CN101735200B - Quinazoline compound - Google Patents

Quinazoline compound Download PDF

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CN101735200B
CN101735200B CN2008101776387A CN200810177638A CN101735200B CN 101735200 B CN101735200 B CN 101735200B CN 2008101776387 A CN2008101776387 A CN 2008101776387A CN 200810177638 A CN200810177638 A CN 200810177638A CN 101735200 B CN101735200 B CN 101735200B
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quinazoline
furans
amine
phenyl
ethyl
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CN101735200A (en
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岑均达
唐家邓
吴雪松
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Priority to PCT/CN2009/000975 priority patent/WO2010054528A1/en
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
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    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Abstract

The invention relates to a quinazoline compound, in particular to a compound with a general formula (I) and a preparation method thereof, wherein R1 and Y are defined as the specifications, and a medicine combination of the compound (I) and the purpose thereof are included in a preparation method of the compound. The invention further relates to a compound with a general formula (II), which is the intermediate for preparing the compound with the general formula (I), wherein Ar, R2, R3, m, n and T are defined as the specifications.

Description

Quinazoline compounds
Technical field
The present invention relates to a series of new quinazoline compounds, their preparation method, contain their medical composition and its use; The invention still further relates to the synthetic new used intermediate of quinazoline compound.
Technical background
The phosphorylation of specific tyrosyl residue in the protein tyrosine kinase catalysis various albumen relevant with the adjusting of Growth of Cells and differentiation.Protein tyrosine kinase can roughly be divided into acceptor (such as EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-acceptor (such as c-src, lck, zap70) kinases.Show many these type of kinase whose improper or uncontrolled activation of arriving, that is, for example can cause uncontrolled cells produce by the unusual protein tyrosine kinase activity due to overexpression or the sudden change.
Protein tyrosine kinase, relevant with people's malignant tumour such as the abnormal activity of c-erbB-2, c-src, c-met, EGFr, PDGFr.For example, the EGFr of rising is active relevant with the neck cancer with nonsmall-cell lung cancer, bladder cancer and head, the c-erbB-2 activity of rising and the related to cancer of mammary gland, ovary, stomach and pancreas.Therefore, the arrestin Tyrosylprotein kinase should be able to provide the treatment to above-mentioned tumour.
The paraprotein tyrosine kinase activity is also relevant with other various diseases: psoriasis, fibroid degeneration, atherosclerosis, restenosis, autoimmune disorder, allergy, asthma etc. have shown by the effect of some receptor tyrosine kinases and can control these diseases.
Chinese patent 99803887.3 has openly been reported a series of compounds, and they have protein tyrosine kinase and suppress active, and activity is higher, bioavailability is higher, absorb better this type of new compound also is very important but develop.
Summary of the invention
The object of the present invention is to provide the quinazoline compounds shown in the general formula (I), their preparation method and its usage.
The present invention also aims to provide a kind of pharmaceutical composition that contains the new quinazoline compounds shown in effective dose, the general formula (I), and their application in the diseases such as treatment cancer, malignant tumour and psoriasis;
The present invention also aims to provide synthetic general formula (I) compound used intermediate, they are represented by general formula (II).
The invention discloses general formula (I) compound:
Figure G2008101776387D00021
Wherein
R 1Expression
Figure G2008101776387D00022
, wherein Ar is selected from and is substituted base replacement or unsubstituted furans, thiophene, pyrroles or thiazole, and described substituting group is selected from halogen atom, C 1-4Alkyl or C 1-4Alkoxyl group, substituent number are 1 or 2; M, n are 0,1 or 2 independently of one another; R 2, R 3Be independently from each other
(1) hydrogen,
(2) alkyl,
(3) thiazolinyl,
(4) alkynyl,
(5) alkoxyl group,
(6) alkoxyalkyl,
(7) cycloalkyl,
(8) cycloalkylalkyl,
(9) the alkyl sulphonyl alkyl,
(10) amino acid,
(11) amino acids formed peptide chain,
(12) carbalkoxy,
(13) alkoxycarbonyl alkyl, or
(14) R 2, R 3The ring that becomes with the N atom that links to each other;
But R 2, R 3Be not hydrogen simultaneously;
Y is selected from optional by R 4, R 5The phenyl, pyridyl, 3H-imidazolyl, indyl, 1H-indazolyl or 2, the 3-dihydro-1H-indazolyl that replace; Wherein, R 4Be selected from benzyl, halo-, dihalo-or three halogeno-benzyls, halo-, dihalo-or three halo benzyloxies, pyridylmethyl, pyridyl methoxyl group, 2-picoline oxygen base or benzyloxy; R 5Be selected from hydrogen, hydroxyl, halogen atom, C 1-4Alkyl, C 1-4Alkoxyl group, amino, cyano group or trifluoromethyl.
In preferred version of the present invention, Ar is selected from and is substituted base replacement or unsubstituted furans, thiophene or thiazole, and described substituting group is selected from halogen atom, C 1-4Alkyl or C 1-4Alkoxyl group, substituting group number are 1, more preferably unsubstituted furans or thiazole.
In preferred version of the present invention, m=0 or 1, n=1 or 2.
In the preferred scheme of the present invention, R 2, R 3Be selected from
(1) hydrogen,
(2) C 1-4Alkyl,
(3) C 2-5Thiazolinyl,
(4) C 1-4Alkoxyl group,
(5) C 1-4Alkoxy C 1-4Alkyl,
(6) C 3-8Cycloalkyl,
(7) C 3-8Cycloalkyl-C 1-4Alkyl,
(8) C 1-4Alkyl sulphonyl-C 1-4Alkyl,
(9) natural amino acid,
(10) amino acids formed peptide chain,
(11) C 1-5Carbalkoxy,
(12) C 1-5Carbalkoxy-C 1-4Alkyl, or
(13) R 2, R 3The 3-6 unit heterocycle that becomes with the N atom that links to each other;
But R 2, R 3Be not hydrogen simultaneously.
Wherein, preferably Valine and ALANINE of amino acid; Amino acids formed peptide chain is 2-10 the formed peptide chain of natural amino acid preferably, more preferably 2-5 formed peptide chain of amino acid, and these peptide chains are selected from the aminoacid sequence that sequence SEQ ID NO.1-12 forms.
In preferred version of the present invention, Y is selected from by R 4, R 5The phenyl, pyridyl, 1H-indazolyl or 2, the 3-dihydro-1H-indazolyl that replace; More preferably phenyl or 1H-indazolyl; R 4Be selected from benzyl, halo-benzyl, halo-benzyloxy, pyridylmethyl, pyridyl methoxyl group, 2-picoline oxygen base or benzyloxy; Preferred halo-benzyl, halo-benzyloxy or pyridyl methoxyl group; R 5Be selected from hydrogen, halogen atom, C 1-4Alkyl or C 1-4Alkoxyl group.
In the scheme of invention, preferred compound comprises:
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 426);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 431);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 432);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 433);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 427);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-diethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 434);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, the N-dipropyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 435);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 428);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 436);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 437);
N-(1-(5-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylsulfonyl) ethyl)-2-amino-3-methylbutyryl amine (compound 429);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-(methylsulfonyl)-1-(2-(methylsulfonyl) ethylamino) ethyl) furans-2-yl) quinazoline-4-amine (compound 430);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 524);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 525);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 526);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 527);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(dimethylamino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 528);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 529);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 457);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 458);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propyl group is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 459);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 461);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(cyclopropyl methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 460);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 464);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 465);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propargyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 466).
Preferred compound comprises:
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 426);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 431);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 433);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 427);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 428);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 436);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 437);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-(methylsulfonyl)-1-(2-(methylsulfonyl) ethylamino) ethyl) furans-2-yl) quinazoline-4-amine (compound 430).
In general formula disclosed by the invention (I) compound, can there be with stereoisomer form (can contain one or more unsymmetrical carbons such as them and maybe can show the cis-trans isomerization phenomenon) in some compound.Single steric isomer (enantiomer and diastereomer) and the mixture of these steric isomers are included in the scope of the present invention.Equally, should be appreciated that formula (I) compound can be to be not that the tautomeric forms shown in the formula exists, this is also contained in the scope of the invention.
In the present invention,
" alkyl " refers to side chain or straight chain representative examples of saturated aliphatic hydrocarbon-based; Preferred carbon atom is 1-4 side chain or straight chain representative examples of saturated aliphatic alkyl, such as methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-etc.;
" thiazolinyl " refers to contain at least side chain, straight chain or the ring-type non-aromatic hydrocarbon group of a carbon-carbon double bond, such as vinyl, propenyl, allyl group, butenyl, tetrahydrobenzene etc.;
" alkynyl " refers to contain at least side chain, straight chain or the ring-type hydrocarbon group of a carbon carbon triple bond, such as ethynyl, proyl, butynyl, 3-methyl butynyl, alkynes butyl, propargyl etc.
