CN100420687C - Pyridino [2, 3-D] pyrimidine derivatives as selective KDR and FGFR inhibitors - Google Patents

Pyridino [2, 3-D] pyrimidine derivatives as selective KDR and FGFR inhibitors Download PDF

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CN100420687C
CN100420687C CNB2003801069786A CN200380106978A CN100420687C CN 100420687 C CN100420687 C CN 100420687C CN B2003801069786 A CNB2003801069786 A CN B2003801069786A CN 200380106978 A CN200380106978 A CN 200380106978A CN 100420687 C CN100420687 C CN 100420687C
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CN1729189A (en
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刘进军
陆建春
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F Hoffmann La Roche AG
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Abstract

Disclosed are novel dihydropridinone compounds of the formula (I) wherein Ar, Ar' and R<1> are as defined in the description, that are selective inhibitors of both KDR and FGFR kinases. These compounds and their pharmaceutically acceptable salts are anti-proliferative agents useful in the treatment or control of solid tumors, in particular breast, colon lung and prostate tumors. Also, disclosed are pharmaceutical compositions containing these compounds and their preparation.

Description

Pyrido [2,3-D] pyrimidine derivatives as selectivity KDR and FGFR inhibitor
The present invention relates to dihydropyridine ketone compound or its pharmaceutical salts of new formula I:
Wherein Ar and Ar ' are independently selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement, and condition is for Ar, and described heteroaryl can not be the 2-pyridyl, and the heteroaryl that replaces can not be the 2-pyridyl that replaces;
R 1Be selected from:
H；
C 1-10Alkyl;
Independently by at the most three be selected from aryl, heteroaryl, heterocycle, cycloalkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 1-10Alkyl, wherein aryl, heteroaryl, heterocycle and cycloalkyl can be respectively independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2Substituting group replace;
Aryl;
Independently by at the most three be selected from low alkyl group, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The aryl that replaces of substituting group;
Heteroaryl;
Independently by at the most three be selected from low alkyl group, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The heteroaryl that replaces of substituting group;
Heterocycle;
Independently by at the most three be selected from low alkyl group, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The heterocycle that replaces of substituting group;
C 3-10Cycloalkyl;
Independently by three low alkyl group, NR that are selected from low alkyl group, replacement at the most 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 3-10Cycloalkyl;
C 2-10Alkenyl;
Independently by three cycloalkyl, heterocyclic radical, the Heterocyclylalkyl of replacement, NR that are selected from cycloalkyl, replacement at the most 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 2-10Alkenyl;
C 2-10Alkynyl; With
Independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 2-10Alkynyl;
R 8, R 9And R 10Be H or low alkyl group independently;
R 11And R 12Be independently selected from:
H；
Unsubstituted low alkyl group; By hydroxyl, alkoxyl group or NR 21R 22The low alkyl group that replaces;
Unsubstituted cycloalkyl; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The cycloalkyl that replaces;
Unsubstituted heterocycle; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The heterocycle that replaces;
Alternatively, NR 11R 12Formation has the ring of 3 to 7 atoms, and described ring does not have or have at least one other heteroatoms, and condition is if heteroatoms is N, and heteroatoms can be by one or more low alkyl group, OR of being selected from 13, COR 14, CO 2R 14, CONR 14R 15, SO 2R 14And SO 2NR 14R 15Substituting group replace;
R 13Be selected from:
H；
COR 14；
CONR 14R 15；
Unsubstituted low alkyl group; By hydroxyl, alkoxyl group or NR 21R 22The low alkyl group that replaces;
Unsubstituted cycloalkyl; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The cycloalkyl that replaces;
Unsubstituted heterocycle; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The heterocycle that replaces;
R 14And R 15Be independently selected from:
H；
Unsubstituted low alkyl group; By hydroxyl, alkoxyl group or NR 21R 22The low alkyl group that replaces;
Unsubstituted cycloalkyl; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The cycloalkyl that replaces;
Unsubstituted heterocycle; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The heterocycle that replaces;
Alternatively, NR 14R 15Formation has the ring of 3 to 7 atoms, and described ring does not have or have at least one heteroatoms, and condition is if heteroatoms is N, and heteroatoms can be by one or more low alkyl group, OR of being selected from 23, COR 23, CO 2R 23, CONR 23R 24, SO 2R 23, SO 2NR 23R 24Substituting group replace;
R 21Be selected from H, low alkyl group, COR 23Or CO 2R 23
R 22, R 23And R 24Be independently selected from H or low alkyl group;
Alternatively, NR 21R 22Or NR 23R 24Form the ring with 3 to 7 atoms independently, described ring does not have or has at least one other heteroatoms that is selected from N, O and S, and condition is if heteroatoms is N, heteroatoms can for-NH or NR 25Form, if heteroatoms is S, heteroatoms can be S (O) mForm, m=0,1 or 2 wherein; With
R 25Be low alkyl group.
Have been found that formula I compound can suppress KDR (kinase insert domain-containingreceptor) and FGFR (fibroblast growth factor acceptor) kinases.These compounds and pharmaceutical salts thereof have antiproliferative activity, and effective in treatment or control cancer, especially solid tumor.And these compounds have favourable bioavailability curve.The invention still further relates to pharmaceutical composition and treatment or control cancer, particularly treatment that contains described compound or the method for controlling mammary cancer, lung cancer, colorectal carcinoma and prostate cancer.
Protein kinase is the albumen (enzyme) that a class can be regulated the various kinds of cell function.It is to cause the conformational change of substrate protein to be realized by amino acid specific on the phosphorylated protein substrate.Conformational change is regulated substrate activity or substrate protein and other the interactional ability of partner (binding partners) that is connected.The enzymic activity of described protein kinase refers to that this kinases joins phosphate the speed of substrate.It can be by for example determining to be transformed into the substrate on the product amount and the function of time measure.The phosphorylation of substrate is carried out at the avtive spot of protein kinase.
Tyrosylprotein kinase is the subclass of the terminal phosphate of Triphosaden on the catalytic protein substrate (ATP) to the protein kinase of tyrosine residues transfer.These kinases play an important role in the propagation of cytokine signaling, and described cytokine signaling causes cell proliferation, differentiation and moves.
For example, fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) have been considered to the important medium of the vasculogenesis of tumour.To activate a kind of in the described two kinds of highly affine acceptors of endotheliocyte be that kinases inserts Chimerical receptor (KDR) to VEGF by send signal to two kinds of highly affine acceptors.Referring to people's such as Hennequin L. F. J.Med.Chem.2002, the 45 (6), 1300th page.FGF is by giving FGF acceptor (FGFR) signal activation endotheliocyte.Solid tumor relies on the formation (vasculogenesis) of neovascularity and grows.Therefore, acceptor FGFR and KDR inhibitor influence the transduction of grown cell signal, thereby slow down or stop vasculogenesis, and described inhibitor is an efficacious agents in prevention and treatment solid tumor.Referring to people's such as Klohs W.E. Current Opinion inBiotechnology 1999,10, the 544th page.
The example that the micromolecular inhibitor of some protein kinase catalytic activitys is arranged.Especially, micromolecular inhibitor is by with the tight effect of protein kinase A TP binding site (or " avtive spot) and typically block the phosphorylation of substrate.Referring to people such as WO 98/24432 and Hennequin L.F., J.Med.Chem.2002,45 (6), ppl300.In these compounds some suppresses a plurality of target spots.For example WO99/61444 (Warner-Lambert) discloses the bicyclic pyrimidine and two rings 3 of following formula, 4-dihydro-pyrimidin
Figure C20038010697800171
It is said its cyclin-dependent kinase Cdk1 capable of inhibiting cell, Cdk2 and Cdk4 and growth factor acceptor Tyrosylprotein kinase PDGFR and FGFR.It is said that some compound also can suppress Cdk6.
WO01/55148A1 discloses the method for neurodegenerative disease in the treatment Mammals, and it comprises the cyclin dependent kinase inhibitors of bestowing significant quantity, preferably uses the Cdk inhibitor of following formula:
Figure C20038010697800181
U.S. Patent No. 6,150373 discloses two ring nitrogen heterocyclics of following formula:
Figure C20038010697800182
It is said that it can suppress T-cell Tyrosylprotein kinase p56 1ck
WO 02/18380 discloses the 7-oxo pyridopyrimidines of following formula:
Figure C20038010697800183
It is said that it can suppress the cell function of p38 mediation, so it is the inhibitor of cell proliferation.
The 6-aryl-pyridine of WO 96/34867 disclosed following formula is [2,3-d] pyrimidine 7-imines, 7-ketone and and 7-thioketones also
Figure C20038010697800184
Be the inhibitor of protein kinase, and effective in the disease of treatment cell proliferation mediation.
WO 98/33798 discloses pyrido [2,3-d] pyrimidine and the 4-aminopyrimidine as inhibition of cell proliferation.Particularly, this application discloses 7,8 dihydros-2-(amino and sulfenyl) pyrido [2,3-d] pyrimidine and 2, the 4-di-amino-pyrimidine, it is effective inhibitor of cyclin dependent kinase (Cdks) and cell growth mediation kinases (growth mediated kinase).
WO01/64679 A1 discloses 1 of following formula, and 5-is dibasic-3,4-dihydro-1H-Mi Dingbing [4,5-D] pyrimidyl-2-ketone compound:
Figure C20038010697800191
It is said that it is effective in the kinase mediated disease of treatment CSBP/P38.
WO02/12237A2 discloses preparation 2-(4-pyridyl) amino-6-dialkoxy phenyl-pyrido [2,3-d] method of pyrimidin-7-ones, WO 02/12238 A2 discloses 2-(4-pyridyl) amino-6-dialkoxy phenyl-pyrido [2,3-d] pyrimidin-7-ones of formula (I)
Figure C20038010697800192
It is said that these compounds cause in the disease of non-controlling cell growth effectively in treatment.
Still need be used for the treatment of the effectively easy synthetic of the solid tumor of one or more types, the compound of small molecular weight in the kinase whose catalytic activity of arrestin, described protein kinase is FGFR and KDR especially.Urgent expectation provides the energy selectivity to suppress the inhibitor of the small molecular weight of FGFR and KDR.This is can provide better effectiveness because participate in effective same period of the restraining effect of the target spot of vasculogenesis.On the other hand, toxicity and other undesired complication may produce behind a plurality of target spots of inhibition.Preferably the inhibitor of small molecular weight also can have favourable bioavailability feature.Therefore, expectation provides such compound and contains these compound compositions.
The present invention relates to and selectivity to suppress KDR and the active new dihydropyridine ketone compound of FGFR.These compounds can be effectively used to treatment or control cancer, especially treatment or controlled entity knurl.Especially, the present invention relates to formula I and formula II compound:
Figure C20038010697800201
Condition is that Ar can not be the 2-pyridyl of 2-pyridyl or replacement.
The invention still further relates to and contain one or more formula I and the compound of formula II and the composition of pharmaceutically acceptable carrier or vehicle for the treatment of significant quantity.
The invention still further relates to formula I or the compound of II and/or the method that its pharmaceutical salts is treated solid tumor of bestowing the patient's significant quantity that needs treatment, described solid tumor is mastadenoma, lung knurl, prostate tumor or colon knurl especially.
The invention still further relates to the new intermediate compound in the preparation of formula I and formula II compound.
Following term should have following definitions as used herein:
" alkenyl " expression has the straight or branched aliphatic hydrocarbon of at least one group of carbon-carbon double bond, for example vinyl, crotyl and 3-methyl-2-butene base.
" alkynyl " expression has at least one group of carbon carbon triple-linked straight or branched aliphatic hydrocarbon, for example ethynyl and 2-butyne base.
" alkyl " expression has 1 to 10, and preferred 1 to 6, the more preferably saturated aliphatic hydrocarbon of straight or branched of 1 to 4 carbon atom.Alkyl with 1 to 6 carbon atom is also referred to as " low alkyl group " in this article.Low alkyl group comprises methyl, ethyl, propyl group, sec.-propyl, butyl, tert-butyl, 2-butyl, amyl group and hexyl.Specified C in the example as used herein 1-4Alkyl refers to have the alkyl of 1 to 4 carbon atom.
" alkoxyl group " refers to be connected to alkyl on the molecule residue, for example methoxyl group, oxyethyl group by oxygen (RO-).
" aryl " refers to the aromatic carbon cyclic group, for example 6-10 unit's aromatic ring or part aromatic ring system.The part aromatic ring system refers to a kind of system with two condensed ring, and wherein in two rings is an aromatic ring, for example tetrahydrochysene-naphthyl.Preferred aryl groups includes, but are not limited to phenyl, naphthyl, tolyl and xylyl.
" cycloalkyl " refers to contain the non-aromatics of 3 to 8 carbon atoms, partially or completely saturated annular aliphatic hydrocarbon.The example of cycloalkyl comprises cyclopropyl, cyclopentyl and cyclohexyl.
" significant quantity " or " treatment significant quantity " refers at least a compound or pharmaceutically acceptable salt thereof among formula I and the II or the consumption of ester.This amount can suppress to comprise the propagation of human tumour cell line's tumour cell significantly.
" halogen " refers to fluorine, chlorine, bromine, iodine, preferred chlorine or fluorine.
" heteroatoms " refers to be selected from the atom of N, O and S, preferred N.If heteroatoms is N, its can for-NH-or-the N-low alkyl group-.If heteroatoms is S, it can be S, SO or SO 2
" heteroaryl " refers to contain the aromatic nucleus system of 2 rings at the most.Preferred heteroaryl includes, but are not limited to thienyl, furyl, indyl, pyrryl, pyridyl, pyrazinyl, oxazolyl, thiaxolyl, quinolyl, pyrimidyl, imidazolyl and tetrazyl.
" heterocycle " or " heterocyclic radical " refer to have 1 to 3 heteroatomic 3-to 10-unit saturated or the undersaturated non-aromatic unit price of part cyclic group, described heteroatoms is selected from nitrogen, oxygen or sulphur or its combination.Preferred heterocyclic example is piperidines, piperazine, tetramethyleneimine and morpholine.
" hydroxyl " is the appellation of expression unit price OH base.
" IC 50" refer to that needs according to the present invention suppress the concentration of the active specific compound of 50% particular measurement.IC 50Can be determined, especially as hereinafter described in the embodiment 15.
