  • Test conditions Approximately 10-15 mg of sample was used for DVS detection.
  • Very hygroscopic Wet weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • Slightly hygroscopic Wet weight gain is less than 2% but not less than 0.2%
  • No or almost no hygroscopicity Wet weight gain is less than 0.2%
  • HPLC High Performance Liquid Chromatograph
  • the analysis method is as follows:
  • Figure 1 is an XRPD spectrum of the crystalline form of Compound A of formula (I).
  • Figure 2 is a DSC chart of the crystalline form of Compound A of formula (I).
  • Figure 3 is a TGA spectrum of the crystalline form of Compound A of formula (I).
  • Figure 4 is an XRPD spectrum of the crystalline form of Compound B of formula (II).
  • Figure 5 is a DSC chart of the crystalline form of Compound B of formula (II).
  • Figure 6 is a TGA spectrum of the compound B crystal form of formula (II).
  • Figure 7 is an XRPD spectrum of the crystalline form of Compound C of formula (III).
  • Figure 8 is a DSC chart of the crystalline form of Compound C of formula (III).
  • Figure 9 is a TGA spectrum of the crystalline form of Compound C of formula (III).
  • the intermediate 1-K (2.4 kg, 3.93 mol) was added in portions to a solution of methanesulfonic acid (758.66 g, 7.89 mol) in methanol (7.2 L).
  • the reaction mixture was heated to 50 ° C for 2 hours, LCMS detection
  • methanol (16.8 liters) sodium acetate (645.54 g, 7.87 mol), formaldehyde (639.63 g, 7.88 mol, 37% aqueous solution) and triacetoxyborohydride were sequentially added to the reaction mixture.
  • Sodium (1.25 kg, 5.91 mol) the reaction mixture was stirred for 16 hours, and the reaction was completed by LCMS.
  • the reaction solution was filtered, and aqueous ammonia (3 liters) and water (4.5 liters) were successively added dropwise to the filtrate and stirred for 6 hours, and filtered, and the cake was washed with water and dried.
  • the solid was added to tetrahydrofuran (13 liters), heated to 50 ° C to dissolve, and added with thiourea resin (650 g), stirred for 2 hours, and then filtered, and a thiourea resin (650 g) was added to the filtrate, and the mixture was stirred at 50 ° C for 2 hours, and then filtered.
  • the weighing bottle was placed overnight and the precision weighed weights were taken out, respectively m 1 1 , m 1 2 and m 1 3 .
  • a suitable amount of Compound A of the formula (I) was placed in a weighing bottle of a predetermined weight (the thickness of the sample was about 1 mm), and then the weights were precisely weighed to be m21, m 2 2 and m 2 3 , respectively.
  • the weighing bottle was placed open, and the bottle cap was placed in a desiccator with a saturated solution of ammonium chloride in the lower part, the desiccator lid was covered, and the desiccator was placed in an incubator at 25 ° C for 24 hours.
  • Table 9 shows the wettability of the compound A of the formula (I)
  • the wetted average value of the compound A of the formula (I) was 0.060% ( ⁇ 0.2%), so that the compound A of the formula (I) had no or almost no hygroscopicity.
  • the crystal form of the compound of the formula (I) is soluble in water or N-methylpyrrolidone, dissolved in 0.1 N HCl, slightly soluble in tetrahydrofuran or trifluoroacetic acid, in ethyl acetate, acetonitrile or ethanol.
  • the medium is slightly soluble; it is almost insoluble or insoluble in n-hexane, diethylamine or 0.1N sodium hydroxide solution.
  • Tracer236 (LotNumber: 10815978)
  • This experiment utilizes the Lantha Screen TMEu Kinase Binding Assay, as shown in Figure 1, to detect AlexaFluor conjugate or kinase "tracer" binding by the addition of an Eu-labeled antibody.
  • the binding of the tracer and antibody to the kinase results in a high degree of FRET, whereas the use of a kinase inhibitory compound in place of the tracer results in FRET loss.
  • test compound preparation 10 mM test compound and reference compound were diluted to 0.667 mM with 100% DMSO, using a fully automated microplate pretreatment system ECHO for 3-fold dilution, 8 concentration gradients, double double wells, 75 nL per well .
  • Test compound c-METIC 50 (nM) Compound of formula (I) 1.09
  • Example 10 Cell proliferation inhibition assay of a compound of formula (I)
  • This experiment is to investigate the inhibitory effect of the compound of formula (I) on AKT overexpressing prostate cancer cell line LNCaP.
  • Cell culture DMEM medium, fetal bovine serum, DPBS
  • Detection reagent live cell detection kit CellTiter-Glo
  • MHCC97-H cells were separately seeded in 384-well plates containing 500 cells per well. The cell plates were placed in a carbon dioxide incubator for overnight culture.
  • Compounds were transferred to cell plates at a starting concentration of 10 [mu]M.
  • the cell plates were incubated in a carbon dioxide incubator for 3 days.
  • Promega Cell Titer-Glo reagent was added to the cell plate and incubated for 10 minutes at room temperature to stabilize the luminescence signal. Readings were performed using a Perkin Elmer Envision multi-label analyzer.
  • MHCC97H cells were cultured in vitro in a single layer, cultured in RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 1% penicillin-streptomycin double antibody, and cultured at 37 ° C 5% CO 2 . Passage was routinely digested with trypsin-EDTA twice a week. When the cells are in the exponential growth phase, the cells are harvested, counted, and inoculated.
  • mice BALB/c nude mice, male. 6-8 weeks old, weighing 18-22 grams.
  • 0.2 ml of a cell suspension containing 5 x 10 ⁇ 6 MHCC97H was subcutaneously inoculated into the right back of each mouse.
  • Group administration was initiated when the average tumor volume reached approximately 172 mm 3 .
  • the experimental grouping and dosing schedule are shown in the table below.
  • the experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured twice a week using vernier calipers.
  • the antitumor effect (TGI) of the compounds was evaluated by TC (days) and T/C (%).
  • the compound of formula (I) has better metabolic stability than Tepotinib.
  • the compound of formula (I) has a t 1/2 of liver particle metabolism in human, rat, and mouse species of 62.1 minutes, 36.5 minutes, and 49.1 minutes, respectively, under the same conditions, tepotinib in human, rat, and mouse.
  • the t 1/2 of liver particle metabolism of each species was 48.3 minutes, 10.5 minutes, and 12.4 minutes, respectively.
  • the compound of the present invention has an increased half-life, an extended action time for the target, enhanced metabolic stability, and more excellent inhibitory activity. The prolongation of the half-life will keep the blood concentration for a longer period of time. It can be predicted that the compound will be used in tumor treatment, and the patient's medication dose or dose will be reduced compared with the same drug, and patient compliance will be significantly improved.
  • c-MET binds to HGF, it activates MAPK, PI3K/AKT, Cdc42/Rac1 and other pathways, resulting in cancer cell survival and proliferation, thereby accelerating tumor growth. Therefore, pyridone compounds as c-MET inhibitors have great application prospects in targeted therapeutic drugs such as liver cancer, non-small cell lung cancer, and gastric cancer. Especially in the treatment of liver cancer, this compound has a precise therapeutic effect on liver cancer with high expression of c-MET. Therefore, the compound of the formula (I), as a c-MET inhibitor of pyridone, is expected to be a new drug which is more effective than similar products in view of its remarkable inhibitory activity in vivo and in vitro and good metabolic stability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明公开了一种c-MET抑制剂的晶型及其盐型和制备方法，具体涉及式(I)所示化合物及其盐型、晶型，还包括所述晶型和盐型在制备***药物中的应用。

