WO2021180008A1 - Composé cyclique tri-aromatique contenant une structure d'urée et utilisation associée - Google Patents

Composé cyclique tri-aromatique contenant une structure d'urée et utilisation associée Download PDF

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Publication number
WO2021180008A1
WO2021180008A1 PCT/CN2021/079354 CN2021079354W WO2021180008A1 WO 2021180008 A1 WO2021180008 A1 WO 2021180008A1 CN 2021079354 W CN2021079354 W CN 2021079354W WO 2021180008 A1 WO2021180008 A1 WO 2021180008A1
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alkyl
group
substituted
aryl
independently selected
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PCT/CN2021/079354
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English (en)
Chinese (zh)
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蔡倩
张章
吴开富
肖国荣
何蕊
黄晶
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暨南大学
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Priority to CN202180002962.9A priority Critical patent/CN113966331B/zh
Publication of WO2021180008A1 publication Critical patent/WO2021180008A1/fr

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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 field of medicinal chemistry, in particular to a triaromatic ring compound containing a urea structure and its application.
  • RET receptor tyrosine kinase RET
  • PTC papillary thyroid carcinoma
  • NSCLC non-small cell lung cancer
  • RET mutations is associated with multiple endocrine tumors type 2 (MEN2) and sporadic medullary thyroid Different phenotypes of MTC are related. Therefore, RET is an attractive therapeutic target for patients whose RET changes cause cancer.
  • MKIs multikinase inhibitors
  • RET inhibitor activity such as cabozantinib and vandetanib
  • Selpercatinib a highly selective RET kinase inhibitor developed by Loxo Oncology, was approved by the FDA in May 2020; it is used to treat advanced RET fusion-positive NSCLC and RET mutant/fusion-positive MTC.
  • Pralsetinib Another highly selective RET kinase inhibitor, Pralsetinib, developed by Blueprint Medicines, was approved by the FDA in September 2020.
  • the present invention provides a new class of triaromatic ring compounds containing urea structure, which have good inhibitory activity on RET wild and mutant kinases.
  • Z is selected from: O, S, or NR 2 ;
  • R 1 is selected from: Or R 1 and D 1 together form the following structure: Wherein, m and n are each independently selected from: an integer between 0-6, and Z 1 is selected from: O, S, or NR 2 ;
  • Each R 2 is independently selected from: H, C 1 ⁇ C 8 alkyl, C 3 ⁇ C 6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1 ⁇ C 8 acyl, C 1 ⁇ C 8 sulfonate Acyl, C 6 ⁇ C 18 aryl, C 6 ⁇ C 18 aryl substituted C 1 ⁇ C 6 alkyl, or 5 to 18 membered heteroaryl; when R 2 is not hydrogen, said R 2 is independent Optionally substituted by one or more R 7;
  • Each R 3 is independently selected from: H, halogen, C 1 to C 18 alkyl, C 3 to C 18 cycloalkyl, 3 to 18 membered heterocycloalkyl, C 1 to C 18 alkoxy, C 1 ⁇ C 18 alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonamido, C 6 ⁇ C 18 aryl, C 6 ⁇ C 18 aryl substituted C 1 ⁇ C 18 alkyl, 5 to 18 membered heteroaryl, or -SR 8 ; when R 3 is selected from C 1 to C 18 alkyl, C 3 to C 18 cycloalkyl, 3 to 18 membered heterocycloalkyl, C 1 ⁇ C 18 alkoxy, C 1 ⁇ C 18 alkylamino, C 6 ⁇ C 18 aryl, C 6 ⁇ C 18 aryl substituted C 1 ⁇ C 18 alkyl group or 5 ⁇ 18 membered hetero
