CN108794496B - CDK inhibitor, pharmaceutical composition, preparation method and application thereof - Google Patents
CDK inhibitor, pharmaceutical composition, preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a CDK inhibitor, a pharmaceutical composition, a preparation method and application thereof. The invention provides a compound shown in the following formula A, a stereoisomer, a racemate, a tautomer, an isotopic marker, a nitrogen oxide, a solvate or a pharmaceutically acceptable salt thereof,
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a CDK inhibitor, a pharmaceutical composition, a preparation method and application thereof.
Background
Cyclin-dependent kinases (CDKs) are a class of serine (Ser)/threonine (Thr) kinases, which are involved in the growth, proliferation, dormancy or apoptosis of cells as CDK-cyclin complexes formed by important signal transduction molecules and cyclins in the cells. In the process of cell cycle, cyclins are periodically and continuously expressed and degraded, and are respectively combined with CDKs which are instantaneously activated by the cyclins, and the phosphorylation of different substrates is catalyzed through the activity of the CDKs, so that the promotion and conversion effects on different phases of the cell cycle are realized.
Over the past decades, CDK kinase targeted drug development has received widespread attention, with some drugs entering different stages of clinical research. However, the clinical application of these CDK inhibitors is limited by their low inhibitory activity, poor selectivity, poor absorption in vivo, or certain toxic and side effects on individual CDK family subtypes. In recent years, drug development in this field has become a hot spot again due to the improved selectivity and inhibitory activity of CDK inhibitors on individual CDK family subtypes, in particular the discovery of selective inhibitors targeting CDK 4/6.
CDK4/6 is overexpressed in many cancers leading to uncontrolled cell proliferation, and thus, inhibition of CDK4/6 may effect inhibition of cell proliferation downstream from the signaling pathway. Currently, the pfbeciclib-CDKs 4/6 inhibitor Palbociclib, which is the first CDK4/6 inhibitor to be marketed, is approved by FDA as a first-line drug for the treatment of ER-positive, HER 2-negative breast cancers, and the congeneric drugs, Abemaciclib and Ribociclib from novartis, are also marketed.
Therefore, research and development of a pharmaceutically acceptable CDK kinase inhibitor having good CDK-modulating activity is of great social significance.
Disclosure of Invention
In order to improve the above problems, the present invention provides a compound represented by the following formula a, a stereoisomer, a racemate, a tautomer, an isotopic label, an oxynitride, a solvate, or a pharmaceutically acceptable salt thereof,
wherein each R is1Identical or different, independently of one another, represent H, -F, -Cl, -Br, -I, unsubstituted or substituted by one or more RaSubstituted C1-40An alkyl group;
R2、R4、R5identical or different, independently of one another, represent H, -F, -Cl, -Br, -I, -CN, -NO2Unsubstituted or optionally substituted by one or more RbSubstituted of the following groups: c1-40Alkyl radical, C1-40Alkoxy radical, C3-20Cycloalkyl, 3-20 membered heterocyclyl, C6-20Aryl, 5-20 membered heteroaryl, or-NRcRd；
R3、R6Identical or different, independently of one another, represents H, unsubstituted or optionally substituted by one or more ReSubstituted C1-40An alkyl group;
x is CRf；
Each Ra、RbIdentical or different, independently of one another, from the group formed by-F, -Cl, -Br, -I, -CN, -O, -NO2Or the following groups: c1-40Alkyl radical, C1-40Alkyloxy, C1-40Alkylthio radical, C2-40Alkenyl radical, C2-40Alkenyloxy radical, C2-40Alkenylthio radical, C2-40Alkynyl, C2-40Alkynyloxy, C2-40Alkynylthio, C3-20Cycloalkyl radical, C3-20Cycloalkyl oxy, C3-20Cycloalkylthio, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, 3-20 membered heterocyclylthio, C6-20Aryl radical, C6-20Aryloxy radical, C6-20Arylthio, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy, 5-20 membered heteroarylthio;
each Rc、Rd、ReIdentical or different, independently of one another, from H, or the following radicals: c1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-20Cycloalkyl, 3-20 membered heterocyclyl, C6-20Aryl, 5-20 membered heteroaryl;
or, RcAnd RdTogether with the nitrogen atom to which they are attached form a group selected from unsubstituted or optionally substituted by one or more RgSubstituted ring systems of: 3-20 membered heterocyclyl, 5-20 membered heteroaryl;
Rgselected from-F, -Cl, -Br, -I, -CN, -O, -NO2Or the following groups: c1-40Alkyl radical, C2-40Alkenyl radical, C2-40Alkynyl, C3-20Cycloalkyl, 3-20 membered heterocyclyl, C6-20Aryl, 5-20 membered heteroaryl;
Rfselected from H, ═ O, or optionally substituted with one or more RaSubstituted C1-40An alkyl group.
