WO2016173557A1 - 一类具有激酶抑制活性的化合物、制备方法和用途 - Google Patents

一类具有激酶抑制活性的化合物、制备方法和用途 Download PDF

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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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unsubstituted
compound
substituted
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PCT/CN2016/080792
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French (fr)
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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/zh

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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.

Abstract

本发明公开了一种如通式I所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、其制备方法及在药学上的应用，其中各基团的定义如说明书中所述。本发明的化合物具有较佳的CDK激酶抑制活性，具有较好的开发及应用前景。

Description

一类具有激酶抑制活性的化合物、制备方法和用途 技术领域
本发明属于药物化学领域，具体地，涉及一类具有激酶抑制活性的化合物、制备方法和用途。
背景技术
细胞周期异常是癌症的一个标志性特征，周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)是一类丝氨酸/苏氨酸激酶，在细胞周期中起中心作用，主导细胞周期的启动、进行和结束。CDK家族是细胞内重要的信号转导分子，其与周期素(cyclin)形成的CDK-cyclin复合物，参与细胞的生长、增殖、休眠和凋亡。
在过去的20年中，以CDK激酶为肿瘤治疗靶点的药物开发已经得到了广泛的关注，如Flavopiridol(Alvocidib),Seliciclib(CYC202),Dinaciclib(SCH727965)和Milciclib(PHA-848125)等都进入不同阶段临床研究。但是由于早期发现的CDK抑制剂对各CDK家族亚型抑制活性不高，或者缺乏一定的选择性，或者体内吸收不佳等情况而限制了临床应用。近几年，由于提高了CDK抑制剂对于各CDK家族亚型的选择性或者提高了CDK激酶的抑制活性，尤其是靶向CDK4/6的选择性抑制剂的发现，使得这一领域的药物研发再次成为热点。
CDK4/6在许多癌症中均过度活跃，导致细胞增殖失控。因此，抑制CDK4/6可以实现从信号通路的下游抑制细胞增殖。目前辉瑞公司的CDK4/6抑制剂Palbociclib(商品名Ibrance)成为了第一个上市的CDK4/6抑制剂，被FDA批准其作为一线药物治疗ER阳性、HER2阴性乳腺癌。同类药物礼来公司的LY-2835219(临床三期)和诺华公司的LEE-011(临床三期)预计也将在2017年左右上市。
鉴于与CDK激酶相关的研究已经成为热点，因此，本领域迫切需要研究和开发新的高效低毒、抗耐药性、具有临床应用价值的CDK激酶抑制剂。
发明内容
本发明的目的是提供一类具有激酶抑制活性的化合物其制备方法和用途。
本发明的第一方面提供了一种如通式I所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
Figure PCTCN2016080792-appb-000001
式中：
R1选自下组：氢、取代或未取代的C1-C6烷基和C3-C8环烷基、取代或未取代 的4～8元杂环或4～8元碳环；
R2、R3和R4各自独立地选自：氢、卤素、取代或未取代的C1-C6烷基和C3-C8环烷基、氨基、取代或未取代的C1-C6烷氧基；
M、M5、M6各自独立地选自：CRa或N；
M1、M2、M3、M4各自独立地选自：CRa或N，并且其中至少有一个为N；
Ra为H、卤素、取代或未取代的C1-C6烷基和C3-C8环烷基；
m为取代基R3的数目，且为0、1、2或3,优选地m为0或1；
n为取代基R4的数目，当M5为CRa时，n为0、1、2或3；当M5为N时，n为0、1或2；优选地n为0或1；
Y为H或取代或未取代的C1-C6烷基；
L选自下组：无或连接基团；
W选自下组：氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6链烯基或链炔基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环、取代羰基、取代磺酰基、取代或未取代的氨基；其中，所述的杂环包含1-3个选自下组的杂原子：N、O、S、P或B；
上述的任一“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、-OH、-NH2、-N(未取代的C1-C6烷基)2、-CN、-Boc、未取代或卤代的C1-C8烷基、未取代或卤代的C1-C8烷氧基-C1-C8烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C3-C8环烷基-C1-C8烷基、未取代或卤代的C1-C8烷氧基、未取代或卤代的C2-C6烯基、未取代或卤代的C2-C6炔基、未取代或卤代的C2-C6酰基、未取代或卤代的5～8元芳基、未取代或卤代的5～8元杂芳基、未取代或卤代的4～8元饱和杂环或碳环、未取代的C1-C6烷基O(C＝O)-C1-C8烷基、HO(C＝O)-C1-C8烷基、未取代的C1-C6烷基N(C＝O)-C1-C8烷基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O或S，所述的杂环包含1-3个选自下组的杂原子：N、O或S。
在另一优选例中，优选的M、M5分别为N。
在另一优选例中，L选自下组：取代或未取代的C1-C6亚烷基、取代或未取代的C2-C4亚烯基或C2-C4亚炔基、-O-、-S-、取代或未取代的-NH-、取代或未取代的二价C3-C8环烷基、取代或未取代的4-12元杂环、取代羰基、取代氨基、取代磺酰基；所述的杂环包含1-3个选自下组的杂原子：N、O、S、P或B。
在另一优选例中，L为二价连接基团。
在另一优选例中，L为三价连接基团。
在另一优选例中，所述的杂环或碳环为5元、6元或7元环。
本发明的一种优选情况为：R1为甲基、乙基、正丙基、异丙基、环丙基、环丁基、异丁基、叔丁基、环戊基、环丙基甲基、环丁基甲基、卤代环丁基(优选
Figure PCTCN2016080792-appb-000002
)、
Figure PCTCN2016080792-appb-000003
四氢呋喃基，优选地R1为异丙基、异丁基、环丙基甲基、环丁基、环戊基、
Figure PCTCN2016080792-appb-000004
Figure PCTCN2016080792-appb-000005
和/或
R2为H、F、Cl或CH3；和/或
R3和R4分别为H、F、Cl、NH2、OCH3、CH3或环丙基；和/或
M1、M2、M3、M4分别为：M2＝N，M1＝M3＝M4＝CH；或M1＝M2＝N，M3＝M4＝CH；或M1＝M3＝N，M2＝M4＝CH；或M2＝N，M1＝M3＝M4＝CRa；或M1＝M2＝N，M3＝M4＝CRa；或M1＝M3＝N，M2＝M4＝CRa；或M1＝M4＝N，M2＝M3＝CRa；其中Ra的定义同前；和/或
L选自：无、-CR’R”-、-O-、-NR’-、和－CR’＝，其中R’和R”各自独立地为H、F、氘(D)、C1-C6烷基或杂环烷基或相邻的R’和R”形成环状基团；和/或
W选自：卤素、取代或未取代的C1-C6烷基和环烷基、取代或未取代的4-6元杂环，更优选地W为环戊烷、环己烷、四氢吡咯环、四氢呋喃环、哌啶环、1,2,3,6-四氢吡啶基、哌嗪环、***啉环。
在另一优选例中，所述的W选自下组：
Figure PCTCN2016080792-appb-000006
其中，
R5、R6各自独立地选自：氢、卤素、NO2、-R7、-CN、-COOH、-OH、-SH、-OR7、-C(O)-R7、-C(O)O-R7、-OC(O)-R7、-S(O)x-R7、-NH2、-NHR7、-N(R7)2、-NHC(O)R7、-NHC(O)OR7、-NR7C(O)R8；其中，
x为0、1或2；
p、q、t分别独立地选自0、1、2、3、4、5或6；优选地为1或2；
Q选自：C、O、S、N、P、B或Si，并且Q可以被一个或多个R7取代；
或者，R5、R6中任一个可独立地与环上其它原子形成3-8元环系，所述环系是未取代的或被一个或多个-R7取代；
R7、R8分别独立地选自：(a)卤素、(b)取代或未取代的以下基团：磷酸酯基、硫酸酯基、C1-C6烷基和C3-C8环烷基、C1-C6杂环基、芳基或杂芳基，且所述“取代 的”指R7、R8分别任选地被一个或多个选自下组的基团取代：卤素、-OH、-CN、-NH2、烷基、单烷基氨基、二烷基氨基、环烷基、杂环基、烷氧基、羟基烷基、烷氧基烷基、羟基烷氧基烷基、氨基烷基、二烷基氨基烷基、烷氧基羰基氨基烷基、环烷基烷基、杂环基烷基、芳烷基、烷基环烷基、环烷基羰基、烷氧基羰基、烷氧基羰基杂环基、(烷氧羰基)(烷基)氨基、(烷氧基烷基)(烷基)氨基。
在另一优选例中，所述的烷基或烷氧基含有1-4个碳原子(较佳地1-3个)；所述的环烷基含有3-8个碳原子(较佳地3-6个)。
在另一优选例中，所述的W为取代或未取代的含氮杂环，较佳地，为含1-2个氮原子的杂环。
在另一优选例中，W为桥环取代基。
在另一优选例中，W为螺环取代基。
在另一优选例中，R’和R”为H。
在另一优选例中，所述的R7或R8包括C1-C4烷基或卤代烷基。
在另一优选例中，所述化合物具有通式II、III所示的结构：
Figure PCTCN2016080792-appb-000007
其中，各基团的定义如上所述。
在另一优选例中，所述通式I化合物具有如下结构：
Figure PCTCN2016080792-appb-000008
Figure PCTCN2016080792-appb-000009
Figure PCTCN2016080792-appb-000010
Figure PCTCN2016080792-appb-000011
本发明的第二方面提供了一种制备式I化合物的方法，其特征在于，所述方法包括步骤：
a1)将式1a化合物与式3a化合物或者将式2a化合物与式4a化合物，在金属催化剂或者酸/碱存在的反应条件下进行偶联，从而形成中间体5a；和
a2)将中间体5a与式6a化合物在催化剂存在的反应条件下进行偶联，得到式I化合物；
Figure PCTCN2016080792-appb-000012
各式中，
X和LG各自独立地为离去基团，且选自下组：卤素、磺酸酯、硼酸、硼酸酯；
FG选自下组：硼酸、硼酸酯、硼盐、有机锡、有机锌；
其他各基团R1、R2、R3、R4、M、M1、M2、M3、M4、M5、L、W及m、n的定义如上所述；
或
b1)将式1b化合物与式3b化合物或者将式2b化合物与式3b化合物，在金属催化剂或者酸/碱存在的反应条件下进行偶联，从而形成中间体4b或5b；和
b2)将中间体4b与式6b化合物或中间体5b与式7b化合物，在催化剂存在的反应条件下进行偶联，得到式I化合物；
Figure PCTCN2016080792-appb-000013
各式中，
X和LG各自独立地为离去基团，且选自下组：卤素、磺酸酯、硼酸、硼酸酯；
FG选自下组：硼酸、硼酸酯、硼盐、有机锡、有机锌；
其他各基团R1、R2、R3、R4、M、M1、M2、M3、M4、M5、L、W及m、n的定义如上所述。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在溶剂中进行，且所述溶剂选自下组：水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在相同的溶剂中进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在不同的溶剂中进行。
在另一优选例中，所述金属催化剂选自下组：三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、1，2-二(二苯基膦基)乙烷二氯化钯，或其组合物。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在相同的催化剂存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在不同的催化剂存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在催化剂配体存在下进行。
在另一优选例中，所述催化剂配体选自下组：三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、三邻苯甲基膦，或其组合物。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在相同的催化剂配体存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在不同的催化剂配体存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在碱存在下进行。在另一优选例中，所述碱包括无机碱和有机碱。
在另一优选例中，所述无机碱选自下组：氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠，或其组合物。
在另一优选例中，所述有机碱选自下组：吡啶，三乙胺，N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶，或其组合物。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在相同的碱存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在不同的碱存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在酸存在下进行。
在另一优选例中，所述酸选自下组：盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸、乙酸，或其组合物。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在相同的酸存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在不同的酸存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自反应的温度为-78℃～250℃。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在1℃～30℃下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在加热条件下进行，所述加热包括电加热、微波加热。
本发明的第三方面提供了如本发明第一方面所述的式I化合物的用途，其特征在于，用于：
(a)制备治疗与CDK激酶活性或表达量相关的疾病的药物；
(b)制备CDK激酶靶向抑制剂；
(c)体外非治疗性地抑制CDK激酶的活性；
(d)体外非治疗性地抑制肿瘤细胞增殖；和/或
(e)治疗与CDK激酶活性或表达量相关的疾病。
在另一优选例中，所述CDK激酶选自下组：CDK1、CDK4、CDK6，或其组合。
本发明的第四方面提供了一种药物组合物，其特征在于，所述的药物组合物包括：
(i)有效量的式I化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药；和
(ii)药学上可接受的载体。
本发明的第五方面提供了一种抑制CDK激酶活性的方法，其特征在于，包括步骤：对抑制对象施用抑制有效量的如权利要求1所述的式I化合物或其药学上可接受的盐，或对抑制对象施用抑制有效量的如权利要求8所述的药物组合物。
应理解、在本发明范围内中、本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合、从而构成新的或优选的技术方案。限于篇 幅、在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，制备了一类具有式I所示结构的化合物，并发现其具有CDK激酶抑制活性。且所述的化合物在极低浓度(可低至≤100nmol/L)下，即对一系列CDK激酶产生抑制作用，抑制活性相当优异，因而可以用于治疗与CDK激酶活性或表达量相关的疾病如肿瘤。基于上述发现，发明人完成了本发明。