  • Each R is independently selected from: H, halogen, C 1 to C 18 alkyl, C 3 to C 18 cycloalkyl, 3 to 18 membered heterocycloalkyl, C 1 to C 18 alkoxy, C 1 to C 18 alkylamino group, amino group, hydroxyl group, cyano group, nitro group, ester group, amide group, sulfonyl group, sulfonylamino group, C 6 ⁇ C 18 aryl, C 6 ⁇ C 18 aryl substituted C 1 ⁇ C 18 alkyl, or 5 to 18 membered heteroaryl; when R is selected from C 1 to C 18 alkyl, C 3 to C 18 cycloalkyl, 3 to 18 membered heterocycloalkyl, C 1 to C 18 alkoxy In the case of a C 1 ⁇ C 18 alkylamino group, a C 6 ⁇ C 18 aryl group, a C 6 ⁇ C 18 aryl substituted C 1 ⁇ C 18 al
  • Q is selected from:
  • X 1 , X 2 , X 3 , X 4 and X 5 together form a heteroaryl group
  • Y 1 , Y 2 and Y 3 are each independently selected from: N, or CR;
  • Q 1 , Q 2 , Q 3 , Q 4 , Q 5 and Q 6 are each independently selected from: N, or CR;
  • Z is selected from: O, S, or NR 2 ;
  • R 1 is selected from: Or R 1 and D 1 together form the following structure: Wherein, m and n are each independently selected from: an integer between 0-6, and Z 1 is selected from: O, S, or NR 2 ;
  • Each R 3 is independently selected from: H, halogen, C 1 to C 18 alkyl, C 3 to C 18 cycloalkyl, 3 to 18 membered heterocycloalkyl, C 1 to C 18 alkoxy, C 1 ⁇ C 18 alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonamido, C 6 ⁇ C 18 aryl, C 6 ⁇ C 18 aryl substituted C 1 ⁇ C 18 alkyl, 5 to 18 membered heteroaryl, or -SR 8 ; when R 3 is selected from C 1 to C 18 alkyl, C 3 to C 18 cycloalkyl, 3 to 18 membered heterocycloalkyl, C 1 ⁇ C 18 alkoxy, C 1 ⁇ C 18 alkylamino, C 6 ⁇ C 18 aryl, C 6 ⁇ C 18 aryl substituted C 1 ⁇ C 18 alkyl group or 5 ⁇ 18 membered hetero
  • R 4 is selected from: H, C 1 ⁇ C 18 alkyl, C 3 ⁇ C 18 cycloalkyl, 3 to 18 membered heterocycloalkyl, C 1 ⁇ C 18 alkoxy, C 1 ⁇ C 18 alkylamino , Amino, hydroxy, cyano, nitro, ester, C 1 ⁇ C 8 acyl, amide, sulfonyl, sulfonamido, C 6 ⁇ C 18 aryl, C 6 ⁇ C 18 aryl substituted C 1 ⁇ C 18 alkyl group, or 5 ⁇ 18 membered heteroaryl group; when R 4 is selected from C 1 ⁇ C 18 alkyl group, C 3 ⁇ C 18 cycloalkyl group, 3 ⁇ 18 membered heterocycloalkyl group, C 1 ⁇ C In the case of 18 alkoxy, C 1 ⁇ C 18 alkylamino, C 6 ⁇ C 18 aryl, C 6 ⁇ C 18 aryl substituted C 1 ⁇
  • Each R 5 and R 6 are independently selected from: H, C 1 ⁇ C 8 alkyl, hydroxy substituted C 1 ⁇ C 8 alkyl, C 1 ⁇ C 8 alkoxy substituted C 1 ⁇ C 8 alkyl , C 3 to C 8 cycloalkyl, 3 to 18 membered heterocycloalkyl, C 1 to C 8 acyl, alkenyl acyl, C 1 to C 8 sulfonyl, 5 to 18 membered heteroaryl, or R 5 , R 6 and the N atom to which it is connected together form one or more R 7 substituted or unsubstituted 3-10 membered heterocycloalkyl groups, or R 5 , R 6 and the N atom to which they are connected together form 1 or Multiple R 7 substituted or unsubstituted 5-10 heteroaryl groups;
  • Each R 7 is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkylamino, C 6 ⁇ C 18 aryl;