" cycloalkyl " refers to contain the representative examples of saturated aliphatic hydrocarbon-based of monocycle, and preferred carbon atom is 3-8 cycloalkyl, such as cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, ethyl-cyclopentyl, cyclohexyl etc.;
" alkoxyl group " refers to the group that the straight or branched alkyl links to each other with Sauerstoffatom, such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy etc.;
" C 1-4Alkyl sulphonyl-C 1-4Alkyl " be methylsulfonyl methyl, methylsulfonylethyl, ethylsulfonyl methyl, ethylsulfonyl ethyl etc.;
" C 1-5Alkoxy carbonyl " be methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxy carbonyl, tert-butoxycarbonyl or pentyloxy carbonyl etc.;
" C 1-5Alkoxy carbonyl-C 1-4Alkyl " be methoxycarbonyl methyl, dion e, ethoxy carbonyl methyl, propoxycarbonyl methyl, butoxy carbonyl methyl, tert-butoxycarbonyl methyl or pentyloxy carbonyl methyl etc.;
" halogen atom " refers to fluorine, chlorine, bromine, iodine atom;
" amino acid " refers to natural or non-natural amino acid, natural amino acid preferably, i.e. and common described 21 amino acid are such as L-glycine, Pidolidone, L-arginine, Valine etc.
Another purpose of the present invention provides the method for preparation formula (I) compound, and the method may further comprise the steps:
With formula (II) compound and oxidant reaction, with preparation formula (I) compound,
Figure G2008101776387D00061
R wherein 1, Y, Ar, R 2, R 3, m, n be such as above-mentioned definition, T represents sulphur atom or sulfinyl.In this programme, the reaction that sulphur atom or sulfinyl is oxidized to alkylsulfonyl is well-known to those skilled in the art, and used oxygenant is selected from: metachloroperbenzoic acid, Peracetic Acid, hydrogen peroxide, potassium hydrogen persulfate etc., but potassium hydrogen persulfate preferably.
Another purpose of the present invention provides the method for preparation formula (I) compound, and the method comprises the following steps:
With formula (III) compound and suitable reagent react, with preparation formula (I) compound,
Figure G2008101776387D00062
R wherein 1, Y, Ar, R 2, R 3, m, n be such as above-mentioned definition.In this programme, in formula (III) compound-NH 2React with suitable reagent, wherein, " suitable reagent " refers to that general formula is R 2-L or R 3The compound of-L, they and formula (III) compound generation nucleophilic reaction or Michael reaction obtain formula (I) compound, according to R 2, R 3The difference of representative group, the group that reacts selected condition and L representative is not identical yet, and the classes of compounds of " suitable reagent " representative is not identical yet.
A) work as R 2, R 3When representing the groups such as alkyl, thiazolinyl, alkynyl, alkoxyl group, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, alkoxy carbonyl alkyl, L represents leavings group well-known to those skilled in the art, such as halogen atom (such as fluorine, chlorine, bromine, iodine atom), sulfonyloxy (such as mesyloxy, tolysulfonyl oxygen base) etc.; This reaction is carried out under alkaline condition, and used alkali is selected from mineral alkali (such as sodium bicarbonate, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide etc.) or organic bases (such as ethamine, triethylamine, diisopropylethylamine etc.);
B) work as R 2, R 3During the groups such as represented amino acid, amino acids formed peptide chain or carbalkoxy, these groups link to each other with amino by amido linkage, L represents carboxylic acid or activated carboxylic group well-known to those skilled in the art, such as acyl chlorides, p-nitrophenyl phenolic ester, trifluoro-benzene phenolic ester, the inferior carboxylic acid amide esters of succinyl etc.When L represented hydroxy-acid group, reaction was carried out under the condition that condensing agent exists, and used condensing agent includes but not limited to following kind: DCC, CDI, DIC, EDC, Ph 3P+DIAD, Ph 3P+DEAD etc.; When L representation carboxy activating group, reaction is carried out under alkaline condition, and used alkali is selected from mineral alkali (such as sodium bicarbonate, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide etc.) or organic bases (such as ethamine, triethylamine, diisopropylethylamine etc.);
Another purpose of the present invention provides the used intermediate of synthetic general formula (I) compound, and they are represented by general formula (II), is the key intermediate of preparation general formula (I) compound.
Figure G2008101776387D00071
Wherein Y, Ar, R 2, R 3, m, n such as general formula (I) definition, T represents sulphur atom or sulfinyl.
In the present invention, preferred formula (II) comprising:
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 1);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 2);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 3);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 4);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 5);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-diethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 6);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, the N-dipropyl is amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 7);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 8);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 9);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl is amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 10);
N-(1-(5-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethyl)-2-amino-3-methylbutyryl amine (compound 105);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine (compound 135);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine (compound 136);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine (compound 137);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine (compound 138);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine (compound 139);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine (compound 142);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 53);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(ethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 54);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propyl group is amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 55);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N, N-dimethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 57);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(cyclopropyl methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 56);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 60);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(allyl amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 61);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propargyl is amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine (compound 62);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 240);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 241);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 242);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 243);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 244);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-diethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 245);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, the N-dipropyl is amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 246);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 247);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 248);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl is amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 249);
N-(1-(5-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methanesulfinyl) ethyl)-2-amino-3-methylbutyryl amine (compound 346);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 374);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 375);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 376);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 377);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 378);
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine (compound 381);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(methylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 292);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(ethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 293);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propyl group is amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 294);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N, N-dimethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 296);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(cyclopropyl methylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 295);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 299);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(allyl amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 300);
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propargyl is amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine (compound 301).
Another purpose of the present invention provides a kind of pharmaceutical composition, and it contains general formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of effective dose.
Another purpose of the present invention provides formula (I) compound or the purposes of its pharmacy acceptable salt in the medicine of preparation treatment adjusting c-erbB-2 and/or EGF-R protein tyrosine kinase activity relative disease.
Another purpose of the present invention provides the purposes of pharmaceutical composition in the medicine of preparation treatment adjusting c-erbB-2 and/or EGF-R protein tyrosine kinase activity relative disease that contains general formula (I) compound or its pharmacy acceptable salt.
Another purpose of the present invention provides general formula (I) compound or its pharmacy acceptable salt for the preparation of the purposes in the medicine for the treatment of cancer and malignant tumour.
Another purpose of the present invention provides general formula (I) compound or its pharmacy acceptable salt for the preparation of the purposes in the antipsoriatics thing.
Another purpose of the present invention provides the pharmaceutical composition that contains general formula (I) compound or its pharmacy acceptable salt for the preparation of the purposes in the medicine for the treatment of cancer and malignant tumour.
Another purpose of the present invention provides the pharmaceutical composition that contains general formula (I) compound or its pharmacy acceptable salt for the preparation of the purposes in the antipsoriatics thing.
Medicinal preparations involved in the present invention can exist with unit dosage form, and per unit dosage contains the activeconstituents of predetermined amount.Such unit can contain, for example 0.5mg-1g, the specifically factors such as the age of how much depending on the disease, route of administration and the patient that receive treatment of consumption, body weight, the state of an illness.
Medicinal preparations can give by any suitable approach, gives such as approach such as oral, rectum, nasal cavity, part or parenteral (comprising subcutaneous, muscle, vein or transdermal).Above-mentioned various preparation can pass through the known any method of pharmacy field, for example, and by activeconstituents and carrier or mixed with excipients are prepared.
The compounds of this invention or its pharmacy acceptable salt can give separately or unite use with the other treatment agent of the above-mentioned disease for the treatment of.Especially, in antineoplastic treatment, should consider and other chemotherapeutics, hormone or antibody drug drug combination.
Embodiment
In order to illustrate in greater detail the present invention, provide following example.But scope of the present invention is not to be defined in this.