术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
在本申请中，术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(＝O)-基团。
“硝基”是指-NO2。
“氰基”是指-CN。
“氨基”是指-NH2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯 基等。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、 二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸 盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。
通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中，术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”，“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活 性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
式I化合物
本发明提供了一种如通式I所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
Figure PCTCN2016080792-appb-000014
式中：
R1选自下组：氢、取代或未取代的C1-C6烷基和C3-C8环烷基、取代或未取代的4～8元杂环或4～8元碳环；
R2、R3和R4各自独立地选自：氢、卤素、取代或未取代的C1-C6烷基和C3-C8环烷基、氨基、取代或未取代的C1-C6烷氧基；
M、M5、M6各自独立地选自：CRa或N；
M1、M2、M3、M4各自独立地选自：CRa或N，并且其中至少有一个为N；
Ra为H、卤素、取代或未取代的C1-C6烷基和C3-C8环烷基；
m为取代基R3的数目，且为0、1、2或3,优选地m为0或1；
n为取代基R4的数目，当M5为CRa时，n为0、1、2或3；当M5为N时，n为0、1或2；优选地n为0或1；
Y为H或取代或未取代的C1-C6烷基；
L选自下组：无或连接基团；
W选自下组：氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6链烯基或链炔基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环、取代羰基、取代磺酰基、取代或未取代的氨基；其中，所述的杂环包含1-3个选自下组的杂原子：N、O、S、P或B；
上述的任一“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、-OH、-NH2、-N(未取代的C1-C6烷基)2、-CN、-Boc、未取代或卤代的C1-C8烷基、未取代或卤代的C1-C8烷氧基-C1-C8烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C3-C8环烷基-C1-C8烷基、未取代或卤代的C1-C8烷氧基、未取代或卤代的C2-C6烯基、未取代或卤代的C2-C6炔基、未取代或卤代的C2-C6酰基、未取代或卤代的5～8元芳基、未取代或卤代的5～8元杂芳基、未取代或卤代的4～8元饱和杂环或碳环、未取代的C1-C6烷基O(C＝O)-C1-C8烷基、HO(C＝O)-C1-C8烷基、未取代的C1-C6烷基N(C＝O)-C1-C8烷基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O或S，所述的杂环包含1-3个选自下组的杂原子：N、O或S。
在另一优选例中，优选的M、M5分别为N。
在另一优选例中，L选自下组：取代或未取代的C1-C6亚烷基、取代或未取代的C2-C4亚烯基或C2-C4亚炔基、-O-、-S-、取代或未取代的-NH-、取代或未取代的二价C3-C8环烷基、取代或未取代的4-12元杂环、取代羰基、取代氨基、取代磺酰基；所述的杂环包含1-3个选自下组的杂原子：N、O、S、P或B。
在另一优选例中，L为二价连接基团。
在另一优选例中，L为三价连接基团。
在另一优选例中，所述的杂环或碳环为5元、6元或7元环。
本发明的一种优选情况为：R1为甲基、乙基、正丙基、异丙基、环丙基、环丁基、异丁基、叔丁基、环戊基、环丙基甲基、环丁基甲基、卤代环丁基(优选
Figure PCTCN2016080792-appb-000015
)、
Figure PCTCN2016080792-appb-000016
四氢呋喃基，优选地R1为异丙基、异丁基、环丙基甲基、环丁基、环戊基、
Figure PCTCN2016080792-appb-000017
Figure PCTCN2016080792-appb-000018
和/或
R2为H、F、Cl或CH3；和/或
R3和R4分别为H、F、Cl、NH2、OCH3、CH3或环丙基；和/或
M1、M2、M3、M4分别为：M2＝N，M1＝M3＝M4＝CH；或M1＝M2＝N，M3＝M4＝CH；或M1＝M3＝N，M2＝M4＝CH；或M2＝N，M1＝M3＝M4＝CRa；或M1＝M2＝N，M3＝M4＝CRa；或M1＝M3＝N，M2＝M4＝CRa；或M1＝M4＝N，M2＝M3＝CRa；其中Ra的定义同权利要求1；和/或
L选自：无、-CR’R”-、-O-、-NR’-、和－CR’＝，其中R’和R”各自独立地为H、F、氘(D)、C1-C6烷基或杂环烷基或相邻的R’和R”形成环状基团；和/或
W选自：卤素、取代或未取代的C1-C6烷基和环烷基、取代或未取代的4-6元杂环，更优选地W为环戊烷、环己烷、四氢吡咯环、四氢呋喃环、哌啶环、1,2,3,6-四氢吡啶基哌嗪环、***啉环。
在另一优选例中，所述的W选自下组：
Figure PCTCN2016080792-appb-000019
其中，
R5、R6各自独立地选自：氢、卤素、NO2、-R7、-CN、-COOH、-OH、-SH、-OR7、-C(O)-R7、-C(O)O-R7、-OC(O)-R7、-S(O)x-R7、-NH2、-NHR7、-N(R7)2、-NHC(O)R7、-NHC(O)OR7、-NR7C(O)R8；其中，
x为0、1或2；
p、q、t分别独立地选自0、1、2、3、4、5或6；优选地为1或2；
Q选自：C、O、S、N、P、B或Si，并且Q可以被一个或多个R7取代；
或者，R5、R6中任一个可独立地与环上其它原子形成3-8元环系，所述环系是未取代的或被一个或多个-R7取代；
R7、R8分别独立地选自：(a)卤素、(b)取代或未取代的以下基团：磷酸酯基、硫酸酯基、C1-C6烷基和C3-C8环烷基、C1-C6杂环基、芳基或杂芳基，且所述“取代的”指R7、R8分别任选地被一个或多个选自下组的基团取代：卤素、-OH、-CN、-NH2、烷基、单烷基氨基、二烷基氨基、环烷基、杂环基、烷氧基、羟基烷基、烷氧基烷基、羟基烷氧基烷基、氨基烷基、二烷基氨基烷基、烷氧基羰基氨基烷基、环烷基烷基、杂环基烷基、芳烷基、烷基环烷基、环烷基羰基、烷氧基羰基、烷氧基羰基杂环基、(烷氧羰基)(烷基)氨基、(烷氧基烷基)(烷基)氨基。
在另一优选例中，所述的烷基或烷氧基含有1-4个碳原子(较佳地1-3个)；所述的环烷基含有3-8个碳原子(较佳地3-6个)。
在另一优选例中，所述的W为取代或未取代的含氮杂环，较佳地，为含1-2个氮原子的杂环。
在另一优选例中，W为桥环取代基。
在另一优选例中，W为螺环取代基。
在另一优选例中，R’和R”为H。
在另一优选例中，所述的R7或R8包括C1-C4烷基或卤代烷基。
在另一优选例中，所述化合物具有通式II、III所示的结构：
Figure PCTCN2016080792-appb-000020
其中，各基团的定义如上所述。
在另一优选例中，所述通式I化合物为实施例1～实施例60制备的化合物。
式I化合物的制备
本发明提供了一种制备式I化合物的方法，其特征在于，所述方法包括步骤：
a1)将式1a化合物与式3a化合物或者将式2a化合物与式4a化合物，在金属催化剂或者酸/碱存在的反应条件下进行偶联，从而形成中间体5a；和
a2)将中间体5a与式6a化合物在催化剂存在的反应条件下进行偶联，得到式I化合物；
Figure PCTCN2016080792-appb-000021
各式中，
X和LG各自独立地为离去基团，且选自下组：卤素、磺酸酯、硼酸、硼酸酯；
FG选自下组：硼酸、硼酸酯、硼盐、有机锡、有机锌；
其他各基团R1、R2、R3、R4、M、M1、M2、M3、M4、M5、L、W及m、n的定义如上所述；
或
b1)将式1b化合物与式3b化合物或者将式2b化合物与式3b化合物，在金属催化剂或者酸/碱存在的反应条件下进行偶联，从而形成中间体4b或5b；和
b2)将中间体4b与式6b化合物或中间体5b与式7b化合物，在催化剂存在的反应条件下进行偶联，得到式I化合物；
Figure PCTCN2016080792-appb-000022
各式中，
X和LG各自独立地为离去基团，且选自下组：卤素、磺酸酯、硼酸、硼酸酯；
FG选自下组：硼酸、硼酸酯、硼盐、有机锡、有机锌；
其他各基团R1、R2、R3、R4、M、M1、M2、M3、M4、M5、L、W及m、n的定义如上所述。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在溶剂中进行，且所述溶剂选自下组：水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在相同的溶剂中进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在不同的溶剂中进行。
在另一优选例中，所述金属催化剂选自下组：三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、1，2-二(二苯基膦基)乙烷二氯化钯，或其组合物。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在相同的催化剂存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在不同的催化剂存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在催化剂配体存在下进行。
在另一优选例中，所述催化剂配体选自下组：三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、三邻苯甲基膦，或其组合物。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在相同的催化剂配体存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在不同的催化剂配体存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在碱存在下进行。在另一优选例中，所述碱包括无机碱和有机碱。
在另一优选例中，所述无机碱选自下组：氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸 氢钠，或其组合物。
在另一优选例中，所述有机碱选自下组：吡啶，三乙胺，N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶，或其组合物。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在相同的碱存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在不同的碱存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在酸存在下进行。
在另一优选例中，所述酸选自下组：盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸、乙酸，或其组合物。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在相同的酸存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在不同的酸存在下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自反应的温度为-78℃～250℃。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在1℃～30℃下进行。
在另一优选例中，所述步骤a1)、a2)和步骤b1)、b2)各自在加热条件下进行，所述加热包括电加热、微波加热。
式I化合物的用途
本发明提供了式I化合物的用途，用于：
(a)制备治疗与CDK激酶活性或表达量相关的疾病的药物；
(b)制备CDK激酶靶向抑制剂；
(c)体外非治疗性地抑制CDK激酶的活性；
(d)体外非治疗性地抑制肿瘤细胞增殖；和/或
(e)治疗与CDK激酶活性或表达量相关的疾病。
在另一优选例中，所述CDK激酶选自下组：CDK1、CDK4、CDK6，或其组合。
本发明的主要优点包括：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的CDK激酶抑制剂及其制备和应用，所述的抑制剂对CDK激酶或Colo-205细胞均有较高抑制活性。
3.提供了一类治疗与CDK激酶活性相关疾病的药物组合物。
下面结合具体实施例、进一步阐述本发明。应理解、这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法、通常按照常规条件、或按照制造厂商所建议的条件。除非另外说明、否则百分比和份数是重量百分比和重量份数。
中间体的制备
中间体1
Figure PCTCN2016080792-appb-000023
第一步：5-溴-N-环丁基-3-氟-2-硝基苯胺
在干燥的100ml茄形瓶中室温下依次加入5-溴-1,3-二氟-2-硝基苯(500mg，2.11mmol),碳酸钾(291mg，2.11mmol)，环丁基胺(150mg，2.11mmol)乙腈(40ml)，室温反应2小时。反应液加饱和食盐水，用乙酸乙酯萃取。有机相浓缩得到5-溴-N-环丁基-3-氟-2-硝基苯胺(570mg，红色固体)所得残余物不经纯化直接用于下一步反应,LCMS:290(M+H)。
第二步：5-溴-N1-环丁基-3-氟苯-1,2-二胺
将5-溴-N-环丁基-3-氟-2-硝基苯胺(570mg，1.97mmol)加入到50ml的乙酸溶液中，然后加入还原铁粉(1.10g，19.7mmol),40摄氏度反应2小时。过滤掉铁粉，滤液减压浓缩。所得残余物溶于乙酸乙酯，用饱和碳酸钾水溶液洗涤，有机相浓缩得到5-溴-N1-环丁基-3-氟苯-1,2-二胺粗品500mg，不经纯化直接用于下一步反应,LCMS:261(M+H)。
第三步：6-溴-1-环丁基-4-氟-2-甲基-1H-苯并[d]咪唑
在干燥的100mL圆底烧瓶中室温下将5-溴-N1-环丁基-3-氟苯-1,2-二胺(500mg，1.93mmol)加入到乙酸和盐酸溶液中(V:V＝1:1)，升温到100摄氏度反应6小时。反应液减压浓缩，残余物溶于乙酸乙酯中，用饱和碳酸钠溶液洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。所得残余物经硅胶柱色谱法纯化得到6-溴-1-环丁基-4-氟-2-甲基-1H-苯并[d]咪唑(400mg)，LCMS:284(M+H)。
第四步：1-环丁基-4-氟-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-苯并[d]咪唑
在干燥的100mL圆底烧瓶中室温下依次将6-溴-1-环丁基-4-氟-2-甲基-1H-苯并[d]咪唑(400mg，1.41mmol)，醋酸钾(414mg，0.141mmol),联硼酸频那醇酯(538mg，2.12mmol)，三环己基膦(59mg，0.212mmol),醋酸钯(32mg，0.141mmol)加入到二甲基亚砜中加热到100摄氏度反应2.5小时。加入饱和食盐水，乙酸乙酯萃取(多次)。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。加入正己烷打浆得到1-环丁基-4-氟-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-苯并[d]咪唑(400mg，土黄色粉末)，LCMS:249(M-82),331(M+H)。
采用中间体1相同的方法制备，可以得到以下中间体：
中间体2
Figure PCTCN2016080792-appb-000024
该中间体是由5-溴-1,3-二氟-2-硝基苯与异丙胺为原料参照中间体1的方法合成得到。1H-NMR(400MHz,DMSO-d6)δ7.67(s,1H),7.13(d,J＝11.2Hz,1H),4.90-4.80(m,1H),2.60(s,3H),1.55(d,J＝6.8Hz,6H),1.32(s,12H).
