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WO2016173557A1 - Composé ayant une activité d'inhibition de kinase, procédé de préparation et utilisations - Google Patents

Composé ayant une activité d'inhibition de kinase, procédé de préparation et utilisations Download PDF

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Publication number
WO2016173557A1
WO2016173557A1 PCT/CN2016/080792 CN2016080792W WO2016173557A1 WO 2016173557 A1 WO2016173557 A1 WO 2016173557A1 CN 2016080792 W CN2016080792 W CN 2016080792W WO 2016173557 A1 WO2016173557 A1 WO 2016173557A1
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group
unsubstituted
compound
substituted
formula
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PCT/CN2016/080792
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Chinese (zh)
Inventor
曹建华
耿美玉
程鹏
黄敏
江磊
万惠新
李磊
陈筑熙
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 WO2016173557A1 publication Critical patent/WO2016173557A1/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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero 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
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention belongs to the field of medicinal chemistry, and in particular, 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.
  • a first aspect of the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvent thereof Compound, polymorph or prodrug,
  • R1 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl, substituted or unsubstituted 4-8 yuan heterocyclic ring or 4-8 yuan carbon ring;
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl, amino, substituted or unsubstituted C 1 -C 6 alkoxy;
  • M, M5, M6 are each independently selected from: CRa or N;
  • M1, M2, M3, M4 are each independently selected from: CRa or N, and at least one of them is N;
  • Ra is H, halogen, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl;
  • n is the number of substituents R3 and is 0, 1, 2 or 3, preferably m is 0 or 1;
  • n is the number of substituents R4, when M5 is CRa, n is 0, 1, 2 or 3; when M5 is N, n is 0, 1 or 2; preferably n is 0 or 1;
  • Y is H or a substituted or unsubstituted C1-C6 alkyl group
  • L is selected from the group consisting of: no or a linking group
  • W is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl or alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted Or an unsubstituted 4-8 membered heterocyclic ring, substituted carbonyl group, substituted sulfonyl group, substituted or unsubstituted amino group; wherein said heterocyclic ring contains 1-3 heteroatoms selected from the group consisting of N, O, S , P or B;
  • 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 , -N (unsubstituted C1-C6 alkyl) 2 , -CN, -Boc, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy-C1-C8 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl , unsubstituted or halogenated C3-C8 cycloalkyl-C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstitute
  • preferred M and M5 are each N.
  • L is selected from the group consisting of substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C4 alkenylene or C2-C4 alkynylene, -O-, -S a substituted or unsubstituted -NH-, substituted or unsubstituted divalent C3-C8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclic ring, substituted carbonyl group, substituted amino group, substituted sulfonyl group;
  • the heterocycle contains 1-3 heteroatoms selected from the group consisting of N, O, S, P or B.
  • L is a divalent linking group.
  • L is a trivalent linking group.
  • the heterocyclic ring or carbocyclic ring is a 5-, 6- or 7-membered ring.
  • R1 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclopropylmethyl , cyclobutylmethyl, halocyclobutyl (preferred ), Tetrahydrofuranyl, preferably R1 is isopropyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, and / or
  • R2 is H, F, Cl or CH 3 ;
  • R3 and R4 are each H, F, Cl, NH 2 , OCH 3 , CH 3 or cyclopropyl; and/or
  • W is selected from the group consisting of halogen, substituted or unsubstituted C1-C6 alkyl and cycloalkyl, substituted or unsubstituted 4-6 membered heterocyclic ring, more preferably W is cyclopentane, cyclohexane, tetrahydropyrrole ring , tetrahydrofuran ring, piperidine ring, 1,2,3,6-tetrahydropyridyl, piperazine ring, morpholine ring.