THF.................. tetrahydrofuran (THF);
DMF.................N, dinethylformamide;
(BOC) 2O............ di-tert-butyl dicarbonic acid ester;
EDC...........1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride;
DCC...............N, the N-dicyclohexylcarbodiimide;
DIC...............N, the N-DIC;
CDI...............N, the N-carbonyl dimidazoles;
DIAD............ diisopropyl azodiformate;
DEAD............ diethyl azodiformate;
The HOBT...............1-hydroxybenzotriazole;
Sar............... sarkosine;
Gly............... glycine;
Leu.................. leucine;
Phe............ phenylalanine
Preparation example 1
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine
Add 6-iodo-3H-quinazoline-4-one (100g) in the 2000mL flask, be dissolved in the mixed solvent of thionyl chloride (1000ml) and DMF (20ml), reflux is to the reaction solution clear.Steam thionyl chloride, do twice with the toluene band, for subsequent use.
Intermediate for subsequent use is dissolved in the Virahol (2000ml), adds 3-chloro-4-(3-fluoro-benzyloxy)-anilinechloride (70g), add the 150g anhydrous K under the mechanical stirring 2CO 3, reflux is spent the night.Be cooled to room temperature with reaction solution next day, and decompress filter is with filter cake water making beating flush away K 2CO 3To neutral, decompress filter, vacuum-drying obtains title product: 95g, off-white color solid.
m/z(M+1) +：506
Preparation example 2
The preparation of N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-iodine quinazoline-4 amine
Method is with preparation example 1, and difference is to change 3-chloro-4-(3-fluoro-benzyloxy)-anilinechloride into 1-(3-luorobenzyl)-1H-indazole-5 amine hydrochlorate.
m/z(M+1) +：496。
Preparation example 3
The preparation of 6-iodo-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine
Method is with preparation example 1, and difference is to change 3-chloro-4-(3-fluoro-benzyloxy)-anilinechloride into 3-methyl-4-(6-picoline-3-oxygen base) anilinechloride.
m/z(M+1) +：469。
Preparation example 4
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-boric acid quinazoline-4-amine
Preparation example 1 gained compound N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine (2.0g) and dried THF (20ml) are put in the reaction flask, obtained yellow solution after the dissolving.Be cooled to 0 ℃, in reaction solution, add ethylmagnesium bromide/THF solution (4.75ml), obtain bright yellow solution.
Be cooled to-78 ℃, add fast triisopropyl boron (3.73ml) in reaction solution, then add n-Butyl Lithium/hexane solution (2.5M, 3.95ml), insulation reaction is complete.
Add acetic acid (0.84ml) in the reaction solution that reacts completely, stir half an hour, add saturated sodium bicarbonate aqueous solution and transfer pH=8, fully extract with ethyl acetate, merge organic layer, the gained organic layer washs with saturated brine, anhydrous sodium sulfate drying.Filter, filtrate decompression is concentrated into dried, and the resistates column chromatography purification gets N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-boric acid quinazoline-4-amine: 1.1g.
m/z(M+1) +：423
Preparation example 5
The preparation of N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-boric acid quinazoline-4 amine
Method is with preparation example 4, and difference is to change reaction raw materials into preparation example 2 compound Ns-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-iodine quinazoline-4 amine by preparation example 1 gained compound N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine.
m/z(M+1) +：413
Preparation example 6
The preparation of 6-boric acid-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine
Method is with preparation example 4, and difference is to change reaction raw materials into preparation example 3 compound 6-iodo-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine by preparation example 1 gained compound N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-iodine quinazoline-4 amine.
m/z(M+1) +：386
Preparation example 7
The preparation of 5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-aldehyde
With preparation example 1 compound (50g), 5-boric acid-2-furfural (21g), Pd (PPh 3) 2Cl 2(6.2g), triethylamine (62ml), methyl alcohol (1000ml) is put in the reaction flask, back flow reaction 2 hours, the TLC detection reaction is complete.Cool to room temperature filters, and filter cake is used first a small amount of methanol wash, then in 50 ℃ of oven dry, gets title compound: 40g, yellow solid.
m/z(M+1) +：473。
Preparation example 8
The preparation of 5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) thiophene-2-aldehyde
Method is with preparation example 7, and difference is to change reaction raw materials 5-boric acid-2-furfural into 5-boric acid-2-thiophene aldehyde.
m/z(M+1) +：489
Preparation example 9
The preparation of 5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) pyrroles-2-aldehyde
Method is with preparation example 7, and difference is to change reaction raw materials 5-boric acid-2-furfural into 5-boric acid-2-pyrroles's aldehyde.
m/z(M+1) +：471
Preparation example 10
The preparation of 2-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) thiazole-5-aldehyde
With preparation example 4 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-boric acid quinazoline-4-amine (50g), 2-bromo-5-thiazole aldehyde (21g), Pd (PPh 3) 2Cl 2(6.2g), triethylamine (62ml), methyl alcohol (1000ml) is put in the reaction flask, back flow reaction 2 hours, the TLC detection reaction is complete.Cool to room temperature filters, and filter cake is used first a small amount of methanol wash, then in 50 ℃ of oven dry, gets title compound: 30g.
m/z(M+1) +：490
Preparation example 11
The preparation of 5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) thiazole-2-aldehyde
Method is with preparation example 10, and difference is to change 2-bromo-5-thiazole aldehyde into 5-bromo-2-thiazole aldehyde.
m/z(M+1) +：490
Preparation example 12
The preparation of 2-(4-(1-(3-luorobenzyl)-1H-indazole-5-base is amino) quinazoline-6-yl) thiazole-5-aldehyde
Method is with preparation example 10, and difference is to change raw material into preparation example 5 compound Ns-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-boric acid quinazoline-4 amine by preparation example 4 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-boric acid quinazoline-4-amine.
m/z(M+1) +：480
Preparation example 13
The preparation of 2-(4-(3-methyl-4-(2-picoline-4-oxygen base) phenyl amino) quinazoline-6-yl) thiazole-5-aldehyde
Method is with preparation example 10, and difference is to change raw material into preparation example 6 compound 6-boric acid-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine by preparation example 4 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-boric acid quinazoline-4-amine.
m/z(M+1) +：453
Preparation example 14
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine
With preparation example 7 compound 5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-aldehyde (47.3g), t-butyl sulfonamide (14.5g), tetraisopropoxy titanium (85g), THF (1000ml) puts in the reaction flask, and room temperature reaction spends the night.Next day, process: add water 50ml, ethyl acetate 500ml stirs 10min, filters, and filter cake is washed 3 times with THF.Filtrate adds anhydrous magnesium sulfate drying, filters, and the concentrated yellow oil 50g that to get is directly used in the lower step to feed intake.
Dimethyl sulfone (37.6g) is dissolved in anhydrous THF (2000ml), under the nitrogen protection, is cooled to-20 ℃, drip n-BuLi (0.3mol).Drip and finish insulated and stirred 30min.The cooling reaction solution is to below-80 ℃, and insulation 5min adds upper step gained yellow oil fast, keeps below Nei Wen-80 ℃.Insulated and stirred reaction 10min processes.In reaction solution impouring saturated aqueous common salt 3000ml, add ethyl acetate 2000ml, separatory; Organic layer is washed with saturated aqueous common salt 2000ml, anhydrous magnesium sulfate drying.Filter, filtrate decompression concentrates to get yellow solid 40g.TLC condition: chloroform/methanol=10/1, R The f raw material=0.8, R The f product=0.65.
Gained yellow solid of upper step (40g) is dissolved among the THF (1500ml), transfers pH=1 with HCl-ethanol, stirring at room 2 hours is processed.Add strong aqua and transfer pH=9, add saturated aqueous common salt 2000ml, ethyl acetate 1500ml, separatory, organic layer anhydrous magnesium sulfate drying.Filter, filtrate decompression is concentrated, and the resistates silica gel column chromatography (eluent: ethyl acetate--ethyl acetate/THF=3/1), collect qualified component, concentrated, get title compound: 20g, yellow solid.
