CN1313449C - Novel quinazoline derivative, pharmaceutical composition containing same and application thereof - Google Patents
Novel quinazoline derivative, pharmaceutical composition containing same and application thereof Download PDFInfo
- Publication number
- CN1313449C CN1313449C CNB2005100121810A CN200510012181A CN1313449C CN 1313449 C CN1313449 C CN 1313449C CN B2005100121810 A CNB2005100121810 A CN B2005100121810A CN 200510012181 A CN200510012181 A CN 200510012181A CN 1313449 C CN1313449 C CN 1313449C
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- China
- Prior art keywords
- group
- alkyl
- quinazoline
- methyl
- methoxyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to quinazoline derivatives shown as a general formula I, and an optically active body, a racemate, a diastereoisomer mixture or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein a substituent R1、R2A, X and Q1Have the meanings given in the description. The derivatives of formula I can be used for preparing protein tyrosine kinase inhibitors and application in preparing medicaments for treating and/or preventing cancers and other proliferative diseases.
Description
Technical field
The present invention relates to the anilinoquinazoline analog derivative that 4-replaces, and be the pharmaceutical composition of activeconstituents with this derivative, with and at the preparation protein tyrosine kinase inhibitor and be used for the treatment of and/or prevent purposes in the medicine of various cancers and other proliferative disease.
Background technology
Cancer is called malignant tumour again, is a class common disease of serious threat human health, and the mortality ratio of cancer still rising, also lacks effective medicine to common solid tumor at present.By some link kill cancer cell of interference cell fission process, its action target spot there is no essential distinction to existing chemotherapeutics in cancer cells and normal cell, in kill cancer cell, also can produce toxic side effect mostly.
Protein tyrosine kinase (protein tyrosine kinase) is a kind of a kind of enzyme that can optionally make the tyrosine residues phosphorylation of different substrates.Tyrosine phosphorylation plays an important role in many cell regulate processes.Processes such as the picked-up of the transduction of activation, reaction, mitotic division, cytodifferentiation and the formation of present T cell of these acting bodies and B cell, blood vessel hyperplasia, neurotransmitter, the growth control of cell cycle, transcriptional regulatory, glucose, the generation of tumour and apoptosis to external irritant.Under the normal circumstances, the Tyrosylprotein kinase phosphorylation of cell is to be regulated and kept equilibrated by Tyrosylprotein kinase and tyrosine phosphatase antagonism.But, as pathomechanisms such as transgenation, gene fusion, autocrine and paracrine circulations, can cause the continuous activation of protein tyrosine kinase, thereby block the regulatory function of its pair cell differentiation, growth and apoptosis etc., induced tumor.In view of the vital role of Tyrosylprotein kinase on tumour molecule etiology, potent tyrosine kinase inhibitor has significance in tumor treatment.In recent years, protein tyrosine kinase is used as the target spot of antitumor drug widely.
4-anilinoquinazoline analog derivative is the novel tyrosine kinase inhibitor of a class that AstraZeneca company screens in its compound library, wherein Iressa (chemistry 4-(3-chloro-4-fluoroanilino) by name-7-methoxyl group-6-[3-(4-morpholinyl) propoxy-] quinazoline) in 2003 at Japanese official listing, be used for the treatment of nonsmall-cell lung cancer.Experiment in vitro confirms, but Iressa inducing cell cycle arrest, promotion apoptosis and angiogenesis inhibitor, a series of tumor cell lines are demonstrated the growth-inhibiting effect, as prostate cancer, mammary cancer, ovarian cancer, colorectal carcinoma, small cell lung cancer and nonsmall-cell lung cancer etc.
The present invention has synthesized the anilinoquinazoline analog derivative that a series of 4-replaces, and suppresses screening active ingredients and anti tumor activity in vitro screening through external protein tyrosine kinase, shows to have arrestin tyrosine kinase activity and anti-tumor activity.
Summary of the invention
The derivative of the general formula I that the present invention relates to be defined as follows, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
6Alkyl, another one is-R
3YR
4Q
2
A is C
1-C
4Alkyl, H;
X is a direct key or C
1-C
4Alkylidene group, described alkylidene group can be selected from hydroxyl, halogen, nitro, C by 1-3
1-C
4The substituting group of alkoxyl group is optional to be replaced;
Q
1Be phenyl, naphthyl or 5-10 unit heteroaryl, described heteroaryl can contain 1-3 heteroatoms that is selected from O, N and S, and Q
1Can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
6Alkylidene group, described alkylidene group can be selected from hydroxyl, halogen, nitro, C by 1-3
1-C
4The substituting group of alkoxyl group is optional to be replaced;
Y is-S-,
Q
2Be furyl, pyrryl, thienyl, can choose 1-3 R wantonly
6Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, (C
1-C
4) alkyl sulfenyl, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkoxy methyl, C
1-C
4Alkyl acyl, formamyl, N-C
1-C
4Alkyl-carbamoyl, N, N-two C
1-C
4Alkyl-carbamoyl, amino-sulfonyl, N-C
1-C
4Alkyl amino sulfonyl, N, N-two C
1-C
4Alkyl amino sulfonyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, piperidyl, imidazolidyl and pyrazolidyl, and this saturated heterocyclyl can have individual oxo, hydroxyl, halogen, the C of being selected from of 1-2
1-C
3Alkyl, C
1-C
3The substituting group of alkoxyl group, trifluoromethyl, nitro;
R
6Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N-C
1-C
4Alkylamino, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkoxy methyl, C
1-C
4Alkyl acyl, formamyl, N-C
1-C
4Alkyl-carbamoyl, N, N-two C
1-C
4Alkyl-carbamoyl, amino-sulfonyl, N-C
1-C
4Alkyl amino sulfonyl, N, N-two C
1-C
4Alkyl amino sulfonyl, perhaps R
6For-CH
2NR
7R
8
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-10 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
The present invention preferably relates to the general formula I derivative that is defined as follows, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
6Alkyl, another one is-R
3YR
4Q
2
A is H;
X is a direct key or C
1-C
4Alkylidene group;
Q
1Be phenyl, naphthyl or 5-10 unit heteroaryl, described heteroaryl can contain 1-3 heteroatoms that is selected from O, N and S, and Q
1Can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2Be furyl, pyrryl, thienyl, can choose 1-3 R wantonly
6Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkoxy methyl, C
1-C
4Alkyl acyl, formamyl, N-C
1-C
4Alkyl-carbamoyl, N, N-two C
1-C
4Alkyl-carbamoyl, amino-sulfonyl, N-C
1-C
4Alkyl amino sulfonyl, N, N-two C
1-C
4Alkyl amino sulfonyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, piperidyl, imidazolidyl and pyrazolidyl, and this saturated heterocyclyl can have individual oxo, hydroxyl, halogen, the C of being selected from of 1-2
1-C
3Alkyl, C
1-C
3The substituting group of alkoxyl group, trifluoromethyl, nitro;
R
6Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N-C
1-C
4Alkylamino, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkoxy methyl, C
1-C
4Alkyl acyl, formamyl, N-C
1-C
4Alkyl-carbamoyl, N, N-two C
1-C
4Alkyl-carbamoyl, amino-sulfonyl, N-C
1-C
4Alkyl amino sulfonyl, N, N-two C
1-C
4Alkyl amino sulfonyl, perhaps R
6For-CH
2NR
7R
8
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-10 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
The present invention especially preferably relates to the general formula I derivative that is defined as follows, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
4Alkyl, another one is-R
3YR
4Q
2
A is H;
X is a direct key or C
1-C
4Alkylidene group;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2Be furyl, pyrryl, thienyl, can choose 1-3 R wantonly
6Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
6Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N-C
1-C
4Alkylamino, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkoxy methyl, C
1-C
4Alkyl acyl, formamyl, N-C
1-C
4Alkyl-carbamoyl, N, N-two C
1-C
4Alkyl-carbamoyl, amino-sulfonyl, N-C
1-C
4Alkyl amino sulfonyl, N, N-two C
1-C
4Alkyl amino sulfonyl, perhaps R
6For-CH
2NR
7R
8
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-10 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
The present invention especially preferably relates to the general formula I derivative that is defined as follows, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
4Alkyl, another one is-R
3YR
4Q
2
X is a direct key or methylene radical;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2Be furyl, pyrryl, thienyl, can choose 1-3 R wantonly
6Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, N methyl piperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
6Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N-C
1-C
4Alkylamino, N, N-two C
1-C
4Alkylamino or R
6For-CH
2NR
7R
8
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-6 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
The present invention especially preferably also relates to the general formula I derivative that is defined as follows, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
4Alkyl, another one is-R
3YR
4Q
2
A is H;
X is a direct key or methylene radical;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2For containing furyl, can choose 1-3 R wantonly
6Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
6Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N-C
1-C
4Alkylamino, N, N-two C
1-C
4Alkylamino or R
6For-CH
2NR
7R
8
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-6 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
The present invention especially preferably also relates to the general formula I derivative that is defined as follows, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
4Alkyl, another one is-R
3YR
4Q
2
A is H;
X is a direct key or methylene radical;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2Be furyl, and on 5 quilt-CH
2NR
7R
8Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-6 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
The present invention especially preferably also relates to the general formula I derivative that is defined as follows, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is a methyl, and another one is-R
3YR
4Q
2
A is H;
X is a direct key;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2Be furyl, and on 5 quilt-CH
2NR
7R
8Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, or R
7And R
8Form 5-6 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
The present invention especially preferably also relates to the general formula I derivative that is defined as follows, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is a methyl, and another one is-R
3YR
4Q
2
A is H;
X is a direct key;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3Be C
1-C
3Alkylidene group;
R
4Be methylene radical;
Y is-S-,
Q
2Be furyl, and on 5 quilt-CH
2NR
7R
8Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, or R
7And R
8Form pyrrolidyl, morpholinyl, piperidyl and 4-methylpiperazine base with the nitrogen-atoms that is connected with them.
The present invention's following general formula I derivative and optically active body or raceme, non-enantiomer mixture very particularly preferably, or its pharmacy acceptable salt, hydrate or solvate:
4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[(5-dimethylin) methyl furan-2-] methylthio group] propoxy-] quinazoline (embodiment 1);
4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] propoxy-] quinazoline (embodiment 2)
4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] quinazoline (embodiment 3)
4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] quinazoline (embodiment 4)
4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] quinazoline (embodiment 5)
4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] propoxy-] quinazoline (embodiment 6)
4-(3-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] quinazoline (embodiment 12)
4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(4-methyl isophthalic acid-piperazinyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (embodiment 15)
4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (embodiment 16)
4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (embodiment 18)
4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(piperidino) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (embodiment 19)
4-(4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (embodiment 20)
4-(3,5-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (embodiment 27)
4-(3,5-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] oxyethyl group] quinazoline oxalate (embodiment 28)
4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(dimethylin) methyl furan food in one's mouth-2-] methylthio group] oxyethyl group] quinazoline (embodiment 29)
4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(N methyl pmpyl amine base) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (embodiment 30)
4-(3,4-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (embodiment 31)
4-(3,4-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(dimethylin) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (embodiment 32)
4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[2-[5-(N methyl pmpyl amine base) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (embodiment 35)
4-(3-trifluoromethylbenzene amido)-7-methoxyl group-6-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] quinazoline (embodiment 45)
4-(3-trifluoromethylbenzene amido)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] quinazoline (embodiment 46)
4-(3,4-difluoroaniline base)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] quinazoline (embodiment 48)
And according to some usual methods in field under the present invention, the quinazoline derivative of following formula I of the present invention can generate its pharmacy acceptable salt with acid.Acid can comprise mineral acid or organic acid, and the salt that forms with following acid is particularly preferred: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, acetate, propionic acid, lactic acid, trifluoroacetic acid, toxilic acid, citric acid, fumaric acid, oxalic acid, Tartaric acid, Phenylsulfonic acid, phenylformic acid or tosic acid etc.