According to an exemplary embodiment of the invention, each R is1Identical or different, independently of one another, represent H, -F, -Cl, -Br, -I, unsubstituted or substituted by one or more C1-12Alkyl substituted C1-12Alkyl radicals, e.g. R1Selected from H, -F, -Cl, or-Br;
according to an exemplary embodiment of the invention, R2、R4、R5Identical or different, independently of one another, represent H, -CN, unsubstituted or optionally substituted by one or more C1-12Alkyl-substituted the following groups: c1-12Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, di- (C)1-12Alkyl) amino-, C1-12Alkylamino-, or di- (C)1-12Alkyl) two C's of amino1-12Alkyl groups may also form, together with the nitrogen atom to which they are attached, a substituent selected from unsubstituted or optionally substituted by one or more C1-12An alkyl-substituted 3-20 membered heterocyclyl;
for example R2、R4、R5Identical or different, independently of one another, represent H, -CN, or the following radicals:
wherein the content of the first and second substances,
is a bond linking the substitution sites;
according to an exemplary embodiment of the invention, R3、R6Represents H, unsubstituted or optionally substituted by one or more C1-12Alkyl substituted C1-12An alkyl group;
for example R3、R6Identical or different, independently of one another, represent-CH3、-CH2CH3、-CH(CH3)2or-C (CH)3)3；
According to an exemplary embodiment of the invention, X is selected from CRfWherein R isfIndependently represent H, ═ O, or C1-12An alkyl group;
for example RfSelected from H, ═ O and-CH3or-CH2CH3。
As an example, the compound of formula a is selected from the group including, but not limited to, the following compounds:
the invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of one or more of the compounds shown in the formula A, stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, solvates or pharmaceutically acceptable salts thereof.
According to the present invention, the pharmaceutical composition further optionally comprises pharmaceutically acceptable excipients thereof, such as carriers, excipients; the auxiliary material is selected from one or more of the following materials: disintegrants, glidants, lubricants, diluents or fillers, binders, colorants.
The invention also provides application of one or more of the compound shown in the formula A, a stereoisomer, a racemate, a tautomer, an isotopic marker, a nitrogen oxide, a solvate or pharmaceutically acceptable salt thereof in preparing a medicament.
According to an embodiment of the invention, the agent is a CDK inhibitor.
According to an embodiment of the invention, said CDK inhibitor is used for the treatment and/or prevention of hepatitis b.
The present invention also provides a method of treating and/or preventing a disease comprising administering to a patient in need of such treatment and/or prevention a therapeutically effective amount of one or more of a compound of formula a, a stereoisomer, a racemate, a tautomer, an isotopic label, a nitroxide, a solvate, or a pharmaceutically acceptable salt thereof.
According to an embodiment of the invention, the disease is hepatitis b.
The invention also provides a preparation method of the compound of the formula A, which comprises the following steps:
(1) reacting the compound V with the compound VI to obtain a compound A;
wherein R is1、R2、R3、R4、R5、R6And X is as defined above.
In the step (1), the step (c),
the reaction may be a Buchwald reaction;
the reaction may be carried out at a temperature of 20 ℃ to 100 ℃;
the reaction may be carried out in a solvent selected from one, two or more of amide solvents, ether solvents, aromatic hydrocarbon solvents; for example, one, two or more selected from DMF, dioxane, tetrahydrofuran, toluene, and the like;
the reaction may be carried out in the presence of a catalyst and a ligand; the catalyst is selected from PdCl2(PPh3)2、Pd(PPh3)4、Pd(dba)2、Pd(OAc)2、Pd(dppf)2Cl2One, two or more of; the ligand is selected from one, two or more of 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (SPhos) and 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene (XantPhos);
the reaction may also be carried out in the presence of a base; the alkali is one or two or more of cesium carbonate, sodium tert-butoxide, potassium phosphate and sodium acetate.