  • the W is selected from the group consisting of:
  • R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, NO 2 , -R7, -CN, -COOH, -OH, -SH, -OR7, -C(O)-R7, -C(O)O-R7. , -OC(O)-R7, -S(O)x-R7, -NH 2 , -NHR7, -N(R7) 2 , -NHC(O)R7, -NHC(O)OR7, -NR7C(O )R8; among them,
  • x 0, 1 or 2;
  • p, q, t are each independently selected from 0, 1, 2, 3, 4, 5 or 6; preferably 1 or 2;
  • Q is selected from: C, O, S, N, P, B or Si, and Q may be substituted by one or more R7;
  • any of R5, R6 may independently form a 3-8 membered ring system with other atoms on the ring, said ring system being unsubstituted or substituted by one or more -R7;
  • R7, R8 are each independently selected from: (a) halogen, (b) substituted or unsubstituted groups: phosphate group, sulfate group, C1-C6 alkyl group and C3-C8 cycloalkyl group, C1-C6 Heterocyclyl, aryl or heteroaryl, and said "substituted" means that R7, R8 are each optionally substituted by one or more groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , alkyl, monoalkylamino, dialkylamino, cycloalkyl, heterocyclic, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, dioxane Alkylaminoalkyl, alkoxycarbonylaminoalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, alkylcycloal
  • 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 W is a substituted or unsubstituted nitrogen-containing heterocyclic ring, preferably a heterocyclic ring having 1-2 nitrogen atoms.
  • W is a bridged ring substituent.
  • W is a spiro ring substituent.
  • R' and R" are H.
  • the R7 or R8 comprises a C1-C4 alkyl group or a haloalkyl group.
  • the compound has the structure shown in Formula II, III:
  • each group is as described above.
  • the compound of formula I has the structure:
  • a second aspect of the invention provides a process for the preparation of a compound of formula I, characterized in that it comprises the steps of:
  • X and LG are each independently a leaving group and are selected from the group consisting of halogen, sulfonate, boric acid, borate;
  • FG is selected from the group consisting of boric acid, boric acid ester, boron salt, organic tin, and organic zinc;
  • X and LG are each independently a leaving group and are selected from the group consisting of halogen, sulfonate, boric acid, borate;
  • FG is selected from the group consisting of boric acid, boric acid ester, boron salt, organic tin, and organic zinc;
  • the steps a1), a2) and the steps b1), b2) 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-dimethyl An amide, a dioxane, or a combination 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,
  • the steps a1), a2) and the steps b1), b2) are each carried out in the same solvent.
  • the steps a1), a2) and the steps b1), b2) 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.
  • steps a1), a2) and steps b1), b2) are each carried out in the presence of the same catalyst.
  • said steps a1), a2) and steps b1), b2) are each carried out in the presence of a different catalyst.
  • the steps a1), a2) and the steps b1), b2) are each carried out in the presence of a catalyst ligand.
  • 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.
  • said steps a1), a2) and steps b1), b2) are each carried out in the presence of the same catalyst ligand.
  • the steps a1), a2) and steps b1), b2) are each carried out in the presence of different catalyst ligands.
  • the steps a1), a2) and the steps b1), b2) 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 a1), a2) and the steps b1), b2) are each carried out in the presence of the same base.
  • the steps a1), a2) and the steps b1), b2) are each carried out in the presence of a different base.
  • the steps a1), a2) and steps b1), b2) 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 a1), a2) and steps b1), b2) are each carried out in the presence of the same acid.
  • the steps a1), a2) and the steps b1), b2) are each carried out in the presence of a different acid.
  • the temperature at which each of the steps a1), a2) and b1), b2) is reacted is -78 ° C to 250 ° C.
  • the steps a1), a2) and the steps b1), b2) are each carried out at 1 ° C to 30 ° C.
  • the steps a1), a2) and the steps b1), b2) are each carried out under heating, the heating comprising electric heating, microwave heating.
  • a third aspect of the invention provides the use of a compound of formula I according to the first aspect of the invention, characterized in that it is used for:
  • the CDK kinase is selected from the group consisting of CDK1, CDK4, CDK6, or a combination thereof.
  • a fourth aspect of the invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises:
  • a fifth aspect of the invention provides a method of inhibiting CDK kinase activity, comprising the steps of: administering to a subject, an inhibitory effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, of claim 1. Or administering an inhibitory effective amount of the pharmaceutical composition of claim 8 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 -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.
  • 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 , mercapto, quinolyl, isoquinolyl, Dianaphthyl, naphthyridyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridinyl, phenazinyl, is
  • 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, hydrochloride, hydrobromide, sulfuric acid Salts, nitrates, phosphates, etc.
  • organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoic acid Salt, citrate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, Maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate , pyroglutamate, aspartate, benzoate, methane
  • “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.
  • pharmaceutical combination means a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes live Fixed and unfixed combinations of sexual components.
  • 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 compound of the formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polycrystal thereof Shape or prodrug,
  • R1 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 ring or 4-8-membered carbocyclic ring;
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl, amino, substituted or unsubstituted C 1 -C 6 alkoxy;
  • M, M5, M6 are each independently selected from: CRa or N;
  • M1, M2, M3, M4 are each independently selected from: CRa or N, and at least one of them is N;
  • Ra is H, halogen, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl;
  • n is the number of substituents R3 and is 0, 1, 2 or 3, preferably m is 0 or 1;
  • n is the number of substituents R4, when M5 is CRa, n is 0, 1, 2 or 3; when M5 is N, n is 0, 1 or 2; preferably n is 0 or 1;
  • Y is H or a substituted or unsubstituted C1-C6 alkyl group
  • L is selected from the group consisting of: no or a linking group
  • W is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl or alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted Or an unsubstituted 4-8 membered heterocyclic ring, substituted carbonyl group, substituted sulfonyl group, substituted or unsubstituted amino group; wherein said heterocyclic ring contains 1-3 heteroatoms selected from the group consisting of N, O, S , P or B;
  • 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 , -N (unsubstituted C1-C6 alkyl) 2 , -CN, -Boc, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy-C1-C8 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl , unsubstituted or halogenated C3-C8 cycloalkyl-C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstitute
  • preferred M and M5 are each N.
  • L is selected from the group consisting of substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C4 alkenylene or C2-C4 alkynylene, -O-, -S a substituted or unsubstituted -NH-, substituted or unsubstituted divalent C3-C8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclic ring, substituted carbonyl group, substituted amino group, substituted sulfonyl group;
  • the heterocycle contains 1-3 heteroatoms selected from the group consisting of N, O, S, P or B.
  • L is a divalent linking group.
  • L is a trivalent linking group.
  • the heterocyclic ring or carbocyclic ring is a 5-, 6- or 7-membered ring.
  • R1 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, isobutyl, tert-butyl, cyclopentyl, cyclopropylmethyl , cyclobutylmethyl, halocyclobutyl (preferred ), Tetrahydrofuranyl, preferably R1 is isopropyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, and / or
  • R2 is H, F, Cl or CH 3 ;
  • R3 and R4 are each H, F, Cl, NH 2 , OCH 3 , CH 3 or cyclopropyl; and/or
  • W is selected from the group consisting of halogen, substituted or unsubstituted C1-C6 alkyl and cycloalkyl, substituted or unsubstituted 4-6 membered heterocyclic ring, more preferably W is cyclopentane, cyclohexane, tetrahydropyrrole ring , tetrahydrofuran ring, piperidine ring, 1,2,3,6-tetrahydropyridyl piperazine ring, morpholine ring.
  • the W is selected from the group consisting of:
  • R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, NO 2 , -R7, -CN, -COOH, -OH, -SH, -OR7, -C(O)-R7, -C(O)O-R7. , -OC(O)-R7, -S(O)x-R7, -NH 2 , -NHR7, -N(R7) 2 , -NHC(O)R7, -NHC(O)OR7, -NR7C(O )R8; among them,
  • x 0, 1 or 2;
  • p, q, t are each independently selected from 0, 1, 2, 3, 4, 5 or 6; preferably 1 or 2;
  • Q is selected from: C, O, S, N, P, B or Si, and Q may be substituted by one or more R7;
  • any of R5, R6 may independently form a 3-8 membered ring system with other atoms on the ring, said ring system being unsubstituted or substituted by one or more -R7;
  • R7, R8 are each independently selected from: (a) halogen, (b) substituted or unsubstituted groups: phosphate group, sulfate group, C1-C6 alkyl group and C3-C8 cycloalkyl group, C1-C6 Heterocyclyl, aryl or heteroaryl, and said "substituted" means that R7, R8 are each optionally substituted by one or more groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , alkyl, monoalkylamino, dialkylamino, cycloalkyl, heterocyclic, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, dioxane Alkylaminoalkyl, alkoxycarbonylaminoalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, alkylcycloal
  • 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 W is a substituted or unsubstituted nitrogen-containing heterocyclic ring, preferably a heterocyclic ring having 1-2 nitrogen atoms.