Description

一种c-MET抑制剂的晶型及其盐型和制备方法
本申请要求申请日为2018年4月26日的中国专利申请CN201810387693.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种c-MET抑制剂的晶型及其盐型和制备方法，还包括所述晶型和盐型在制备***药物中的应用。
背景技术
原癌基因Met编码的c-Met是一种具有高度结合性的受体酪氨酸激酶，属于RON亚族，是散射因子或肝细胞生长因子(HGF)唯一已知的受体。HGF与c-Met胞外域结合后，诱导c-Met发生磷酸化，在C-端多功能区域募集多种细胞间质因子，如GAB1(生长因子受体结合蛋白-1)、GAB2(生长因子受体结合蛋白-2)等，进一步吸引SHP2、PI3K等分子结合在此，由此激活RAS/MAPK、PI3K/AKT、JAK/STAT通路等，从而调控着细胞的生长、迁移、增殖和存活。c-Met通路异常会诱发肿瘤的发生和转移，在多种人类恶性肿瘤如膀胱癌、胃癌、肺癌、乳腺癌中发现异常高水平表达的c-Met。
此外，c-Met还与肿瘤对多种激酶抑制剂的耐药性相关。c-Met和多种膜受体之间存在相互作用(crosstalk)，构成了复杂的网络体系。c-Met和黏附受体CD44之间的相互作用，放大了信号肽的应答作用；与脑蛋白受体从蛋白的相互作用激活了非依赖配体HGF的c-Met，增强了侵袭作用；与促凋亡受体FAS之间的相互作用加快了细胞凋亡；与多种受体酪氨酸激酶如EGFR、VEGFR等的作用使得彼此间激活受到调控，血管生成过程受到影响。c-Met与这些膜受体之间的相互作用促进了肿瘤的发生和转移，诱导产生耐药性。
目前针对c-Met通路的抗肿瘤治疗药物有两种:一种是抗HGF或c-Met的单克隆抗体；一种是针对c-Met的小分子抑制剂。在研的或已进入临床研究的c-Met小分子抑制剂有PF-2341066、EMD-1214063、XL-184或ARQ-197等。其中，Tepotinib抗肿瘤活性最优，对多种c-MET高表达的肿瘤细胞有很强的抑制作用(c-MET酶活性IC 50＝3.67nM,MHCC97-H细胞IC 50＝6.2nM)，目前已经进入临床Ⅱ期研究阶段。但是，Tepotinib虽然具有高选择性，其仍然存在代谢稳定性不高、体内清除率大的缺点。因此，临床亟需代谢稳定的c-Met抑制剂来弥补这一缺憾。
发明内容
本发明提供式(I)所示化合物的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.54°±0.2°、13.70°±0.2°、17.84±0.2°、21.24°±0.2°和26.62±0.2°。
Figure PCTCN2019084515-appb-000001
在本发明的一些方案中，上述A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.54°±0.2°、13.70°±0.2°、15.14±0.2°、17.84±0.2°、18.40°±0.2°、21.24°±0.2°、24.06°±0.2°、26.62±0.2°和27.44±0.2°。
在本发明的一些方案中，上述A晶型，其X射线粉末衍射图谱如图1所示。
在本发明的一些方案中，上述A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.538°、9.021°、11.300°、13.699°、15.141°、16.640°、17.840°、18.399°、19.039°、19.620°、20.441°、21.241°、22.598°、24.060°、24.962°、25.660°、26.621°、27.440°、28.258°、29.159°、31.081°、32.465°、34.780°、35.400°、36.920°和38.760°。
在本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示。
表1 式(I)化合物A晶型的XRPD解析数据
Figure PCTCN2019084515-appb-000002
在本发明的一些方案中，上述A晶型也可以用DSC进行表征，起始温度为171.90℃，峰值温度为173.09℃。
在本发明的一些方案中，上述A晶型，其差示扫描量热曲线在171.90℃±3℃处有一个吸热峰。
在本发明的一些方案中，上述A晶型，其差示扫描量热曲线图谱如图2所示。
在本发明的一些方案中，上述A晶型也可以用TGA进行表征，TGA图谱显示加热至223.23℃时，重量减少了0.1870％，加热至305.06℃时，重量又减少了10.03％，在205.06℃以后开始出现较大的重量损失。
在本发明的一些方案中，上述A晶型，其热重分析曲线在223.23℃±3℃时，失重达0.1870％，在305.06℃±3℃时，失重达10.22％。
在本发明的一些方案中，上述A晶型，其热重分析曲线图谱如图3所示。
本发明的一些方案中，上述A晶型的红外光谱图包含在3046cm -1±5cm -1、2938cm - 1±5cm -1、2914cm -1±5cm -1、2884cm -1±5cm -1、2849cm -1±5cm -1、2780cm -1±5cm -1、2734cm -1±5cm -1、2679cm -1±5cm -1、2242cm -1±5cm -1、1732cm -1±2cm -1、1716cm -1±2cm -1、1671cm - 1±2cm -1、1631cm -1±2cm -1、1595cm -1±2cm -1、1556cm -1±2cm -1、1547cm -1±2cm -1、1507cm - 1±2cm -1、1482cm -1±2cm -1、1387cm -1±2cm -1、1070cm -1±2cm -1和1196cm -1±2cm -1处的特征吸收峰。
本发明还提供式(II)所示化合物。
Figure PCTCN2019084515-appb-000003
本发明还提供式(II)所示化合物的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.34°±0.2°、12.99°±0.2°、15.35°±0.2°和25.50°±0.2°。
在本发明的一些方案中，上述B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.34°±0.2°、6.50°±0.2°、8.65°±0.2°、10.82°±0.2°、12.99°±0.2°、15.35°±0.2°、17.96°±0.2°和25.50°±0.2°。
在本发明的一些方案中，上述B晶型，其X射线粉末衍射图谱如图4所示。
在本发明的一些方案中，上述B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.335°、6.502°、8.645°、10.816°、12.986°、15.349°、15.782°、16.109°、17.955°、18.447°、19.057°、19.534°、19.816°、20.531°、21.16°、22.265°、22.752°、23.907°、24.407°、 25.499°、26.248°、26.886°、27.725°、28.004°、28.653°、29.127°、29.779°、30.432°、31.064°、33.734°和37.02°。