  • R 8 is selected from: H, C 1 ⁇ C 6 alkyl, 3 to 8-membered heterocycloalkyl substituted with C 1 ⁇ C 6 alkyl group;
  • Each R is independently selected from: H, halogen, C 1 to C 18 alkyl, C 3 to C 18 cycloalkyl, 3 to 18 membered heterocycloalkyl, C 1 to C 18 alkoxy, C 1 to C 18 alkylamino group, amino group, hydroxyl group, cyano group, nitro group, ester group, amide group, sulfonyl group, sulfonylamino group, C 6 ⁇ C 18 aryl, C 6 ⁇ C 18 aryl substituted C 1 ⁇ C 18 alkyl, or 5 to 18 membered heteroaryl; when R is selected from C 1 to C 18 alkyl, C 3 to C 18 cycloalkyl, 3 to 18 membered heterocycloalkyl, C 1 to C 18 alkoxy In the case of a C 1 ⁇ C 18 alkylamino group, a C 6 ⁇ C 18 aryl group, a C 6 ⁇ C 18 aryl substituted C 1 ⁇ C 18 al
  • the triaromatic ring compound containing a urea structure has a structure represented by formula (II), (III), (IV) or (V):
  • Y 1 is N
  • Y 3 is CR
  • Z is O
  • Y 2 is CR
  • Y 1 is N
  • Y 2 is CR 9
  • Y 3 is CR 10
  • Z is O
  • R 9 and R 10 are each independently selected from: H, or C 1 ⁇ C 10 alkane base.
  • a 1 , A 2 , B 1 , B 2 , D 1 , D 2 , E 1 and E 2 are all CR 11 ; wherein each R 11 is independently selected from: H, C 1 -C 10 alkyl, nitro, C 1 -C 10 alkoxy or halogen.
  • one of A 1 , B 1 , D 1 and E 1 is CR 12 , the other three are CH, and R 12 is selected from: H, fluorine, chlorine, bromine, C 1 ⁇ C 3 alkane Group, nitro group, C 1 ⁇ C 3 alkoxy group.
  • one of A 2 , B 2 , D 2 and E 2 is CR 13 , the other three are CH, and R 13 is selected from: H, fluorine, chlorine, bromine, C 1 ⁇ C 3 alkane Group, nitro group, C 1 ⁇ C 3 alkoxy group.
  • R 5 and R 6 are each independently selected from: H, C 1 ⁇ C 6 alkyl, hydroxy substituted C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy substituted C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 1 to C 3 acyl, C 1 to C 3 sulfonyl, 5 to 10 membered heteroaryl, or R 5.
  • R 6 and the N atom to which it is connected together form one or more R 7 substituted or unsubstituted 5-6 membered heterocyclic groups, or R 5 and R 6 and the N atom to which it is connected together form one Or multiple R 7 substituted or unsubstituted 5- to 6-membered heteroaryl groups.
  • R 5 and R 6 are each independently selected from: C 1 ⁇ C 3 alkyl, or R 5 , R 6 and the N atom to which they are connected together form a 5- to 6-membered heterocyclic group.
  • R 1 is selected from: Or R 1 and D 1 together form the following structure:
  • each R 3 is independently selected from: H, C 1 ⁇ C 6 alkyl, or -SR 8 ;
  • R 8 is selected from: H, C 1 ⁇ C 3 alkyl, or 5-6 A C 1 -C 3 alkyl substituted with a membered heterocycloalkyl group.
  • the present invention also provides applications of the above-mentioned compounds.
  • the kinases are: FLT3 kinase, CSF1R kinase, DDR1 kinase, KIT kinase, PDGFRA kinase, PDGRFB kinase, PIP5K2B kinase, RET kinase.
  • the kinase is RET kinase.
  • the RET kinase is: wild-type RET kinase and mutant RET kinase.
  • the above-mentioned triaromatic compound containing urea structure or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule or its metabolite or its solvate is used in the preparation of prevention and/or treatment of RET kinase, FLT3 kinase and/or Or the application of KIT kinase-related diseases in medicine.