  • W is a bridged ring substituent.
  • W is a spiro ring substituent.
  • R' and R" are H.
  • the R7 or R8 comprises a C1-C4 alkyl group or a haloalkyl group.
  • the compound has the structure shown in Formula II, III:
  • each group is as described above.
  • the compound of formula I is a compound prepared in Examples 1 to 60.
  • the present invention provides a process for the preparation of a compound of formula I, characterized in that it comprises the steps of:
  • X and LG are each independently a leaving group and are selected from the group consisting of halogen, sulfonate, boric acid, borate;
  • FG is selected from the group consisting of boric acid, boric acid ester, boron salt, organic tin, and organic zinc;
  • X and LG are each independently a leaving group and are selected from the group consisting of halogen, sulfonate, boric acid, borate;
  • FG is selected from the group consisting of boric acid, boric acid ester, boron salt, organic tin, and organic zinc;
  • the steps a1), a2) and the steps b1), b2) 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-dimethyl An amide, a dioxane, or a combination 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,
  • the steps a1), a2) and the steps b1), b2) are each carried out in the same solvent.
  • the steps a1), a2) and the steps b1), b2) 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.
  • steps a1), a2) and steps b1), b2) are each carried out in the presence of the same catalyst.
  • said steps a1), a2) and steps b1), b2) are each carried out in the presence of a different catalyst.
  • the steps a1), a2) and the steps b1), b2) are each carried out in the presence of a catalyst ligand.
  • 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.
  • said steps a1), a2) and steps b1), b2) are each carried out in the presence of the same catalyst ligand.
  • the steps a1), a2) and steps b1), b2) are each carried out in the presence of different catalyst ligands.
  • the steps a1), a2) and the steps b1), b2) 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, carbonic acid Sodium hydrogenate, 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 a1), a2) and the steps b1), b2) are each carried out in the presence of the same base.
  • the steps a1), a2) and the steps b1), b2) are each carried out in the presence of a different base.
  • the steps a1), a2) and steps b1), b2) 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 a1), a2) and steps b1), b2) are each carried out in the presence of the same acid.
  • the steps a1), a2) and the steps b1), b2) are each carried out in the presence of a different acid.
  • the temperature at which each of the steps a1), a2) and b1), b2) is reacted is -78 ° C to 250 ° C.
  • the steps a1), a2) and the steps b1), b2) are each carried out at 1 ° C to 30 ° C.
  • the steps a1), a2) and the steps b1), b2) are each carried out under heating, the heating comprising electric heating, microwave heating.
  • the CDK kinase is selected from the group consisting of CDK1, CDK4, CDK6, or a combination thereof.
  • 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).
  • This intermediate is synthesized by the method of referring to the intermediate 1 from 5-bromo-1,3-difluoro-2-nitrobenzene and isopropylamine.
  • This intermediate is synthesized by the method of referring to the intermediate 1 from 5-bromo-1,3-difluoro-2-nitrobenzene and 3,3-difluorocyclobutan-1-amine. LCMS: 367.3 (M+H)
  • This intermediate is synthesized by the method of referring to the intermediate 1 from 5-bromo-1,3-difluoro-2-nitrobenzene and 2-methylpropan-1-amine.
  • This intermediate is synthesized by the method of referring to the intermediate 1 from 5-bromo-1,3-difluoro-2-nitrobenzene and cyclopentylamine. LCMS: 345.3 (M+H).
  • the present invention can be prepared by the same synthesis method as the intermediate 9 of the present invention:
  • the fourth step 5-((4-ethylpiperazin-1-yl)methyl)pyrazine-2-amine
  • the invention can be synthesized by the same method as the intermediate 18 to obtain the following intermediates:
  • This compound was synthesized from 1-methylpiperazine and tert-butyl(5-(bromomethyl)pyrazin-2-yl)carbamate as a starting material by the method of Intermediate 18, LCMS: 208.2 (M. +H).