在本发明的一些方案中，上述B晶型的XRPD图谱解析数据如表2所示。
表2 式(II)化合物B晶型的XRPD解析数据
Figure PCTCN2019084515-appb-000004
在本发明的一些方案中，上述B晶型，其差示扫描量热曲线在43.98℃±3℃和219.64℃±3℃处有吸热峰。
在本发明的一些方案中，上述B晶型，其差示扫描量热曲线图谱如图5所示。
在本发明的一些方案中，上述B晶型，其热重分析曲线在73.64℃±3℃时，失重达0.5270％，在230.90℃±3℃时，失重达1.542％。
在本发明的一些方案中，上述B晶型，其热重分析曲线图谱如图6所示。
本发明还提供式(III)所示化合物。
Figure PCTCN2019084515-appb-000005
本发明还提供式(III)所示化合物的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.94°±0.2°、19.08°±0.2°、21.05°±0.2°和24.73°±0.2°。
在本发明的一些方案中，上述C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.94°±0.2°、9.94°±0.2°、17.29°±0.2°、18.04°±0.2°、19.08°±0.2°、21.05°±0.2°、24.12°±0.2°和24.73°±0.2°。
在本发明的一些方案中，上述C晶型，其X射线粉末衍射图谱如图7所示。
在本发明的一些方案中，上述C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.94°、9.94°、13.36°、15.271°、16.83°、17.286°、18.038°、18.767°、19.082°、20.605°、21.054°、21.884°、22.615°、23.228°、24.118°、24.728°、25.182°、25.813°、28.182°、30.757°、31.498°、33.318°、33.77°和34.595°。
在本发明的一些方案中，上述C晶型的XRPD图谱解析数据如表3所示。
表3 式(III)化合物C晶型的XRPD解析数据
Figure PCTCN2019084515-appb-000006
在本发明的一些方案中，上述C晶型，其差示扫描量热曲线在198.16℃±3℃处有一 个吸热峰。
在本发明的一些方案中，上述C晶型，其差示扫描量热曲线图谱如图8所示。
在本发明的一些方案中，上述C晶型，其热重分析曲线在204.73℃±3℃时，失重达0.4541％。
在本发明的一些方案中，上述C晶型，其热重分析曲线图谱如图9所示。
本发明还提供了一种上述化合物或晶型在制备治疗癌症药物中的应用。
本发明还提供了一种用于治疗癌症的上述化合物或晶型。
本发明还提供了一种通过给予上述化合物或晶型治疗癌症的方法。
本发明中，术语癌症优选肝癌。
技术效果
本发明所述式(I)所示化合物的盐型及晶型的制备工艺简单，并且所述晶型相对比较稳定、受高温和高湿，便于制剂。
定义和说明
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。
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。
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。
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。
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。
本发明采用下述缩略词：
(R)-CBS：(3aR)-1-甲基-3,3-二苯基-3a,4,5,6-四氢吡咯[1,2-c][1,3,2]恶唑硼烷；
DIEA：N,N-二异丙基乙基胺；
DMF：N,N-二甲基甲酰胺；
THF：四氢呋喃；
Pd(dppf)Cl2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯；
Pd(PPh3)2Cl2：双(三苯基膦)二氯化钯。
化合物经手工或者
Figure PCTCN2019084515-appb-000007
软件命名，市售化合物采用供应商目录名称。
本发明粉末X-射线衍射(X-raypowderdiffractometer,XRPD)方法
仪器型号：BrukerD8AdvanceX-射线衍射仪
测试方法：大约10～20mg样品用于XRPD检测。
详细的XRPD参数如下：
光管：Cu,kα,
Figure PCTCN2019084515-appb-000008
光管电压：40kV，光管电流：40mA
发散狭缝：0.60mm
探测器狭缝：10.50mm
防散射狭缝：7.10mm
扫描范围：3或4-40deg
步径：0.02deg
步长：0.12秒
样品盘转速：15rpm
本发明差热分析(DifferentialScanningCalorimeter,DSC)方法
仪器型号：TADSCQ2000差示扫描量热仪
测试方法：取样品(0.5～1mg)置于DSC铝锅内进行测试，在50mL/minN2条件下，以10℃/min的升温速率，加热样品从室温(25℃)到300℃或350℃。
本发明热重分析(ThermalGravimetricAnalyzer,TGA)方法
仪器型号：TAQ5000热重分析仪
测试方法：取样品(2～5mg)置于TGA铂金锅内进行测试，在25mL/minN2条件下，以10℃/min的升温速率，加热样品从室温(25℃)到300℃，350℃或失重20％。
本发明动态气体吸附仪(DVS)
仪器型号：DVSAdvantage-1(SMS)
测试条件：大约10-15mg样品用于DVS检测。
平衡dm/dt：0.01％/min：(时间：10min最大180min)
干燥：0％RH，120min
RH(％)测量梯度：10％
RH(％)测量梯度范围：0％～90％～0％
下列表4为引湿性的判断标准：
表4 引湿性的判断标准
引湿性分类 引湿增重*
潮解 吸收足量水分形成液体
极具引湿性 引湿增重不小于15％
有引湿性 引湿增重小于15％但不小于2％
略有引湿性 引湿增重小于2％但不小于0.2％
无或几乎无引湿性 引湿增重小于0.2％
*在25℃/80％RH下的引湿增重。
本发明高效液相色谱(HighPerformanceLiquidChromatograph,HPLC)方法
仪器型号：安捷伦1200高效液相色谱仪
分析方法如下：
表5 有关物质含量测试的HPLC分析方法
Figure PCTCN2019084515-appb-000009
附图说明
图1为式(I)化合物A晶型的XRPD谱图。
图2为式(I)化合物A晶型的DSC谱图。
图3为式(I)化合物A晶型的TGA谱图。
图4为式(II)化合物B晶型的XRPD谱图。
图5为式(II)化合物B晶型的DSC谱图。
图6为式(II)化合物B晶型的TGA谱图。
