WO2016192630A1 - Composé présentant une activité inhibitrice de kinase, son procédé de préparation, et utilisation de celui-ci - Google Patents

Composé présentant une activité inhibitrice de kinase, son procédé de préparation, et utilisation de celui-ci Download PDF

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Publication number
WO2016192630A1
WO2016192630A1 PCT/CN2016/084356 CN2016084356W WO2016192630A1 WO 2016192630 A1 WO2016192630 A1 WO 2016192630A1 CN 2016084356 W CN2016084356 W CN 2016084356W WO 2016192630 A1 WO2016192630 A1 WO 2016192630A1
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fluoro
group
methyl
benzo
unsubstituted
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PCT/CN2016/084356
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English (en)
Chinese (zh)
Inventor
万惠新
耿美玉
程鹏
黄敏
江磊
曹建华
陈筑熙
李磊
唐帅
苏毅
曹文杰
刘磊
陈春麟
丁健
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中国科学院上海药物研究所
上海海和药物研究开发有限公司
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Publication of WO2016192630A1 publication Critical patent/WO2016192630A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention belongs to the field of medicine, and in particular, the present invention relates to a class of compounds having a kinase inhibitory activity, a preparation method and use thereof.
  • Cyclin-dependent kinase is a type of serine/threonine kinase that plays a central role in the cell cycle, leading to the initiation and progression of the cell cycle. End.
  • the CDK family is an important signal transduction molecule in the cell, and its CDK-cyclin complex with cyclin is involved in cell growth, proliferation, dormancy and apoptosis.
  • CDK kinase As a therapeutic target for cancer has received extensive attention, such as Flavopiridol (Alvocidib), Seliciclib (CYC202), Dinaciclib (SCH727965) and Milciclib (PHA-848125). Clinical studies at different stages. However, due to the early detection of CDK inhibitors, the inhibition activity of each CDK family subtype is not high, or lack of certain selectivity, or poor absorption in vivo, which limits the clinical application. In recent years, drug discovery in this field has been made by increasing the selectivity of CDK inhibitors for each CDK family subtype or increasing the inhibitory activity of CDK kinase, especially the selective inhibitors targeting CDK4/6. Become a hot spot again.
  • CDK4/6 is overactive in many cancers, leading to uncontrolled cell proliferation. Thus, inhibition of CDK4/6 can achieve inhibition of cell proliferation downstream of the signaling pathway.
  • Pfizer's CDK4/6 inhibitor Palbociclib (trade name Ibrance)
  • Palbociclib trade name Ibrance
  • the similar drug Lilly's LY-2835219 (clinical phase III) and Novartis's LEE-011 (clinical phase III) are also expected to be available around 2017.
  • the object of the present invention is to provide a novel CDK kinase inhibitor with high efficacy, low toxicity, resistance to drug resistance and clinical application value.
  • a nitrogen-containing heterocyclic compound of the formula I or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer or tautomer thereof Isomer, solvate, polymorph or prodrug,
  • R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl, substituted or unsubstituted 4-8-membered heterocyclic;
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl;
  • M, M 1 , M 2 , M 3 are each independently selected from: CRa or N; and Ra is H, halogen, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl;
  • n is the number of substituents R 3 and is 0, 1, 2 or 3, preferably m is 0 or 1;
  • n is the number of substituents R 4 , when M 2 is CRa, n is 0, 1, 2 or 3; when M 2 is N, n is 0, 1 or 2; preferably n is 0 or 1;
  • Y is selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl;
  • Ar is selected from: a substituted or unsubstituted fused ring wherein the fused ring is a 6-8 membered aryl or heteroaryl group and is formed by 1-2 saturated or unsaturated 4-8 membered carbocyclic or heterocyclic rings;
  • the fused ring is a substituted or unsubstituted 6-8 membered aryl or heteroaryl group and formed by a 4-8 membered saturated or unsaturated carbocyclic or heterocyclic ring; more preferably the fused ring is substituted or unsubstituted a 6-8 membered aryl or heteroaryl group formed by a 5-7 membered saturated or unsaturated heterocyclic ring; the above heterocyclic group, heteroaryl or heterocyclic ring containing 1-3 selected from the group consisting of Atom: N, O, S, P or B;
  • the Ar has 0-3 substituents selected from the group consisting of halogen, -OH, NH 2 , -CN, substituted or unsubstituted carbonyl, substituted amino, substituted or unsubstituted C1-C4 alkyl or C3 -C6 cycloalkyl or heterocycloalkyl;
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, NH 2 , CN, unsubstituted or halogenated C1-C8 alkyl, Unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted, halogenated or C2-C6 alkenyl substituted by C2-C4 ester, unsubstituted or halogen a C2-C6 alkynyl group, an unsubstituted, halogenated or hydroxy substituted C2-C6 acyl group, an unsubstituted or halogenated C2-C6 amide group, an unsubstituted or halogenated 5- to 8-membered aryl group, unsubstituted Or halogenated 5- to 8-
  • M is N.
