WO2017084640A1 - Composé hétérocyclique azoté, procédé de préparation associé, et application dans l'inhibition de l'activité kinase - Google Patents

Composé hétérocyclique azoté, procédé de préparation associé, et application dans l'inhibition de l'activité kinase Download PDF

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WO2017084640A1
WO2017084640A1 PCT/CN2017/070372 CN2017070372W WO2017084640A1 WO 2017084640 A1 WO2017084640 A1 WO 2017084640A1 CN 2017070372 W CN2017070372 W CN 2017070372W WO 2017084640 A1 WO2017084640 A1 WO 2017084640A1
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汪舰
别建波
郎明
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清华大学
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    • 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
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention relates to a nitrogen-containing heterocyclic compound, a preparation method thereof and application thereof in inhibiting kinase activity, and belongs to the technical field of medicinal chemistry.
  • Tumor molecular targeted therapy is a therapeutic method based on the key protein related to tumorigenesis and development, which selectively acts on signal proteins by chemical means to kill tumor cells.
  • the characteristics of targeted therapy are: high specificity, strong selectivity, and low toxic side effects compared with traditional chemotherapeutic drugs; when combined, it can enhance the efficacy of traditional chemotherapy; targeted inhibitor drugs are clinically prone to drug resistance and therapeutic drugs Invalid.
  • Non-small cell lung cancer accounts for about 85% of all lung cancer pathological types.
  • the cause of non-small cell lung cancer is complex, multi-gene, multi-target regulation and easy mutation to produce resistance.
  • Non-small cell lung cancer treatments mainly include traditional chemotherapeutic drugs such as platinum, paclitaxel, antibodies, neovascular inhibitors and targeted inhibitors, but with the emergence of drug-resistant patients caused by a large number of mutations in the clinic, it was found And looking for anti-drug resistant non-small cell lung cancer treatment drugs is still a hot area of the industry.
  • traditional chemotherapeutic drugs such as platinum, paclitaxel, antibodies, neovascular inhibitors and targeted inhibitors
  • ALK inhibitors such as crizotinib, ceritinib, etc.
  • third-generation EGFR inhibitors currently in the late clinical stage, such as AZD9219, CO1686, etc., but currently There are still problems with poor efficacy or low selectivity, so it is urgent to find and find a new type of therapeutic drug with high mutation resistance selectivity or multiple target inhibition activity.
  • the object of the present invention is to provide a nitrogen-containing heterocyclic compound, a preparation method thereof and the use thereof for inhibiting kinase activity, and the nitrogen-containing hybrid compound can be used as a proliferation inhibitor of various tumor cells, and is a novel mechanism of action. Multi-target tumor treatment drugs.
  • the present invention provides a nitrogen-containing heterocyclic compound, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, a polymorph or a prodrug thereof, wherein
  • the general formula of the nitrogen-containing heterocyclic compound is as shown in Formula I or Formula I':
  • R 1 , R 2 , R 3 , R 4 are independently selected from any of hydrogen, halogen, cyano, hydroxy, amino and substituted or unsubstituted C1-C6 alkyl, and R 1 , R 2 , R 3 , any two groups of R 4 can form a 3-10 yuan ring system;
  • M 1 , M 2 , M 3 are independently selected from CRa or N, and at least one of M 1 , M 2 and M 3 is N;
  • Ra is hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkane a group and one of a substituted or unsubstituted C3-C8 cycloalkyl group;
  • W is selected from any of the following groups: a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, an unsubstituted or halogenated 4-8 membered alkynyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 4-8 membered heterocyclic group, a 5-10 membered aryl or heteroaryl group, a substituted carbonyl group, a substituted sulfonyl group, a substituted or unsubstituted amino group
  • the heterocyclic group contains 1-3 heteroatoms selected from the group consisting of N, O, S, P and B;
  • the substituent is one or more groups in the group substituted with at least one substituent selected from the group consisting of halogen, hydroxy, amino, cyano, unsubstituted or halogenated C1-C8 alkyl, unsubstituted Substituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstituted Substituted or halogenated C2-C6 acyl group, unsubstituted or halogenated 5- to 8-membered aryl group, unsubstituted or halogenated 5- to 8-membered heteroaryl group, unsubstituted or halogenated 4-8 membered saturated heterocyclic ring a 4- to 8-membered carbocyclic
  • R 1 , R 2 , R 3 , R 4 may specifically be hydrogen.
