WO2021018003A1 - Inhibiteur d'egfr, composition et procédé de préparation correspondant - Google Patents

Inhibiteur d'egfr, composition et procédé de préparation correspondant Download PDF

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Publication number
WO2021018003A1
WO2021018003A1 PCT/CN2020/103856 CN2020103856W WO2021018003A1 WO 2021018003 A1 WO2021018003 A1 WO 2021018003A1 CN 2020103856 W CN2020103856 W CN 2020103856W WO 2021018003 A1 WO2021018003 A1 WO 2021018003A1
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Prior art keywords
compound
amino
cancer
methoxy
dimethylphenyl
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PCT/CN2020/103856
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English (en)
Chinese (zh)
Inventor
刘湘永
仇长勇
申其超
刘孟强
盛海同
宋晓东
杜国龙
王家炳
丁列明
Original Assignee
贝达药业股份有限公司
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Application filed by 贝达药业股份有限公司 filed Critical 贝达药业股份有限公司
Priority to CN202080050136.7A priority Critical patent/CN114430740B/zh
Publication of WO2021018003A1 publication Critical patent/WO2021018003A1/fr

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides

Definitions

  • the present invention relates to pharmaceutically active compounds, deuterated compounds (hydrogen replaced by deuterium) and pharmaceutically acceptable salts thereof, which can be used to treat or prevent diseases or medical conditions mediated by certain mutant forms of epidermal growth factor receptor ( For example, L858R activating mutant, Exon19 deletion activating mutant, T790M resistance mutant and C797S resistance mutant).
  • the present invention also relates to a pharmaceutical composition containing the compound and a method of using the compound, deuterated compound and salt thereof to treat diseases mediated by various forms of EGFR mutants.
  • Epidermal growth factor receptor is a transmembrane glycoprotein belonging to the ErbB family of tyrosine kinase receptors. Activation of EGFR leads to autophosphorylation of receptor tyrosine kinases, which initiates a cascade of downstream signaling pathways involved in regulating cell proliferation, differentiation, and survival. EGFR is abnormally activated by various mechanisms, such as receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation, and is associated with the development of a variety of human cancers.
  • Inhibition of EGFR is one of the key goals of cancer treatment. Although the previous generations of EGFR-TKIs developed rapidly, the problem of drug resistance also appeared along with the development of drugs. Most drug resistance is the T790M mutation of the ATP receptor. Recently developed third-generation irreversible inhibitors against T790M, such as osimertinib, have very good inhibitory activity, but drug resistance will inevitably appear.
  • EGFR-C797S mutation is the most common secondary mutation leading to third-generation TKI resistance. C797S is a missense mutation in which cysteine is replaced by serine at position 797 of exon 20 of EGFR. It is located in the tyrosine kinase region of EGFR. The mutation of C797S prevents osimertinib from continuing to form covalent bonds in the ATP binding domain, thus losing Inhibit the effect of EGFR activation, leading to the occurrence of drug resistance.
  • the present invention relates to compounds capable of inhibiting EGFR, and these compounds can be used to treat cancer and infectious diseases.
  • the compound of formula I or its stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof.
  • R 1 is selected from -NR 7 R 8 , -C 5-6 heterocyclyl and The -NR 7 R 8 and -C 5-6 heterocyclyl are optionally substituted by -C 4-6 cycloalkyl, -C 4-6 heterocyclyl and -NR 7 R 8 ;
  • R 2 is selected from halogen, CN, NH 2 , -C 1-6 alkyl and -C 1-6 haloalkyl;
  • R 3 is selected from hydrogen, halogen, -C 1-6 alkyl and -C 1-6 haloalkyl;
  • R 7 , R 8 and R 9 are each independently selected from hydrogen, -C 1-6 alkyl and -C 1-6 haloalkyl;
  • X is selected from CH and N;
  • s is selected from 1 and 2.
  • the embodiment compound of formula I is characterized in that R 1 is selected from -C 5-6 heterocyclyl.
  • Example compounds of formula I characterized in that R 1 is selected from
  • Example compounds of formula I characterized in that R 1 is selected from
  • Example compounds of formula I characterized in that R 1 is selected from
  • the example compounds of formula I are characterized in that R 2 is -C 1-3 alkyl or -C 1-3 haloalkyl.
  • the example compound of formula I is characterized in that R 2 is -CH 3 , -C 2 H 5 ,
  • the example compound of formula I is characterized in that R 2 is -CH(CH 3 ) 2 or
  • the example compounds of formula I are characterized in that R 3 is selected from halogen.
  • R 3 is selected from Cl and Br.
  • Example compounds of formula I are characterized in that R 3 is selected from hydrogen.
  • the example compounds of formula I are characterized in that R 7 , R 8 and R 9 are each independently selected from -C 1-6 alkyl.
  • the example compounds of formula I are characterized in that R 7 , R 8 and R 9 are independently selected from methyl and ethyl.
  • the present invention also provides a pharmaceutical composition, including any one of the compounds of the present invention, or a pharmaceutically acceptable salt or its stereoisomer compound, and at least one pharmaceutically acceptable carrier or excipient .
  • the present invention additionally provides methods for inhibiting various forms of EGFR, which refer to mutant forms of EGFR, including L858R, ⁇ 19del, T790M, and C797S, and any combination thereof, and the method includes administering the present invention to a patient
  • the compound or pharmaceutically acceptable salt or stereoisomer thereof of any one of the inventions are particularly useful as pharmaceuticals.