Derivative of the present invention can exist with stereoisomer form, and these stereoisomeric forms in any ratio can be enantiomorph or diastereomer.The present invention had both related to enantiomorph or diastereomer, also related to their mixtures separately, as diastereomer, can racemic form be separated into stereomeric one-component according to self known method.
In addition, the present invention also comprises the prodrug of derivative of the present invention.According to the present invention, prodrug is the derivative of general formula I, they self may have more weak active or even do not have activity, but after administration, (for example by metabolism, solvolysis or other mode) is converted to corresponding biologically active form under physiological condition.
Unless otherwise noted, term used herein " halogen " is meant fluorine, chlorine, bromine or iodine generation; " alkyl " is meant the alkyl of straight or branched; " alkylidene group " is meant the alkylidene group of straight or branched; " cycloalkyl " is meant and replaces or unsubstituted cycloalkyl; Heteroaryl comprises the heteroatoms that contains one or more O of being selected from, N and S, wherein the ring-type system of each heteroaryl can be monocycle or polycyclic, the ring-type system is an aromaticity, can enumerate for example imidazolyl, pyridyl, pyrimidyl, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrryl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl-, benzothiazolyl, indyl, quinolyl etc.; Saturated heterocyclyl comprises the heteroatoms that contains one or more O of being selected from, N and S, and the ring-type system can be monocycle or polycyclic, can enumerate for example pyrrolidyl, morpholinyl, piperazinyl, piperidyl, pyrazolidyl, imidazolidyl and thiazolinyl etc.
Specific derivatives of the present invention can have asymmetric center, and therefore the form with different enantiomorphs and diastereomer exists.The present invention relates to all optically active isomers, raceme of derivative of the present invention and composition thereof." raceme " is meant the mixture of a pair of enantiomer that contains equivalent.
The present invention includes pharmaceutical composition, said composition contains the quinazoline derivative of following formula I, and optically active body or raceme, non-enantiomer mixture or its pharmacy acceptable salt, hydrate or solvate be as activeconstituents, and pharmaceutically acceptable excipient.Described pharmaceutically acceptable excipient is meant any thinner, auxiliary and/or carrier that can be used for pharmaceutical field.Derivative of the present invention can be used in combination with other activeconstituentss, as long as they do not produce other disadvantageous effect, for example anaphylaxis.
Pharmaceutical composition of the present invention can be mixed with some kinds of formulations, wherein contains some vehicle commonly used in the pharmaceutical field; For example, oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, adding water for injection before injection can use immediately); Topical formulations (for example ointment or solution).
The carrier that is used for pharmaceutical composition of the present invention is the available common type of pharmaceutical field, comprising: the tackiness agent that oral preparations is used, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives etc.; The sanitas that injectable formulation is used, solubilizing agent, stablizer etc.; The matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under the stomach condition, it can be mixed with enteric coated tablets.
We have found that The compounds of this invention has the arrestin tyrosine kinase activity, so The compounds of this invention has anti-hyperplasia character.The compounds of this invention can be used for the protein tyrosine kinase receptor inhibitor separately or the disease or the treatment of conditions that are situated between between part, and promptly compound can be used to produce the protein tyrosine kinase receptor restraining effect in the mammalian body of this class treatment of needs.
The compounds of this invention can be used to provide the treatment for cancer of anti-proliferative effect, especially treats the cancer of protein tyrosine kinase receptor sensitivity such as the cancer of mammary gland, lung, colon, rectum, stomach, prostate gland, bladder, pancreas and ovary.The compounds of this invention also is supposed to be used for the treatment of other cell proliferative diseases such as psoriasis, benign prostatauxe, atherosclerosis and restenosis.Expect in addition that quinazoline derivant of the present invention will have leukemia, lymph is pernicious and solid tumor as in the activity of tissue as cancer in liver, kidney, prostate gland and the pancreas and sarcoma scope.
In addition, expect that also The compounds of this invention can be used for treating the disease of other hyperplasia,, comprise the also distortion cell of undetermined receptor protein tyrosine kinase comprising by the receptor protein tyrosine kinase mark.This class disease comprises, for example, inflammation, vasculogenesis, vascular restenosis, amynologic disease, pancreas disease, ephrosis and embryo are ripe and transplant.
The anti tumor activity in vitro test shows that the quinazoline derivative of following formula I of the present invention has antitumous effect, and therefore, it can treat and/or prevent the medicine of cancer as preparation.
Derivative according to the present invention can be used as activeconstituents and is used for preparation and treats and/or prevents various cancers, the present invention also provides treatment or prevents the method for above-mentioned disease, comprise suffer from or easily suffer from this sick patient significant quantity according to derivative of the present invention.The clinical dosage that the quinazoline derivative of following formula I is used for the patient must rely on the main body of being treated, administration concrete approach, treat severity of disease and is changed, and optimal dose is definite by the concrete patient's of treatment doctor.
Active compound of the present invention can be used as unique cancer therapy drug and uses, and perhaps can unite use with one or more other antitumor drugs.Combination therapy realizes by each being treated component while, order or separating administration.
The compounds of this invention and preparation method thereof is further illustrated and illustrated to embodiment that hereinafter provides and preparation example.The scope that should be appreciated that following embodiment and preparation example also limits the scope of the invention never in any form.In the following embodiments, except as otherwise noted, otherwise the molecule with a chiral centre exists with the form of racemic mixture.Except as otherwise noted, otherwise the molecule with two or more chiral centres is a racemic mixture as diastereomer exists.Independent enantiomorph/diastereomer can obtain by method known to those skilled in the art.
Following synthetic route A-D has described the preparation of formula I derivative of the present invention, and all raw materials all are the method preparation known by the method for describing in these synoptic diagram, by the organic chemistry filed those of ordinary skill or commercially available.All final derivative of the present invention all is to prepare by the method for describing in these synoptic diagram or by method similar with it, and these methods are that the organic chemistry filed those of ordinary skill is known.Whole variable factors of using in these synoptic diagram are as hereinafter definition or as the definition in the claim.
According to formula I derivative of the present invention, in route A, R
1Be C
1-C
6Alkoxyl group, R
2For-R
3YR
4Q
2, Y is-S--SO-,-SO
2-, other substituting group such as summary of the invention part definition.With 3-alkoxyl group-4-methyl hydroxybenzoate (A-1) is starting raw material, with the dimethyl formamide is reaction solvent, Anhydrous potassium carbonate exists down, with chloro bromo alkane generation substitution reaction, generate 3-alkoxyl group-4-chlorinated alkoxy methyl benzoate (A-2), then through nitrated, the ferrous acid reduction obtains 2-amino-4-chlorinated alkoxy-5-alkoxybenzoic acid methyl esters (A-4), this compound carries out cyclization with the acetate carbonamidine in dehydrated alcohol, prepare 6-alkoxyl group-7-chlorinated alkoxy quinazoline-4-one (A-5), A-5 is through chlorination, obtain amido-6-alkoxyl group-7-chlorinated alkoxy quinazoline (A-7) that 4-replaces with the amine prepared in reaction that replaces then, the thiophenol of A-7 and replacement or mercaptan generation substitution reaction, can obtain derivative A-8, through oxidizing reaction, by the amount and control reaction conditions and the time (carrying out with the thin layer monitoring reaction) that change used oxygenant, A-8 makes single oxidation products A-9 and dioxygen product A-10 through the hydrogen peroxide oxidation in acetate.
Route A
According to formula I derivative of the present invention, in route B, R
1Be C
1-C
6Alkoxyl group, R
2For-R
3YR
4Q
2, Y is-S--SO-,-SO
2-, Q
2Be furyl, and the substituting group on 5 is-CH
2NR
7R
8, R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, or R
7And R
8Form 5-6 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement, other substituting group such as the summary of the invention part definition.At first prepare A-7 according to route A, the mercaptan generation substitution reaction that replaces with furans then, obtain B-1, react through Mannich, obtain compd B-2, through oxidizing reaction, amount and control reaction conditions and time (carrying out) by changing used oxygenant, can prepare B-3 and B-4 with the thin layer monitoring reaction.
Route B
According to formula I derivative of the present invention, in route C, R
1For-R
3YR
4Q
2, R
2Be C
1-C
6Alkoxyl group, Y are-S--SO-, SO
2-, other substituting group such as summary of the invention part definition.With 4-alkoxyl group-3-methyl hydroxybenzoate (C-1) is starting raw material, with the dimethyl formamide is reaction solvent, Anhydrous potassium carbonate exists down, with chloro bromo alkane generation substitution reaction, generate 4-alkoxyl group-3-chlorinated alkoxy methyl benzoate (C-2), then through nitrated, the ferrous acid reduction obtains 2-amino-5-chlorinated alkoxy-4-alkoxybenzoic acid methyl esters (C-4), this compound carries out cyclization with acetic acid list carbonamidine in dehydrated alcohol, prepare 7-alkoxyl group-6-chlorinated alkoxy quinazoline-4-one (C-5), C-5 is through chlorination, obtain amido-7-alkoxyl group-6-chlorinated alkoxy quinazoline (C-7) that 4-replaces with the amine prepared in reaction that replaces then, the thiophenol of C-7 and replacement or mercaptan generation substitution reaction, can obtain derivative C-8, through oxidizing reaction, by the amount and the controlling reaction time (carrying out with the thin layer monitoring reaction) that change used oxygenant, C-8 makes single oxidation products C-9 and dioxygen product C-10 through the hydrogen peroxide oxidation in acetate.
According to formula I derivative of the present invention, in route D, R
1For-R
3YR
4Q
2, R
2Be C
1-C
6Alkoxyl group, Y are-S--SO-,-SO
2-, Q
2Be furyl, and the substituting group on 5 is-CH
2NR
7R
8, R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, or R
7And R
8Form 5-6 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement, other substituting group such as the summary of the invention part definition.At first prepare C-7 according to route C, feed the mercaptan generation substitution reaction that replaces with furan then, obtain D-1, react through Mannich, obtain Compound D-2, through oxidizing reaction, amount and controlling reaction time (carrying out with the thin layer monitoring reaction) by changing used oxygenant can prepare D-3 and D-4.
Route D
Embodiment
Embodiment is intended to set forth rather than limit the scope of the invention.The proton nmr spectra of derivative is measured with Bruker ARX-300, and mass spectrum is measured with Agilent 1100 LC/MSD; Agents useful for same is analytical pure or chemical pure.
Embodiment 1:4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[(5-dimethylin) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
Steps A: the preparation of 3-methoxyl group-4-(3-chlorine propoxy-) methyl benzoate
In dimethyl formamide (DMF) 150mL, add 3-methoxyl group-4-methyl hydroxybenzoate 9.1g (0.05mol), 1,3-bromo-chloropropane 15.8g (0.1mol), Anhydrous potassium carbonate 10.4g (0.075mol), 70～80 ℃ of left and right sides stirring reaction 6h.Reaction is finished, and in reaction solution impouring frozen water, dichloromethane extraction merges organic phase, washing, and anhydrous magnesium sulfate drying, steaming desolventizes, and drying gets product 12.3g (yield: 95.3%).
