CN108794496A - A kind of CDK inhibitor, its pharmaceutical composition, Preparation method and use - Google Patents
A kind of CDK inhibitor, its pharmaceutical composition, Preparation method and use Download PDFInfo
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- CN108794496A CN108794496A CN201810403252.7A CN201810403252A CN108794496A CN 108794496 A CN108794496 A CN 108794496A CN 201810403252 A CN201810403252 A CN 201810403252A CN 108794496 A CN108794496 A CN 108794496A
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract
The invention belongs to medicinal chemistry arts, and in particular to a kind of CDK inhibitor, its pharmaceutical composition, Preparation method and use.The present invention provides following formula A compounds represented, its stereoisomer, raceme, tautomer, isotopic label, nitrogen oxides, solvate or its pharmaceutically acceptable salt,
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of CDK inhibitor, its pharmaceutical composition, preparation method and
Purposes.
Background technology
Cyclin accordance with tolerance kinases (CDK) is a kind of serine (Ser)/threonine (Thr) kinases, as intracellular weight
The CDK-cyclin compounds that the signal transducers wanted and period plain (cyclin) are formed participate in the growth of cell, proliferation, stop
Dormancy or apoptosis.During cell cycle, periodically continued cyclins expression and degradation, and be respectively incorporated to by them
On the CDK of instant activation, by CDK activity, be catalyzed different substrate phosphorylations, realize cell cycle difference phase propulsion and
Transformation.
In past many decades, extensive concern is obtained by the drug development of target spot of CDK kinases, some drugs enter
The clinical research of different phase.However these CDK inhibitor are not high to each CDK families hypotype inhibitory activity or poor selectivity,
Either body absorption is bad or has certain toxic side effect etc. to limit its clinical application.In recent years, due to improving CDK
Inhibitor especially targets the discovery of the selective depressant of CDK4/6 to the selectivity and inhibitory activity of each CDK families hypotype,
So that the medicament research and development in this field becomes hot spot again.
CDK4/6 is over-expressed in many cancers, leads to uncontrolled cellular proliferation, therefore, CDK4/6 is inhibited to may be implemented
Inhibit cell Proliferation from the downstream of signal path.The CDK4/6 inhibitor Palbociclib of Pfizer becomes first listing at present
CDK4/6 inhibitor, by FDA approvals as first-line drug treatment ER positive, HER2 negative breast cancers, what similar drugs gift came
Abemaciclib and the Ribociclib of Novartis Co., Ltd have also been listed.
Therefore, there is good CDK to adjust activity for research and development, have suitable for medicinal CDK kinase inhibitors larger
Social effect.
Invention content
In order to improve the above problem, the present invention provides following formula A compounds represented, its stereoisomer, raceme, change
Isomers, isotopic label, nitrogen oxides, solvate or its pharmaceutically acceptable salt,
Wherein, each R1It is identical or different, H ,-F ,-Cl ,-Br ,-I, unsubstituted or by one is represented independently of one another
Or multiple RaSubstituted C1-40Alkyl；
R2、R4、R5It is identical or different, H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO are represented independently of one another2, it is unsubstituted or optional
By one or more RbSubstituted following groups：C1-40Alkyl, C1-40Alkoxy, C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Virtue
Base, 5-20 unit's heteroaryls or-NRcRd；
R3、R6It is identical or different, H, unsubstituted or optionally by one or more R is represented independently of one anothereSubstituted C1-40Alkane
Base；
X is CRf；
Each Ra、RbIt is identical or different, it is independently from each other-F ,-Cl ,-Br ,-I ,-CN ,=O ,-NO2Or it is following
Group：C1-40Alkyl, C1-40Alkyl oxy, C1-40Alkyl sulfenyl, C2-40Alkenyl, C2-40Alkenyl oxygroup, C2-40Enylsulfanyl, C2-40
Alkynyl, C2-40Alkynyl oxygroup, C2-40Alkynyl sulfenyl, C3-20Naphthenic base, C3-20Cycloalkyl oxy, C3-20Cycloalkylsulfanyl, 3-20 members
Heterocycle, 3-20 circle heterocyclic ring bases oxygroup, 3-20 circle heterocyclic ring bases sulfenyl, C6-20Aryl, C6-20Aryloxy, C6-20Artyl sulfo, 5-
20 unit's heteroaryls, 5-20 unit's heteroaryls oxygroup, 5-20 unit's heteroaryl sulfenyls；
Each Rc、Rd、ReIt is identical or different, it is independently from each other H or following groups：C1-40Alkyl, C2-40Alkenyl,
C2-40Alkynyl, C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Aryl, 5-20 unit's heteroaryls；
Alternatively, RcAnd RdIt is formed selected from unsubstituted or optionally by one or more R together with the nitrogen-atoms connected with itgIt takes
The following ring system in generation：3-20 circle heterocyclic rings base, 5-20 unit's heteroaryls；
RgSelected from-F ,-Cl ,-Br ,-I ,-CN ,=O ,-NO2Or following groups：C1-40Alkyl, C2-40Alkenyl, C2-40Alkynyl,
C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Aryl, 5-20 unit's heteroaryls；
RfSelected from H ,=O or optionally by one or more RaSubstituted C1-40Alkyl.
According to exemplary embodiment of the subject disclosure, each R1It is identical or different, represent independently of one another H ,-F ,-
It is Cl ,-Br ,-I, unsubstituted or by one or more C1-12Alkyl-substituted C1-12Alkyl, such as R1Selected from H ,-F ,-Cl or-Br；
According to exemplary embodiment of the subject disclosure, R2、R4、R5It is identical or different, H ,-CN, nothing are represented independently of one another to be taken
Generation or optionally by one or more C1-12Alkyl-substituted following groups：C1-12Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings base, two-
(C1-12Alkyl) amino-, C1-12Alkyl amino-or two-(C1-12Alkyl) two C in amino1-12Alkyl can also be with its institute
The nitrogen-atoms of connection is formed together selected from unsubstituted or optionally by one or more C1-12Alkyl-substituted 3-20 circle heterocyclic rings base；
Such as R2、R4、R5It is identical or different, H ,-CN or following group are represented independently of one another：
Wherein,For the key in connection substitution site；
According to exemplary embodiment of the subject disclosure, R3、R6Represent H, unsubstituted or optionally by one or more C1-12Alkyl
Substituted C1-12Alkyl；
Such as R3、R6It is identical or different, representative-CH independently of one another3、-CH2CH3、-CH(CH3)2Or-C (CH3)3；
According to exemplary embodiment of the subject disclosure, X is selected from CRf, wherein RfIndependently represent H ,=O or C1-12Alkyl；
Such as RfSelected from H ,=O ,-CH3Or-CH2CH3。
As example, it includes but not limited to following compound that the compound shown in formula A, which is selected from,：
The present invention also provides a kind of pharmaceutical compositions, and it includes the compound shown in formula A of therapeutically effective amount, its solid are different
In structure body, raceme, tautomer, isotopic label, nitrogen oxides, solvate or its pharmaceutically acceptable salt
It is one or more kinds of.