图7为式(III)化合物C晶型的XRPD谱图。
图8为式(III)化合物C晶型的DSC谱图。
图9为式(III)化合物C晶型的TGA谱图。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
实施例1：式(I)化合物A晶型的制备
Figure PCTCN2019084515-appb-000010
Figure PCTCN2019084515-appb-000011
1-B的制备：
-30℃氮气保护，搅拌下，向化合物1-A(4千克，25.19摩尔)的二氯甲烷(20升)溶液中滴加二异丙基乙基胺(2.9千克，22.67摩尔)和甲烷磺酰氯(2.2千克，19.51摩尔)。滴加完毕后在-10℃下搅拌1小时。LCMS检测反应完毕。反应液用饱和氯化铵溶液(12升*2)洗涤，无水硫酸钠干燥，过滤并浓缩，得到中间体1-B直接用于下一步骤无需进一步纯化。LCMS(ESI)m/z:316.0[M+Na] +
1-C的制备：
氮气保护下，往中间体1-B(5.45千克，18.58摩尔)和2-氯嘧啶-5-醇(2.42千克，18.56摩尔)的DMF(25升)液中，加入碳酸钾(1.54千克，11.15摩尔)。反应液在90℃下反应16小时，LCMS检测反应完毕。将反应液倒入水(75升)中搅拌16小时后过滤，滤饼加入水(20升)中搅拌16小时，过滤，滤饼烘干得到中间体1-C。LCMS(ESI)m/z:328.1[M+H] +； 1HNMR(400MHz,CDCl 3)δppm 1.21-1.36(m,2H)1.44-1.49(m,9H)1.81(br d,J＝12.10Hz,2H)1.91-2.08(m,1H)2.75(br t,J＝11.98Hz,2H)3.90(d,J＝6.24Hz,2H)4.01-4.37(m,2H)8.28(s,2H)
1-E的制备：
-30℃氮气保护下，往(R)-CBS(12.5升，1摩尔每升)和硼烷二甲硫醚(5升，10摩尔每升)的混合液中，加入化合物1-D(5千克，25.19摩尔)的四氢呋喃(5升)溶液。反应液在-30℃下反应1小时，LCMS检测反应完毕。向反应液中滴加甲醇(10升)淬灭反应后减压浓缩，往残余物中加入乙酸乙酯(2升)和正己烷(20)溶解后，加入盐酸(10升，2摩尔每升)并搅拌1小时，过滤，滤液用盐酸(12升*3，2摩尔每升)和饱和食盐水(15升)洗涤后，有机层用无水硫酸钠干燥，过滤，浓缩得到中间体1-E。 1HNMR(400MHz,DMSO-d 6)δppm 1.31(d,J＝6.53Hz,3H),4.61-4.84(m,1H),5.30(d,J＝4.39Hz,1H),7.25-7.31(m,1H),7.31-7.37(m,1H),7.41(brd,J＝7.65Hz,1H),7.53(s,1H).
1-F的制备：
氮气保护下，往中间体1-E(1.2千克，5.97摩尔)的甲苯(30升)液中，依次加入3-氟-1氢-吡啶-2-酮(723.39克，6.4摩尔)、三正丁基膦(1.39千克，6.88摩尔)和偶氮二甲酰二哌啶(1.74千克，6.89摩尔)。反应液升温至90℃反应2小时，LCMS检测反应完毕。反应液降温至室温后离心，滤液用盐酸(9升*2，4摩尔每升)洗涤后减压浓缩，残渣加入甲基叔丁基醚(12升)溶解后，用盐酸(9升*3，4摩尔每升)和饱和食盐水(9升*2)分别洗涤，有机相经无水硫酸钠干燥，过滤后减压浓缩，残余物加入正己烷(10升)搅拌16小时后过滤，滤饼烘干后得到中间体1-F。LCMS(ESI)m/z:297.9[M+H] +； 1HNMR(400MHz,DMSO-d 6)δppm 1.74(d,J＝7.09Hz,3H),6.10(td,J＝7.24,4.58Hz,1H),6.46(q,J＝7.01Hz,1H),6.95(dt,J＝7.09,1.53Hz,1H),7.08(ddd,J＝9.20,7.43,1.71Hz,1H),7.22-7.32(m,2H),7.43-7.53(m,2H).
1-G的制备：
氮气保护下，中间体1-F(2千克，6.75摩尔)、双联频哪醇硼酸酯(1.89千克，7.43摩尔)，双三苯基膦二氯化钯(48.51克，67.54毫摩尔)和乙酸钾(1.34千克，13.51摩尔)的1,4-二氧六环(20升)溶液升温至90℃反应2小时，LCMS检测反应完毕。化合物1-G的反应液直接用于下一步反应无需处理。
1-H的制备：
氮气保护下，向化合物1-G的反应液中依次加入中间体1-C(2.44千克，7.43摩尔)、碳酸钠(1.43千克，13.51摩尔)、Pd(dppf)Cl 2(299.60克，405.22毫摩尔)和水(4升)，反应液升温至100℃反应16小时。LCMS检测反应完毕。反应液降温至80℃后过滤，搅拌下往滤液中滴加水(12升)搅拌16小时后过滤，滤饼经水洗、干燥后加入甲基叔丁基醚(35升)和丙酮(1升)并搅拌16小时，过滤，收集滤饼烘干后得中间体1-H。LCMS(ESI)m/z:531.1[M+Na] +； 1HNMR(400MHz,DMSO-d 6)δppm 1.10-1.26(m,2H)1.40(s,9H)1.77(brd,J＝7.15Hz,5H)1.97(brd,J＝3.64Hz,1H)2.63-2.90(m,2H)3.88-4.03(m,2H)4.06(d,J＝6.40Hz,2H),6.17-6.36(m,2H),7.31-7.63(m,4H),8.17-8.30(m,2H),8.64(s,2H)。
1-I的制备：
30℃氮气保护下，往中间体1-H(2.63千克，5.17摩尔)的DMF(27升)溶液加入1，3-二溴-5,5-二甲基咪唑啉-2,4-二酮(1千克，3.5摩尔)，反应液30℃反应1小时，LCMS 检测反应完毕。向反应液中滴加水(16.2升)后搅拌16小时，过滤，滤饼经水洗涤后干燥，滤饼加入丙酮(17.6升)中，加热至回流搅拌1小时后滴加水(12升)并搅拌16小时，过滤，滤饼烘干后得中间体1-I。LCMS(ESI)m/z:611.1[M+Na] +； 1HNMR(400MHz,DMSO-d 6)δppm 1.10-1.27(m,2H),1.40(s,9H),1.71-1.87(m,5H),1.93-2.06(m,1H),2.67-2.85(m,2H),3.99(brd,J＝11.67Hz,2H),4.07(brd,J＝6.27Hz,2H),6.23(q,J＝6.86Hz,1H),7.42-7.57(m,2H),7.71(dd,J＝9.29,1.76Hz,1H),7.85(s,1H),8.18-8.30(m,2H),8.65(s,2H)。
1-J的制备：
氮气保护下，中间体1-I(2.1千克，3.58摩尔)、双联频哪醇硼酸酯(1.82千克，7.17摩尔)，四三苯基膦钯(127.09克，110毫摩尔)和乙酸钾(719.68克，7.16摩尔)的1,2-二甲氧基乙烷(21升)溶液升温至85℃反应2小时，LCMS检测反应完毕。化合物1-K的反应液直接用于下一步反应无需处理。
1-K的制备：
