WO2018049861A1 - 酪氨酸激酶抑制剂及其应用 - Google Patents

酪氨酸激酶抑制剂及其应用 Download PDF

Info

Publication number
WO2018049861A1
WO2018049861A1 PCT/CN2017/089501 CN2017089501W WO2018049861A1 WO 2018049861 A1 WO2018049861 A1 WO 2018049861A1 CN 2017089501 W CN2017089501 W CN 2017089501W WO 2018049861 A1 WO2018049861 A1 WO 2018049861A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
cancer
mmol
tyrosine kinase
Prior art date
Application number
PCT/CN2017/089501
Other languages
English (en)
French (fr)
Inventor
孙芳
占有妮
Original Assignee
上海翔锦生物科技有限公司
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 上海翔锦生物科技有限公司 filed Critical 上海翔锦生物科技有限公司
Priority to KR1020217037589A priority Critical patent/KR102382039B1/ko
Priority to EP17850066.6A priority patent/EP3511327B1/en
Priority to KR1020197010451A priority patent/KR20190045354A/ko
Priority to JP2019515307A priority patent/JP2019529435A/ja
Priority to US16/333,050 priority patent/US10882853B2/en
Priority to AU2017325641A priority patent/AU2017325641B2/en
Priority to ES17850066T priority patent/ES2902549T3/es
Publication of WO2018049861A1 publication Critical patent/WO2018049861A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to the technical field of medicine, in particular to a tyrosine kinase inhibitor and application thereof.
  • Protein kinase is a phosphotransferase that transfers the gamma phosphate of ATP to a specific amino acid residue to achieve phosphorylation of the protein, thereby achieving its physiological and biochemical functions.
  • Protein kinases have important functions in information transmission. Abnormal protein kinases are unable to transmit normal signals and may cause pathological changes such as tumor cell proliferation, cell death, inflammation, cardiovascular disease and other protein kinases. Protein kinases fall into two main categories: protein tyrosine kinase PTKs and receptor tyrosine kinase RTKs.
  • ROS1/C-MET in MET family protein kinase is an important sub-family of RTPs, also known as hHGFR and RON; ROS1/C-MET can play an important role in the growth and metabolism of the starting tumor cells. Target of clinical research.
  • ROS1/C-MET kinase inhibitors especially tyrosine kinase inhibitors of small molecule compounds, are urgently needed in the field of biomedical technology.
  • the technical problem to be solved by the present invention is to provide a tyrosine kinase inhibitor capable of inhibiting various tyrosines involved in signal transduction such as C-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC, and the like.
  • the activity of acid kinase can effectively inhibit the proliferation of tumor cells and achieve better results in clinical cancer treatment.
  • K is selected from the group consisting of a cycloalkane group Haloalkane Or N-R6; the b, d are the numbers 1, 2, 3, or 4; E, G are one of hydrogen, halogen, hydroxy, alkoxy, ketone, fluorenyl, alkyl fluorenyl, but E, G is not hydrogen at the same time; R6 is one of hydrogen, a lower halogenated alkane group, a lower halogenated cycloalkane group, a lower alkane group, and a lower cycloalkane group;
  • R1, R2, R3, R4 and R5 are each independently hydrogen, halogen, lower halogenated alkane, lower halogenated cycloalkane, lower alkane, lower cycloalkane, hydroxy, lower alkoxy, lower cycloalkoxy, lower olefin One or more of a base, a lower alkyne group;
  • X is one of CR, C-(CN), N, and the R is hydrogen, halogen, lower halogenated alkane group, lower halogenated cycloalkane group, lower alkane group, lower cycloalkane group, hydroxyl group, lower alkoxy group One of a lower cycloalkoxy group, a lower alkene group, and a lower alkyne group;
  • Y is one of O, S, N-R6 or is empty, M is O or is empty;
  • a, c represent the numbers 0, 1, 2, or 3, respectively; e is the number 1 or 2.
  • At least one of E and G is halogen F.
  • the Y is O or is empty.
  • the compound of formula (I) comprises a compound of the following specific structure:
  • composition comprising a safe and effective amount of the above compound and a pharmaceutically acceptable carrier.
  • the above acceptable carriers are non-toxic, can aid in administration and have no adverse effect on the therapeutic effect of the compound.
  • Such carriers can be any solid excipient, liquid excipient, semi-solid excipient or a gaseous excipient in an aerosol composition which is generally available to those skilled in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, stearyl glyceryl ester, sodium chloride , anhydrous skim milk, etc.
  • the liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including those derived from petroleum, animal, vegetable, or synthetic oils, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like, preferably Liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycol. It is also possible to add other adjuvants such as flavoring agents, sweeteners and the like to the composition.
  • the compounds of the invention are administered in a therapeutically effective amount, which may be administered orally, systemically (e.g., through the skin, nasally, or with a suppository) or parenterally (e.g., intramuscularly, intravenously or subcutaneously). ).
  • the preferred mode of administration is oral, which can be adjusted depending on the extent of the disease.
  • the actual amount of application (i.e., active ingredient) of a compound of the invention depends on a number of factors, such as the severity of the condition to be treated, the age and relative health of the subject being treated, the potency of the compound employed, the route and form of administration, and the like. factor.
  • the various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional methods in the pharmaceutical arts.
  • the compound is mixed with one or more carriers and then formulated into a desired dosage form such as a tablet, a pill, a capsule, a semisolid, a powder, a sustained release dosage form, a solution, a suspension, a formulation, a gas Aerosol and so on.
  • tyrosine kinase inhibitor comprising the above compound.
  • the tyrosine kinases include C-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC kinase.
  • tyrosine kinase is a currently effective antitumor drug target, and the compound of the present invention has significant tyrosine kinase inhibitory activity, it has been confirmed by experiments that these compounds have an inhibitory effect on proliferation of various cancer cells, and thus the compound of the present invention Suitable for treating a variety of cancers. Especially for lung cancer, gastric cancer, ovarian cancer, colon cancer, malignant glioma has a better therapeutic effect.
  • the compounds of the present invention have good biological activities with various signal transduction kinases such as C-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC, etc., and are associated with various signal transduction pathways, and thus The disease has therapeutic effects such as cancer, inflammation, lymphedema, diabetes, and the like.
  • signal transduction kinases such as C-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC, etc.
  • the tyrosine kinase inhibitor of the present invention can inhibit the biological activities of various signal transduction kinases such as C-MET, VEGF, and KDR, can effectively inhibit cell proliferation, and has a good therapeutic effect on various diseases such as cancer, especially Lung cancer, stomach cancer, Ovarian cancer, malignant glioma and the like have significant therapeutic effects, and the application prospect is very broad.
  • various signal transduction kinases such as C-MET, VEGF, and KDR
  • FIG. 1 is a graph showing a fitting curve for proliferation inhibition of human lung adenocarcinoma cell line HCC78 of Example 10 of the present invention
