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WO2019034075A1 - Inhibiteur de fgfr et egfr - Google Patents

Inhibiteur de fgfr et egfr Download PDF

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Publication number
WO2019034075A1
WO2019034075A1 PCT/CN2018/100637 CN2018100637W WO2019034075A1 WO 2019034075 A1 WO2019034075 A1 WO 2019034075A1 CN 2018100637 W CN2018100637 W CN 2018100637W WO 2019034075 A1 WO2019034075 A1 WO 2019034075A1
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WIPO (PCT)
Prior art keywords
acid
compound
group
pharmaceutically acceptable
acceptable salt
Prior art date
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PCT/CN2018/100637
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English (en)
Chinese (zh)
Inventor
王一恺
张杨
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of FGFR and EGFR inhibitors and their use in the manufacture of a medicament for the treatment of diseases associated with FGFR and EGFR. Specifically, it relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof.
  • the fibroblast growth factor receptor is a receptor for fibroblast growth factor (FGF) signaling, and its family consists of four members (FGFR1, FGFR2, FGFR3, FGFR4), which are composed of extracellular immunoglobulins ( Ig) a glycoprotein consisting of a domain, a hydrophobic transmembrane region, and an intracellular portion comprising a tyrosine kinase domain.
  • FGF fibroblast growth factor
  • FGF signaling pathway abnormalities high expression, gene amplification, gene mutation, chromosome recombination, etc.
  • pathological processes such as tumor cell proliferation, migration, invasion and angiogenesis. Therefore, FGFR has become an important therapeutic target and has attracted a wide range of research and development interests.
  • Epidermal growth factor receptor is a receptor for epidermal growth factor (EGF) signaling and belongs to the ErbB receptor family, which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2) , HER3 (ErbB-3) and HER4 (ErbB-4).
  • EGFR is widely distributed on the surface of epithelial cells, fibroblasts, glial cells, keratinocytes, etc.
  • EGF plays an important role in regulating the growth, proliferation and differentiation of cells through these receptors.
  • Many studies have shown that there are high expression of EGFR or gene mutation in a variety of solid tumors, which is related to tumor cell proliferation, angiogenesis, tumor invasion, metastasis and inhibition of apoptosis.
  • a series of compounds having inhibitory activity against FGFR including reference compound 1, are reported in WO2015008844.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from the group consisting of H, F, Cl, Br, and I.
  • R 2 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 .
  • R 3 is selected from H, halogen, OH, NH 2 , CN, or selected from C 1 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R 4 is selected from H, halogen, OH, NH 2 , CN, or selected from C 1 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , N(CH 3 ) 2 ,
  • hetero of the C 1-3 heteroalkyl group is independently selected from: -NH-, N, -O-, -S-;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • R 3 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, R is as defined in the invention.
  • R 3 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 ,
  • R 4 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, R is as defined in the invention.
  • R 4 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 ,
  • the structural unit From:
  • R 3 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, other variables are as defined above.
  • R 3 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Other variables are as defined above.
  • R 4 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, other variables are as defined above.
  • R 4 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Other variables are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • the present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof:
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating a disease associated with FGFR.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating diseases associated with FGFR and EGFR.
  • the FGFR and EGFR related diseases are referred to as solid tumors.
  • One of the corresponding isomers of the present invention exhibits a good inhibitory activity against FGFR, while the other corresponding isomer exhibits a good inhibitory activity against EGFR.
  • the combined use of the racemates of these compounds can simultaneously inhibit FGFR and EGFR, and has a better anti-proliferative effect than inhibition of FGFR or EGFR alone.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • the 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 set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Diisopropyl azodicarboxylate (7.8 g, 38 mmol, 7.4 mL, 2.0 eq) was added dropwise to dissolved Compound D (5.0 g, 19 mmol, 1.0 eq), Compound C1 (3.86 g). 19.16 mmol, 1.00 eq.) and a solution of triphenylphosphine (10 g, 38 mmol, 2.0 eq) in anhydrous tetrahydrofurane (100 mL). After the reaction was stirred at room temperature for 16 hr, ethyl acetate (20 mL) was evaporated. The organic phase was dried over anhydrous sodium sulfate.
  • WXR3-1 200 mg, 450 ⁇ mol, 1.0 eq
  • Compound B1 96 mg, 540 ⁇ mol, 1.2 eq
  • sodium carbonate 95 mg, 900 ⁇ mol, 2.0 eq
  • tetratriphenylphosphine palladium 52 mg, 45 ⁇ mol, 0.1 eq
  • ethylene glycol dimethyl ether/ethanol/water 2.25 mL, 6/2/1
  • the compound WX006 was synthesized by the synthesis method of the step 3 in Example 1, and separated by chirality (column: AS (250 mm * 30 mm, 10 ⁇ m); mobile phase: [0.1% ammonia methanol]; B% : 35% - 35%) Compound WX006A (retention time: 5.70 minutes) and compound WX006B (retention time: 6.23 minutes)
  • the compound WX007 was synthesized by the synthesis method of the step 3 in Example 1, and separated by chirality (column: AS (250 mm * 30 mm, 5 ⁇ m); mobile phase: [0.1% aqueous isopropyl alcohol]; B%: 40%-40%) Compound WX007A (retention time: 5.91 minutes) and WX007B (retention time: 6.52 minutes) (column: Chiralpak AS-H 150*4.6 mm ID, 5 ⁇ m, mobile phase: A: CO2B: Isopropanol (0.05% diethanolamine), gradient: 5% B for 0.5 minutes, from 5% to 40% in 3.5 minutes, at 2.5% for 2.5 minutes, to 5% B for 1.5 minutes, flow rate: 3 mL/ Min column temperature: 40 ° C)
  • test compound The ability of the test compound to inhibit human FGFR1, FGFR4, EGFR (L858R/T790M) was evaluated by measuring the IC 50 value using a 33 P isotope-labeled kinase activity assay (Reaction Biology Corp).
  • Buffer conditions 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.
  • Test procedure The test compound was dissolved in DMSO at room temperature to prepare a 10 mM solution for use.
  • the substrate is dissolved in a freshly prepared buffer, and the kinase to be tested is added thereto and mixed well.
  • a DMSO solution in which the test compound was dissolved was added to the above mixed reaction solution by an acoustic technique (Echo 550).
  • the concentration of the compound in the reaction solution was 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 0.370 ⁇ M, 0.123 ⁇ M, 41.2 nM, 13.7 nM, 4.57 nM, 1.52 nM, 0.508 nM, or 10 ⁇ M, 2.50 ⁇ M, 0.62 ⁇ M, 0.156 ⁇ M, 39.1 nM. , 9.8 nM, 2.4 nM, 0.61 nM, 0.15 nM, 0.038 nM. After 15 minutes of incubation, 33 P-ATP (activity 0.01 ⁇ Ci/ ⁇ l, corresponding concentrations listed in Table 1) was added to initiate the reaction.
  • the supplier number, lot number, and concentration information in the reaction solution of FGFR1, FGFR4, EGFR (L858R/T790M) and their substrates are listed in Table 1.
  • the reaction solution was spotted on a P81 ion exchange filter paper (Whatman #3698-915). After repeatedly washing the filter paper with a 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured.
  • the kinase activity data was expressed as an alignment of the kinase activity of the test compound and the kinase activity of the blank group (DMSO only), and the IC50 value was obtained by curve fitting by Prism4 software (GraphPad), and the experimental results are shown in Table 2.
  • One of the corresponding isomers of the present invention exhibits a good inhibitory activity against FGFR, while the other corresponding isomer exhibits a good inhibitory activity against EGFR.
  • the racemates of these compounds can simultaneously inhibit FGFR and EGFR.