" pharmaceutical salts " refers to conventional acid salt or base addition salt, the biological effectiveness and the character of the compound of its hold mode I, and it can be by suitable non-toxicity organic or inorganic acid or the preparation of organic or inorganic alkali.The example of acid salt comprises derived from mineral acid with derived from those salt of organic acid, described mineral acid is spirit of salt, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, phosphoric acid and nitric acid for example, and described organic acid is for example right-toluenesulphonic acids, Whitfield's ointment, methylsulfonic acid, oxalic acid, Succinic Acid, citric acid, toxilic acid, lactic acid, fumaric acid etc.The example of base addition salt comprises the salt derived from ammonium, potassium, sodium and quaternary ammonium hydroxide, for example tetramethyl ammonium hydroxide.With medicinal compound (being medicine) modification salify is physics and chemical stability, water absorbability, flowability and the deliquescent technology that the well-known acquisition compound of pharmacist improves.Pharmaceutical dosage form and drug delivery system (6th Ed.1995) the 196th and 1456-1457 page or leaf referring to people such as for example H.Ansel.
" pharmaceutically useful " for example the specific compound bestowed of finger such as pharmaceutically acceptable carrier, vehicle is pharmaceutically useful or atoxic basically.
" replacement " herein, the for example alkyl of Qu Daiing, low alkyl group, aryl, cycloalkyl, cyclophane base and heteroaryl, refer to replace and to take place in one or more positions, and except as otherwise noted, the substituting group that replaces the site at each is to be independently selected from specific position.
In one embodiment.The present invention relates to the compound or pharmaceutically acceptable salt thereof of formula I,
Figure C20038010697800221
Wherein Ar and Ar ' are independently selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement, and condition is for Ar, and described heteroaryl can not be the 2-pyridyl, and the heteroaryl that replaces can not be the 2-pyridyl that replaces;
R 1Be selected from:
H；
C 1-10Alkyl;
Independently by at the most three be selected from aryl, heteroaryl, heterocycle, cycloalkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 1-10Alkyl, wherein aryl, heteroaryl, heterocycle and cycloalkyl can be respectively independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2Substituting group replace;
Aryl;
Independently by at the most three be selected from low alkyl group, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The aryl that replaces of substituting group;
Heteroaryl;
Independently by at the most three be selected from low alkyl group, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The heteroaryl that replaces of substituting group;
Heterocycle;
Independently by at the most three be selected from low alkyl group, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The heterocycle that replaces of substituting group;
C 3-10Cycloalkyl;
Independently by three low alkyl group, NR that are selected from low alkyl group, replacement at the most 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 3-10Cycloalkyl;
C 2-10Alkenyl;
Independently by three cycloalkyl, heterocyclic radical, the Heterocyclylalkyl of replacement, NR that are selected from cycloalkyl, replacement at the most 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 2-10Alkenyl;
C 2-10Alkynyl; With
Independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 2-10Alkynyl;
R 8, R 9And R 10Be H or low alkyl group independently;
R 11And R 12Be independently selected from:
H；
Unsubstituted low alkyl group; By hydroxyl, alkoxyl group or NR 21R 22The low alkyl group that replaces;
Unsubstituted cycloalkyl; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The cycloalkyl that replaces;
Unsubstituted heterocycle; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The heterocycle that replaces;
Alternatively, NR 11R 12Formation has the ring of 3 to 7 atoms, and described ring does not have or have at least one other heteroatoms, and condition is if heteroatoms is N, and heteroatoms can be by one or more low alkyl group, OR of being selected from 13, COR 14, CO 2R 14, CONR 14R 15, SO 2R 14And SO 2NR 14R 15Substituting group replace;
R 13Be selected from:
H；
COR 14；
CONR 14R 15；
Unsubstituted low alkyl group; By hydroxyl, alkoxyl group or NR 21R 22The low alkyl group that replaces;
Unsubstituted cycloalkyl; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The cycloalkyl that replaces;
Unsubstituted heterocycle; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The heterocycle that replaces;
R 14And R 15Be independently selected from:
H；
Unsubstituted low alkyl group; By hydroxyl, alkoxyl group or NR 21R 22The low alkyl group that replaces;
Unsubstituted cycloalkyl; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The cycloalkyl that replaces;
Unsubstituted heterocycle; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The heterocycle that replaces;
Alternatively, NR 14R 15Formation has the ring of 3 to 7 atoms, and described ring does not have or have at least one heteroatoms, and condition is if heteroatoms is N, and heteroatoms can be by one or more low alkyl group, OR of being selected from 23, COR 23, CO 2R 23, CONR 23R 24, SO 2R 23, SO 2NR 23R 24Substituting group replace;
R 21Be selected from H, low alkyl group, COR 23Or CO 2R 23
R 22, R 23And R 24Be independently selected from H or low alkyl group;
Alternatively, NR 21R 22Or NR 23R 24Form the ring with 3 to 7 atoms independently, described ring does not have or has at least one other heteroatoms that is selected from N, O and S, and condition is if heteroatoms is N, heteroatoms can for-NH or NR 25Form, if heteroatoms is S, heteroatoms can be S (O) mForm, m=0,1 or 2 wherein;
R 25Be low alkyl group.
Ar is selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement, and condition is for Ar, and heteroaryl can not be the 2-pyridyl, and the heteroaryl that replaces can not be the 2-pyridyl that replaces.
Preferably, Ar is selected from aryl,
Quilt is 2 aryl that are selected from following substituting group replacement at the most, and described substituting group is selected from NR 11R 12OR 13SR 16Halogen; COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14CN; NO 2(CH 2) nHeteroaryl; (CH 2) nHeterocycle; C 1-C 10Alkyl; C 3-C 10Cycloalkyl; C 2-C 10Alkenyl; C 2-C 10Alkynyl; Wherein n is 0,1,2 or 3, and described heteroaryl, heterocycle, alkyl, cycloalkyl, alkenyl and alkynyl be unsubstituted or by at the most three be selected from NR 11R 12OR 13SR 16Halogen; COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14CN; And NO 2Substituting group replace.
Heteroaryl,
With by at the most two be selected from NR 11R 12OR 13SR 16Halogen; COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14CN; NO 2(CH 2) nHeteroaryl; (CH 2) nHeterocycle; C 1-C 10Alkyl; C 3-C 10Cycloalkyl; C 2-C 10Alkenyl; C 2-C 10The heteroaryl of alkynyl substituted, wherein n is 0,1,2 or 3, and described aryl, heteroaryl, heterocycle, alkyl, cycloalkyl, alkenyl and alkynyl be unsubstituted or by at the most three be selected from NR 11R 12OR 13SR 16Halogen; COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14CN and NO 2Substituting group replace,
Condition is for Ar, and described heteroaryl can not be the 2-pyridyl, and the heteroaryl of replacement can not be the 2-pyridyl that replaces.
In one embodiment, the present invention relates to the compound of formula I, wherein Ar is the heteroaryl of replacement, and condition is that the heteroaryl of described replacement can not be the 2-pyridyl.
In a preferred embodiment, the 3-pyridyl of Ar for replacing.
In another preferred embodiment, the present invention relates to the compound of formula I, wherein Ar ' is the aryl of aryl or replacement.
Preferably, Ar ' for aryl or by at the most four be selected from H; Unsubstituted low alkyl group is by the low alkyl group of hydroxyl, alkoxy or halogen replacement; NR 21R 22OR 23SR 23Halogen; NO 2COR 23CO 2R 23CONR 23R 24SO 2NR 23R 24SO 2R 23With the aryl that the substituting group of CN replaces, condition is when Ar is the 4-pyridine of 4-pyridyl or replacement, and Ar ' can not be for by OR 23The phenyl that replaces.
Preferably, Ar ' is the phenyl of phenyl or replacement.
More preferably, Ar ' for phenyl or by at the most four be selected from H; Unsubstituted low alkyl group is by the low alkyl group of hydroxyl, alkoxy or halogen replacement; NR 21R 22OR 23SR 23Halogen; NO 2COR 23CO 2R 23CONR 23R 24SO 2NR 23R 24SO 2R 23With the phenyl that the substituting group of CN replaces, condition is when Ar is the 4-pyridine of 4-pyridyl or replacement, and Ar ' can not be for by OR 23The phenyl that replaces.
In another embodiment, the present invention relates to the compound of formula I, wherein R 1Aryl or heteroaryl for aryl, replacement.
In a preferred embodiment, R 1Be phenyl.
In another embodiment, the present invention relates to the compound of formula I, wherein R 1Be C 1-10Alkyl or independently by at the most three be selected from aryl, heteroaryl, heterocycle, cycloalkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 1-10Alkyl, wherein said aryl, heteroaryl, heterocycle and cycloalkyl respectively independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2Substituting group replace R wherein 8, R 9, R 10, R 11And R 12Be H or low alkyl group independently.
In another embodiment, the present invention relates to have the compound or pharmaceutically acceptable salt thereof of formula II,
Wherein, R 1Be selected from:
H；
C 1-10Alkyl;
Independently by at the most three be selected from aryl, heteroaryl, heterocycle, cycloalkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 1-10Alkyl, wherein aryl, heteroaryl, heterocycle and cycloalkyl can be respectively independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2Substituting group replace;
Aryl;
Independently by at the most three be selected from low alkyl group, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The aryl that replaces of substituting group;
Heteroaryl;
Independently by at the most three be selected from low alkyl group, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The heteroaryl that replaces of substituting group;
Heterocycle;
Independently by at the most three be selected from low alkyl group, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The heterocycle that replaces of substituting group;
C 3-10Cycloalkyl;
Independently by three low alkyl group, NR that are selected from low alkyl group, replacement at the most 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 3-10Cycloalkyl;
C 2-10Alkenyl;
Independently by three cycloalkyl, heterocyclic radical, the Heterocyclylalkyl of replacement, NR that are selected from cycloalkyl, replacement at the most 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces 2-10Alkenyl;
C 2-10Alkynyl; With
Independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 2-10Alkynyl; And R 8, R 9And R 10Be H or low alkyl group independently;
R 2And R 3Be independently selected from:
NR 11R 12；
OR 13；
SR 16；
Halogen;
COR 14；
CO 2R 14；
CONR 14R 15；
SO 2NR 14R 15；
SO 2R 14；
CN；
NO 2；
(CH 2) nHeteroaryl;
(CH 2) nHeterocycle;
C 1-C 10Alkyl;
C 3-C 10Cycloalkyl;
C 2-C 10Alkenyl;
C 2-C 10Alkynyl;
Wherein n is 0,1,2 or 3, and described aryl, heteroaryl, heterocycle, alkyl, cycloalkyl, alkenyl and alkynyl be unsubstituted or by at the most three be selected from NR 11R 12OR 13SR 16Halogen; COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14CN; And NO 2Substituting group replace;
Alternatively, R 2And R 3Form the connected phenyl ring condensed ring with 3 to 7 atoms together, described ring does not have or has at least one other heteroatoms, and condition is that heteroatoms can be selected from low alkyl group by at least one if heteroatoms is N; By hydroxyl, alkoxyl group or NR 11R 12The low alkyl group that replaces; NR 11R 12OR 13SR 16COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14Replace with the substituting group of CN;
R 4, R 5, R 6, R 7And R 26Be independently selected from following radicals, wherein R 4, R 5, R 6, R 7And R 26In at least one is H, described group comprises:
H；
Unsubstituted low alkyl group; By the low alkyl group of hydroxyl, alkoxy or halogen replacement;
NR 21R 22；
OR 23；
SR 23；
Halogen;
NO 2；
COR 23；
CO 2R 23；
CONR 23R 24；
SO 2NR 23R 24；
SOR 23With
CN；
R 8, R 9And R 10Be H or low alkyl group independently;
R 11And R 12Be independently selected from:
H；
Unsubstituted low alkyl group; By hydroxyl, alkoxyl group or NR 21R 22The low alkyl group that replaces;
Unsubstituted cycloalkyl; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The cycloalkyl that replaces;
Unsubstituted heterocycle; With by hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The heterocycle that replaces;
Alternatively, NR 11R 12Formation has the ring of 3 to 7 atoms, and described ring does not have or have at least one other heteroatoms, and condition is if heteroatoms is N, and heteroatoms can be by one or more low alkyl group, COR of being selected from 14, CO 2R 14, CONR 14R 15, SO 2R 14And SO 2NR 14R 15Substituting group replace;
R 13Be selected from:
H；
COR 14；
CONR 14R 15；
Unsubstituted low alkyl group; By hydroxyl, alkoxyl group or NR 21R 22The low alkyl group that replaces;
Unsubstituted cycloalkyl; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The cycloalkyl that replaces;
Unsubstituted heterocycle; With by hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The heterocycle that replaces;
R 14And R 15Be independently selected from:
H；
Unsubstituted low alkyl group; By hydroxyl, alkoxyl group or NR 21R 22The low alkyl group that replaces;
Unsubstituted cycloalkyl; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The cycloalkyl that replaces;
Unsubstituted heterocycle; With by hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The heterocycle that replaces;
Alternatively, NR 14R 15Formation has the ring of 3 to 7 atoms, and described ring does not have or have at least one other heteroatoms, and condition is if heteroatoms is N, and heteroatoms can be by one or more low alkyl group, COR of being selected from 23, CO 2R 23, CONR 23R 24, SO 2R 23And SO 2NR 23R 23Substituting group replace;
R 16Be selected from:
Unsubstituted low alkyl group; By hydroxyl, alkoxyl group or NR 21R 22The low alkyl group that replaces;
Unsubstituted cycloalkyl; By hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The cycloalkyl that replaces;
Unsubstituted heterocycle; With by hydroxyl, alkoxyl group, low alkyl group or NR 21R 22The heterocycle that replaces;
R 21Be selected from H, low alkyl group, COR 23Or CO 2R 23
R 22, R 23And R 24Be independently selected from H or low alkyl group,
Alternatively, NR 21R 22Or NR 23R 24Form the ring with 3 to 7 atoms independently, described ring does not have or has at least one other heteroatoms that is selected from N, O and S, and condition is if heteroatoms is N, heteroatoms can for-NH or NR 25Form, if heteroatoms is S, heteroatoms can be S (O) mForm, m=0,1 or 2 wherein; With
R 25Be low alkyl group.