According to the present invention, the process as described above further comprises the preparation of a compound of formula V, comprising:
(2) synthesis of intermediate III
Reacting the compound I with the compound II to obtain a compound III;
(3) synthesis of intermediate IV
The compound III and the compound R obtained in the step (2)3I, reacting to obtain a compound IV;
(4) synthesis of intermediate V
Reacting the compound IV obtained in the step (3) to obtain a compound V;
in the step (2),
the reaction may be a condensation reaction;
the condensation reaction may be carried out at a temperature of 20 ℃ to 100 ℃;
the condensation reaction may be carried out in the presence of a condensing agent; the condensing agent used may be selected from one, two or more of edci. hcl (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride), HATU (2- (7-oxabenzotriazol) -N, N '-tetramethyluronium hexafluorophosphate), BOP-Cl (bis (2-oxo-3-oxazolidinyl) phosphinic chloride), DCC (N, N' -dicyclohexylcarbodiimide);
the base used in the condensation reaction may be selected from one, two or more of triethylamine, diisopropylethylamine, N-methylmorpholine, DMAP;
in the step (3), the step (c),
the reaction may be carried out at a temperature of 20 ℃ to 100 ℃;
the reaction may be carried out in the presence of a base; the alkali is selected from one, two or more of sodium hydride, sodium hydroxide, potassium carbonate, lithium hexamethylamide and sodium hexamethylamide;
the reaction may be carried out in a solvent selected from one, two or more of amide solvents, ether solvents, aromatic hydrocarbon solvents; for example, one, two or more selected from DMF, dioxane, tetrahydrofuran, toluene, and the like;
in the step (4), the step (c),
the reaction may be carried out in the presence of magnesium powder and a lewis acid;
the reaction may be carried out at a temperature of 20 ℃ to 100 ℃;
the Lewis acid is selected from one or two of lithium chloride and zinc chloride;
the reaction may be carried out in a solvent selected from ether solvents; for example, one, two or more selected from diethyl ether, dioxane and tetrahydrofuran.
Advantageous effects
The compound of the invention has good CDK regulation activity, is suitable for medicine and has clinical application value. In addition, the compound has simple synthesis steps, so the compound has good economic utilization value.
Definition and description of terms
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.
The term "C1-40Alkyl is understood to preferably mean a straight-chain or branched, saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms, preferably C1-10An alkyl group. "C1-10Alkyl "is understood to preferably mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a 1, 2-dimethylpropyl group, a neopentyl group, a 1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a 2, 2-dimethylbutyl group, a 1, 1-dimethylbutyl group, a 2, 3-dimethylbutyl group, a 1, 3-dimethylbutyl group or a 1, 2-dimethylbutyl group. In particular, the radicals have 1,2, 3,4, 5,6 carbon atoms ("C)1-6Alkyl groups) such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly groups having 1,2 or 3 carbon atoms ("C)1-3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "C2-40Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more double bonds and having from 2 to 40 carbon atoms, preferably" C2-10Alkenyl ". "C2-10Alkenyl "is understood to preferably mean a straight-chain or branched, monovalent hydrocarbon radical which contains one or more double bonds and has 2,3, 4,5, 6, 7, 8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms (" C2-3Alkenyl "), it being understood that in the case where the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, m-n-2-enyl, m-n-1-enyl, m-n-E-4-enyl, m-n-2-, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl group and 1-isopropylvinyl group.
The term "C2-40Alkynyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more triple bonds and having from 2 to 40 carbon atoms, preferably" C2-C10Alkynyl ". The term "C2-C10Alkynyl "is understood as preferably meaning a straight-chain or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2,3, 4,5, 6, 7, 8, 9 or 10 carbon atoms, in particular 2 or 3 carbon atoms (" C2-C3-alkynyl "). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, prop-2-ynyl, but-3-methylbut-1-ynyl, and so-1-ethylprop, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-1-ynyl, 3-methylpent-1-, 1, 1-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
The term "C3-20Cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C3-10Cycloalkyl groups ". The term "C3-10Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. Said C is3-10Cycloalkyl groups may be monocyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin rings.
The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5 heteroatoms independently selected from N, O and S, preferably "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a 5,5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic radical is non-aromatic.
The term "C6-20 aryl "is understood to mean preferably a mono-, bi-or tricyclic hydrocarbon ring having a monovalent aromatic or partially aromatic character of 6 to 20 carbon atoms, preferably" C6-14 aryl ". The term "C6-14 aryl "is understood to mean preferably a mono-, bi-or tricyclic hydrocarbon ring having a monovalent aromatic or partially aromatic character with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" C6-14 aryl "), in particular a ring having 6 carbon atoms (" C ")6Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C9Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C10Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C13Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)14Aryl), such as anthracenyl.