  • Figure 2 is a graph showing the fitting of proliferation inhibition of human malignant glioma cell line U87MG of Example 10 of the present invention
  • Figure 3 is a graph showing the fitting of proliferation inhibition of human gastric cancer cell MKN-45 according to Example 10 of the present invention.
  • Figure 4 is a graph showing the fitting of proliferation inhibition of human lung adenocarcinoma cell line HCC78 of Example 10 of the present invention.
  • Figure 5 is a graph showing the fitting of proliferation inhibition of human ovarian cancer cell line SK-OV-3 of Example 10 of the present invention.
  • Figure 6 is a graph showing the fitting of proliferation inhibition of human colon cancer cell HCT116 of Example 10 of the present invention.
  • Fig. 7 is a graph showing the growth inhibition fit curve of human lung adenocarcinoma cell line A549 according to Example 10 of the present invention.
  • compound A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • Step one 1.3 g, 7 mmol of compound 19 was dissolved in 50 ml of methanol, compound 19 was trans-1,2-cyclopropanedicarboxylic acid diethyl ester, and then 1 N of 1 mol/L sodium hydroxide was added to the above solution.
  • the solution was stirred at room temperature overnight; then the reaction mixture after the night was diluted with water and extracted with ethyl acetate; the organic phase extracted was washed with saturated brine, water After washing, anhydrous sodium sulfate was added to dryness, and then concentrated to dryness.
  • Step 2 1 g, 6 mmol of compound 20 was dissolved in 30 mL of dimethylformamide DMF, and then 4.6 g, 12 mmol of polypeptide condensation reagent HATU and 3 mL of triethylamine were added to the above solution, stirred at room temperature for 0.5 h, and then added.
  • Step 3 1 g, 4 mmol of compound 21 was dissolved in 30 mL of THF, and 1 N of a 1 mol/L lithium aluminum hydride LAH solution was added thereto under ice-cooling, and stirred at room temperature for 2 hours; then the uniformly stirred reaction solution was quenched with sodium sulfate decahydrate.
  • the organic phase obtained by the extraction is washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, and then evaporated and evaporated to dryness.
  • the purification was carried out to obtain 0.5 g of a colorless liquid compound 22 in a yield of 66%.
  • Compound 22 was (1s, 2s)-2-morpholinemethyl)cyclopropylmethanol, and the specific reaction formula was as follows:
  • Step 4 0.3 g, 1.7 mmol of compound 22 was dissolved in 30 mL of dichloromethane, and then 0.3 g, 3.4 mmol of N-methylpyrrole and 0.3 g of 1.7 mmol of p-toluenesulfonyl chloride were added to the above solution, and stirred at room temperature overnight. Then, the reaction solution after the night was diluted with water, and extracted with ethyl acetate; the organic phase extracted was washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness.
  • Step 5 0.1 g, 0.2 mmol of Compound A, Compound A is N-p-fluorophenyl-N-3-fluoro-4-(6-methoxy-7-hydroxyquinolin-4-)oxybenzene
  • the cyclopropane-1,1-dimethylformamide and 0.1 g of 0.3 mmol of the compound 23 are dissolved in 10 mL of acetonitrile, and then 0.2 g of 0.5 mmol of cesium carbonate is added to the above solution, and the mixture is stirred under reflux overnight; After the solution was diluted with water, extracted with ethyl acetate; the organic phase extracted was washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, and then evaporated to dryness, and evaporated to dryness.
  • Step 1 1 g, 5.2 mmol of Compound 1, Compound 1 is 3-(benzyloxymethyl)cyclobutan-1-one and 0.46 g, 5.2 mmol of morphinan was dissolved in 30 mL of dichloroethane, and then 3.3 g, 15.6 mmol of sodium borohydride and 1 drop of acetic acid were added to the above solution, and the mixture was stirred under reflux overnight; then the reaction solution after overnight was diluted with water, and acetic acid was used. Ethyl acetate extraction; the organic phase obtained by extraction is washed with saturated brine, washed with water, dried with anhydrous sodium sulfate, and then concentrated and evaporated to dryness.
  • Step 2 1 g, 3.8 mmol of Compound 2 was dissolved in 30 mL of methanol, and then 0.1 g of palladium black and 2 mL of formic acid were added to the above solution, and the mixture was stirred under reflux overnight; then, the reaction solution after overnight was diluted with water, and ethyl acetate was used.
  • the organic phase obtained by the extraction is washed with a saturated saline solution, washed with water, dried over anhydrous sodium sulfate, and then evaporated to dryness. After evaporated to dryness, the concentrated organic phase is purified by silica gel column chromatography. g, 46% yield of colorless liquid compound 3, compound 3 is 3-morpholine-cyclobutylmethanol, the specific reaction formula is as follows:
  • Step 3 0.3 g, 1.7 mmol of compound 3 was dissolved in 30 mL of dichloromethane, and then 0.3 g, 3.4 mmol of N-methylpyrrole and 0.3 g of 1.7 mmol of p-toluenesulfonyl chloride were added to the above solution, and stirred at room temperature overnight; Then, the reaction mixture after the overnight reaction was diluted with water and extracted with ethyl acetate; the organic phase extracted was washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness.
  • Step 4 0.1 g, 0.2 mmol of Compound A, Compound A is N-p-fluorophenyl-N-3-fluoro-4-(6-methoxy-7-hydroxyquinolin-4-)oxyphenyl Cyclopropane-1,1-dimethylformamide and 0.1 g, 0.3 mmol of compound 4 were dissolved in 10 mL of acetonitrile, 0.2 g, 0.5 mmol of cesium carbonate were added, and the mixture was stirred at reflux overnight; then the reaction solution after overnight was diluted with water, and acetic acid was used.
  • Step 1 1 g, 5.2 mmol of compound 6, compound 6 is 3-benzyloxycyclobutan-1-one and 0.46 g, 5.2 mmol of morphinan are dissolved in 30 mL of dichloroethane, and then 3.3 g is added to the above solution. 15.6 mmol of sodium borohydride hydride and 1 drop of acetic acid, and stirred at room temperature overnight; then, the reaction mixture after the night was diluted with water, and extracted with ethyl acetate; the extracted organic phase was washed with saturated brine, washed with water and then anhydrous sulfuric acid was added. The sodium was dried, and then concentrated to dryness.
  • Step 2 1 g, 3.8 mmol of compound 7 was dissolved in 30 mL of methanol, and then 0.1 g of palladium was added to the above solution. Black and 2 mL of formic acid were stirred at reflux overnight; then the reaction mixture was diluted with water and then extracted with ethyl acetate. The extracted organic phase was washed with saturated brine, washed with water and dried over anhydrous sodium sulfate and then evaporated. Drying; after evaporation to dryness, the above-mentioned concentrated and evaporated organic phase is purified by silica gel column chromatography to obtain 0.3 g, 46% yield of colorless liquid compound 8 and compound 8 is 3-morpholine-cyclobutanol.
  • the reaction formula is as follows:
  • Step 3 0.3 g, 1.7 mmol of compound 8 was dissolved in 30 mL of dichloromethane, and then 0.3 g, 3.4 mmol of N-methylpyrrole and 0.3 g of 1.7 mmol of p-toluenesulfonyl chloride were added to the above solution, and stirred at room temperature overnight; Then, the reaction mixture after the overnight reaction was diluted with water and extracted with ethyl acetate; the organic phase extracted was washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness.
  • the concentrated and evaporated organic phase was purified by an analytical method to obtain 0.1 g of a white solid compound 9 in 18% yield, and the compound 9 was p-toluenesulfonic acid (3-morpholine-cyclobutyl) ester.