In a preferred embodiment, the present invention relates to wherein R 6Be OR 23The compound of formula II.
R wherein 4And R 26For the compound of the formula II of halogen also is preferred.
In a preferred embodiment, the present invention relates to wherein R 5And R 7Be OR 23The compound of formula II.
And, R wherein 26For the compound of the formula II of unsubstituted low alkyl group also is preferred.
In another preferred embodiment, the present invention relates to wherein R 4, R 5, R 6And R 26Compound for the formula II of H.
R wherein 5And R 26Be OR 23The compound of formula II also be preferred.
In another preferred embodiment, the present invention relates to wherein R 26Be OR 23The compound of formula II.
The compound of preferred formula II is R wherein 6And R 7Be OR 23Compound.
And, R wherein 6Be OR 23The compound of formula II be preferred.
According to the present invention, following compound is an embodiment preferred:
6-(4-methoxyl group-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 1f);
6-(2,6-two chloro-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 2c);
6-(3,5-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 3d);
8-phenyl-2-phenyl amino-6-O-tolyl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 4c);
6,8-phenylbenzene-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 5c);
6-(2,5-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 6c);
6-(2-methoxyl group-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 7c);
6-(3,5-di-trifluoromethyl-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 8d);
8-phenyl-2-phenyl amino-6-pyridin-4-yl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 9c);
8-phenyl-2-phenyl amino-6-pyridin-3-yl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 10c);
6-(3,4-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 11c);
6-(4-methoxyl group-phenyl)-2-(6-methoxyl group-pyridin-3-yl amino)-8-phenyl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 12d);
8-isobutyl--6-(4-methoxyl group-phenyl)-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 13b); With
8-cyclopropyl methyl-6-(4-methoxyl group-phenyl)-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones (embodiment 14b).
In one embodiment, the present invention relates to contain the compound of the formula I that treats significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier or vehicle.Preferably compound wherein is suitable for bestowing the patient's who suffers from cancer pharmaceutical composition.
In another embodiment, the present invention relates to treat method for cancer, comprise the above-claimed cpd of the patient treatment significant quantity of bestowing this treatment of needs.Described cancer is mammary cancer, lung cancer, colorectal carcinoma or prostate cancer.
In another embodiment, the present invention relates to control method for cancer, comprise the above-claimed cpd of the patient treatment significant quantity of bestowing this treatment of needs.Described cancer is mammary cancer, lung cancer, colorectal carcinoma or prostate cancer.
In another embodiment, the present invention relates to the purposes of compound in the medicine of preparation treatment and control cancer of formula I.Preferably, the present invention relates to the purposes of compound in the medicine of preparation treatment and control mammary cancer, lung cancer, colorectal carcinoma or prostate cancer of formula I.Most preferably, described cancer is mammary cancer or colorectal carcinoma.
In a preferred embodiment, the present invention relates to the method for preparation I compound, it comprises makes following formula: compound and acid-respons
Figure C20038010697800321
Wherein R is a low alkyl group, Ar, Ar ' and R 1Aforesaid definition obtains the compound of formula I as this paper
Figure C20038010697800322
Wherein Ar, Ar ' and R 1As the aforesaid definition of this paper, if desired, formula I compound is changed into its pharmaceutical salts.
The invention still further relates to the following new intermediate of the compound that is used for synthesis type I and formula II:
3-(2,4-two chloro-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (embodiment 1d);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (embodiment 1e);
2-(2,6-two chloro-phenyl)-3-(2,4-two chloro-pyrimidine-5-yl)-methyl propionate (embodiment 2a);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2,6-two chloro-phenyl)-methyl propionate (embodiment 2b);
3-(2,4-two chloro-pyrimidine-5-yl)-2-(3,5-dimethoxy-phenyl)-methyl propionate (embodiment 3b);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,5-dimethoxy-phenyl)-methyl propionate (embodiment 3c);
3-(2,4-two chloro-pyrimidine-5-yl)-2-O-tolyl-methyl propionate (embodiment 4a);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-O-tolyl-methyl propionate (embodiment 4b)
3-(2,4-two chloro-pyrimidine-5-yl)-2-phenyl-methyl propionate (embodiment 5a);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-phenyl-methyl propionate (embodiment 5b);
3-(2,4-two chloro-pyrimidine-5-yl)-2-(2,5-dimethoxy-phenyl)-ethyl propionate (embodiment 6a);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2,5-dimethoxy-phenyl) ethyl propionates (embodiment 6b);
3-(2,4-two chloro-pyrimidine-5-yl)-2-(2-methoxyl group-phenyl)-methyl propionate (embodiment 7a);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2-methoxyl group-phenyl) ethyl propionate (embodiment 7b);
2-(3,5-di-trifluoromethyl-phenyl)-3-(2,4-two chloro-pyrimidine-5-yl)-methyl propionate (embodiment 8b);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,5-di-trifluoromethyl-phenyl)-methyl propionate (embodiment 8c);
3-(2,4-two chloro-pyrimidine-5-yl)-2-pyridin-4-yl-ethyl propionate (embodiment 9a);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-pyridin-4-yl-ethyl propionate (embodiment 9b);
3-(2,4-two chloro-pyrimidine-5-yl)-2-pyridin-3-yl-ethyl propionate (embodiment 10a);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-pyridin-3-yl-ethyl propionate (embodiment 10b);
3-(2,4-two chloro-pyrimidine-5-yl)-2-(3,4-dimethoxy-phenyl)-ethyl propionate (embodiment 11a);
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,4-dimethoxy-phenyl)-ethyl propionate (embodiment 11b);
3-(4-chloro-2-phenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (embodiment 12a);
3-(2-chloro-4-phenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (embodiment 12b);
3-[2-(6-methoxyl group-pyridin-3-yl amino)-4-phenyl amino-pyrimidine-5-yl]-2-(4-methoxyl group-phenyl)-methyl propionate (embodiment 12c);
3-(2-phenyl amino-4-isobutylamino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (embodiment 13a); With
3-(2-phenyl amino-4-cyclopropyl methylamino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (embodiment 14a).
Compound of the present invention can prepare by ordinary method.The proper method of synthetic these compounds provides in an embodiment.Usually, the compound of formula I can be according to following synthetic route preparation.
Reaction scheme 1
Figure C20038010697800341
Reaction scheme 2
Reaction scheme 3
Figure C20038010697800343
Reaction scheme 4
Figure C20038010697800344
In another embodiment, the present invention relates to contain the medicinal compositions of at least one formula I compound or pharmaceutically acceptable salt thereof or ester.
These pharmaceutical compositions can be taken orally, for example the form of tablet, coating tablet, drageeing, hard or soft capsule, solution, emulsion or suspensoid.They also can rectal administration, for example form of suppository, or parenteral admin, for example form of injection liquid.
The pharmaceutical composition of the present invention that contains the compound or its salt of formula I and formula II can prepare with methods known in the art, for example with conventional mixing, enclose capsule, dissolving, granulation, emulsification, seal (entrapping), system drageeing or freeze-drying.These pharmaceutical preparations can with therapeutic inertia, inorganic or organic carrier preparation.Lactose, W-Gum or derivatives thereof, talcum, stearic acid or its salt can be used as the carrier that is used for tablet, coating tablet, drageeing and hard gelatin capsule.The appropriate carrier that is used to prepare soft capsule comprises vegetables oil, wax and fatty oil.According to the character of activeconstituents, when the preparation soft capsule, do not need carrier usually.The appropriate carrier that is used for solution or syrup is water, polyvalent alcohol, Nulomoline and lactose.The appropriate carrier that is used for injection is water, alcohol, polyvalent alcohol, glycerine, vegetables oil, phosphoric acid and tensio-active agent.The appropriate carrier that is used for suppository is natural oil or winterized stearin, wax, fatty oil and semi-solid polyvalent alcohol.
Pharmaceutical preparation also can contain sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, seasonings, the salt that is used to improve osmotic pressure, buffer reagent, Drug coating or antioxidant.They also can contain the valuable material of other therapeutics, comprise other activeconstituents different with formula II compound with formula I.
The compound that the invention still further relates to formula I and formula II is used for the treatment of cancer, the purposes of mammary cancer, lung cancer, colorectal carcinoma and prostate cancer especially, and it is realized by the formula I compound or its salt of bestowing the patient treatment significant quantity that needs this treatment.
As mentioned above, compound of the present invention (compound that comprises formula I and formula II) is used for the treatment of or controls especially tumor disease of cell breeding disease.These compounds and the preparation that contains described compound are in treatment or controlled entity knurl, and be for example particularly useful in mastadenoma, lung knurl, colon knurl and the prostate tumor.Therefore, the invention still further relates to by bestowing the formula I that suffers from significant quantity that needs treatment and the method for formula II compound and/or the described solid tumor of its salts for treating.
According to the present invention, the compound of treatment significant quantity refers to that the consumption of compound is used to prevent, slow down or the life that improves the symptom of disease or prolong the patient who is treated is effective.Determine the treatment significant quantity by those skilled in the art.
Treatment significant quantity or dosage according to compound of the present invention can change in wide scope, and it can be determined with means known in the art.This dosage is adjusted according to individual need under every kind of particular case, and described particular case comprises particular compound, route of administration, situation of bestowing of being treated and the patient who is treated.Usually, when oral or parenteral were bestowed the grownup of about 70Kg, about 10mg was to about 10,000mg, and preferably about 200mg is to about 1, and the dosage of 000mg should be suitable, although when indicating, the upper limit may exceed.Every day, dosage can be determined with individually dosed or separate doses, perhaps for administered parenterally, can give with the form that continues infusion.
Embodiment
Following embodiment explains the preferable methods that is used for synthetic compound of the present invention and preparation.
Embodiment 1a
5-(methylol)-1,3-dihydro-pyrimidin-2,4-diketone
Figure C20038010697800361
To 2-L, mechanical stirrer, thermometer, condenser are housed and advance the uridylic (185.0g that packs in the three-necked flask of nitrogen bubbler, 1650mMol) (Aldich), paraformaldehyde (61.50g, be equivalent to formaldehyde 2050mMol, and potassium hydroxide (86.9% (Aldrich)), 59.95g, the 928.5mMol) aqueous solution of (Aldrich) (1.445L).Under 50-52 ℃, stirred the mixture 68 hours.TLC analysis revealed complete reaction.When under 6 ℃/14mm Hg, being concentrated into the about 500mL of volume, resistates is diluted with acetone (500mL).Filter and collect the precipitation that obtains,, under 50 ℃/25mM Hg, obtain crude product 5-(methylol)-1,3-dihydro-pyrimidin-2,4-diketone (250g), white solid then with washing with acetone and by the suction strainer drying.Blended mother liquor and washings are concentrated into the about 100mL of volume, add hydroxylamine hydrochloride (27.52g, 396.0mMol, aqueous solution Aldrich) (100mL).Filter and collect the precipitation that obtains, use washing with acetone, and dry second part of crude product 5-(methylol)-1,3-dihydro-pyrimidin-2,4-diketone (34g), the white solid of obtaining of suction strainer.Mix two parts of products (244g, 4% weight), be directly used in next step.
Embodiment 1b
2,4-two chloro-5-(chloromethyl) pyrimidines
Figure C20038010697800371
Attention: this compound is a highly corrosive agents.
To 1-L, mechanical stirrer, feed hopper, thermometer are housed and advance the crude product 5-(methylol)-1 that packs in the three-necked flask of nitrogen bubbler, 3-dihydro-pyrimidin-2,4-diketone (50.25g, about 340mMol) (from the above embodiments la), phosphorus oxychloride (164.8mL, 1768mMol) (Aldrich) and toluene (100mL).Added N in 10 minutes in this mixture, (184.7mL, 1060mMol) (Aldrich) use water-bath to keep the temperature of mixture to be lower than 70 ℃ to the N-diisopropylethylamine simultaneously.After adding is finished, remove cooling tank, with mixture heating up backflow (113-116 ℃) 1 hour.Remove toluene (about 35mL) by ℃ distillation of rising reaction mixture temperature to 120, mixture stirred 5 hours at 120-123 ℃.The TLC analysis revealed reacts completely.After mixture is cooled to ambient temperature overnight, in two-phase mixture, use ice-water bath to maintain the temperature at 17 ℃ to 21 ℃ simultaneously more than water (200mL) that mixture was joined carefully in 67 minutes stirring and isopropyl acetate (150mL).At 18-21 ℃ and every now and then with after stirring 80 minutes under the frozen water cooling, with toluene (4 * 150mL) extraction mixtures.Dry (sodium sulfate) blended organic phase is filtered, and under reduced pressure is concentrated into drying then, obtains crude product 2,4-two chloro-5-(chloromethyl)-pyrimidines, and white solid contains polar impurity.(productive rate 56.1g, 83.6% productive rate is from uridylic).
With crude product 2,4-two chloro-5-(chloromethyl) pyrimidines (70.39g) are dissolved in the methylene dichloride (80mL), and the solution of acquisition filters by a slice TLC gradient silica gel (100g).Use methylene dichloride then: hexane (1L, 7: 3) eluting silica gel under reduced pressure is concentrated into drying with blended filtrate and elutriant and obtains 2,4-two chloro-5-(chloromethyl) pyrimidines, white solid.
(69.8% overall yield is from uridylic for productive rate 58.77g, 83.5% rate of recovery).
Embodiment 1c
2,4-two chloro-5-(iodomethyl) pyrimidines
Figure C20038010697800372
To 500-mL, magnetic stirrer, condenser are housed and advance pack in the round-bottomed flask of nitrogen bubbler sodium iodide (38.5g, 256.9mMol) (Aldrich) and acetone (300mL).After obtaining settled solution, disposable adding 2,4-two chloro-5-(chloromethyl) pyrimidine (50.0g, 253.2mMol) (from the above embodiments 1b)., after 20 minutes mixture heating up was refluxed 15 minutes in stirring at room.NMR analysis revealed 98% transforms.After being cooled to room temperature, the precipitation (sodium-chlor) that obtains being removed by filter by medium-sized-sintered glass funnel, and use washing with acetone.Blended filtrate and washings are concentrated into about 75g weight.Spissated 2 with what obtain, the acetone soln of 4-two chloro-5-(iodomethyl) pyrimidines is with toluene (20mL) dilution.