The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5 to 20 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: which has 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which comprises 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, can be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl, and pyridinylene-4-yl; thienyl or thienylene includes thien-2-yl, thien-3-yl and thien-3-yl.
The target compound may be isolated according to known methods, for example by extraction, filtration or column chromatography.
Depending on their molecular structure, the compounds of the invention may be chiral and may therefore exist in various enantiomeric forms. These compounds may thus be present in racemic or optically active form. The compounds of the invention or intermediates thereof may be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from mixtures by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulphonic acids. The chromatographic enantiomeric resolution can also advantageously be carried out with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers, which are immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
Pharmaceutically acceptable salts may be acid addition salts of the compounds of the invention having sufficient basicity, for example having a nitrogen atom in the chain or ring, for example with the following inorganic acids: for example hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfates, or acid addition salts with organic acids such as: such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, Mandelic acid, ascorbic acid, glucoheptylic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.
Since the compound of the present invention may exist at a plurality of salt-forming sites, the "pharmaceutically acceptable salt" includes not only the salt formed at 1 salt-forming site among the compounds of the present invention but also the salt formed at 2,3 or all of the salt-forming sites among them. For this purpose, the molar ratio of the "pharmaceutically acceptable salt" of the compound of formula (I) to the cation of the acid (anion) or base required for salt formation may vary within wide limits, and may be, for example, 4:1 to 1:4, such as 3:1, 2:1, 1:2, 1:3, etc.
According to the present invention, the pharmaceutically acceptable anion includes anions selected from the group consisting of those generated by ionization of inorganic or organic acids. The "inorganic acid" includes, but is not limited to, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, or nitric acid. The "organic acid" includes, but is not limited to, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, maleic, Fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.
The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.
The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to effect the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc., can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the dosage regimen to be followed, whether to administer it in combination with other compounds, the timing of administration, the tissue to be administered and the physical delivery system carried.
The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of types of excipients include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients enhance the handling characteristics of the pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flowability and/or cohesiveness. Examples of typical pharmaceutically acceptable carriers suitable for use in the above formulations are: sugars such as lactose, sucrose, mannitol, and sorbitol; starches, such as corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates, such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; a glycol polymer; fatty alcohols; and grain hydrolyzed solids and other nontoxic compatible excipients commonly used in pharmaceutical formulations, such as fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants, and the like.
Detailed Description
The compounds of the general formula and the preparation and use thereof according to the present invention will be described in further detail with reference to the following examples. The following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1
Preparation of 6-methyl-10- ((5- (4-methylpiperidin-1-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
(1) Synthesis of intermediate 1c
Dissolving compound 1a (21.6g, 100mmol), 1b (15.9g, 100mmol), DIPEA (19.4g, 150mmol) in DMF (200ml), adding HATU (45.6g, 120mmol) at room temperature, stirring for 4 hours, detecting the reaction by TLC, adding water (200ml) after the reaction is finished to quench the reaction, extracting with ethyl acetate (300mlx2), combining organic layers, drying the organic layers, filtering, concentrating, and performing column chromatography to obtain off-white solid 28.5g with yield of 79.9%.
(2) Synthesis of intermediate 1d
Compound 1c (28.0g, 75.8mmol) was dissolved in DMF (200ml), sodium hydride (3.8g, 94.2mmol) was added under ice bath, stirred for reaction for 30 min, iodomethane (10.8g, 75.8mmol) was added at room temperature, stirred for reaction for 6h, TLC detected, after the reaction was completed, water (100ml) was added to quench the reaction, ethyl acetate (500mlx2) was extracted, organic layers were combined, dried, concentrated, column chromatography separated to give 23.2g of off-white solid with a yield of 82.6%.
(3) Synthesis of intermediate 1e
Dissolving compound 1d (23.0g, 62.1mmol) and lithium chloride (0.5g, 12.4mmol) in tetrahydrofuran (200ml), adding magnesium powder (1.8g, 74.5mmol) aqueous solution (300ml) at room temperature, heating to 50 ℃, stirring for reaction for 8 hours, detecting the reaction by TLC, adding saturated ammonium chloride solution after the reaction is finished, quenching the reaction, adding ethyl acetate (300mlx2), extracting, combining organic layers, concentrating, and performing column chromatography to obtain a white-like solid 12.4g, wherein the yield is 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)2(120mg, 0.2mmol) and 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (120mg, 0.2mmol) are dissolved in DMF (20ml), the temperature is raised to 100 ℃, the reaction is stirred for 12 hours, the TLC detection reaction is carried out, after the reaction is finished, the reaction liquid is poured into water (20ml), ethyl acetate (500mlx2) is extracted, the organic phases are combined, dried, filtered, concentrated and separated by column chromatography to obtain the off-white solid 760mg, and the yield is 41.2%. MS-ESI (M/z) 446.5[ M +1]]。
Example 2
Preparation of 10- ((5- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) -6-methyl- [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Prepared by the method of reference example 1, MS-ESI: M/z 460.5[ M +1 ].