m/z(M+1) +：567
By the identical method of preparation example 14, the preparation following compounds:
Numbering Title Molecular weight (g/mol)
Preparation example 15 N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) thiophene-2-yl) quinazoline-4-amine 583
Preparation example 16 N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl) quinazoline-4-amine 584
Preparation example N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(first 584
17 Alkylsulfonyl) ethyl) thiazole-5-yl) quinazoline-4-amine
Preparation example 18 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine 556
Preparation example 19 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) thiophene-2-yl) quinazoline-4-amine 572
Preparation example 20 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl) quinazoline-4-amine 573
Preparation example 21 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) thiazole-5-yl) quinazoline-4-amine 573
Preparation example 22 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) pyrroles-2-yl) quinazoline-4-amine 555
Preparation example 23 6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine 529
Preparation example 24 6-(5-(1-amino-2-(methylsulfonyl) ethyl) thiophene-2-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine 545
Preparation example 25 6-(5-(1-amino-2-(methylsulfonyl) ethyl) thiazol-2-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine 546
Preparation example 26 6-(5-(1-amino-2-(methylsulfonyl) ethyl) thiazole-5-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine 546
Preparation example 27 6-(5-(1-amino-2-(methylsulfonyl) ethyl) pyrroles-2-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine 528
Preparation example 28
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine
Under the nitrogen atmosphere; with preparation example 4 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-boric acid quinazoline-4-amine (16.9g), 1-(5-bromine furans-2-yl)-3-(methylsulfonyl) propyl group-2-aminocarbamic acid tert-butyl ester (15.3g) and Pd (Ph 3P) 2Cl 2(1.0g) be dissolved in 1 under the stirring, in the mixed solvent of 2-glycol dimethyl ether (400ml) and methyl alcohol (200ml), stir the lower triethylamine (14mL) that adds, mixed solution is heated to 55 ℃, stirring is spent the night, and reacts complete.In reaction solution, add entry (300mL), stirring has yellow solid to separate out, after stirring 10min, leave standstill 30min, filter, mother liquor under reduced pressure is spin-dried for, and (normal hexane: acetone: triethylamine=200:100:1) further separation and purification obtains yellow solid to the solid that obtains: 10.4g by column chromatography;
Yellow solid of upper step (6.8g) is dissolved in the 50mL HCl methanol solution (compound method: drip 90mL methyl alcohol in the 54mL Acetyl Chloride 98Min., get wherein 50mL), stirs under the room temperature and spend the night.Reaction solution is evaporate to dryness under reduced pressure, obtains title compound: 5.2g.
m/z(M+1) +：581
By the identical method of preparation example 28, the preparation following compounds:
Numbering Title Molecular weight (g/mol)
Preparation example N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-amino-3-(first 596
29 Alkylsulfonyl) propyl group) thiophene-2-yl) quinazoline-4-amine
Preparation example 30 N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl) quinazoline-4-amine 597
Preparation example 31 N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) thiazole-5-yl) quinazoline-4-amine 597
Preparation example 32 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine 570
Preparation example 33 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) thiophene-2-yl) quinazoline-4-amine 586
Preparation example 34 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl) quinazoline-4-amine 587
Preparation example 35 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) thiazole-5-yl) quinazoline-4-amine 587
Preparation example 36 N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(2-amino-3-(methylsulfonyl) propyl group) pyrroles-2-yl) quinazoline-4-amine 569
Preparation example 37 6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine 529
Preparation example 38 6-(5-(2-amino-3-(methylsulfonyl) propyl group) thiophene-2-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine 559
Preparation example 39 6-(5-(2-amino-3-(methylsulfonyl) propyl group) thiazol-2-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine 560
Preparation example 40 6-(5-(2-amino-3-(methylsulfonyl) propyl group) thiazole-5-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine 560
Preparation example 41 6-(5-(2-amino-3-(methylsulfonyl) propyl group) pyrroles-2-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine 542
Preparation example 42
The preparation of tetrapeptide Gly-Phe-Leu-Gly
Use balance to take by weighing 2-Chlorotrityl Chloride Resin resin (20g) (theoretical substitution value 1m mol/g) and soak 30min with DCM (200ml), drain.Take by weighing Fmoc-Gly-OH (3g) and DIPEA (50mmol), be dissolved among the DCM (200ml), nitrogen bubble was washed three times with the DCM/MeOH/DIPEA=17:2:1 mixing solutions after 1 hour, each 200ml, and then anhydrous diethyl ether 200ml washing is 3 times.Then resin vacuumizes drying, weighs, and calculating and loading molar weight is 10mmol.
Add hexahydropyridine/DMF (20%) mixed solution 200ml in above-mentioned resin, reaction solution is drained in nitrogen bubble reaction 5 minutes, adds hexahydropyridine/DMF (20%) mixed solution 200ml again, reacts 20 minutes.Drain reaction solution, resin washs four times with DMF (200ml), after draining, put into the small test tube that is added with ninhydrin reagent with the resin (about 30～50) that kapillary takes a morsel, small test tube is put into the heating of 103 ℃ of blocked well heaters take out after 5 minutes and observe the aobvious opaque atropurpureus of ninhydrin reagent.
Take by weighing Fmoc-Leu-OH (10.6g) and be dissolved in 0.4M HOBT/DMF (75ml) solution, moltenly join in the above-mentioned resin after clear, add subsequently 0.4M DIC/DM (75ml) solution.Solvent was drained in the nitrogen bubble reaction in 4 hours.With alternately washing of DMF, IPA, to drain, the resin triketohydrindene hydrate detects.
Add hexahydropyridine/DMF (20%) mixed solution 200ml in above-mentioned resin, reaction solution is drained in nitrogen bubble reaction 5 minutes, adds hexahydropyridine/DMF (20%) mixed solution 200ml again, reacts 20 minutes.Drain reaction solution, resin washs four times with DMF (200ml), and after draining, triketohydrindene hydrate detects.
Take by weighing Fmoc-Phe-OH (11.7g) and be dissolved in 0.4M HOBT/DMF (75ml) solution, moltenly join in the above-mentioned resin after clear, add subsequently 0.4M DIC/DM (75ml) solution.Solvent was drained in the nitrogen bubble reaction in 6 hours.Alternately drain solvent after the washing with DMF, IPA, triketohydrindene hydrate detects.
Add hexahydropyridine/DMF (20%) mixed solution 200ml in above-mentioned resin, reaction solution is drained in nitrogen bubble reaction 5 minutes, adds hexahydropyridine/DMF (20%) mixed solution 200ml again, reacts 20 minutes.Drain reaction solution, resin washs four times with 200ml DMF, and after draining, triketohydrindene hydrate detects.
Take by weighing Fmoc-Gly-OH (9g) and be dissolved in 0.4M HOBT/DMF (75ml) solution, moltenly join in the above-mentioned resin after clear, add subsequently 0.4M DIC/DM (75ml) solution.Solvent was drained in the nitrogen bubble reaction in 4 hours.Alternately drain solvent after the washing with DMF, IPA, triketohydrindene hydrate detects.
Add hexahydropyridine/DMF (20%) mixed solution 200ml in above-mentioned resin, reaction solution is drained in nitrogen bubble reaction 5 minutes, adds hexahydropyridine/DMF (20%) mixed solution 200ml again, reacts 20 minutes.Drain reaction solution, resin washs four times with 200ml DMF, and after draining, triketohydrindene hydrate detects.
And then it is dry to wash twice final vacuum with the 200ml ether. treat the resin peptide complete drying, take out weighing resin peptide weight and be 25.1g. then in above-mentioned resin peptide, add the cutting solution of TFA:TIS:H2O:EDT=90:2.5:2.5:5.Nitrogen bubble reaction 3 hours, react complete after, drain solution, again with twice of 25ml cutting solution washing resin. merge and cut solution, be evaporated to 100ml.Solution punching after concentrated is analysed in the 1000ml cold diethyl ether, place refrigerator after 2 hours, centrifugal or filtration obtains the crude product peptide of solid, gets 4.1g crude product peptide (Gly-Leu-Leu-Gly) after vacuum-drying.