The preparation of step B:2-nitro-4-(3-chlorine propoxy-)-5-methoxyl methyl benzoate
In chloroform 100mL, add 3-methoxyl group-4-(3-chlorine propoxy-) methyl benzoate 12.3g (0.048mol), stirring and dissolving.Be chilled to about 10 ℃, slowly splash into the nitration mixture that the 65% concentrated nitric acid 6.9g (0.071mol) and 98% vitriol oil (10mL) are made in the vigorous stirring downhill reaction liquid.Drip and finish 20 ℃ of following stirring reaction 4h.Reaction is finished, and in reaction solution impouring frozen water, branch vibration layer, chloroform layer use saturated sodium bicarbonate aqueous solution, water washing to neutral successively, anhydrous magnesium sulfate drying, and evaporated under reduced pressure gets light yellow product 12.9g (yield: 89.6%).
The preparation of step C:2-amino-4-(3-chlorine propoxy-)-5-methoxyl methyl benzoate
In 95% ethanol 300mL, add Glacial acetic acid 5mL and reduced iron powder 28g (0.5mol), after leaving standstill 15min under the room temperature, add 2-nitro-4-(3-chlorine propoxy-)-5-methoxyl methyl benzoate 19g (0.063mol), stirring and refluxing reaction 12h, reaction is finished, while hot suction filtration, the filtrate decompression evaporate to dryness gets solid 15.8g (yield: 92.4%).
The preparation of step D:6-methoxyl group-7-(3-chlorine propoxy-) quinazoline-4-one
2-amino-4-(3-chlorine propoxy-)-5-methoxyl methyl benzoate 17.0g (0.06mol) and acetate carbonamidine 9.7g (0.09mol) are added among the dehydrated alcohol 200mL, reflux 20h, reaction is finished, reaction solution is cooled to room temperature, suction filtration, cold absolute ethanol washing, drying gets solid 15.2g (yield: 91.0%).
Step e: the preparation of 4-chloro-6-methoxyl group-7-(3-chlorine propoxy-) quinazoline
6-methoxyl group-7-(3-chlorine propoxy-) quinazoline-4-one 15.0g (0.056mol) is added among the new steaming thionyl chloride 150mL back flow reaction 3h.Reaction is finished, remove thionyl chloride under reduced pressure after, add frozen water 200mL, stir light yellow solid, suction filtration is washed to neutrality, drying obtains product 13.4g (yield: 83.8%).
The preparation of step F: 4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-(3-chlorine propoxy-) quinazoline
In Virahol 150mL, add 4-chloro-6-methoxyl group-7-(3-chlorine propoxy-) quinazoline 7.8g (0.027mol) and 3-chloro-4-fluoroaniline 4.7g (0.032mol), stir, back flow reaction 3h, reaction is finished, and the cooling reaction solution is to room temperature, suction filtration, the cold isopropanol washing, drying gets solid 8.9g (yield: 82.4%).
Step G:4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[3-(furans-2-methylthio group) propoxy-] preparation of quinazoline
In dehydrated alcohol 150mL, add furans thiomethyl alcohol 3.6g (0.03mol) and sodium hydroxide 1.7g (0.04mol), low-grade fever, stirring made solid molten entirely in 5 minutes, added 4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-(3-chlorine propoxy-) quinazoline 8.3g (0.02mol) in reaction solution, stirring and refluxing reaction 1.5h, reaction is finished, and with the reaction solution cooling, pours in the cold water, separate out a large amount of solids, suction filtration, washing gets light yellow product 9.5g (yield: 96.0%) after the drying.
Step H:4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[(5-dimethylamino methyl) furans-2-] methylthio group] propoxy-] preparation of quinazoline oxalate
In Glacial acetic acid 25mL, the dimethylamine agueous solution 0.7g (5mmol) of adding 33% and 36% formalin 0.2g (2.3mmol), stirring at room 5 minutes, add 4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[3-(furans-2-methylthio group) propoxy-] quinazoline 1.0g (2mmol), be warming up to 50 ℃ of reaction 24h, reaction is finished, remove solvent under reduced pressure, in debris, add the less water dilution, with 0.1mol/L aqueous sodium hydroxide solution adjust pH to 10, dichloromethane extraction merges organic phase, washing, anhydrous magnesium sulfate drying.The evaporated under reduced pressure solvent gets oily matter, and with small amount of acetone solution oily matter, dripping oxalic acid acetone soln adjusting pH value is 2-3, and leave standstill and separate out solid, suction filtration, small amount of acetone is washed, and drying gets embodiment 1 compound 1.0g (yield: 83.3%).
1H-NMR(DMSO)：2.09(m，2H)，2.69(s，8H)，3.85(s，2H)，4.05(s，3H)，4.24(t，2H)，4.33(s，2H)，6.41(d，1H)，6.65(d，1H)，7.50(d，1H)，7.56(d，1H)，7.81(d，1H)，8.07(d，1H)，8.54(s，1H)，8.88(s，1H)，11.86(s，1H)；MS：531.1(M+H).
Method according to embodiment 1, with 3-methoxyl group-4-methyl hydroxybenzoate and 1,3-bromo-chloropropane or 1, the 2-bromochloroethane is a starting raw material, at first prepare 4-chloro-6-methoxyl group-7-(3-chlorine alkoxyl group) quinazoline, then with the amine generation substitution reaction that is fit to, again with furans thiomethyl alcohol generation substitution reaction, and then carry out Mannich with the aliphatic amide that is fit to and react, make embodiment 2-39 compound respectively:
Embodiment 2:4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.20(t，3H)，2.05(m，2H)，2.62(s，3H)，2.68(t，2H)，2.99(q，2H)，3.82(s，2H)，3.96(s，3H)，4.19(t，2H)，4.29(s，2H)，6.39(d，1H)，6.61(d，1H)，7.20(s，1H)，7.44(t，1H)，7.81(m，1H)，7.86(s，1H)，8.13(dd，1H)，8.51(s，1H)；MS：545.2(M+H).
Embodiment 3:4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.89(s，4H)，2.06(m，2H)，2.67(t，2H)，3.22(s，4H)，3.83(s，2H)，3.97(s，3H)，4.21(t，2H)，4.38(s，2H)，6.38(d，1H)，6.60(d，1H)，7.22(s，1H)，7.46(t，1H)，7.82(m，1H)，7.88(s，1H)，8.15(dd，1H)，8.53(s，1H)；MS：557.1(M+H).
Embodiment 4:4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：2.06(m，2H)，2.69(s，8H)，3.84(s，2H)，3.98(s，3H)，4.21(t，3H)，4.29(s，2H)，6.40(d，1H)，6.60(d，1H)，7.23(s，1H)，7.41(d，2H)，7.91(s，1H)，7.94(d，2H)，8.51(s，1H)；MS：563.2(M+H).
Embodiment 5:4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.89(s，4H)，2.05(m，2H)，2.68(t，2H)，3.22(s，4H)，3.83(s，2H)，3.98(s，3H)，4.21(t，2H)，4.38(s，2H)，6.39(d，1H)，6.59(d，1H)，7.23(s，1H)，7.41(d，2H)，7.90(s，1H)，7.94(d，2H)，8.52(s，1H)；MS：589.1(M+H).
Embodiment 6:4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.22(t，3H)，2.09(m，2H)，2.68(m，5H)，3.03(m，2H)，3.84(s，2H)，3.98(s，3H)，4.20(t，2H)，4.33(s，2H)，6.41(d，1H)，6.64(d，1H)，7.26(s，1H)，7.42(d，2H)，7.92(s，1H)，7.94(d，2H)，8.54(s，1H)；MS：577.2(M+H).
Embodiment 7:4-(4-trifluoromethylbenzene amido)-6-methoxyl group-7-[[3-[5-(4-morpholinyl) the methyl furan food in one's mouth-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：2.05(m，2H)，2.67(t，2H)，2.77(s，4H)，3.68(s，4H)，3.82(s，2H)，3.93(s，2H)，3.99(s，3H)，4.22(t，2H)，6.33(d，1H)，6.42(d，1H)，7.24(s，1H)，7.76(d，2H)，7.91(s，1H)，8.11(d，2H)，8.58(s，1H)；MS：589.2(M+H).
Embodiment 8:4-(3-fluoroanilino)-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：2.05(m，2H)，2.76(m，8H)，3.84(s，2H)，3.98(s，2H)，4.22(m，4H)，6.40(s，1H)，6.60(s，1H)，6.93(t，3H)，7.22(s，1H)，7.42(m，1H)，7.64(t，1H)，7.89(s，1H)，7.92(s，1H)，8.54(s，1H)；MS：497.2(M+H).
Embodiment 9:4-(3-fluoroanilino)-6-methoxyl group-7-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.88(s，4H)，2.09(m，2H)，2.70(t，2H)，3.22(s，4H)，3.84(s，2H)，3.96(s，3H)，4.24(t，2H)，4.37(s，2H)，6.37(s，1H)，6.58(s，1H)，7.24(s，1H)，7.45(m，1H)，7.63(t，1H)，7.92(s，1H)，8.25(m，2H)，8.55(s，1H)；MS：523.4(M+H).
Embodiment 10:4-(3-fluoroanilino)-6-methoxyl group-7-[[3-[5-(N methyl pmpyl amine base) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：0.85(t，3H)，1.61(m，2H)，2.09(m，2H)，2.63(s，3H)，2.71(t，2H)，2.86(t，2H)，3.84(s，2H)，3.96(s，3H)，4.23(t，2H)，4.27(s，2H)，6.38(d，1H)，6.60(d，1H)，7.25(s，1H)，7.45(d，1H)，7.63(t，1H)，7.90(s，1H)，8.21(m，1H)，8.24(s，1H)，8.54(s，1H)；MS：525.2(M+H).
Embodiment 11:4-(4-fluoroanilino)-6-methoxyl group-7-[[3-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.18(t，3H)，2.05(m，2H)，2.57(s，2H)，2.67(m，4H)，2.92(s，2H)，3.83(s，2H)，3.96(s，3H)，4.20(t，2H)，6.38(s，1H)，6.56(s，1H)，7.22(m，3H)，7.79～7.86(m，3H)，8.44(s，1H)，9.60(brs，1H)；MS：511.4(M+H).
Embodiment 12:4-(3-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
MS：563.3(M+H).
Embodiment 13:4-(3-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(N-methyl isopropyl amido) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
MS：591.2(M+H).
The amido of embodiment 14:4-[(quinoline-5-)]-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：2.07(m，2H)，2.69(m，8H)，3.82(s，2H)，3.99(s，3H)，4.23～4.28(m，4H)，6.41(d，1H)，6.61(d，1H)，7.25(s，1H)，7.51(m，1H)，7.68(d，1H)，7.85(t，1H)，7.80(s，1H)，8.02(s，1H)，8.27(s，1H)，8.29(d，1H)，8.94(d，1H)；MS：529.9(M+H).
Embodiment 15:4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(4-methyl isophthalic acid-piperazinyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline
MS：588.3(M+H).
Embodiment 16:4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：559.3(M+H).
Embodiment 17:4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(N-methylbutylamine base) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：575.2(M+H).
Embodiment 18:4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：547.2(M+H).
Embodiment 19:4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(piperidino) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：573.2(M+H).
Embodiment 20:4-(4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：509.2(M+H).
Embodiment 21:4-(4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(4-methyl isophthalic acid-piperazinyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：2.72(m，7H)，2.92(t，2H)，3.56(m，4H)，3.82(s，2H)，3.94(s，2H)，3.96(s，3H)，4.28(t，2H)，6.26(d，2H)，6.30(d，2H)，7.19(s，1H)，7.24(t，2H)，7.78(dd，2H)，7.86(s，1H)，8.45(s，1H)，9.59(s，1H)；MS：538.1(M+H).