Example 3
Preparation of 6-methyl-10- ((5- (piperazin-1-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Prepared by the method of reference example 1, MS-ESI: M/z 432.4[ M +1 ].
Example 4
Preparation of 6-methyl-10- ((5-morpholinylpyridin-2-yl) amino) - [1,3] dioxolano [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Prepared by the method of reference example 1, MS-ESI: M/z 433.4[ M +1 ].
Example 5
Preparation of 6-methyl-10- ((5- (piperazin-4-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Prepared by the method of reference example 1, MS-ESI: M/z 431.5[ M +1 ].
Example 6
Preparation of 2, 2-difluoro-6-methyl-10- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Prepared by the method of reference example 1, MS-ESI: M/z 482.5[ M +1 ].
Example 7
Preparation of 10- ((5- (4-ethylpiperidin-1-yl) pyridin-2-yl) amino) -2, 2-difluoro-6-methyl- [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Prepared by the method of reference example 1, MS-ESI: M/z 496.5[ M +1 ].
Example 8
Preparation of 2, 2-difluoro-6-methyl-10- ((5- (piperazin-1-yl) pyridin-2-yl) amino) - [1,3] dioxolano [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Prepared by the method of reference example 1, MS-ESI: M/z 468.4[ M +1 ].
Example 9
2, 2-difluoro-6-methyl-10- ((5-morpholinylpyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Prepared by the method of reference example 1, MS-ESI: M/z 469.4[ M +1 ].
Example 10
Preparation of 2, 2-fluoro-6-methyl-10- ((5- (piperidin-4-yl) pyridin-2-yl) amino) - [1,3] dioxolano [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Prepared by the method of reference example 1, MS-ESI: M/z 467.5[ M +1 ].
Example 11
Preparation of 6-isopropyl-10- ((5- (piperidin-4-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Prepared by the method of reference example 1, MS-ESI: M/z 459.2[ M +1 ].
Example 12
Preparation of 6-isopropyl-10- ((5- (1-methyl-piperidin-4-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Referring to the procedure of example 1, MS-ESI: M/z 473.2[ M +1 ].
Example 13
Preparation of 6-isopropyl-10- ((5- (1-ethylpiperidin-4-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Referring to the procedure of example 1, MS-ESI: M/z 487.2[ M +1 ].
Example 14
Preparation of 6-isopropyl-10- ((5- (tetrahydro-2H-pyran-4-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Referring to the procedure of example 1, MS-ESI: M/z 460.2[ M +1 ].
Example 15
Preparation of 6-isopropyl-10- ((5- (2, 6-dimethylpiperidin-4-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Referring to the procedure of example 1, MS-ESI: M/z 487.2[ M +1 ].
Example 16
Preparation of 2, 2-difluoro-6-isopropyl-10- ((5- (piperazin-1-yl) pyridin-2-yl) amino) - [1,3] dioxolano [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Referring to the procedure of example 1, MS-ESI: M/z 496.2[ M +1 ].
Example 17
Preparation of 2, 2-difluoro-6-isopropyl-10- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Referring to the procedure of example 1, MS-ESI: M/z 510.2[ M +1 ].
Example 18
Preparation of 2, 2-difluoro-6-isopropyl-10- ((5- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Referring to the procedure of example 1, MS-ESI: M/z 524.2[ M +1 ].
Example 19
Preparation of 2, 2-difluoro-6-isopropyl-10- ((5-morpholinylpyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Referring to the procedure of example 1, MS-ESI: M/z 497.2[ M +1 ].
Example 20
Preparation of 2, 2-difluoro-6-isopropyl-10- ((3, 5-dimethylpiperazin-1-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Referring to the procedure of example 1, MS-ESI: M/z 524.2[ M +1 ].
Example 21
Preparation of 2, 2-difluoro-6-isopropyl-10- ((5- (piperidin-4-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
Referring to the procedure of example 1, MS-ESI: M/z 495.2[ M +1 ].
