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WO2020156319A1 - Dérivé de n-formamide, son procédé de préparation et son utilisation médicale - Google Patents

Dérivé de n-formamide, son procédé de préparation et son utilisation médicale Download PDF

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Publication number
WO2020156319A1
WO2020156319A1 PCT/CN2020/073191 CN2020073191W WO2020156319A1 WO 2020156319 A1 WO2020156319 A1 WO 2020156319A1 CN 2020073191 W CN2020073191 W CN 2020073191W WO 2020156319 A1 WO2020156319 A1 WO 2020156319A1
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Prior art keywords
compound
pharmaceutically acceptable
tautomers
stereoisomers
cancer
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English (en)
Chinese (zh)
Inventor
张盼盼
颜孙力
李英
郭陈莉
钱文建
叶成
胡泰山
陈磊
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Zhejiang Hisun Pharmaceutical Co Ltd
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Zhejiang Hisun Pharmaceutical Co Ltd
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D487/08—Bridged systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medical technology, in particular to an N-formamide derivative which can be used as a selective RET kinase inhibitor, its preparation method and its medical use.
  • RET gene The rearrangement gene (RET gene) during transfection is a proto-oncogene that encodes a tyrosine kinase receptor in the human body and regulates cell reproduction and survival.
  • the activation of this gene needs to interact with glial cell-derived neurotrophic factor family receptors and the family of ⁇ receptors to form dimers, through phosphorylation, regulate signal pathways, exercise signal transduction and regulate life The function of the activity.
  • Abnormal expression of RET gene is associated with many cancer diseases. This gene is fused with other genes through chromosomal rearrangement or through site-specific mutation, and can be continuously activated independently of the ligand, leading to abnormal signaling pathways, leading to excessive cell proliferation and cancer.
  • RET gene fusion and mutation are the driving force of some cancers, and they do not overlap with other driver genes and have significant specificity.
  • RET gene fusion is more common in papillary thyroid cancer and non-small cell lung cancer. For example, 30% of sporadic papillary thyroid cancer, 70% of radiation-induced papillary thyroid cancer and about 2% of non-small cell lung cancer are driven by RET fusion genes .
  • Mutations of RET gene are more common in medullary thyroid cancer. For example, more than 50% of medullary thyroid cancer and nearly all congenital medullary carcinoma and multiple endocrine neoplasia are caused by site-directed mutations of RET gene.
  • the present invention provides a compound represented by formula (I) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:
  • X is selected from CH or N;
  • R 1 , R 1' , R 2 , R 2' , R 3 , R 3' , R 4 , R 4' are each independently selected from hydrogen, C 1 -C 6 alkyl or C 1 -C 3 hydroxyalkane base,
  • R 1 and R 1 ', R 2 and R 2', R 3 and R a group of connections 3 ', R 4 and R 4' together form a cyclopropyl, cyclobutyl or oxetanyl ,
  • q 1, 2 or 3;
  • Ring D is selected from aryl or heteroaryl, the aryl or heteroaryl is optionally further substituted by one or more R 5 , each of R 5 is independently selected from halogen, cyano, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group or C 1 -C 3 halogen-containing alkyl group.
  • a preferred embodiment of the present invention provides a compound represented by formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein the B ring is selected from the following structures:
  • One end and two ends are optionally connected to the A ring.
  • a preferred embodiment of the present invention provides a compound represented by formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein the B ring is selected from the following structures:
  • One end and two ends are optionally connected to the A ring.
  • a preferred embodiment of the present invention provides a compound represented by formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein the D ring is selected from phenyl, Or a six-membered heteroaryl group containing 1 to 3 N atoms, the phenyl group, Or a six-membered heteroaryl group containing 1 to 3 N atoms is optionally further substituted by one or more R 5 , and R 5 is independently selected from halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 3 halogen-containing alkyl group, R 5 is preferably halogen, more preferably fluorine.
  • the present invention provides a method for preparing a compound represented by formula (I), the preparation method comprising: in an organic solvent under alkaline conditions, a compound of formula (IB) or a salt thereof, a compound of formula (IA) or a salt thereof And triphosgene to prepare the compound of formula (I),
  • ring D, X, R 1 , R 1' , R 2 , R 2' , R 3 , R 3' , R 4 and R 4' are defined as in formula (I) in any one of the foregoing technical solutions Said.
  • the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, preferably dichloromethane;
  • the base used in the alkaline conditions is diisopropylethyl Amine or triethylamine, preferably diisopropylethylamine;
  • the reaction temperature of the reaction is -60 to 0°C.
  • the present invention provides a pharmaceutical composition which contains an effective dose of a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier , Excipients or their combination.
  • the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or its pharmaceutical composition (that is, the pharmaceutical composition provided by the above technical scheme of the present invention) in preparation Use of rearrangement kinase inhibitors during transfection.
  • the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof for preparing drugs for treating diseases driven by gene rearrangement during transfection
  • the disease is preferably cancer
  • the cancer is preferably lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
  • the present invention provides a use of a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or its pharmaceutical composition in the treatment of diseases driven by gene rearrangement during transfection ,
  • said disease is preferably cancer
  • said cancer is preferably lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
  • the present invention provides a method for the treatment of diseases driven by gene rearrangement during transfection, which includes the use of a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical combinations thereof
  • the substance is administered to the subject; wherein the disease is preferably cancer, and the cancer is preferably lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
  • Alkyl when regarded as a group or a part of a group means to include a C 1 -C 20 straight chain or branched aliphatic hydrocarbon group. It is preferably a C 1 -C 10 alkyl group, and more preferably a C 1 -C 6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.
  • Cycloalkyl refers to saturated or partially saturated monocyclic, fused, bridged, and spirocyclic carbocyclic rings. It is preferably a C 3 -C 12 cycloalkyl group, and more preferably a C 3 -C 6 cycloalkyl group.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc., preferably cyclopropyl, cyclo Hexenyl.
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, where the rings can be joined together in a fused manner.
  • aryl includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl.
  • the aryl group is a C 6 -C 10 aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5- to 6-membered monocyclic ring or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include but are not limited to furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , Oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzoin Dioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl
  • Hydroxyalkyl refers to an alkyl group containing at least one hydroxy group as a substituent, wherein the definition of the alkyl group is as described above.
  • Halogen refers to fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and fluorine, more preferably fluorine.
  • Halo-containing alkyl group refers to an alkyl group containing at least one halogen atom as a substituent, wherein the definitions of halogen and alkyl are as described above.
  • Cyano refers to -CN.