氮气保护下，向化合物1-J的反应液中依次加入2-溴吡啶-4-甲腈(707克，3.86摩尔)、碳酸钠(741克，6.99摩尔)、四三苯基膦钯(163克，141毫摩尔)和水(4.2升)，反应液升温至85℃反应16小时。LCMS检测反应完毕。反应液降温至50℃后向反应液中滴加水(12.6升)并搅拌16小时，过滤，滤饼烘干后加入异丙醇：水＝30:1的混合溶剂打浆三次后收集固体烘干后得到中间体1-K。LCMS(ESI)m/z:633.2[M+Na] +； 1HNMR(400MHz,DMSO-d 6)δppm 1.09-1.26(m,2H),1.40(s,9H),1.76(brd,J＝11.17Hz,2H),1.91(d,J＝7.15Hz,3H),1.93-2.05(m,1H),2.57-2.92(m,2H)3.98(brd,J＝10.92Hz,2H),4.05(d,J＝6.40Hz,2H),6.35(q,J＝7.03Hz,1H),7.47-7.56(m,2H),7.73(dd,J＝5.02,1.00Hz,1H),8.19(dd,J＝11.29,2.13Hz,1H),8.22-8.27(m,1H),8.30(s,1H),8.40(s,1H),8.48(s,1H),8.64(s,2H),8.79(d,J＝5.02Hz,1H)。
式(I)化合物的制备：
氮气保护下，中间体1-K(2.4千克，3.93摩尔)分批加入甲烷磺酸(758.66克，7.89摩尔)的甲醇(7.2升)溶液中，反应液加热至50℃搅拌2小时，LCMS检测显示中间体1-K消耗完毕后依次向反应液中加入甲醇(16.8升)、乙酸钠(645.54克，7.87摩尔)、甲醛(639.63克，7.88摩尔，37％水溶液)和三乙酰氧基硼氢化钠(1.25千克，5.91摩尔)，反应液搅拌反应16小时，LCMS检测反应完毕。反应液过滤，向滤液中依次滴加氨水(3 升)和水(4.5升)并搅拌6小时，过滤，滤饼经水洗涤后烘干。固体加入四氢呋喃(13升)中，加热至50℃溶解，加入硫脲树脂(650克)搅拌2小时后过滤，向滤液中加入硫脲树脂(650克)于50℃搅拌2小时后过滤，滤液加入硫脲树脂(650克)于50℃搅拌16小时后过滤，再向滤液中加入活性炭粉(150克)并加热至66℃搅拌2小时，过滤，滤液减压浓缩，残渣加入乙酸乙酯(16.8升)，回流温度下搅拌至溶清，趁热过滤，滤液缓慢降温至20℃后过滤，收集滤饼烘干后得到式(I)化合物。LCMS(ESI)m/z:525.2[M+H] +； 1HNMR(400MHz,CD 3OD)δppm 8.72(d,J＝5.01Hz,1H),8.52(s,2H),8.38(s,1H),8.24-8.33(m,2H),8.06-8.15(m,2H),7.46-7.57(m,3H),6.49(q,J＝7.17Hz,1H),4.03(d,J＝5.75Hz,2H),2.95(brd,J＝11.74Hz,2H),2.31(s,3H),2.04-2.14(m,2H),1.96(d,J＝7.09Hz,3H),1.80-1.92(m,3H),1.40-1.58(m,2H).
式(I)化合物A晶型的制备：
将式(I)化合物(850克)加入乙酸乙酯(6.8升)中，加热至回流温度下搅拌2小时后反应液缓慢降温至35℃并搅拌16小时，过滤，收集滤饼烘干，得到式(I)化合物A晶型。 1H NMR(400MHz,DMSO-d 6)δppm 1.23-1.40(m,2H),1.65-1.78(m,3H),1.79-1.89(m,2H),1.91(d,J＝7.21Hz,3H),2.15(s,3H),2.78(br d,J＝11.25Hz,2H),4.03(d,J＝5.99Hz,2H),6.35(d,J＝7.09Hz,1H),7.46-7.58(m,2H),7.73(dd,J＝5.01,1.22Hz,1H),8.18(dd,J＝11.31,2.14Hz,1H),8.21-8.27(m,1H),8.30(s,1H),8.40(d,J＝1.34Hz,1H),8.48(s,1H),8.63(s,2H),8.79(d,J＝5.01Hz,1H).
实施例2：式(II)化合物B晶型的制备
Figure PCTCN2019084515-appb-000012
称量400mg式(I)化合物加入40mL小瓶中，加入6mL的THF，将样品置于磁力搅拌器上(40℃)进行搅拌5min,使其溶解，然后缓慢加入适量的盐酸(式(I)化合物与盐酸的摩尔比为1:1.05，THF稀释后加入)并观察现象。将样品置于磁力搅拌器上(40℃)进行搅拌过夜。反应液有白色固体析出。将样品溶液快速离心，弃去上清液，将所得固体置于30℃真空干燥箱干燥过夜得式(II)化合物B晶型。
实施例3：式(III)化合物C晶型的制备
Figure PCTCN2019084515-appb-000013
称量400mg式(I)化合物加入40mL小瓶中，加入6mL的THF，将样品置于磁力搅拌器上(40℃)进行搅拌5min,使其溶解，然后缓慢加入适量的磷酸(式(I)化合物与磷酸的摩尔比为1:1.05，THF稀释后加入)并观察现象。将样品置于磁力搅拌器上(40℃)进行搅拌过夜。反应液有白色固体析出。将样品溶液快速离心，弃去上清液，将所得固体置于30℃真空干燥箱干燥过夜得式(III)化合物C晶型。 1HNMR(400MHz,DMSO-d 6)δppm1.49(q,J＝10.88Hz,2H),1.71-2.05(m,6H),2.28-2.49(m,6H),3.07(brd,J＝10.79Hz,2H),4.06(brd,J＝6.27Hz,2H),6.34(q,J＝6.94Hz,1H),7.44-7.62(m,2H),7.73(dd,J＝4.89,1.13Hz,1H),8.18(dd,J＝11.29,2.26Hz,1H),8.21-8.27(m,1H),8.29(s,1H),8.40(s,1H),8.47(s,1H),8.64(s,2H),8.78(d,J＝5.02Hz,1H)。
实施例4：式(I)化合物A晶型的稳定性试验
称取式(I)化合物A晶型约10mg放置于稳定性试验条件下，分别在10天、1月和2月取样分析，实验结果见表6。
表6 式(I)化合物A晶型的稳定性试验结果
Figure PCTCN2019084515-appb-000014
注：空白表示未检出
从实验结果可以看出，式(I)化合物A晶型在高温和高湿条件下杂质含量无显著变化，稳定性良好。
实施例5：式(II)化合物B晶型的稳定性试验
称取式(II)化合物B晶型约10mg放置于稳定性试验条件下，分别在5天、10天、1月取样分析，实验结果见表7。
表7 式(II)化合物B晶型的稳定性试验结果
Figure PCTCN2019084515-appb-000015
注：空白表示未检出
从实验结果可以看出，式(II)化合物B晶型在高温和光照条件稳定。
实施例6：式(III)化合物C晶型的稳定性试验
称取式(III)化合物C晶型约10mg放置于稳定性试验条件下，分别在5天、10天、1月取样分析，实验结果见表8。
表8 式(III)化合物C晶型的稳定性试验结果
Figure PCTCN2019084515-appb-000016
Figure PCTCN2019084515-appb-000017
注：空白表示未检出
从实验结果可以看出，式(III)化合物C晶型分别在高温和高湿条件下相对稳定。
实施例7：式(I)化合物A晶型的吸湿性研究
取3只干燥的具塞玻璃称量瓶(外径为50mm，高为30mm)置于下部放置氯化铵饱和溶液的干燥器内，称量瓶敞口放置，盖好干燥器盖子，然后将干燥器置于25℃的恒温箱内，放置过夜。