According to the present invention, described pharmaceutical composition also optionally includes its pharmaceutically acceptable auxiliary material, such as carrier, figuration
Agent；The auxiliary material is selected from one of the following or a variety of：Disintegrant, glidant, lubricant, diluent or filler, adhesive,
Colorant.
The present invention also provides compound shown in formula A, its stereoisomer, raceme, tautomer, isotope labellings
The purposes of one or more of object, nitrogen oxides, solvate or its pharmaceutically acceptable salt in medicine preparation.
Embodiment according to the present invention, the drug are CDK inhibitor.
Embodiment according to the present invention, the CDK inhibitor is for treating and/or preventing hepatitis B.
The present invention also provides a kind for the treatment of and/or the methods of prevention disease comprising to such treatment of needs and/or prevention
Patient give the compound shown in formula A of therapeutically effective amount, its stereoisomer, raceme, tautomer, isotope mark
Remember one or more of object, nitrogen oxides, solvate or its pharmaceutically acceptable salt.
Embodiment according to the present invention, the disease are hepatitis B.
The present invention also provides the preparation methods of the formula A compounds, including：
(1) compound V and compound VI carries out that compound A is obtained by the reaction；
Wherein, R1、R2、R3、R4、R5、R6, X have as described above definition.
In step (1),
The reaction can be that Buchwald reacts；
The reaction can carry out at a temperature of 20 DEG C to 100 DEG C；
The reaction can carry out in a solvent, and the solvent is in amide solvent, ether solvent, aromatic hydrocarbon solvent
One, two, or more；Such as one kind in DMF, dioxane, tetrahydrofuran, toluene etc., two or more
Kind；
The reaction can carry out in the presence of catalyst and ligand；The catalyst is selected from PdCl2(PPh3)2、Pd
(PPh3)4、Pd(dba)2、Pd(OAc)2、Pd(dppf)2Cl2In one, two, or more；It is bicyclic that the ligand is selected from 2-
Hexyl phosphine -2', 4', 6'- tri isopropyl biphenyl (XPhos), 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyls (SPhos), 4,
One, two, or more in the bis- diphenylphosphine -9,9- xanthphos (XantPhos) of 5-；
The reaction can also carry out in the presence of base；The alkali is selected from cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, phosphorus
One, two, or more in sour potassium, sodium acetate.
According to the present invention, method as described above further includes the preparation of Formula V compound, including：
(2) synthesis of intermediate III
Compound III is obtained by the reaction in compound I and compound II；
(3) synthesis of intermediate compound IV
The compound III and compound R that step (2) obtains3Compound IV is obtained by the reaction in I；
(4) synthesis of intermediate V
Compound V is obtained by the reaction in the compound IV that step (3) obtains；
In step (2),
The reaction can be condensation reaction；
The condensation reaction can carry out at a temperature of 20 DEG C to 100 DEG C；
The condensation reaction can carry out in the presence of condensing agent；The condensing agent used can be selected from EDCI.HCl (1-
Ethyl-(3- dimethylaminopropyls) carbodiimide hydrochloride), HATU (2- (7- aoxidize benzotriazole)-N, N, N', N'- tetra-
Methylurea hexafluorophosphoric acid ester), BOP-Cl (bis- (2- oxo -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychlorides), DCC (N, N'- dicyclohexyl phosphinylidynes
Imines) in one, two, or more；
The alkali used in condensation reaction can be selected from one in triethylamine, diisopropylethylamine, N-methylmorpholine, DMAP
It plants, two or more；
In step (3),
The reaction can carry out at a temperature of 20 DEG C to 100 DEG C；
The reaction can carry out in the presence of base；The alkali is selected from sodium hydride, sodium hydroxide, potassium hydroxide, carbonic acid
One, two, or more in potassium, hexamethyl lithium amide, hexamethyl Sodamide；
The reaction can carry out in a solvent, and the solvent is in amide solvent, ether solvent, aromatic hydrocarbon solvent
One, two, or more；Such as one kind in DMF, dioxane, tetrahydrofuran, toluene etc., two or more
Kind；
In step (4),
The reaction can carry out in the presence of magnesium powder and Lewis acid；
The reaction can carry out at a temperature of 20 DEG C to 100 DEG C；
The one kind or two kinds of the lewis acid in lithium chloride, zinc chloride；
The reaction can carry out in a solvent, and the solvent is selected from ether solvent；Such as selected from ether, dioxane,
One, two, or more in tetrahydrofuran.
Advantageous effect
There is the compounds of this invention good CDK to adjust activity, suitable for medicinal, with clinical value.Also, this hair
Bright compound synthesis step is simple, therefore has good economic use value.
Term defines and explanation
Unless otherwise indicated, the group described in present specification and claims and term definition, including its work
For the defining of example, illustratively definition, preferred definition, the definition described in table, particular compound determines in embodiment
Justice etc. arbitrarily can be combined and be combined each other.Group definition after such combination and combination and compound structure, should
Belong in the range of present specification record.
Term " C1-40Alkyl " is interpreted as the preferred linear chain or branched chain saturation monovalent hydrocarbon for indicating to have 1~40 carbon atom
Base, preferably C1-10Alkyl."C1-10Alkyl " is interpreted as preferred indicate with 1,2,3,4,5,6,7,8,9 or 10 carbon atom
Linear chain or branched chain be saturated monovalent hydrocarbon.The alkyl be for example methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl,
Isobutyl group, sec-butyl, tertiary butyl, isopentyl, 2- methyl butyls, 1- methyl butyls, 1- ethyl propyls, 1,2- dimethyl propyls,
Neopentyl, 1,1- dimethyl propyls, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 2- ethyl-butyls,
1- ethyl-butyls, 3,3- dimethylbutyls, 2,2- dimethylbutyls, 1,1- dimethylbutyls, 2,3- dimethylbutyls, 1,3- bis-
Methyl butyl or 1,2- dimethylbutyls etc. or their isomers.Particularly, the group have 1,2,3,4,5,6, a carbon
Atom (" C1-6Alkyl "), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl group, sec-butyl, tertiary butyl, more particularly,
The group has 1,2 or 3 carbon atom (" C1-3Alkyl "), such as methyl, ethyl, n-propyl or isopropyl.