中间体3
Figure PCTCN2016080792-appb-000025
该中间体是由5-溴-1,3-二氟-2-硝基苯与3,3-二氟环丁-1-胺为原料参照中间体1的方法合成得到。LCMS:367.3(M+H)
中间体4
Figure PCTCN2016080792-appb-000026
该中间体是由5-溴-1,3-二氟-2-硝基苯与2-甲基丙-1-胺为原料参照中间体1的方法合成得到。LCMS:333.2(M+H)；1H-NMR(400MHz,CDCl3)δ7.52(s,1H),7.35(d,J＝10.4Hz,1H),3.93(d,J＝7.6Hz,2H),2.62(s,3H),1.26(s,9H),0.96(d,J＝6.8Hz,6H).
中间体5
Figure PCTCN2016080792-appb-000027
该中间体是由5-溴-1,3-二氟-2-硝基苯与环戊胺为原料参照中间体1的方法合成得到。LCMS:345.3(M+H)。
中间体6
Figure PCTCN2016080792-appb-000028
该中间体是由5-溴-1,3-二氟-2-硝基苯与四氢呋喃-3-胺为原料参照中间体1的方法合成得到，LCMS:347.3(M+H)。
中间体7
Figure PCTCN2016080792-appb-000029
该中间体是由1-溴-2-氯-5-氟-4-硝基苯与异丙胺为原料参照中间体1的方法合成，LCMS:335(M+1)。
中间体8
Figure PCTCN2016080792-appb-000030
该中间体是由1-溴-2-氯-5-氟-4-硝基苯与1-甲基环丙胺为原料参照中间体1的方法合成，LCMS:331.1(M+H)。
中间体9
Figure PCTCN2016080792-appb-000031
在干燥的150mL圆底烧瓶中室温下依次加入4-氟-1-异丙基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-苯并[d]咪唑(2.3g，7.22mmol)，1,4-二氧六环(40.0mL)和水(10.0mL)，4,6-二氯-5-氟嘧啶(1.32g，7.94mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(528mg，0.72mmol)，碳酸钠(2.29g，21.66mmol)，氮气置换3次。升温至80摄氏度，搅拌4小时。反应液减压浓缩，倒入100mL水，用乙酸乙酯萃取(150mLx3)。合并有机相，用100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用柱色谱法以洗脱剂体系(乙酸乙酯:石油醚＝1:4)纯化所得残余物，得到化合物6-(6-氯-5-氟吡啶-4-基)-4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑(902mg)，LCMS:323(M+H)。
本发明使用中间体9相同的合成方法可制备得到如下中间体：
中间体10
Figure PCTCN2016080792-appb-000032
该化合物是由中间体2与6-氯嘧啶-4-胺为原料参照中间体9的方法合成。LCMS:286(M+H)；1H-NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.10(s,1H),7.57(d,J＝12.4Hz,1H)，6.98(s,1H),6.88(s,1H),4.80-4.85(m,1H),2.62(s,3H),1.60(d,J＝6.8Hz,6H,).
中间体11
Figure PCTCN2016080792-appb-000033
该化合物是由中间体2与4,6-二氯-5-甲氧基嘧啶为原料参照中间体9的方法合成。LCMS:335.0(M+H)
中间体12
Figure PCTCN2016080792-appb-000034
该化合物是由中间体2与4,6-二氯-5-甲基嘧啶为原料参照中间体9的方法合成。LCMS:323(M+H)。
中间体13
Figure PCTCN2016080792-appb-000035
该化合物是由中间体2与2-氯-4-碘吡啶为原料参照中间体9的方法合成,LCMS:304(M+H)。
中间体14
Figure PCTCN2016080792-appb-000036
该化合物是由中间体2与4,6-二氯嘧啶-5-胺为原料参照中间体9的方法合成，LCMS:319(M+H)。
中间体15
Figure PCTCN2016080792-appb-000037
该化合物是由中间体2与2-氯-5-氟-4-碘吡啶为原料参照中间体9的方法合成，1H-NMR(400MHz,CDCl3)δ8.33(d,J＝2.4Hz,1H),7.51(s,1H),7.46(d,J＝5.6Hz,1H),7.15(d,J＝11.2Hz,1H),4.68-4.75(m,1H),2.68(s,3H),1.68(d,J＝6.8Hz,6H)。
中间体16
Figure PCTCN2016080792-appb-000038
该化合物是由中间体1与4,6-二氯嘧啶为原料参照中间体9的方法合成，LCMS:317(M+H)。
中间体17
Figure PCTCN2016080792-appb-000039
该化合物是由中间体2与4,6-二氯嘧啶为原料参照中间体9的方法合成，LCMS:305(M+H)；1H-NMR(400MHz,CDCl3)δ9.016(s,1H),8.170(d,J＝1.2Hz,1H),7.733(s,1H),7.560-7.591(m,1H),4.739-4.773(m,1H),2.698(s,3H),1.649-1.726(m,6H)。
中间体18
Figure PCTCN2016080792-appb-000040
第一步：叔丁基(5-甲基吡嗪-2-基)氨基甲酸
在干燥的250mL圆底烧瓶中室温下依次加入5-甲基吡嗪-2-羧酸(5g，36.2mmol),叠氮磷酸二苯酯(9ml),三乙胺(15ml，108mmol),叔丁醇(34ml，362mmol)和甲苯(100ml)，升温至100摄氏度，搅拌6小时。反应液加入100mL水，用乙酸乙酯萃取(150mL x3)，合并有机相，用100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用柱色谱法以洗脱剂体系(乙酸乙酯:石油醚＝5:1)纯化所得残余物得到化合物叔丁基(5-甲基吡嗪-2-基)氨基甲酸(5.8g)，LCMS:208.1(M+H)。
第二步：叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸
在干燥的250mL圆底烧瓶中室温下依次加入叔丁基(5-甲基吡嗪-2-基)氨基甲酸(2.1g，10mmol)，四氯化碳(100ml)，N-溴代丁二酰亚胺(1.96g，11mmol)和偶氮二异丁腈(1.6g，10mmol)。升温至80摄氏度，搅拌16小时。反应液减压浓缩得褐色粗产品叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸(2.8g)，产物不经纯化直接进行下一步反应，LCMS:288.1(M+H)。
第四步：5-((4-乙基哌嗪-1-基)甲基)吡嗪-2-胺
在干燥的50mL圆底烧瓶中室温下依次加入叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸(2.8g，10mmol)，乙腈(15ml)，1-乙基哌嗪(2.28g，20mmol)，室温下搅拌2小时。反应液过滤，得到白色化合物叔丁基(5-((4-甲基哌嗪-1-基甲基)吡嗪-2-基)氨基甲酸(750mg)，LCMS:322.3(M+H)。将白色产物经盐酸甲醇溶液脱掉叔丁氧羰基得到5-((4-乙基哌嗪-1-基)甲基)吡嗪-2-胺,LCMS:222.2(M+H)。
本发明采用中间体18相同的方法合成可制备得到如下中间体：
中间体19
Figure PCTCN2016080792-appb-000041
该化合物是由1-甲基哌嗪与叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸酯为原料，参照中间体18的方法合成得到，LCMS:208.2(M+H)。
中间体20
Figure PCTCN2016080792-appb-000042
该化合物是由5-溴-2-甲基嘧啶与1-乙基哌嗪为原料参照中间体18的制备方法合成得到，LCMS:287.1(M+H)。
中间体21
Figure PCTCN2016080792-appb-000043
该化合物是由N，N-二甲基哌啶-4-胺与叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸为原料，参照中间体18的制备方法合成，LCMS:236.2(M+H)。
中间体22
Figure PCTCN2016080792-appb-000044
该化合物是由乙基2-(哌嗪-1-基)乙酸乙酯与叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸为原料，参照中间体18的制备方法合成，LCMS:280.3(M+H)
中间体23
Figure PCTCN2016080792-appb-000045
该化合物是由叔丁基(6-甲基哒嗪-3-基)氨基甲酸与1-乙基哌嗪为原料，参照中间体18的制备方法合成，LCMS:222(M+H)
中间体24
Figure PCTCN2016080792-appb-000046
该中间体是由吗啉与叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸为原料，参照中间体18的制备方法合成，LCMS:195(M+H)。
中间体25
Figure PCTCN2016080792-appb-000047
该中间体是由1,2-二甲基哌嗪与叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸为原料，参照中间体18的制备方法合成，LCMS:222.2(M+H)。
中间体26
Figure PCTCN2016080792-appb-000048
该中间体是由1-异丙基哌嗪与叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸为原料，参照中间体18的制备方法合成。LCMS：236.2(M+H)。
中间体27
Figure PCTCN2016080792-appb-000049
该中间体是由1-(环丙基甲基)哌嗪与叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸为原料，参照中间体18的制备方法合成，LCMS:248.2(M+H)。
中间体28
Figure PCTCN2016080792-appb-000050
该中间体是由1-(2-甲氧基乙基)哌嗪与叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸为原料，参照中间体18的方法合成，LCMS:252(M+H)。
中间体29
Figure PCTCN2016080792-appb-000051
该中间体是由1-(2,2,2-三氟乙基)哌嗪与叔丁基(5-(溴甲基)吡嗪-2-基)氨基甲酸为原料，参照中间体18的方法合成，LCMS:276.2(M+H)。
中间体30
Figure PCTCN2016080792-appb-000052
该中间体是由1，2,6-三甲基哌嗪与叔丁基(5-(溴甲基)吡啶-2-基)氨基甲酸为原料，采用中间体18相同的方法制备得到，LCMS：235.3(M+H)。
中间体31
Figure PCTCN2016080792-appb-000053
该中间体是由4-(吡咯烷-1-基)哌啶与叔丁基(5-(溴甲基)吡啶-2-基)氨基甲酸为原料，参照中间体18的制备方法合成，LCMS:261.3(M+H)。
中间体32
Figure PCTCN2016080792-appb-000054
该中间体是由1-环戊基哌嗪为原料，采用中间体18相同的方法制备得到，LCMS:262(M+H)。
中间体33
Figure PCTCN2016080792-appb-000055
该中间体是由1-乙基哌嗪为原料，采用中间体18相同的方法制备得到，LCMS:222.1(M+H)。
中间体34
Figure PCTCN2016080792-appb-000056
在干燥的圆底烧瓶中冰水浴下依次加入1-乙基哌啶-4-醇(200mg，1.55mmol)，干燥的四氢呋喃(10mL)，60％钠氢(124mg，3.1mmol)，混合物在0摄氏度下反应0.5小时。再加入2,5-二氯吡嗪(231mg，1.55mmol)，反应过夜。反应液用冰水淬灭，二氯甲烷萃取，有机相浓缩得到2-氯-5-((1-乙基哌啶-4-基)氧基)吡嗪(330mg,白色固体)。LCMS:242.1(M+H)。
实施例1
Figure PCTCN2016080792-appb-000057
在干燥的微波管中室温下依次加入6-(6-氯-嘧啶-4-基)-4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑(50mg，0.155mmol)，三(二亚苄基丙酮)二钯(14mg，0.015mmol)，5-氯吡嗪-2-胺(24mg，0.186mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(17mg，0.029mmol)，碳酸铯(101mg，0.31mmol)和干燥的二氧六环(1mL)，氮气置换3次。120摄氏度下微波反应2小时。反应液中加入10mL水，用二氯甲烷萃取(20mL*3)，合并有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用反相高效液相色谱法纯化得到目标化合物。LCMS:498(M+H)；1H-NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.12(s,1H),8.89(s,1H),8.55(s,1H),8.20(s,1H),8.02(s,1H),7.62(d,J＝11.6Hz,1H),7.93(d,J＝1.2Hz,1H),7.63(s,1H),4.82-4.89(m,1H),2.64(s,3H),1.63(d,J＝6.8Hz,6H)。
实施例2
Figure PCTCN2016080792-appb-000058
以6-(6-氯-5-氟吡啶-4-基)-4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑(50mg，0.155mmol)和5-((4-乙基哌嗪-1-基)甲基)吡嗪-2-胺(41mg，0.186mmol)为原料，采用实施例1相同的方法合成得到目标化合物N-(5-((4-乙基哌嗪-1-基)甲基)吡嗪-2-基)-5-氟-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺(30mg)。LCMS:508.2(M+H)+。1H-NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.29(s,1H),8.63(s,1H),8.42(s,1H),8.15(s,1H),7.64(d,J＝12.4Hz,1H),4.83-4.86(m,1H),3.62(s,2H),2.64(s,3H),2.38-2.46(m,8H),2.27-2.33(m,2H),1.60(d,J＝7.2Hz,6H),0.97(t,J＝7.2Hz,3H)。
以上述不同的合成砌块为原料，采用实施例1相同的合成方法，制备可得到如下实施例化合物：
实施例3
氮-(5-((4-乙基哌嗪-1-基)甲基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000059
1H-NMR(400MHz,CD3OD)δ9.16(s,1H),8.81(s,1H),8.41(s,1H),8.23(s,1H),8.04(s,1H),7.60(d,J＝11.6Hz,1H),4.87-4.91(m,1H),3.70(s,2H),2.68(s,3H),2.63(br,8H),2.49(q,J＝7.2Hz,2H),1.73(d,J＝7.2,6H),1.12(t,J＝7.2Hz,3H)。
实施例4
5-((4-乙基哌嗪-1-基)甲基)-氮-(6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)嘧啶 -4-基)嘧啶-2-胺
Figure PCTCN2016080792-appb-000060
1H-NMR:(400MHz,CD3OD)δ8.79(d,J＝3.2Hz,2H),8.57(s,2H),8.19(s,1H),7.13(d,J＝10.8Hz,1H),4.87-4.89(m,1H),3.49(s,2H),2.67(s,3H),2.63-2.67(m,8H),2.36(q,J＝7.2Hz,2H),1.71(d,J＝6.8Hz,6H),1.12(t,J＝7.2Hz,3H)。
实施例5