  • the RET kinase, FLT3 kinase and/or KIT kinase related diseases are tumors.
  • the present invention has the following beneficial effects:
  • the urea structure-containing triaromatic compound and its pharmaceutically acceptable salts, solvates, isomers, acids, esters, metabolites or prodrugs provided by the present invention can effectively inhibit kinases, especially RET kinases, including wild With mutant RET kinase and other kinases such as FLT3 kinase, Kit kinase, etc., it can regulate the activation of multiple downstream pathways, and can be used to prepare drugs for preventing and treating various diseases related to RET kinase, FLT3 kinase and/or Kit kinase. , Such as leukemia, tumors.
  • any variable such as R 1 , R 2, etc.
  • the definition of each occurrence thereof is independent of the definition of every other occurrence.
  • combinations of substituents and variables are allowed as long as the combination stabilizes the compound.
  • the line drawn from the substituent into the ring system indicates that the bond in question can be connected to any substitutable ring atom. If the ring system is polycyclic, it means that this bond is only connected to any suitable carbon atom of the adjacent ring. It should be understood that those of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the present invention to provide chemically stable compounds that can be easily synthesized from readily available raw materials by the techniques in the art and the methods proposed below.
  • substituents themselves are substituted by more than one group, it should be understood that these groups may be on the same carbon atom or on different carbon atoms, as long as the structure is stabilized.
  • the phrase "optionally substituted with one or more substituents” is considered equivalent to the phrase “optionally substituted with at least one substituent” and the preferred embodiment in this case will have 0-3 substituents.
  • alkyl as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms.
  • the definition of “C 1 -C 6 "in “C 1 -C 6 alkyl” includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a linear or branched chain.
  • “C 1 -C 6 alkyl” specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.
  • heterocycloalkyl is a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, wherein one or more ring atoms are selected from N, O or S(O)m (where m is 0-2 Integer), the remaining ring atoms are carbon, for example: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydroisothiazolyl, Hydroxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazole Group, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, di
  • heteroaryl refers to an aromatic ring containing one or more heteroatoms selected from O, N or S.
  • Heteroaryl groups within the scope of the present invention include but are not limited to: quinolinyl, pyrazolyl, and pyrrolyl , Thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl; "heteroaryl” is also understood to include any nitrogen-containing N-oxide derivatives of heteroaryl groups. The attachment of heterocyclic substituents can be achieved through carbon atoms or through heteroatoms.
  • halogen means chlorine, fluorine, bromine and iodine.
  • alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl substituents may be unsubstituted or substituted.
  • the C 1 -C 6 alkyl group may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidinyl and the like.
  • the present invention includes the free forms of the compounds of formula I-XI, as well as their pharmaceutically acceptable salts and stereoisomers.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form” refers to amine compounds in non-salt form.
  • the included pharmaceutically acceptable salts include not only the exemplary salts of the specific compounds described herein, but also the typical pharmaceutically acceptable salts of all the compounds of formula I-XI in the free form.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form of the salt can be regenerated by treating the salt with a suitable dilute aqueous solution of alkali, such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, a dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • a suitable dilute aqueous solution of alkali such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, a dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the compound of the present invention containing a basic part or an acidic part by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in a suitable solvent or a combination of solvents.
  • the salt of an acidic compound is formed by reacting with a suitable inorganic or organic base.
  • the pharmaceutically acceptable salt of the compound of the present invention includes the conventional non-toxic salt of the compound of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid.
  • conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., as well as salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl Salts prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic
  • the appropriate "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganous salt, potassium salt, sodium salt, zinc salt, etc. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as refined Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , Piperidine, quama, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • the deprotonated acidic moieties such as carboxyl groups can be anionic, and this charge can then be protonated or alkylated basic moieties with cations inside, such as four
  • the valence of the nitrogen atom balances out, so it should be noted that the compounds of the present invention are potential internal salts or zwitterions.