Term " C2-40Alkenyl " is interpreted as the preferred monovalent hydrocarbon for indicating linear chain or branched chain, and it includes one or more double
Key and have 2~40 carbon atoms, preferably " C2-10Alkenyl "."C2-10Alkenyl " is interpreted as preferred expression linear chain or branched chain
Monovalent hydrocarbon it includes one or more double bonds and has 2,3,4,5,6,7,8,9 or 10 carbon atom, especially 2 or 3
Carbon atom (" C2-3Alkenyl "), it should be appreciated that in the case where the alkenyl includes more than one double bond, the double bond can mutually divide
From or conjugation.The alkenyl is such as vinyl, allyl, (E) -2- methyl ethylenes, (Z) -2- methyl ethylenes, (E) -
But-2-ene base, (Z)-but-2-ene base, (E)-but-1-ene base, (Z)-but-1-ene base, amyl- 4- alkenyls, (E)-amyl- 3- alkenyls,
(Z)-amyl- 3- alkenyls, (E)-amyl- 2- alkenyls, (Z)-amyl- 2- alkenyls, (E)-amyl- 1- alkenyls, (Z)-amyl- 1- alkenyls, hex- 5- alkene
Base, (E)-hex- 4- alkenyls, (Z)-hex- 4- alkenyls, (E)-hex- 3- alkenyls, (Z)-hex- 3- alkenyls, (E)-hex- 2- alkenyls, (Z)-
Hex- 2- alkenyls, (E)-hex- 1- alkenyls, (Z)-hex- 1- alkenyls, isopropenyl, 2- methyl propyl- 2- alkenyls, 1- methyl propyl- 2- alkene
Base, 2- methyl propyl- 1- alkenyls, (E) -1- methyl propyl- 1- alkenyls, (Z) -1- methyl propyl- 1- alkenyls, 3- methyl butyl- 3- alkenyls, 2-
Methyl butyl- 3- alkenyls, 1- methyl butyl- 3- alkenyls, 3- methyl but-2-enes base, (E) -2- methyl but-2-enes base, (Z) -2- methyl
But-2-ene base, (E) -1- methyl but-2-enes base, (Z) -1- methyl but-2-enes base, (E) -3- methyl but-1-enes base, (Z) -3-
Methyl but-1-ene base, (E) -2- methyl but-1-enes base, (Z) -2- methyl but-1-enes base, (E) -1- methyl but-1-enes base,
(Z) -1- methyl but-1-ene base, 1,1- dimethyl propylene -2- alkenyls, 1- ethyl propyl- 1- alkenyls, 1- propyl ethylenes base, 1- isopropyls
Vinyl.
Term " C2-40Alkynyl " is understood to mean that the monovalent hydrocarbon of linear chain or branched chain, and it includes one or more three keys simultaneously
And there is 2~40 carbon atoms, preferably " C2-C10Alkynyl ".Term " C2-C10Alkynyl " is interpreted as preferably indicating linear chain or branched chain
Monovalent hydrocarbon, it includes one or more three keys and there are 2,3,4,5,6,7,8,9 or 10 carbon atom, especially 2 or 3
A carbon atom (" C2-C3Alkynyl ").The alkynyl is such as acetenyl, propyl- 1- alkynyls, Propargyl, butyl- 1- alkynyls, butyl-
2- alkynyls, butyl- 3- alkynyls, amyl- 1- alkynyls, amyl- 2- alkynyls, amyl- 3- alkynyls, amyl- 4- alkynyls, hex- 1- alkynyls, hex- 2- alkynyls,
Hex- 3- alkynyls, hex- 4- alkynyls, hex- 5- alkynyls, 1- methyl Propargyl, 2- methyl butyl- 3- alkynyls, 1- methyl butyl- 3- alkynes
Base, 1- methyl butyl- 2- alkynyls, 3- methyl butyl- 1- alkynyls, 1- ethyls Propargyl, the amyl- 4- alkynyls of 3- methyl, 2- methyl are amyl-
The amyl- 4- alkynyls of 4- alkynyls, 1- methyl, the amyl- 3- alkynyls of 2- methyl, the amyl- 3- alkynyls of 1- methyl, the amyl- 2- alkynyls of 4- methyl, 1- methyl
The amyl- 1- alkynyls of amyl- 2- alkynyls, 4- methyl, the amyl- 1- alkynyls of 3- methyl, 2- ethyl butyl- 3- alkynyls, 1- ethyl butyl- 3- alkynyls, 1-
Ethyl butyl- 2- alkynyls, 1- propyl Propargyl, 1- isopropyls Propargyl, 2,2- dimethyl butyrate -3- alkynyls, 1,1- diformazans
Base butyl- 3- alkynyls, 1,1- dimethyl butyrate -2- alkynyls or 3,3- dimethyl butyrate -1- alkynyls.Particularly, the alkynyl be acetenyl,
Propyl- 1- alkynyls or Propargyl.
Term " C3-20Naphthenic base " is understood to mean that the monovalent monocyclic of saturation or bicyclic hydrocarbon ring, has 3~20 carbon
Atom, preferably " C3-10Naphthenic base ".Term " C3-10Naphthenic base " is understood to mean that the monovalent monocyclic of saturation or bicyclic hydrocarbon ring,
With 3,4,5,6,7,8,9 or 10 carbon atoms.The C3-10Naphthenic base can be monocycle alkyl, such as cyclopropyl, cyclobutyl, ring
Amyl, cyclohexyl, suberyl, cyclooctyl, cyclononyl or cyclodecyl or for example decahydronaphthalene naphthalene nucleus of bicyclic alkyl.