  • the compound is synthesized from N,N-dimethylpiperidin-4-amine and tert-butyl(5-(bromomethyl)pyrazin-2-yl)carbamic acid, and is prepared by referring to the preparation method of the intermediate 18, LCMS: 236.2 (M+H).
  • the compound is prepared from ethyl 2-(piperazin-1-yl)acetate and tert-butyl(5-(bromomethyl)pyrazin-2-yl)carbamic acid as a starting material, and the preparation method of reference intermediate 18 Synthesis, LCMS: 280.3 (M+H)
  • This intermediate was synthesized from the morpholine and tert-butyl (5-(bromomethyl)pyrazin-2-yl)carbamic acid as a starting material, mp 195 (M+H).
  • the intermediate is synthesized from 1,2-dimethylpiperazine and tert-butyl (5-(bromomethyl)pyrazin-2-yl)carbamic acid, and is synthesized according to the preparation method of intermediate 18, LCMS: 222.2 (M+H).
  • the intermediate is synthesized from 1-(cyclopropylmethyl)piperazine and tert-butyl (5-(bromomethyl)pyrazin-2-yl)carbamic acid, and is synthesized according to the preparation method of intermediate 18, LCMS : 248.2 (M+H).
  • the intermediate is synthesized from 1-(2-methoxyethyl)piperazine and tert-butyl (5-(bromomethyl)pyrazin-2-yl)carbamic acid by the method of Intermediate 18, LCMS: 252 (M+H).
  • the intermediate is prepared from 1-(2,2,2-trifluoroethyl)piperazine and tert-butyl(5-(bromomethyl)pyrazin-2-yl)carbamic acid as reference material for intermediate 18 Method synthesis, LCMS: 276.2 (M+H).
  • the intermediate is prepared by the same method as Intermediate 18 from 1,2,6-trimethylpiperazine and tert-butyl (5-(bromomethyl)pyridin-2-yl)carbamic acid as the starting material, LCMS : 235.3 (M+H).
  • the intermediate is synthesized from 4-(pyrrolidin-1-yl)piperidine and tert-butyl(5-(bromomethyl)pyridin-2-yl)carbamic acid, and is synthesized according to the preparation method of intermediate 18, LCMS : 261.3 (M+H).
  • This intermediate was prepared from 1-cyclopentylpiperazine in the same manner as Intermediate 18, LCMS: 262 (M+H).
  • This intermediate was prepared in the same manner as the intermediate 18 from 1-ethylpiperazine, LCMS: 222.1 (M+H).
  • Example 2 Using the above different synthetic blocks as raw materials, the same synthesis method as in Example 1 was used to prepare the following compounds:
  • the target compound was synthesized by referring to the production methods of Example 1 and Example 2.
  • the target compound was synthesized by referring to the production methods of Example 1 and Example 2.
  • the molecule was prepared from the intermediate 17 and the intermediate 19, and the target molecule was prepared by the method of Example 1.
  • the molecule was prepared from the intermediate 17 and the intermediate 24, and the target molecule was prepared by the method of Example 1.
  • the target molecule was prepared by the method of Example 10.
  • the target molecule was prepared by the method of Example 10.
  • 6-(4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-4-amine and 2-chloro-5-(1-ethylpiperidin Pyridin-4-yl)oxy)pyrazine was used as a starting material, and the same procedure as in Example 1 was used to synthesize nitrogen-(5-(1-ethylpiperidin-4-yl)oxy)pyrazin-2-yl) -6-(4-Fluoro-1-isopropyl-2-methyl-1H-imidazolebenzo[d]pyrimidin-6-yl)-4-amine.
  • the molecule was prepared from the intermediate 13 and the intermediate 18, and the target molecule was prepared by the method of Example 1.
  • the molecule was prepared from the intermediate 10 and the intermediate 20, and the target molecule was prepared by the method of Example 1.
  • the target molecule was prepared by the method of Example 1.