  • R 1 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, cyclopropyl.
  • Methyl, cyclobutylmethyl, Tetrahydrofuranyl more preferably R1 is isopropyl, isobutyl, tert-butyl, cyclopropylmethyl or tetrahydrofuranyl, cyclopentyl, cyclohexyl; and/or
  • R 2 is H, F, Cl or CH 3 ;
  • R 3 and R 4 are each H, F, Cl, CH 3 or cyclopropyl; and/or
  • M 3 is -CF or -CH
  • M 1 and M 2 are -CF, -CH or N.
  • M 1 or M 2 is N.
  • Ar is a substituted or unsubstituted pyridotetrahydropyridine, pyrazinotetrahydropyridine, pyridazine tetrahydropyridine, pyrimidotetrahydropyridine, benzotetrahydropyridine ring or the like.
  • Ar has the structure shown by the formulas IA, IB, IC, ID, IIA, IIB, IIC, IID, IIIA, IIIB, IIIC, IIID:
  • R 6 , R 7a , R 7b , R 7c , R 8a , R 8b , R 8c , R 8d , R 8e , R 8f are each independently selected from:
  • the alkyl or alkoxy group has 1 to 4 carbon atoms (preferably 1 to 3); the cycloalkyl group has 3 to 8 carbon atoms (preferably 3-6).
  • the haloalkyl group contains from 1 to 4 carbon atoms (preferably from 1 to 3); the heterocycloalkyl group contains from 1 to 3 heteroatoms including, but not limited to, N. S, P, O, B, Si.
  • the compound has the structure:
  • Compound 1a is coupled with Compound 1b under metal catalyzed or acid/base catalyzed reaction conditions to form a compound of formula I;
  • X is a leaving group and is selected from the group consisting of halogen, sulfonate, boric acid, borate;
  • compound 2a and compound 2b are coupled under metal catalyzed or acid/base catalyzed reaction conditions to form a compound of formula I;
  • X is a leaving group and is selected from the group consisting of halogen, sulfonate, boric acid, borate;
  • the steps 1) and 2) are each 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, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane , or a composition thereof.
  • the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone. , dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane
  • the steps 1) and 2) are each carried out in the same solvent.
  • the steps 1) and 2) are each carried out in a different solvent.
  • the metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), 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, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, or a combination thereof.
  • the steps 1) and 2) are each carried out in the presence of the same catalyst.
  • the steps 1) and 2) are each carried out in the presence of a different catalyst.
  • the catalyst ligand is selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, Tricyclohexylphosphine, tri-o-phenylmethylphosphine, or a combination thereof.
  • the steps 1) and 2) are each carried out in the presence of the same catalyst ligand.
  • the steps 1) and 2) are each carried out in the presence of different catalyst ligands.
  • the steps 1) and 2) are each carried out in the presence of a base.
  • the base includes an inorganic base and 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, Potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, or a combination thereof.
  • the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec carbon -7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.
  • the steps 1) and 2) are each carried out in the presence of the same base.
  • the steps 1) and 2) are each carried out in the presence of a different base.
  • the steps 1) and 2) are each carried out in the presence of an acid.
  • the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, or a combination thereof.
  • the steps 1) and 2) are each carried out in the presence of the same acid.
  • the steps 1) and 2) are each carried out in the presence of a different acid.
  • the temperature at which each of the step 1) and the step 2) is reacted is -78 ° C to 250 ° C.
  • the steps 1) and 2) are each carried out at 1 ° C to 30 ° C.
  • the steps 1) and 2) are each carried out under heating, the heating comprising electric heating, microwave heating.
  • the CDK kinase activity or expression associated with the disease is selected from the group consisting of cancer; preferably colon cancer.