Term " 3-20 circle heterocyclic rings base " means the monovalent monocyclic of saturation or bicyclic hydrocarbon ring, and it includes 1-5 to be independently selected from N, O
With the hetero atom of S, preferably " 3-10 circle heterocyclic rings base ".Term " 3-10 circle heterocyclic rings base " means the monovalent monocyclic or dicyclic hydrocarbon of saturation
Ring, it is a that it includes 1-5, the preferably 1-3 hetero atoms for being selected from N, O and S.The heterocycle can pass through appointing in the carbon atom
One or nitrogen-atoms (if present) are connect with the rest part of molecule.Particularly, the heterocycle may include but not
It is limited to：4 membered rings, such as azetidinyl, oxetanyl；5 membered rings, such as tetrahydrofuran base, dioxa cyclopentenyl, pyrroles
Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl；Or 6 membered rings, as THP trtrahydropyranyl, piperidyl, morpholinyl, dithianyl,
Thio-morpholinyl, piperazinyl or trithiane base；Or 7 membered rings, such as Diazesuberane base.Optionally, the heterocycle can be
Benzo-fused.The heterocycle can be it is bicyclic, such as, but not limited to 5,5 membered rings, such as hexahydro cyclopentano [c] pyrroles -2
(1H)-basic ring or 5,6 membered bicyclics, such as hexahydropyrrolo simultaneously [1,2-a] pyrazine -2 (1H)-basic ring.The ring of nitrogen atom can be
Part is undersaturated, i.e., it can include one or more double bonds, such as, but not limited to 2,5- dihydro -1H- pyrrole radicals, 4H- [1,
3,4] thiadiazine base, 4,5- dihydro-oxazoles base or 4H- [Isosorbide-5-Nitrae] thiazinyl, alternatively, it can be benzo-fused, such as but not
It is limited to dihydro-isoquinoline base.According to the present invention, the heterocycle is no armaticity.
Term " C6- 20 aryl " are interpreted as the preferred monovalence armaticity or part virtue for indicating to have 6~20 carbon atoms
The monocyclic, bicyclic or tricyclic hydrocarbon ring of fragrance, preferably " C6- 14 aryl ".Term " C6- 14 aryl ", which are interpreted as preferred expression, to be had
6,7,8,9,10,11,12, the 13 or 14 monovalence armaticity of carbon atom or monocyclic, bicyclic or tricyclic hydrocarbon rings of partial aromatic
(“C6- 14 aryl "), especially the ring (" C with 6 carbon atoms6Aryl "), such as phenyl；Or xenyl, or have 9
The ring (" C of a carbon atom9Aryl "), such as indanyl or indenyl, or the ring (" C with 10 carbon atoms10Aryl "), example
Such as tetrahydro naphthyl, ihydro naphthyl or naphthalene, or the ring (" C with 13 carbon atoms13Aryl "), such as fluorenyl, or
It is the ring (" C with 14 carbon atoms14Aryl "), such as anthryl.
Term " 5-20 unit's heteroaryls " is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring system：It has
There are 5~20 annular atoms and includes the 1-5 hetero atoms for being independently selected from N, O and S, such as " 5-14 unit's heteroaryls ".Term " 5-14
Unit's heteroaryl " is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring system：It has 5,6,7,8,9,10,11,
12, the carbon atom of 13 or 14 annular atoms, especially 5 or 6 or 9 or 10, and it includes 1-5, preferably 1-3 be respectively independently selected from N,
The hetero atom of O and S also, in addition can be benzo-fused at each occurrence.Particularly, heteroaryl is selected from thienyl, furan
It mutters base, pyrrole radicals, oxazolyls, thiazolyl, imidazole radicals, pyrazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, triazolyl, thiophene
Di azoly, thiophene -4H- pyrazolyls etc. and their benzo derivative, such as benzofuranyl, benzothienyl, benzoxazole
Base, benzoxazine, benzimidazolyl, benzotriazole base, indazolyl, indyl, isoindolyl etc.；Or pyridyl group, pyridazine
Base, pyrimidine radicals, pyrazinyl, triazine radical etc. and their benzo derivative, such as quinolyl, quinazolyl, isoquinolyl
Deng；Or azocine base, indolizine base, purine radicals etc. and their benzo derivative；Or cinnoline base, phthalazinyl, quinazolyl, quinoline
Quinoline base, naphthyridines base, pteridyl, carbazyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazine groups etc..
Unless otherwise indicated, heterocycle, heteroaryl or inferior heteroaryl include its all possible isomeric form, such as its position
Set isomers.Therefore, for some illustrative non-limiting examples, pyridyl group or sub-pyridyl group include pyridine -2- bases, sub- pyrrole
Pyridine -2- bases, pyridin-3-yl, sub- pyridin-3-yl, pyridin-4-yl and sub- pyridin-4-yl；Thienyl or sub- thienyl include thiophene
Pheno -2- bases, Asia thiophene -2- bases, thiene-3-yl and sub- thiene-3-yl.
It can according to known methods, such as by extraction, filtering or column chromatography come isolating target compound.
According to its molecular structure, the compound of the present invention can be chiral, it is thus possible to which there are various enantiomters
Form.Thus these compounds can exist with racemate form or optical active forms.The compound of the present invention or in which
Body can be by the way that well known to a person skilled in the art chemically or physically methods to be separated into enantiomter compound, or with this shape
Formula is for synthesizing.In the case of racemic amine, by being reacted with optically active resolution reagent, it is made non-right from mixture
Reflect isomers.The example of resolution reagent appropriate is optically active acid, such as R and the tartaric acid of S-shaped formula, diacetyl tartaric
Amino acid (such as the N- benzoyl proline of acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, N-protected appropriate
Or N- benzenesulfonyls proline) or various optically active camphorsulfonic acids.It (such as is fixed on by optically active resolution reagent
The derivative or chirality of dinitrobenzoyl phenylglycine, cellulose triacetate or other carbohydrate on silica gel spread out
Biochemical methacrylate polymers), it also can advantageously carry out chromatography Chiral Separation.Eluant, eluent appropriate for this purpose
It is aqueous or containing alcohol solvent mixture, for example, hexane/isopropyl alcohol/acetonitrile.