  • the present invention further provides a method for treating EGFR-driven cancer, the method comprising administering a therapeutically effective amount of any compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof to a patient in need thereof.
  • the EGFR-driven cancer is characterized by the presence of one or more mutations selected from: (i) C797S, (ii) L858R and C797S, (iii) C797S and T790M, (iv) L858R, T790M , And C797S, or (v) ⁇ 19del, T790M and C797S.
  • the EGFR-driven cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.
  • the lung cancer is EGFR L858R / T790M / C797S or EGFR ⁇ 19del / T790M / C797S mutant NSCLC.
  • the present invention provides a method for inhibiting mutant EGFR in a patient, the method comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof to a patient in need thereof.
  • the invention also provides the use of the compound of the invention or its pharmaceutical composition in the preparation of medicines.
  • the drug is used to treat or prevent cancer.
  • cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.
  • the lung cancer is EGFR L858R / T790M / C797S or EGFR ⁇ 19del / T790M / C797S mutant NSCLC.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • Preferred halogen groups include F, Cl and Br.
  • alkyl group as used herein includes saturated monovalent hydrocarbon groups having linear, branched or cyclic moieties.
  • alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 -Methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • C 1-8 alkyl C 1-8 is defined as the group identified as having a straight-chain or branched 1,2,3,4,5,6,7 or 8 carbon atoms, Chain arrangement.
  • the alkoxy group is an oxyether formed from the aforementioned linear, branched or cyclic alkyl group.
  • aryl refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing carbon ring atoms.
  • Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.
  • heteroaryl as used herein means an unsubstituted or substituted stable five- or six-membered monocyclic aromatic ring system or an unsubstituted or substituted nine- or ten-membered benzo-fused heteroaromatic ring Department or bicyclic heteroaromatic ring system.
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to produce a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl , Benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
  • cycloalkyl refers to a cyclic saturated alkyl chain having 3-12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclobutyl, cyclobutyl.
  • substituted refers to a group in which one or more hydrogen atoms are each independently substituted with the same or different substituents.
  • the substituents are independently selected from -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy , Isobutoxy, t-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, CF 3 , -OCF 3 , amino, dimethyl Amino, methylthio, sulfonyl and acetyl.
  • composition is intended to encompass products that contain specific ingredients in specific amounts, as well as any product that is directly or indirectly produced by a combination of specific ingredients in specific amounts. Therefore, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods for preparing the compounds of the present invention are also part of the present invention.
  • some crystalline forms of the compound may exist as polymorphs and are therefore intended to be included in the present invention.
  • some compounds may form solvates (ie, hydrates) or common organic solvents with water, and these solvates are also included in the scope of the present invention.
  • substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.
  • substituted alkoxy groups include, but are not limited to, aminomethoxy, tetrafluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
  • the compounds of the present invention may also exist in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts".
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • the pharmaceutically acceptable acid/anionic salt usually takes a form in which the basic nitrogen is protonated with an inorganic acid or an organic acid.
  • organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, apple Acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid , Salicylic acid, saccharin or trifluoroacetic acid.
  • Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc.
  • the prodrug of the compound of the present invention is included in the protection scope of the present invention.
  • the prodrug refers to a functional derivative that is easily converted into a desired compound in the body. Therefore, in the treatment method of the present invention, the term "administration” shall include the treatment of various conditions described with specific disclosed compounds or the use of compounds that may not be specifically disclosed, but which are converted into specific compounds in vivo after administration to the subject Compound.
  • the conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs” (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
  • the compounds of the present invention may contain one or more asymmetric centers, and may produce diastereomers and optical isomers from this.
  • the present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the above formula I does not exactly define the three-dimensional structure of a certain position of the compound.
  • the present invention includes all stereoisomers of the compound represented by formula I and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or in the process of racemization or epimerization known to those of ordinary skill in the art, the product obtained may be a mixture of stereoisomers.
  • the present invention includes any possible tautomers, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the present invention includes any possible solvate and polymorph.