  • the specific reaction formula is as follows:
  • Step 4 0.1 g, 0.2 mmol of Compound A is dissolved in 10 mL of dioxane, and Compound A is N-p-fluorophenyl-N-3-fluoro-4-(6-methoxy-7-hydroxyquinoline -4-)oxyphenylcyclopropane-1,1-dimethylformamide, then adding 0.02 g of 0.2 mmol of potassium t-butoxide to the above solution, stirring at room temperature for half an hour, and then adding 0.1 g, 0.3 mmol of compound 9, The mixture was stirred at 50 ° C overnight; then the reaction mixture was diluted with water and extracted with ethyl acetate; the organic phase extracted was washed with saturated brine, washed with water and dried over anhydrous sodium sulfate After evaporation to dryness, the above-mentioned concentrated and evaporated organic phase was purified by reverse preparation to give 0.1 g, 8% yield of yellow solid compound 10, and compound 10 as N-p-flu
  • the compound B has the following structural formula:
  • Step 2 1 g, 3.8 mmol of compound 35 was dissolved in 30 mL of methanol, and then 0.1 g of palladium black and 2 mL of formic acid were added to the above solution, and the mixture was stirred under reflux overnight; then, the reaction mixture after overnight was diluted with water and extracted with ethyl acetate. The organic phase obtained by the extraction is washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, and then evaporated to dryness, and evaporated to dryness. 46% yield of colorless liquid compound 36, compound 36 is 3-morpholine-cyclobutanol, the specific reaction formula is as follows:
  • Step 3 0.3 g, 1.7 mmol of compound 36 was dissolved in 30 mL of dichloromethane, 0.3 g, 3.4 mmol of N-methylpyrrole and 0.3 g of 1.7 mmol of p-toluenesulfonyl chloride were added, and the mixture was stirred at room temperature overnight;
  • the reaction solution was diluted with water and extracted with ethyl acetate.
  • the organic phase extracted was washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness.
  • the evaporated organic phase was purified to give 0.1 g, 18% yield of white solid compound 37.
  • Compound 37 was 3-morpholine-cyclobutylbenzyl ether.
  • Step 4 0.1 g, 0.2 mmol of Compound B is dissolved in 10 mL of dioxane, and Compound B is N-p-fluorophenyl-N-3-fluoro-4-(6-methoxy-7-hydroxyquinoline -4-)oxyphenylcyclobutane-1,1-dimethylformamide, adding 0.02 g, 0.2 mmol of potassium t-butoxide, stirring at room temperature for half an hour, then adding 0.1 g, 0.3 mmol of compound 33, compound 33 is p-toluene
  • the acid (3-morpholine-cyclobutyl) ester was stirred at 50 ° C overnight; then the reaction mixture was diluted with water and extracted with ethyl acetate; the extracted organic phase was washed with saturated brine, washed with water and then added.
  • Step 2 1.5 g, 7 mmol of compound 12 was dissolved in 30 mL of tetrahydrofuran THF, and 1 mol/L of 28 mL, 28 mmol of LAH was added thereto under ice-cooling, and stirred at room temperature for 2 hours; then, the reaction mixture after overnight was quenched with sodium sulfate decahydrate.
  • the organic phase obtained by the extraction is washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, and then evaporated to dryness. After evaporated to dryness, the concentrated organic phase is purified by silica gel column chromatography. g, 41% yield of colorless liquid compound 13, compound 13 is 2,2-difluoro-3-morpholine-1-propanol, the specific reaction formula is as follows:
  • Step 3 0.3 g, 1.7 mmol of compound 13 was dissolved in 30 mL of dichloromethane, and then 0.3 g, 3.4 mmol of N-methylpyrrole and 0.3 g of 1.7 mmol of p-toluenesulfonyl chloride were added to the above solution, and stirred at room temperature overnight; Then, the reaction mixture after the overnight reaction was diluted with water and extracted with ethyl acetate; the organic phase extracted was washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness.
  • Step 4 0.1 g, 0.2 mmol of Compound A and 0.1 g, 0.3 mmol of Compound 14 are dissolved in 10 mL of acetonitrile, and Compound A is N-p-fluorophenyl-N-3-fluoro-4-(6-methoxy- 7-Hydroxyquinolin-4-yloxyphenylcyclopropane-1,1-dimethylformamide, then 0.2 g, 0.5 mmol of cesium carbonate were added to the above solution, and stirred under reflux overnight; then the reaction solution after overnight was used.
  • Step 1 0.1 g, 1 mmol of compound 25 and 0.18 g, 1 mmol of 1,2-dibromoethane were dissolved in 10 mL of acetonitrile, compound 25 was N-aminomorpholine, and then 0.65 g of 2 mmol of cesium carbonate was added to the above solution. The mixture was stirred overnight at room temperature; then, the reaction mixture was diluted with water and extracted with ethyl acetate; the organic phase extracted was washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, then evaporated and evaporated.
  • step two 0.1 g, 0.2 mmol of compound A and 0.06 g, 0.3 mmol of compound 26 are dissolved in 10 mL of acetonitrile, and compound A is N-p-fluorophenyl-N-3-fluoro-4-(6-methoxy- 7-Hydroxyquinolin-4-yloxyphenylcyclopropane-1,1-dimethylformamide, then 0.2 g, 0.5 mmol of cesium carbonate were added to the above solution, and stirred under reflux overnight; then the reaction solution after overnight was used.
  • Step one 0.1 g, 1 mmol of compound 28 and 0.18 g, 1 mmol of 1,2-dibromoethane were dissolved in 10 mL of acetonitrile, compound 28 was 4-aminomorpholin-3-one, and then 0.65 g was added to the above solution. 2 mmol of cesium carbonate, stirred at room temperature overnight; then, the reaction mixture after the night was diluted with water, and extracted with ethyl acetate; the organic phase extracted was washed with saturated brine, washed with water, dried over anhydrous sodium sulfate, and then evaporated.
  • 0.1 g, 0.7 mmol of compound 31 and 0.12 g, 0.7 mmol of 1,2-dibromoethane are dissolved in 10 mL of acetonitrile, and compound 31 is 3-morpholineazetane, and then added to the above solution.
  • 0.65 g, 2 mmol of cesium carbonate stirred at room temperature overnight; then, the reaction mixture was diluted with water and then extracted with ethyl acetate; the organic phase extracted was washed with saturated brine, washed with water and dried over anhydrous sodium sulfate and then dried.
  • Step 2 0.1 g, 0.2 mmol of Compound A and 0.06 g, 0.24 mmol of Compound 32 were dissolved in 10 mL of acetonitrile, and Compound A was N-p-fluorophenyl-N-3-fluoro-4-(6-methoxy- 7-Hydroxyquinolin-4-yloxyphenylcyclopropane-1,1-dimethylformamide, then 0.2 g, 0.5 mmol of cesium carbonate were added to the above solution, and stirred under reflux overnight; then the reaction solution after overnight was used.
  • the PHERAstar FS instrument reads the 665 nm and 620 nm signals
  • the compounds of the above examples of the present invention have inhibitory activities against tyrosine kinases such as C-MET and KDR.
  • Cell culture cells such as human lung adenocarcinoma cell line HCC78, human malignant glioma cell line U87MG, human gastric cancer cell line MKN-45, human umbilical vein endothelial cell line HUVEC, human lung adenocarcinoma cell line A549, etc.
  • the medium was cultured under the conditions of 37 ° C, 5% CO 2 .
  • test compound was added: 10 ⁇ L/well, cultured for 72 hours, and each group was provided with 3 parallel wells.
  • test results of each test compound are summarized in Table 3-6 below:
  • the compound of the present invention can effectively inhibit human lung adenocarcinoma cells, human gastric cancer cells, human colon cancer cells, and human ovarian cancer by inhibiting the activity of tyrosine kinases such as C-MET and KDR.
  • the proliferation of various cancer cells such as cells and human malignant glioma cells is particularly suitable for the treatment of cancer.