Pharmaceutically acceptable salt can be the present invention with enough alkalinity with nitrogen-atoms for example in chain or ring
Compound acid-addition salts, such as with following inorganic acid formed acid-addition salts：Such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydrogen iodine
Acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid or disulfate or the acid-addition salts formed with following organic acid：Such as formic acid,
Acetic acid, acetoacetate, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, lauric acid, benzoic acid, bigcatkin willow
Acid, 2- (4- hydroxy benzoyls) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, didextrose acid, 3- hydroxyl -2- naphthalene first
Acid, niacin flutter acid, pectinic acid, persulfuric acid, 3- phenylpropionic acids, picric acid, pivalic acid, 2- ethylenehydrinsulfonic acids, itaconic acid, ammonia
Base sulfonic acid, trifluoromethanesulfonic acid, dodecyl sulphate, ethanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, 2- naphthalene sulfonic acids, naphthalene two
Sulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, algae
Acid, maleic acid, fumaric acid, D- gluconic acids, mandelic acid, ascorbic acid, glucoheptose, phosphoglycerol, aspartic acid, sulfosalisylic
Acid, hemisulfic acid or thiocyanic acid.
Since the compound of the present invention may be present multiple at salt site, " pharmaceutically acceptable salt " includes not only this
Invention compound wherein 1 includes wherein 2,3 or all at being formed on salt site at the salt formed on salt site
Salt.For this purpose, formula (I) compound and the radical ion (anion) or alkali at the acid needed for salt in " pharmaceutically acceptable salt "
Cation mole ratio can change in the larger context, such as can be 4:1~1:4, such as 3:1,2:1,1:1,1:2,1:3
Deng.
According to the present invention, pharmaceutically acceptable anion include selected from by inorganic acid or organic acid ionization generate it is cloudy from
Son." inorganic acid " includes but not limited to hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid.
" organic acid " includes but not limited to formic acid, acetic acid, acetoacetate, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptan
Acid, hendecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4- hydroxy benzoyls) benzoic acid, camphoric acid, cinnamic acid, ring penta
Alkane propionic acid, didextrose acid, 3- hydroxy-2-naphthoic acids, niacin, flutter acid, pectinic acid, persulfuric acid, 3- phenylpropionic acids, picric acid,
It is pivalic acid, 2- ethylenehydrinsulfonic acids, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulphate, ethanesulfonic acid, benzene sulfonic acid, right
Toluenesulfonic acid, methanesulfonic acid, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, third
Diacid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D- gluconic acids, mandelic acid, ascorbic acid, glucoheptose,
Phosphoglycerol, aspartic acid, sulfosalicylic acid, hemisulfic acid or thiocyanic acid.
Term " tautomer " refers to because of a certain atom is generated in the rapid movement in two positions in molecule functional group
Isomers.The compounds of this invention can express out tautomerism.Tautomeric compound there may be two or more can
The type mutually converted.The migration of prototropictautomer hydrogen atom of covalent bonding between two atoms.Change
Isomers generally exists with equilibrium form, attempts to generally produce a kind of mixture, physics and chemistry when detaching single tautomer
The mixture of matter and compound is consistent.The position of balance depends on the chemical characteristic of intramolecular.For example, in many aliphatic aldehydes
In ketone such as acetaldehyde, ketone type is dominant；And in phenol, enol form is dominant.The present invention includes all tautomerisms of compound
Form.
Term " effective quantity " or " therapeutically effective amount " refer to being enough to realize that intended application (includes but not limited to such as to give a definition
Disease treatment) compound of the present invention amount.Therapeutically effective amount can change depending on following factor：Intended application
The weight and age of (in vitro either in vivo) or the subject treated and disease symptom such as subject, disease symptom it is tight
Principal characteristic and administering mode etc. can be readily determined by those of ordinary skill in the art.Specific dosage will depend on it is following because
Element and change：Selected specific compound, based on dosage regimen, whether with other compound combinations administration, administration
Arrangement of time, the tissue being administered and the physical delivery system carried.
Term " auxiliary material " refers to pharmaceutically acceptable inert fraction.The example of categories of excipients includes without limitation adhesive, collapses
Solve agent, lubricant, glidant, stabilizer, filler and diluent etc..Excipient can enhance the operating characteristic of pharmaceutical preparation, i.e.,
Preparation is set to be more suitable for directly compressing by increasing mobility and/or adherence.Typical suitable for above-mentioned preparation pharmaceutically may be used
The example of the carrier of receiving is：Carbohydrate, such as lactose, sucrose, mannitol and sorbierite；Starch, such as cornstarch, cassava
Starch and potato starch；Cellulose and its derivates, such as sodium carboxymethylcellulose, ethyl cellulose and methylcellulose；Phosphorus
Sour calcium class, such as Dicalcium Phosphate and tricalcium phosphate；Sodium sulphate；Calcium sulfate；Polyvinylpyrrolidone；Polyvinyl alcohol；Stearic acid；Firmly
Resin acid alkali salt, such as magnesium stearate and calcium stearate；Stearic acid；Plant oil, such as peanut oil, cottonseed oil, sesame
Oil, olive oil and corn oil；Nonionic, cation and anionic surfactant；Ethylene glycol polymer；Aliphatic alcohols；And paddy
Object hydrolyze solid content and other nontoxic compatible fillers, adhesive, disintegrant, buffer, preservative, antioxidant,
The commonly used auxiliary material in pharmaceutical preparation such as lubricant, colorant.
Specific implementation mode
The general formula compound and its preparation method and application of the present invention is done further below in conjunction with specific embodiment
Detailed description.The following example is merely illustrative the ground description and interpretation present invention, and is not necessarily to be construed as protecting the present invention
The limitation of range.In the range of all technologies realized based on the above of the present invention are encompassed by the present invention is directed to protect.
Unless otherwise indicated, the raw materials and reagents used in following embodiment are commercial goods, or can be by
It is prepared by perception method.
Embodiment 1
- [1,3] dioxolane is simultaneously [4,5-f] by 6- methyl-1s 0- ((5- (4- methyl piperidine -1- bases) pyridine -2- bases) amino)
The preparation of pyrimido [5,4-c] quinoline -7 (6H) -one
(1) intermediate 1c is synthesized
By compound 1a (21.6g, 100mmol), 1b (15.9g, 100mmol), DIPEA (19.4g, 150mmol) is dissolved in
In DMF (200ml), HATU (45.6g, 120mmol) is added at room temperature, is stirred to react 4 hours, TLC detection reactions, reaction finishes
Water (200ml) is added afterwards, reaction is quenched, ethyl acetate extracts (300mlx2), merges organic layer, and organic layer drying is filtered, dense
Contracting, column chromatography for separation obtain off-white powder 28.5g, yield 79.9%.