5-((4-乙基哌嗪-1-基)甲基)-氮-(5-氟-6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)嘧啶-4-基)嘧啶-2-胺
Figure PCTCN2016080792-appb-000061
1H-NMR:(400MHz,CDCl3)δ8.86(s,1H),8.63(s,2H),8.15(s,1H),8.01(s,1H),7.75(d,J＝12.0Hz,1H),4.73-4.76(m,1H),3.51(s,2H),2.70(s,3H),2.40-2.53(m,10H),1.71(d,J＝6.8Hz,6H),1.09(t,J＝7.2Hz,3H)。
实施例6
5-((4-乙基哌嗪-1-基)甲基)-氮-(6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)-5-甲基嘧啶-4-基)嘧啶-2-胺
Figure PCTCN2016080792-appb-000062
1H-NMR:(400MHz,CDCl3-d)δ8.97(s,1H),8.58(s,2H),7.56(s,1H),7.54(s,1H),7.13(d,J＝10.8Hz,1H),4.69-4.75(m,1H),3.52(s,2H),2.69(s,3H),2.64-2.69(m,10H),2.36(s,3H),1.67(d,J＝6.8Hz,6H),1.19(s,3H)。
实施例7
氮-(5-((4-乙基哌嗪-1-基)甲基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)-5-甲基嘧啶-4-胺
Figure PCTCN2016080792-appb-000063
1H-NMR:(400MHz,CDCl3-d)δ9.86(s,1H),8.80(s,1H),8.31(s,1H),7.49(s,1H),7.31(s,1H),7.09(d,J＝10.8Hz,1H),4.68-4.75(m,1H),3.73(s,2H),2.69(s,3H),2.47-2.69(m,10H),2.37(s,3H),1.67(d,J＝7.2Hz,6H),1.10-1.14(t,J＝6.8Hz,3H)。
实施例8
氮4-(5-((4-乙基哌嗪-1-基)甲基)嘧啶-2-基)-6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)嘧啶-4,5-二胺
Figure PCTCN2016080792-appb-000064
1H-NMR:(400MHz,CDCl3-d)δ8.61(s,1H),8.48(s,2H),7.79(s,1H),7.64(s,1H),7.31(d,J＝10.4Hz,1H),4.69-4.76(m,1H),4.50(s,2H),3.48(s,2H),2.69(s,3H),2.53-2.69(m,10H),1.67(d,J＝6.8Hz,6H),1.17-1.19(m,3H)。
实施例9
5-((4-乙基哌嗪-1-基)甲基)-氮-(6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)-5-甲氧基嘧啶-4-基)嘧啶-2-胺
Figure PCTCN2016080792-appb-000065
1H-NMR:(400MHz,CDCl3-d)δ8.87(s,1H),8.63(s,2H),8.46(s,1H),8.14(s,1H),7.79(d,J＝11.2Hz,1H),4.73-4.80(m,1H),3.68(s,3H),3.58(s,2H),2.81-2.94(m,10H),2.72(s,3H),1.72(d,J＝7.2Hz,6H),1.32-1.34(m,3H)。
实施例10
5-氟-6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)-氮-(5-(哌嗪-1-基)吡嗪-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000066
在微波管中加入N-(5-氯吡啶-2-基)-5-氟-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺(42mg，0.1mmol)与哌嗪(86mg，1mmol)以正丁醇(0.5mL)作反应溶剂，120度微波加热2小时反应得到目标化合物。LCMS:466.3(M+H)；1H-NMR:(400MHz,CDCl3-d)δ9.30(s,1H),8.59(s,1H),8.10(s,1H),7.87(s,1H),7.71(d,J＝12.0Hz,1H),7.45(s,1H),4.73-4.76(m,1H),3.54-3.56(t,J＝5.0Hz,4H),3.03-3.05(t,J＝5.0Hz,4H),2.69(s,3H),1.70(d,J＝7.2Hz,6H)。
实施例11
5-氟-6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)-氮-(5-(4-甲基哌嗪-1-基)吡嗪-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000067
以N-(5-氯吡啶-2-基)-5-氟-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺与N-甲基哌嗪为原料，参照实施例10的方法制备得到目标化合物。LCMS:480.1(M+H)；1H-NMR:(400MHz,CDCl3)δ9.22(s,1H),8.52(s,1H),8.03(s,1H),7.81(s,1H), 7.64(d,J＝11.6Hz,1H),7.38(s,1H),4.65-4.69(m,1H),3.52-3.54(t,J＝4.8Hz,4H),2.62(s,3H),2.49-2.51(t,J＝4.8Hz,4H),2.31(s,3H),1.63(d,J＝6.8Hz,6H)。
实施例12
氮-(5-(4-乙基哌嗪-1-基)吡嗪-2-基)-5-氟-6-(4-氟-1异丙基-2-甲基-1氢-苯并咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000068
以N-(5-氯吡啶-2-基)-5-氟-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺与N-乙基哌嗪为原料，参照实施例10的方法制备得到目标化合物。1H-NMR:(400MHz,DMSO-d6)δ9.94(s,1H),8.69(s,1H),8.48(s,1H),8.17(s,1H),8.14(s,1H),7.60(d,J＝11.6Hz,1H),7.38(s,1H),4.83-4.86(m,1H),3.52-3.54(t,J＝4.6Hz,4H),2.62(s,3H),2.49-2.51(t,J＝4.6Hz,4H),2.36-2.41(q,2H),1.61(d,J＝6.8Hz,6H),1.03-1.07(t,J＝7.2Hz,3H)。
实施例13
氮-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000069
参照实施例1和实施例2的制备方法合成得到目标化合物。1H-NMR:(400MHz,CDCl3-d)δ8.86(s,1H),8.27(s,1H),8.19(s,1H),8.11(s,1H),7.71(s,2H),7.60(d,J＝10.8Hz,1H),4.73-4.80(m,1H),3.65(s,2H),3.48-3.51(m,2H),3.05-3.10(m,4H),2.84-2.96(m,4H),2.70(s,3H),1.72(d,J＝7.2Hz,6H),1.47-1.51(t,J＝7.0Hz,3H)。
实施例14
叔丁基4-(5-(5-氟-6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)嘧啶-4-基胺)吡嗪-2-基)哌嗪-1-羧酸酯
Figure PCTCN2016080792-appb-000070
以N-(5-氯吡啶-2-基)-5-氟-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺与N-Boc-哌嗪为原料，参照实施例10的方法制备得到目标化合物。1H-NMR:(400MHz,CDCl3-d)δ9.32(s,1H),8.60(s,1H),8.13(s,1H),7.88(s,1H),7.74(d,J＝11.2Hz,1H),7.48(s,1H),4.73-4.80(m,1H),3.56-3.58(m,8H),2.73(s,3H),1.71(d,J＝6.8Hz,6H),1.50(s,9H).
实施例15
5-((4-乙基哌嗪-1-基)甲基)-氮-(4-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)吡啶-2-基)吡啶-2-胺
Figure PCTCN2016080792-appb-000071
参照实施例1和实施例2的制备方法合成得到目标化合物。1H-NMR:(400MHz,CDCl3)δ8.31(d,J＝4.4Hz,1H),8.19(s,1H),7.84(s,1H),7.59-7.63(m,1H),7.53(s,2H),7.48(s,1H),7.22(m,1H),7.07-7.10(m,1H),4.71-4.76(m,1H),3.47(s,2H),2.68(s,3H),2.30-2.62(m,10H),1.70(d,J＝6.8Hz,6H),1.07-1.10(t,J＝6.8Hz,3H)。
实施例16
氮-(5-(4-乙基哌嗪-1-基)吡啶-2-基)-6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000072
该分子是由5-(4-甲基哌嗪-1-基)吡啶-2-胺与中间体17为原料，采用实施例1相同的方法合成制备得到，1H-NMR:(400MHz,CD3OD)δppm 8.64(d,J＝1.2Hz,1H),8.13(s,1H),8.01(d,J＝2.8Hz,1H),7.85(s,1H),7.64(d,J＝8.0Hz,1H),7.54(d,J＝12.0Hz,1H),7.39-7.42(m,1H),4.83-4.86(m,1H),3.18-3.20(m,4H),2.84-2.86(m,7H),2.49(q,J＝7.2Hz,2H),1.69(d,J＝7.2Hz,6H),1.13(t,J＝7.2Hz,3H).
实施例17
叔丁基4-(6-(6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)嘧啶-4-基胺)吡啶-3-基)哌嗪-1-羧酸酯
Figure PCTCN2016080792-appb-000073
该分子是由叔丁基4-(6-氨基吡啶-3-基)哌嗪-1-甲酸酯与中间体17为原料，采用实施例1相同的方法合成制备得到，1H-NMR:(400MHz,CD3OD)δ8.63(d,J＝1.2Hz,1H),8.13(s,1H),8.01(d,J＝2.8Hz,1H),7.86(s,1H),7.65(d,J＝8.8Hz,1H),7.49-7.52(m,1H),7.39-7.42(m,1H),4.83-4.86(m,1H),3.55-3.57(m,4H),3.07-3.10(m,4H),2.49(q,J＝7.2Hz,2H),2.64(s,3H),1.69(d,J＝7.2Hz,6H),1.47(s,9H).
实施例18
6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)-氮-(5-(哌嗪-1-基)吡啶-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000074
将实施例17(35毫克)溶于二氯甲烷(5毫升)中，冰浴冷却下加入1毫升三氟乙酸，搅拌至反应完全，浓缩除去过量溶剂和三氟乙酸，干燥得到实施例18。1H-NMR:(400MHz,CD3OD)δ8.65(d,J＝1.6Hz,1H),8.16(d,J＝1.2Hz,1H),8.02(d,J＝2.4Hz,1H),7.88(s,1H),7.68(d,J＝8.4Hz,1H),7.53-7.56(m,1H),7.43-7.46(m,1H),4.83-4.86(m,1H),3.13-3.17(m,4H),2.98-3.00(m,4H),2.95(s,3H),1.70(d,J＝7.2Hz,6H),1.47(s,9H)。
实施例19
6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)-氮-(5-((4-甲基哌嗪-1-基)甲基)吡嗪-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000075
该分子是由中间体17与中间体19为原料，参照实施例1的方法制备得到目标分子。1H-NMR:(400MHz,CDCl3-d)δ8.97(s,1H),8.89(s,1H),8.30(s,1H),8.21(s,1H),8.10(s,1H),7.75(s,1H),7.57(d,J＝10.4Hz,1H),4.73-4.78(m,1H),3.80(s,2H),3.44-3.49(m,2H),3.01(s,6H),2.79(s,3H),2.70(s,3H),1.73(d,J＝7.2Hz,6H)。
实施例20
6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)-氮-(5-(***啉甲基)吡嗪-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000076
该分子是由中间体17与中间体24为原料，参照实施例1的方法制备得到目标分子。1H-NMR:(400MHz,CDCl3)δ8.97(s,1H),8.88(s,1H),8.45(s,1H),8.20(s,1H),8.09(s,1H),7.90(s,1H),7.57(d,J＝11.2Hz,1H),4.73-4.80(m,1H),3.82(s,6H),2.60-2.70(m,7H),1.72(d,J＝6.8Hz,6H)。
实施例21
6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)-氮-(5-(哌嗪-1-基)吡嗪-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000077
参照实施例10的方法制备得到目标分子。1H-NMR:(400MHz,CDCl3)δ8.80(s,1H),8.58(s,1H),8.17(s,1H),7.92(s,1H),7.63(s,1H),7.49(d,J＝11.2Hz,1H),4.73-4.80(m,1H),3.53-3.56(t,J＝5.0Hz,4H),3.08(s,1H),3.04-3.07(t,J＝5.0Hz,4H),2.69(s,3H),1.71(d,J＝7.2Hz, 6H)。
实施例22
6-(4-氟-1-异丙基-2-甲基-1氢-苯并咪唑-6-基)-氮-(5-(4-甲基哌嗪-1-基)吡嗪-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000078
参照实施例10的方法制备得到目标分子。1H-NMR:(400MHz,CDCl3)δ8.80(s,1H),8.58(s,1H),8.17(s,1H),7.92(s,1H),7.63(s,1H 1H-NMR:(400MHz,CDCl3)δ8.80(s,1H),8.58(s,1H),8.17(s,1H),7.93(s,1H),7.63(s,1H),7.49(d,J＝11.6Hz,1H),7.29(s,1H),4.73-4.78(m,1H),3.58-3.61(t,J＝5.0Hz,4H),2.69(s,3H),2.57-2.60(t,J＝5.0Hz,4H),2.38(s,3H),1.70(d,J＝6.8Hz,6H)。
实施例23
氮–(5-(1-乙基哌啶-4-基)氧基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-咪唑苯并[d]嘧啶-6-基)-4-胺
Figure PCTCN2016080792-appb-000079
以6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺与2-氯-5-(1-乙基哌啶-4-基)氧基)吡嗪为原料，采用实施例1相同的方法合成得到氮–(5-(1-乙基哌啶-4-基)氧基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-咪唑苯并[d]嘧啶-6-基)-4-胺。LCMS：491(M+H)；1H-NMR:(400MHz,CDCl3)δ8.83(s,1H),8.70(s,1H),8.15(s,1H),8.98(s,1H),7.56(s,1H),7.50-7.52(d,J＝11.2Hz,1H),7.41(s,1H),5.05(s,1H),4.73-7.76(m,1H),2.83(s,2H),2.68(s,3H),2.49(s,2H),2.13(s,2H),1.90(s,2H),1.66-1.71(m,8H),1.15(t,J＝7.2Hz,3H).