Abstract

本发明公开了一种具有下述通式（I）的化合物，其中，K选自：环烷烃基aa、bb、卤代烷烃基cc、或N-R6。本发明还公开了包含上述化合物的酪氨酸激酶抑制剂及该化合物在制备治疗癌症的药物中的应用。本发明的酪氨酸激酶抑制剂，能够抑制C-MET、VEGF、KDR等多种信号传导激酶的生物活性，能有效抑制细胞增殖，对多种疾病如癌症具有良好的治疗效果，尤其是对肺癌、胃癌、卵巢癌、恶性胶质瘤等具有显著的治疗效果，应用前景非常广阔。

Description

酪氨酸激酶抑制剂及其应用 技术领域
本发明涉及医药技术领域，具体涉及一种酪氨酸激酶抑制剂及其应用。
背景技术
蛋白激酶是一种磷酸转移酶，转移三磷酸腺苷ATP的伽马磷酸脂基到特定的氨基酸残基，用以实现蛋白的磷酸化，从而实现其生理和生化功能。
蛋白激酶在信息传导上有着重要功能。反常的蛋白激酶不能进行正常的信号传递，可能会引起病变，例如：肿瘤细胞增生、细胞死亡、炎症、心血管疾病等蛋白激酶。蛋白激酶主要分为两类：蛋白酪氨酸激酶PTKs和受体酪氨酸激酶RTKs。MET族蛋白激酶中的ROS1/C-MET是RTPs的一个重要亚系，也称作hHGFR和RON；ROS1/C-MET能够对起始肿瘤细胞的生长和代谢起到重要作用，是多种药物临床研究的目标靶点。
因此，生物医疗技术领域急需ROS1/C-MET激酶抑制剂，尤其是小分子化合物的酪氨酸激酶抑制剂。
发明内容
本发明要解决的技术问题是提供一种酪氨酸激酶抑制剂，该激酶抑制剂能够抑制C-MET、VEGF、KDR、RON、KIT、PDGF、FGF、SRC等多种参与信号传导的酪氨酸激酶的活性，能有效抑制肿瘤细胞的增殖，使临床癌症治疗取得更好效果。
为了解决上述技术问题，本发明通过如下技术方案实现:
在本发明的一个方面，提供了一种具有通式(I)的化合物
Figure PCTCN2017089501-appb-000001
或其药学上可接受的盐，其中，
K选自下述基团：环烷烃基
Figure PCTCN2017089501-appb-000002
卤代烷烃基
Figure PCTCN2017089501-appb-000003
或N-R6；所述b、d为数字1、2、3、或4；E、G为氢、卤素、羟基、烷氧基、酮、巯基、烷基巯基中的一种，但E、G不同时为氢；R6为氢、低级卤代烷烃基、低级卤代环烷烃基、低级烷烃基、低级环烷烃基中的一种；
R1、R2、R3、R4、R5分别为氢、卤素、低级卤代烷烃基、低级卤代环烷烃基、低级烷烃基、低级环烷烃基、羟基、低级烷氧基、低级环烷氧基、低级烯烃基、低级炔烃基中的一种或多种；
X为C-R、C-(CN)、N中的一种，所述R为氢、卤素、低级卤代烷烃基、低级卤代环烷烃基、低级烷烃基、低级环烷烃基、羟基、低级烷氧基、低级环烷氧基、低级烯烃基、低级炔烃基中的一种；
Y为O、S、N-R6中的一种或为空，M为O或为空；
a、c分别表示数字0、1、2、或3；e为数字1或2。
优选的，所述E和G至少有一个为卤素F。
优选的，所述Y为O或为空。
优选的，所述通式(I)化合物包括下述具体结构的化合物：
Figure PCTCN2017089501-appb-000004
Figure PCTCN2017089501-appb-000005
在本发明的另一方面，还提供了一种药物组合物，该组合物包含安全有效量的上述化合物和药学上可接受的载体。
上述可接受的载体是无毒的、能辅助施用并且对化合物的治疗效果没有不利影响。此类载体可以是本领域的技术人员通常能得到的任何固体赋形剂、液体赋形剂、半固体赋形剂或者在气雾剂组合物中的气体赋形剂。固体药物赋形剂包括淀粉、纤维素、滑石、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻米、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、甘油硬脂酰酯、氯化钠、无水脱脂乳等。液体和半固体赋形剂可以选自甘油、丙二醇、水、乙醇和各种油，包括那些源于石油、动物、植物或人工合成的油，例如，花生油、豆油、矿物油、芝麻油等、优选的液体载体，特别是用于可注射溶液的，包括水、盐水、葡萄糖水溶液和甘醇。另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
本发明的化合物以治疗上的有效量施用，其施用方式可以是口服、全身施用(例如，透过皮肤的、鼻吸入的或者用栓剂)或肠胃外施用(例如，肌肉内、静脉内或皮下)。优选的施用方式是口服，它可根据疾病程度调节。
本发明的化合物的实际施用量(即活性组分)依赖于许多因素，如待治疗疾病的严重性、治疗对象的年龄和相对健康程度、所使用的化合物的效能、施用途径和形式，以及其他因素。
本发明药物组合物的各种剂型可以按照药学领域的常规方法制备。例如使该化合物与一种或者多种载体混合，然后将其制成所需的剂型，如片剂、药丸、胶囊、半固体、粉末、缓释剂型、溶液、混悬液、配剂、气雾剂等等。
在本发明的另一方面，还提供了一种包含上述化合物的酪氨酸激酶抑制剂。
所述酪氨酸激酶包括C-MET、VEGF、KDR、RON、KIT、PDGF、FGF、SRC激酶。
在本发明的另一方面，还提供了上述化合物在制备治疗癌症的药物中的应用。
由于酪氨酸激酶是目前效果明显的抗肿瘤药物靶点，而本发明的化合物具有显著的酪氨酸激酶抑制活性，通过实验证实这些化合物对各种癌细胞增殖具有抑制作用，因此本发明化合物适用于治疗各种癌症。尤其是对于肺癌、胃癌、卵巢癌、结肠癌、恶性胶质瘤具有较好的治疗效果。
在本发明的另一方面，还提供了上述化合物在制备治疗炎症的药物中的应用。
本发明化合物与多种信号传导激酶如C-MET、VEGF、KDR、RON、KIT、PDGF、FGF、SRC等都具有良好的生物活性作用，并与多种信号传导路径相关联，因此对多种疾病有治疗效果，如癌症、炎症、淋巴水肿、糖尿病等。
本发明的酪氨酸激酶抑制剂，能够抑制C-MET、VEGF、KDR等多种信号传导激酶的生物活性，能有效抑制细胞增殖，对多种疾病如癌症具有良好的治疗效果，尤其是对肺癌、胃癌、 卵巢癌、恶性胶质瘤等具有显著的治疗效果，应用前景非常广阔。
附图说明
下面结合附图和具体实施方式对本发明作进一步详细的说明。
图1是本发明实施例10的人肺腺癌细胞HCC78的增殖抑制拟合曲线图；
图2是本发明实施例10的人恶性胶质瘤细胞U87MG的增殖抑制拟合曲线图；
图3是本发明实施例10的人胃癌细胞MKN-45的增殖抑制拟合曲线图；
图4是本发明实施例10的人肺腺癌细胞HCC78的增殖抑制拟合曲线图；
图5是本发明实施例10的人卵巢癌细胞SK-OV-3的增殖抑制拟合曲线图；
图6是本发明实施例10的人结肠癌细胞HCT116的增殖抑制拟合曲线图；
图7是本发明实施例10的人肺腺癌细胞A549的增殖抑制拟合曲线。
具体实施方式
实施例1 酪氨酸激酶抑制剂化合物24的合成
Figure PCTCN2017089501-appb-000006
其中，化合物A为
Figure PCTCN2017089501-appb-000007
包括如下步骤：
步骤一，将1.3g、7mmol的化合物19溶于50ml甲醇中，化合物19为反式-1，2-环丙二羧酸二乙酯，然后向上述溶液中加入1N的1mol/L氢氧化钠溶液，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水 洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到1g、77％产率的黄色油状物20，化合物20为反式-1，2-环丙二羧酸单乙酯，具体反应式如下：
Figure PCTCN2017089501-appb-000008
步骤二，将1g、6mmol的化合物20溶于30mL二甲基甲酰胺DMF中，然后向上述溶液中加入4.6g、12mmol多肽缩合试剂HATU和3mL三乙胺，室温下搅拌0.5h后，再加入0.6g、6mmol的吗啡啉，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到1g、77％产率的无色液体化合物21，化合物21为(1s,2s)-2-吗啡啉-4-羰基)环丙烷乙酯，具体反应式如下：
Figure PCTCN2017089501-appb-000009
步骤三，将1g，4mmol化合物21溶于30mL THF中，冰浴下加入1N的1mol/L氢化铝锂LAH溶液，室温搅拌2h；然后将搅拌均匀的反应液用十水硫酸钠淬灭后进行过滤；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；硅胶柱层析纯化，蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.5g、66％产率的无色液体化合物22，化合物22为(1s,2s)-2-吗啡啉甲基)环丙基甲醇，具体反应式如下：
Figure PCTCN2017089501-appb-000010
步骤四，将0.3g、1.7mmol的化合物22溶于30mL二氯甲烷中，然后向上述溶液中加入0.3g、3.4mmol N-甲基吡咯和0.3g、1.7mmol对甲苯磺酰氯，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.1g、18％产率的白色固体化合物23，化合物23为(1s,2s)-2-吗啡啉甲基)环丙基对甲基苯磺酸甲酯，具体反应式如下：