  • the type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts.
  • Non-toxic organic bases capable of being derivatized into salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents.
  • non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pyruvic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid.
  • citric acid Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound of formula I will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% purity, more suitable purity is at least 75%, and particularly suitable purity is at least 98% (% is weight ratio) .
  • the pharmaceutical composition provided by the present invention includes the compound represented by formula I (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants.
  • the pharmaceutical composition of the present invention includes oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration).
  • the pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
  • the compound of formula I of the present invention can be used as an active component and mixed with a drug carrier to form a pharmaceutical composition.
  • the pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may adopt a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of bringing into association the active ingredient and the carrier which constitutes one or more necessary ingredients.
  • the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both.
  • the product can be easily prepared into the desired appearance.
  • the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula I or its stereoisomers, tautomers, polymorphs, solvates, and pharmaceutically acceptable salts thereof, Its prodrug.
  • a pharmaceutically acceptable carrier and a compound represented by formula I or its stereoisomers, tautomers, polymorphs, solvates, and pharmaceutically acceptable salts thereof, Its prodrug.
  • the combination of the compound represented by formula I or its pharmaceutically acceptable salt, and one or more other compounds with therapeutic activity is also included in the pharmaceutical composition of the present invention.
  • the drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier.
  • Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil and water.
  • the gas carrier includes carbon dioxide and nitrogen.
  • any pharmacologically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants, etc.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here.
  • standard aqueous or non-aqueous formulation techniques can be used for tablet coating.
  • the tablet containing the compound or pharmaceutical composition of the present invention can be compressed or molded, and optionally, can be made into a tablet together with one or more auxiliary components or adjuvants.
  • the active ingredient is in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surface active agent or dispersant, and compressed in a suitable machine to make compressed tablets.
  • the powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to make a molded tablet.
  • each tablet contains about 0.05 mg to 5 g of active ingredient
  • each cachet or capsule contains about 0.05 mg to 5 g of active ingredient.
  • a formulation intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 95% of the total pharmaceutical composition.
  • the unit dosage form generally contains about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • the present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems.
  • the above-mentioned pharmaceutical composition can be prepared into a sterile powder form for immediate preparation of sterile injection or dispersion.
  • the final injection form must be sterile, and for easy injection, it must be easy to flow.
  • the pharmaceutical composition must be stable during preparation and storage. Therefore, it is preferable that the pharmaceutical composition be stored under conditions of anti-microbial contamination such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
  • the pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device.
  • These preparations can be prepared by using the compound represented by the formula I of the present invention, or a pharmaceutically acceptable salt thereof, through conventional processing methods.
  • a cream or ointment is prepared by adding about 5 wt% to 10 wt% of a hydrophilic material and water to produce a cream or ointment with the desired consistency.
  • the pharmaceutical composition provided by the present invention may take a solid as a carrier and is suitable for rectal administration.
  • a unit dose suppository is the most typical dosage form.
  • Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by mixing the pharmaceutical composition with softened or melted auxiliary materials, then cooling and molding.
  • the above formulations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants and preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood.
  • additional adjuvant components such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants and preservatives (including antioxidants), etc.
  • other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood.
  • the pharmaceutical composition comprising the compound represented by formula I, or a pharmaceutically acceptable salt thereof, can be prepared in the form of powder or concentrate.
  • the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day.
  • the effective treatment drug dosage level is 0.01mg/kg body weight to 50mg/kg body weight per day, or 0.5mg to 3.5g per patient per day.
  • the specific dosage level and treatment plan for any particular patient will depend on many factors, including the activity of the specific compound used, age, weight, overall health, gender, diet, time of administration, route of administration, excretion rate, drug combination The condition and severity of the specific disease being treated.