称量瓶放置过夜后取出精密称定重量，分别为m 11、m 12和m 13。
取式(Ⅰ)化合物A晶型适量，平铺于已称定重量的称量瓶中(样品的厚度约1mm)，然后精密称定重量，分别为m21、m 22和m 23。
将称量瓶敞口放置，并于瓶盖一起置于下部放置氯化铵饱和溶液的干燥器内，盖好干燥器盖子，然后将干燥器置于25℃的恒温箱内，放置24小时。
放置24小时后，盖好称量瓶盖，然后取出精密称定重量，分别记为m 31、m 32和m 33。
引湿性增重计算，计算公式如下：
增重百分率＝100％×(m 3-m 2)/(m 2-m 1)
表9式(I)化合物A晶型的引湿情况表
Figure PCTCN2019084515-appb-000018
根据引湿性测试结果，式(I)化合物A晶型的引湿平均值0.060％(<0.2％)，故式 (I)化合物A晶型无或几乎无引湿性。
实施例8：式(I)化合物A晶型的溶解度试验
称取10mg式(I)化合物A晶型放入玻璃瓶中，加入1mL溶剂，于25℃±2℃下，每隔5分钟强力振摇30秒，观察30分钟内的溶解现象。记录相应数据于表格中。
对于不溶解的样品，另称取1mg式(I)化合物的晶型放入玻璃瓶中，加入适当溶剂，于25℃±2℃下，每隔5分钟强力振摇30秒，观察30分钟内的溶解现象。记录相应数据于表10中。
表10 式(I)化合物A晶型在不同溶剂中的溶解度情况
Figure PCTCN2019084515-appb-000019
从实验结果可以看出，式(I)化合物A晶型在水或N-甲基吡咯烷酮中易溶，在0.1NHCl中溶解，在四氢呋喃或三氟乙酸中略溶，在乙酸乙酯、乙腈或乙醇中极微溶解；在正己烷、二乙胺或0.1N氢氧化钠溶液中几乎不溶或不溶。
实施例9：式(I)化合物的酶学活性测试
试剂和耗材:
c-MET(invitrogenPV3143)
Tracer236(LotNumber:10815978)
Eu-Anti-HisAB(MAbAnti6HIS-K)
PerkinElmer公司Envison检测665nm和615nm
384孔板_检测板(PerkinElmer#6007299)
实验原理:
本实验利用Lantha Screen TMEu激酶结合实验(Lantha Screen TMEu Kinase Binding Assay)，如图1所示，通过添加Eu标记抗体检测AlexaFluor偶联物或激酶“示踪剂”结 合。示踪剂和抗体与激酶的结合导致高度的FRET，反之使用激酶抑制化合物代替示踪剂会造成FRET丢失。
实验方法:
1)稀释抗体Eu-Anti-HisAB，酶c-MET，示踪剂Tracer236。
2)化合物配制：将10mM受试化合物及参考化合物用100％DMSO稀释至0.667mM，使用全自动微孔板预处理***ECHO进行3倍稀释，8个浓度梯度，设置双复孔，每孔75nL。
3)在化合物板中加入7.5uL抗体(1/375nM)与激酶(10nM)混合物，再加入7.5uLTracer(60nM)。反应终浓度：c-MET:5nM，Tracer236:30nM，Eu-Anti-HisAB(MAbAnti6HIS-K):1/750nM。
4)4℃孵育60分钟后，用多标记微孔板检测仪Envision读数(将665nm/615nm信号值用Prism5进行数据分析；Ex激发光:Lasermirror446Em发射光:615and665nM)。
实验结果:见表11。
表11 式(I)化合物对激酶活性抑制的IC 50值
受试化合物 c-METIC 50(nM)
式(I)化合物 1.09
实验结果显示，式(I)化合物对c-MET酶有较强的抑制活性。
实施例10：式(I)化合物的细胞增殖抑制实验
本实验拟研究式式(I)化合物对AKT过度表达的***癌细胞LNCaP的抑制作用。
试剂和耗材:
1.细胞培养：DMEM培养基、胎牛血清、DPBS
2.细胞系：MHCC97-H
3.检测试剂：活细胞检测试剂盒CellTiter-Glo
4.其他主要耗材及试剂：化合物稀释板，中间板，检测板，DMSO
实验方法:
1.制备细胞板
将MHCC97-H细胞分别种于384孔板中，每孔包含500个细胞。细胞板置于二氧化碳培养箱中过夜培养。
2.准备化合物
用Echo进行4倍稀释，9个化合物浓度，设置双复孔实验。
3.化合物处理细胞
将化合物转移到细胞板中，化合物起始浓度为10μM。细胞板置于二氧化碳培养箱中培养3天。
4.检测
向细胞板中加入Promega Cell Titer-Glo试剂，室温孵育10分钟使发光信号稳定。采用Perkin Elmer Envision多标记分析仪读数。
实验结果:见表12。
表12 式(I)化合物对细胞增殖抑制的IC 50值
Figure PCTCN2019084515-appb-000020
本实验结果显示：式(I)化合物对MHCC97H细胞的显示出较好的抑制活性。
实施例11：式(I)化合物的体内药效研究
细胞培养：
MHCC97H细胞体外单层培养，培养条件为RPMI1640培养基中加10％热灭活胎牛血清、1％青霉素-链霉素双抗，37℃5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞呈指数生长期时，收取细胞，计数，接种。
动物：
BALB/c裸小鼠，雄性。6－8周龄，体重18-22克。
肿瘤接种：
将0.2ml含5×10^6个MHCC97H的细胞悬液皮下接种于每只小鼠的右后背。肿瘤平均体积达到约172mm 3时开始分组给药。实验分组和给药方案见下表。
实验指标：
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效(TGI)用T-C(天)和T/C(％)评价。
实验结果:见表13。
表13 受试药物对人肝癌MHCC97H细胞异种移植瘤模型的抑瘤药效评价
(基于给药后第24天肿瘤体积计算得出)
Figure PCTCN2019084515-appb-000021
注：a.平均值±SEM；b.p值根据肿瘤体积计算。
结论：式(I)化合物在MHCC97H肝癌细胞皮下异种移植肿瘤模型的药效实验中显示比Tepotinib更好的肿瘤抑制作用。
式(I)化合物比Tepotinib有更好的代谢稳定性。式(I)化合物在人、大鼠、和小鼠三个物种肝微粒代谢的t 1/2分别为62.1分钟、36.5分钟、49.1分钟，同等条件下，tepotinib在人、大鼠和小鼠三个物种肝微粒代谢的t 1/2分别为48.3分钟、10.5分钟、12.4分钟。本发明化合物半衰期增大，针对靶点的作用时间延长，代谢稳定性增强，具有更优异的抑制活性。半衰期的延长将会使血药浓度维持更长时间，由此可以预测，该化合物运用于肿瘤治疗，与同类药物相比，将减少病人的服药量或服药次数，病人依从性将得到显著提高。
由于c-MET与HGF结合后,激活MAPK、PI3K/AKT、Cdc42/Rac1等通路,导致癌细胞存活与增殖,从而加速肿瘤生长。因此，作为c-MET抑制剂的吡啶酮类化合物在肝癌、非小细胞肺癌、胃癌等靶向治疗药物中具有较大的应用前景。特别是在治疗肝癌上，该类化合物对c-MET高表达的肝癌具有精准的治疗作用。所以，式(I)化合物作为吡啶酮类的c-MET抑制剂，鉴于其在体内外的显著的抑制活性及良好的代谢稳定性，有望成为比同类产品治疗效果更好的新药。