Above-mentioned crude product peptide is dissolved in the 4200ml pure water, then is prepared purifying
The column chromatography condition:
Instrument: Waters Delta-4000
Chromatographic column: Phenomenex Luna C18 10 μ (50*300mm)
Eluent: 0.1% trifluoroacetic acid aqueous solution (A) and 0.1% trifluoroacetic acid acetonitrile (B)
Detect wavelength: 220nm
Flow velocity: 100ml/min
Gradient condition:
Time (minute) A B
0 15％ 85％
15 30％ 70％
16 70％ 30％
18 70％ 30％
19 15％ 85％
After the preparation, merge positive component, concentrating under reduced pressure goes out organic phase (bath temperature＜40 ℃), and lyophilize gets Gly-Phe-Leu-Gly elaboration peptide 1g
By the identical method of preparation example 42, prepare other polypeptide compounds:
Numbering Peptide sequence SEQ?ID?NO
Preparation example 43 Gly-Gly 1
Preparation example 44 Gly-Phe-Gly 2
Preparation example 45 Gly-Phe-Phe 3
Preparation example 46 Gly-Leu-Gly 4
Preparation example 47 Gly-Val-Ala 5
Preparation example 48 Gly-Phe-Ala 6
Preparation example 49 Gly-Leu-Phe 7
Preparation example 50 Gly-Phe-Leu-Phe 8
Preparation example 51 Gly-Gly-Gly 9
Preparation example 52 Gly-Leu-Ala 10
Preparation example 53 Sar-Gly 11
Preparation example 42 Gly-Phe-Leu-Gly 12
Embodiment one
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4 amine (compound 1)
THF (100ml) after preparation example 7 compound 5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-aldehyde (4.7g) and the drying processing is put in the reaction flask, be cooled to about-20 ℃, drip methylthiomethyl magnesium chloride/THF solution (1.3mol/l, 7.8ml), drip off rear insulation reaction 2 hours.The sodium dihydrogen phosphate that adds 1N in this reaction solution is to pH=5-6, and then concentrate under reduced pressure at low temperature fully extracts with ethyl acetate, merges organic layer, saturated brine washing, anhydrous magnesium sulfate drying.Filter, filtrate decompression is concentrated to be done, and column chromatography purification gets 1-(5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethanol: 3.2g.m/z(M+1) +：536
Reaction of upper step gained compound 1-(5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethanol (5.4g) is dissolved in the mixed solvent (1:1 of methylene dichloride/THF, 100ml), be cooled to 0-5 ℃, be added dropwise to triethylamine (2.0ml), then be added dropwise to methane sulfonyl chloride (1.2ml), drip off and naturally be warming up to room temperature reaction 2 hours afterwards.Reaction solution is successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated brine washing, drying.Filter, filtrate is concentrated does, and is directly used in the next step.
Route one:
Reactant of upper step is joined CH 3-NH 2In/the methanol solution, stirring at room reacts completely, and concentrating under reduced pressure is done, and column chromatography purification gets title compound: 2.6g.
m/z(M+1) +：549
Route two:
Reactant of upper step is joined NH 3In/the methanol solution, stirring at room reacts completely, and concentrating under reduced pressure is done, and column chromatography purification gets 1-(5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethamine: 2.8g;
Method A: with gained compound 1-of upper step (5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethamine (2.0g), methyl iodide (0.5g) and triethylamine (0.7g) are dissolved among the THF (150ml), be heated to backflow, raw material reaction is complete behind the 2h.Stopped heating adds saturated aqueous common salt in reaction solution, add ethyl acetate extraction, organic phase saturated aqueous common salt washed twice, drying.Filtering and concentrating, (chloroform/methanol=100:1) get title compound 1.5g is numbered compound 1 to the resistates column chromatography purification.
Method B: gained compound 1-of upper step (5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethamine (5.4g) is dissolved among the DMSO (50ml), add formaldehyde (6ml), formic acid (3ml), the stirring at room reaction is spent the night.Reaction solution is punched in the frozen water (500ml), filters, drain, after filter cake dissolves with THF, silica gel sand processed, column chromatography purification gets title compound: 4.2g is numbered compound 1.
Press embodiment one similar approach, take 1-(5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethamine as starting raw material, with the reaction reagent reaction, finish the preparation of following compound:
Figure G2008101776387D00191
Figure G2008101776387D00192
Figure G2008101776387D00201
Figure G2008101776387D00202
Take 1-(5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) thiophene-2-yl)-2-(methylthio group) ethamine as starting raw material, with the reaction reagent reaction, finish the preparation of following compound:
Figure G2008101776387D00203
Figure G2008101776387D00211
Figure G2008101776387D00212
Take 1-(5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) pyrroles-2-yl)-2-(methylthio group) ethamine as starting raw material, with the reaction reagent reaction, finish the preparation of following compound:
Figure G2008101776387D00213
Figure G2008101776387D00221
Take N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(amino)-2-(methylthio group) ethyl) thiazol-2-yl) quinazoline-4-amine as starting raw material, and the reaction reagent reaction, finish the preparation of following compound:
Figure G2008101776387D00223
Take N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine as starting raw material, with the reaction reagent reaction, finish the preparation of following compound:
Figure G2008101776387D00231
Figure G2008101776387D00232
Take N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(amino)-2-(methylthio group) ethyl) thiazol-2-yl) quinazoline-4-amine as starting raw material, with the reaction reagent reaction, finish the preparation of following compound:
Figure G2008101776387D00233
Figure G2008101776387D00241
Figure G2008101776387D00242
Take 6-(5-(1-amino-2-(methylthio group) ethyl) furans-2-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine as starting raw material, with the reaction reagent reaction, finish the preparation of following compound:
Figure G2008101776387D00251
Figure G2008101776387D00252
Take 6-(5-(1-amino-2-(methylthio group) ethyl) thiazol-2-yl)-N-(3-methyl-4-(6-picoline-3-oxygen base) phenyl) quinazoline-4-amine as starting raw material, with the reaction reagent reaction, finish the preparation of following compound:
Figure G2008101776387D00253
Embodiment two
The preparation of N-(1-(5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethyl)-2-amino-3-methylbutyryl amine (compound 105)
The first compound 1-that embodiment one is obtained (5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethamine (5.7g); the α-amino-isovaleric acid (2.2g) of BOC protection; EDC.HCl (5.7g); HOBT (4.0g) is dissolved among the DMF (250ml); stirring is spent the night, and is complete to the raw material primitive reaction.Add the rear stirring of saturated aqueous common salt (250ml) in reaction solution, add ethyl acetate (250ml * 2) and extract, the organic phase that obtains saturated aqueous common salt washed twice re-uses anhydrous sodium sulfate drying.Filtration treatment, filtrate decompression is concentrated into dried, obtains the second compound, and this second compound is directly used in the lower step and feeds intake.
With second compound of THF (150ml) dissolving as intermediate, stir, and to wherein adding ethanol/HCL, the conditioned reaction system be about pH=1, continue stirring 1 hour, after question response is complete, drip ammoniacal liquor to reaction system and regulate about pH to pH=10, continue to add ethyl acetate (150ml * 2), extractive reaction system to reaction system, the organic phase that obtains saturated aqueous common salt washed twice, anhydrous sodium sulfate drying.Filter, filtrate decompression is concentrated, and (ether stirs the resistates column chromatography purification, gets title compound: 4.2g for chloroform/methanol=50:1), collect positive component, concentrate drying.
m/z(M+1) +：634
Press embodiment two similar approach, finish the preparation of following compound:
Figure G2008101776387D00262
Figure G2008101776387D00263
Figure G2008101776387D00272
Figure G2008101776387D00273
Figure G2008101776387D00281
Embodiment three
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-(methylamino-)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine (compound 135)
2-(5-bromine furans-2-yl) acetic acid (1.54g) and THF (200ml) are put in the reaction flask, be cooled to 0 ℃.Insulation is lower to add DCC (2.28g), N successively, and O-dimethyl hydroxyl semicarbazide hydrochloride (1.1g) and DIPEA (9.0ml) in 0 ℃ of reaction 1 hour, then spend the night in room temperature reaction.Filter, solid washs with cold THF, and filtrate merges, and concentrating under reduced pressure is dry, and column chromatography purification gets 1-(5-bromine furans-2-yl)-3-methoxyl group fourth-2-ketone: 1.4g.
Under nitrogen protection, intermediate 1-of upper step (5-bromine furans-2-yl)-3-methoxyl group fourth-2-ketone (24.8g) and the THF (200ml) that processed are put in the reaction flask; with extremely-30 to-40 ℃ of cooled reaction solutions; in this solution, drip methylthiomethyl magnesium chloride/THF solution (1.3mol/l; 77.0ml); after dripping fully, continued the reaction soln insulation reaction 2 hours.The sodium dihydrogen phosphate that adds 1N in this reaction soln is to pH=5-6, and concentrate under reduced pressure at low temperature it, then fully extract with ethyl acetate, merge the organic layer that extraction obtains, saturated brine washing organic layer, this organic layer of anhydrous magnesium sulfate drying.Filter, filtrate decompression is concentrated to be done, and gets 1-(5-bromine furans-2-yl)-3-(methylthio group) third-2-ketone: 15.4g.
Intermediate 1-of upper step (5-bromine furans-2-yl)-3-(methylthio group) third-2-ketone (24.9g), pyridine (20ml), oxammonium hydrochloride (10g) and ethanol (100ml) are put in the reaction flask, complete to back flow reaction.The reaction solution concentrating under reduced pressure is done, and adds entry and methylene dichloride in residual solution, makes it layering, and the back extraction water layer merges the organic layer that obtains and washs with saturated brine, and adds anhydrous sodium sulfate drying.Filter, filtrate decompression is concentrated to be done, and the enriched material that obtains is directly used in the next step.