  • DIEA N,N-diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • PE petroleum ether
  • n-BuOH n-butanol
  • TsOH p-toluenesulfonic acid
  • K 2 CO 3 potassium carbonate
  • HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
  • Pd/C Palladium on carbon
  • NMP N-methyl-2-pyrrolidone
  • Xantphos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
  • the synthesis method of compound 2-1 is the same as that of compound 1-9, except that the raw material 1-methyl-4-(4-piperidinyl)piperazine dihydrochloride is replaced with 4-dimethylaminopiperidine.
  • the synthesis method of compound 2-2 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 2-1.
  • the synthesis method of compound 3-1 is the same as that of compound 1-9, except that the raw material 1-methyl-4-(4-piperidinyl)piperazine dihydrochloride is replaced with morpholine.
  • the synthesis method of compound 3-2 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 3-1.
  • the synthesis method of compound 4-1 is the same as that of compound 1-9, except that the raw material 1-methyl-4-(4-piperidinyl)piperazine dihydrochloride is replaced with N,N,N'-tri Methyl ethylene diamine.
  • the synthesis method of compound 5-1 is the same as that of compound 1-9, except that the raw material 1-methyl-4-(4-piperidinyl)piperazine dihydrochloride is replaced with N-methylpiperazine.
  • the synthesis method of compound 5-2 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 5-1.
  • the synthesis method of compound 5 is the same as that of compound 1, except that the starting material compound 1-10 is replaced with compound 5-2.
  • the synthesis method of compound 6-1 is the same as that of compound 1-9, except that the raw material 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene is replaced with 1-fluoro-5-methoxy Base-2-ethyl-4-nitrobenzene.
  • the synthesis method of compound 6-2 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 6-1.
  • the synthesis method of compound 7-3 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 7-2.
  • the synthesis method of compound 8-3 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 8-2.
  • the synthesis method of compound 9-3 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 6-1.
  • the synthetic method of compound 14-1 is the same as that of compound 10-2, except that the raw material 1A is replaced with 14-0.
  • the synthesis method of compound 15-1 is the same as that of compound 10-2, except that the raw material 10-1 is replaced with isopropenyl boronic acid.
  • the following comparative compound B was prepared according to the method described in Example 41 in WO2019015655.
  • test compound concentration gradient the test compound test starting concentration is 3000nM or 100nM, diluted to 100% DMSO solution of 100 times final concentration in 384source plate, and then use Precision to dilute the compound 3 times, 10 concentrations. Use a dispenser Echo 550 to transfer 250 nL 100 times the final concentration of the compound to the target plate OptiPlate-384F.
  • Conversion%_sample is the conversion rate reading of the sample
  • Conversion%_min the average value of the negative control wells, representing the conversion rate readings of the wells without enzyme activity
  • Conversion%_max the average value of the positive control wells, representing the conversion rate readings of the wells without compound inhibition.
  • the fitted dose-response curve takes the log value of the concentration as the X-axis and the percentage inhibition rate on the Y-axis.
  • the log(inhibitor) vs.response–Variable slope of the analysis software GraphPad Prism 5 is used to fit the dose-effect curve to obtain each compound pair IC50 value of enzyme activity.
  • IC 50 values are expressed as IC 50 values, as shown in Table 1. As illustrated in the examples, the compounds of the present invention show IC 50 values within the following range: "A” represents “IC 50 ⁇ 1nM”;”B” represents “1nM ⁇ IC 50 ⁇ 100nM”;”C” represents “IC 50” >100nM”.
  • Cell line Ba/F3 cell line with stable overexpression of ⁇ 19del/T790M/C797S or L858R/T790M/C797S mutation gene (named Ba/F3- ⁇ 19del/T790M/C797S and Ba/F3-L858R/T790M/C797S ), and Ba/F3EGFR wild-type cell line and A431EGFR wild-type cell line.
  • test compound (20mM stock solution) was diluted to 10mM with 100% DMSO as the starting concentration, and then serially diluted 3 times with the "9+0" concentration.
  • a 96-well dilution plate (Cat#P-05525, Labcyte);
  • step 2 The compound prepared in step 2 is added to a 15 ⁇ L cell plate per well, and the final concentration is 1000, 333, 111.1, 37, 12.3, 4.1, 1.4, 0.5, 0.2 and 0 nM, and the final concentration of DMSO is 0.1%.
  • the blank control well is medium (0.1% DMSO);
  • X logarithm of compound concentration
  • Y luminescence value
  • IC 50 Cell proliferation assay results are expressed by IC 50, as shown in Table 2.
  • the compounds of the present invention illustrated in the examples show that the IC 50 value is in the following range: "A” represents “IC 50 ⁇ 50nM”;”B” represents “50nM ⁇ IC 50 ⁇ 100nM”;”C” represents “IC 50 ⁇ 100nM”.
  • the blood collection time points for oral administration are: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 7 hours and 24 hours, the administration dose is 5 mpk, and the blood collection volume is 300 ⁇ L.
  • the blood was centrifuged at 4000 rpm for 5 minutes, and about 100 ⁇ L was placed at -20°C for testing.
  • Use WinNonlin (V4.1, Pharsight) software with a non-compartmental model to analyze the plasma concentration-time data of individual animals and calculate the pharmacokinetic parameters of the test compound.
  • the PK properties of the compounds in rats are shown in Table 3.