步骤五，将0.1g、0.2mmol的化合物A，化合物A为N-对氟苯基-N-3-氟-4-(6-甲氧基-7-羟基喹啉-4-)氧基苯基环丙-1，1-二甲酰胺和0.1g、0.3mmol的化合物23溶于10mL乙腈中，然后向上述溶液中加入0.2g、0.5mmol碳酸铯，回流搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用反向制备法对上述浓缩蒸干的有机相进行纯化，得到0.01g、8％产率的黄色固体化合物24，化合物24为N-对氟苯基-N-3-氟-4-【6-甲氧基-7-(1S，2S)-2-吗啉甲基环丙基甲氧基喹啉-4-】氧基苯基环丙-1，1-二甲酰胺，具体反应式如下：
Figure PCTCN2017089501-appb-000012
实施例2 酪氨酸激酶抑制剂化合物5的合成
Figure PCTCN2017089501-appb-000013
包括如下步骤：
步骤一，将1g、5.2mmol化合物1，化合物1为3-(苄氧基甲基)环丁-1-酮和0.46g、 5.2mmol吗啡啉溶于30mL二氯乙烷中，然后向上述溶液中加入3.3g、15.6mmol醋酸硼氢化钠和1滴乙酸，回流搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到1g、73％产率的无色液体化合物2，化合物2为(3-吗啉-环丁基-1-)甲基苄基醚，具体反应式如下：
Figure PCTCN2017089501-appb-000014
步骤二，将1g、3.8mmol的化合物2溶于30mL甲醇中，然后向上述溶液中加入0.1g钯黑和2mL甲酸，回流搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.3g、46％产率的无色液体化合物3，化合物3为3-吗啉-环丁基甲醇，具体反应式如下：
Figure PCTCN2017089501-appb-000015
步骤三，将0.3g、1.7mmol化合物3溶于30mL二氯甲烷中，然后向上述溶液中加入0.3g、3.4mmol N-甲基吡咯和0.3g、1.7mmol对甲苯磺酰氯，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.2g、35％产率的白色固体化合物4，化合物4为N-对氟苯基-N-3-氟-4-(6-甲氧基-7-羟基喹啉-4-)氧基苯基环丙-1，1-二甲酰胺，具体反应式如下：
Figure PCTCN2017089501-appb-000016
步骤四，将0.1g、0.2mmol化合物A，化合物A为N-对氟苯基-N-3-氟-4-(6-甲氧基-7-羟基喹啉-4-)氧基苯基环丙-1，1-二甲酰胺和0.1g、0.3mmol化合物4溶于10mL乙腈中，加入0.2g、0.5mmol碳酸铯，回流搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓 缩蒸干；蒸干后采用反向制备法对上述浓缩蒸干的有机相进行纯化，得到0.02g、16％产率的黄色固体化合物5，化合物5为N-对氟苯基-N-3-氟-4-【6-甲氧基-7-(3-吗啉-环丁基)甲氧基喹啉-4-】氧基苯基环丙-1，1-二甲酰胺，具体反应式如下：
Figure PCTCN2017089501-appb-000017
实施例3 酪氨酸激酶抑制剂化合物10的合成
Figure PCTCN2017089501-appb-000018
包括如下步骤：
步骤一，将1g、5.2mmol化合物6，化合物6为3-苄氧基环丁-1-酮和0.46g、5.2mmol吗啡啉溶于30mL二氯乙烷中，然后向上述溶液中加入3.3g、15.6mmol醋酸硼氢化钠和1滴乙酸，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到1.1g、80％产率的无色液体化合物7，化合物7为3-吗啉-环丁基苄基醚，具体反应式如下：
Figure PCTCN2017089501-appb-000019
步骤二，将1g、3.8mmol化合物7溶于30mL甲醇中，然后向上述溶液中加入0.1g钯 黑和2mL甲酸，回流搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.3g、46％产率的无色液体化合物8，化合物8为3-吗啉-环丁醇，具体反应式如下：
Figure PCTCN2017089501-appb-000020
步骤三，将0.3g、1.7mmol化合物8溶于30mL二氯甲烷中，然后向上述溶液中加入0.3g、3.4mmol N-甲基吡咯和0.3g、1.7mmol对甲苯磺酰氯，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.1g、18％产率的白色固体化合物9，化合物9为对甲苯磺酸(3-吗啉-环丁)酯，具体反应式如下：
Figure PCTCN2017089501-appb-000021
步骤四，将0.1g、0.2mmol化合物A溶于10mL二氧六环中，化合物A为N-对氟苯基-N-3-氟-4-(6-甲氧基-7-羟基喹啉-4-)氧基苯基环丙-1，1-二甲酰胺，然后向上述溶液中加入0.02g、0.2mmol叔丁醇钾，室温搅拌半小时后，加入0.1g、0.3mmol化合物9，50℃条件下搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用反向制备法对上述浓缩蒸干的有机相进行纯化，得到0.1g、8％产率的黄色固体化合物10，化合物10为N-对氟苯基-N-3-氟-4-【6-甲氧基-7-(3-吗啉-环丁基)氧基喹啉-4-】氧基苯基环丙-1，1-二甲酰胺，具体反应式如下：
Figure PCTCN2017089501-appb-000022
实施例4 酪氨酸激酶抑制剂化合物38的合成
Figure PCTCN2017089501-appb-000023
其中，化合物B具有下述结构式：
Figure PCTCN2017089501-appb-000024
包括如下步骤：
步骤一，将1g，5.2mmol化合物34和0.46g、5.2mmol吗啡啉溶于30mL二氯乙烷中，化合物34为3-苄氧基环丁-1-酮，然后向上述溶液中加入3.3g、15.6mmol醋酸硼氢化钠和1滴乙酸，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到1.1g、80％产率的无色液体化合物35，化合物35为3-吗啉-环丁基苄基醚，具体反应式如下：
Figure PCTCN2017089501-appb-000025
步骤二，将1g、3.8mmol化合物35溶于30mL甲醇中，然后向上述溶液中加入0.1g钯黑和2mL甲酸，回流搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.3g，46％产率的无色液体化合物36，化合物36为3-吗啉-环丁醇，具体反应式如下：
Figure PCTCN2017089501-appb-000026
步骤三，将0.3g、1.7mmol化合物36溶于30mL二氯甲烷中，加入0.3g、3.4mmol N-甲基吡咯和0.3g、1.7mmol对甲苯磺酰氯，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.1g，18％产率的白色固体化合物37，化合物37为3-吗啉-环丁基苄基醚，具体反应式如下：
Figure PCTCN2017089501-appb-000027
步骤四，将0.1g、0.2mmol化合物B溶于10mL二氧六环中，化合物B为N-对氟苯基-N-3-氟-4-(6-甲氧基-7-羟基喹啉-4-)氧基苯基环丁-1，1-二甲酰胺，加入0.02g、0.2mmol叔丁醇钾，室温搅拌半小时后加入0.1g、0.3mmol化合物33，化合物33为对甲苯磺酸(3-吗啉-环丁)酯，50℃条件下搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用反向制备法对上述浓缩蒸干的有机相进行纯化，得到0.01g，8％产率的黄色固体化合物38，化合物38为，N-对氟苯基-N-3-氟-4-【6-甲氧基-7-(3-吗啉-环丁基)氧基喹啉-4-】氧基苯基环丁-1，1-二甲酰胺.具体反应式如下：
Figure PCTCN2017089501-appb-000028
实施例5 酪氨酸激酶抑制剂化合物15的合成
Figure PCTCN2017089501-appb-000029
包括如下步骤：
步骤一，将2g，12mmol化合物11和1g、12mmol吗啡啉溶于30mL DMF中，化合物11为2,2-二氟丙二酸二甲酯，100℃条件下搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到1.5g，57％产率的无色液体化合物12，化合物12为2,2-二氟-3-吗啉-3-氧代丙酸甲酯，具体反应式入下：
Figure PCTCN2017089501-appb-000030
步骤二，将1.5g、7mmol化合物12溶于30mL四氢呋喃THF中，冰浴下加入1mol/L的28mL、28mmol LAH，室温搅拌2h；然后将过夜后的反应液用十水硫酸钠淬灭后，过滤；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.5g，41％产率的无色液体化合物13，化合物13为2,2-二氟-3-吗啉-1-丙醇，具体反应式如下：
Figure PCTCN2017089501-appb-000031
步骤三，将0.3g、1.7mmol化合物13溶于30mL二氯甲烷中，然后向上述溶液中加入0.3g，3.4mmol N-甲基吡咯和0.3g、1.7mmol对甲苯磺酰氯，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.1g、18％产率的白色固体化合物14，化合物14为对甲苯磺酸(2,2-二氟-3-吗啉-1-)丙酯，具体反应式如下：