实施例24
6-(1-异丙基-4-氟-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-((4-乙基哌嗪-1-基)甲基)吡嗪-2-胺)吡啶-4-胺
Figure PCTCN2016080792-appb-000080
该分子是由中间体13与中间体18为原料，参照实施例1的方法制备得到目标分子。LCMS:489(M+H)；1H-NMR(400MHz,CDCl3-d)8.87(s，1H),8.34(d,J＝5.6Hz,1H),8.23(s,1H),7.93(s,1Hz),7.52(s,1H),7.16(d,J＝1.2Hz,1H),4.73(q,J＝7.2Hz,1H),3.67(s,2H),2.41-2.68(m,13H),1.69(s,3H),1.65(s,3H),1.14(s,3H)。
实施例25
N-(2-((4-乙基哌啶-1-基)甲基)嘧啶-5-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000081
该分子是由中间体10与中间体20为原料，参照实施例1的方法制备得到目标分子。LCMS:490.3(M+H)；1H-NMR(400MHz,CDCl3)δ9.09(s,2H),8.83(d,J＝4.4Hz,1H),8.16(s,1H),7.44(d,J＝11.2Hz,1H),7.12(s,1H),4.73-4.77(m,1H),3.88(s,2H),2.42-2.84(m,15H),1.70(d,6H,J＝6.8Hz),1.20(s,3H).
实施例26
6-(5-氯-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-((4-乙基哌嗪-1-基)吡啶-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000082
参照实施例1的方法制备得到目标分子。LCMS:505(M+H)；1H-NMR(400MHz,CDCl3)δ10.344(s,1H),8.826(s,1H),8.174(s,1H),8.031(s,1H),7.876(s,1H),7.801(d,J＝7.2Hz,1H),7.730(s,1H),7.686(d,J＝9.6Hz,1H,),4.783-4.817(m,1H),3.415-3.594(m,2H),2.579-2.697(m,4H),2.236-2.368(m,9H),1.526-1.601(m,6H),0.952-0.987(m,3H).
实施例27
N-(2-((1-乙基哌啶-4-基烯基)甲基)嘧啶-5-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000083
第一步：5-溴-2-(甲基)嘧啶基磷酸二乙酯
在干燥的5mL玻璃封管中依次加入5-溴-2-(溴甲基)嘧啶(100mg，0.40mmol)，亚磷酸三乙酯(1.0mL)和乙腈(1.0mL)。升温至100摄氏度，搅拌4小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯:石油醚＝1:2)纯化所得残余物，得到产物5-溴-2-(甲基)嘧啶基磷酸二乙酯(100mg，白色固体),LCMS:311(M+H)。
第二步：5-溴-2-((1-乙基哌啶-4-亚甲基)甲基嘧啶
在干燥的50mL圆底烧瓶中室温下依次加入5-溴-2-(甲基)嘧啶基磷酸二乙酯(100mg，0.324mmol)，无水四氢呋喃(5ml)和N-乙基-4-哌啶酮(49.3mg，0.388mmol)，冷却至0摄氏度。缓慢加入60％钠氢(25.9mg，0.648mmol),室温搅拌6小时。加入 30mL冰水，用乙酸乙酯萃取(50mL×3)，合并有机相，饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯:石油醚＝1:1)纯化所得残余物，得到产物5-溴-2-((1-乙基哌啶-4-亚甲基)甲基嘧啶(60mg，白色固体)，LCMS：284(M+H)。
第三步：N-(2-((1-乙基哌嗪-4-烯基)甲基)嘧啶-5-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
以6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑)嘧啶-4-胺(50mg，0.175mmol)，和5-溴-2-((1-乙基哌啶-4-烯基)甲基嘧啶(60mg，0.213mmol)为原料，参照实施例第二步的方法制备得到目标化合物N-(2-((1-乙基哌嗪-4-烯基)甲基)嘧啶-5-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺(12.5mg，白色固体)。LCMS:487.3(M+H)；1H-NMR(400MHz,MeOD-d4)δ9.21(s,2H),8.85(s,1H),8.36(s,1H),7.86(d,J＝11.2Hz,1H),7.38(s,1H),6.54(s,1H),5.00～5.09(m,1H),3.71～3.76(m,2H),3.22～3.27(m,2H),3.03～3.12(m,2H),2.87(s,3H),2.58～2.84(m,4H),1.79(d,J＝6.8Hz,6H),1.39(t,J＝7.4Hz,3H)。
实施例28
N-(5-((1-乙基哌嗪-4-烯基)甲基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000084
参照实施例27的制备方法合成得到目标分子LCMS:487.4(M+H)；1H-NMR:(400MHz,CDCl-d)δ8.91(s,1H),8.87(s,1H),8.20(s,1H),8.18(s,1H),8.04(s,1H),7.59(s,1H),7.57(d,J＝11.6Hz,1H),6.28(s,1H),4.72～4.78(m,1H),2.98～3.02(m,2H),2.69(s,3H),2.52～2.63(m,8H),1.72(d,J＝6.8Hz,6H),1.16(t,J＝7.0Hz,3H)。
实施例29
N-(5-((1-乙基哌嗪-4-亚甲基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000085
以N-(5-((1-乙基哌嗪-4-烯基))吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺为原料，经钯碳催化氢化还原得到N-(5-((1-乙基哌嗪-4-亚甲基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺。LCMS:489.4(M+H)；1H-NMR(400MHz,CDCl3)δ8.90(s,1H),8.87(s,1H),8.20(s,1H),8.17(s,1H),8.04(s,1H),7.60(s,1H),7.56(d,J＝12.0Hz,1H),6.28(s,1H),4.72～4.78(m,1H),2.98～3.01(m,2H),2.72～2.74(m,2H),2.69(s,3H),2.43～2.45(m,2H),1.79～2.00(m, 7H),1.72(d,J＝7.2Hz,6H),1.11(t,J＝7.2Hz,3H)。
实施例30
[5-(3,4-二甲基-哌嗪-1-基甲基)-吡嗪-2-基]-6-(7-氟-3-异丙基-2-甲基-3H-咪唑-5-基)-嘧啶-4-基]-胺
Figure PCTCN2016080792-appb-000086
该分子是由中间体17与中间体25为原料，参照实施例1的制备方法合成得到目标分子。LCMS:490.6(M+H)；1H-NMR(400MHz,CDCl3)δ8.89(s,1H),8.80(s,1H),8.37(s,1H),8.21(s,1H),8.12(s,1H),7.77(s,1H),7.56(d,J＝11.4Hz,1H),4.74～4.78(m,1H),3.67(s,2H),275-2.85(m,3H),2.70(s,3H),2.36～2.40(m,2H),2.30(s,3H),2.26-2.28(m,1H),2.00-2.05(m,2H),1.73(s,1H),1.71(s,1H),1.05(d,J＝6.0Hz,3H)。
实施例31
N-(4-氯-5((4-乙基哌嗪-1-基)甲基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000087
第一步：4,6-二氯-3-吡啶甲醇
在干燥的50mL圆底烧瓶中室温下依次加入4,6-二氯烟酸甲酯(2.5g，12.0mmol)，四氢呋喃(50ml)，硼氢化钠(2.3g，60.0mmol)，然后冰水浴滴加甲(50ml)，室温下搅拌1小时。用饱和氯化铵溶液淬灭，加水50ml，用乙酸乙酯萃取(50mL×3)。合并有机相，饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物4,6-二氯-3-吡啶甲醇(2.03g，黄色固体)。LCMS:179.9(M+H)；1H-NMR:(400MHz,CDCl3)δ8.47(s,1H),7.37(s,1H),4.81(s,2H)。
第二步：4,6-二氯吡啶-3-甲醛
在干燥的50mL圆底烧瓶中室温下依次加入4,6-二氯-3-吡啶甲醇(2.03g，11.4mmol)，氯仿(50ml)，活性二氧化锰(9.91g，114.0mmol)，然后回流搅拌4小时。过滤，滤液用无水硫酸钠干燥，过滤，滤液减压浓缩得到产物4,6-二氯吡啶-3-甲醛(960mg，黄色固体)。1H-NMR:(400MHz,CDCl3-d)δ10.44(s,1H),8.85(s,1H),7.50(s,1H)。
第三步：1-(4,6-二氯吡啶-3-甲基)-4-乙基哌嗪
在干燥的50mL圆底烧瓶中室温下依次加入4,6-二氯吡啶-3-甲醛(352mg，2.0mmol),乙醇(5ml)，1-乙基哌嗪(342mg，3.0mmol)，三乙酰氧基硼氢化钠(161.2mg， 2.6mmol)，冰乙酸(144mg，2.4mmol)，120摄氏度下回流4小时。加入20ml水，用乙酸乙酯萃取(30mL×3)。合并有机相，饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，薄层色谱法纯化残余物得到产物1-(4,6-二氯吡啶-3-甲基)-4-乙基哌嗪(31mg,黄色固体)。LCMS:275.0(M+H)。
第四步：N-(4-氯-5((4-乙基哌嗪-1-基)甲基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
以6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-4-胺(28.5mg，0.1mmol)，和1-(4,6-二氯吡啶-3-甲基)-4-乙基哌嗪(30.0mg，0.1mmol)为原料，采用实施例1相同的方法制备得N-(4-氯-5((4-乙基哌嗪-1-基)甲基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺(8.0mg，淡黄色固体)。LCMS:524(M+H)；1H-NMR:(400MHz,CDCl3)δ8.87(s,1H),8.24(s,1H),8.19(s,1H),7.97(s,1H),7.88(s,1H),7.55(d,J＝11.2Hz,1H),4.74-4.81(m,1H),3.70(s,2H),3.54-3.60(m,2H),2.97-3.10(m,8H),2.69(s,3H),1.71(d,J＝7.2Hz,6H),1.47(t,J＝5.6Hz,3H).
实施例32
6-(1-环丁基-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)嘧
啶-4-胺
Figure PCTCN2016080792-appb-000088
该分子是由5-((4-乙基哌嗪-1-基)甲基)吡啶-2-胺与中间体16为原料，采用实施例1相同的方法制备得到。LCMS:502(M+H)；1H-NMR(400MHz,CDCl3)δ8.94(s,1H),8.88(s,1H),8.28(d,J＝12.8Hz,2H),8.13(s,1H),7.90(s,1H),7.59(d,J＝11.2Hz,2H),4.94(t,J＝8.8Hz,1H),3.75(s,2H),2.89-3.00(m,11H),2.61-2.70(m,6H),2.15(d,J＝9.6Hz,1H),2.12(d,J＝10.4Hz,1H),1.33(s,3H)。
实施例33
5-((4-(二甲基氨基)哌啶-1-基)甲基)-N-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-2-基)吡嗪-2-胺
Figure PCTCN2016080792-appb-000089
该分子是由中间体13与中间体21为原料，参照实施例1相同的方法制备得到目标化合物。LCMS:503.4(M+H)；1H-NMR(400MHz,DMSO-d6)δ10.53(s,1H),10.21(brs,1H),9.21(s,1H),8.42(s,1H),8.39(d,J＝5.6Hz,1H),8.06(s,1H),7.88(s,1H),7.49(d,J＝5.2Hz,1H),7.42(d,J＝11.6Hz,1H),4.85～4.92(m,1H),4.42(s,2H),3.62(m,2H),3.37～3.40(m,1H),3.09～3.11(m,2H),2.78(s,6H),2.67(s,3H),2.21～2.24(m,2H),1.84～1.95(m,2H),1.64(d,J＝7.2Hz,6H)。
实施例34
N-(5-(1-(4-乙基哌嗪-1-基)乙基)吡嗪)-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000090
第一步：5-氯-2-羧酸吡嗪
在干燥的50mL圆底烧瓶中室温下依次加入5-氯吡嗪-2-羧酸甲酯(3.5g，20.0mmol)，四氢呋喃(50ml)，滴加一水合氢氧化锂(839.2mg，20.0mmol)，室温下搅拌2小时。反应液减压浓缩，然后用1M HCl调节PH<3，用乙酸乙酯萃取(50mL×3)。合并有机相，饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物5-氯-2-羧酸吡嗪(3.09g，白色固体)。1H-NMR:(400MHz,DMSO-d)δ14.0(br,1H),9.03(s,1H),8.93(s,1H).
第二步：5-氯-N-甲氧基-N-甲基-吡嗪-2-酰胺
在干燥的50mL圆底烧瓶中室温下依次加入5-氯-2-羧酸吡嗪(1.50g，9.61mmol)，甲苯(50ml)，二氯亚砜(6.5ml)，然后滴加催化量的N,N-二甲基甲酰胺，回流反应3小时，反应液减压浓缩不经纯化直接用于下一步反应。
在干燥的50mL圆底烧瓶中室温下依次加入二甲羟胺盐酸盐(1.40g，14.41mmol)，二氯甲烷(50ml)，三乙胺(6.7ml)，然后滴加5-氯吡啶-2-羰基氯，室温搅拌1小时。加入50mL水，用乙酸乙酯萃取(50mL×3)。合并有机相，饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯:石油醚＝1:2)纯化所得残余物，得到产物5-氯-N-甲氧基-N-甲基-吡嗪-2-酰胺(960mg，黄色固体)。1H-NMR:(400MHz,CDCl3-d)δ8.71(s,1H),8.60(s,1H),3.75(s,1H),3.40(s,1H).
第三步：1-(5-氯-2吡嗪)-乙酮
在氩气保护冰水浴条件下，向干燥的25mL圆底烧瓶中依次加入5-氯-N-甲氧基-N-甲基-吡嗪-2-酰胺(402mg，2.0mmol),干燥的四氢呋喃(5ml)，然后滴加甲基溴化镁(0.8ml，3M***溶液)。0摄氏度反应1小时。加入20ml水，用乙酸乙酯萃取(20mL×3)。合并有机相，饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯:石油醚＝1:2)纯化所得残余物，得到产物1-(5-氯-2吡嗪)乙酮(162mg，白色固体)。1H-NMR:(400MHz,CDCl3-d)δ8.94(s,1H),8.56(s,1H),2.63(s,3H).