  • M 1 , M 2 are independently selected from CH or N, and at least one of M 1 and M 2 is N;
  • M 3 is selected from CF, C-CF 3 , C-Cl Any of CH, N and N;
  • W is selected from any of the following groups: a substituted or unsubstituted C1-C6 alkyl or cycloalkyl group, a substituted or unsubstituted 4-10 membered heterocyclic ring, a spiro or bridged ring formed by a substituted or unsubstituted 4-10 membered cycloalkyl group and a substituted or unsubstituted 4-10 membered heterocycloalkyl group; W is specifically a substituted or unsubstituted one of the following groups Species: cyclopentane, cyclohexane, tetrahydropyrrole ring, tetrahydrofuran ring, piperidine ring, tetrahydropiperidine ring, piperazine ring, morpholine ring, pyrazole ring, indazole ring, benzene ring or pyridine ring;
  • substitution means that the substituent is independently selected from at least one of the following groups: halogen, hydroxy, cyano, amino, alkyl, monoalkylamino, dialkylamino), cycloalkyl, heterocyclic Alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, cycloalkylalkyl, heterocyclyl Alkyl, aralkyl, alkylcycloalkyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylheterocyclyl, (alkoxycarbonyl)(alkyl)amino, (alkoxyalkyl) ( Alkyl) amino group.
  • the compound of the formula I may specifically be any one of the compounds of the following formula I-a to the compound of the formula I-j1:
  • the compound of the formula I' may specifically be any of the following formulas I'-a to I'-f:
  • the invention further provides a compound of formula I or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable thereof. Salt; or
  • a method of the compound of Formula I' or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof, comprising the steps :
  • X and LG are each independently a leaving group, and are selected from any of halogen, sulfonate, boric acid, and boric acid ester;
  • X is as defined in Formula IV; M 1 , M 2 and M 3 are the same as Formula I or Formula I';
  • a compound of the formula III is coupled with a compound of the formula II or a compound of the formula II' in the presence of a transition metal catalyst and/or an acid/base (acid/base represents an acid or a base).
  • R1, R2, R3, R4, L and W are as defined in Formula I; in Formula II', R 1 , R 2 , R 3 , R 4 , L and W are as defined in Formula I′.
  • the coupling reaction is carried out in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, At least one of 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dioxane;
  • the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, At least one of 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dioxane;
  • the transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, Palladium triphenylphosphine acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(tri-o-phenylmethylphosphine)palladium dichloride and At least one of 1,2-bis(diphenylphosphino)ethanedichloropalladium; the catalyst ligand is selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate, and tri-n-butyl At least one of phosphine, triphenylphos
  • the base is an inorganic base or an organic base;
  • the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, At least one of potassium carbonate, potassium hydrogencarbonate, sodium carbonate, and sodium hydrogencarbonate;
  • the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diaza At least one of cyclo[5.4.0]undec-7-ene, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and lutidine;
  • the acid is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid.
  • the invention further provides a compound of formula I or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof;
  • the invention further provides a kinase inhibitor comprising a compound of formula I or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug thereof or a pharmaceutically acceptable salt; or
  • the invention further provides a compound of formula I or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof;
  • the tumor may be 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 interstitial Any of tumor, leukemia, lymphoma, and nasopharyngeal cancer.
  • the invention still further provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the present invention also provides a method of inhibiting EGFR mutant kinase activity and/or ALK kinase activity, which comprises the step of administering to a recipient animal (e.g., a mammal, a human) a compound of formula I as described in any one of the above, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof;
  • a recipient animal e.g., a mammal, a human
  • a compound of formula I as described in any one of the above, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof;
  • the invention also provides a method of preventing and/or treating a tumor comprising the steps of administering to a recipient animal (e.g., a mammal, a human) a compound of formula I as described in any one of the above, which is pharmaceutically acceptable a salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof; or
  • the tumor may be 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 interstitial Any of tumor, leukemia, lymphoma, and nasopharyngeal cancer.