步骤四，将0.1g、0.2mmol化合物A和0.1g、0.3mmol化合物14溶于10mL乙腈中，化合物A为N-对氟苯基-N-3-氟-4-(6-甲氧基-7-羟基喹啉-4-)氧基苯基环丙-1，1-二甲酰胺，然后向上述溶液中加入0.2g、0.5mmol碳酸铯，回流搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用反向制备法对上述浓缩蒸干的有机相进行纯化，得到0.01g、8％产率的黄色固体化合物15，化合物15为N-对氟苯基-N-3-氟-4-【6-甲氧基-7-(2,2-二氟-3-吗啉-1-)丙氧基喹啉-4-】氧基苯基环丙-1，1-二甲酰胺，具体反应式如下：
Figure PCTCN2017089501-appb-000033
实施例6 酪氨酸激酶抑制剂化合物27的合成
化合物A为
Figure PCTCN2017089501-appb-000034
Figure PCTCN2017089501-appb-000035
包括如下步骤：
步骤一，将0.1g、1mmol化合物25和0.18g、1mmol 1,2-二溴乙烷溶于10mL乙腈中，化合物25为N-氨基吗啡啉，然后向上述溶液中加入0.65g、2mmol碳酸铯，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法法对上述浓缩蒸干的有机相进行纯化，得到0.1g、50％产率的无色液体化合物26，化合物26为N-(2-溴乙基)吗啡啉-4-胺，具体反应式如下：
Figure PCTCN2017089501-appb-000036
步骤二，将0.1g、0.2mmol化合物A和0.06g、0.3mmol化合物26溶于10mL乙腈中，化合物A为N-对氟苯基-N-3-氟-4-(6-甲氧基-7-羟基喹啉-4-)氧基苯基环丙-1，1-二甲酰胺，然后向上述溶液中加入0.2g、0.5mmol碳酸铯，回流搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用反向制备法对上述浓缩蒸干的有机相进行纯化，得到0.01g、8％产率的黄色固体化合物27，化合物27为，N-对氟苯基-N-3-氟-4-【6-甲氧基-7-(吗啉-4-胺)乙氧基喹啉-4-】氧基苯基环丙-1，1-二甲酰胺,具体反应式如下：
Figure PCTCN2017089501-appb-000037
实施例7 酪氨酸激酶抑制剂化合物30的合成
Figure PCTCN2017089501-appb-000038
包括如下步骤：
步骤一，将0.1g、1mmol化合物28和0.18g、1mmol 1,2-二溴乙烷溶于10mL乙腈中，化合物28为4-氨基吗啉-3-酮，然后向上述溶液中加入0.65g、2mmol碳酸铯，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法法对上述浓缩蒸干的有机相进行纯化，得到0.1g、50％产率的无色液体化合物29，化合物29为(2-溴乙胺基)吗啉-3-酮，具体反应如下：
Figure PCTCN2017089501-appb-000039
步骤二，将0.1g、0.2mmol化合物A和0.06g，0.3mmol化合物29溶于10mL乙腈中，化合物A为N-对氟苯基-N-3-氟-4-(6-甲氧基-7-羟基喹啉-4-)氧基苯基环丙-1，1-二甲酰胺，然后向上述溶液中加入0.2g、0.5mmol碳酸铯，回流搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用反向制备法法对上述浓缩蒸干的有机相进行纯化，得到0.012g、9％产率的黄色固体化合物30，化合物30为N-对氟苯基-N-3-氟-4-【6-甲氧基-7-(3-氧代吗啉胺)乙氧基喹啉-4-】氧基苯基环丙-1，1-二甲酰胺，具体反应式如下：
Figure PCTCN2017089501-appb-000040
实施例8 酪氨酸激酶抑制剂化合物33的合成
Figure PCTCN2017089501-appb-000041
包括如下步骤：
步骤一，将0.1g、0.7mmol化合物31和0.12g、0.7mmol 1,2-二溴乙烷溶于10mL乙腈中，化合物31为3-吗啉氮杂环丁烷，然后向上述溶液中加入0.65g、2mmol碳酸铯，室温搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用硅胶柱层析法对上述浓缩蒸干的有机相进行纯化，得到0.1g、50％产率的无色液体化合物32，化合物32为溴乙基氮杂环丁烷基吗啉，具体反应式如下：
Figure PCTCN2017089501-appb-000042
步骤二，将0.1g、0.2mmol化合物A和0.06g、0.24mmol化合物32溶于10mL乙腈中，化合物A为N-对氟苯基-N-3-氟-4-(6-甲氧基-7-羟基喹啉-4-)氧基苯基环丙-1，1-二甲酰胺，然后向上述溶液中加入0.2g、0.5mmol碳酸铯，回流搅拌过夜；然后将过夜后的反应液用水稀释后，采用乙酸乙酯萃取；将萃取得到的有机相用饱和食盐水洗，水洗后加入无水硫酸钠进行干燥，然后浓缩蒸干；蒸干后采用反向制备法对上述浓缩蒸干的有机相进行纯化，得到0.09g、8％产率的黄色固体化合物33，化合物33为N-对氟苯基-N-3-氟-4-【6-甲氧基-7-(吗啉-3-氮杂环丁烷-1-)乙氧基喹啉-4-】氧基苯基环丙-1，1-二甲酰胺，具体反应式如下：
Figure PCTCN2017089501-appb-000043
实施例9 酪氨酸激酶抑制活性检测
将上述实施例的化合物应用于对C–MET和KDR激酶抑制活性的检测和筛选。
1.方法
(1)向384孔板中加入4μL配制的激酶缓冲溶液，或是4μL的激酶溶液(100％抑制对照)；向孔中加入2μL的化合物，或是2μL不含化合物的buffer(0％inhibition对照)；以上所有样品或对照均设2复孔。
(2)25℃孵育5min；
(3)向孔中加入2μL的ATP/底物/MgCl2/MnCl2/SEB/DTT混合液；
(4)1000rpm离心1min，30℃震荡孵育30min；
(5)向孔中加入8μL XL-665/抗体的混合液；
(6)25℃孵育1h；
(7)PHERAstar FS仪器读取665nm和620nm信号；
(8)根据试剂盒说明书分析数据，并用GraphPad Prism5拟合计算IC50。
Ratio＝665nm/620nm
Figure PCTCN2017089501-appb-000044
2.实验结果
各送检化合物及参比化合物的检测结果总结如下表1和表2所示，其中对照化合物是现有的C–MET激酶抑制剂Foretinib(结构式如下)。For-Oxide、For-Methyl的化学结构式也分别如下。
Figure PCTCN2017089501-appb-000045
表1化合物对C–MET的抑制活性
Figure PCTCN2017089501-appb-000046
表2化合物对KDR的抑制活性
Figure PCTCN2017089501-appb-000047
由表1-2的数据可知，本发明上述实施例的化合物具有C–MET、KDR等酪氨酸激酶的抑制活性。
实施例10 对肿瘤细胞增殖抑制试验
1.方法
(1)细胞培养：将肿瘤细胞(如人肺腺癌细胞HCC78、人恶性胶质瘤细胞U87MG、人胃癌细胞MKN-45、人脐静脉内皮细胞HUVEC、人肺腺癌细胞A549等)用细胞培养基培养，培养条件为37℃，5％CO2。
(2)细胞接种：取处于指数生长期，状态良好的细胞，加入适量胰酶消化细胞，收集细胞离心，弃上清。用含血清的培养液重新混悬细胞，然后计数并取细胞悬液按3000/孔接种于96孔板上，90μL/孔。将培养板转入恒温CO2培养箱中，在37℃，5％CO2及饱和湿度条件下培养24小时。
(3)加入受试化合物：10μL/孔，培养72小时，每组设3个平行孔。
(4)结果测定：化合物作用72小时后，加入10μL/孔的CCK8，置于培养箱中孵育适当时间，在450nm处测吸光值。
2.实验结果
各送检化合物的检测结果总结如下表3-6所示：
表3人肺腺癌细胞HCC78的增殖抑制结果(对应的拟合曲线见图1)
化合物编号 HCC78IC50(μM) 95％置信区间(μM)
Foretinib 0.1886 0.1253to 0.2839
For-Oxide 0.1182 0.06890to 0.2030
For-Methyl >10 /
化合物10 0.1072 0.06939to 0.1656
SCR-1510 1.779 1.001to 3.160
表4人恶性胶质瘤细胞U87MG、人胃癌细胞MKN-45、人肺腺癌细胞HCC78的增殖抑制结果(对应的拟合曲线见图2-4)
Figure PCTCN2017089501-appb-000048
表5人卵巢癌细胞SK-OV-3的增殖抑制结果(对应的拟合曲线见图5)
Figure PCTCN2017089501-appb-000049
表6人结肠癌细胞HCT116、人肺腺癌细胞A549的增殖抑制结果(对应的拟合曲线见图6、7)
Figure PCTCN2017089501-appb-000050
由上述表3-6的数据可知，本发明的化合物通过抑制C–MET、KDR等酪氨酸激酶的活性，能够有效抑制人肺腺癌细胞、人胃癌细胞、人结肠癌细胞、人卵巢癌细胞、人恶性胶质瘤细胞等各种癌细胞的增殖，特别适用于癌症的治疗。
以上所述实施例仅表达了本发明的实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准