Embodiment 22:4-(4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(4-morpholinyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：2.63(m，4H)，2.93(t，2H)，3.62(m，4H)，3.78(s，2H)，3.97(s，3H)，4.29(t，2H)，6.34(d，1H)，6.35(d，1H)，7.22(dd，2H)，7.24(s，1H)，7.77(m，2H)，7.87(s，1H)，8.47(s，1H)，9.64(s，1H)；MS：525.1(M+H).
Embodiment 23:4-(2-fluoroanilino)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：1.88(m，4H)，2.94(t，2H)，3.20(m，4H)，3.94(s，3H)，3.99(s，2H)，4.31(t，2H)，4.37(s，2H)，6.42(d，1H)，6.59(d，1H)，7.20(s，1H)，7.26～7.33(m，3H)，7.54(t，1H)，7.85(s，1H)，8.35(s，1H)；MS：509.2(M+H).
Embodiment 24:4-(2-fluoroanilino)-6-methoxyl group-7-[[2-[5-(dimethylin) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：2.67(s，6H)，2.94(t，2H)，3.95(s，3H)，3.99(s，2H)，4.26(s，2H)，4.31(t，2H)，6.43(d，1H)，6.60(d，1H)，7.20(s，1H)，7.27～7.34(m，3H)，7.52(t，1H)，7.85(s，1H)，8.36(s，1H)；MS：483.1(M+H).
Embodiment 25:4-(2-fluoroanilino)-6-methoxyl group-7-[[2-[5-(4-morpholinyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：2.60(m，4H)，2.93(t，2H)，3.61(m，4H)，3.74(s，2H)，3.95(s，3H)，3.96(s，2H)，4.29(t，2H)，6.34(s，2H)，7.19(s，1H)，7.29～7.34(m，3H)，7.54(t，1H)，7.85(s，1H)，8.37(s，1H)；MS：524.9(M+H).
Embodiment 26:4-(2-fluoroanilino)-6-methoxyl group-7-[[2-[5-(N methyl pmpyl amine base) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：0.86(t，3H)，1.63(m，2H)，2.64(s，3H)，2.87(t，2H)，2.92(t，2H)，3.95(s，3H)，4.00(s，2H)，4.28(s，2H)，4.31(t，2H)，6.44(d，1H)，6.62(d，1H)，7.20(s，1H)，7.26～7.33(m，3H)，7.54(t，1H)，7.85(s，1H)，8.36(s，1H)；MS：511.2(M+H).
Embodiment 27:4-(3,5-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：527.2(M+H).
Embodiment 28:4-(3,5-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：515.1(M+H).
Embodiment 29:4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(dimethylin) methyl furan-2-] methylthio group] oxyethyl group] quinazoline
1H-NMR(DMSO)：2.50(s，6H)，2.94(t，2H)，3.97(m，7H)，4.31(t，2H)，6.40(s，1H)；6.49(s，1H)，7.21(s，1H)，7.45(t，1H)，7.79(m，1H)，7.84(s，1H)，8.13(m，1H)，8.52(s，1H)，9.58(s，1H)；MS：517.1(M+H).
Embodiment 30:4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(N methyl pmpyl amine base) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：545.1(M+H).
Embodiment 31:4-(3,4-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：1.90(m，4H)，2.95(t，2H)，3.24(m，4H)，3.98(m，5H)，4.32(t，2H)，4.40(t，2H)，6.43(s，1H)；6.60(s，1H)，7.24(s，1H)，7.46(m，1H)，7.58(m，1H)，7.88(s，1H)，8.06(m，1H)，8.53(s，1H)；MS：527.1(M+H).
Embodiment 32:4-(3,4-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(dimethylin) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：501.1(M+H).
Embodiment 33:4-(4-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(4-methyl isophthalic acid-piperazinyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：588.2(M+H).
Embodiment 34:4-(4-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(N-methyl cyclopropyl amino) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate.
1H-NMR(DMSO)：0.57(m，4H)，2.29(m，2H)，2.56(s，3H)，2.94(t，2H)，3.99(m，5H)，4.09(s，2H)，4.63(t，2H)，6.38(s，1H)，6.44(s，1H)，7.25(s，1H)，7.76(d，2H)，7.91(s，1H)，8.11(d，2H)，8.58(s，1H)；MS：559.2(M+H).
Embodiment 35:4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[2-[5-(N methyl pmpyl amine base) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：577.2(M+H).
Embodiment 36:4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[2-[5-(dimethylin) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：549.1(M+H).
Embodiment 37:4-(1-phenyl-ethyl amine base)-6-methoxyl group-7-[[2-[5-(4-morpholinyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：1.63(d，3H)，2.59(m，4H)，2.92(t，2H)，3.60(m，4H)，3.72(s，2H)，3.95(s，5H)，4.26(t，2H)，5.68(m，1H)，6.32(s，2H)，7.16(s，1H)，7.24(t，1H)，7.34(t，2H)，7.44(d，2H)，7.87(s，1H)，8.46(s，1H)，8.73(d，1H)；MS：535.1(M+H).
Embodiment 38:4-(4-anisole methylamino)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline
MS：535.4(M+H).
Embodiment 39:4-(4-fluorobenzene methylamino)-6-methoxyl group-7-[[2-[5-(piperidino) methyl furan-2-] methylthio group] oxyethyl group] quinazoline (YL-365)
MS：537.5(M+H).
According to the method for embodiment 1, with 3-hydroxyl-4-methoxyl methyl benzoate and 1,3-bromo-chloropropane or 1, the 2-bromochloroethane is a starting raw material, makes embodiment 40-65 compound:
Embodiment 40:4-(3-fluoroanilino)-7-methoxyl group-6-[[3-[5-(4-morpholinyl) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：2.07(m，2H)，2.69～2.72(m，6H)，3.65(m，4H)，3.82(s，2H)，3.87(s，2H)，3.95(s，3H)，4.22(t，2H)，6.31(d，1H)，6.38(d，1H)，6.94(t，1H)，7.24(s，1H)，7.43(dd，1H)，7.61(d，1H)，7.87(d，1H)，7.95(s，1H)，8.56(s，1H)；MS：539.1(M+H).
Embodiment 41:4-(3-fluoroanilino)-7-methoxyl group-6-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：2.09(m，2H)，2.66(m，8H)，3.84(s，2H)，3.95(s，3H)，4.26(m，4H)，6.39(d，1H)，6.58(d，1H)，6.93(t，1H)，7.24(s，1H)，7.42(dd，1H)，7.61(d，1H)，7.87(d，1H)，7.91(s，1H)，8.53(s，1H)；MS：497.3(M+H).
Embodiment 42:4-(3-fluoroanilino)-7-methoxyl group-6-[[3-[5-(N methyl pmpyl amine base) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：0.85(t，3H)，1.60(m，2H)，2.07(m，2H)，2.61(s，3H)，2.67(t，2H)，2.84(m，2H)，3.82(s，2H)，3.93(s，3H)，4.21(t，2H)，4.25(s，2H)，6.38(d，1H)，6.59(d，1H)，6.94(t，1H)，7.22(s，1H)，7.40(dd，1H)，7.61(d，1H)，7.86(s，1H)，7.89(d，1H)，8.52(s，1H)；MS：525.2(M+H).
Embodiment 43:4-(4-fluoroanilino)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.85(m，2H)，2.07(m，2H)，2.67(t，2H)，3.17(m，4H)，3.82(s，2H)，3.93(s，3H)，4.19(t，2H)，4.33(s，2H)，6.36(d，1H)，6.55(d，1H)，7.19～7.25(m，3H)，7.75(m，2H)，7.84(s，1H)，8.43(s，1H)；MS：523.4(M+H).
Embodiment 44:4-(3-bromobenzene amido)-7-methoxyl group-6-[[3-[5-(piperidino) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.47(m，2H)，1.70(m，4H)，2.08(m，2H)，2.72(t，2H)，3.03(m，4H)，3.84(s，2H)，3.95(s，3H)，4.26(m，4H)，6.38(d，1H)，6.58(d，1H)，7.24(s，1H)，7.30～7.38(m，3H)，7.88(m，2H)，8.15(s，1H)，8.54(s，1H)；MS：599.1(M+H).
Embodiment 45:4-(3-trifluoromethylbenzene amido)-7-methoxyl group-6-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：2.09(m，2H)，2.67(m，8H)，3.84(m，2H)，3.96(s，3H)，4.26(m，4H)，6.39(d，1H)，6.59(d，1H)，7.24(s，1H)，7.44(d，1H)，7.62(t，1H)，7.89(s，1H)，8.24(m，2H)，8.55(s，1H)；MS：547.3(M+H).
Embodiment 46:4-(3-trifluoromethylbenzene amido)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.79(m，4H)，2.09(m，2H)，2.70(t，2H)，2.91(m，4H)，3.82(m，2H)，3.96(s，3H)，4.05(s，2H)，4.23(t，2H)，6.31(d，1H)，6.42(d，1H)，7.24(s，1H)，7.45(d，1H)，7.63(t，1H)，7.91(s，1H)，8.24(m，2H)，8.54(s，1H)；MS：573.1(M+H).
Embodiment 47:4-(3-trifluoromethylbenzene amido)-7-methoxyl group-6-[[3-[5-(N methyl pmpyl amine base) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
MS：575.2(M+H).
Embodiment 48:4-(3,4-difluoroaniline base)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
MS：541.2(M+H).
Embodiment 49:4-(3,4-difluoroaniline base)-7-methoxyl group-6-[[3-[5-(N-methylbutylamine base) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
MS：557.2(M+H).
Embodiment 50:4-(3,4-difluoroaniline base)-7-methoxyl group-6-[[3-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
MS：529.2(M+H).
Embodiment 51:4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[[3-[5-(4-morpholinyl) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
MS：573.2(M+H).
Embodiment 52:4-(3-trifluoromethyl-4-fluoroanilino)-7-methoxyl group-6-[[3-[5-(piperidino) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.46(m，2H)，1.68(m，4H)，2.08(m，2H)，2.68(t，2H)，3.01(m，4H)，3.83(s，2H)，3.95(s，3H)，4.23(m，4H)，6.38(d，1H)，6.56(d，1H)，7.24(s，1H)，7.54(t，1H)，7.88(s，1H)，8.25(d，2H)，8.53(s，1H)；MS：605.2(M+H).
Embodiment 53:4-(3,5-bis trifluoromethyl anilino)-7-methoxyl group-6-[[3-[5-(4-morpholinyl) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
MS：656.8(M+H).
Embodiment 54:4-(3,4-methylenedioxyphenyl amido)-7-methoxyl group-6-[[3-[5-(piperidino) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate.
1H-NMR(DMSO)：1.47(m，2H)，1.69(m，4H)，2.08(m，2H)，2.70(t，2H)，3.03(m，4H)，3.84(s，2H)，3.94(s，3H)，4.20(t，2H)，4.26(s，2H)，6.04(s，2H)，6.39(d，1H)，6.58(d，1H)，6.94(d，1H)，7.10(d，1H)，7.22(s，1H)，7.40(s，1H)，7.87(s，1H)，8.46(s，1H)；MS：562.9(M+H).