Claims (24)

  1. 式(I)所示化合物的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.54°±0.2°、13.70°±0.2°、17.84±0.2°、21.24°±0.2°和26.62±0.2°；
    Figure PCTCN2019084515-appb-100001
  2. 如权利要求1所述的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.54°±0.2°、13.70°±0.2°、15.14±0.2°、17.84±0.2°、18.40°±0.2°、21.24°±0.2°、24.06°±0.2°、26.62±0.2°和27.44±0.2°。
  3. 如权利要求1或2所述的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.538°、9.021°、11.300°、13.699°、15.141°、16.640°、17.840°、18.399°、19.039°、19.620°、20.441°、21.241°、22.598°、24.060°、24.962°、25.660°、26.621°、27.440°、28.258°、29.159°、31.081°、32.465°、34.780°、35.400°、36.920°和38.760°。
  4. 根据权利要求1-3中至少一项所述的A晶型，其差示扫描量热曲线在171.90℃±3℃处有一个吸热峰的起始点。
  5. 根据权利要求1-4中至少一项所述的A晶型，其差示扫描量热曲线图谱如图2所示。
  6. 根据权利要求1-5中至少一项所述的A晶型，其热重分析曲线在223.23℃±3℃时，失重达0.1870％，在305.06℃±3℃时，失重达10.22％。
  7. 根据权利要求1-6中至少一项所述的A晶型，其热重分析曲线图谱如图3所示。
  8. 式(II)所示化合物
    Figure PCTCN2019084515-appb-100002
  9. 如权利要求8所述的式(II)所示化合物的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.34°±0.2°、12.99°±0.2°、15.35°±0.2°和25.50°±0.2°；
    Figure PCTCN2019084515-appb-100003
  10. 如权利要求9所述的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.34°±0.2°、6.50°±0.2°、8.65°±0.2°、10.82°±0.2°、12.99°±0.2°、15.35°±0.2°、17.96°±0.2°和25.50°±0.2°。
  11. 如权利要求9或10所述的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.335°、6.502°、8.645°、10.816°、12.986°、15.349°、15.782°、16.109°、17.955°、18.447°、19.057°、19.534°、19.816°、20.531°、21.16°、22.265°、22.752°、23.907°、24.407°、25.499°、26.248°、26.886°、27.725°、28.004°、28.653°、29.127°、29.779°、30.432°、31.064°、33.734°和37.02°。
  12. 根据权利要求9-11中至少一项所述的B晶型，其差示扫描量热曲线在在43.98℃±3℃和219.64℃±3℃处有吸热峰的起始点。
  13. 根据权利要求9-12中至少一项所述的B晶型，其差示扫描量热曲线图谱如图5所示。
  14. 根据权利要求9-11中至少一项所述的B晶型，其热重分析曲线在其热重分析曲线在73.64℃±3℃时，失重达0.5270％，在230.90℃±3℃时，失重达1.542％。
  15. 根据权利要求9-14中至少一项所述的B晶型，其热重分析曲线图谱如图6所示。
  16. 式(III)所示化合物
    Figure PCTCN2019084515-appb-100004
  17. 如权利要求16所述的式(III)所示化合物的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.94°±0.2°、19.08°±0.2°、21.05°±0.2°和24.73°±0.2°；
    Figure PCTCN2019084515-appb-100005
  18. 如权利要求17所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.94°±0.2°、9.94°±0.2°、17.29°±0.2°、18.04°±0.2°、19.08°±0.2°、21.05°±0.2°、24.12°±0.2°和24.73°±0.2°。
  19. 如权利要求17或18所述的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.94°、9.94°、13.36°、15.271°、16.83°、17.286°、18.038°、18.767°、19.082°、20.605°、21.054°、21.884°、22.615°、23.228°、24.118°、24.728°、25.182°、25.813°、28.182°、30.757°、31.498°、33.318°、33.77°和34.595°。
  20. 根据权利要求17-19中至少一项所述的C晶型，其差示扫描量热曲线在198.16℃±3℃处有一个吸热峰的起始点。
  21. 根据权利要求17-20中至少一项所述的C晶型，其差示扫描量热曲线图谱如图8所示。
  22. 根据权利要求17-19中至少一项所述的C晶型，其热重分析曲线在204.73℃±3℃时，失重达0.4541％。
  23. 根据权利要求17-22中至少一项所述的C晶型，其热重分析曲线图谱如图9所示。
  24. 根据权利要求1-23中至少一项所述的化合物或晶型，其在制备治疗癌症药物中的应用。
PCT/CN2019/084515 2018-04-26 2019-04-26 一种c-MET抑制剂的晶型及其盐型和制备方法 WO2019206268A1 (zh)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU2019260240A AU2019260240B2 (en) 2018-04-26 2019-04-26 Crystal form of c-MET inhibitor and salt form thereof and preparation method therefor
CA3098336A CA3098336C (en) 2018-04-26 2019-04-26 Crystal form of c-met inhibitor and salt form thereof and preparation method therefor
EA202092558A EA039713B1 (ru) 2018-04-26 2019-04-26 Кристаллическая форма ингибитора c-met, его солевая форма и способ их получения
EP19791723.0A EP3786155B1 (en) 2018-04-26 2019-04-26 Crystal form of c-met inhibitor and salt form thereof and preparation method therefor
US17/049,579 US11465986B2 (en) 2018-04-26 2019-04-26 Crystal form of c-MET inhibitor and salt form thereof and preparation method therefor
ES19791723T ES2962679T3 (es) 2018-04-26 2019-04-26 Forma cristalina del inhibidor de c-MET y su forma salina y método de preparación de las mismas
KR1020207033747A KR102374933B1 (ko) 2018-04-26 2019-04-26 c-Met 억제제의 결정형과 이의 염 형태 및 제조 방법
JP2020560239A JP7118349B2 (ja) 2018-04-26 2019-04-26 ｃ－ＭＥＴ阻害剤の結晶形、及びその塩形、並びに調製方法
CN201980027588.0A CN112004801B (zh) 2018-04-26 2019-04-26 一种c-MET抑制剂的晶型及其盐型和制备方法
ZA2020/07037A ZA202007037B (en) 2018-04-26 2020-11-11 Crystal form of c-met inhibitor and salt form thereof and preparation method therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810387693.2 2018-04-26
CN201810387693 2018-04-26