  • Benzyl refers to -CH 2 -phenyl.
  • Ester group refers to -C(O)O(alkyl) or (cycloalkyl), wherein the definitions of alkyl and cycloalkyl are as described above.
  • DMSO dimethyl sulfoxide
  • Boc means tert-butoxycarbonyl
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms independently of each other substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • substituted or “substituted” mentioned in this specification, unless otherwise specified, mean that the group can be substituted by one or more groups selected from the group consisting of halogen, cyano, alkyl, cycloalkyl, Ester group, hydroxyl group or alkoxy group, etc.;
  • the compounds of the present invention may contain asymmetric centers or chiral centers, so there are different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers and their mixtures, such as racemic mixtures, constitute the present invention Part.
  • Diastereomers can be separated into individual diastereomers by methods such as chromatography, crystallization, distillation or sublimation based on their physical and chemical differences.
  • Enantiomers can be separated to convert a chiral isomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (for example, a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride) , Separate diastereomers, and convert individual diastereomers into corresponding pure enantiomers.
  • a suitable optically active compound for example, a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride
  • the intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included in the scope of the present invention.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center.
  • the prefixes d, l or (+), (-) are used to name the symbols of the plane-polarized light rotation of the compound.
  • (-) or l means that the compound is levorotatory
  • the prefix (+) or d means that the compound is dextrorotatory.
  • the atoms or atomic groups of these stereoisomers are connected in the same order, but their stereo structures are different.
  • a specific stereoisomer may be an enantiomer, and a mixture of isomers is usually called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers, lacking optical activity.
  • Tautomers or “tautomeric forms” mean that isomers of different energy structures can be converted into each other through a low energy barrier.
  • proton tautomers ie, tautomers of proton transfer
  • interconversions by proton migration such as keto-enol and imine-enamine isomerization
  • Valence (valency) tautomers include the interconversion of recombined bond electrons.
  • the structural formula described in the present invention includes all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R and S configurations containing asymmetric centers, The (Z) and (E) isomers of the double bond, and the (Z) and (E) conformational isomers. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers, or geometric isomers all belong to the scope of the present invention.
  • “Pharmaceutically acceptable salts” refer to certain salts of the above compounds that can maintain the original biological activity and are suitable for medical use.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) may be an amine salt formed with a suitable acid.
  • Suitable acids include inorganic and organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, and citric acid.
  • Ethanesulfonic acid fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid , Sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients. Shape agent. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • DIPEA diisopropylethylamine
  • Triphosgene refers to: trichloromethyl carbonate, abbreviated as BTC.
  • T-BuXPhos refers to: 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl.
  • KAc means: potassium acetate
  • DMA means: N,N-dimethylacetamide.
  • PCy 3 means: tricyclohexylphosphine.
  • the examples show the preparation of representative compounds represented by formula (I) and related structure identification data. It must be noted that the following examples are used to illustrate the present invention but not to limit the present invention.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the 1 H NMR spectrum was measured with a Bruker instrument (400MHz), the chemical shift was expressed in ppm, and the tetramethylsilane internal standard (0.00ppm) was used.
  • a FINNIGAN LCQAd (ESI) mass spectrometer manufactured: Thermo, model: Finnigan LCQ advantage MAX was used for mass spectrometry.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm silica gel preparation board.
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.
  • the reactions are carried out in an open atmosphere under an air atmosphere.
  • the solution in the reaction refers to an aqueous solution.
  • reaction temperature is room temperature.
  • the temperature range of room temperature is 20-30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC), and the developing agent system used is: dichloromethane and methanol system, or n-hexane and ethyl acetate system, the volume ratio of the developing agent is based on the compound It can be adjusted for different polarity, and it can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents.
  • TLC thin-layer chromatography
  • the intermediate compound (A) of the present invention is prepared by referring to the process of patent WO2016127074A1.
  • Step 2 Synthesis of tert-butyl 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperazine-1-carboxylate
  • the third step Synthesis of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(1-piperazinyl)pyrimidin-4-amine hydrochloride
  • Step 1 Synthesis of tert-butyl 4-(6-bromo-4-methylpyridin-2-yl)piperazine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)piperidine-1-carboxylate
  • the third step Synthesis of 4-methyl-N-(5-methyl-1H-pyrazol-3-yl)-6-(1-piperazinyl)pyridin-2-amine hydrochloride
  • the third step Synthesis of (S)-1-(6-(4-fluorophenyl)pyridin-3-yl)ethyl-1-amine hydrochloride
  • Test Example 1 Determination of the inhibition of RET kinase activity by the compound of the present invention
  • This test case uses Cisbio's The tyrosine kinase kit (Cat. No. 62TK0PEB) is used to determine the degree of phosphorylation of the biotinylated polypeptide substrate by the time-resolved-fluorescence energy resonance transfer method (TR-FRET).
  • TR-FRET time-resolved-fluorescence energy resonance transfer method
  • Human RET protein (RET kinase) was purchased from Carna bioscience (Japan, Item No. 08-159-5 ⁇ g).
  • the compound to be tested (the compound of the present invention and the compound 164 in WO2018017983A1 as a control) was dissolved in 100% DMSO to a final concentration of 10 mM.
  • step (2) Dissolve 4 ⁇ L of the test compound solution prepared in step (1) with 46 ⁇ L of 100% DMSO, and number the solution obtained in this step as No. 2.
  • the dilution factor is 20 times (that is, take out 1 ⁇ L from the solutions numbered 3-11, and add to the 19 ⁇ L of buffer solution from III to XI).
  • the concentration range of the compound to be tested in the solution system III to XI is 8000nM ⁇ 0.02048nM (9 gradients), and the final concentration of DMSO is 5%.
  • step (4) the 9 gradient concentrations of the test compound solutions numbered from III to XI are sequentially added to the 384-well plate according to the concentration, 4 ⁇ L per well, and two replicate wells are set.
  • the selected control kinase is another receptor tyrosine kinase KDR with similar structure to RET kinase. Purchased from Carna bioscience (Japan, article number 08-191-5 ⁇ g). The step of gradient dilution is the same as that of RET kinase, so that the final concentration range of the test compound in the reaction system is 16000nM ⁇ 0.04nM (use No. 2-10 solution for the gradient dilution of step 4), other reaction conditions are the same as above, and the final concentration of DMSO is 2 %. The same calculation method of the IC 50 values for a test compound value calculation 50 and the RET kinase inhibiting KDR kinase inhibition IC.
  • the compound of the present invention has a significant inhibitory effect on RET kinase activity, and the inhibitory effect is better than compound 164 in WO2018017983A1.
  • the inhibitory activity of the compound of the present invention on RET kinase is better than that on KDR kinase. Therefore, the compounds of the present invention can be used as a kind of effective selective RET kinase inhibitors.