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Abstract

L'invention concerne un composé de formule I, un procédé d'utilisation de ce composé en tant qu'inhibiteur d'EGFR et une composition pharmaceutique contenant ce composé. Le composé peut être utilisé pour traiter, prévenir ou faire régresser des maladies ou des états tels que le cancer ou des infections.
PCT/CN2020/103856 2019-07-26 2020-07-23 Inhibiteur d'egfr, composition et procédé de préparation correspondant WO2021018003A1 (fr)

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WO2023006088A1 (fr) * 2021-07-30 2023-02-02 浙江大学智能创新药物研究院 Composé pour inhibiteur de kinase egfr, composition et utilisation associées
WO2023011610A1 (fr) * 2021-08-06 2023-02-09 南京红云生物科技有限公司 Composé de benzodioxane, son procédé de préparation et son application
WO2023025164A1 (fr) * 2021-08-27 2023-03-02 成都地奥九泓制药厂 Formes cristallines, procédé de préparation et application d'un composé d'oxyde d'aryle phosphine

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CN113501808A (zh) * 2021-06-04 2021-10-15 清远中大创新药物研究中心 一种新型亚磺酰基苯胺基的嘧啶衍生物及其在制备抗肿瘤药物中的应用
CN113501808B (zh) * 2021-06-04 2024-06-11 清远中大创新药物研究中心 一种亚磺酰基苯胺基的嘧啶衍生物及其在制备抗肿瘤药物中的应用
WO2023006088A1 (fr) * 2021-07-30 2023-02-02 浙江大学智能创新药物研究院 Composé pour inhibiteur de kinase egfr, composition et utilisation associées
CN115677772A (zh) * 2021-07-30 2023-02-03 浙江大学智能创新药物研究院 一种用于egfr激酶抑制剂的化合物、组合物及其应用
CN115677772B (zh) * 2021-07-30 2023-08-18 浙江大学智能创新药物研究院 一种用于egfr激酶抑制剂的化合物、组合物及其应用
WO2023011610A1 (fr) * 2021-08-06 2023-02-09 南京红云生物科技有限公司 Composé de benzodioxane, son procédé de préparation et son application
WO2023025164A1 (fr) * 2021-08-27 2023-03-02 成都地奥九泓制药厂 Formes cristallines, procédé de préparation et application d'un composé d'oxyde d'aryle phosphine

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