CN102311395B - Quinazoline ring substituted diphenylurea derivative and its purpose - Google Patents

Quinazoline ring substituted diphenylurea derivative and its purpose Download PDF

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CN102311395B
CN102311395B CN201110187118.6A CN201110187118A CN102311395B CN 102311395 B CN102311395 B CN 102311395B CN 201110187118 A CN201110187118 A CN 201110187118A CN 102311395 B CN102311395 B CN 102311395B
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phenyl
trifluoromethyl
urea
oxygen
quinazolyl
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CN102311395A (en
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张爱华
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Abstract

The invention discloses a quinazoline ring substituted diphenylurea derivative and its purpose. The quinazoline ring substituted diphenylurea derivative has a structure as formula I, wherein, R1 is hydrogen, amino, acrylamido, straight chain alkoxyalkoxy or straight chain morpholine substituent alkyloxy; R2 is straight chain alkoxyalkoxy or straight chain morpholine substituent alkyloxy; R3 is halogen. The quinazoline ring substituted diphenylurea derivative can be used for treating tumour or leukemia.

Description

Cyclosubstituted sym-diphenylurea analog derivative of quinazoline and uses thereof
Technical field
The invention belongs to vitochemical heterogeneous ring compound field, be specifically related to the cyclosubstituted sym-diphenylurea analog derivative of a kind of quinazoline with and uses thereof.
Background technology
Malignant tumour is the major disease of harm people life and health, and the research and development of antitumor drug are in current life science, to be rich in challenge and far reaching field.In recent years, along with the development that molecular weight tumor is learned, malignant tumour occurs, the mechanism of development is just progressively illustrated, and great change has also occurred the research and development theory of tumour medicine.Along with molecular biological development, people have had further understanding to the pathogeny of cancer, find that proto-oncogene and cancer suppressor gene are present in each human body, cancer be to cause transgenation due to physics, chemistry or the stimulation such as biological, thereby the signal transduction pathway in body is got muddled, make the Normocellular process that can not complete apoptosis, therefore the unconfined propagation of meeting, forms tumour.Therefore current research is mainly for targeted therapy, and targeted therapy is to using some and the closely-related molecule of tumour generation, growth, transfer and apoptosis or gene as the methods for the treatment of of drug screening target spot,
Along with sharpening understanding to tumour molecular mechanism, the research of tumour molecular targeted therapy has been obtained to major progress. kinases inhibitor is one of target therapeutic agent of recently researching and developing, by molecule conduction path in block cell, affect the survival of tumour cell, propagation and progression of disease. in Raf/MEK/ERK signal transduction pathway, although Raf kinases is being brought into play vital effect. in healthy tissues, the kinase whose function of Raf is not yet bright and clear, but existing basis and clinical study result all show, the rise of Raf gene and the overexpression of albumen thereof are present among multiple noumenal tumour, comprise renal cell carcinoma, hepatocellular carcinoma, melanoma and nonsmall-cell lung cancer etc. Xarelto is the first oral Raf kinase inhibitor in the whole world. in addition, as target drug more than, Xarelto has for the extensive tyrosine kinase receptor inhibit feature that comprises VEGFR and PDGFR simultaneously. and current U.S. FDA has been ratified Xarelto and has been used for the treatment of metastatic renal cell carcinoma. liver cancer, in addition, this medicine is for melanoma, , in the clinical study of carcinoma of the pancreas and nonsmall-cell lung cancer, also demonstrated certain curative effect.
In Chinese patent CN1344254, disclose some and there is the quinazoline derivant of antitumous effect, but this compounds only to neural keracele cell, VEGF is stimulated in the vascular endothelial cell cause MAPK activation and KDR phosphorylation to have to suppress active.Chinese patent CN200810129360.6 and CN200910026748.8 also disclose some and have had the quinazoline derivant of antitumous effect, but this compounds is only inhibited to mouse S 180 sarcoma and human colon carcinoma HT-29 Nude Mice.
Summary of the invention
The object of the invention is on the basis of existing technology, provide a class to there is more wide spectrum and the better cyclosubstituted sym-diphenylurea analog derivative of quinazoline that suppresses activity, has more pharmaceutical use, many target spots to tumour cell.
Another object of the present invention is to provide a kind of above-claimed cpd aspect preparation treatment tumour or leukemia medicament, the particularly application aspect lung cancer or liver-cancer medicine.
Object of the present invention can reach by following measures:
Compound or pharmaceutically acceptable salt thereof or the solvate of general formula [I],
Figure BDA0000073876040000021
Wherein,
R 1for hydrogen, amino, acrylamido, straight chain alkoxyalkoxy group or straight chain morpholino base alkoxyl group;
R 2for straight chain alkoxyalkoxy group or straight chain morpholino base alkoxyl group;
R 3for halogen.
Alkyl in the present invention, as be not particularly limited, generally referring to the alkyl of 1～6 carbonatoms, this definition comprises the alkyl being encompassed in other groups, as alkoxyl group, straight chain morpholino base alkoxyl group or alkoxyalkoxy group.Alkyl of the present invention is the preferred alkyl of 1～4 carbonatoms further, as methyl, ethyl, n-propyl etc.