Be concentrated into about 85g so that after removing remaining acetone, this is spissated 2, and the toluene solution of 4-two chloro-5-(iodomethyl) pyrimidines can be directly used in next step.
Embodiment 1d
3-(2,4-two chloro-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate
Figure C20038010697800381
Under 78 ℃ and nitrogen, (720mg, 5.0mMol) (10mL) just adding-butyllithium (hexane solution of 2.5M, 2.0mL, 5.0mMol) (Aldrich) in the anhydrous tetrahydrofuran solution of (Aldrich) to N-sec.-propyl hexahydroaniline.After 30 minutes, by injector to inject add 4-p-methoxy-phenyl methyl acetate (900mg, the 5.0mMol) tetrahydrofuran solution of (Aldrich) (3mL), under-78 ℃, reaction mixture restir 30 minutes.At-78 ℃, in this reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (722.5mg, 2.5mMol) tetrahydrofuran solution (3mL) of (from the above embodiments 1c), stirred reaction mixture is 1 hour under same temperature, slowly is warming up to-30 ℃ then, and stirs 10 minutes.(100mL) dilutes this reaction mixture with ethyl acetate, and uses saturated aqueous ammonium chloride solution (50mL), water (30mL) and salt solution (30mL) washing continuously, uses anhydrous sodium sulfate drying, filters and vacuum concentration.Resistates obtains 3-(2,4-two chloro-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate, yellow oily by the rapid column chromatography purifying.(productive rate 620mg, 72.7%).
Embodiment 1e
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate
Figure C20038010697800391
At 110 ℃, (0.54g, 1.58mMol) (0.67g, 7.11mmol) mixture of (Aldrich) heat is 30 minutes for (from the above embodiments 1d) and aniline with 3-(2,4-two chloro-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate.With hexane (50mL * 3) diluted reaction mixture, decant supernatant liquid after each washing.Resistates is dissolved in the ethyl acetate (100mL), and uses saturated aqueous ammonium chloride solution (30mL), water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Crude product obtains 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate, white amorphous solid by rapid column chromatography (silica gel) purifying.(productive rate 0.49g, 68.1%).
Embodiment 1f
6-(4-methoxyl group-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
Figure C20038010697800392
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (227.3mg, 0.5mMol) the disposable adding vitriol oil (0.2mL) in Glacial acetic acid (15mL) solution of (from the above embodiments 1e).With this reaction mixture 80 ℃ of heated overnight.Use ethyl acetate (50mL) to dilute this reaction mixture then, and react with the cancellation of 2N aqueous sodium hydroxide solution.Separate organic layer, water (10mL) and salt solution (10mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration, obtain crude product, recrystallization obtains 6-(4-methoxyl group-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2 from ethyl acetate-hexane, 3-d] pyrimidin-7-ones, brown crystalline solid.(productive rate 174.2mg, 82.4%).
HRMS m/z C 26H 22N 40 2[(M+H) +] theoretical value: 423.1816.Measured value: 423.1817.
Embodiment 2a
2-(2,6-two chloro-phenyl)-3-(2,4-two chloro-pyrimidine-5-yl)-methyl propionate
Figure C20038010697800401
Under-78 ℃ and argon gas, (1.44g, 10.0mMol) (20mL) just adding-butyllithium (hexane solution of 2.5M, 4.0mL, 10.0mMol) (Aldrich) in the anhydrous tetrahydrofuran solution of (Aldrich) to N-sec.-propyl hexahydroaniline.After 30 minutes, add 2 by injector to inject, and 6-two chloro-phenylacetic acid methyl esters (2.19g, the 10.0mMol) tetrahydrofuran solution of (TCI-US) (5mL), under-78 ℃, reaction mixture restir 30 minutes.Under-78 ℃, in this reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (1.45g, 5.0mMol) tetrahydrofuran solution (5mL) of (from the above embodiments 1c), stirred reaction mixture is 1 hour under same temperature, slowly is warming up to-30 ℃ then, and stirs 10 minutes.(100mL) dilutes this reaction mixture with ethyl acetate, and uses saturated aqueous ammonium chloride solution (100mL), water (50mL) and salt solution (50mL) washing continuously, uses anhydrous sodium sulfate drying, filters and vacuum concentration.Resistates obtains 2-(2,6-two chloro-phenyl)-3-(2,4-two chloro-pyrimidine-5-yl)-methyl propionate, colorless oil by the rapid column chromatography purifying.(productive rate 1.57g, 82.6%).
Embodiment 2b
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2,6-two chloro-phenyl)-methyl propionate
Figure C20038010697800402
At 110 ℃, (0.20g, 0.53mMol) (from the above embodiments 2a) and aniline (2.0ml) mixture heating up (Aldrich) are 2 hours with 2-(2,6-two chloro-phenyl)-3-(2,4-two chloro-pyrimidine-5-yl)-methyl propionate.Wash this reaction mixture with hexane (50mL * 3), and after each washing, decant supernatant liquid.Then resistates is dissolved in ethyl acetate (100mL), continuously with saturated aqueous ammonium chloride solution (30mL), water (30mL) and salt solution (30mL) washing, use anhydrous sodium sulfate drying, filter and vacuum concentration acquisition crude product 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2,6-two chloro-phenyl)-and methyl propionate, brown caramel need not be further purified and promptly can be used for next step.(productive rate 0.18g, 69.3%).
Embodiment 2c
6-(2,6-two chloro-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3d] pyrimidin-7-ones
Figure C20038010697800411
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2,6-two chloro-phenyl)-methyl propionate (0.18g, 0.36mMol) disposable adding vitriol oil (0.1mL) in the glacial acetic acid solution (2mL) of (from the above embodiments 2b).Spend the night at 135 ℃ of these reaction mixtures of heating, and 145 ℃ of reheat 4 hours.After the cooling, with ethyl acetate (50mL) diluted reaction mixture, with 2N aqueous sodium hydroxide solution cancellation reaction.Separate organic layer, water (10mL) and salt solution (10mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration acquisition crude product, obtain 6-(2,6-two chloro-phenyl)-8-phenyl-2-phenyl amino-5 with ethyl acetate-hexane recrystallization, 8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, gray solid (productive rate 61.2mg, 36.3%).
HRMS m/z, C 25H 18C 12N 4The theoretical value of O (M+): 461.0931.Measured value: 461.0934.
Embodiment 3a
3,5-Dimethoxyphenyl methyl acetate
Figure C20038010697800412
To 3, (1.99g 10.0mMol) adds the vitriol oil (1.0mL) to 5-dimethoxy benzene guanidine-acetic acid in the methanol solution of (Transworld) (20mL), the reacting by heating mixture was refluxed 24 hours.This reaction mixture of vacuum concentration, then resistates is diluted with ethyl acetate (100mL), water (50mL) and salt solution (50mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration acquisition crude product 3,5-Dimethoxyphenyl methyl acetate, dark oil need not be further purified and just can be used for next step.(productive rate 2.05g, 97.6%).
Embodiment 3b
3-(2,4-two chloro-pyrimidine-5-yl)-2-(3,5-dimethoxy-phenyl)-methyl propionate
Figure C20038010697800421
Under-78 ℃ and argon gas, (1.44g 10.0mMol) is just adding in the anhydrous tetrahydrofuran solution of (Aldrich) (20mL)-butyllithium (hexane solution of 2.5M, 4.0mL, 10.0mmol) (Aldrich) to N-sec.-propyl hexahydroaniline.After 30 minutes, inject 3 by syringe, and 5-dimethoxy-phenyl-acetic acid methyl esters (2.05g, the 9.76mMol) tetrahydrofuran solution (5mL) of (from the above embodiments 3a), under-78 ℃, restir reaction mixture 30 minutes.At-78 ℃, in this reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (1.45g, 5.0mMol) tetrahydrofuran solution (5mL) of (from the above embodiments 1c), and under same temperature stirred reaction mixture 1 hour, slowly be warming up to-30 ℃ then, and stirred 10 minutes.With ethyl acetate (100mL) diluted reaction mixture, use saturated aqueous ammonium chloride solution (100mL), water (50mL) and salt solution (50mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Resistates obtains 3-(2,4-two chloro-pyrimidine-5-yl)-2-(3,5-dimethoxy-phenyl)-methyl propionate, colorless oil by the rapid column chromatography purifying.(productive rate 1.45g, 78.0%).
Embodiment 3c
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,5-dimethoxy-phenyl)-methyl propionate
Figure C20038010697800431
At 110 ℃, (186mg, 0.50mMol) (from the above embodiments 3b) and aniline (2.0mL) mixture heating up (Aldrich) are 2 hours with 3-(2,4-two chloro-pyrimidine-5-yl)-2-(3,5-dimethoxy-phenyl)-methyl propionate.Wash this reaction mixture with hexane (50mL * 3), and after each washing, decant supernatant liquid.Resistates is dissolved in ethyl acetate (100mL), and use saturated aqueous ammonium chloride solution (30mL), water (30mL) and salt solution (30mL) to wash continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration acquisition crude product 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,5-dimethoxy-phenyl)-and methyl propionate, pale solid need not be further purified and just can be used for next step.(productive rate 241.5mg, 99.7%).
Embodiment 3d
6-(3,5-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
Figure C20038010697800432
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,5-dimethoxy-phenyl)-methyl propionate (0.11mg, 0.23mMol) the disposable adding vitriol oil (0.1mL) in the glacial acetic acid solution (2mL) of (from the above embodiments 3c).Under 120 ℃, the reacting by heating mixture overnight.Use ethyl acetate (50mL) dilution then, and react with the cancellation of 2N aqueous sodium hydroxide solution.Separate organic layer, water (10mL) and salt solution (10mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration acquisition crude product, obtain 6-(3,5-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2 with ethyl acetate-hexane recrystallization, 3-d] pyrimidin-7-ones, light brown solid.(productive rate 73.3mg, 71.4%).
HRMS m/z C 27H 24N 4O 3[(M+H) +] theoretical value: 453.1921.Measured value: 453.1926.
Embodiment 4a
3-(2,4-two chloro-pyrimidine-5-yl)-2-O-tolyl-methyl propionate
Figure C20038010697800441
Under-78 ℃ and argon gas, (1.44g 10.0mMol) is just adding in the anhydrous tetrahydrofuran solution of (Aldrich) (20mL)-butyllithium (hexane solution of 2.5M, 4.0mL, 10.0mMol) (Aldrich) to N-sec.-propyl hexahydroaniline.After 30 minutes, by syringe inject O-tolyl-methyl acetate (1.64g, the 10.0mMol) tetrahydrofuran solution of (Lancaster) (5mL), under-78 ℃, restir reaction mixture 30 minutes.Under-78 ℃, in this reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (1.45g, 5.0mMol) tetrahydrofuran solution (5mL) of (from the above embodiments 1c), under same temperature, reaction mixture stirred 1 hour, slowly be warming up to-30 ℃ then, and stirred 10 minutes.With ethyl acetate (100mL) diluted reaction mixture, use saturated aqueous ammonium chloride solution (100mL), water (50mL) and salt solution (50mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Resistates obtains 3-(2,4-two chloro-pyrimidine-5-yl)-2-O-tolyl-methyl propionate, colorless oil by the rapid column chromatography purifying.(productive rate 1.25g, 77.2%).
Embodiment 4b
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-O-tolyl-methyl propionate
Under 120 ℃, (0.28g, 0.86mMol) (from the above embodiments 4a) and aniline (2.0mL) mixture heating up (Aldrich) are 1 hour with 3-(2,4-two chloro-pyrimidine-5-yl)-2-O-tolyl-methyl propionate.Wash this reaction mixture with hexane (50mL * 3), and after each washing, decant supernatant liquid.The solid that filter to collect obtains with the ether washing, obtains crude product 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-O-tolyl-methyl propionate, and white solid need not be further purified and just can be used for next step.(productive rate 412mg).
Embodiment 4c
8-phenyl-2-phenyl amino-6-O-tolyl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-O-tolyl-methyl propionate (170mg, 0.39mMol) the disposable adding vitriol oil (0.2mL) in the glacial acetic acid solution (3mL) of (from the above embodiments 4b).Under 110 ℃, with this reacting by heating mixture overnight. use ethyl acetate (50mL) dilution then, and react with the cancellation of 2N aqueous sodium hydroxide solution. separate the washing of continuous water of organic layer (10mL) and salt solution (10mL), use anhydrous sodium sulfate drying, filtration and vacuum concentration.Obtain crude product,, obtain 8-phenyl-2-phenyl amino-6-O-tolyl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, white solid with ethyl acetate-hexane recrystallization.(productive rate 122.6mg, 77.7%).
HRMS m/z C 26H 22N 4O[(M+H) +] theoretical value: 407.1867.Measured value 407.1866.
Embodiment 5a
3-(2,4-two chloro-pyrimidine-5-yl)-2-phenyl-methyl propionate
Under-78 ℃ and argon gas, (1.44g 10.0mMol) is just adding in the anhydrous tetrahydrofuran solution of (Aldrich) (20mL)-butyllithium (hexane solution of 2.5M, 4.0mL, 10.Ommol) (Aldrich) to N-sec.-propyl hexahydroaniline.After 30 minutes, inject phenylacetic acid methyl esters (1.50g, the 10.0mMol) tetrahydrofuran solution of (Aldrich) (5mL), and under-78 ℃, restir reaction mixture 30 minutes by syringe.Under-78 ℃, in this reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (1.45g, 5.0mMol) tetrahydrofuran solution (5mL) of (from the above embodiments 1c supra), under same temperature, reaction mixture stirred 1 hour, slowly was warming up to-30 ℃ then, and stirred 10 minutes.With ethyl acetate (100mL) diluted reaction mixture, use saturated aqueous ammonium chloride solution (100mL), water (50mL) and salt solution (50mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Resistates obtains 3-(2,4-two chloro-pyrimidine-5-yl)-2-phenyl-methyl propionate, colorless oil by the rapid column chromatography purifying.(productive rate 1.00g, 64.5%).