  • the compound having the structural formula represented by Formula I or the structural formula represented by Formula I' provided by the present invention can inhibit various tumor cells, especially lung cancer cells which can selectively act on EGFR T790M mutation and ALK positive, A multi-target lung cancer treatment drug with a novel mechanism of action.
  • reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH 2 O- is equivalent to -OCH 2 -.
  • C1-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • halogen means fluoro, chloro, bromo or iodo.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group as defined below which is substituted by a hydroxy group (-OH).
  • Niro means -NO 2 .
  • Amino means -NH 2 .
  • Substituted amino means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroarylalkylamino, (alkoxycarbonyl)(alkyl)amino, (alkoxyalkyl)(alkyl)amino.
  • Carboxyl means -COOH.
  • alkyl group means consisting only of carbon atoms and hydrogen atoms, and is not unsaturated.
  • a bond a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and attached to the remainder of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.
  • alkenyl as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, vinyl, propylene Alkyl group, allyl group, but-1-enyl group, but-2-enyl group, penten-1-alkenyl group, pentane-1,4-dienyl group and the like.
  • alkynyl as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one.
  • a linear or branched hydrocarbon chain having one or more double bonds having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and attached to the remainder of the molecule by a single bond Groups such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.
  • cycloalkyl as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include condensing a ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be suitably employed
  • the carbon atom is connected to the rest of the molecule by a single bond.
  • a carbon atom in a cycloalkyl group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo[2.2.1]hept
  • heterocyclyl as a group or part of another group means consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
  • one or more of the rings may be an aryl or heteroaryl group as defined hereinafter, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, tetrahydropiperidinyl, thiomorpholinyl, 2,7-diaza - Spiro[3.5]decane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane- 2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroiso
  • aryl as a group or part of another group means a conjugate having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • Hydrocarbon ring system group for the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 selected
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, diaza naphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Base, phenazinyl
  • heteroarylalkyl refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.
  • heterocycloalkyl refers to an alkyl group as defined above which is substituted by a heterocyclic group as defined above.
  • optionally or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition.
  • optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.
  • a chemical moiety refers to a particular fragment or functional group in a molecule.
  • a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • the compounds of the present invention are intended to include E- and Z-geometric isomers unless otherwise stated.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
  • the compounds of the invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof.
  • the preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, me
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base which is capable of retaining the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
  • ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Polymorph refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of the compound of the invention and one or more solvent molecules.
  • the solvent may be water, and the solvate in this case is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the invention may form true solvates, but in some cases, it is also possible to retain only a defined amount of water or a mixture of water plus a portion of the indefinite solvent.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
  • the invention also includes prodrugs of the above compounds.
  • prodrug means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis.
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention.
  • Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood.
  • Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxy protecting groups.
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government authorities for acceptable use by humans or livestock. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • tumor include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • preventing include the possibility of reducing the occurrence or progression of a disease or condition by a patient.
  • treatment and other similar synonyms as used herein includes the following meanings:
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • the terms “pharmaceutical combination”, “drug combination”, “combination”, “administering other treatments”, “administering other therapeutic agents” and the like as used herein mean by mixing or combining more than one active ingredient.
  • the medical treatment obtained includes both fixed and unfixed combinations of the active ingredients.
  • the term “fixed combination” refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • the term “unfixed combination” refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • Figure 1 is a scheme for the synthesis of a compound of formula II or a compound of formula II'.
  • Figure 2 is a road map for the synthesis of the compound of formula III.
  • Figure 3 is a scheme for the synthesis of a compound of formula I or a compound of formula I'.
  • Example 11 50 mg, 0.19 mmol
  • Intermediate 21 71 mg, 0.24 mmol
  • Example 2 84 mg as a white solid.
  • Example 11 (40 mg, 0.15 mmol) and Intermediate 22 (54 mg, 0.19 mmol) were used as the starting material, and the same procedure as in Example 1 was used to give Example 3: 35 mg of white solid, yield 45%.