Embodiment 55:4-(benzene methanamine base)-7-methoxyl group-6-[[3-[5-(14-morpholinyl) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：2.05(m，2H)，2.66(m，4H)；3.64(m，4H)，3.80(m，4H)，3.92(s，2H)，3.94(s，3H)，4.16(t，2H)，4.87(s，2H)，6.28(d，1H)，6.35(d，1H)，7.27(s，1H)，7.29～7.40(m，5H)，7.82(s，1H)，8.59(s，1H)，9.45(s，1H)；MS：535.3(M+H).
Embodiment 56:4-(benzene methanamine base)-7-methoxyl group-6-[[3-[5-(piperidino) methyl furan-2-] methylthio group] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.45(m，2H)，1.65(m，4H)，2.07(m，2H)，2.67(t，2H)，2.30(m，4H)，3.81(s，2H)，3.92(s，3H)，4.17(m，4H)，4.81(s，2H)，6.35(d，1H)，6.54(d，1H)，7.20(s，1H)，7.24～7.379m，5H)，7.76(s，1H)，8.42(s，1H)；MS：523.6(M+H).
Embodiment 57:4-(4-trifluoromethylbenzene amido)-7-methoxyl group-6-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline
1H-NMR(DMSO)：1.63(m，4H)，2.49(m，4H)，2.97(t，2H)，3.57(s，2H)，3.95(m，5H)，4.31(t，2H)，6.18(d，1H)，6.26(d，1H)，7.25(s，1H)，7.75(d，1H)，7.89(s，1H)，8.11(d，1H)，8.56(s，1H)，9.74(s，1H)；MS：559.2(M+H).
Embodiment 58:4-(4-fluoro-3-chloroanilino)-7-methoxyl group-6-[[2-[5-(piperidino) methyl furan-2-] methylthio group] oxyethyl group] quinazoline
1H-NMR(DMSO)：1.29(m，2H)，1.42(m，4H)，2.27(m，4H)，2.96(t，2H)，3.35(s，2H)，3.94(m，5H)，4.29(t，2H)，6.15(d，1H)，6.24(d，1H)，7.22(s，1H)，7.44(t，1H)，7.81(m，1H)，7.87(s，1H)，8.13(dd，1H)，8.50(s，1H)，9.76(s，1H)；MS：557.2(M+H).
Embodiment 59:4-(2,4 dichloro benzene amido)-7-methoxyl group-6-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline
1H-NMR(DMSO)：1.61(m，4H)，2.40(m，4H)，2.95(t，3H)，3.50(s，2H)，3.93(s，2H)，3.94(s，3H)，4.25(t，2H)，6.15(d，1H)，6.24(d，1H)，7.20(s，1H)，7.50(dd，1H)，7.58(d，1H)，7.74(s，1H)，7.82(s，1H)，8.32(s，1H)，9.55(s，1H)；MS：559.4(M+H).
Embodiment 60:4-(3,5-difluoroaniline base)-7-methoxyl group-6-[[2-[5-(4-morpholinyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline
1H-NMR(DMSO)：2.32(m，4H)，2.97(t，2H)，3.41(s，2H)，3.51(m，4H)，3.95(m，5H)，4.30(t，2H)，6.19(d，1H)，6.26(d，1H)，6.92(t，1H)，7.25(s，1H)，7.71(d，2H)，7.82(s，1H)，8.59(s，1H)，9.66(s，1H)；MS：543.1(M+H).
Embodiment 61:4-(3,4-methylenedioxyphenyl amido)-7-methoxyl group-6-[[2-[5-(4-morpholinyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：2.79(m，4H)，2.79(t，2H)，3.68(m，4H)，3.95(m，7H)，4.30(t，2H)，6.06(s，2H)，6.36(d，1H)，6.43(d，1H)，6.96(d，1H)，7.08(d，1H)，7.28(s，1H)，7.37(s，1H)，7.91(s，1H)，8.54(s，1H)；MS：551.2(M+H).
Embodiment 62:4-(3-fluoro-4-bromobenzene amido)-7-methoxyl group-6-[[2-[5-(dimethylin) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：2.70(s，6H)，2.99(t，2H)，3.96(s，3H)，4.00(s，2H)，4.31(m，4H)，6.44(d，1H)，6.62(d，1H)，7.25(s，1H)，7.66(m，2H)，7.90(s，1H)，8.12(d，1H)，8.58(s，1H)；MS：561.1(M+H).
Embodiment 63:4-(2,4,5-trifluoro-benzene amido)-7-methoxyl group-6-[[2-[5-(4-morpholinyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：2.80(m，4H)，2.98(t，2H)，3.68(m，4H)，3.96(s，7H)，4.30(t，2H)，6.37(d，1H)，6.44(d，1H)，7.26(s，1H)，7.39(m，2H)，7.84(s，1H)，8.43(s，1H)；MS：260.9(M+H).
Embodiment 64:4-[3-fluoro-4-(4-morpholinyl) anilino]-7-methoxyl group-6-[[2-[5-(N-methylbutylamine base) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：610.0(M+H)
Embodiment 65:4-(4-anisole methylamino)-7-methoxyl group-6-[[2-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate
MS：523.2(M+H).
Embodiment 66:4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylsulfinyl] propoxy-] quinazoline
Prepare 4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[(-(dimethylin) methyl furan-2-according to embodiment 1 method] methylthio group] propoxy-] the quinazoline oxalate, then this compound 1.0g (1.8mmol) is added among the Glacial acetic acid 30mL, stirring makes its dissolving, 0～10 ℃ drips 30% hydrogen peroxide 0.3g (2.8mmol) in reaction solution, 0-5 ℃ of reaction 6-8h, the thin layer monitoring reaction carries out.Reaction is finished, and removes glacial acetic acid under reduced pressure, debris is diluted with less water, with 0.1mol/L aqueous sodium hydroxide solution adjust pH to 10, dichloromethane extraction merges organic phase, washing, anhydrous magnesium sulfate drying, evaporated under reduced pressure gets light yellow solid powder 0.5g (yield: 52.1%).
1H-NMR(CDCl
3)：2.23(s，6H)，2.35(m，2H)，2.91(m，2H)，3.42(s，2H)，3.94(s，3H)，4.09(s，2H)，4.22(t，2H)，6.20(d，1H)，6.35(d，1H)，7.12～7.18(m，2H)，7.19(s，1H)，7.63(m，1H)，7.87(dd，1H)，7.97(s，1H)，8.59(s，1H)；MS：547.1(M+H).
Select proper raw material, at first the method according to embodiment 1 prepares the compound that methylthio group replaces, and carries out oxidizing reaction according to embodiment 66 methods then, makes embodiment 67-104 compound respectively:
Embodiment 67:4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylsulfinyl] propoxy-] quinazoline
1H-NMR(DMSO)：1.75(s，4H)，2.32(m，2H)，2.53(m，2H)，2.67(m，2H)，2.88(m，2H)，3.60(s，2H)，3.91(s，3H)，4.18(t，2H)，4.35(s，2H)，6.21(d，1H)，6.33(d，1H)，7.11(s，1H)，7.22(s，1H)，7.27(d，2H)，7.80(d，2H)，8.59(s，1H)；MS：605.1(M+H).
Embodiment 68:4-(3-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylsulfinyl] propoxy-] the quinazoline oxalate
MS：579.2(M+H).
Embodiment 69:4-(3-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(piperidino) methyl furan-2-] methylsulfinyl] propoxy-] the quinazoline oxalate
MS：619.2[M+H].
Embodiment 70:4-(4-trifluoromethylbenzene amido)-6-methoxyl group-7-[[3-[5-(4-morpholinyl) methyl furan-2-] methylsulfinyl] propoxy-] quinazoline
1H-NMR(CDCl
3)：2.37(m，2H)，2.44(m，4H)，2.90(m，2H)，3.49(s，2H)，3.69(m，4H)，3.96(s，3H)，4.09(s，2H)，4.22(t，2H)，6.22(d，1H)，6.36(d，1H)，7.15(s，1H)，7.17(s，1H)，7.64(d，2H)，7.91(d，2H)，8.55(s，1H)；MS：605.1[M+H].
Embodiment 71:4-(3-fluoroanilino)-6-methoxyl group-7-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylsulfinyl] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.61(m，4H)，2.25(m，2H)，2.41(m，4H)，2.88(m，1H)，2.99(m，1H)，3.52(s，2H)，3.96(s，3H)，4.15(d，1H)，4.27(d，1H)，4.30(d，1H)，6.24(d，1H)，6.36(d，1H)，7.24(d，1H)，7.44(d，1H)，7.63(t，1H)，7.89(d，1H)，8.20～8.25(m，2H)，8.54(s，1H)，9.66(s，1H)；MS：539.5[M+H].
Embodiment 72:4-(4-fluoroanilino)-6-methoxyl group-7-[[3-[5-(N methyl pmpyl amine base) methyl furan-2-] methylsulfinyl] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：0.85(t，3H)，1.59(m，2H)，2.21(m，2H)，2.56(s，3H)，2.78(t，2H)，2.89(m，1H)，2.989(m，1H)，3.97(s，3H)，4.18(s，2H)，4.32～4.37(m，4H)，6.52(d，1H)，6.64(d，1H)，7.23(d，1H)，7.27(s，1H)，7.78(t，2H)，7.87(s，1H)，8.45(s，1H)；MS：541.2[M+H].
The amido of embodiment 73:4-[(quinoline-5-)]-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylsulfinyl] propoxy-] the quinazoline oxalate
1H-NMR(CDCl
3)：2.24(m，2H)，2.71(s，6H)，2.90(m，1H)，3.01(m，1H)，3.40(s，3H)，4.19(d，1H)，4.34(m，4H)，4.36(d，1H)，6.55(d，1H)，6.71(d，1H)，7.31(s，1H)，7.51(dd，1H)，7.69(d，1H)，7.86(t，1H)，8.03(d，1H)，8.32(s，1H)，8.95(d，1H)；MS：546.3[M+H].
Embodiment 74:4-(4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(4-morpholinyl) methyl furan-2-] methylsulfinyl] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：2.58(m，4H)，3.16(m，1H)，3.42(m，1H)，3.61(m，4H)，3.73(s，2H)，3.97(s，3H)，4.27(d，1H)，4.43(d，1H)，4.47(m，1H)，4.58(m，1H)，6.42(d，1H)，6.46(d，1H)，7.24(t，2H)，7.30(s，1H)，7.77(dd，2H)，7.88(s，1H)，8.47(s，1H)，9.64(s，1H)；MS：541.2(M+H).
Embodiment 75:4-(4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(4-methyl isophthalic acid-piperazinyl) methyl furan-2-] methylsulfinyl] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：2.72(m，7H)，3.13(m，4H)，3.16(m，1H)，3.42(m，1H)，3.59(d，3H)，3.83(s，2H)，3.97(s，3H)，4.24(d，1H)，4.39(d，1H)，4.43(m，1H)，4.58(m，1H)，6.36(d，1H)，6.43(d，1H)，7.24(t，2H)，7.30(s，1H)，7.78(dd，2H)，7.88(s，1H)，8.46(s，1H)，9.61(s，1H)；MS：554.1(M+H).
Embodiment 76:4-(4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(N-methyl cyclopropyl amino) methyl furan-2-] methylsulfinyl] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：0.50～0.56(m，4H)，2.14(m，1H)，2.48(s，3H)，3.20(m，1H)，3.43(m，1H)，3.96(s，3H)，3.99(s，2H)，4.27(d，1H)，4.45(d，1H)，4.48(m，1H)，4.59(m，1H)，6.47(s，2H)，7.25(t，2H)，7.31(s，1H)，7.77(dd，2H)，7.89(s，1H)，8.49(s，1H)，9.70(s，1H)；MS：525.1(M+H).