Embodiment 5b
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-phenyl-methyl propionate
Figure C20038010697800461
Under 120 ℃, (0.31g, 1.0mMol) (from embodiment 5a supra) and aniline (3.0mL) mixture heating up (Aldrich) are 1 hour with 3-(2,4-two chloro-pyrimidine-5-yl)-2-phenyl-methyl propionate.Wash this reaction mixture with hexane (50mL * 3), and after each washing, decant supernatant liquid.Then resistates is dissolved in ethyl acetate (100mL), uses saturated aqueous ammonium chloride solution (30mL), water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Crude product obtains 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-phenyl-methyl propionate, white amorphous solid by rapid column chromatography (silica gel) purifying.(productive rate 0.35g, 82.3%).
Embodiment 5c
6,8-phenylbenzene-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
Figure C20038010697800471
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-phenyl-methyl propionate (100mg, the glacial acetic acid solution (3mL) of (from the above embodiments 5b) disposable adding 5% vitriol oil in solution 0.24mMol).At 60 ℃, with this reacting by heating mixture overnight.After the cooling, (50mL) dilutes this reaction mixture with ethyl acetate, and reacts with the cancellation of 2N aqueous sodium hydroxide solution.Organic layer is continuous water (10mL) and salt solution (10mL) washing respectively, uses anhydrous sodium sulfate drying, filters and vacuum concentration, obtains crude product, with ethyl acetate-hexane recrystallization, obtain 6,8-phenylbenzene-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, light brown solid.(productive rate 61.2mg, 66.2%).HRMSm/z C 25H 20N 4O[(M+H) +] theoretical value: 393.1710.Measured value: 393.1714.
Embodiment 6a
3-(2,4-two chloro-pyrimidine-5-yl)-2-(2,5-dimethoxy-phenyl)-ethyl propionate
Figure C20038010697800472
Under-78 ℃ and argon gas, (1.44g 10.0mMol) is just adding in the anhydrous tetrahydrofuran solution of (Aldrich) (20mL)-butyllithium (hexane solution of 2.5M, 4.0mL, 10.Ommol) (Aldrich) to N-sec.-propyl hexahydroaniline.After 30 minutes, inject 2 by syringe, 5-Dimethoxyphenyl ethyl acetate (2.24g, the 10.0mMol) tetrahydrofuran solution of (Aldrich) (5mL), and under-78 ℃, restir reaction mixture 30 minutes.Under-78 ℃, in this reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (1.45g, 5.0mMol) tetrahydrofuran solution (5mL) of (from the foregoing description 1c), under same temperature, reaction mixture stirred 1 hour, slowly be warming up to-30 ℃ then, and stirred 10 minutes.With ethyl acetate (100mL) diluted reaction mixture, use saturated aqueous ammonium chloride solution (100mL), water (50mL) and salt solution (50mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Resistates obtains 3-(2,4-two chloro-pyrimidine-5-yl)-2-(2,5-dimethoxy-phenyl)-ethyl propionate, colorless oil by the rapid column chromatography purifying.(productive rate 1.00g, 51.9%).
Embodiment 6b
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2,5-dimethoxy-phenyl) ethyl propionate
Figure C20038010697800481
(0.36g, 0.94mMol) (from the foregoing description 6a) and aniline (2.0mL) mixture heating up (Aldrich) are 2 hours with 3-(2,4-two chloro-pyrimidine-5-yl)-2-(2,5-dimethoxy-phenyl)-ethyl propionate under 120 ℃.Wash this reaction mixture with hexane (50mL * 3), and after each washing, decant supernatant liquid.Resistates is dissolved in the ethyl acetate (100mL), and uses saturated aqueous ammonium chloride solution (30mL), water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Crude product and ethyl acetate-hexane are ground.Filter and collect the solid that obtains.With ether washing, obtain 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2,5-dimethoxy-phenyl) ethyl propionate, yellow solid need not be further purified and just can be used for next step.(productive rate 437.6mg, 93.9%).
Embodiment 6c
6-(2,5-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
Figure C20038010697800482
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2,5-dimethoxy-phenyl) ethyl propionate (100mg, 0.20mMol) glacial acetic acid solution (2mL) of disposable adding 5% vitriol oil in (from the above embodiments 6b).In 110 ℃ of reacting by heating mixtures 2.5 hours.Use ethyl acetate (50mL) dilution then, and react with the cancellation of 2N aqueous sodium hydroxide solution.Separate organic layer, water (10mL) and salt solution (10mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration, obtain crude product, with ethyl acetate-hexane recrystallization, obtain 6-(2,5-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, pale solid.(productive rate 75.6mg, 83.5%).
HRMS m/z:C 27H 24N 40 3The theoretical value of [(M+H)+]: 453.1921.Measured value: 453.1925.
Embodiment 7a
3-(2,4-two chloro-pyrimidine-5-yl)-2-(2-methoxyl group-phenyl)-methyl propionate
Under-78 ℃ and argon gas, (1.44g 10.0mMol) is just adding in the anhydrous tetrahydrofuran solution of (Aldrich) (20mL)-butyllithium (hexane solution of 2.5M, 4.0mL, 10.0mmol) (Aldrich) to N-sec.-propyl hexahydroaniline.After 30 minutes, by syringe inject 2-p-methoxy-phenyl methyl acetate (1.8g, the 10.0mMol) tetrahydrofuran solution of (TCI-US) (5mL), under-78 ℃, restir reaction mixture 30 minutes.Under-78 ℃, in reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (1.45g, 5.0mMol) tetrahydrofuran solution (5mL) of (from the above embodiments 1c), under same temperature, reaction mixture stirred 1 hour, slowly be warming up to-30 ℃ then, and stirred 10 minutes.With ethyl acetate (100mL) diluted reaction mixture, use saturated aqueous ammonium chloride solution (100mL), water (50mL) and salt solution (50mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Resistates obtains 3-(2,4-two chloro-pyrimidine-5-yl)-2-(2-methoxyl group-phenyl)-methyl propionate, yellow oily by the rapid column chromatography purifying.(productive rate 1.40g, 82.3%).
Embodiment 7b
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2-methoxyl group-phenyl) ethyl propionate
Figure C20038010697800501
Under 120 ℃, (0.34g, 1.0mMol) (from the above embodiments 7a) and aniline (2.0mL) mixture heating up (Aldrich) are 1 hour with 3-(2,4-two chloro-pyrimidine-5-yl)-2-(2-methoxyl group-phenyl)-methyl propionate.Wash this reaction mixture with hexane (50mL * 3), and after each washing, decant supernatant liquid.Resistates is dissolved in the ethyl acetate (100mL), uses saturated aqueous ammonium chloride solution (30mL), water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Crude product and ethyl acetate-hexane grinds.The solid that filter to collect obtains with the ether washing, obtains 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2-methoxyl group-phenyl) methyl propionate, and yellow solid need not be further purified and just can be used for next step.(productive rate 340.0mg, 74.9%).
Embodiment 7c
6-(2-methoxyl group-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
Figure C20038010697800502
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2-dimethoxy-phenylpropionic acid methyl esters (181.8mg, 0.40mMol) glacial acetic acid solution (3mL) of disposable adding 5% vitriol oil in (from the above embodiments 7b).Under 110 ℃, with reaction mixture heating 3 hours.After the cooling, with ethyl acetate (100mL) diluted reaction mixture, with 2N aqueous sodium hydroxide solution cancellation reaction.Separate organic layer, anhydrous sodium sulfate drying is used in water (30mL) and salt solution (30mL) washing continuously, filters and vacuum concentration acquisition crude product.Crude product obtains 6-(2-methoxyl group-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, pale solid with ethyl acetate-hexane recrystallization.(productive rate 119.4mg, 67.2%).
HRMS m/z C 26H 22N 4O 2(M +) theoretical value: 422.1743.Measured value: 422.1747.
Embodiment 8a
3,5-di-trifluoromethyl phenylacetic acid methyl esters
Figure C20038010697800511
To 3, (3.0g 11.03mMol) adds the vitriol oil (1.0mL) to 5-di-trifluoromethyl phenylacetic acid in the methanol solution of (Aldrich) (20mL), the reacting by heating mixture is refluxed spend the night.The vacuum concentration reactant, resistates dilutes with ethyl acetate (100mL), and anhydrous sodium sulfate drying is used in water (50mL) and salt solution (50mL) washing continuously, filters and vacuum concentration.Thick material obtains 3,5-di-trifluoromethyl phenylacetic acid methyl esters, colorless oil by the rapid column chromatography purifying.(productive rate 2.27g, 72.1%).
Embodiment 8b
2-(3,5-di-trifluoromethyl-phenyl)-3-(2,4-two chloro-pyrimidine-5-yl)-methyl propionate
Under-78 ℃ and argon gas, (1.44g 10.0mMol) is just adding in the anhydrous tetrahydrofuran solution of (Aldrich) (20mL)-butyllithium (hexane solution of 2.5M, 4.0mL, 10.0mmol) (Aldrich) to N-sec.-propyl hexahydroaniline.After 10 minutes, inject 3 by syringe, 5-di-trifluoromethyl phenylacetic acid methyl esters (2.20g, the 7.7mMol) tetrahydrofuran solution (5mL) of (from embodiment 8a supra), and under-78 ℃, restir reaction mixture 10 minutes.At-78 ℃, in reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (1.45g, 5.0mMol) tetrahydrofuran solution (5mL) of (from the above embodiments 1c), and, slowly be warming up to-20 ℃ then same temperature stirred reaction mixture 2 hours, stirred 10 minutes.With ethyl acetate (100mL) diluted reaction mixture, use saturated aqueous ammonium chloride solution (100mL), water (50mL) and salt solution (50mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Resistates obtains 2-(3,5-di-trifluoromethyl-phenyl)-3-(2,4-two chloro-pyrimidine-5-yl)-methyl propionate, colorless oil by the rapid column chromatography purifying.(productive rate 1.71g, 76.5%).
Embodiment 8c
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,5-di-trifluoromethyl-phenyl)-methyl propionate
Figure C20038010697800521
Under 120 ℃, (0.35g, 0.78mMol) (from the above embodiments 8b) and aniline (2.0mL) mixture heating up (Aldrich) are 1 hour with 2-(3,5-di-trifluoromethyl-phenyl)-3-(2,4-two chloro-pyrimidine-5-yl)-methyl propionate.Wash this reaction mixture with hexane (50mL * 3), and after each washing, decant supernatant liquid.Resistates is dissolved in the ethyl acetate (100mL), uses saturated aqueous ammonium chloride (30mL), water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Then crude product and ethyl acetate-hexane are ground.The solid that filter to collect obtains with the ether washing, obtains crude product 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,5-di-trifluoromethyl-phenyl)-methyl propionate, and pale solid need not be further purified and just can be used for next step.(productive rate 0.47g).
Embodiment 8d
6-(3,5-di-trifluoromethyl-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3d] pyrimidin-7-ones
Figure C20038010697800522
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,5-di-trifluoromethyl-phenyl)-methyl propionate (0.20g, 0.36mMol) glacial acetic acid solution (3mL) of disposable adding 5% vitriol oil in (from the above embodiments 8c).Under 120 ℃, reacting by heating mixture 3 hours.Use ethyl acetate (100mL) diluted reaction mixture then, with 2N aqueous sodium hydroxide solution cancellation reaction.Separate organic layer, and continuously water (30mL) and salt solution (anhydrous sodium sulfate drying is used in the 30mL washing, filtration and vacuum concentration.Obtain crude product,, obtain 6-(3,5-di-trifluoromethyl-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, pale solid with ethyl acetate-own recrystallization.(productive rate 130.3mg, 70.5%).
HRMSm/z C 27H 18F 6N 4O[(M+H) +] theoretical value: 529.1458.Measured value: 529.1464.
Embodiment 9a
3-(2,4-two chloro-pyrimidine-5-yl)-2-pyridin-4-yl-ethyl propionate
Figure C20038010697800531
Under-78 ℃ and argon gas, (720mg 5.0mMol) is just adding in the anhydrous tetrahydrofuran solution of (Aldrich) (10mL)-butyllithium (hexane solution of 2.5M, 2.0mL, 5.0mMol) (Aldrich) to N-sec.-propyl hexahydroaniline.After 30 minutes, by syringe inject 4-pyridyl ethyl acetate (826mg, the 5.0mMol) tetrahydrofuran solution of (Lancaster) (3mL), under-78 ℃, restir reaction mixture 30 minutes.Under-78 ℃, in reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (722.5mg, 2.5mMol) tetrahydrofuran solution (3mL) of (from the above embodiments 1c), same temperature restir reaction mixture 1 hour, slowly be warming up to-30 ℃ then, stirred 10 minutes.With ethyl acetate (100mL) diluted reaction mixture, use saturated aqueous ammonium chloride (50mL), water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Obtain crude product 3-(2,4-two chloro-pyrimidine-5-yl)-2-pyridin-4-yl-ethyl propionate, need not be further purified and just can be used for next step.(productive rate .43g, 83.6%).
Embodiment 9b
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-pyridin-4-yl-ethyl propionate
Figure C20038010697800541
Under 120 ℃, (0.68g, 2.0mMol) (from the above embodiments 9a) and aniline (3.0mL) mixture heating up (Aldrich) are 2 hours with 3-(2,4-two chloro-pyrimidine-5-yl)-2-pyridin-4-yl-ethyl propionate.Wash this reaction mixture with hexane (50mL * 3), and after each washing, decant supernatant liquid.Then resistates is dissolved in ethyl acetate (100mL), uses saturated aqueous ammonium chloride solution (30mL), water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Crude product and ethyl acetate are ground.The solid that filter to collect obtains with the ether washing, obtains 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-pyridin-4-yl-ethyl propionate, and brown solid need not be further purified and just can be used for next step.(productive rate 0.54g, 83.1%).
Embodiment 9c
8-phenyl-2-phenyl amino-6-pyridin-4-yl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
Figure C20038010697800542
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-pyridin-4-yl-ethyl propionate (200mg, 0.46mMol) glacial acetic acid solution (3mL) of disposable adding 5% vitriol oil in the solution of (from the above embodiments 9b).Under 80 ℃, the reaction mixture heated overnight.Use ethyl acetate (100mL) diluted reaction mixture then, with 2N aqueous sodium hydroxide solution cancellation reaction.Separate organic layer, anhydrous sodium sulfate drying is used in water (30mL) and salt solution (30mL) washing continuously, filters and vacuum concentration.Obtain crude product,, obtain 8-phenyl-2-phenyl amino-6-pyridin-4-yl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, yellow solid with ethyl acetate-hexane recrystallization.(productive rate 140mg, 78.2%).