Publications (1)

Publication Number Publication Date
WO2019206268A1 true WO2019206268A1 (zh) 2019-10-31

Family

ID=68294814

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/084515 WO2019206268A1 (zh) 2018-04-26 2019-04-26 一种c-MET抑制剂的晶型及其盐型和制备方法

Country Status (12)

Country Link
US (1) US11465986B2 (zh)
EP (1) EP3786155B1 (zh)
JP (1) JP7118349B2 (zh)
KR (1) KR102374933B1 (zh)
CN (1) CN112004801B (zh)
AU (1) AU2019260240B2 (zh)
CA (1) CA3098336C (zh)
EA (1) EA039713B1 (zh)
ES (1) ES2962679T3 (zh)
TW (1) TWI768205B (zh)
WO (1) WO2019206268A1 (zh)
ZA (1) ZA202007037B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3109746C (en) * 2018-08-23 2023-07-11 Fujian Cosunter Pharmaceutical Co., Ltd. Crystal form of tri-cycle compound and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1930126A (zh) * 2004-03-05 2007-03-14 万有制药株式会社 吡啶酮衍生物

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007032507A1 (de) 2007-07-12 2009-04-02 Merck Patent Gmbh Pyridazinonderivate
DE102008062826A1 (de) 2008-12-23 2010-07-01 Merck Patent Gmbh Pyridazinonderivate
KR101829595B1 (ko) * 2009-01-08 2018-02-14 메르크 파텐트 게엠베하 3-（1-｛3-［5-（1-메틸-피페리딘-4일메톡시）-피리미딘-2-일］-벤질｝-6-옥소-1,6-디히드로-피리다진-3-일）-벤조니트릴 히드로클로라이드 염의 신규한 다형체 및 이의 제조 방법
WO2013057101A1 (de) * 2011-10-17 2013-04-25 Bayer Intellectual Property Gmbh Substituierte oxadiazolylpyridinone und - pyridazinone als hif - hemmer
PL3533787T3 (pl) * 2016-10-27 2021-03-08 Fujian Cosunter Pharmaceutical Co., Ltd. Związek pirydonowy jako inhibitor c-Met

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1930126A (zh) * 2004-03-05 2007-03-14 万有制药株式会社 吡啶酮衍生物

Also Published As

Publication number Publication date
EA039713B1 (ru) 2022-03-03
EP3786155B1 (en) 2023-08-16
CN112004801A (zh) 2020-11-27
ES2962679T3 (es) 2024-03-20
JP2021522265A (ja) 2021-08-30
ZA202007037B (en) 2021-10-27
EP3786155A4 (en) 2021-05-19
CA3098336C (en) 2024-03-19
EA202092558A1 (ru) 2021-02-24
AU2019260240A1 (en) 2020-12-17
CA3098336A1 (en) 2019-10-31
EP3786155A1 (en) 2021-03-03
TW201945359A (zh) 2019-12-01
US20210238163A1 (en) 2021-08-05
JP7118349B2 (ja) 2022-08-16
US11465986B2 (en) 2022-10-11
TWI768205B (zh) 2022-06-21
CN112004801B (zh) 2023-09-08
KR20210005142A (ko) 2021-01-13
KR102374933B1 (ko) 2022-03-15
AU2019260240B2 (en) 2023-05-11

Similar Documents

Publication Publication Date Title
WO2018218963A1 (zh) 一种egfr抑制剂的药用盐及其晶型、制备方法和应用
UA105763C2 (uk) 8-ЗАМІЩЕНІ ПІРИДО[2,3-b]ПІРАЗИНИ ТА ЇХ ЗАСТОСУВАННЯ
WO2019001425A1 (zh) 一种氘代奥斯替尼衍生物及其应用
WO2019206336A1 (zh) 一种***并嘧啶类化合物的晶型、盐型及其制备方法
CN108602815A (zh) 吡啶并[1,2-a]嘧啶酮类似物、其晶型、其中间体及其制备方法
WO2023160727A1 (zh) 吲唑类化合物用于治疗银屑病的用途
WO2021023194A1 (zh) 吡嗪-2(1h)-酮类化合物的c晶型和e晶型及其制备方法
CA3069602C (en) Formylpyridine derivative having fgfr4 inhibitory activity, preparation method therefor and use thereof
WO2019206268A1 (zh) 一种c-MET抑制剂的晶型及其盐型和制备方法
US20210079021A1 (en) Crystal form and salt form of tgf-bri inhibitor and preparation method therefor
WO2021023195A1 (zh) 吡嗪-2（1h）-酮类化合物的d晶型及其制备方法
WO2023083356A1 (zh) 固体形式的氮杂稠环酰胺类化合物及其用途
WO2020238802A1 (zh) 一种c-MET/AXL抑制剂的晶型
WO2022022687A1 (zh) 含嘧啶基团的三并环类化合物的盐型、晶型及其制备方法
WO2022048545A1 (zh) 一种吡啶并嘧啶化合物的晶型
WO2022135580A1 (zh) 吡啶并吡咯类化合物的晶型、制备方法及其应用
CN109516991A (zh) 一种枸橼酸托法替尼晶型化合物及其制备方法
CN112105365A (zh) 某些化学实体、组合物和方法
WO2023093859A1 (zh) Axl激酶抑制剂的盐、其制备方法和用途
WO2020224585A1 (zh) 一种mTORC1/2双激酶活性抑制剂的盐型、晶型及其制备方法
CN114945576B (zh) 氘代噻吩并吡啶类化合物
WO2021139794A1 (zh) 一种吡咯烷基脲衍生物的晶型及其应用
WO2021190623A1 (zh) Fgfr4抑制剂的盐型、晶型及其用途
WO2023083357A1 (zh) 氮杂稠环酰胺类化合物的盐、其结晶形式及其用途
WO2020192762A1 (zh) 一种a2a受体拮抗剂的盐型、晶型及其制备方法

Legal Events

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

Ref document number: 19791723

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3098336

Country of ref document: CA

Ref document number: 2020560239

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20207033747

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2019791723

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2019791723

Country of ref document: EP

Effective date: 20201126

ENP Entry into the national phase

Ref document number: 2019260240

Country of ref document: AU

Date of ref document: 20190426

Kind code of ref document: A