Embodiment 77:4-(2-fluoroanilino)-6-methoxyl group-7-[[2-[5-(dimethylin) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
1H-NMR(CDCl
3)：2.35(s，6H)，3.13(m，1H)，3.32(m，1H)，3.58(s，2H)，4.02(s，3H)，4.19(d，1H)，4.38(d，1H)，4.57(m，1H)，4.65(m，1H)，6.32(d，1H)，6.48(d，1H)，7.07(s，1H)，7.11～7.23(m，3H)，7.30(s，1H)，7.39(s，1H)，8.51(t，1H)，8.69(s，1H)；MS：449.2(M+H).
Embodiment 78:4-(2-fluoroanilino)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
1H-NMR(CDCl
3)：1.82(m，4H)，2.62(m，4H)，3.13(m，1H)，3.30(m，1H)，3.68(s，2H)，4.02(s，3H)，4.20(d，1H)，4.37(d，1H)，4.57(m，1H)，4.65(m，1H)，6.27(d，1H)，6.45(d，1H)，7.05(s，1H)，7.09～7.21(m，3H)，7.30(s，1H)，7.34(s，1H)，8.53(t，1H)，8.71(s，1H)；MS：525.2(M+H).
Embodiment 79:4-(2-fluoroanilino)-6-methoxyl group-7-[[2-[5-(4-morpholinyl) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
1H-NMR(CDCl
3)：2.50(m，4H)，3.16(m，1H)，3.34(m，1H)，3.56(s，2H)，3.74(m，4H)，4.03(s，3H)，4.22(d，1H)，4.40(d，1H)，4.58(m，1H)，4.66(m，1H)，6.27(d，1H)，6.47(d，1H)，7.08(s，1H)，7.11～7.25(m，3H)，7.32(s，1H)，7.42(s，1H)，8.50(t，1H)，8.71(s，1H)；MS：541.1(M+H).
Embodiment 80:4-(2-fluoroanilino)-6-methoxyl group-7-[[2-[5-(N methyl pmpyl amine base) methyl furan-2-] methylsulfinyl] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：0.88(t，3H)，1.64(m，2H)，2.66(s，3H)，2.89(m，2H)，3.17(s，2H)，3.21(m，1H)，3.45(m，1H)，3.95(s，3H)，4.30(d，1H)，4.48(d，1H)，4.58(m，2H)，6.57(d，1H)，6.71(d，1H)，7.31(m，4H)，7.54(t，1H)，7.87(s，1H)，8.37(s，1H)；MS：527.2(M+H).
The amido of embodiment 81:4-[(quinoline-5-)]-6-methoxyl group-7-[[2-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylsulfinyl] oxyethyl group] the quinazoline oxalate
1H-NMR(DMSO)：1.23(t，3H)，2.69(s，3H)，3.05(m，2H)，3.21(m，1H)，3.47(m，1H)，3.99(s，3H)，4.32(d，1H)，4.37(t，3H)，4.49(d，1H)，4.52(m，1H)，4.61(m，1H)，6.59(d，1H)，6.74(d，1H)，7.37(s，1H)，7.51(dd，1H)，7.69(d，1H)，7.85(t，1H)，8.00(s，1H)，8.05(m，1H)，8.29(m，2H)，8.95(m，1H)；MS：546.1(M+H).
Embodiment 82:4-(3,4-dichlorobenzene amido)-6-methoxyl group-7-[[2-[5-(piperidino) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
MS：589.0(M+H).
Embodiment 83:4-(3,5-bis trifluoromethyl anilino)-6-methoxyl group-7-[[2-[5-(dipropyl amido) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
MS：643.1(M+H).
Embodiment 84:4-[3-fluoro-4-(4-morpholinyl) anilino]-6-methoxyl group-7-[[2-[5-(N methyl pmpyl amine base) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
MS：612.4(M+H).
Embodiment 85:4-[3-fluoro-4-(piperidino) anilino]-6-methoxyl group-7-[[2-[5-(4-methyl isophthalic acid-piperazinyl) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
MS：637.3(M+H).
Embodiment 86:4-(3-fluoroanilino)-7-methoxyl group-6-[[3-[5-(N methyl pmpyl amine base) methyl furan-2-] methylsulfinyl] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：0.85(t，3H)，1.61(m，2H)，2.09(m，2H)，2.68(s，3H)，2.70(t，2H)，2.86(t，2H)，3.84(s，2H)，3.96(s，3H)，4.23(t，2H)，4.28(s，2H)，6.40(d，1H)，6.61(d，1H)，7.25(s，1H)，7.45(d，1H)，7.63(t，1H)，7.90(s，1H)，8.22～8.24(m，2H)，8.55(s，1H)；MS：541.2(M+H).
Embodiment 87:4-(3-fluoroanilino)-7-methoxyl group-6-[[3-[5-(4-morpholinyl) methyl furan-2-] methylsulfinyl] propoxy-] quinazoline
1H-NMR(DMSO)：2.26(m，2H)，2.33(m，4H)，2.88(m，1H)，3.01(m，1H)，3.44(s，2H)，3.51(m，4H)，3.96(s，3H)，4.15(d，1H)，4.27～4.31(m，3H)，6.29(d，1H)，6.38(d，1H)，7.24(s，1H)，7.44(d，1H)，7.63(t，1H)，7.88(s，1H)，8.20～8.24(m，2H)，8.54(s，1H)，9.65(s，1H)；MS：555.1(M+H).
Embodiment 88:4-(4-fluoroanilino)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylsulfinyl] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：1.87(m，4H)，2.08(m，2H)，2.69(t，2H)，3.19(m，4H)，3.83(s，2H)，3.94(s，3H)，4.21(t，2H)，4.34(s，2H)，6.37(d，1H)，6.57(d，1H)，7.21(s，1H)，7.23(d，2H)，7.78(t，2H)，7.87(s，1H)，8.45(s，1H)；MS：539.4(M+H).
Embodiment 89:4-(3-bromobenzene amido)-7-methoxyl group-6-[[3-[5-(piperidino) methyl furan-2-] methylsulfinyl] propoxy-] quinazoline
1H-NMR(DMSO)：1.29(m，2H)，1.41(m，4H)，2.23(t，2H)，2.29(s，2H)，2.78(m，1H)，2.97(m，1H)，3.38(m，4H)，3.95(s，3H)，4.16(d，1H)，4.28(d，1H)，4.29(s，2H)，6.24(d，1H)，6.36(d，1H)，7.23(s，1H)，7.28(d，1H)，7.35(t，1H)，7.86～7.89(m，2H)，8.16(s，1H)，8.53(s，1H)，9.51(s，1H)；MS：613.5(M+H).
Embodiment 90:4-(3-trifluoromethylbenzene amido)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) the methyl furan food in one's mouth-2-] methylsulfinyl] propoxy-] quinazoline
MS：589.2(M+H).
Embodiment 91:4-(3-trifluoromethylbenzene amido)-7-methoxyl group-6-[[3-[5-(N methyl pmpyl amine base) methyl furan-2-] methylsulfinyl] propoxy-] quinazoline
MS：591.2(M+H).
Embodiment 92:4-(3-trifluoromethylbenzene amido)-7-methoxyl group-6-[[3-[5-(dimethylin) methyl furan food in one's mouth-2-] methylsulfinyl] propoxy-] quinazoline
MS：563.2(M+H).
Embodiment 93:4-(3,4-difluoroaniline base)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) the methyl furan food in one's mouth-2-] methylsulfinyl] propoxy-] quinazoline
MS：557.2(M+H).
Embodiment 94:4-(3-fluoro-4-bromobenzene amido)-7-methoxyl group-6-[[3-[5-(4-morpholinyl) methyl furan-2-] methylsulfinyl] propoxy-] quinazoline
1H-NMR(DMSO)：2.24(t，2H)，2.40(m，4H)，2.89(m，1H)，3.00(m，1H)，3.52(m，6H)，3.96(s，3H)，4.16(d，1H)，4.29(s，2H)，4.30(d，1H)，6.32(d，1H)，6.39(d，1H)，7.24(s，1H)，7.64(dd，1H)，7.69(t，1H)，7.86(s，1H)，8.12(d，1H)，8.56(s，1H)，9.62(s，1H)；MS：634.8(M+H).
Embodiment 95:4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[[3-[5-(dimethylin) methyl furan-2-] methylsulfinyl] propoxy-] quinazoline
MS：547.2(M+H).
Embodiment 96:4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylsulfinyl] propoxy-] quinazoline
MS：573.1(M+H).
Embodiment 97:4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[[3-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylsulfinyl] propoxy-] quinazoline
MS：561.2(M+H).
Embodiment 98:4-(3-trifluoromethyl-4-fluoroanilino)-7-methoxyl group-6-[[3-[5-(dimethylin) methyl furan-2-] methylsulfinyl] propoxy-] the quinazoline oxalate
1H-NMR(DMSO)：2.10(s，6H)，2.24(m，2H)，2.90(m，1H)，2.96(m，1H)，3.37(t，2H)，3.95(s，3H)，4.14(d，1H)，4.25-4.29(m，3H)，6.26(d，1H)，6.37(d，1H)，7.22(s，1H)，7.53(t，1H)，7.92(s，1H)，8.26(m，2H)，8.51(s，1H)；MS：581.3(M+H).
Embodiment 99:4-(2,4 dichloro benzene amido)-7-methoxyl group-6-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
1H-NMR(DMSO)：1.65(m，4H)，2.43(m，4H)，3.19(m，1H)，3.42(m，1H)，3.54(s，2H)，3.94(s，3H)，4.24(d，1H)，4.41(d，1H)，4.53(s，2H)，6.26(d，1H)，6.39(d，1H)，7.22(s，1H)，7.50(d，1H)，7.59(d，1H)，7.75(s，1H)，7.93(s，1H)，8.34(s，1H)，9.56(s，1H)；MS：547.8(M+H).
Embodiment 100:4-(3,5-difluoroaniline base)-7-methoxyl group-6-[[2-[5-(4-morpholinyl) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
1H-NMR(DMSO)：2.49(m，4H)，3.23(m，1H)，3.47(m，1H)，3.58(m，6H)，3.96(s，3H)，4.27(d，1H)，4.45(d，1H)，4.57(s，2H)，6.37(d，1H)，6.44(d，1H)，6.92(t，1H)，7.27(s，1H)，7.92(d，2H)，8.61(s，1H)，9.67(s，1H)；MS：559.4(M+H).
Embodiment 101:4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
1H-NMR(DMSO)：1.66(m，4H)，2.47(m，4H)，3.23(m，1H)，3.35(m，1H)，3.57(s，2H)，3.95(s，3H)，4.25(d，1H)，4.43(d，1H)，4.56(t，2H)，6.28(d，1H)，6.41(d，1H)，7.24(s，1H)，7.45(t，1H)，7.78(m，1H)，7.92(s，1H)，8.13(dd，1H)，8.52(s，1H)，9.57(s，1H)；MS：559.1(M+H).
Embodiment 102:4-[3-fluoro-4-(piperidino) anilino]-7-methoxyl group-6-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
MS：608.3(M+H).
Embodiment 103:4-(4-fluorobenzene methylamino)-7-methoxyl group-6-[[2-[5-(N-methylbutylamine base) methyl furan-2-] methylsulfinyl] oxyethyl group] quinazoline
MS：539.6(M+H).