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Abstract

L'invention concerne un inhibiteur de FGFR et EGFR, un composé de formule I et son sel pharmaceutiquement acceptable. L'invention concerne aussi ses applications dans la préparation d'un médicament indiqué pour le traitement des maladies associées à FGFR et EGFR, telles que des tumeurs solides.
PCT/CN2018/100637 2017-08-15 2018-08-15 Inhibiteur de fgfr et egfr Ceased WO2019034075A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2020245208A1 (fr) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de cd9 en tant que biomarqueur et en tant que biocible dans la glomérulonéphrite ou la glomérulosclérose
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021089005A1 (fr) * 2019-11-08 2021-05-14 石药集团中奇制药技术（石家庄）有限公司 Utilisation d'un inhibiteur de fgfr
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022127261A1 (fr) * 2020-12-16 2022-06-23 天津济坤医药科技有限公司 Composé, son procédé de préparation et son utilisation dans la préparation d'un médicament anticancéreux thérapeutique
RU2821945C1 (ru) * 2020-12-16 2024-06-28 Тяньцзинь Цзикунь Медикал Текнолоджи Ко., Лтд. Соединение, способ его получения и его применение для получения противоракового лекарственного средства

Citations (2)

* Cited by examiner, † Cited by third party
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WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2020245208A1 (fr) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de cd9 en tant que biomarqueur et en tant que biocible dans la glomérulonéphrite ou la glomérulosclérose
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WO2021089005A1 (fr) * 2019-11-08 2021-05-14 石药集团中奇制药技术（石家庄）有限公司 Utilisation d'un inhibiteur de fgfr
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022127261A1 (fr) * 2020-12-16 2022-06-23 天津济坤医药科技有限公司 Composé, son procédé de préparation et son utilisation dans la préparation d'un médicament anticancéreux thérapeutique
JP2023516483A (ja) * 2020-12-16 2023-04-19 天津済坤医薬科技有限公司 化合物とその調製方法及びそれらの抗がん剤の調製における応用
RU2821945C1 (ru) * 2020-12-16 2024-06-28 Тяньцзинь Цзикунь Медикал Текнолоджи Ко., Лтд. Соединение, способ его получения и его применение для получения противоракового лекарственного средства
JP7525630B2 (ja) 2020-12-16 2024-07-30 天津済坤医薬科技有限公司 化合物とその調製方法及びそれらの抗がん剤の調製における使用

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