  • Example 7 The compound of Example 7 was obtained by the same procedure as in Example 1 using Intermediate 11 (50 mg, 0.19 mmol) and 26 (75 mg, 0.24 mmol) as the starting material. The body was 74 mg and the yield was 72%.
  • the intermediate 14 (40 mg, 0.17 mmol) and 26 (67 mg, 0.21 mmol) were used as the starting materials, and the same procedure as in Example 1 was used to obtain the compound of Example 8 as a white solid (yield: 46%).
  • Example 10 60 mg of white solid.
  • Example 16 The intermediate 16 (30 mg, 0.13 mmol) and 26 (50 mg, 0.16 mmol) were used as the starting materials, and the same procedure as in Example 1 was used to obtain the compound of Example 12: 25 mg of white solid, yield 38%.
  • Example 13 28 mg as a white solid.
  • Example 14 (28 mg, 0.05 mmol) was dissolved in DCM (4 mL). After cooling to room temperature, the solvent was evaporated to give a white crystallite.
  • Example 15 (40 mg, 0.06 mmol) was dissolved in DCM (4 mL). After cooling to room temperature, the solvent was evaporated to give a white crystal.
  • Test Example 1 Determination of the activity of ALK wt /ALK L1196M kinase by the compound of the present invention
  • the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 ⁇ g/mL, 125 ⁇ L/well coated with the enzyme label. The plate was reacted at 37 ° C for 12-16 hours. Discard the liquid in the well. The plate was washed, and the plate was washed three times with T-PBS (0.1% Tween-20 in potassium-free PBS, 200 ⁇ L/well) for 5 minutes each time. The enzyme plate was dried in an oven at 37 ° C for 1-2 hours;
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
  • 50 ⁇ L of ALK wt /ALK L1196M kinase domain recombinant protein diluted in reaction buffer was added to initiate the reaction, and two wells without ATP control wells were required for each experiment.
  • the reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm). Discard the liquid in the well and wash the plate three times with T-PBS;
  • IC 50 values were obtained by four-parameter regression using the software attached to the microplate reader. 0 ⁇ IC50 ⁇ 100 nM, denoted as “+++”; 100 nM ⁇ IC50 ⁇ 500 nM, denoted “++”; IC50 > 500 nM, denoted "+”. The experimental results are shown in Table 1.
  • Test Example 2 Inhibitory activity of compounds against other kinases
  • the inhibitory activities of kinases such as ALK L1152 , ALK G1202 , ALK F1245 , ALK C1156 , ALK G1269 , ALK S1206 , EGFR wt , EGFR TT90M , EGFR T790M/L858R and ROS were tested by a kinase screening method similar to that of Test Example 1.
  • Test Example 3 Compound inhibiting cell proliferation activity
  • the activity of the example compounds against cell proliferation inhibition was assessed by Cell Titer 96 single solution cell proliferation assay. 24 hours after seeding, cells were treated with the example compounds and grown for 72 hours. The cell count was corrected at time zero (treatment time), and the percent growth data of the Microsoft Excel was plotted against the control group (DMSO) using XLfit version 4.2.2, and the concentration (GI50 value) for inhibiting 50% growth was determined.
  • the results showed that the compounds of Examples 7, 8, 9, 12, 13, 16 had strong proliferation inhibitory activity against cell lines such as NCI-H3122 and EML4-ALK G1202 , and the IC50 was less than 100 nM; meanwhile, the above compounds were against H1975, A431. Cell lines such as SK-N-SH also have good inhibitory activity with an IC50 of less than 500 nM.
  • the compound having the structural formula represented by Formula I or the structural formula represented by Formula I' provided by the present invention can inhibit various tumor cells, especially lung cancer cells which can selectively act on EGFR T790M mutation and ALK positive, A multi-target lung cancer treatment drug with a novel mechanism of action.