  • the present invention provides a compound having formula I-XI and a pharmaceutically acceptable salt thereof for the treatment of hyperproliferative diseases or symptoms such as tumors in humans or other mammals.
  • the compounds of the present invention and pharmaceutically acceptable salts thereof can be used to treat or control non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer , Skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histocytic lymphoma, nasopharyngeal carcinoma and other transitional proliferative diseases.
  • the compounds of formula I-XI can be combined with other drugs known to treat or improve similar conditions.
  • the original drug administration mode & dosage remain unchanged, while the compound of formula I-XI is administered at the same time or subsequently.
  • the compound of formula I-XI is administered with one or more other drugs at the same time, it is preferable to use a pharmaceutical composition containing one or more known drugs and the compound of formula I-VIII at the same time.
  • the combination of drugs also includes taking the compound of formula I-XI with one or more other known drugs in overlapping time periods.
  • the dose of the compound of formula I-XI or the known drug may be lower than the dose when they are used alone.
  • the drugs or active ingredients that can be used in combination with the compounds of formula I-XI include but are not limited to:
  • the drugs or active ingredients that can be used in combination with the compound of formula I-XI include but are not limited to: aldesleukin, alendronic acid, interferon, atranoin, allopurinol, allopurinol, Sodium purine, palonosetron hydrochloride, hexamethylmelamine, aminogluminide, amifostine, amrubicin, an acridine, anatozole, dolastron, aranesp, arglabin, Arsenic trioxide, Aroxin, 5-azacytidine, azathioprine, BCG or tice BCG, betamethasone, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromuria Glycine, bortezomib, busulfan, calcitonin, alemtuzumab injection, capecitabine, carboplatin, constellation, cefe
  • step b and step c in Example 1 to synthesize compound WKF-201.
  • Dissolve compound 18 (500mg, 1.11mmol), N-(2-chloroethyl)morpholine hydrochloride (600mg, 3.3mmol), K 2 CO 3 (460mg, 3.33mmol) and TBAI (13mg, 0.1mmol)
  • 10ml DMF heat the reaction at 60°C until most of the raw materials are transformed and stop the reaction.
  • Add water to the reaction system extract twice with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and pass through the column after concentration under reduced pressure.
  • the compound WKF-202 (300mg, yield 40%) was isolated.
  • the excitation wavelength is 400nm, and the emission wavelength is 445nm and 520nm, respectively.
  • Experiments were set up with test wells (adding compound, enzyme, substrate and ATP), 0% phosphorylation wells (adding DMSO, substrate and ATP) 100% phosphorylation wells (only adding phosphorylated substrate), and 0% inhibition rate wells (Add DMSO, enzyme, substrate and ATP). Calculate the inhibition rate of the compound to the enzyme reaction according to the fluorescence ratio, analyze and calculate the IC 50 value of the compound with GraphPad software.
  • the inhibitory results of the compounds on FLT3-ITD kinase are shown in Table 3.
  • the compounds used in the control test are as follows:
  • the compounds of the present invention can effectively inhibit the proliferation of MV4-11 tumor cells at the cellular level.

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Abstract

L'invention concerne un composé cyclique tri-aromatique contenant une structure d'urée ayant la structure représentée dans la formule (I) ou un sel ou un stéréoisomère ou une molécule de promédicament ou un métabolite ou un solvate pharmaceutiquement acceptable de celui-ci. Le composé peut inhiber de manière efficace une kinase, en particulier la kinase FLT3 et RET de manière à réguler l'activation d'une pluralité de voies en aval. Le composé peut être utilisé pour préparer des médicaments pour prévenir et traiter diverses maladies liées à la kinase RET, la kinase FLT3 et/ou la kinase Kit, telles que la leucémie et les tumeurs.
PCT/CN2021/079354 2020-03-11 2021-03-05 Composé cyclique tri-aromatique contenant une structure d'urée et utilisation associée WO2021180008A1 (fr)

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