  • the CDK kinase is selected from the group consisting of CDK1, CDK4, CDK6, or a combination thereof.
  • a pharmaceutical composition comprising:
  • a fifth aspect of the invention provides a method of inhibiting CDK kinase activity, the method comprising the steps of administering an inhibitory effective amount of a compound of formula I according to the first aspect of the invention to a subject, or a pharmaceutically acceptable thereof
  • the salt, or an inhibitory effective amount of a pharmaceutical composition according to the fourth aspect of the invention is administered to the subject.
  • the present inventors prepared a class of compounds having the structure shown in Formula I and found that they have CDK kinase inhibitory activity. And the compound can inhibit the activity of CDK kinase activity or expression at a very low concentration (as low as ⁇ 100 nmol/L), that is, to inhibit a series of CDK kinases, and the inhibitory activity is quite excellent. Such as tumors. Based on the above findings, the inventors completed the present invention.
  • 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 -CH2O- is equivalent to -OCH2-.
  • 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 -NO2.
  • Amino means -NH2.
  • 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.
  • 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 only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) And 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, propenyl, allyl, butyl- 1-Alkenyl, but-2-enyl, pent-1-enyl, pentane-1,4-dienyl 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 or more double bonds, 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 bonded to the remainder of the molecule by a single bond, such as, but not limited to, an ethynyl group , 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, thiomorpholinyl, 2,7-diaza-spiro[3.5]fluorene.
  • Alkan-7-yl 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.
  • aryl as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • 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.
  • 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 salts, sodium salts, 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.
  • pharmaceutical combination means a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients.
  • 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.
  • 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.
  • the present invention provides a nitrogen-containing heterocyclic compound of the formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, solvent thereof Compound, polymorph or prodrug.
  • R 1 , R 2 , R 3 , R 4 , M, M 1 , M 2 , M 3 , m, n, Y, Ar are each independently corresponding to the compounds of Example 1 - Example 107 Group.
  • the drug is preferably the compound of Example 1-Example 107.
  • the invention also provides a process for the preparation of a compound of formula I, the process comprising the steps of:
  • Compound 1a is coupled with Compound 1b under metal catalyzed or acid/base catalyzed reaction conditions to form a compound of formula I;
  • X is a leaving group and is selected from the group consisting of halogen, sulfonate, boric acid, borate;
  • compound 2a and compound 2b are coupled under metal catalyzed or acid/base catalyzed reaction conditions to form a compound of formula I;
  • X is a leaving group and is selected from the group consisting of halogen, sulfonate, boric acid, borate;
  • CDK kinase inhibitor which has high inhibitory activity against CDK kinase or Colo-205 cells, and its preparation and use.
  • a class of pharmaceutical compositions for treating diseases associated with CDK kinase activity is provided.
  • the third step 6-bromo-1-cyclobutyl-4-fluoro-2-methyl-1H-benzo[d]imidazole
  • 6-Bromo-1-cyclobutyl-4-fluoro-2-methyl-1H-benzo[d]imidazole 400 mg, 1.41 mmol
  • potassium acetate 414 mg
  • pinacol borate 538 mg, 2.12 mmol
  • tricyclohexylphosphine 59 mg, 0.212 mmol
  • palladium acetate 32 mg, 0.141 mmol
  • Saturated brine was added, and ethyl acetate was extracted (multiple times).
  • the third step 2-(1-benzyl-3-oxopipyridin-4-yl)acetic acid
  • Example 5 N-(4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl) Pyrimidin-2-yl)-6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine (12.4 mg, pale yellow solid).
  • Example 7 1-(2-(4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole- 6-yl)pyrimidin-2-yl)amine-7,8-dihydro-1,6-naphthyridin-6(5H)propyl-2-ol (12.7 mg, pale yellow solid).
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine was added sequentially to a dry 25 mL round bottom flask.
  • 2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine 44 mg, 0.10 mmol
  • 2-bromoethyl methyl ether 32 mg, 0.22 mmol
  • potassium carbonate 42 mg, 0.30 mmol
  • acetonitrile 10 mL
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine was added sequentially to a dry 25 mL round bottom flask.
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl) was added sequentially in a dry 25 mL round bottom flask at room temperature.
  • Pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine (43.5 mg, 0.10 mmol)
  • acetonitrile 5 ml
  • potassium carbonate 27.6 mg, 0.2 mmol
  • 2-Chloro-N-methylacetamide (21.4 mg, 0.2 mmol) was reacted at room temperature for 2 hours.
  • This example is composed of N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-5 ,6,7,8-Tetrahydro-1,6-naphthyridin-2-amine and 2-chloroacetic acid ethyl ester were synthesized according to the procedure of Example 15.
  • Tetrahydropyrrole 500 mg, 7.04 mmol
  • bromoacetic acid 979 mg, 7.04 mmol
  • sodium hydroxide 845 mg, 21.12 mmol
  • water 20 mL
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- was added sequentially to a 10 mL round bottom flask.
  • -5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine (20 mg, 0.046 mmol)
  • methyl 4-bromocrotonate (10 mg, 0.055 mmol)
  • triethylamine (9 mg , 0.092 mmol)
  • dichloromethane (1 mL
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl) was added sequentially in a dry 25 mL round bottom flask at room temperature.
  • Pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine (43.5 mg, 0.10 mmol)
  • 1,2-dichloroethane (5 ml)
  • sodium triacetoxyborohydride 42.38 mg, 0.2 mmol
  • Second step 1-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- Amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-(piperidin-1-yl)ethan-1-one
  • the third step 3-((2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazolyl-6-yl)pyrimidine-2) -yl)amino)-7,8- Dihydro-1,6-naphthyridin-6(5H)-yl)methyl)-1-methylpyrrole-2-one
  • N-(5-fluoro-4-(4-fluoro-1-isobutyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 was added sequentially in a dry microwave tube.
  • -yl)-6-(piperidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine 50 mg, 0.094 mmol
  • potassium carbonate 26 mg, 0.188 mmol
  • 1,2-propylene oxide 55 mg, 0.94 mmol
  • tetrahydrofuran (4 mL) and water (1 mL
  • microwave reaction at 80 ° C for 5 min.
  • Second step 1-(2-((4-(1-cyclobutyl-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-5-fluoropyrimidin-2- Amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)propan-2-ol
  • N-(4-(1-cyclobutyl-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-5-fluoropyrimidine-2 was added sequentially to a dry microwave tube.
  • -yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine 100 mg, 0.224 mmol
  • potassium carbonate 31 mg, 0.224 mmol
  • 1,2- propylene oxide 130 mg , 2.24 mmol
  • tetrahydrofuran (4 mL) and water (1 mL)
  • microwave reaction at 80 ° C for 5 min. 30 mL of water was added, extracted with dichloromethane (30 mL x 2), and the organic phases were combined.
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 was added sequentially to a dry round bottom flask.
  • -yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine 500 mg, 1.15 mmol
  • 1,2-dichloroethane 50 mL
  • N-tert-butoxycarbonyl 4-piperidone (1.14 g, 5.75 mmol)
  • glacial acetic acid 0.5 mL
  • sodium borohydride (1.22 g, 5.75 mmol
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 was added sequentially to a dry round bottom flask.
  • -Amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)piperidine-1-carboxylic acid tert-butyl ester 50 mg, 0.081 mmol
  • methanol 5 mL
  • hydrochloric acid Methanol (6 M, 2 mL) was reacted at room temperature for 4 hours.
  • the reaction mixture was concentrated under reduced vacuo.
  • the organic phase was combined, washed with brine, and then evaporated.
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- was added sequentially to a dry microwave tube. 6-(piperidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine (100 mg, 0.18 mmol), N,N-diisopropyl Ethylamine (232 mg, 1.8 mmol), N,N-dimethylformamide (2 mL) and 2-bromoethanol (0.5 mL) were reacted for 60 min. The reaction mixture was poured into aq.
  • N-(5-fluoro-4-(4-fluoro-1-isobutyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 was added sequentially to a dry sealed glass tube.
  • -yl)-6-yl)pyrimidin-2-yl)-6-(piperidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine hydrochloride Salt 100 mg, 0.188 mmol
  • potassium carbonate 52 mg, 0.376 mmol
  • bromoacetone (20 mg, 0.150 mmol
  • acetonitrile 6 mL
  • Second step 1-(4-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)pyrimidin-2-) Amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)piperidin-1-yl ⁇ -2-methylpropan-2-ol
  • the reaction was carried out at zero degrees Celsius for 1 hour. After completion of the reaction, 30 mL of ice water was added, and extracted with dichloromethane (30 mL ⁇ 2), and the organic phases were combined. Dry over anhydrous sodium sulfate, filter, and the filtrate was evaporated.