Example 22
Preparation of 2, 2-difluoro-6-isopropyl-10- ((5- (1-methylpiperidin-4-yl) pyridin-2-yl) amino) - [1,3] dioxolan [4,5-f ] pyrimido [5,4-c ] quinolin-7 (6H) -one
With reference to the procedure of example 1, MS-ESI: M/z 509.2[ M +1 ].
Example 23 biological Activity assay
CDK/6 enzyme Activity assay
The inhibition activity of the compound on CDK/6 enzyme is tested by adopting a Caliper Mobility Shift Assay method, the technology applies the basic concept of capillary electrophoresis to a dimensional fluid environment, and an enzymology experiment is detected without adding a termination reagent. The substrate used for the experiment is polypeptide with fluorescent label, under the action of enzyme in the reaction system, the substrate is converted into product, the charge of the product is correspondingly changed, the Caliper-Shift Assay utilizes the difference of the charge of the substrate and the charge of the product to separate the substrate and the product and respectively detect the substrate and the product.
The experimental method comprises the following steps:
determination of ATP apparent Km on Mobilty Shift 384 plates 5. mu.L/well of 2Xenzy was added&And (3) peptide mixed solution. The reaction was started by adding a 5. mu.L/well triple gradient of 2XATP solution. Centrifuging at room temperature for 1 minute, placing the mixture into an incubator at 23 ℃ for incubation for 60 minutes, adding 5 mu L/hole of 3 XBtop buffer (100mm HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating reagent # 3; 50mm EDTA) to terminate the reaction, and placing the mixture on a Caliper EZ Reader I for detection; the compound was diluted in a gradient of 4 times at 5 μm concentration in a 96-well plate, 1005 μ L of 100% DMSO was added as a compound-free kinase-free control, 10 μ L of the compound was added to a new 96-well plate, and 905 μ L of 1Xkinase base buffer (20mm HEPES, pH 7.5; 0.01% Triton X-100; 10mm MgCl. RTM.) was added2(ii) a 2mmDTT), place the plate on a shaker for 10 minutes to mix the compounds; mu.L of the mixture was added to 384 wells per well. Then 10. mu.L of 2.5Xenzymesol was added to the microwellsAnd (4) resolution. After incubation for 10 min at room temperature, 10. mu.L of 2.5 Xpolypeptide solution (FAM-labeled peptide and ATP in 1Xkinase base buffer) was added to each well. The kinase reaction was stopped at the indicated times, incubated at 30 ℃ and stopped by adding 25. mu.L of stopbuffer. And (4) placing the sample on a Caliper EZ Reader I for detection.
The results show that the compounds of the invention inhibit the IC of CDK4/6 kinase50The value is usually 25. mu.M or less. Examples 1-22 IC inhibition of CDK4 kinase by Compounds50Values below 1 μ M, where the compounds of examples 1,2, 6, 9, 11, 14, 16 and 19 inhibit the IC of CDK4 kinase50IC of less than 10nM, in particular of the compounds of examples 6, 9, 1950Less than 8 nM.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. The following compounds:
2. a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of claim 1;
the pharmaceutical composition is a CDK inhibitor.
3. The pharmaceutical composition of claim 2, further comprising a pharmaceutically acceptable excipient thereof.
4. The pharmaceutical composition of claim 3, wherein the excipient is selected from one or more of the following: disintegrants, glidants, lubricants, diluents or fillers, binders, colorants.
5. Use of one or more compounds of claim 1 for the preparation of a medicament;
the agent is a CDK inhibitor.
6. Use according to claim 5, wherein the CDK inhibitor is for the treatment and/or prevention of hepatitis B disease.
7. A process for the preparation of a compound as claimed in claim 1, comprising:
(1) reacting the compound V with the compound VI to obtain a compound A;
wherein R is1、R2、R3、R4、R5、R6X has the meaning indicated in claim 1.
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| CN1575177A (en) * | 2000-12-11 | 2005-02-02 | 图拉里克公司 | Cxcr3 antagonists |
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| CN102448952A (en) * | 2009-03-25 | 2012-05-09 | 雅培制药有限公司 | Antiviral compounds and uses thereof |
| US20130345240A1 (en) * | 2010-04-27 | 2013-12-26 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
| CN104710423A (en) * | 2009-12-14 | 2015-06-17 | 默沙东有限责任公司 | Mk2 inhibitors |
| 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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| 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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