HRMS m/z C 24H 19N 5O[(M+H) +] theoretical value: 394.1663.Measured value: 394.1662.
Embodiment 10a
3-(2,4-two chloro-pyrimidine-5-yl)-2-pyridin-3-yl-ethyl propionate
Figure C20038010697800551
Under-78 ℃ and argon gas, (1.44g 10.0mMol) is just adding in the anhydrous tetrahydrofuran solution of (Aldrich) (20mL)-butyllithium (hexane solution of 2.5M, 4.0mL, 10.0mmol) (Aldrich) to N-sec.-propyl hexahydroaniline.After 10 minutes, by syringe inject 2-pyridin-3-yl-ethyl acetate (1.65g, the 10.0mMol) tetrahydrofuran solution of (Acros) (5mL), at-78 ℃, reaction mixture restir 10 minutes.Under-78 ℃, in reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (1.45g, 5.0mMol) tetrahydrofuran solution (5mL) of (from the above embodiments 1c), again under same temperature, stirred reaction mixture 2 hours, slowly be warming up to-20 ℃ then, stirred 10 minutes.With ethyl acetate (100mL) diluted reaction mixture, use saturated aqueous ammonium chloride solution (100mL), water (50mL) and salt solution (50mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Resistates obtains 3-(2,4-two chloro-pyrimidine-5-yl)-2-pyridin-3-yl-ethyl propionate, the brown oily by the rapid column chromatography purifying.(productive rate 1.10g, 68.0%).
Embodiment 10b
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-pyridin-3-yl-ethyl propionate
Figure C20038010697800552
Under 120 ℃, with 3-(2,4-two chloro-pyrimidine-5-yl)-2-pyridin-3-yl-ethyl propionate (326mg, 1.0mMol) (from the above embodiments 10a supra) and aniline (2.0mL) mixture heating up (Aldrich) 1 hour. wash this reaction mixture with hexane (50mL * 3), and after each washing, decanting supernatant liquid.Then resistates is dissolved in ethyl acetate (100mL), uses saturated aqueous ammonium chloride solution (30mL), water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Crude product obtains 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-pyridin-3-yl-ethyl propionate by preparation thin-layer chromatography purifying, and brown solid need not be further purified and just can be used for next step.(productive rate 60mg, 13.7%).
Embodiment 10c
8-phenyl-2-phenyl amino-6-pyridin-3-yl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-pyridin-3-yl-ethyl propionate (60mg, 0.36mMol) glacial acetic acid solution (3mL) of disposable adding 5% vitriol oil in the solution of (from the above embodiments 10b).Under 120 ℃, with this reaction mixture heating 3 hours.Use ethyl acetate (100mL) diluted reaction mixture then, with 2N aqueous sodium hydroxide solution cancellation reaction.Separate organic layer, and water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration.Obtain crude product,, obtain 8-phenyl-2-phenyl amino-6-pyridin-3-yl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, white solid with ethyl acetate-hexane recrystallization.(productive rate 37.3mg, 69.3%).
HRMSm/z C 24H 19N 5O (M +) theoretical value: 393.1590.Measured value: 393.1586.
Embodiment 11a
3-(2,4-two chloro-pyrimidine-5-yl)-2-(3,4-dimethoxy-phenyl)-ethyl propionate
Under-78 ℃ and argon gas, (720mg 5.0mmol) is just adding in the anhydrous tetrahydrofuran solution of (Aldrich) (10mL)-butyllithium (hexane solution of 2.5M, 2.0mL, 5.0mMol) (Aldrich) to N-sec.-propyl hexahydroaniline.After 30 minutes, inject 3 by syringe, and 4-Dimethoxyphenyl ethyl acetate (1.12g, the 5.0mMol) tetrahydrofuran solution of (Lancaster) (3mL), under-78 ℃, restir reaction mixture 30 minutes.Under-78 ℃, in reaction mixture, add 2,4-two chloro-5-iodomethyl-pyrimidine (722.5mg, 2.5mMol) tetrahydrofuran solution (3mL) of (from the above embodiments 1c), under same temperature, reaction mixture stirred 1 hour, slowly be warming up to-30 ℃ then, and stirred 10 minutes.After the cooling,, use saturated aqueous ammonium chloride (50mL), water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration with ethyl acetate (100mL) diluted reaction mixture.Resistates obtains 3-(2,4-two chloro-pyrimidine-5-yl)-2-(3,4-dimethoxy-phenyl)-ethyl propionate by the rapid column chromatography purifying.(productive rate 440mg, 46.0%).
Embodiment 11b
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,4-dimethoxy-phenyl)-ethyl propionate
Figure C20038010697800571
At 110 ℃, (440mg, 1.1mMol) (from the above embodiments 11a) and aniline (2.0mL) mixture heating up (Aldrich) are 2 hours with 3-(2,4-two chloro-pyrimidine-5-yl)-2-(3,4-dimethoxy-phenyl)-ethyl propionate.Wash this reaction mixture with hexane (50mL * 3), and after each washing, decant supernatant liquid.Then resistates is dissolved in ethyl acetate (100mL), continuously with saturated aqueous ammonium chloride (30mL), water (30mL) and salt solution (30mL) washing, use anhydrous sodium sulfate drying, filter and vacuum concentration, resistates obtains crude product 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3 by the rapid column chromatography purifying, 4-dimethoxy-phenyl)-and ethyl propionate, pale solid.(productive rate 470mg, 86%).
Embodiment 11c
6-(3,4-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
Figure C20038010697800581
To 3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,4-dimethoxy-phenyl)-ethyl propionate (470mg, 0.94mmol) the disposable adding vitriol oil (0.1mL) in the glacial acetic acid solution (3mL) of (from the above embodiments 11b).Under 80 ℃, the reacting by heating mixture overnight.After the cooling, with ethyl acetate (50mL) diluted reaction mixture, with 2N aqueous sodium hydroxide solution cancellation reaction.Separate organic layer, water (10mL) and salt solution (10mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration acquisition crude product, obtain 6-(3,4-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2 with ethyl acetate-hexane recrystallization, 3-d] pyrimidin-7-ones, light brown solid.(productive rate 335mg, 78.8%).
HRMS m/z C 27H 24N 4O 3(M +) theoretical value: 452.1848.Measured value: 452.1844.
Embodiment 12a
3-(4-chloro-2-phenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate
To 3-(2,4-two chloro-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (341mg, 1.0mmol) (from the above embodiments 1d) just-add aniline (200mg in the butanol solution (10mL), 2.15mMol) (Aldrich), then add N, N-diisopropyl ethyl amine (258mg, 2.0mMol) (Aldrich), at 100 ℃, reaction mixture heating 12 hours.After the cooling,, use saturated aqueous ammonium chloride solution (30mL), water (30mL) and salt solution (30mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration with ethyl acetate (100mL) diluted reaction mixture.Crude product obtains 3-(4-chloro-2-phenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate by rapid column chromatography (silica gel) purifying.(productive rate 45.1mg, 11.3%).
Embodiment 12b
3-(2-chloro-4-phenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate
Figure C20038010697800591
To obtain the second product 3-(2-chloro-4-phenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate, canescence amorphous solid from above-mentioned reaction mixture (from the above embodiments 12a) rapid column chromatography.(productive rate 310mg, 77.9%).
Embodiment 12c
3-[2-(6-methoxyl group-pyridin-3-yl amino)-4-phenyl amino-pyrimidine-5-yl]-2-(4-methoxyl group-phenyl)-methyl propionate
Figure C20038010697800592
At 110 ℃, with 3-(2-chloro-4-phenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (40mg, 0.1mMol) (37.2mg, 0.3mMol) mixture heating up of (Aldrich) is 4 hours for (from the above embodiments 12b) and 5-amino-2-methoxypyridine.After the cooling, with ethyl acetate (50mL) diluted reaction mixture, continuously with saturated aqueous ammonium chloride (10mL), water (10mL) and salt solution (10mL) washing, use anhydrous sodium sulfate drying, filter and vacuum concentration, obtain crude product 3-[2-(6-methoxyl group-pyridin-3-yl amino)-4-phenyl amino-pyrimidine-5-yl]-2-(4-methoxyl group-phenyl)-methyl propionate, the garnet solid need not be further purified and just can be used for next step.(productive rate 47.1mg, 96.8%).
Embodiment 12d
6-(4-methoxyl group-phenyl)-2-(6-methoxyl group-pyridin-3-yl amino)-8-phenyl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
To 3-[2-(6-methoxyl group-pyridin-3-yl amino)-4-phenyl amino-pyrimidine-5-yl]-2-(4-methoxyl group-phenyl)-methyl propionate (45.0mg, 0.09mMol) the disposable adding vitriol oil (0.1mL) in the glacial acetic acid solution (1mL) of (from the above embodiments 12c).,, react after 3 hours 80 ℃ of heating with the cancellation of 2N aqueous sodium hydroxide solution with ethyl acetate (50mL) diluted reaction mixture.Separate organic layer, anhydrous sodium sulfate drying is used in water (10mL) and salt solution (10mL) washing continuously, filters and vacuum concentration, obtains crude product.By preparation thin-layer chromatography purifying crude product, obtain 6-(4-methoxyl group-phenyl)-2-(6-methoxyl group-pyridin-3-yl amino)-8-phenyl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, brown powder.(productive rate 5.2mg, 12.4%).
HRMS m/z C 26H 23N 5O 3[(M+H) +] theoretical value: 454.1874.Measured value: 454.1878.
Embodiment 13a
3-(2-phenyl amino-4-isobutylamino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate
With
Embodiment 13b
8-isobutyl--6-(4-methoxyl group-phenyl)-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3d] pyrimidin-7-ones
Figure C20038010697800611
(40mg, 0.1mMol) (from the above embodiments 12a) and isobutylamine (2.0mL) mixture heating up (Aldrich) refluxed 3 hours with 3-(4-chloro-2-phenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate.The vacuum concentration reactant by preparation thin-layer chromatography purifying, obtains 8-isobutyl--6-(4-methoxyl group-phenyl)-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones; (productive rate 4.6mg, 11.4%); And 3-(2-phenyl amino-4-isobutylamino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate. (productive rate 18.2mg, 41.9%).
To 3-(2-phenyl amino-4-isobutylamino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (17.1mg, the disposable adding vitriol oil (0.1mL) in glacial acetic acid solution 0.04mMol) (1mL).Under 85 ℃, this reaction mixture heated overnight.After the cooling, with ethyl acetate (50mL) diluted reaction mixture, with 2N aqueous sodium hydroxide solution cancellation reaction.Separate organic layer, anhydrous sodium sulfate drying is used in water (10mL) and salt solution (10mL) washing continuously, filter and vacuum concentration acquisition 8-isobutyl--6-(4-methoxyl group-phenyl)-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, brown solid.(14.3mg，90.5％)。
HRMS m/z C 24H 26N 4O 2[M+H) +] theoretical value: 403.2129.Measured value: 403.2131.
Embodiment 14a
3-(2-phenyl amino-4-cyclopropyl methylamino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate
At room temperature, (45mg, 0.11mMol) (from the above embodiments 12a) and cyclopropyl methylamine (1.0mL) mixture (Lancaster) stirred 24 hours with 3-(4-chloro-2-phenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate.Use ethyl acetate (50mL) dilution then, and water (10mL) and salt solution (10mL) washing continuously, use anhydrous sodium sulfate drying, filter and vacuum concentration, obtain crude product 3-(2-phenyl amino-4-cyclopropyl methylamino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate, need not be further purified and just can be used for next step.(productive rate 51.3mg).
Embodiment 14b
8-cyclopropyl methyl-6-(4-methoxyl group-phenyl)-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones
Figure C20038010697800621
The disposable adding vitriol oil (0.1mL) in the glacial acetic acid solution (1mL) of crude product 3-(2-phenyl amino-4-cyclopropyl methylamino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate (51.3mg) (from the above embodiments 14a).Heated these reaction mixtures 3 hours at 85 ℃.Reaction mixture is with ethyl acetate (50mL) dilution, with 2N aqueous sodium hydroxide solution cancellation reaction. and separate organic layer, anhydrous sodium sulfate drying is used in water (10mL) and salt solution (10mL) washing continuously, filters and vacuum concentration.Resistates obtains 8-cyclopropyl methyl-6-(4-methoxyl group-phenyl)-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones, light yellow amorphous solid by preparation thin-layer chromatography purifying.(productive rate 6.7mg, 14.8%, 2 step).
HRMS m/z C 24H 24N 4O 2[(M+H) +] theoretical value: 401.1972.Measured value: 401.1973.
Antiproliferative activity
Confirm among the antiproliferative activity of the The compounds of this invention embodiment 15 and 16 below.These activity show that compound of the present invention is effective in treatment cancer, especially solid tumor such as mastadenoma and colon knurl.
Embodiment 15
Kinase assay
In order to determine KDR, FGFR, EGFR and the active restraining effect of PDGFR, use HTRF (Homogeneous Time Resolved Fluorescence) test to carry out kinase assay.This test is described in the 1998,3 (7), the 333rd page at people's such as A.J.Kolb Drug Discovery Today.Before the kinase reaction, (50mM HEPES, pH 7.4,1mM DTT, 10% glycerine, 150mM NaCI, 0.1mM EDTA, 26mmMgCl there being the activation damping fluid 2With 4mM ATP) the following KDR that activates the EEE-mark of reorganization.This enzyme was hatched under 4 ℃ 1 hour.
Kinase activity is to be that (Falcon) carries out on the 96-hole polypropylene version of 90 μ L at every hole cumulative volume.Every hole is contained 1 μ M KDR substrate (Biotin-EEEEYFELVAKKKK), the active KDR of 1nM and is had from the test compounds of 8 experimental concentration of 100 μ M to 128pM (1: 5 serial dilution).The kinase activity test can exist 100mM HEPES, pH 7.4,1mMDTT, 0.1mM Na 2VO 4, 25mMmgCl 2, 50mM NaCl (from the KDR stock solution), 1%DMSO (from compound), 0.3mM ATP (K mConcentration) and under the situation of 0.02%BSA carry out.Reactant was hatched 30 minutes at 37 ℃.In order to end KDR reaction, the reaction mixture of 72 μ L is transferred in the STOP plate of the new damping fluid (anti--pY antibody (ultimate density 2nM) and 100nM streptavidin (ultimate density 20nM) of 20mM EDTA, 50mM HEPES, pH7.4,0.02%BSA, 10nM Eu-mark) that contains 18 μ L.After the mixing, the solution of 35 μ L is transferred on the 384-hole black plate of diplopore (Costar), and read to read plate in the 615/665nM place on the plate device at Wallac Victor 5.