Claims (12)

  1. 具有通式(I)的化合物
    Figure PCTCN2017089501-appb-100001
    或其药学上可接受的盐，其中，
    K选自下述基团：环烷烃基
    Figure PCTCN2017089501-appb-100002
    卤代烷烃基
    Figure PCTCN2017089501-appb-100003
    或N-R6；所述b、d为数字1、2、3、或4；E、G为氢、卤素、羟基、烷氧基、酮、巯基、烷基巯基中的一种，但E、G不同时为氢；R6为氢、低级卤代烷烃基、低级卤代环烷烃基、低级烷烃基、低级环烷烃基中的一种；
    R1、R2、R3、R4、R5分别为氢、卤素、低级卤代烷烃基、低级卤代环烷烃基、低级烷烃基、低级环烷烃基、羟基、低级烷氧基、低级环烷氧基、低级烯烃基、低级炔烃基中的一种或多种；
    X为C-R、C-(CN)、N中的一种，所述R为氢、卤素、低级卤代烷烃基、低级卤代环烷烃基、低级烷烃基、低级环烷烃基、羟基、低级烷氧基、低级环烷氧基、低级烯烃基、低级炔烃基中的一种；
    Y为O、S、N-R6中的一种或为空，M为O或为空；
    a、c分别表示数字0、1、2、或3；e为数字1或2。
  2. 根据权利要求1所述的化合物，其特征在于，所述E和G至少有一个为卤素F。
  3. 根据权利要求1所述的化合物，其特征在于，所述Y为O或为空。
  4. 根据权利要求1所述的化合物，其特征在于，所述通式(I)化合物包括：
    Figure PCTCN2017089501-appb-100004
    Figure PCTCN2017089501-appb-100005
  5. 一种药物组合物，其特征在于，该组合物包含安全有效量的权利要求1所述化合物和药学上可接受的载体。
  6. 一种酪氨酸激酶抑制剂，包含权利要求1-4中任一项所述的化合物。
  7. 根据权利要求6所述的酪氨酸激酶抑制剂，其特征在于，所述酪氨酸激酶包括C-MET、VEGFR、KDR、RON、KIT、PDGF、FGF、SRC激酶。
  8. 权利要求1-4中任一项所述化合物在制备治疗癌症的药物中的应用。
  9. 根据权利要求8所述的应用，其特征在于，所述癌症包括肺癌、胃癌、卵巢癌、结肠癌、胰腺癌、食管腺癌、恶性胶质瘤。
  10. 权利要求1-4中任一项所述化合物在制备治疗炎症的药物中的应用。
  11. 权利要求5所述药物组合物在制备治疗癌症的药物中的应用。
  12. 权利要求5所述药物组合物在制备治疗炎症的药物中的应用。
PCT/CN2017/089501 2016-09-13 2017-06-22 酪氨酸激酶抑制剂及其应用 WO2018049861A1 (zh)

Priority Applications (7)

Application Number Priority Date Filing Date Title
KR1020217037589A KR102382039B1 (ko) 2016-09-13 2017-06-22 티로신 키나아제 저해제 및 이의 응용
EP17850066.6A EP3511327B1 (en) 2016-09-13 2017-06-22 Tyrosine kinase inhibitor and application thereof
KR1020197010451A KR20190045354A (ko) 2016-09-13 2017-06-22 티로신 키나아제 저해제 및 이의 응용
JP2019515307A JP2019529435A (ja) 2016-09-13 2017-06-22 チロシンキナーゼ阻害剤及びその応用
US16/333,050 US10882853B2 (en) 2016-09-13 2017-06-22 Tyrosine kinase inhibitor and application thereof
AU2017325641A AU2017325641B2 (en) 2016-09-13 2017-06-22 Tyrosine kinase inhibitor and application thereof
ES17850066T ES2902549T3 (es) 2016-09-13 2017-06-22 Inhibidor de tirosina cinasa y aplicación del mismo