(2) intermediate 1d is synthesized
Compound 1c (28.0g, 75.8mmol) is dissolved in DMF (200ml), under ice bath be added sodium hydride (3.8g,
94.2mmol), it is stirred to react 30 minutes, iodomethane (10.8g, 75.8mmol) is added at room temperature and is stirred to react 6 hours, TLC inspections
Reaction is surveyed, after completion of the reaction, water (100ml) is added, reaction is quenched, ethyl acetate (500mlx2) extraction merges organic layer, does
Dry, concentration, column chromatography for separation obtains off-white powder 23.2g, yield 82.6%.
(3) intermediate 1e is synthesized
Compound 1d (23.0g, 62.1mmol), lithium chloride (0.5g, 12.4mmol) are dissolved in tetrahydrofuran (200ml)
In, magnesium powder (1.8g, 74.5mmol) aqueous solution (300ml) is added at room temperature, is warming up to 50 DEG C and is stirred to react 8 hours, TLC detections
Reaction is added saturated ammonium chloride solution and reaction is quenched, ethyl acetate (300mlx2) is added and extracts, merges organic after completion of the reaction
Layer, concentration, column chromatography for separation obtain off-white powder 12.4g, yield 68.9%.
(4) synthesis of compound 1
Compound 1e (1.2g, 4.1mmol), compound 1f (0.8g, 4.1mmol), cesium carbonate (2.0g, 6.2mmol), Pd
(dba)2Bis- diphenylphosphine -9, the 9- xanthphos (120mg, 0.2mmol) of (120mg, 0.2mmol), 4,5- are dissolved in DMF
It in (20ml), is warming up to 100 DEG C and is stirred to react 12 hours, reaction solution is poured into water (20ml) by TLC detection reactions after completion of the reaction
In, ethyl acetate (500mlx2) extraction merges organic relevant dry, filtering, concentration, and column chromatography for separation obtains off-white powder
760mg, yield 41.2%.MS-ESI:M/z=446.5 [M+1].
Embodiment 2
- 6- methyl-[1,3] dioxolane is simultaneously [4,5-f] by 10- ((5- (4- ethyl piperazidine -1- bases) pyridine -2- bases) amino)
The preparation of pyrimido [5,4-c] quinoline -7 (6H) -one
Prepared by the method for reference implementation example 1, MS-ESI:M/z=460.5 [M+1].
Embodiment 3
6- methyl-1s 0- ((5- (piperazine -1- bases) pyridine -2- bases) amino)-[1,3] dioxolane simultaneously [4,5-f] pyrimido
The preparation of [5,4-c] quinoline -7 (6H) -one
Prepared by the method for reference implementation example 1, MS-ESI:M/z=432.4 [M+1].
Embodiment 4
6- methyl-1s 0- ((5- morpholine yl pyridines -2- bases) amino)-[1,3] dioxolane simultaneously [4,5-f] pyrimido [5,4-
C] quinoline -7 (6H) -one preparation
Prepared by the method for reference implementation example 1, MS-ESI:M/z=433.4 [M+1].
Embodiment 5
6- methyl-1s 0- ((5- (piperazine -4- bases) pyridine -2- bases) amino)-[1,3] dioxolane simultaneously [4,5-f] pyrimido
The preparation of [5,4-c] quinoline -7 (6H) -one
Prepared by the method for reference implementation example 1, MS-ESI:M/z=431.5 [M+1].
Embodiment 6
Bis- fluoro- 6- methyl-1s 0- of 2,2- ((5- (4- methylpiperazine-1-yls) pyridine -2- bases) amino)-[1,3] dioxolane
And the preparation of [4,5-f] pyrimido [5,4-c] quinoline -7 (6H) -one
Prepared by the method for reference implementation example 1, MS-ESI:M/z=482.5 [M+1].
Embodiment 7
Two fluoro- 6- methyl-[1,3] dioxolanes of 10- ((5- (4- ethyl piperidine -1- bases) pyridine -2- bases) amino) -2,2-
And the preparation of [4,5-f] pyrimido [5,4-c] quinoline -7 (6H) -one
Prepared by the method for reference implementation example 1, MS-ESI:M/z=496.5 [M+1].
Embodiment 8
Bis- fluoro- 6- methyl-1s 0- of 2,2- ((5- (piperazine -1- bases) pyridine -2- bases) amino)-[1,3] dioxolane simultaneously [4,
5-f] pyrimido [5,4-c] quinoline -7 (6H) -one preparation
Prepared by the method for reference implementation example 1, MS-ESI:M/z=468.4 [M+1].
Embodiment 9
Simultaneously [4,5-f] is phonetic for-[1,3] dioxolane by bis- fluoro- 6- methyl-1s 0- of 2,2- ((5- morpholine yl pyridines -2- bases) amino)
Pyridine simultaneously [5,4-c] quinoline -7 (6H) -one
Prepared by the method for reference implementation example 1, MS-ESI:M/z=469.4 [M+1].
Embodiment 10
The fluoro- 6- methyl-1s 0- of 2,2- ((5- (piperidin-4-yl) pyridine -2- bases) amino)-[1,3] dioxolane simultaneously [4,5-
F] pyrimido [5,4-c] quinoline -7 (6H) -one preparation
Prepared by the method for reference implementation example 1, MS-ESI:M/z=467.5 [M+1].
Embodiment 11
6- isopropyls -10- ((5- (piperidin-4-yl) pyridine -2- bases) amino)-[1,3] dioxolane simultaneously [4,5-f] pyrimidine
And the preparation of [5,4-c] quinoline -7 (6H) -one
Prepared by the method for reference implementation example 1, MS-ESI:M/z=459.2 [M+1].
Embodiment 12
6- isopropyls -10- ((5- (1- methyl-pi -4- bases) pyridine -2- bases) amino)-[1,3] dioxolane simultaneously [4,
5-f] pyrimido [5,4-c] quinoline -7 (6H) -one preparation
The method of reference implementation example 1, MS-ESI:M/z=473.2 [M+1].