FGFR, EGFR and PDGFR activity test are similar to the above-mentioned KDR activity test that is used for to be carried out, and the two has following difference.The FGFR enzyme of GST-mark in room temperature in following activation damping fluid: 100mM HEPES, pH 7.4,50mM NaCl, 20mMmgCl 2Be activated among the 4mM ATP 1 hour.The enzymic activity test is to have 100mM HEPES, 1mM DTT, 0.4mMmgCl 2, 0.4mM MnCl 2, 50mM NaCl, 1%DMSO, 10 μ M ATP (Km=8.5 μ M is for FGFR), 0.1mMNa 2VO 4Under 0.02%BSA, in the cumulative volume of 90 μ L, carry out with 1 μ M substrate (Biotin-EEEEYFELV), 1.5nM activatory FGFR and test compounds.Experimental test carries out with the method identical with the KDR test.
The EGFR kinase activity is tested with 1 μ M substrate (Biotin-EEEEYFELV), 1.5nMEGFR, test compounds, 100mM HEPES, pH 7.4,1mM DTT, 5mMmgCl 2, 2mM MnCl 2, 1%DMSO, 0.5 μ M ATP (Km is for EGFR), 0.1mM Na 2VO 4Carry out with 0.02%BSA.Experimental test carries out with the method identical with the KDR test.
The PDGFR kinase activity is tested with 1 μ M substrate (Biotin-EEEEYFELV), 1.0nMEGFR, test compounds, 100mM HEPES, pH 7.4,1mM DTT, 5mMmgCl 2, 2mM MnCl 2, 1%DMSO, 2.3 μ M ATP (Km is for PDGFR), 0.1mM Na 2VO 4Carry out with 0.02%BSA.Experimental test carries out with the method identical with the KDR test.
The IC of compound 50Value is used two groups of data and is become equation Y=[(a-b with fitting data by use Excel)/{ 1+ (X/c) d}+b determines that wherein a and b are respectively the enzymic activity when not having the test inhibitor compound and having endless inhibitor test compounds, and c is IC 50, d is the Hill constant of compound reaction.IC 50Value refers under the test condition of describing, the concentration of the test compounds of enzymic activity reduction by 50%.
The result of aforementioned in vitro tests comprises IC 50Value is listed in following table 1.
Table 1
Enzyme inhibition=IC 50Value
Figure C20038010697800641
Embodiment 16
The HUVEC proliferation test that VEGF and FGF-stimulate
Test compound of the present invention is being measured assessment based on the proliferation activity in the mensuration of cell by the BrdU that uses BrdU test kit (Roche Biochemicals 1-647-229).Human umbilical vein endothelial cells (Clonetics CC-2519) cultivation is spent the night in EGM-2 (Clonetics CC-3162) substratum that the flat volume that hangs down plate (Costar 3595) in 96-hole is 200 μ L in EGM-2 (Clonetics CC-3162) substratum and with 10000 cell inoculations in every hole.At 37 ℃ of following 5%CO 2Cultivate after 24 hours, by aspirating slow removal incubation substratum, EBM-2 (CloneticsCC-3156) with 300 μ L preheatings washs the content in each hole, and this EBM-2 contains gentamicin and the 50ng/mL amphotericin-B (Clonetics CC-4083) of 50 μ g/mL.Subsequently, once more the remaining substratum of sucking-off and with the clear substratum of ischemic in 160 μ l/ holes (EBM-2 replenishes 1% hot deactivation FBS (CloneticsCC-4102), 50 μ g/mL gentamicins and 50ng/mL amphotericin-B (Clonetics CC-4083), the Wyeth-Ayerst heparin (NDC0641-0391-25) of 10 units/mL and 2mM L-glutaminate (GIBCO 25030-081) are replaced.Make cell lack serum after 24 hours, the serum that is containing 2.5%DMSO of adding 20 μ L 10X experimental concentration lacks the test compound in the substratum in suitable cell.Control cells contains the serum shortage substratum that 20 μ L contain 2.5%DMSO.Flat board was returned incubator 2 hours.With cell and test compound preincubation after 2 hours, add the serum that is diluted in that 20 μ L10X measure concentration and lack somatomedin in the substratum, the FGF of 50ng/mL, or the VEGF of 200ng/mL (R ﹠amp; D systems 293-VE).The final concentration of FGF is 5ng/mL in the mensuration, and the final concentration of VEGF is 20ng/mL in the mensuration.The serum that the control wells of no somatomedin contains the 20ng/ hole lack substratum and with the BSA of the hole same amount that contains somatomedin.Plate was back to incubator other 22 hours.
BrdU ELISA (BrdU enzyme-linked immunosorbent assay)
Be exposed to test compound after 24 hours, by the BrdU labelled reagent of dilution (1: 100) in serum shortage substratum that adds 20 μ L/ holes, with BrdU (Roche Biochemicals1-647-229) labeled cell.Plate was back to incubator 4 hours then.By being drained, substratum on paper handkerchief, removes the mark substratum.Fix by adding 200 μ L/denaturing soln is to each hole, and incubation 45 minutes at room temperature, with cell fixation and DNA sex change.To fix/denaturing soln drains to paper handkerchief, in each hole, add 100 μ L anti--BrdU-POD and with hole incubation 2 hours at room temperature.Remove antibody-solutions and each hole is washed 3-4 time with 300 μ LPBS.100 μ L tmb substrate solution are added each hole and with hole at room temperature incubation 5-8 minute.Then by adding the 1M phosphoric acid termination reaction in 100 μ L/ holes.Read flat board at 450nm, reference wavelength is 650nm.By from deduct the absorbancy of blank (acellular) porose, deduct each with 1 then and test the inhibition per-cent that double mean light absorbency and merchant of contrast mean value calculate every kind of test compound.End-result multiply by 100 (% inhibition=(1-tests double mean light absorbency/contrast mean value) 100) then.IC 50Value is to suppress the concentration of the test compound of 50%BrdU mark, is measuring of cell inhibitory effect.From the linear regression of concentration, measure IC to the logarithmic curve of inhibition per-cent 50IC 50Value shows in following table 2.
Table 2
The IC of the HUVEC proliferation test that VEGF and FGF-excite 50
Figure C20038010697800661
Embodiment 17
Tablet
*Compd A is represented compound of the present invention.
Preparation process:
In suitable mixing tank, mix the 1st, 2 and 3 15 minutes.
The powdered mixture and 20% 30 POVIDONE K 30 BP/USP, 30 solution (the 4th) of step 1 are granulated.
At the particle of 50 ℃ of dryings from step 2.
Will be from the grinding equipment of particle by suiting of step 3.
The 5th is joined in the step 4 in the levigated particle, mixed 3 minutes.
Will be on suitable tabletting machine from the particle compressing tablet of step 5.
Embodiment 18
Capsule
Figure C20038010697800671
*Compd A is represented compound of the present invention.
Preparation process:
In suitable mixing tank, mix the 1st, 2 and 3 15 minutes.
Add the 4th and 5, mixed 3 minutes.
Be packed into suitable capsule.
Embodiment 19
The preparation of injection liquid/emulsion
{。##.##1}, Composition mg/ml
1 Compd A * 1mg
2 PEG400 10-50mg
3 Yelkin TTS 20-50mg
4 Soybean oil 1-5mg
5 Glycerine 8-12mg
6 Water is an amount of 1ml
*Compd A is represented compound of the present invention.
Preparation process:
Be dissolved in the 2nd with the 1st.
In the 6th of the 3rd, 4 and 5 adding, mix up to dispersion, even then.
To join from the solution of step 1 in the mixture from step 2, it is translucent homogenizing up to dispersion.
Filter sterilised by 0.2 μ m is filtered the bottle of packing into.
Embodiment 20
The preparation of injection liquid/emulsion
{。##.##1}, Composition mg/ml
1 Compd A * 1mg
2 Glycofurol 10-50mg
3 Yelkin TTS 20-50mg
4 Soybean oil 1-5mg
5 Glycerine 8-12mg
6 Water In right amount to 1ml
*Compd A is represented compound of the present invention.
Preparation process:
Be dissolved in the 2nd with the 1st.
In the 6th of the 3rd, 4 and 5 adding, mix up to dispersion, even then.
To join from the solution of step 1 in the mixture from step 2, it is translucent homogenizing up to dispersion.
Filter sterilised by 0.2 μ m is filtered the bottle of packing into.
Although by illustrating the present invention, it will be appreciated by those skilled in the art that and by normal experiment and to implement the present invention and to carry out variations and modifications with reference to concrete and preferred embodiment.Therefore, this invention is intended to not be subjected to above description to limit, but limit by appended claim and their equivalent.

Claims (26)

1. formula I compound or pharmaceutically acceptable salt thereof
Figure C2003801069780002C1
Wherein Ar and Ar ' are independently selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement, and condition is for Ar, and described heteroaryl is not the 2-pyridyl, and the heteroaryl that replaces is not the 2-pyridyl that replaces;
The aryl of wherein said replacement is quilt 2 aryl that are selected from following substituting group replacement at the most, and described substituting group is selected from NR 11R 12OR 13SR 16Halogen; COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14CN; NO 2(CH 2) nHeteroaryl; (CH 2) nHeterocyclic radical; C 1-C 10Alkyl; C 3-C 10Cycloalkyl; C 2-C 10Alkenyl; C 2-C 10Alkynyl; Wherein n is 0,1,2 or 3, and described heteroaryl, heterocyclic radical, alkyl, cycloalkyl, alkenyl and alkynyl be unsubstituted or by at the most three be selected from NR 11R 12OR 13SR 16Halogen; COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14CN; And NO 2Substituting group replace;
The heteroaryl of described replacement for by at the most two be selected from NR 11R 12OR 13SR 16Halogen; COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14CN; NO 2(CH 2) nHeteroaryl; (CH 2) nHeterocyclic radical; C 1-C 10Alkyl; C 3-C 10Cycloalkyl; C 2-C 10Alkenyl; C 2-C 10The heteroaryl of alkynyl substituted, wherein n is 0,1,2 or 3, and described heteroaryl, heterocyclic radical, alkyl, cycloalkyl, alkenyl and alkynyl be unsubstituted or by at the most three be selected from NR 11R 12OR 13SR 16Halogen; COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14CN and NO 2Substituting group replace,
R 1Be selected from:
H；
C 1-10Alkyl;
Independently by at the most three be selected from aryl, heteroaryl, heterocyclic radical, C 3-C 8Cycloalkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 1-10Alkyl, wherein aryl, heteroaryl, heterocyclic radical and cycloalkyl be unsubstituted or respectively independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2Substituting group replace;
Aryl;
Independently by at the most three be selected from C 1-6-alkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The aryl that replaces of substituting group;
Heteroaryl;
Independently by at the most three be selected from C 1-6-alkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The heteroaryl that replaces of substituting group;
Heterocyclic radical;
Independently by at the most three be selected from C 1-6-alkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The heterocyclic radical that replaces of substituting group;
C 3-10Cycloalkyl;
Independently by at the most three be selected from C 1-6The C of-alkyl, replacement 1-6-alkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 3-10Cycloalkyl;
C 2-10Alkenyl;
Independently by at the most three be selected from C 3-C 8The C of cycloalkyl, replacement 3-C 8The heterocyclic radical C of cycloalkyl, heterocyclic radical, replacement 3-C 8Cycloalkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 2-10Alkenyl;
C 2-10Alkynyl; With
Independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 2-10Alkynyl;
R 8, R 9And R 10Be H or C independently 1-6-alkyl;
R 11And R 12Be independently selected from:
H；
Unsubstituted C 1-6-alkyl; By hydroxyl, C 1-10-alkoxyl group or NR 21R 22The C that replaces 1-6-alkyl;
Unsubstituted C 3-C 8Cycloalkyl; By hydroxyl, C 1-10-alkoxyl group, C 1-6-alkyl or NR 21R 22The C that replaces 3-C 8Cycloalkyl;
Unsubstituted heterocyclic; By hydroxyl, C 1-10-alkoxyl group, C 1-6-alkyl or NR 21R 22The heterocyclic radical that replaces;
Alternatively, NR 11R 12Formation has the ring of 3 to 7 atoms, and described ring does not have or have at least one other heteroatoms, and condition is if heteroatoms is N, and heteroatoms is unsubstituted or by one or more C of being selected from 1-6-alkyl, OR 13, COR 14, CO 2R 14, CONR 14R 15, SO 2R 14And SO 2NR 14R 15Substituting group replace;
R 13Be selected from:
H；
COR 14；
CONR 14R 15；
Unsubstituted C 1-6-alkyl; By hydroxyl, C 1-10-alkoxyl group or NR 21R 22The C that replaces 1-6-alkyl;
Unsubstituted C 3-C 8Cycloalkyl; By hydroxyl, C 1-10-alkoxyl group, C 1-6-alkyl or NR 21R 22The C that replaces 3-C 8Cycloalkyl;
Unsubstituted heterocyclic; By hydroxyl, C 1-10-alkoxyl group, C 1-6-alkyl or NR 21R 22The heterocyclic radical that replaces;
R 14And R 15Be independently selected from:
H；
Unsubstituted C 1-6-alkyl; By hydroxyl, C 1-10-alkoxyl group or NR 21R 22The C that replaces 1-6-alkyl;
Unsubstituted C 3-C 8Cycloalkyl; By hydroxyl, C 1-10-alkoxyl group, C 1-6-alkyl or NR 21R 22The C that replaces 3-C 8Cycloalkyl;
Unsubstituted heterocyclic; By hydroxyl, C 1-10-alkoxyl group, C 1-6-alkyl or NR 21R 22The heterocyclic radical that replaces;
Alternatively, NR 14R 15Formation has the ring of 3 to 7 atoms, and described ring does not have or have at least one heteroatoms, and condition is if heteroatoms is N, and heteroatoms is unsubstituted or by one or more C of being selected from 1-6-alkyl, OR 23, COR 23, CO 2R 23, CONR 23R 24, SO 2R 23, SO 2NR 23R 24Substituting group replace;
R 16Be selected from:
Unsubstituted C 1-6-alkyl; By hydroxyl, C 1-C 10Alkoxyl group or NR 21R 22The C that replaces 1-6-alkyl;
Unsubstituted C 3-C 8Cycloalkyl; By hydroxyl, C 1-C 10Alkoxyl group, C 1-6-alkyl or NR 21R 22The C that replaces 3-C 8Cycloalkyl;
Unsubstituted heterocyclic; With by hydroxyl, C 1-C 10Alkoxyl group, C 1-6-alkyl or NR 21R 22The heterocyclic radical that replaces;
R 21Be selected from H, C 1-6-alkyl, COR 23Or CO 2R 23
R 22, R 23And R 24Be independently selected from H or C 1-6-alkyl;
Alternatively, NR 21R 22Or NR 23R 24Form the ring with 3 to 7 atoms independently, described ring does not have or has at least one other heteroatoms that is selected from N, O and S, and condition is that heteroatoms is-NH or NR if heteroatoms is N 25Form, if heteroatoms is S, heteroatoms is S (O) mForm, m=0,1 or 2 wherein; With
R 25Be C 1-6-alkyl;
Wherein said aryl is meant 6-10 unit's aromatic ring or part aromatic ring system;
Described heteroaryl is meant and contains the aromatic nucleus system of 2 rings at the most;
Described heterocyclic radical be meant have 1 to 3 heteroatomic 3-to 10-unit saturated or the undersaturated non-aromatic unit price of part cyclic group, described heteroatoms is selected from nitrogen, oxygen or sulphur or its combination.