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610822529.0 2016-09-13
CN201610822529.0A CN107235896B (zh) 2016-09-13 2016-09-13 酪氨酸激酶抑制剂及其应用

Publications (1)

Publication Number Publication Date
WO2018049861A1 true WO2018049861A1 (zh) 2018-03-22

Family

ID=59982910

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/089501 WO2018049861A1 (zh) 2016-09-13 2017-06-22 酪氨酸激酶抑制剂及其应用

Country Status (8)

Country Link
US (1) US10882853B2 (zh)
EP (1) EP3511327B1 (zh)
JP (1) JP2019529435A (zh)
KR (2) KR102382039B1 (zh)
CN (2) CN110437145A (zh)
AU (1) AU2017325641B2 (zh)
ES (1) ES2902549T3 (zh)
WO (1) WO2018049861A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020247418A1 (en) * 2019-06-04 2020-12-10 Exelixis, Inc. Compounds for the treatment of kinase-dependent disorders

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019016071A1 (en) 2017-07-18 2019-01-24 Bayer Pharma Aktiengesellschaft SUBSTITUTED PYRROLOPYRIDINE DERIVATIVES
JP7321165B2 (ja) * 2018-01-26 2023-08-04 エグゼリクシス， インコーポレイテッド キナーゼ依存的障害を処置するための化合物
CN111936487A (zh) 2018-01-26 2020-11-13 埃克塞里艾克西斯公司 用于治疗激酶依赖性病症的化合物
IL302626A (en) 2018-01-26 2023-07-01 Exelixis Inc Compounds for the treatment of kinase-dependent disorders
CN112358469A (zh) * 2020-03-18 2021-02-12 北京康辰药业股份有限公司 血管生成抑制剂、其制备方法及其应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010045095A1 (en) * 2008-10-14 2010-04-22 Ning Xi Compounds and methods of use

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2210607T3 (da) * 2003-09-26 2011-12-12 Exelixis Inc N-[3-fluor-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(4-fluorphenyl)cyclopropan-1,1-dicarboxamid til behandling af kræft
UY31800A (es) * 2008-05-05 2009-11-10 Smithkline Beckman Corp Metodo de tratamiento de cancer usando un inhibidor de cmet y axl y un inhibidor de erbb
AU2010229147B2 (en) * 2009-03-21 2012-07-05 Sunshine Lake Pharma Co., Ltd. Amino ester derivatives, salts thereof and methods of use
US8664244B2 (en) * 2010-09-12 2014-03-04 Advenchen Pharmaceuticals, LLC Compounds as c-Met kinase inhibitors
CN105884695B (zh) * 2015-02-13 2019-02-26 山东轩竹医药科技有限公司 杂环衍生物类酪氨酸激酶抑制剂
CN104817497B (zh) * 2015-03-20 2017-03-08 南京众睿缘生物科技有限公司 一种炔代喹啉衍生物及其制备方法和用途
CN105017163A (zh) * 2015-08-25 2015-11-04 佛山市赛维斯医药科技有限公司 双乙氧基苯并喹唑啉类酪氨酸激酶抑制剂、制备方法及其用途
CN105001168A (zh) * 2015-08-25 2015-10-28 佛山市赛维斯医药科技有限公司 三烷氧基取代的苯并喹唑啉类酪氨酸激酶抑制剂及其用途
CN105218445B (zh) * 2015-08-25 2018-05-22 江苏中邦制药有限公司 一种酪氨酸激酶抑制剂Foretinib的制备方法
CN105085416A (zh) * 2015-08-25 2015-11-25 佛山市赛维斯医药科技有限公司 一类硝基取代的双烷氧苯并喹唑啉类酪氨酸激酶抑制剂及用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010045095A1 (en) * 2008-10-14 2010-04-22 Ning Xi Compounds and methods of use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020247418A1 (en) * 2019-06-04 2020-12-10 Exelixis, Inc. Compounds for the treatment of kinase-dependent disorders

Also Published As

Publication number Publication date
EP3511327A4 (en) 2019-08-07
US10882853B2 (en) 2021-01-05
CN107235896B (zh) 2019-11-05
KR20190045354A (ko) 2019-05-02
KR102382039B1 (ko) 2022-04-01
CN110437145A (zh) 2019-11-12
JP2019529435A (ja) 2019-10-17
EP3511327B1 (en) 2021-10-27
AU2017325641A1 (en) 2019-04-11
AU2017325641B2 (en) 2021-08-26
EP3511327A1 (en) 2019-07-17
ES2902549T3 (es) 2022-03-28
CN107235896A (zh) 2017-10-10
KR20210143935A (ko) 2021-11-29
US20190248772A1 (en) 2019-08-15

Similar Documents

Publication Publication Date Title
WO2018049861A1 (zh) 酪氨酸激酶抑制剂及其应用
KR20210065097A (ko) 치환된 인돌 및 이의 사용 방법
EA029771B1 (ru) Химические соединения
IL229988A (en) 4,4,4- Triplofluoro- n - [(1s) - 2 [[(7s) - 5 (2 - Hydroxyethyl) - 6 - Oxo - 7 h - Pyrido [2,3 - d] [3] Benzazepine - 7 - [] Amino] -1-methyl-2-oxo-ethyl] butanamide, used in the manufacture of cancer drugs and its hydrate crystals
WO2018184585A1 (zh) 一种能抑制ido的化合物、其制备方法及其用途
CN108976172B (zh) 一类4-嘧啶二胺类小分子有机化合物及其衍生物及其应用
WO2019154395A1 (zh) 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途
JPWO2015083833A1 (ja) 新規キナゾリン誘導体
EP2928466B1 (en) Use of maleimide derivatives for preventing and treating leukemia
MX2015003151A (es) Compuestos cristalinos.
WO2019024876A1 (zh) 一种具有fgfr4抑制活性的醛基吡啶衍生物、其制备方法和应用
CN112876458B (zh) 细胞程序性死亡-配体-1拮抗剂化合物
JP2013534928A (ja) 新規テトラヒドロキノリン誘導体
CN109096272B (zh) 一种具有抗肿瘤活性的吲哚异羟肟酸类化合物及其应用
WO2009100655A1 (zh) 芳环并三嗪类衍生物及其应用
JP2019518026A (ja) プロテインキナーゼ活性を抑制する化合物の結晶形態、及びその適用
WO2018059022A1 (zh) 酪氨酸激酶抑制剂及其应用
CN111247137A (zh) 一种嘧啶类化合物、其制备方法及其医药用途
WO2019034179A1 (zh) 一种含吲哚环的ido抑制剂及其制备方法
CN108101889A (zh) 氘代n-[5-(嘧啶-2-氨基)-2,4-二取代苯基]-反式-2,4-戊二烯酰胺
WO2020098658A1 (zh) 20位取代的喜树碱衍生物及其制备方法和应用
WO2021082181A1 (zh) Set8赖氨酸甲基转移酶抑制剂及其制备方法和用途
CN112512999A (zh) 新型联苯衍生物化合物及其用途
KR102576102B1 (ko) Uch37 탐지용 프로브 및 이의 용도
CN110256416B (zh) 组蛋白去乙酰化酶抑制剂及其制备方法与用途

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: 17850066

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019515307

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: 2017325641

Country of ref document: AU

Date of ref document: 20170622

Kind code of ref document: A

Ref document number: 20197010451

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2017850066

Country of ref document: EP

Effective date: 20190412