Embodiment 13
6- isopropyls -10- ((5- (1- ethyl piperidine -4- bases) pyridine -2- bases) amino)-[1,3] dioxolane simultaneously [4,5-
F] pyrimido [5,4-c] quinoline -7 (6H) -one preparation
The method of reference implementation example 1, MS-ESI:M/z=487.2 [M+1].
Embodiment 14
6- isopropyls -10- ((5- (tetrahydrochysene -2H- pyrans -4- bases) pyridine -2- bases) amino)-[1,3] dioxolane simultaneously [4,
5-f] pyrimido [5,4-c] quinoline -7 (6H) -one preparation
The method of reference implementation example 1, MS-ESI:M/z=460.2 [M+1].
Embodiment 15
- [1,3] dioxolane is simultaneously by 6- isopropyls -10- ((5- (lupetidine -4- bases) pyridine -2- bases) amino)
The preparation of [4,5-f] pyrimido [5,4-c] quinoline -7 (6H) -one
The method of reference implementation example 1, MS-ESI:M/z=487.2 [M+1].
Embodiment 16
- [1,3] dioxolane is simultaneously by bis- fluoro- 6- isopropyls -10- of 2,2- ((5- (piperazine -1- bases) pyridine -2- bases) amino)
The preparation of [4,5-f] pyrimido [5,4-c] quinoline -7 (6H) -one
The method of reference implementation example 1, MS-ESI:M/z=496.2 [M+1].
Embodiment 17
Bis- fluoro- 6- isopropyls -10- of 2,2- ((5- (4- methylpiperazine-1-yls) pyridine -2- bases) amino)-[1,3] dioxy penta
The preparation of alkane simultaneously [4,5-f] pyrimido [5,4-c] quinoline -7 (6H) -one
The method of reference implementation example 1, MS-ESI:M/z=510.2 [M+1].
Embodiment 18
Bis- fluoro- 6- isopropyls -10- of 2,2- ((5- (4- ethyl piperazidine -1- bases) pyridine -2- bases) amino)-[1,3] dioxy penta
The preparation of alkane simultaneously [4,5-f] pyrimido [5,4-c] quinoline -7 (6H) -one
The method of reference implementation example 1, MS-ESI:M/z=524.2 [M+1].
Embodiment 19
- [1,3] dioxolane is simultaneously [4,5-f] by bis- fluoro- 6- isopropyls -10- of 2,2- ((5- morpholine yl pyridines -2- bases) amino)
The preparation of pyrimido [5,4-c] quinoline -7 (6H) -one
The method of reference implementation example 1, MS-ESI:M/z=497.2 [M+1].
Embodiment 20
Bis- fluoro- 6- isopropyls -10- of 2,2- ((3,5- lupetazin -1- bases) pyridine -2- bases) amino)-[1,3] dioxy
The preparation of pentane simultaneously [4,5-f] pyrimido [5,4-c] quinoline -7 (6H) -one
The method of reference implementation example 1, MS-ESI:M/z=524.2 [M+1].
Embodiment 21
- [1,3] dioxolane is simultaneously by bis- fluoro- 6- isopropyls -10- of 2,2- ((5- (piperidin-4-yl) pyridine -2- bases) amino)
The preparation of [4,5-f] pyrimido [5,4-c] quinoline -7 (6H) -one
The method of reference implementation example 1, MS-ESI:M/z=495.2 [M+1].
Embodiment 22
Bis- fluoro- 6- isopropyls -10- of 2,2- ((5- (1- methyl piperidine -4- bases) pyridine -2- bases) amino)-[1,3] dioxy penta
The preparation of alkane simultaneously [4,5-f] pyrimido [5,4-c] quinoline -7 (6H) -one
The method of reference implementation example 1, MS-ESI:M/z=509.2 [M+1].
23 biological activity determination of embodiment
CDK/6 enzyme assays
Inhibitory activity of the compound to CDK/6 enzymes is tested using Caliper Mobility Shift Assay methods, it should
The basic concept of Capillary Electrophoresis is applied in dimension fluid environment by technology, and zymetology is detected in the case where being added without termination reagent
Experiment.Substrate for experiment is the polypeptide with fluorescent marker, and in the reaction system under the action of enzyme, substrate is changed into product,
Institute is electrically charged also has occurred corresponding variation for it, Caliper-Shift Assay using the electrically charged difference of substrate and product,
The two detach and be detected respectively.
Experimental method：
The apparent Km of ATP on Mobility Shift are measured, the 2Xenzy&peptide in 5 holes μ L/ is added in 384 microwell plates
Mixed liquor.The 2XATP solution of 5 holes μ L/ three times gradients is added, starts reaction.Room temperature centrifuges 1 minute, is put into 23 DEG C of culture box temperatures
It educates after sixty minutes, 5 holes μ L/ 3Xstop buffer (100mm HEPES, pH7.5 is added；0.015%Brij-35；0.2%
CoatingReagent#3；50mm EDTA) reaction is terminated, it is placed on Caliper EZ Reader I and is detected；It is micro- 96
4 times of gradient dilutions are carried out in 5 μm of concentration to compound in orifice plate, 1005 μ L 100%DMSO are added as no compound without kinases
Control group takes 10 μ L compounds to be added to a 96 new microwell plates, adds 905 μ L, 1Xkinase base buffer
(20mmHEPES,PH 7.5；0.01%Triton X-100；10mm MgCl2；2mmDTT), which is placed on 10 on shaking table
Minute with by compound mixing；5 μ L mixed liquors are taken to be added in 384 micropores per hole.Then 10 μ L are added in micropore,
2.5Xenzymesolution.It is incubated the polypeptide solution that 10 μ L, 2.5X are added in each hole again after ten minutes at room temperature
(FAM-labeled peptide and ATP are added in 1Xkinase base buffer).Kinase reaction, specified time stop, incubating
30 DEG C are educated, 25 μ L stopbuffer is added to terminate reaction.It is placed on Caliper EZ Reader I and is detected.
The results show that the compounds of this invention inhibits the IC of CDK4/6 kinases50Value is usually at 25 μM or less.Embodiment 1-22ization
Close the IC that object inhibits CDK4 kinases50Value is less than 1 μM, and wherein embodiment 1,2,6,9,11,14,16 and 19 compounds inhibits CDK4 to swash
The IC of enzyme50Less than 10nM, the especially IC of 6,9,19 compound of embodiment50Less than 8nM.
More than, embodiments of the present invention are illustrated.But the present invention is not limited to the above embodiments.It is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in the guarantor of the present invention
Within the scope of shield.