  • the third step N-(2-((1-ethylpiperazin-4-enyl)methyl)pyrimidin-5-yl)-6-(4-fluoro-1-isopropyl-2-methyl -1H-benzo[d]imidazol-6-yl)pyrimidine-4-amine
  • the molecule was synthesized from the intermediate 17 and the intermediate 25, and the target molecule was synthesized by the preparation method of Example 1.
  • LCMS 490.6 (M+H); 1 H-NMR (400 MHz, CDCl 3 ) ⁇ 8.89 (s, 1H), 8.80 (s, 1H), 8.37 (s, 1H), 8.21.
  • 6-(4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-4-amine (28.5 mg, 0.1 mmol)
  • 6-Dichloropyridine-3-methyl)-4-ethylpiperazine (30.0 mg, 0.1 mmol) was used as a starting material, and N-(4-chloro-5((4-) was obtained by the same procedure as in Example 1.
  • Ethyl piperazin-1-yl)methyl)pyrazin-2-yl)-6-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl Pyrimidine-4-amine (8.0 mg, pale yellow solid).
  • Step 5 1-(5-((6-(4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-4-yl)amine) Pyrazin-2-yl)ethanol
  • Step 6 N-(5-(1-chloroethylpyrazine)-2-yl)-6-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole -6-yl)pyrimidine-4-amine
  • Step 7 N-(5-(1-(4-ethylpiperazin-1-yl)ethyl)pyrazine)-2-yl)-6-(4-fluoro-1-isopropyl-2 -methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-4-amine
  • Second step tert-butyl 4-(5-((6-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-4-yl) Amine)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carbonate
  • the third step 6-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(5-1,2,3,6-four Hydropyridine-4-yl)pyrazin-2-yl)pyridin-4-amine
  • 6-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(5-( 1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-ylpyrimidin-4-amine 50.0 mg, 0.119 mmol
  • aqueous acetaldehyde 40%, 3 ml
  • triacetoxy boron Sodium hydride 50.2 mg, 0.238 mmol
  • 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 sulfone 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 26 NA 389.0 Example 27 NA 399.2 Example 28 73.0 3.8 Example 29 126.0 2.4 Example 30 165.6 2.5 Example 31 433.0 7.3 Example 34 2075.0 10.9 Example 35 36.8 1.1 Example 36 800.9 5.2 Example 37 2429 13.8 Example 38 454.9 2.4 Example 39 97.2 1.6 Example 40 109.1 3.7 Example 41 56.5 2.7 Example 42 112.6 3.9 Example 43 103.1 2.9 Example 44 197.0 3.0 Example 45 139.7 3.7 Example 46 44.0 1.6 Example 47 1671.5 12.1 Example 48 266.4 3.1 Example 49 147.8 5.8 Example 50 1961.0 11.8 Example 51 150.6 5.6 Example 52 651.3 4.8 Example 53 162.8 6.5 Example 54 732.0 2.9 Example 55 2060.0 35.9 Example 56 393.4 4 Example 57 38.3 3.1 Example 58 212.0 16.4 Example 59 100.5 2.2 Example 60 393.4 4.0 Example 59 100.5 2.2 Example 60 393.4 4.0 Example 59 100.5 2.2 Example 60 393.4 4.0 Example 59 100.5 2.2 Example 60 39
  • Test Example 2 Inhibition of proliferation of tumor cell line Colo205/MDA-MB-468 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/MDA-MB-468 cells (Chinese Academy of Sciences, Culture Collection Committee Cell Bank) were seeded in 96-well culture plates at a suitable cell concentration of 2000 cells/well, 90 ⁇ L medium per well, in a carbon dioxide incubator. After incubation at 37 ° C overnight, 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 IC 50 value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.