Embodiment 104:4-(3,4-difluoroaniline base)-7-methoxyl group-6-[[2-[5-(N-methyl ethyl-amine base) methyl furan-2-] methyl sulphonyl] oxyethyl group] quinazoline
Prepare 4-(3 according to embodiment 1 method, 4-difluoroaniline base)-and 7-methoxyl group-6-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] the quinazoline oxalate, then this compound 1.05g (2.0mmol) is added among the Glacial acetic acid 30mL, stirring makes its dissolving, 25-30 ℃ drips 30% hydrogen peroxide 0.6g (2.8mmol) in reaction solution, 25 ℃ of reaction 8-12h, the thin layer monitoring reaction carries out.Reaction is finished, and removes glacial acetic acid under reduced pressure, debris is diluted with less water, with 0.1mol/L aqueous sodium hydroxide solution adjust pH to 10, dichloromethane extraction merges organic phase, washing, anhydrous magnesium sulfate drying, evaporated under reduced pressure gets light yellow solid powder 0.45g (yield: 40.6%).
1H-NMR(DMSO)：1.69(m，4H)，2.57(m，4H)，3.70(s，2H)，3.79(t，2H)，3.95(s，3H)，4.56(t，2H)，4.82(s，2H)，6.38(d，1H)，6.55(d，1H)，7.27(s，1H)，7.47(dd，1H)，7.56(m，1H)，7.92(s，1H)，8.06(m，1H)，8.54(s，1H)，9.62(s，1H)；MS：559.1(M+H).
Embodiment 105:4-(3-fluoro-4-bromobenzene amido)-7-methoxyl group-6-[[2-[5-(4-morpholinyl) methyl furan-2-] methyl sulphonyl] oxyethyl group] quinazoline
Method preparation according to embodiment 104.
1H-NMR(DMSO)：2.86(d，2H)，3.46(m，4H)，3.66(d，2H)，3.95(s，3H)，4.07(m，2H)，4.30(d，1H)，4.44～4.51(m，5H)，6.55(d，1H)，6.68(d，1H)，7.25(s，1H)，7.66(m，2H)，7.95(s，1H)，8.12(d，1H)，8.56(s，1H)，9.77(s，1H)；MS：636.7(M+H).
The pharmacological research of product of the present invention
Quinazoline derivative according to following formula I of the present invention is carried out external protein tyrosine kinase suppressed screening active ingredients and anti tumor activity in vitro screening.
One, protein tyrosine kinase suppresses screening active ingredients
(1) the kinase reaction liquid of adding 50uL in every hole of 96 orifice plates.Add given the test agent 10uL (concentration is 9 μ g/mL) at the 2-11 of 96 orifice plates row, add kinase reaction liquid 10uL at 1 and 12 row with the volley of rifle fire.The rat cerebral tissue's tyrosine extracting solution [protein content is about 0.4mg/mL] that in every hole of 96 orifice plates, adds 50uL.The vibration mixing.Hatched 1 hour for 37 ℃.Wash 3 times with the elutriant of 200uL.
(2) in every hole of 96 orifice plates, add the anti-polypeptide phosphate antibody liquid that is connected with horseradish peroxidase (HRP) of 100uL with personal pipettor with 2000 times of dilutions of elutriant.The vibration mixing.Incubated at room 30 minutes.
(3) wash 3 times with elutriant.
(4) every hole adds the 100uL o-phenylenediamine solution.Lucifuge was hatched 7-10 minute under the room temperature.
(5) add 100uL 1mol/L sulfuric acid in every hole with termination reaction.
(6) in 30 minutes, be determined at the absorbancy at 492nm place with microplate reader.
(7) calculate the inhibiting rate of medicine by the sample absorbancy of microplate reader mensuration with the contrast absorbancy that does not add medicine that plate is measured to protein tyrosine kinase.Method of calculation are as follows:
Inhibiting rate %=(contrast OD-sample OD)/(the blank OD of contrast OD-) * 100%
Described reference substance is the Iressa as EGF-R ELISA Tyrosine kinase inhibitor of Astra Zeneca company development, and structural formula is as follows,
Experiment in vitro proves that it can suppress prostate cancer, mammary cancer, ovarian cancer, colorectal carcinoma, small cell lung cancer and nonsmall-cell lung cancer.
The part of compounds arrestin tyrosine kinase activity of Xuan Zeing the results are shown in Table 1 at random.
Table 1
| The embodiment sequence number | Concentration (μ g/mL) | Inhibiting rate (%) |
| Iressa (reference substance) | 9 | 80 |
| Embodiment 1 | 9 | 81 |
| Embodiment 4 | 9 | 82 |
| Embodiment 18 | 9 | 79 |
| Embodiment 29 | 9 | 72 |
| Embodiment 33 | 9 | 76 |
| Embodiment 35 | 9 | 86 |
| Embodiment 45 | 9 | 85 |
| Embodiment 49 | 9 | 84 |
| Embodiment 51 | 9 | 85 |
| Embodiment 57 | 9 | 80 |
| Embodiment 69 | 9 | 86 |
| Embodiment 90 | 9 | 79 |
| Embodiment 91 | 9 | 84 |
| Embodiment 92 | 9 | 81 |
| Embodiment 93 | 9 | 85 |
| Embodiment 95 | 9 | 80 |
| Embodiment 96 | 9 | 79 |
| Embodiment 104 | 9 | 79 |
Two, external anti-oral carcinoma and cancer of the stomach tumor promotion test
(1) cell recovery and go down to posterity 2-3 time stable after, with trypsin solution (0.25%) it is digested bottom culturing bottle.Cell dissociation buffer poured into then add nutrient solution in the centrifuge tube to stop digestion.With centrifuge tube centrifugal 3min under 1300r/min, add the 5mL nutrient solution gently after the abandoning supernatant, piping and druming mixing cell is drawn in the 10uL cell suspension adding cell counting count board and is counted, and adjusting cell concn is 10
4Individual/hole.Removing the A1 hole in 96 orifice plates is that blank well does not add the extracellular, and all the other all add the 100uL cell suspension.96 orifice plates are put into incubator cultivate 24h.
(2) with 50 μ l dmso solution given the test agent, add an amount of nutrient solution then, make sample dissolution become the 2mg/mL soup.In 24 orifice plates, be 16,8,4,2 then with diluted sample, 1 μ g/mL.Each concentration adds 3 holes, and wherein two row, two row cell growing ways are affected by environment bigger on every side, only uses as blank cell hole.96 orifice plates are put into incubator cultivate 24h.
(3) will be in 96 orifice plates band medicine nutrient solution discard, with cell flushing twice, in every hole, add MTT (tetrazole) (0.5mg/mL) after 100uL puts into incubator 4h with phosphate buffer solution (PBS), discard MTT solution, add dimethyl sulfoxide (DMSO) 100uL.Vibration is fully dissolved survivaling cell and MTT reaction product Jia Za on the magnetic force vibrator, puts into the microplate reader measurement result.Can obtain medicine IC by the Bliss method
50Value.
The inhibition oral carcinoma and the stomach cancer cell activity of compound the results are shown in Table 2.
Table 2
| The embodiment sequence number | IC 50KB (cancer cell of oral cavity) (ug/mL) | IC 50SGC-7901 (stomach cancer cell) (ug/mL) |
| Iressa (reference substance) | 7.86 | 6.11 |
| Embodiment 1 | 2.43 | 1.95 |
| Embodiment 2 | 5.02 | 3.63 |
| Embodiment 3 | 5.06 | 4.53 |
| Embodiment 4 | 3.38 | 5.27 |
| Embodiment 5 | 4.47 | 4.23 |
| Embodiment 6 | 2.23 | 8.76 |
| Embodiment 12 | 2.94 | 9.07 |
| Embodiment 15 | 5.16 | 7.20 |
| Embodiment 16 | 3.42 | 2.90 |
| Embodiment 17 | 7.2 | 8.53 |
| Embodiment 18 | 0.2 | 0.02 |
| Embodiment 19 | 3.93 | 3.68 |
| Embodiment 20 | 6.59 | 6.87 |
| Embodiment 27 | 5.90 | 2.61 |
| Embodiment 28 | 4.45 | 5.84 |
| Embodiment 29 | 2.25 | 3.21 |
| Embodiment 30 | 3.09 | 5.09 |
| Embodiment 31 | 4.35 | 4.81 |
| Embodiment 32 | 5.05 | 4.78 |
| Embodiment 33 | 6.23 | 3.96 |
| Embodiment 35 | 1.39 | 3.88 |
| Embodiment 36 | 8.15 | 6.19 |
| Embodiment 45 | 2.81 | 1.91 |
| Embodiment 46 | 3.56 | 4.32 |
| Embodiment 47 | 7.87 | 5.6 |
| Embodiment 48 | 0.79 | 1.43 |
| Embodiment 49 | 7.05 | 6.41 |
| Embodiment 57 | 2.93 | 3.89 |
| Embodiment 68 | 2.03 | 2.42 |
| Embodiment 69 | 1.7 | 0.39 |
| Embodiment 90 | 6.46 | 6.61 |
| Embodiment 92 | 6.72 | 4.77 |
| Embodiment 93 | 7.02 | 6.25 |
| Embodiment 95 | 5.80 | 6.23 |
| Embodiment 96 | 3.67 | 4.67 |
| Embodiment 97 | 7.19 | 7.14 |
| Embodiment 105 | 3.56 | 4.69 |
Three, compound anti-hepatoma cytoactive test
(1) selects adherent people's liver cancer tumour cell Bel-7402 of logarithmic phase for use, after trysinization, be made into the cell suspension of 40000/mL, be seeded in 96 well culture plates every hole inoculation 200uL, 37 ℃, 5%CO with the RPMI1640 nutrient solution of 10% calf serum
2Cultivate 24h.
(2) nutrient solution that contains the 5ng/mL sample that experimental group renews, control group then changes the nutrient solution that contains the equal-volume solvent, and 3～5 multiple holes, 37 ℃, 5%CO are established in every hole
2Cultivate 3d.
(3) abandoning supernatant, every hole adds the serum-free medium of the freshly prepared 0.5mg/mL MTT of 100uL, and 37 ℃ are continued to cultivate 4h.Carefully abandon supernatant liquor, and add 200uL dmso solution MTT Jia Za precipitation, behind miniature ultrasonic vibrator mixing, on microplate reader, measure the optical density value at wavelength 544nm place.The results are shown in Table 3.
Bel-7402 growth of tumour cell inhibiting rate (%)=(OD
Contrast-OD
Experiment)/(OD
Contrast-OD
Blank) * 100%
Table 3
| The embodiment sequence number | Bel-7402 growth inhibition ratio (%) | The embodiment sequence number | Bel-7402 growth inhibition ratio (%) |
| Embodiment 1 | 86.31 | Embodiment 33 | 89.09 |
| Embodiment 2 | 85.19 | Embodiment 34 | 74.27 |
| Embodiment 3 | 80.87 | Embodiment 35 | 69.33 |
| Embodiment 4 | 78.93 | Embodiment 36 | 87.94 |
| Embodiment 5 | 90.80 | Embodiment 45 | 87.57 |
| Embodiment 6 | 92.36 | Embodiment 46 | 87.48 |
| Embodiment 12 | 89.06 | Embodiment 47 | 84.50 |
| Embodiment 15 | 81.48 | Embodiment 48 | 71.80 |
| Embodiment 16 | 75.26 | Embodiment 49 | 69.25 |
| Embodiment 17 | 64.13 | Embodiment 50 | 75.19 |
| Embodiment 18 | 82.20 | Embodiment 51 | 78.29 |
| Embodiment 19 | 70.57 | Embodiment 57 | 86.53 |
| Embodiment 20 | 78.59 | Embodiment 68 | 79.58 |
| Embodiment 27 | 61.51 | Embodiment 69 | 86.35 |
| Embodiment 28 | 60.66 | Embodiment 90 | 87.80 |
| Embodiment 29 | 89.09 | Embodiment 92 | 86.80 |
| Embodiment 30 | 85.97 | Embodiment 95 | 72.79 |
| Embodiment 31 | 84.46 | Embodiment 96 | 66.30 |
| Embodiment 32 | 84.32 | Embodiment 97 | 73.21 |
Can clearly be seen that from above-mentioned test-results the compound of the claimed general formula of the present invention (I) has excellent protein tyrosine kinase and suppresses activity and antitumour activity.In addition, the compound of the claimed general formula of the present invention (I) also has certain treatment and/or prevents arteriosclerosis and psoriasic pharmacologically active.Therefore compound of the present invention has better industrial application prospect.