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine was added sequentially to a dry 25 mL round bottom flask.
  • 2-yl)amino)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine 52 mg, 0.12 mmol
  • N,N-diisopropylethylamine 62 mg, 0.48 mmol
  • chloroacetyl chloride (20 mg, 0.13 mmol) was added dropwise to the above reaction mixture.
  • Second step 2-(diethylamino)-1(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-) 6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethan-1-one
  • N-(4-(1-cyclopentyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl)- was added sequentially to a 100 mL round bottom flask. 6-(piperidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine (100 mg 0.1006 mmol), dichloromethane (20 ml), triethylamine (5 -6 drops), 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (60 mg, 0.4081 mmol), was allowed to react at room temperature overnight.
  • the third step 1-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- Amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-methyl-2-(pyrrolidin-1-yl)propan-1-one
  • the microwave was heated to 130 ° C and reacted for 2 hours. 30 mL of water was added, extracted with dichloromethane (30 mL x 2), and the organic phases were combined. Dry over anhydrous sodium sulfate, filter, and the filtrate was evaporated.
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- was added sequentially to the dried reaction flask.
  • -5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine 500 mg, 1.15 mmol
  • 3-formylpyrrolidin-1-carboxylic acid tert-butyl ester 300 mg, 1.50 mmol
  • 1,2-dichloroethane 50 mL
  • acetic acid a few drops were added dropwise, and the mixture was reacted at room temperature for 1 hour, and then sodium triacetoxyborohydride (1219 mg, 5.75 mmol) was added, and the mixture was reacted at room temperature for 16 hours.
  • Test Example 1 Determination of the Activity of Different CDK Kinases by the Compounds of the Invention
  • CDK1/CyclinB invitrogen
  • CDK4/Cyclin D1 invitrogen
  • CDK6/Cyclin D1 invitrogen
  • Test method The test compound was dissolved in dimethyl sulfoxide and diluted to each concentration gradient with buffer (50 mM HEPES, 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT and 0.01% Tween 20) according to the test.
  • the concentration was 4%; the ATP and the substrate ULight-4E-BP1 were mixed with buffer to prepare a mixture of 800 ⁇ M ATP and 200 nM substrate solution for use; 2.5 ⁇ L of substrate and ATP mixture were added to the reaction well.
  • the inhibition rate of the test compound on different kinase activities was obtained by the following formula:
  • Example 1 258.8 2.8 Example 2 5.3 3.9 Example 3 834.8 4.2 Example 4 13.1 3.9 Example 5 670.2 2.6 Example 6 13.3 4.7 Example 7 874.4 3.0 Example 8 12.0 8.4 Example 9 466.6 1.5 Example 10 39.9 9.8 Example 11 507.1 3.2 Example 12 368.4 4.3 Example 13 319.8 3.6 Example 14 486.7 2.1 Example 15 635.4 7 Example 16 648.4 2.6 Example 17 5082 6.7 Example 18 600.6 2.2 Example 19 15565 7.8 Example 20 1021.6 5.7 Example 22 1344 9.5 Example 23 >100000 52.5 Example 25 390 4.7 Example 28 11495 6.4 Example 29 400.6 1.1 Example 30 805 1.3 Example 31 388.5 2.2 Example 32 327.5 2 Example 33 1179 3 Example 34 300.9 1.1 Example 35 254 1.3 Example 36 236.4 1.6 Example 37 1921 3.8 Example 38 355.2 5.2 Example 39 252.3 3.4 Example 400.6 1.1 Example 30 805 1.3 Example 31 388.5 2.2 Example 327.5 2 Example 33 1179 3 Example 34 300.9
  • Example 43 >10000 4
  • Example 44 >10000 4.3
  • Example 45 9102 2.5
  • Example 46 >100000 4.9
  • Example 47 9207 4.7
  • Example 48 5575 3
  • Example 50 10477 2.4
  • Example 51 >10000 3.3
  • Example 52 10440 3.5
  • Example 53 >10000 3.3
  • Example 54 616 3
  • Example 55 391 2.2
  • Example 56 659 3.7
  • Example 58 592 1.6
  • Example 59 1.2
  • Example 60 2.1
  • Example 62 >10000 3.9
  • Example 63 >10000 3.4
  • Example 64 1512 1.2
  • Example 65 988
  • Example 66 1003 1.5
  • Example 68 >10000 2.6
  • Example 69 >10000 2.8
  • Example 70 >10000 3.2
  • Example 71 >10000 2.9
  • Example 72 976 1.8
  • Example 73 195 1.6
  • Example 75 >100
  • Test Example 2 Inhibition of proliferation of cell line MDA-MB-468/Colo205 by the compound of the present invention
  • the proliferation inhibitory activity of the compound of the present invention against human colon cancer cell line Colo205/MDA-MB-468 was measured by the following method.