第四步：1-(5-((6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-基)胺)吡嗪-2-基)乙酮
以6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-4-胺(57.0mg，0.2mmol)和1-(5-氯-2吡嗪)-乙酮(37.44mg，0.24mmol)为原料，采用实施例1第二步相同的方法合成得产物1-(5-((6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-基)胺)吡嗪-2-基)乙酮(70mg，淡黄色固体)，LCMS:405.9(M+H)。
第五步：1-(5-((6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-基)胺)吡嗪-2-基)乙醇
在干燥的50mL圆底烧瓶中室温下依次加入1-(5-((6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-基)胺)吡嗪-2-基)乙酮(51mg，0.126mmol)，四氢呋喃(3ml)，然后在冰水浴条件下滴加甲醇(3ml)，0摄氏度反应1个小时。加入10mL水，用乙酸乙酯萃取(20mL×3)。合并有机相，饱和食盐水洗涤(20mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产物1-(5-((6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-基)胺)吡嗪-2-基)乙醇(48mg粗品，棕色固体)，LCMS:408.0(M+H)。
第六步：N-(5-(1-氯乙基吡嗪)-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
在干燥的25mL圆底烧瓶中室温下依次加入1-(5-((6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-基)胺)吡嗪-2-基)乙醇(48mg，0.118mmol)，甲苯(5ml)，二氯亚砜(1.5ml)，然后滴加催化量的N,N-二甲基甲酰胺，回流反应3小时。反应液减压浓缩得粗产物N-(5-(1-氯乙基吡嗪)-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺(41mg,粗品)备用。LCMS:425.3(M+H).
第七步：N-(5-(1-(4-乙基哌嗪-1-基)乙基)吡嗪)-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
在干燥的25mL圆底烧瓶中室温下依次加入N-(5-(1-氯乙基吡嗪)-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺(41mg，0.097mmol)，乙腈(5ml)，二异丙基乙胺(0.5ml)，然后滴加乙基哌嗪(33.1mg，0.291mmol)，回流反应2小时。加入10ml水，用乙酸乙酯萃取(20mL×3)。合并有机相，饱和食盐水洗涤(20mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物N-(5-(1-(4-乙基哌嗪-1-基)乙基)吡嗪)-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺(5mg，白色固体)，LCMS:504.3(M+H)；1H-NMR:(400MHz,CDCl3)δ8.87(d,J＝7.6Hz,1H),8.35(s,1H),8.21(s,1H)，8.10(s,1H),7.51(s,1H),7.56(d，J＝7.6Hz,1H),4.76-4.78(m,1H),3.71-3.73(m,1H),2.51-2.69(m,11H),2.11(s,2H),1.72(d,J＝6.8Hz,6H),1.47(d,J＝6.4Hz,3H),1.22(s,3H)。
实施例35
5-((4-乙氧基羰基甲基哌嗪-1-(甲基))-N-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-2-基)吡嗪-2-胺
Figure PCTCN2016080792-appb-000091
该分子是由中间体21与中间体22为原料，采用实施例1相同的方法合成得到。LCMS:547.3(M+H)；1H-NMR(400MHz,CDCl3)δ8.86(s,1H),8.35(d,J＝5.2Hz,1H),8.25(s,1H),8.10(s,1H),7.99(s,1H),7.53(s,1H),7.24(d,J＝11.2Hz,1H),7.17(d,J＝4.8Hz,1H),4.70～4.77(m,1H),4.16～4.21(m,2H),3.70(s,2H),3.22(s,2H),2.69(s,9H),1.70(d,J＝6.8Hz,6H),1.27(t,J＝7.0Hz,3H)。
实施例36
6-((4-乙基哌嗪-1-基)甲基)-N-(4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-4-基)哒嗪-3-胺
Figure PCTCN2016080792-appb-000092
该分子是由中间体21与中间体23为原料，参照实施例1相同的方法合成得到目标化合物。LCMS:488(M+H)；1H-NMR(400MHz,CDCl3-d)δ8.90-9.02(m,1H),8.42(d,J＝7.2Hz,1H),8.32(d,J＝5.2Hz,1H),7.72(d,J＝6.8Hz,1H),7.61(d,J＝8.8Hz,1H),7.51(s,1H),7.32(s,1H),7.14(d,J＝5.2Hz,1H),4.69-4.76(m,1H),3.83(s,2H),2.68(s,3H),2.35-2.63(m,10H),1.69(d,J＝6.8Hz,6H),1.07(t,J＝7.2Hz,3H)。
实施例37
6-((4-乙基哌嗪-1-基)甲基)-N-(6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-基)哒嗪-3-胺
Figure PCTCN2016080792-appb-000093
该分子是由中间体17与中间体21为原料，参照实施例1相同的方法合成得到目标化合物。LCMS:490(M+H)；1H-NMR(400MHz,CDCl3-d)δ11.46(s,1H),8.97(d,J＝9.2Hz,1H),8.88(s,1H),8.33(d,J＝4.8Hz,2H),7.77-7.84(m,2H),4.75-4.79(m,1H),4.06(s,2H),2.70(m,3H),2.41-2.68(m,10H),1.73(d,J＝6.8Hz,6H),1.08(t,J＝6.8Hz,3H)。
实施例38
6-(1-环丁基-4-氟-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-((4-乙基哌嗪-1-基)甲基)吡嗪-2-胺)嘧啶-4-胺
Figure PCTCN2016080792-appb-000094
该分子是由中间体16与中间体18为原料，参照实施例1的合成方法制备得到目 标分子。LCMS:502(M+H)；1H-NMR(400MHz,CDCl3)8.94(s,1H),8.88(s,1H),8.28(d,J＝12.8Hz,2H),8.13(s,1H),7.90(s,1H),7.59(d,J＝11.2Hz,2H),4.94(t,J＝8.8Hz,1H),3.75(s,2H),2.89-3.00(m,11H),2.61-2.70(m,6H)，2.15(d,J＝9.6Hz,1H),2.12(d,J＝10.4Hz,1H),1.33(s,3H)。
实施例39
6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基-N-(5-(4-(异丙基哌嗪-1-基)甲基)吡嗪-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000095
该分子是由中间体10与中间体26为原料，参照实施例1的方法合成得到。LCMS:504.7(M+H)；1H-NMR(400MHz,CDCl3)δ8.88(m,2H),8.36(s,1H),8.21(s,1H),8.12(s,1H),7.83(s,1H),7.56(d,J＝11.2Hz,1H),4.73～4.80(m,1H),3.70(s,2H),2.52-2.86(m,12H),1.72(d,J＝6.8Hz,6H),1.07(d,J＝6.4Hz,6H)。
实施例40
5-((4-乙氧基羰基甲基哌嗪-1-(甲基))-N-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)吡嗪-2-胺
Figure PCTCN2016080792-appb-000096
该分子是由中间体10与中间体22为原料，参照实施例1相同的方法合成得到。LCMS:548.3(M+H)；1H-NMR(400MHz,CDCl3-d)δ8.94(s,1H),8.88(s,1H),8.70(s,1H),8.37(s,1H),8.21(s,1H),8.15(s,1H),7.55(d,J＝11.2Hz,1H),4.73～4.77(m,1H),4.18(d,J＝6.8Hz,2H),3.71(s,2H),3.23(s,2H),2.69(s,4H),2.66(s,4H),1.71(d,J＝6.4Hz,6H),1.27(t,J＝6.6Hz,3H).
实施例41
5-((4-羧基甲基哌嗪-1-(甲基))-N-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)吡嗪-2-胺
Figure PCTCN2016080792-appb-000097
在干燥的25mL圆底烧瓶中依次加入2-(4-((5-((6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-基)氨基)吡嗪-2-基)甲基)哌嗪-1-基)醋酸乙酯(100mg,0.183mmol)，四氢呋喃(1mL)和2N的氢氧化锂(1mL)，室温反应16个小时。加入2N的稀盐酸将溶液调成弱酸性(7>pH>5)，溶液冻干得产物(120mg,白色固体)，LCMS:519.3(M+H)。1H-NMR(400MHz,DMSO-d6)δ10.73(s,1H),9.24(s,1H),8.90(s,1H), 8.49(s,1H),8.22(s,1H),8.18(s,1H),7.63(d,J＝11.2Hz,1H),4.85～4.89(m,1H),4.13～4.28(m,2H),3.56～3.64(m,2H),2.85～3.30(m,8H),2.69(s,3H),1.63(d,J＝6.8Hz,6H)。
实施例42
5-((4-乙酸哌嗪-1-(甲基))-N-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-4-基)吡啶-2-基)吡嗪-2-胺
Figure PCTCN2016080792-appb-000098
在干燥的25mL圆底烧瓶中依次加入2-(4-((5-((4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-2-基)氨基)吡嗪-2-基)甲基)哌嗪-1-基)乙酸(70mg,0.126mmol)，二氯甲烷(5mL)，1-羟基苯并***(68mg,0.504mmol)，二异丙基乙胺(162mg,1.26mmol)，2N甲胺的四氢呋喃溶液(0.63mL,1.26mmol)和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(241mg,1.26mmol)，室温反应4个小时。加入饱和碳酸氢钠水溶液，用二氯甲烷萃取(20mL×3)，合并有机相。饱和食盐水洗涤(20mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用反相高效液相色谱纯化得产物(18mg,黄色固体),LCMS:532.4(M+H)；1H-NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.17(s,1H),8.39(s,1H),8.38(d,J＝6.0Hz,1H),8.15(s,1H),8.03(s,1H),7.88(s,1H),7.48(d,J＝5.6Hz,1H),7.42(d,J＝11.6Hz,1H),4.86～4.90(m,1H),4.18(s,2H),3.47(m,2H),2.97～3.15(m,8H),2.66(s,3H),2.64(d,J＝4.4Hz,3H),1.64(d,J＝7.2Hz,6H).
实施例43
6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基-N-(5-(4-(环丙基甲基哌嗪-1-基)甲基)吡嗪-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000099
该分子是由中间体10与中间体27位原料，参照实施例1相同的方法合城得到，LCMS:516.4(M+H)；1H-NMR(400MHz,CDCl3)δ8.88(s,1H),8.37(s,1H),8.21(s,1H),8.10(s,1H),7.55-7.58(m,2H),4.74～4.78(m,1H),3.71(s,2H),2.54-2.70(m,11H),2.28(d,J＝6.4Hz,2H),1.72(d,J＝7.2Hz,6H),0.85-0.87(m,1H),0.49-0.53(m,2H),0.10-0.11(m,2H).
实施例44
N-(5-((4-乙基哌嗪-1-基)甲基)哌啶-2-基)-6-(4-氯-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000100
该分子是由中间体10与中间体18为原料，参照实施例1相同的方法合成得到目标化合物。LCMS:490.6(M+1)；1H-NMR(400MHz,CDCl3)δ8.890(d,J＝8.0Hz,1H),8.361(s,1H),8.208(s,1H),8.113(s,1H),7.738(s,1H),7.567(d,J＝11.2Hz,1H),4.727-4.797(m,1H),3.715(s,2H),2.452-2.782(m,13H),1.719(d,J＝6.8Hz,6H),1.128-1.162(m,3H)。
实施例45
6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-((4-(2-甲氧基乙基)哌嗪-1-基)甲基)吡嗪-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000101
该分子是由中间体10与中间体28为原料，参照实施例1相同的方法合成得到。LCMS:520.3(M+H)；1H-NMR(400MHz,CDCl3-d)δ8.91(s,1H),8.88(s,1H),8.35(s,1H),8.20(s,1H),8.10(s,1H),7.68-7.76(m,1H),7.57(d,J＝11.6Hz,1H),4.73-4.80(m,1H),3.72(s,2H),3.49-3.67(m,2H),3.35(s,3H),2.52-2.88(m,13H),1.72(d,J＝7.2Hz,6H).
实施例46
5-((4-乙基哌嗪-1-基)甲基)-N-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-2-基)吡嗪-2-胺
Figure PCTCN2016080792-appb-000102
该分子是由中间体15与中间体18为原料，参照实施例1相同的方法合成得到目标化合物。LCMS:507.4(M+H)；1H NMR(400MHz,MeOD-d4)δ8.25(d,J＝2.4Hz,1H),8.06(d,J＝9.2Hz,1H),7.97(d,J＝5.6Hz,1H),7.77(s,1H),7.66(d,J＝9.6Hz,1H),7.28(d,J＝11.2Hz,1H),4.86-4.90(m,1H),3.83(s,2H),2.65-3.21(m,13H),1.69(d,J＝6.8Hz,6H),1.29-1.33(t,J＝7.2Hz,3H).
实施例47
6-((4-乙基哌嗪-1-基)甲基)-N-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-4-基)哒嗪-3-胺
Figure PCTCN2016080792-appb-000103
该分子是由中间体15与中间体23为原料，参照实施例1相同的方法合成得到目标化合物。LCMS:507.4(M+H)；1H-NMR(400MHz,CDCl3)δ8.69(d,J＝0.8Hz,1H),8.22(d,J＝1.2Hz,1H),8.18(s,1H),7.99(d,J＝5.6Hz,1H),7.58(s,1H),7.39(s,1H),7.19(d,J＝7.6Hz,1H),4.70-4.74(m,1H),3.68(s,2H),2.56-2.84(m,13H),1.69(d,J＝6.8Hz,6H),1.22-1.25(m,3H).