The enriched material that the upper step was obtained is dissolved in it in methyl alcohol (100ml) as intermediate, is cooled to 0-5 ℃, and gradation adds sodium borohydride reduction and reacts completely in the reaction soln.Continuation slowly adds the unreacted sodium borohydride of water decomposition in the reaction solution, concentrating under reduced pressure, adopt dichloromethane extraction it, merge the organic layer that obtains, use anhydrous sodium sulfate drying.Filter, filtrate decompression is concentrated to be done, and gets 1-(5-bromine furans-2-yl)-3-(methylthio group) third-2-amine: 23.0g, is directly used in the lower step to feed intake.
With intermediate 1-of upper step (5-bromine furans-2-yl)-3-(methylthio group) third-2-amine (25g), triethylamine (20ml), (BOC) 2O (43.6g) and methyl alcohol (100ml) are put in the reaction flask, and the stirring at room reaction is spent the night, and concentrating under reduced pressure is done, and adds methylene dichloride and water, makes it layering, and the back extraction water layer merges the organic layer anhydrous sodium sulfate drying that obtains.Filter, filtrate decompression is concentrated to be done, and column chromatography purification gets 1-(5-bromine furans-2-yl)-3-(methylthio group) third-2-ammonia t-butyl formate: 26.8g.
Under the nitrogen atmosphere, with backbone compounds [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-boric acid-quinazoline-4-yl)-amine (16.9g), side chain intermediate 1-(5-bromine furans-2-yl)-3-(methylthio group) third-2-ammonia t-butyl formate (15.3g), Pd (Ph 3P) 2Cl 2(1.0g) be dissolved in 400mL1 under the stirring, in the mixed solvent of 2-glycol dimethyl ether and 200mL methyl alcohol, stir the lower triethylamine (14ml) that adds, mixed solution is heated to 55 ℃, stirring is spent the night, and reacts complete.In reaction solution, add entry (300ml), stirring has yellow solid to separate out, after stirring 10min, leave standstill 30min, filter, mother liquor under reduced pressure is spin-dried for, and the solid that obtains is by column chromatography (normal hexane: acetone: triethylamine=200:100:1) further separation and purification, positive component is concentrated to be done, and is directly used in the lower step to feed intake.
The concentrated dry thing that obtains is dissolved in the HCl/ methanol solution (compound method: drip 90ml methyl alcohol in the 54ml Acetyl Chloride 98Min., get wherein 50ml) of 50ml 5.23mol/L as intermediate (6.8g), stirs under the room temperature and spend the night.Reaction solution is evaporate to dryness under reduced pressure, obtains N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-(amino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine: 5.4g.
Method A: with gained compound N of upper step-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-(amino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine (2.0g), methyl iodide (0.5g) and triethylamine (0.7g) are dissolved among the THF (150ml), be heated to backflow, raw material reaction is complete behind the 2h.Stopped heating adds saturated aqueous common salt in reaction solution, add ethyl acetate extraction, organic phase saturated aqueous common salt washed twice, drying.Filtering and concentrating, (chloroform/methanol=100:1) get title compound 1.6g is numbered compound 135 to the resistates column chromatography purification.
Method B: gained compound N of upper step-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-(amino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine (5.4g) is dissolved among the DMSO (50ml), add formaldehyde (6ml), formic acid (3ml), the stirring at room reaction is spent the night.Reaction solution is punched in the frozen water (500ml), filters, drain, after filter cake dissolves with THF, silica gel sand processed, column chromatography purification gets title compound: 4.4g is numbered compound 135.
m/z(M+1) +：563
Press embodiment three similar approach, finish the preparation of following compound:
Figure G2008101776387D00301
Figure G2008101776387D0030103746QIETU
Figure G2008101776387D00303
Figure G2008101776387D00304
Figure G2008101776387D00311
Figure G2008101776387D00312
Figure G2008101776387D00322
Figure G2008101776387D00331
Figure G2008101776387D00332
Figure G2008101776387D00333
Figure G2008101776387D00334
Figure G2008101776387D00341
Figure G2008101776387D00343
Figure G2008101776387D00351
Figure G2008101776387D00352
Figure G2008101776387D00353
Figure G2008101776387D00361
Embodiment four
N-(4-(3-fluorine the benzyloxy)-3-chloro-phenyl-)-6-(preparation of 5-(1-(methylamino)-2-(methylsulfinyl ethyl) furans-2-yl) quinazoline-4 amine (compound 240)
Method A: embodiment one preparation gained compound N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4 amine (54.9g) is dissolved in the chloroform (200ml), be cooled to about-30 ℃, drip the solution (3.5g/100ml) of metachloroperbenzoic acid and chloroform, drip off rear insulation reaction 1 hour, add triethylamine (15ml) and saturated aqueous sodium thiosulfate (50ml), stirred 15 minutes, layering, organic layer washs with saturated brine, uses anhydrous magnesium sulfate drying again.Filter, filtrate decompression is concentrated into 1/3 volume, adds ether, stirring and crystallizing.Filter, dry title compound: the 38g that gets, yellow solid is numbered compound 240.
m/z(M+1) +：565
Method B: with embodiment one preparation gained compound N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4 amine (54.9g), CH 2Cl 2(500ml) and Virahol (300ml) put in the reaction flask, stir molten clearly, reaction solution is chilled to 15～25 ℃, drip 25% Peracetic Acid (35g), rate of addition processed makes T In＜25 ℃, dripped off insulation reaction 15 minutes.Add saturated brine (150ml) in reaction solution, stir layering, organic layer is used the salt water washing 2 times again, anhydrous magnesium sulfate drying.Filter, filtrate decompression is concentrated into 1/3 volume, is added dropwise to ether, stirring and crystallizing.Filter dry title compound: 41g, the yellow solid of getting.
Press embodiment four similar approach, with embodiment one, embodiment two, embodiment three compound oxidations, finish the preparation of following compounds
Figure G2008101776387D00362
Figure G2008101776387D00371
Figure G2008101776387D00373
Figure G2008101776387D00381
Figure G2008101776387D00382
Figure G2008101776387D00383
Figure G2008101776387D00391
Figure G2008101776387D00393
Figure G2008101776387D00401
Figure G2008101776387D00402
Figure G2008101776387D00403
Figure G2008101776387D00412
Figure G2008101776387D00421
Figure G2008101776387D00422
Figure G2008101776387D00423
Figure G2008101776387D00424
Figure G2008101776387D00425
Figure G2008101776387D00431
Figure G2008101776387D00432
Figure G2008101776387D00433
Figure G2008101776387D00441
Figure G2008101776387D00442
Figure G2008101776387D00443
Figure G2008101776387D00451
Figure G2008101776387D00452
Figure G2008101776387D00453
Figure G2008101776387D00461
Figure G2008101776387D00462
Figure G2008101776387D00463
Figure G2008101776387D00464
Figure G2008101776387D00471
Embodiment five
N-(4-(3-fluorine the benzyloxy)-3-chloro-phenyl-)-6-(preparation of 5-(1-(methylamino)-2-(methylsulfonyl ethyl) furans-2-yl) quinazoline-4 amine (compound 426)
Route one:
With embodiment one gained compound N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylmercaptoethyl) furans-2-yl) quinazoline-4 amine or embodiment four gained compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(mixed solvent (7:3 of 5-(1-(methylamino)-2-(methylsulfinyl ethyl) furans-2-yl) quinazoline-4 amine each (50g) and methanol/water, 1000ml) put in the reaction flask, after the dissolving, gradation adds oxone (100g), continues at stirring at room reaction 2 hours after adding.Filter, filter cake washs with the mixing solutions of methanol/water, and filtrate is transferred pH=8 with saturated sodium bicarbonate solution, and concentrating under reduced pressure adds ethyl acetate (500ml * 2) and extracts, and merges organic layer, uses anhydrous sodium sulfate drying again.Filter, filtrate decompression is concentrated to be done, column chromatography purification (eluent: chloroform/methanol=100:1) title compound: 40g, yellow solid.Numbering compound 426
m/z(M+1) +：581
Route two:
Method A: with preparation example 14 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (2.0g); methyl iodide (0.5g) and triethylamine (0.7g) are dissolved among the THF (150ml); be heated to backflow, raw material reaction is complete behind the 2h.Stopped heating adds saturated aqueous common salt in reaction solution, add ethyl acetate extraction, organic phase saturated aqueous common salt washed twice, anhydrous sodium sulfate drying.Filter, filtrate decompression is concentrated, and (chloroform/methanol=100:1), get title compound 1.5g is numbered compound 426 to the resistates column chromatography purification.