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Abstract

La présente invention concerne un dérivé de N-formamide, tel que représenté par la formule (I), qui peut agir en tant qu'inhibiteur de kinase RET (réarrangement pendant la transfection) sélectif, son procédé de préparation et son utilisation médicale. Le composé selon la présente invention a un effet inhibiteur significatif sur l'activité de la kinase RET, et son activité inhibitrice vis-à-vis de la kinase RET est meilleure que celle de celle-ci contre d'autres types de kinases, et par conséquent, il peut être utilisé en tant qu'inhibiteur de kinase RET sélectif efficace.
PCT/CN2020/073191 2019-01-31 2020-01-20 Dérivé de n-formamide, son procédé de préparation et son utilisation médicale Ceased WO2020156319A1 (fr)

Applications Claiming Priority (2)

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CN201910097765.4A CN111499613B (zh) 2019-01-31 2019-01-31 N-甲酰胺衍生物、其制备方法及其在医药上的用途
CN201910097765.4 2019-01-31

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CN113135896B (zh) * 2020-01-18 2024-12-06 正大天晴药业集团股份有限公司 作为ret抑制剂的甲基吡唑类衍生物
CN112279836B (zh) * 2020-12-29 2021-04-30 北京鑫开元医药科技有限公司 一种n-(5-甲基-1h-吡唑-3-基)吡啶-2-胺类化合物及其制备方法
CN112656796B (zh) * 2020-12-29 2022-06-24 北京鑫开元医药科技有限公司 一种n-(5-甲基-1h-吡唑-3-基)吡啶-2-胺类药物的制剂组合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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