实施例48
5-(4-乙基-哌嗪-1-基甲基)-吡嗪-2-基]-6-(7-氟-2-甲基-1-环戊基-3H-苯并咪唑-5-基)-嘧啶-4-基]-胺
Figure PCTCN2016080792-appb-000104
该分子是由中间体5与中间体36为原料，参照实施例1相同的方法合成得到目标化合物。LCMS:515.5(M+H)；1H-NMR(400MHz,CDCl3)δ8.84(s,1H),8.29(s,1H),8.17(s,1H),8.08(s,1H),7.95(s,1H),7.62-7.70(m,2H),7.46(d,J＝8.4Hz,1H),4.82-4.86(m,1H),3.51(s,2H),2.69(s,3H),2.43-2.64(m,8H),2.11-2.31(m,8H),1.86-1.89(m,2H),1.10(t,J＝7.2Hz,1H).
实施例49
5-((4-(N-甲基乙酰胺)哌嗪-1-(甲基))-N-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-基)吡嗪-2-胺
Figure PCTCN2016080792-appb-000105
参照实施例41相同的方法合成得到目标化合物。LCMS:533.3(M+H)；1H-NMR(400MHz,CDCl3)δ8.95(s,1H),8.88(s,1H),8.38(s,1H),8.21(s,1H),8.15(s,1H),8.09(s,1H),7.89(s,1H),7.56(dd,J＝11.2,0.8Hz,1H),7.15(s,1H),4.72～4.80(m,1H),3.73(s,2H),3.05(s,2H),2.85(d,J＝5.2,3H),2.70(s,3H),2.63(s,8H),1.72(d,J＝7.2Hz,6H).
实施例50
[5-(4-乙基-哌嗪-1-基甲基)-吡嗪-2-基]-6-(7-氟-2-甲基-3-(四氢呋喃-3基)-3H-苯并咪唑-5-基)-嘧啶-4-基]-胺
Figure PCTCN2016080792-appb-000106
该分子是由中间体6与中间体36为原料，参照实施例1相同的方法合成得到目标化合物。LCMS:517.3(M+H)；1H-NMR(400MHz,CDCl3)δ8.84(s,1H),8.27-8.30(m,2H),8.14(s,1H),7.67-7.78(m,3H),7.51(d,J＝8.4Hz,1H),5.18-5.20(m,1H),4.48-4.51(m,1H),4.36-4.39(m,1H),4.07-4.12(m,1H),3.90-3.92(m,1H),3.52(s,2H),2.72(s,3H),2.35-2.50(m,12H),1.10-1.13(t,J＝7.2Hz,1H).
实施例51
6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-(4-(2,2,2-三氟)哌嗪-1-基)甲基)吡嗪-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000107
该分子是由中间体17与中间体29为原料，采用实施例1相同的方法合成得到。LCMS:544.4(M+H)；1H-NMR(400MHz,CDCl3)8.91(s,1H),8.88(s,1H),8.38(d,J＝12.8Hz,2H),8.21(s,1H),8.10(s,1H),7.85(s，1H),7.56(d,J＝11.2Hz,2H),4.76(t,J＝6.8Hz,1H),3.72(s,2H),3.49(s,2H),2.99(q,J＝9.6Hz,2H),2.63-2.77(m,12H),1.72(d,J＝6.4Hz,6H).
实施例52
6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)-N-5-((3,4,5-三甲基哌嗪-1-基)甲基)吡啶-2-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000108
该分子是由中间体17与中间体30为原料，参照实施例1相同的方法合成得到目标化合物。LCMS:503.3(M+H)；1H-NMR(400MHz,CDCl3-d)δ8.85(s,1H),8.29(d,J＝1.6Hz,1H),8.18(s,1H),8.07(s,1H),7.72(s,1H),7.67～7.69(m,1H),7.53～7.59(m,2H),4.72～4.79(m,1H),3.46(s,2H),2.75(d,J＝11.2Hz,2H),2.69(s,3H),2.28～2.37(m,5H),2.09(brs,2H),1.72(d,J＝7.2Hz,6H),1.15(d,J＝4.4Hz,6H).
实施例53
6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-1，2，3，6-四氢吡啶-4基)吡嗪-2-基)吡啶-4-胺
Figure PCTCN2016080792-appb-000109
第一步：叔丁基4-(5-氯-吡嗪-2基-5,6-二氢吡啶-1(2H)-碳酸酯
在干燥的30mL微波管中室温下依次加入4-(4,4,5,5-四甲基-1，3，2-二氧硼酯-2-基)-5，6-二氢吡啶-1(2H)-碳酸酯(618.4mg，2.0mmol)，乙二醇二甲醚(4mL)和水(1mL)，2,5-二氯吡嗪(357.55mg，2.4mmol)，四(三苯基膦)钯(115.4mg，0.1mmol)，碳酸钾(552.84mg，4.0mmol)，氮气置换3次。升温至100摄氏度，微波反应1个小时。加入20mL水，用乙酸乙酯萃取(20mL×3)，合并有机相。饱和食盐水洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯:石油醚＝1:1)纯化所得残余物得到叔丁基4-(5-氯-吡嗪-2基-5,6-二氢吡啶-1(2H)-碳酸酯(360mg，淡黄色固体)，LCMS:296.1(M+H)
第二步：叔丁基4-(5-((6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4基)胺)吡嗪-2-基)-5,6-二氢吡啶-1(2氢)-碳酸酯
以6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺(171mg，0.6mmol)和叔丁基4-(5-氯-吡嗪-2基-5,6-二氢吡啶-1(2H)-碳酸酯(178.56mg，0.6mmol)为原料，采用实施例1第二步相同的方法合成得目标产物叔丁基4-(5-((6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4基)胺)吡嗪-2-基)-5,6-二氢吡啶-1(2氢)-碳酸酯(156mg，淡黄色固体),LCMS:545.4(M+H)；1H-NMR:(400MHz,CDCl3)δ9.15(s,1H),8.82(s,1H),8.58(s,1H),8.24(s,1H),8.08(s,1H),7.61(d,J＝11.6Hz,1H),6.70(s,1H),4.90-4.93(m,1H),3.89(s,2H),3.44-3.47(m,2H),2.91(s,1H),2.68(s,3H),1.72(d,J＝7.2Hz,6H),1.50(s,9H)。
第三步：6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-1，2，3，6-四氢吡啶-4基)吡嗪-2-基)吡啶-4-胺
在干燥的25mL圆底烧瓶中室温下依次加入叔丁基4-(5-((6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4基)胺)吡嗪-2-基)-5,6-二氢吡啶-1(2氢)-碳酸酯(50mg，0.091mmol)，二氯甲烷(2ml)，然后滴加三氟醋酸(0.8ml)室温搅拌反应1个小时。加入水20ml，用乙酸乙酯萃取(20mL×3)。合并有机相，饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得物用高效液相色谱纯化得到产物6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-1，2，3，6-四氢吡啶-4基)吡嗪-2-基)吡啶-4-胺(11mg，淡黄色固体)。LCMS:445.4(M+H)；1H-NMR:(400MHz,CDCl3)δ9.15(s,1H),8.82(s,1H),8.58(s,1H),8.24(s,1H),8.08(s,1H),7.61(d,J＝11.6Hz,1H),6.70(s,1H),4.90-4.93(m,1H),3.89(s,2H),3.44-3.47(m,2H),2.91(s,1H),2.68(s,3H),1.72(d,J＝7.2Hz,6H).
实施例54
N-(5-(4-乙基哌嗪-1-基)甲基)-吡嗪-2-基)-6-(4-氟-2-甲基-1-(1-甲基环丙基)-1H-苯并[d]咪唑-6-基)-嘧啶-4-胺
Figure PCTCN2016080792-appb-000110
该分子是由中间体8与中间体36为原料，采用实施例1相同的方法合成得到。LCMS:501.3(M+H)；1H-NMR(400MHz,CDCl3)δ8.87(s,1H),8.30(s,1H),8.15(s,1H),8.08(s,1H),7.94(s,1H),7.68～7.70(m,1H),7.54～7.61(m,2H),3.52(s,2H),2.74(s,3H),2.43～2.54(m,10H),1.97(brs,4H),1.22～1.29(m,3H),1.10(t,J＝7.2Hz,3H)。
实施例55
[5-(4-乙基-哌嗪-1-基甲基)-吡嗪-2-基]-6-(7-氟-2-甲基-3-(3,3-二氟环丁基)-3H-苯并咪唑-5-基)-嘧啶-4-基]-胺
Figure PCTCN2016080792-appb-000111
该分子是由中间体3与中间体36为原料，参照实施例1相同的方法合成得到目标化合物。LCMS:537.4(M+H)；1H-NMR(400MHz,CDCl3)δ8.84(s,1H),8.30(s,1H),8.23(s,1H),8.16(s,1H),7.67-7.76(m,3H),7.41(d,J＝8.4Hz,1H),4.95-4.96(m,1H),3.57-3.65(m,2H),3.53(s,2H),3.30-3.38(m,2H),2.70(s,3H),2.54-2.68(m,10H),1.14-1.18(t,J＝7.2Hz,1H)。
实施例56
[5-(4-吡咯烷-1-基-哌啶-1-基甲基)-吡啶-2-基]-6-(7-氟-3-异丙基-2-甲基-3H-咪唑-5-基)-嘧啶-4-基]-胺
Figure PCTCN2016080792-appb-000112
该分子是由中间体17与中间体31为原料，参照实施例1的合成方法制备得到。LCMS:529.5(M+H)；1H-NMR(400MHz,CDCl3)δ8.84(s,1H),8.24(s,1H),8.19(s,1H),8.10(s,1H),8.00-8.10(m,1H),7.70-7.72(m,1H),7.55-7.58(m,2H),4.74～4.78(m,1H),3.50
(s,2H),2.93-3.30(m,7H),2.69(s,3H),2.05-2.17(m,10H),1.72(d,J＝7.2Hz,6H).
实施例57
N-(5-(4-乙基哌嗪-1-基)甲基)-吡嗪-2-基)-6-(4-氟-2-甲基-1-异丁基-1H-苯并[d]咪唑-6-基)-嘧啶-4-胺
Figure PCTCN2016080792-appb-000113
该分子是由中间体4与中间体36为原料，参照实施例1相同的方法合成得到目标化合物。LCMS:503.3(M+H)；1H-NMR(400MHz,CDCl3)δ8.84(s,1H),8.30(s,1H),8.09(s,1H),7.98(s,1H),7.67～7.71(m,2H),7.49～7.60(m,2H),4.00(d,J＝7.6Hz,2H),3.51(s,2H),2.66(s,3H),2.29～2.62(m,11H),1.09(t,J＝7.2Hz,3H),1.00(d,J＝6.8Hz,6H).
实施例58
N-(5-(1-乙基-1，2，3,6-四氢吡啶-4-基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000114
在干燥的25mL圆底烧瓶中室温下依次加入6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-(1，2，3，6-四氢吡啶-4基)吡嗪-2-基)嘧啶-4-胺(50.0mg，0.119mmol)，乙醛水溶液(40％，3ml)，三乙酰氧基硼氢化钠(50.2mg，0.238mmol)，室温反应4小时。加入10mL水，用乙酸乙酯萃取(20mL×3)。合并有机相，饱和食盐水洗涤(20 mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱纯化得到产物N-(5-(1-乙基-1，2，3，6-四氢吡啶-4-基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺(8.20mg)，LCMS:473.3(M+H)；1H-NMR:(400MHz,CDCl3)δ8.86(s,2H),8.41(s,1H),8.20(s,1H),8.08(s,1H),7.64(s,1H),7.56(d,J＝11.6Hz,1H),6.65(s,1H),4.74-4.77(m,1H),3.30(s,4H),2.75-2.82(m,4H),2.69(s,3H),2.61-2.64(m,2H),1.71(d,J＝6.8Hz,1H),1.2(t,J＝7.2Hz,3H)。
实施例59
N-(5-(1-甲基-1，2，3,6-四氢吡啶-4-基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000115
在干燥的25mL圆底烧瓶中室温下依次加入6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)-N-(5-(1，2，3，6-四氢吡啶-4基)吡嗪-2-基)嘧啶-4-胺(40.0mg，0.09mmol)，多聚甲醛(10.8mg)，甲酸(2ml)。加热回流反应2小时。反应液浓缩，然后加入10mL水，用乙酸乙酯萃取(20mL×3)。合并有机相，饱和食盐水洗涤(20mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱纯化得到产物N-(5-(1-甲基-1，2，3，6-四氢吡啶-4-基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-4-胺LCMS:459.46(M+H)；1H NMR:(400MHz,CDCl3)δ8.98(d,J＝4.4Hz,1H),8.88(s,1H),8.42(s,1H),8.19(s,1H),8.04(s,1H),7.57(d,J＝11.6Hz,1H),6.56(s,1Hz),4.74-4.77(m,1H),3.31-3.89(m,4H),3.06(s,2H),2.90(s,2H),2.69(s,3H),1.71(d,J＝6.8Hz,1H).
实施例60
N-(5((4-环戊基哌嗪-1-基)甲基)吡嗪-2-基)-6-(4-氟-1-异丙基-2-甲基-1H-苯并咪唑-6-基)嘧啶-4-胺
Figure PCTCN2016080792-appb-000116
该分子是由中间体17与中间体32为原料，采用实施例1相同的方法合成得到。LCMS:530(M+H)；1H-NMR(400MHz,CDCl3)δ9.22(s,1H),8.90(s,1H),8.47(s,1H),8.24(s,1H),8.16(s,1H),7.96(d,1H)4.89(q,1H),4.03(s,2H),3.54(d,J＝6.8Hz,2H),2.76(s,1H),2.50(s,3H),2.01(d,J＝7.2Hz,2H),1.66(m,14H).