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Abstract

L'invention concerne un composé hétérocyclique azoté, un procédé de préparation associé, et une application dans l'inhibition de l'activité kinase. La formule du composé hétérocyclique azoté est telle que représentée dans la formule I ou formule I', dans laquelle : R1, R2, R3 et R4 sont sélectionnés indépendamment parmi l'un quelconque : hydrogène, halogène, un groupe cyano, un groupe hydroxy, un groupe amino et un groupe alkyle C1-C6 substitué ou non substitué, et deux groupes quelconques parmi R1, R2, R3 et R4 pouvant former un système cycle à 3-10 chaînons; M1, M2 et M3 sont sélectionnés indépendamment entre CRa et N, et M1, et/ou M2 et/ou M3 représentant N; W est sélectionné parmi un groupe alkyle C1-C6 substitué ou non substitué, un groupe alcényle à chaîne C2-C6 substitué ou non substitué, un groupe alkynyle à chaine à 4-8 chaînons non substitué ou halogéné, un groupe cycloalkyle C3-C8 substitué ou non substitué, un groupe hétérocyclyle à 4-8 chaînons substitué ou non substitué, un groupe aryle ou hétéroaryle à 5-10 chaînons, un groupe carbonyle substitué, un groupe sulfonyle substitué et un groupe amino substitué ou non substitué. Le composé hétérocyclique peut inhiber une activité kinase mutante EGFR ou une activité kinase ALK, et est un médicament de traitement de tumeur multi-cible, dont le mécanisme d'action est tout nouveau.
PCT/CN2017/070372 2015-11-17 2017-01-06 Composé hétérocyclique azoté, procédé de préparation associé, et application dans l'inhibition de l'activité kinase WO2017084640A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021018009A1 (fr) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Inhibiteur d'egfr, composition et procédé de préparation correspondant

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102647277B1 (ko) * 2017-07-19 2024-03-12 치아타이 티안큉 파마수티컬 그룹 주식회사 Egfr 키나제 억제제로써의 아릴-인-산소 화합물
JP7085242B2 (ja) * 2017-12-21 2022-06-16 深▲チェン▼市塔吉瑞生物医薬有限公司 キナーゼ活性を阻害するためのアリールホスフィンオキシド
JP2022517396A (ja) * 2019-01-18 2022-03-08 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド Ｅｇｆｒ阻害剤の塩、結晶形及びその製造方法
WO2020216371A1 (fr) * 2019-04-26 2020-10-29 江苏先声药业有限公司 Inhibiteur d'egfr et son utilisation
AU2020385527B2 (en) * 2019-11-21 2023-04-13 Tyk Medicines, Inc. Compound used as EGFR kinase inhibitor and use thereof
CN113527281B (zh) * 2020-04-20 2023-12-22 昆山彭济凯丰生物科技有限公司 杂环化合物及其制备方法和应用
WO2022199589A1 (fr) * 2021-03-23 2022-09-29 南京明德新药研发有限公司 Dérivés de pyrimidine
WO2022253081A1 (fr) * 2021-06-03 2022-12-08 希格生科（深圳）有限公司 Dérivé d'oxyde de phosphine, son procédé de préparation et son application

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1429222A (zh) * 2000-02-17 2003-07-09 安姆根有限公司 激酶抑制剂
CN102105150A (zh) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 用作激酶抑制剂的磷衍生物
CN102131788A (zh) * 2008-04-07 2011-07-20 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
CN103153064A (zh) * 2010-10-14 2013-06-12 阿里亚德医药股份有限公司 抑制egfr导致的癌症中细胞增殖的方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2917210B1 (fr) * 2012-11-06 2019-02-27 Shanghai Fochon Pharmaceutical Co. Ltd Inhibiteurs de kinase alk

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1429222A (zh) * 2000-02-17 2003-07-09 安姆根有限公司 激酶抑制剂
CN102131788A (zh) * 2008-04-07 2011-07-20 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
CN102105150A (zh) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 用作激酶抑制剂的磷衍生物
CN103153064A (zh) * 2010-10-14 2013-06-12 阿里亚德医药股份有限公司 抑制egfr导致的癌症中细胞增殖的方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021018009A1 (fr) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Inhibiteur d'egfr, composition et procédé de préparation correspondant

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