  • Example 1 8.58 NA
  • Example 2 5.6 NA
  • Example 3 0.206 2.6
  • Example 4 3.74 NA
  • Example 5 19.9 NA
  • Example 13 0.26 0.38
  • Example 15 0.146 0.218
  • Example 16 0.25 0.438
  • Example 17 2.19 NA
  • Example 18 0.454 NA
  • Example 19 0.53 1.81
  • Example 20 0.266 0.936
  • Example 21 0.108 0.376
  • Example 22 0.122 0.396
  • Example 24 0.048 0.145
  • Example 28 0.279 0.563
  • Example 29 0.325 0.564
  • Example 30 0.189 0.69
  • Example 31 0.297 0.979
  • Example 32 0.788 2.542
  • Example 33 0.109 0.273
  • Example 34 1.506 3.651
  • Example 35 0.046 0.117
  • Example 36 0.338 0.733
  • Example 37 0.518 2.65
  • Example 38 0.41 >10
  • Example 39 0.143 1.12
  • Example 40 0.317 1.522
  • Example 41 0.0848
  • Example 52 0.324 0.555 Example 53 0.18 0.916 Example 54 0.275 1.052 Example 55 0.466 1.78 Example 56 0.191 1.163 Example 57 0.363 1.553 Example 58 0.099 0.265 Example 59 0.421 1.272 Example 60 0.165 1.055
  • 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 (5 mg/kg) and intragastrically (10 mg/kg), respectively, before and 2 to 1440 min after administration. 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.

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Abstract

L'invention concerne un composé représenté par la formule générale I, un sel pharmaceutiquement acceptable de celui-ci, ou un énantiomère, un diastéréomère, un tautomère, un solvate, un polymorphe ou un promédicament de celui-ci, et un procédé de préparation associé, et des utilisations pharmaceutiques de ceux-ci, les groupes étant tels que définis dans la description. Le composé de la présente invention présente une bonne activité d'inhibition de la kinase CDK, et de bonnes perspectives de développement et d'application.
PCT/CN2016/080792 2015-04-30 2016-04-29 Composé ayant une activité d'inhibition de kinase, procédé de préparation et utilisations WO2016173557A1 (fr)

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US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
EP3620456A4 (fr) * 2017-05-05 2020-03-25 Selection Bioscience LLC Composé présentant une activité inhibitrice de kinase, son procédé de préparation et son utilisation
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
WO2022221194A1 (fr) * 2021-04-12 2022-10-20 A2A Pharmaceuticals, Inc. Compositions et méthodes de traitement du cancer
US11622966B2 (en) 2018-05-25 2023-04-11 A2A Pharmaceuticals, Inc. Highly potent TACC3 inhibitor as a novel anticancer drug candidate
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US11986475B1 (en) 2022-03-24 2024-05-21 A2A Pharmaceuticals, Inc. Compositions and methods for treating cancer
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors

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US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US11858939B2 (en) 2015-07-06 2024-01-02 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10519149B2 (en) 2017-01-11 2019-12-31 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11286256B2 (en) 2017-01-11 2022-03-29 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
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US10793567B2 (en) 2017-01-11 2020-10-06 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11987580B2 (en) 2017-01-11 2024-05-21 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11225479B2 (en) 2017-01-11 2022-01-18 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
EP3620456A4 (fr) * 2017-05-05 2020-03-25 Selection Bioscience LLC Composé présentant une activité inhibitrice de kinase, son procédé de préparation et son utilisation
US11179391B2 (en) 2017-05-05 2021-11-23 Fuyao Zhang Compound with kinase inhibitory activity and preparation method and use thereof
JP2020518672A (ja) * 2017-05-05 2020-06-25 セレクション バイオサイエンス エルエルシー キナーゼ阻害活性を有する化合物、その製造方法及び用途
JP7215687B2 (ja) 2017-05-05 2023-01-31 シャンハイ ベスト－リンク バイオサイエンス エルエルシー キナーゼ阻害活性を有する化合物、その製造方法及び用途
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11912702B2 (en) 2017-08-07 2024-02-27 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11622966B2 (en) 2018-05-25 2023-04-11 A2A Pharmaceuticals, Inc. Highly potent TACC3 inhibitor as a novel anticancer drug candidate
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
WO2022221194A1 (fr) * 2021-04-12 2022-10-20 A2A Pharmaceuticals, Inc. Compositions et méthodes de traitement du cancer
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors
US11986475B1 (en) 2022-03-24 2024-05-21 A2A Pharmaceuticals, Inc. Compositions and methods for treating cancer

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