测试例1本发明化合物对不同CDK激酶活性的测定
本实验采用如下方法测定了实施例化合物对不同CDK激酶：CDK1/CyclinB(invitrogen)、CDK4/Cyclin D1(invitrogen)、CDK6/Cyclin D1(invitrogen)的抑制活性。
测试方法：将受试化合物溶解于二甲亚砜中，并根据试验需要用缓冲液(50mM HEPES、10mM MgCl2、1mM EGTA、2mM DTT and 0.01％Tween 20)稀释至各浓度梯度，二甲亚砜浓度为4％；再用缓冲液稀释ATP和底物ULight-4E-BP1配制成浓度为800μM ATP和200nM底物溶液的混合物待用；在反应孔中加上2.5μL底物和ATP混合液，再加入2.5μL化合物或者4％二甲亚砜的缓冲液(阴性对照孔)，最后加入5μL酶或者缓冲液(阴性对照孔)，室温避光孵育60分钟。每孔加入5μL 1xdetection buffer(LANCE Detection Buffer，10x，PerkinElmer)稀释的EDTA终止液(终浓度6mM)，再加入1xdetection buffer稀释的抗体(终浓度2nM)室温避光孵育60分钟。用PerkinElmer
Figure PCTCN2016080792-appb-000117
TRFRET mode(激发波长:320nm，发射波长:615nm和665nm)测板。IC50值采用酶标仪随机附带软件以四参数法回归求得。
受试化合物对不同激酶活性的抑制率通过下列公式求得：
Figure PCTCN2016080792-appb-000118
表1本发明化合物对不同CDK激酶活性的抑制活性(IC50)或抑制率(％)
化合物标号 CDK1(uM) CDK4(nM)
LY2835219 1523.0 1.9
实施例1 NA 554.0
实施例2 NA 283.0
实施例3 135.5 1.5
实施例4 20225 35.9
实施例5 NA 426.1
实施例6 NA /
实施例7 NA /
实施例8 NA /
实施例9 NA /
实施例10 NA 90％@10uM
实施例11 NA 87％@10uM
实施例12 NA 90％@10uM
实施例13 131.6 5.1
实施例14 NA 36.7
实施例15 300.9 2.9
实施例16 131.6 5.1
实施例17 N/A 36.7
实施例18 75.5 4.2
实施例19 197.0 3.0
实施例20 107.7 2.9
实施例21 32.0 2.3
实施例22 48.0 5.1
实施例23 230.7 8.8
实施例24 35.8 2.1
实施例25 NA 5156.0
实施例26 NA 389.0
实施例27 NA 399.2
实施例28 73.0 3.8
实施例29 126.0 2.4
实施例30 165.6 2.5
实施例31 433.0 7.3
实施例34 2075.0 10.9
实施例35 36.8 1.1
实施例36 800.9 5.2
实施例37 2429 13.8
实施例38 454.9 2.4
实施例39 97.2 1.6
实施例40 109.1 3.7
实施例41 56.5 2.7
实施例42 112.6 3.9
实施例43 103.1 2.9
实施例44 197.0 3.0
实施例45 139.7 3.7
实施例46 44.0 1.6
实施例47 1671.5 12.1
实施例48 266.4 3.1
实施例49 147.8 5.8
实施例50 1961.0 11.8
实施例51 150.6 5.6
实施例52 651.3 4.8
实施例53 162.8 6.5
实施例54 732.0 2.9
实施例55 2060.0 35.9
实施例56 393.4 4
实施例57 38.3 3.1
实施例58 212.0 16.4
实施例59 100.5 2.2
实施例60 393.4 4.0
测试例2本发明化合物对肿瘤细胞株Colo205/MDA-MB-468的增殖抑制测定
本实验采用如下方法测定了本发明化合物对人结肠癌细胞株Colo205/MDA-MB-468的增殖抑制活性。
测定方法：首先将Colo205/MDA-MB-468细胞(中国科学院典型培养物保藏委员会细胞库)以适宜细胞浓度2000个/孔接种在96孔培养板上，每孔90μL培养基，在二氧化碳恒温箱内37℃培养过夜后，加入不同浓度的受试化合物作用96小时，并设定溶剂对照组(阴性对照)。96小时后，可用CCK8(Cell Counting Kit-8)方法进行测试化合物对于抑制细胞增殖活性。IC50值可通过一系列不同浓度下，受试化合物对于细 胞的抑制数值进行计算。
表2本发明部分化合物对Colo205/MDA-MB-468细胞的增殖抑制能力
No Colo-205(uM) MDA-MB-468(uM)
LY2835219 0.46 >10
实施例1 8.58 NA
实施例2 5.6 NA
实施例3 0.206 2.6
实施例4 3.74 NA
实施例5 19.9 NA
实施例13 0.26 0.38
实施例15 0.146 0.218
实施例16 0.25 0.438
实施例17 2.19 NA
实施例18 0.454 NA
实施例19 0.53 1.81
实施例20 0.266 0.936
实施例21 0.108 0.376
实施例22 0.122 0.396
实施例23 0.456 1.253
实施例24 0.048 0.145
实施例28 0.279 0.563
实施例29 0.325 0.564
实施例30 0.189 0.69
实施例31 0.297 0.979
实施例32 0.788 2.542
实施例33 0.109 0.273
实施例34 1.506 3.651
实施例35 0.046 0.117
实施例36 0.338 0.733
实施例37 0.518 2.65
实施例38 0.41 ＞10
实施例39 0.143 1.12
实施例40 0.317 1.522
实施例41 0.0848 0.481
实施例42 ＞10 ＞10
实施例43 0.112 0.691
实施例44 0.206 2.6
实施例45 0.145 1.004
实施例46 0.038 0.175
实施例47 0.625 1.909
实施例48 0.138 0.317
实施例49 0.89 2.237
实施例50 0.464 1.062
实施例51 0.531 1.0553
实施例52 0.324 0.555
实施例53 0.18 0.916
实施例54 0.275 1.052
实施例55 0.466 1.78
实施例56 0.191 1.163
实施例57 0.363 1.553
实施例58 0.099 0.265
实施例59 0.421 1.272
实施例60 0.165 1.055
测试例3本发明部分化合物的药代动力学参数测定
发明人应用LC/MS/MS法测定了小鼠分别灌胃和静注给予实施例化合物后不同时刻血浆中的药物浓度，研究本发明化合物在小鼠体内的药代动力学行为，评价其药动学特征。
实验方案：试验动物为健康成年雄性ICR小鼠；
给药方式及样品采集：分别给于ICR小鼠静脉注射(5mg/kg)和灌胃给药(10mg/kg)，分别于给药前和给药后2～1440min不同时间点于小鼠眼底静脉丛取血；取一定量血浆样品，分别加入含内标的乙腈溶液沉淀蛋白，涡旋10min，6000转/分离心10min；取上清，以6000转/分再次离心10min；取上清液进行LC-MS-MS分析。
Figure PCTCN2016080792-appb-000119
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (9)

  1. 一种如通式I所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
    Figure PCTCN2016080792-appb-100001
    式中：
    R1选自下组：氢、取代或未取代的C1-C6烷基和C3-C8环烷基、取代或未取代的4～8元杂环或4～8元碳环；
    R2、R3和R4各自独立地选自：氢、卤素、取代或未取代的C1-C6烷基和C3-C8环烷基、氨基、取代或未取代的C1-C6烷氧基；
    M、M5、M6各自独立地选自：CRa或N；
    M1、M2、M3、M4各自独立地选自：CRa或N，并且其中至少有一个为N；
    Ra为H、卤素、取代或未取代的C1-C6烷基和C3-C8环烷基；
    m为取代基R3的数目，且为0、1、2或3，优选地m为0或1；
    n为取代基R4的数目，当M5为CRa时，n为0、1、2或3；当M5为N时，n为0、1或2；优选地n为0或1；
    Y为H或取代或未取代的C1-C6烷基；
    L选自下组：无或连接基团；
    W选自下组：氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C2-C6链烯基或链炔基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环、取代羰基、取代磺酰基、取代或未取代的氨基；其中，所述的杂环包含1-3个选自下组的杂原子：N、O、S、P或B；
    上述的任一“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、-OH、-NH2、-N(未取代的C1-C6烷基)2、-CN、-Boc、未取代或卤代的C1-C8烷基、未取代或卤代的C1-C8烷氧基-C1-C8烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C3-C8环烷基-C1-C8烷基、未取代或卤代的C1-C8烷氧基、未取代或卤代的C2-C6烯基、未取代或卤代的C2-C6炔基、未取代或卤代的C2-C6酰基、未取代或卤代的5～8元芳基、未取代或卤代的5～8元杂芳基、未取代或卤代的4～8元饱和杂环或碳环、未取代的C1-C6烷基O(C＝O)-C1-C8烷基、HO(C＝O)-C1-C8烷基、未取代的C1-C6烷基N(C＝O)-C1-C8烷基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O或S，所述的杂环包含1-3个选自下组的杂原子：N、O或S。
  2. 如权利要求1所述的化合物，其特征在于，R1为甲基、乙基、正丙基、异丙基、环丙基、环丁基、异丁基、叔丁基、环戊基、环丙基甲基、环丁基甲基、卤代环丁基(优选
    Figure PCTCN2016080792-appb-100002
    )、
    Figure PCTCN2016080792-appb-100003
    四氢呋喃基，优选地R1为异丙基、异丁基、环丙基甲基、环丁基、环戊基、
    Figure PCTCN2016080792-appb-100004
    和/或
    R2为H、F、Cl或CH3；和/或
    R3和R4分别为H、F、Cl、NH2、OCH3、CH3或环丙基；和/或
    M1、M2、M3、M4分别为：M2＝N，M1＝M3＝M4＝CH；或M1＝M2＝N，M3＝M4＝CH；或M1＝M3＝N，M2＝M4＝CH；或M2＝N，M1＝M3＝M4＝CRa；或M1＝M2＝N，M3＝M4＝CRa；或M1＝M3＝N，M2＝M4＝CRa；或M1＝M4＝N，M2＝M3＝CRa；其中Ra的定义同权利要求1；和/或
    L选自：无、-CR’R”-、-O-、-NR’-、和－CR’＝，其中R’和R”各自独立地为H、F、氘(D)、C1-C6烷基或杂环烷基或相邻的R’和R”形成环状基团；和/或
    W选自：卤素、取代或未取代的C1-C6烷基和环烷基、取代或未取代的4-6元杂环，更优选地W为环戊烷、环己烷、四氢吡咯环、四氢呋喃环、哌啶环、1,2,3,6-四氢吡啶基、哌嗪环、***啉环。
  3. 如权利要求1或2所述的化合物，其特征在于，所述化合物具有通式II、III所示的结构：
    Figure PCTCN2016080792-appb-100005
    其中，各基团的定义如上所述。
  4. 如权利要求1所述的化合物，其特征在于，所述化合物具有如下结构：
    Figure PCTCN2016080792-appb-100006
    Figure PCTCN2016080792-appb-100007
    Figure PCTCN2016080792-appb-100008
    Figure PCTCN2016080792-appb-100009
  5. 一种制备式I化合物的方法，其特征在于，所述方法包括步骤：
    a1)将式1a化合物与式3a化合物或者将式2a化合物与式4a化合物，在金属催化剂或者酸/碱存在的反应条件下进行偶联，从而形成中间体5a；和
    a2)将中间体5a与式6a化合物在催化剂存在的反应条件下进行偶联，得到式I化合物；
    Figure PCTCN2016080792-appb-100010
    各式中，
    X和LG各自独立地为离去基团，且选自下组：卤素、磺酸酯、硼酸、硼酸酯；
    FG选自下组：硼酸、硼酸酯、硼盐、有机锡、有机锌；
    其他各基团R1、R2、R3、R4、M、M1、M2、M3、M4、M5、L、W及m、n的定义如上所述；
    或
    b1)将式1b化合物与式3b化合物或者将式2b化合物与式3b化合物，在金属催化剂或者酸/碱存在的反应条件下进行偶联，从而形成中间体4b或5b；和
    b2)将中间体4b与式6b化合物或中间体5b与式7b化合物，在催化剂存在的反应条件下进行偶联，得到式I化合物；
    Figure PCTCN2016080792-appb-100011
    各式中，
    X和LG各自独立地为离去基团，且选自下组：卤素、磺酸酯、硼酸、硼酸酯；
    FG选自下组：硼酸、硼酸酯、硼盐、有机锡、有机锌；
    其他各基团R1、R2、R3、R4、M、M1、M2、M3、M4、M5、L、W及m、n的定义如上所述。
  6. 如权利要求1所述的式I化合物的用途，其特征在于，用于：
    (a)制备治疗与CDK激酶活性或表达量相关的疾病的药物；
    (b)制备CDK激酶靶向抑制剂；
    (c)体外非治疗性地抑制CDK激酶的活性；
    (d)体外非治疗性地抑制肿瘤细胞增殖；和/或
    (e)治疗与CDK激酶活性或表达量相关的疾病。
  7. 如权利要求6所述的用途，其特征在于，所述CDK激酶选自下组：CDK1、CDK4、CDK6，或其组合。
  8. 一种药物组合物，其特征在于，所述的药物组合物包括：
    (i)有效量的式I化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药；和
    (ii)药学上可接受的载体。
  9. 一种抑制CDK激酶活性的方法，其特征在于，包括步骤：对抑制对象施用抑制有效量的如权利要求1所述的式I化合物或其药学上可接受的盐；或对抑制对象施用抑制有效量的如权利要求8所述的药物组合物。
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