2. the formula I compound of claim 1, the heteroaryl of Ar wherein for replacing, condition is that the heteroaryl that replaces can not be the 2-pyridyl that replaces, wherein substituting group is as defined in claim 1.
3. the formula I compound of claim 2, the 3-pyridyl of Ar wherein for replacing, wherein substituting group is as defined in claim 1.
4. the formula I compound of claim 1, wherein Ar ' is the aryl of aryl or replacement, wherein substituting group is as defined in claim 1.
5. the formula I compound of claim 4, wherein Ar ' is the phenyl of phenyl or replacement, wherein substituting group is as defined in claim 1.
6. the formula I compound of claim 1, wherein R 1Be the aryl or the heteroaryl of aryl, replacement, wherein substituting group as defined in claim 1.
7. the formula I compound of claim 6, wherein R 1Be phenyl.
8. the compound of the formula I of claim 1, wherein R 1Be C 1-10Alkyl or independently by at the most three be selected from aryl, heteroaryl, heterocyclic radical, C 3-C 8Cycloalkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 1-10Alkyl, described aryl, heteroaryl, heterocyclic radical and cycloalkyl respectively independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2Substituting group replace; R wherein 8, R 9, R 10, R 11And R 12Be H or C independently 1-6-alkyl.
9. the formula I compound or pharmaceutically acceptable salt thereof that has the claim 1 of formula II,
Wherein, R 1Be selected from:
H；
C 1-10Alkyl;
Independently by at the most three be selected from aryl, heteroaryl, heterocyclic radical, C 3-C 8Cycloalkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 1-10Alkyl, wherein aryl, heteroaryl, heterocyclic radical and cycloalkyl be unsubstituted or respectively independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2Substituting group replace;
Aryl;
Independently by at the most three be selected from C 1-6-alkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The aryl that replaces of substituting group;
Heteroaryl;
Independently by at the most three be selected from C 1-6-alkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The heteroaryl that replaces of substituting group;
Heterocyclic radical;
Independently by at the most three be selected from C 1-6-alkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The heterocyclic radical that replaces of substituting group;
C 3-10Cycloalkyl;
Independently by at the most three be selected from C 1-6The C of-alkyl, replacement 1-6-alkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 3-10Cycloalkyl;
C 2-10Alkenyl;
Independently by at the most three be selected from C 3-C 8The C of cycloalkyl, replacement 3-C 8The heterocyclic radical C of cycloalkyl, heterocyclic radical, replacement 3-C 8Cycloalkyl, NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces 2-10Alkenyl;
C 2-10Alkynyl; With
Independently by at the most three be selected from NR 8R 9, OR 10, SR 10, halogen, COR 11, CO 2R 11, CONR 11R 12, SO 2NR 11R 12, SOR 11, SO 2R 11, CN and NO 2The C that replaces of substituting group 2-10Alkynyl; And R 8, R 9And R 10Be H or C independently 1-6-alkyl;
R 2And R 3Be independently selected from:
NR 11R 12；
OR 13；
SR 16；
Halogen;
COR 14；
CO 2R 14；
CONR 14R 15；
SO 2NR 14R 15；
SO 2R 14；
CN；
NO 2；
(CH 2) nHeteroaryl;
(CH 2) nHeterocyclic radical;
C 1-C 10Alkyl;
C 3-C 10Cycloalkyl;
C 2-C 10Alkenyl;
C 2-C 10Alkynyl;
Wherein n is 0,1,2 or 3, and described heteroaryl, heterocyclic radical, alkyl, cycloalkyl, alkenyl and alkynyl be unsubstituted or by at the most three be selected from NR 11R 12OR 13SR 16Halogen; COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14CN; And NO 2Substituting group replace;
Alternatively, R 2And R 3Form the connected phenyl ring condensed ring with 3 to 7 atoms together, described ring does not have or has at least one other heteroatoms, and condition is if heteroatoms is N, and heteroatoms is unsubstituted or is selected from C by at least one 1-6-alkyl; By hydroxyl, C 1-C 10Alkoxyl group or NR 11R 12The C that replaces 1-6-alkyl; NR 11R 12OR 13SR 16COR 14CO 2R 14CONR 14R 15SO 2NR 14R 15SO 2R 14Replace with the substituting group of CN;
R 4, R 5, R 6, R 7And R 26Be independently selected from following radicals, wherein R 4, R 5, R 6, R 7And R 26In at least one is H, described group is selected from the group of being made up of following groups:
H；
Unsubstituted C 1-6-alkyl; By hydroxyl, C 1-C 10The C that alkoxy or halogen replaces 1-6-alkyl;
NR 21R 22；
OR 23；
SR 23；
Halogen;
NO 2；
COR 23；
CO 2R 23；
CONR 23R 24；
SO 2NR 23R 24；
SOR 23With
CN；
R 8, R 9And R 10Be H or C independently 1-6-alkyl;
R 11And R 12Be independently selected from:
H；
Unsubstituted C 1-6-alkyl; By hydroxyl, C 1-C 10Alkoxyl group or NR 21R 22The C that replaces 1-6-alkyl;
Unsubstituted C 3-C 8Cycloalkyl; By hydroxyl, C 1-C 10Alkoxyl group, C 1-6-alkyl or NR 21R 22The C that replaces 3-C 8Cycloalkyl;
Unsubstituted heterocyclic; With by hydroxyl, C 1-C 10Alkoxyl group, C 1-6-alkyl or NR 21R 22The heterocyclic radical that replaces;
Alternatively, NR 11R 12Formation has the ring of 3 to 7 atoms, and described ring does not have or have at least one other heteroatoms, and condition is if heteroatoms is N, and heteroatoms is unsubstituted or by one or more C of being selected from 1-6-alkyl, COR 14, CO 2R 14, CONR 14R 15, SO 2R 14And SO 2NR 14R 15Substituting group replace;
R 13Be selected from:
H；
COR 14；
CONR 14R 15；
Unsubstituted C 1-6-alkyl; By hydroxyl, C 1-C 10Alkoxyl group or NR 21R 22The C that replaces 1-6-alkyl;
Unsubstituted C 3-C 8Cycloalkyl; By hydroxyl, C 1-C 10Alkoxyl group, C 1-6-alkyl or NR 21R 22The C that replaces 3-C 8Cycloalkyl;
Unsubstituted heterocyclic; With by hydroxyl, C 1-C 10Alkoxyl group, C 1-6-alkyl or NR 21R 22The heterocyclic radical that replaces;
R 14And R 15Be independently selected from:
H；
Unsubstituted C 1-6-alkyl; By hydroxyl, C 1-C 10Alkoxyl group or NR 21R 22The C that replaces 1-6-alkyl;
Unsubstituted C 3-C 8Cycloalkyl; By hydroxyl, C 1-C 10Alkoxyl group, C 1-6-alkyl or NR 21R 22The C that replaces 3-C 8Cycloalkyl;
Unsubstituted heterocyclic; With by hydroxyl, C 1-C 10Alkoxyl group, C 1-6-alkyl or NR 21R 22The heterocyclic radical that replaces;
Alternatively, NR 14R 15Formation has the ring of 3 to 7 atoms, and described ring does not have or have at least one other heteroatoms, and condition is if heteroatoms is N, and heteroatoms is unsubstituted or by one or more C of being selected from 1-6-alkyl, COR 23, CO 2R 23, CONR 23R 24, SO 2R 23And SO 2NR 23R 23Substituting group replace;
R 16Be selected from:
Unsubstituted C 1-6-alkyl; By hydroxyl, C 1-C 10Alkoxyl group or NR 21R 22The C that replaces 1-6-alkyl;
Unsubstituted C 3-C 8Cycloalkyl; By hydroxyl, C 1-C 10Alkoxyl group, C 1-6-alkyl or NR 21R 22The C that replaces 3-C 8Cycloalkyl;
Unsubstituted heterocyclic; With by hydroxyl, C 1-C 10Alkoxyl group, C 1-6-alkyl or NR 21R 22The heterocyclic radical that replaces;
R 21Be selected from H, C 1-6-alkyl, COR 23Or CO 2R 23
R 22, R 23And R 24Be independently selected from H or C 1-6-alkyl,
Alternatively, NR 21R 22Or NR 23R 24Form the ring with 3 to 7 atoms independently, described ring does not have or has at least one other heteroatoms that is selected from N, O and S, and condition is that heteroatoms is-NH or NR if heteroatoms is N 25Form, if heteroatoms is S, heteroatoms is S (O) mForm, m=0,1 or 2 wherein; With
R 25Be C 1-6-alkyl.
10. the formula II compound of claim 9, wherein R 6Be OR 23
11. the formula II compound of claim 9, wherein R 4And R 26Be halogen.
12. the formula II compound of claim 9, wherein R 5And R 7Be OR 23
13. the formula II compound of claim 9, wherein R 26Be unsubstituted C 1-6-alkyl.
14. the formula II compound of claim 9, wherein R 4, R 5, R 6And R 26Be H.
15. the formula II compound of claim 9, wherein R 5And R 26Be OR 23
16. the formula II compound of claim 9, wherein R 26Be OR 23
17. the formula II compound of claim 9, wherein R 6And R 7Be OR 23
18. the formula II compound of claim 9, wherein R 6Be OR 23
19. the formula I compound of claim 1 is selected from:
6-(4-methoxyl group-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
6-(2,6-two chloro-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
6-(3,5-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
8-phenyl-2-phenyl amino-6-O-tolyl-5,8-dihydro-6H-is than pyridine [2,3-d] pyrimidin-7-ones also;
6,8-phenylbenzene-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
6-(2,5-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
6-(2-methoxyl group-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
6-(3,5-di-trifluoromethyl-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
8-phenyl-2-phenyl amino-6-pyridin-4-yl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
8-phenyl-2-phenyl amino-6-pyridin-3-yl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
6-(3,4-dimethoxy-phenyl)-8-phenyl-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
6-(4-methoxyl group-phenyl)-2-(6-methoxyl group-pyridin-3-yl amino)-8-phenyl-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones;
8-isobutyl--6-(4-methoxyl group-phenyl)-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones; With
8-cyclopropyl methyl-6-(4-methoxyl group-phenyl)-2-phenyl amino-5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-ones.
20. a pharmaceutical composition contains in the claim 1 to 19 for the treatment of significant quantity each compound and pharmaceutically acceptable carrier or vehicle.
21. the pharmaceutical composition of claim 20, wherein said compound is suitable for bestowing the patient who suffers from cancer.
22. each compound is used for the treatment of and controls purposes in the medicine of cancer in preparation in the claim 1 to 19.
23. the purposes of claim 22, wherein said cancer are mammary cancer, lung cancer, colorectal carcinoma or prostate cancer.
24. the purposes of claim 22, wherein said cancer are mammary cancer or colorectal carcinoma.
25. the method for formula I compound or pharmaceutically acceptable salt thereof of preparation claim 1, its preparation process comprises: make formula III compound and acid-respons
Wherein R is C 1-6-alkyl, and Ar, Ar ' and R 1As the definition in the claim 1, obtain formula I compound
Figure C2003801069780012C2
Wherein Ar, Ar ' and R 1As the definition in the claim 1,
Perhaps, further formula I compound is changed into pharmaceutical salts.
26. be selected from following compound:
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate;
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2,6-two chloro-phenyl)-methyl propionate;
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,5-dimethoxy-phenyl)-methyl propionate;
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-O-tolyl-methyl propionate;
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-phenyl-methyl propionate;
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2,5-dimethoxy-phenyl) ethyl propionate;
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(2-methoxyl group-phenyl) ethyl propionate;
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,5-di-trifluoromethyl-phenyl)-methyl propionate;
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-pyridin-4-yl-ethyl propionate;
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-pyridin-3-yl-ethyl propionate;
3-(2,4-diphenyl amino-pyrimidine-5-yl)-2-(3,4-dimethoxy-phenyl)-ethyl propionate;
3-[2-(6-methoxyl group-pyridin-3-yl amino)-4-phenyl amino-pyrimidine-5-yl]-2-(4-methoxyl group-phenyl)-methyl propionate;
3-(2-phenyl amino-4-isobutylamino-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate; With
3-(2-phenyl amino-4-cyclopropyl methyl ammonia-pyrimidine-5-yl)-2-(4-methoxyl group-phenyl)-methyl propionate.
CNB2003801069786A 2002-12-20 2003-12-11 Pyridino [2, 3-D] pyrimidine derivatives as selective KDR and FGFR inhibitors Expired - Fee Related CN100420687C (en)

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