Claims (14)
1, derivative of general formula I, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
6Alkyl, another one is-R
3YR
4Q
2
A is C
1-C
4Alkyl, H;
X is a direct key or C
1-C
4Alkylidene group, described alkylidene group can be selected from hydroxyl, halogen, nitro, C by 1-3
1-C
4The substituting group of alkoxyl group is optional to be replaced;
Q
1Be phenyl, naphthyl or 5-10 unit heteroaryl, described heteroaryl can contain 1-3 heteroatoms that is selected from O, N and S, and Q
1Can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
6Alkylidene group, described alkylidene group can be selected from hydroxyl, halogen, nitro, C by 1-3
1-C
4The substituting group of alkoxyl group is optional to be replaced;
Y is-S-,
Q
2Be furyl, pyrryl, thienyl, can choose 1-3 R wantonly
6Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, (C
1-C
4) alkyl sulfenyl, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkoxy methyl, C
1-C
4Alkyl acyl, formamyl, N-C
1-C
4Alkyl-carbamoyl, N, N-two C
1-C
4Alkyl-carbamoyl, amino-sulfonyl, N-C
1-C
4Alkyl amino sulfonyl, N, N-two C
1-C
4Alkyl amino sulfonyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, piperidyl, imidazolidyl and pyrazolidyl, and this saturated heterocyclyl can have individual oxo, hydroxyl, halogen, the C of being selected from of 1-2
1-C
3Alkyl, C
1-C
3The substituting group of alkoxyl group, trifluoromethyl, nitro;
R
6Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N-C
1-C
4Alkylamino, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkoxy methyl, C
1-C
4Alkyl acyl, formamyl, N-C
1-C
4Alkyl-carbamoyl, N, N-two C
1-C
4Alkyl-carbamoyl, amino-sulfonyl, N-C
1-C
4Alkyl amino sulfonyl, N, N-two C
1-C
4Alkyl amino sulfonyl, perhaps R
6For-CH
2NR
7R
8
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-10 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
2, general formula I derivative of claim 1, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
6Alkyl, another one is-R
3YR
4Q
2
A is H;
X is a direct key or C
1-C
4Alkylidene group;
Q
1Be phenyl, naphthyl or 5-10 unit heteroaryl, described heteroaryl can contain 1-3 heteroatoms that is selected from O, N and S, and Q
1Can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2Be furyl, pyrryl, thienyl, can choose 1-3 R wantonly
6Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkoxy methyl, C
1-C
4Alkyl acyl, formamyl, N-C
1-C
4Alkyl-carbamoyl, N, N-two C
1-C
4Alkyl-carbamoyl, amino-sulfonyl, N-C
1-C
4Alkyl amino sulfonyl, N, N-two C
1-C
4Alkyl amino sulfonyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, piperidyl, imidazolidyl and pyrazolidyl, and this saturated heterocyclyl can have individual oxo, hydroxyl, halogen, the C of being selected from of 1-2
1-C
3Alkyl, C
1-C
3The substituting group of alkoxyl group, trifluoromethyl, nitro;
R
6Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N-C
1-C
4Alkylamino, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkoxy methyl, C
1-C
4Alkyl acyl, formamyl, N-C
1-C
4Alkyl-carbamoyl, N, N-two C
1-C
4Alkyl-carbamoyl, amino-sulfonyl, N-C
1-C
4Alkyl amino sulfonyl, N, N-two C
1-C
4Alkyl amino sulfonyl, perhaps R
6For-CH
2NR
7R
8
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-10 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
3, general formula I derivative of claim 2, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
4Alkyl, another one is-R
3YR
4Q
2
A is H;
X is a direct key or C
1-C
4Alkylidene group;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2Be furyl, pyrryl, thienyl, can choose 1-3 R wantonly
6Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
6Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N-C
1-C
4Alkylamino, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkyl sulphinyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Alkoxy methyl, C
1-C
4Alkyl acyl, formamyl, N-C
1-C
4Alkyl-carbamoyl, N, N-two C
1-C
4Alkyl-carbamoyl, amino-sulfonyl, N-C
1-C
4Alkyl amino sulfonyl, N, N-two C
1-C
4Alkyl amino sulfonyl, perhaps R
6For-CH
2NR
7R
8
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-10 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
4, general formula I derivative of claim 3, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
4Alkyl, another one is-R
3YR
4Q
2
A is H;
X is a direct key or methylene radical;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2Be furyl, pyrryl, thienyl, can choose 1-3 R wantonly
6Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, N methyl piperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
6Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N-C
1-C
4Alkylamino, N, N-two C
1-C
4Alkylamino, perhaps R
6For-CH
2NR
7R
8
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-6 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
5, general formula I derivative of claim 4, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
4Alkyl, another one is-R
3YR
4Q
2
A is H;
X is a direct key or methylene radical;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2For containing furyl, can choose 1-3 R wantonly
6Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
6Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N-C
1-C
4Alkylamino, N, N-two C
1-C
4Alkylamino or R
6For-CH
2NR
7R
8
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-6 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
6, general formula I derivative of claim 5, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is C
1-C
4Alkyl, another one is-R
3YR
4Q
2
A is H;
X is a direct key or methylene radical;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2Be furyl, and on 5 quilt-CH
2NR
7R
8Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
5The optional replacement, or R
7And R
8Form 5-6 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
7, general formula I derivative of claim 6, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is a methyl, and another one is-R
3YR
4Q
2
A is H;
X is a direct key;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3, R
4Be C
1-C
4Alkylidene group;
Y is-S-,
Q
2Be furyl, and on 5 quilt-CH
2NR
7R
8Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, or R
7And R
8Form 5-6 unit saturated heterocyclyl with the nitrogen-atoms that is connected with them, described saturated heterocyclyl except with R
7And R
8Outside the nitrogen-atoms that connects, can contain 1-3 heteroatoms that is selected from O, N and S, can be by 1～3 identical or different R
5The optional replacement.
8, general formula I derivative of claim 7, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate,
Wherein
R
1, R
2One of them is a methyl, and another one is-R
3YR
4Q
2
A is H;
X is a direct key;
Q
1Be phenyl, can choose 1-3 R wantonly
5Replace;
R
3Be C
1-C
3Alkylidene group;
R
4Be methylene radical;
Y is-S-,
Q
2Be furyl, and on 5 quilt-CH
2NR
7R
8Replace;
R
5Be hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, N, N-two C
1-C
4Alkylamino, C
1-C
4Alkyl sulfenyl, C
1-C
4Alkoxy methyl, C
1-C
3Alkylenedioxy group, and the saturated heterocyclyl that is selected from morpholinyl, pyrrolidyl, piperazinyl, 4-methylpiperazine base, piperidyl, imidazolidyl and pyrazolidyl;
R
7, R
8Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, C
3-C
6Cycloalkyl, or R
7And R
8Form pyrrolidyl, morpholinyl, piperidyl and 4-methylpiperazine base with the nitrogen-atoms that is connected with them.
9, following general formula I derivative, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate:
4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[(5-dimethylin) methyl furan-2-] methylthio group] propoxy-] quinazoline;
4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] propoxy-] quinazoline;
4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] quinazoline;
4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] quinazoline;
4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] quinazoline;
4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] propoxy-] quinazoline;
4-(3-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] quinazoline;
4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(4-methyl isophthalic acid-piperazinyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(3-trifluoromethylbenzene amido)-6-methoxyl group-7-[[2-[5-(piperidino) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(3,5-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(3,5-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(N-methyl ethyl-amine base) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(dimethylin) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-[[2-[5-(N methyl pmpyl amine base) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(3,4-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(3,4-difluoroaniline base)-6-methoxyl group-7-[[2-[5-(dimethylin) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(4-trifluoro-methoxyaniline base)-6-methoxyl group-7-[[2-[5-(N methyl pmpyl amine base) methyl furan-2-] methylthio group] oxyethyl group] quinazoline;
4-(3-trifluoromethylbenzene amido)-7-methoxyl group-6-[[3-[5-(dimethylin) methyl furan-2-] methylthio group] propoxy-] quinazoline;
4-(3-trifluoromethylbenzene amido)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] quinazoline;
4-(3,4-difluoroaniline base)-7-methoxyl group-6-[[3-[5-(1-pyrrolidyl) methyl furan-2-] methylthio group] propoxy-] quinazoline.
10, each described general formula I derivative in the claim 1～9, and optically active body or raceme, non-enantiomer mixture, or its pharmacy acceptable salt, hydrate or solvate: wherein said salt is oxalate.
11, a kind of medicinal compositions, the derivative and optically active body or raceme, the non-enantiomer mixture that comprise among the claim 1-10 any one, or its pharmacy acceptable salt, hydrate or solvate are as activeconstituents and pharmaceutically acceptable excipient.
12, the application in the preparation protein tyrosine kinase inhibitor of derivative of any one and optically active body thereof or raceme, non-enantiomer mixture among the claim 1-10, or its pharmacy acceptable salt, hydrate or solvate.
13, derivative of any one and optically active body thereof or raceme, non-enantiomer mixture among the claim 1-10, or its pharmacy acceptable salt, hydrate or solvate treat and/or prevent application in the medicine of various Cancerous diseases in preparation.
14, derivative of any one and optically active body thereof or raceme, non-enantiomer mixture among the claim 1-10, or its pharmacy acceptable salt, hydrate or solvate preparation treatment and/prevention is based on the application in arteriosclerotic disease and the psoriasis medicine.
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| CN102452988B (en) | 2010-10-27 | 2016-01-27 | 中国科学院化学研究所 | A kind of quinazoline derivant and preparation method thereof |
| CA2900652C (en) | 2013-02-15 | 2021-05-04 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
| US9353123B2 (en) | 2013-02-20 | 2016-05-31 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| CN103288759B (en) * | 2013-05-16 | 2015-05-20 | 苏州明锐医药科技有限公司 | Method for preparing dacomitinib |
| US9890173B2 (en) | 2013-11-01 | 2018-02-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| EP3062618B1 (en) | 2013-11-01 | 2020-02-05 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| EP3509421A4 (en) | 2016-09-08 | 2020-05-20 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| WO2018048750A1 (en) | 2016-09-08 | 2018-03-15 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10253036B2 (en) | 2016-09-08 | 2019-04-09 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| CA3059660A1 (en) * | 2017-04-27 | 2018-11-01 | Astrazeneca Ab | Phenoxyquinazoline compounds and their use in treating cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1211239A (en) * | 1996-02-13 | 1999-03-17 | 曾尼卡有限公司 | Quinazoline derivatives as VEGF inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1211239A (en) * | 1996-02-13 | 1999-03-17 | 曾尼卡有限公司 | Quinazoline derivatives as VEGF inhibitors |
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