Method B: preparation example 14 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (5.4g) is dissolved among the DMSO (50ml); add formaldehyde (6ml), formic acid (3ml), the stirring at room reaction is spent the night.Reaction solution is punched in the frozen water (500ml), filters, drain, after filter cake dissolves with THF, silica gel sand processed, column chromatography purification gets title compound: 4.4g.
Embodiment six
N-(4-(3-fluorine the benzyloxy)-3-chloro-phenyl-)-6-(preparation of 5-(1-(N, N-dimethylamino)-2-(methylsulfonyl ethyl) furans-2-yl) quinazoline-4 amine (compound 427)
Route one:
The preparation method is with embodiment five routes one, difference is that ((5-(1-(methylamino)-2-(methylsulfinyl ethyl) furans-2-yl) quinazoline-4 amine changes N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N into to 5-(1-(methylamino)-2-(methylmercaptoethyl) furans-2-yl) quinazoline-4 amine or embodiment four gained compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-by N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-with compound of reaction, the N-dimethylamino)-and 2-(methylmercaptoethyl) furans-2-yl) quinazoline-4 amine or N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, the N-dimethylamino)-and 2-(methylsulfinyl ethyl) furans-2-yl) quinazoline-4 amine, be numbered compound 427.
m/z(M+1) +：595
Route two:
Method A: with preparation example 14 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (2.0g); methyl iodide (1.0g) and triethylamine (1.5g) are dissolved among the THF (150ml); be heated to backflow, raw material reaction is complete behind the 2h.Stopped heating adds saturated aqueous common salt in reaction solution, add ethyl acetate extraction, and organic phase saturated aqueous common salt washed twice is said dried over sodium sulfate with nothing again.Filtering and concentrating, (chloroform/methanol=100:1) get title compound 1.6g is numbered compound 427 to the resistates column chromatography purification.
Method B: preparation example 14 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (5.4g) is dissolved among the DMSO (50ml); add formaldehyde (12ml), formic acid (6ml), the stirring at room reaction is spent the night.Reaction solution is punched in the frozen water (500ml), filters, drain, after filter cake dissolves with THF, silica gel sand processed, column chromatography purification gets title compound: 4.6g.
Embodiment seven
N-(4-(3-fluorine the benzyloxy)-3-chloro-phenyl-)-6-(preparation of 5-(1-(N-methyl, N-ethylamino)-2-(methylsulfonyl ethyl) furans-2-yl) quinazoline-4 amine (compound 428)
Route one:
The preparation method is with embodiment five routes one, difference is that ((5-(1-(methylamino)-2-(methylsulfinyl ethyl) furans-2-yl) quinazoline-4 amine changes N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl into to 5-(1-(methylamino)-2-(methylmercaptoethyl) furans-2-yl) quinazoline-4 amine or embodiment four gained compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-by N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-with compound of reaction, the N-ethylamino)-and 2-(methylmercaptoethyl) furans-2-yl) quinazoline-4 amine or N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, the N-ethylamino)-and 2-(methylsulfinyl ethyl) furans-2-yl) quinazoline-4 amine, be numbered compound 428.
m/z(M+1) +：609
Route two:
With preparation example 14 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (2.0g); iodoethane (1.0g) and triethylamine (1.5g) are dissolved among the THF (150ml); be heated to backflow, raw material reaction is complete behind the 2h.Stopped heating adds saturated aqueous common salt in reaction solution, add ethyl acetate extraction, and organic phase saturated aqueous common salt washed twice is used anhydrous sodium sulfate drying again.Filtering and concentrating is done, and the gained resistates is used THF (150ml) dissolving again, adds methyl iodide (0.5g) and triethylamine (1.5g), back flow reaction 2 hours.After the question response liquid cooling but, add saturated aqueous common salt, ethyl acetate extraction, organic phase saturated brine washed twice is used anhydrous sodium sulfate drying again.Filter, the concentrated dried rear column chromatography purification of filtrate decompression gets title compound: 1.2g.
Embodiment eight
The preparation of N-(1-(5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylsulfonyl) ethyl)-2-amino-3-methylbutyryl amine (compound 429)
Route one:
The preparation method is with embodiment five routes one, difference is that (5-(1-(methylamino)-2-(methylmercaptoethyl) furans-2-yl) quinazoline-4 amine changes into-(1-(5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethyl)-2-amino-3-methylbutyryl amine, is numbered compound 429 by N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-with compound of reaction.
m/z(M+1) +：650
Route two:
The preparation method is with embodiment two, and difference is to change compound 1-(5-(4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethamine into preparation example 14 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine.
Embodiment nine
The preparation of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-(methylsulfonyl)-1-(2-(methylsulfonyl) ethylamino) ethyl) furans-2-yl) quinazoline-4-amine (compound 430)
Preparation example 14 compound Ns-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-amino-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine (2.0g), methylsulfonyl ethene (400mg) and methyl alcohol (50ml) are put in the reaction flask stirring at room reaction 48 hours.Concentrating under reduced pressure is done, and column chromatography purification (eluent: chloroform/methanol=100:1) get title compound: 1.1g, number compound 430.
m/z(M+1) +：687
Press embodiment five, six, seven, all directions method, finish the preparation of following compound:
Figure G2008101776387D00501
Figure G2008101776387D00502
Figure G2008101776387D00511
Figure G2008101776387D00513
Figure G2008101776387D00514
Figure G2008101776387D00521
Figure G2008101776387D00522
Figure G2008101776387D00523
Figure G2008101776387D00533
Figure G2008101776387D00541
Figure G2008101776387D00542
Figure G2008101776387D00543
Figure G2008101776387D00544
Figure G2008101776387D00545
Figure G2008101776387D00551
Figure G2008101776387D00552
Figure G2008101776387D00553
Figure G2008101776387D00562
Figure G2008101776387D00563
Test example one
Anti tumor activity in vitro is estimated
Test method: SRB
Cell strain: SK-BR-3; BT474
Test design: cell and different concns compound incubation 120 hours, the inhibition degree of employing srb assay assessing compound on cell proliferation is calculated inhibiting rate, adopts the Logit method to calculate IC according to inhibiting rate 50, the anti tumor activity in vitro of comparative compound.
Inhibiting rate method of calculation: inhibiting rate (%)=(control group OD value-medication group OD value)/control group OD value * 100%
Test-results
Figure G2008101776387D00581
Test example two
The curative effect of compound 426, compound 427, compound 428,430 pairs of people's lung cancer of compound Calu-3 Nude Mice
1 summary
Estimate and the curative effect of invention compound compound 426, compound 427, compound 428,430 pairs of people's lung cancer of compound Calu-3 Nude Mice relatively, and make comparisons with lapatinibditosylate.
2 compound methods
The military 0.1%Tween-80 of all assessing compounds and distilled water are made into desired concn
3 laboratory animal
The BALB/cA-nude nude mouse, in 6-7 week, ♀ is available from Shanghai Slac Experimental Animal Co., Ltd..Conformity certification number: SCXK (Shanghai) 2007-0005.Feeding environment: SPF level.
4 experimental procedures
Nude mouse subcutaneous vaccination people lung cancer Calu-3 cell treats that tumor growth is to 150-250mm 3After, with animal random packet (d0).Dosage and dosage regimen see Table 1.Survey weekly the knurl volume 2-3 times, claim mouse heavy, record data.Gross tumor volume (V) calculation formula is:
V=1/2 * a * b 2Wherein a, b represent respectively length and width.
5 results
Invention compound 426,427,428,430 all can suppress the growth of people's lung cancer Calu-3 Nude Mice, and wherein the curative effect of compound 428 and compound 430 is better; According to present dosage and scheme, the positive control lapatinibditosylate does not have obvious curative effect to Calu-3.Tumor-bearing mice all can tolerate well to above compound; Compound 426, lapatinibditosylate group mouse are that non-drug-associated is dead.
Table 1. compound 426,427,428,430 and lapatinibditosylate to the curative effect of people's lung cancer Calu-3 Nude Mice
Figure G2008101776387D00601
D0: administration time for the first time; Dn: after the administration 21 days for the first time; TV: gross tumor volume; RTV: relative tumour volume; *P＜0.01vs contrast.