  • Colo205 cells or MDA-MB-468 cells (Chinese Academy of Sciences Type Culture Collection Cell Bank) were inoculated into 96-well culture plates at a suitable cell concentration of 2000 cells/well, 90 ⁇ L medium per well, constant temperature in carbon dioxide. After incubating at 37 ° C overnight in the chamber, different concentrations of the test compound were added for 96 hours, and a solvent control group (negative control) was set. After 96 hours, the test compound was tested for its ability to inhibit cell proliferation using the CCK8 (Cell Counting Kit-8) method. The IC50 value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.
  • Example 1 0.785 0.218
  • Example 2 0.067 0.035
  • Example 3 0.16 0.039
  • Example 4 0.056 0.028
  • Example 5 1.108 0.129
  • Example 6 1.563 0.214
  • Example 7 1.702 0.361
  • Example 8 0.194 0.004
  • Example 9 1.186 0.189
  • Example 10 0.35 0.148
  • Example 11 1.252 0.328
  • Example 12 2.405 0.489
  • Example 13 1.415 0.523
  • Example 14 1.343 0.136
  • Example 15 4.767 0.329
  • Example 16 4.166 0.869
  • Example 17 2.692 0.302
  • Example 18 4.623 0.092
  • Example 19 >10 0.904
  • Example 20 3.744 0.374
  • Example 21 4.125 2.845
  • Example 22 2.73 0.979
  • Example 23 1.696 1.349
  • Example 24 >10 0.667
  • Example 25 1.181 0.309
  • Example 26 4.279 1.828
  • Example 27 5.099 0.87
  • Example 28 3.732 0.562
  • Example 29 1.239 0.157
  • Example 30 >10/26 0.057
  • Example 31 1.446 0.091
  • Example 32 0.63 0.119
  • Example 33 >10 0.961
  • Example 34 >10 0.097
  • Example 35 8.116 0.173
  • Example 36 1.419 0.285
  • Example 37 >10 0.898
  • Example 38 3.042 0.387
  • Example 39 0.791 0.23
  • Example 40 3.096 0.486
  • Example 41 >10 >10
  • Example 42 >10 0.581
  • Example 43 4.745 0.619
  • the inventors measured the drug concentration in plasma at different times after intragastric administration and intravenous administration of the compound of the present invention by LC/MS/MS method, and studied the pharmacokinetic behavior of the compound of the present invention in mice, and evaluated the drug. Dynamic characteristics.
  • test animals were healthy adult male ICR mice;
  • ICR mice were given intravenously (1 mg/kg) and intragastrically (5 mg/kg), respectively, before and after administration at 2-1440 min. Blood was taken from the venous plexus; a certain amount of plasma samples were taken, and the protein was precipitated by adding an internal standard acetonitrile solution, vortexed for 10 min, 6000 rpm/separated for 10 min; the supernatant was taken and centrifuged again at 6000 rpm for 10 min; the supernatant was taken for LC-MS-MS analysis.

Abstract

La présente invention concerne un composé représenté dans une formule générale I, ou un sel pharmaceutiquement acceptable de celui-ci, ou un énantiomère, un diastéréoisomère, un tautomère, un solvate, un polymorphe ou un promédicament de celui-ci, son procédé de préparation, et une application pharmaceutique de celui-ci, les définitions des groupes étant décrites dans la description. Le composé de la présente invention présente une activité souhaitable, donnée à titre d'exemple, d'inhibition de la CDK kinase, et des perspectives relativement bonnes de développement et d'application.
PCT/CN2016/084356 2015-06-01 2016-06-01 Composé présentant une activité inhibitrice de kinase, son procédé de préparation, et utilisation de celui-ci WO2016192630A1 (fr)

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