Claims (10)
1. following formula A compounds represented, its stereoisomer, raceme, tautomer, isotopic label, nitrogen oxides,
Solvate or its pharmaceutically acceptable salt,
Wherein, each R1It is identical or different, H ,-F ,-Cl ,-Br ,-I, unsubstituted or one or more is represented independently of one another
RaSubstituted C1-40Alkyl；
R2、R4、R5It is identical or different, H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO are represented independently of one another2, it is unsubstituted or optionally by one
A or multiple RbSubstituted following groups：C1-40Alkyl, C1-40Alkoxy, C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Aryl,
5-20 unit's heteroaryls or-NRcRd；
R3、R6It is identical or different, H, unsubstituted or optionally by one or more R is represented independently of one anothereSubstituted C1-40Alkyl；
X is CRf；
Each Ra、RbIt is identical or different, it is independently from each other-F ,-Cl ,-Br ,-I ,-CN ,=O ,-NO2Or following groups：
C1-40Alkyl, C1-40Alkyl oxy, C1-40Alkyl sulfenyl, C2-40Alkenyl, C2-40Alkenyl oxygroup, C2-40Enylsulfanyl, C2-40Alkynyl,
C2-40Alkynyl oxygroup, C2-40Alkynyl sulfenyl, C3-20Naphthenic base, C3-20Cycloalkyl oxy, C3-20Cycloalkylsulfanyl, 3-20 circle heterocyclic rings
Base, 3-20 circle heterocyclic ring bases oxygroup, 3-20 circle heterocyclic ring bases sulfenyl, C6-20Aryl, C6-20Aryloxy, C6-20Artyl sulfo, 5-20 members
Heteroaryl, 5-20 unit's heteroaryls oxygroup, 5-20 unit's heteroaryl sulfenyls；
Each Rc、Rd、ReIt is identical or different, it is independently from each other H or following groups：C1-40Alkyl, C2-40Alkenyl, C2-40
Alkynyl, C3-20Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Aryl, 5-20 unit's heteroaryls；
Alternatively, RcAnd RdIt is formed selected from unsubstituted or optionally by one or more R together with the nitrogen-atoms connected with itgSubstitution
Following ring system：3-20 circle heterocyclic rings base, 5-20 unit's heteroaryls；
RgSelected from-F ,-Cl ,-Br ,-I ,-CN ,=O ,-NO2Or following groups：C1-40Alkyl, C2-40Alkenyl, C2-40Alkynyl, C3-20
Naphthenic base, 3-20 circle heterocyclic rings base, C6-20Aryl, 5-20 unit's heteroaryls；
RfSelected from H ,=O or optionally by one or more RaSubstituted C1-40Alkyl.
2. compound according to claim 1, wherein each R1It is identical or different, represent independently of one another H ,-F ,-
It is Cl ,-Br ,-I, unsubstituted or by one or more C1-12Alkyl-substituted C1-12Alkyl, such as R1Selected from H ,-F ,-Cl or-Br.
3. compound according to claim 1 or 2, wherein R2、R4、R5It is identical or different, represent independently of one another H ,-
It is CN, unsubstituted or optionally by one or more C1-12Alkyl-substituted following groups：C1-12Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic rings
Base, two-(C1-12Alkyl) amino, C1-12Alkyl amino or two-(C1-12Alkyl) two C in amino1-12Alkyl can also be with
Its nitrogen-atoms connected is formed together selected from unsubstituted or optionally by one or more C1-12Alkyl-substituted 3-20 circle heterocyclic rings
Base；
Such as R2、R4、R5It is identical or different, H ,-CN or following group are represented independently of one another：
Wherein,For the key in connection substitution site.
4. according to claim 1-3 any one of them compounds, wherein R3、R6Represent H, unsubstituted or optionally by one or more
A C1-12Alkyl-substituted C1-12Alkyl；
Such as R3、R6It is identical or different, representative-CH independently of one another3、-CH2CH3、-CH(CH3)2Or-C (CH3)3。
5. according to claim 1-4 any one of them compounds, wherein X is selected from CRf, wherein RfIndependently represent H ,=O or
C1-12Alkyl；
Such as RfSelected from H ,=O ,-CH3Or-CH2CH3。
6. according to claim 1-5 any one of them compounds, wherein it includes but not limited to followingization that the compound, which is selected from,
Close object：
7. a kind of pharmaceutical composition, it includes claim 1-6 any one of them compound, its solid of therapeutically effective amount are different
In structure body, raceme, tautomer, isotopic label, nitrogen oxides, solvate or its pharmaceutically acceptable salt
It is one or more kinds of；
Preferably, described pharmaceutical composition also optionally includes its pharmaceutically acceptable auxiliary material, such as carrier, excipient；It is described
Auxiliary material is selected from one of the following or a variety of：Disintegrant, glidant, lubricant, diluent or filler, adhesive, colorant.
8. claim 1-6 any one of them compound, its stereoisomer, raceme, tautomer, isotope labelling
The purposes of one or more of object, nitrogen oxides, solvate or its pharmaceutically acceptable salt in medicine preparation.
9. purposes according to claim 8, wherein the drug is CDK inhibitor；
Preferably, the CDK inhibitor is for treating and/or preventing hepatitis B.
10. according to the preparation method of any one of the claim 1-6 compounds, including：
(1) compound V and compound VI carries out that compound A is obtained by the reaction；
Wherein, R1、R2、R3、R4、R5、R6With any one of the claim 1-6 definition.
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| CN1575177A (en) * | 2000-12-11 | 2005-02-02 | 图拉里克公司 | Cxcr3 antagonists |
| CN101448818A (en) * | 2006-05-12 | 2009-06-03 | 捷瑞尼股份公司 | New heterocyclic compounds for the inhibition of integrins and use thereof |
| CN102448952A (en) * | 2009-03-25 | 2012-05-09 | 雅培制药有限公司 | Antiviral compounds and uses thereof |
| CN104710423A (en) * | 2009-12-14 | 2015-06-17 | 默沙东有限责任公司 | Mk2 inhibitors |
| US20130345240A1 (en) * | 2010-04-27 | 2013-12-26 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
| CN104936949A (en) * | 2013-01-25 | 2015-09-23 | 百时美施贵宝公司 | Squaric derivatives for the treatment of hepatitis c |
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