Sequence table
＜110〉all reach Cen
＜120〉quinazoline compounds
<130>880289CG
<160>12
<170>PatentIn?version　3.1
<210>1
<211>2
<212>PRT
＜213〉synthetic
<400>1
Figure G2008101776387D00611
<210>2
<211>3
<212>PRT
＜213〉synthetic
<400>2
Figure G2008101776387D00612
<210>3
<211>3
<212>PRT
＜213〉synthetic
<400>3
<210>4
<211>3
<212>PRT
＜213〉synthetic
<400>4
Figure G2008101776387D00621
<210>5
<211>3
<212>PRT
＜213〉synthetic
<400>5
Figure G2008101776387D00622
<210>6
<211>3
<212>PRT
＜213〉synthetic
<400>6
Figure G2008101776387D00623
<210>7
<211>3
<212>PRT
＜213〉synthetic
<400>7
Figure G2008101776387D00624
<210>8
<211>4
<212>PRT
＜213〉synthetic
<400>8
Figure G2008101776387D00625
<210>9
<211>3
<212>PRT
＜213〉synthetic
<400>9
Figure G2008101776387D00631
<210>10
<211>3
<212>PRT
＜213〉synthetic
<400>10
Figure G2008101776387D00632
<210>11
<211>2
<212>PRT
＜213〉synthetic
<220>
<221>MISC_FEATURE
<222>(1)..(1)
＜223〉X is sarkosine (sar)
<400>11
Figure G2008101776387D00633
<210>12
<211>4
<212>PRT
＜213〉synthetic
<400>12
Figure G2008101776387D00634

Claims (20)

1. general formula (I) compound or its pharmacy acceptable salt:
Figure FSB00000941021400011
Wherein
R 1Expression
Figure FSB00000941021400012
Wherein Ar is selected from and is substituted base replacement or unsubstituted furans, thiophene, pyrroles or thiazole, and described substituting group is selected from halogen atom, C 1-4Alkyl or C 1-4Alkoxyl group, substituent number are 1 or 2; M, n are 0,1 or 2 independently of one another; R 2, R 3Be independently from each other
(1) hydrogen,
(2) C 1-4Alkyl,
(3) C 2-5Thiazolinyl, cyclohexenyl,
(4) ethynyl, proyl, butynyl, 3-methyl butynyl, alkynes butyl, propargyl,
(5) C 1-4Alkoxyl group,
(6) C 1-4Alkoxy C 1-4Alkyl,
(7) C 3-8Cycloalkyl,
(8) C 3-8Cycloalkyl-C 1-4Alkyl,
(9) C 1-4Alkyl sulphonyl-C 1-4Alkyl,
(10) C 1-5Carbalkoxy-C 1-4Alkyl or
(11) R 2, R 3The 3-6 unit heterocycle that becomes with the N atom that links to each other,
But R 2, R 3Be not hydrogen simultaneously;
Y is selected from optional by R 4, R 5The phenyl, pyridyl, 3H-imidazolyl, indyl, 1H-indazolyl or 2, the 3-dihydro-1H-indazolyl that replace; Wherein, R 4Be selected from benzyl, halo-, dihalo-or three halogeno-benzyls, halo-, dihalo-or three halo benzyloxies, pyridylmethyl, pyridyl methoxyl group, 2-picoline oxygen base or benzyloxy;
R 5Be selected from hydrogen, hydroxyl, halogen atom, C 1-4Alkyl, C 1-4Alkoxyl group, amino, cyano group or trifluoromethyl.
2. compound according to claim 1 or its pharmacy acceptable salt is characterized in that Ar is selected to be substituted base and to replace or unsubstituted furans or thiazole that described substituting group is selected from halogen atom, C 1-4Alkyl or C 1-4Alkoxyl group, substituting group number are 1.
3. compound according to claim 1 or its pharmacy acceptable salt is characterized in that Ar is selected from unsubstituted furans or thiazole.
4. compound according to claim 1 and 2 or its pharmacy acceptable salt is characterized in that m=0 or 1, n=1 or 2.
5. compound according to claim 1 or its pharmacy acceptable salt is characterized in that Y is selected from by R 4, R 5The phenyl, pyridyl, 1H-indazolyl or 2, the 3-dihydro-1H-indazolyl that replace; R 4Be selected from benzyl, halo-benzyl, halo-benzyloxy, pyridylmethyl, pyridyl methoxyl group, 2-picoline oxygen base or benzyloxy; R 5Be selected from hydrogen, halogen atom, C 1-4Alkyl or C 1-4Alkoxyl group.
6. compound according to claim 5 or its pharmacy acceptable salt is characterized in that Y is selected from by R 4, R 5The phenyl or the 1H-indazolyl that replace.
7. compound according to claim 5 or its pharmacy acceptable salt is characterized in that R 4Be selected from halo-benzyl, halo-benzyloxy or pyridyl methoxyl group.
8. compound according to claim 1 or its pharmacy acceptable salt is characterized in that described compound comprises:
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-diethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, the N-dipropyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(5-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylsulfonyl) ethyl)-2-amino-3-methylbutyryl amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-(methylsulfonyl)-1-(2-(methylsulfonyl) ethylamino) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-3-(methylsulfonyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propyl group is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(cyclopropyl methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propargyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine.
9. compound according to claim 1 or its pharmacy acceptable salt is characterized in that described compound comprises:
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl is amino)-2-(methylsulfonyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(2-(methylsulfonyl)-1-(2-(methylsulfonyl) ethylamino) ethyl) furans-2-yl) quinazoline-4-amine.
10. preparation is such as the method for claim 1 Chinese style (I) compound, and the method comprises the following steps:
With formula (II) compound
Figure FSB00000941021400041
With oxidant reaction, with preparation formula (I) compound, wherein Y, Ar, R 2, R 3, m, n such as claim 1 definition, T is sulphur atom or sulfinyl.
11. preparation is such as the method for claim 1 Chinese style (I) compound, the method comprises the following steps:
With formula (III) compound
Figure FSB00000941021400051
With suitable reagent react, with preparation formula (I) compound, wherein Y, Ar, m, n such as claim 1 definition.
12. preparation method according to claim 10 is characterized in that described oxygenant is selected from: metachloroperbenzoic acid, Peracetic Acid, hydrogen peroxide or potassium hydrogen persulfate.
13. preparation method according to claim 10 is characterized in that described oxygenant is selected from potassium hydrogen persulfate.
14. general formula (II) compound, described compound is the intermediate of synthetic general formula as claimed in claim 1 (I) compound:
Figure FSB00000941021400052
Wherein Y, Ar, R 2, R 3, m, n such as claim 1 definition, T is sulphur atom or sulfinyl.
15. compound according to claim 14 is characterized in that described compound comprises:
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-diethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, the N-dipropyl is amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl is amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(5-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methylthio group) ethyl)-2-amino-3-methylbutyryl amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-3-(methylthio group) propyl group) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(ethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propyl group is amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N, N-dimethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(cyclopropyl methylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(allyl amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propargyl is amino)-2-(methylthio group) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-diethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, the N-dipropyl is amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(allyl amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propargyl is amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(5-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-is amino) quinazoline-6-yl) furans-2-yl)-2-(methanesulfinyl) ethyl)-2-amino-3-methylbutyryl amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(methylamino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(ethylamino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(propyl group is amino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(cyclopropyl methylamino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N, N-dimethylamino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(5-(1-(N-methyl, N-ethylamino)-3-(methanesulfinyl) propyl group) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(methylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(ethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propyl group is amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N, N-dimethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(cyclopropyl methylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(N-methyl, N-ethylamino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(allyl amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine;
N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-(5-(1-(propargyl is amino)-2-(methanesulfinyl) ethyl) furans-2-yl) quinazoline-4-amine.
16. a medicinal compositions, said composition contain the treatment effective dose according to claim 1-9 in any one described compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
17. each described formula (I) compound or its pharmacy acceptable salt purposes in the medicine of preparation treatment adjusting c-erbB-2 and/or EGF-R protein tyrosine kinase activity relative disease according to claim 1-9.
18. the purposes of pharmaceutical composition according to claim 16 in the medicine of preparation treatment adjusting c-erbB-2 and/or EGF-R protein tyrosine kinase activity relative disease.
19. purposes according to claim 17, wherein said disease are malignant tumour or psoriasis.
20. purposes according to claim 18, wherein said disease are malignant tumour or psoriasis.
CN2008101776387A 2008-11-17 2008-11-17 Quinazoline compound Expired - Fee Related CN101735200B (en)

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CN101787017A (en) * 2009-01-23 2010-07-28 岑均达 Optical pure quinazoline compound
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CN102344445B (en) * 2010-07-23 2015-11-25 岑均达 Optical pure quinazoline compound
CN103483324B (en) * 2012-06-12 2016-03-30 人福医药集团股份公司 The new preparation process of lapatinibditosylate

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