Alkoxyl group in the present invention refers to the alkoxyl group of 1～6 carbonatoms, preferably adopts the alkoxyl group of 1～4 carbonatoms.
Alkoxyalkoxy group in the present invention refers to the group that the oxygen of an alkoxyl group and the carbon atom of another alkoxyl group end are directly connected, and wherein the definition of each alkoxyl group as mentioned above.
Alkoxyl group in straight chain morpholino base alkoxyl group in the present invention refers to that carbonatoms is the straight chain alkoxyl group of 1-6, and the carbon atom of this straight chain alkoxyl group end is directly connected with the nitrogen of morpholinyl, and this group can be expressed as
Figure BDA0000073876040000022
wherein the definition of the alkyl in straight chain alkoxyl group as mentioned above.
R of the present invention 1can more preferably-H ,-NH 2, CH 2=CH-CONH-, CH 3-(CH2) m-O-(CH 2) n-O-or
Figure BDA0000073876040000031
the integer that wherein m is 0～6, is preferably 0～3 integer, and more preferably 0,1 or 2, be further preferably 0 or 1; N is 1～6 integer, is preferably 1～3 integer, more preferably 2 or 3; X is 1～5 integer, is preferably 1,2 or 3, more preferably 2 or 3.
R of the present invention 2cH more preferably 3-(CH2) m '-O-(CH 2) n '-O-or
Figure BDA0000073876040000032
the integer that wherein m ' is 0～6, is preferably 0～3 integer, and more preferably 0,1 or 2, be further preferably 0 or 1; N ' is 1～6 integer, is preferably 1～3 integer, more preferably 2 or 3; Y is 1～5 integer, is preferably 1,2 or 3, more preferably 2 or 3.
R of the present invention 3more preferably F, Cl, Br or I, most preferably be F, Cl or Br.
The preferred example of compound of the present invention is as the compound of recording in embodiment 1-162, and in addition, preferred example can also exemplify out following compound:
(163) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(164) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea
(165) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(166) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(167) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea
(168) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(169) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(170) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea
(171) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(172) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(173) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea
(174) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(175) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(176) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea
(177) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(178) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(179) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea
(180) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(181) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(182) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea
(183) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(184) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(185) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea
(186) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(187) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(188) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea
(189) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(190) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(191) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea
(192) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(193) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(194) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea
(195) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(196) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(197) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea
(198) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(199) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(200) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea
(201) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(202) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(203) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea
(204) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(205) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(206) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea
(207) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(208) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(209) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea
(210) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(211) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(212) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea
(213) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
(214) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea
(215) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea
(216) N-(the iodo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea.
The compounds of this invention can be made its pharmacologically acceptable salt, the preferential example example hydrochloric acid salt of selecting, hydrofluoride, hydrobromate, the halogen acid salts such as hydroiodic acid HI salt; Vitriol, nitrate, the inorganic acid salts such as perchlorate; Mesylate, fluoroform sulphonate, the low-grade alkane sulfonates such as esilate; Benzene sulfonate, the arylsulphonates such as tosilate; Fumarate, succinate, citrate, tartrate, oxalate, maleate, acetate, malate, organic acid salt and the glycinates such as anti-sepsis hydrochlorate, phenylalanine salt, glutaminate, the amino acid saltss such as aspartate etc.
In addition, the compounds of this invention can be made solvate, for example hydrate.
The preparation of compound
Scheme one:
Work as substituent R 1be selected from-H CH 3-(CH2) m-O-(CH 2) n-O-,
Figure BDA0000073876040000071
r 2be selected from CH 3-(CH2) m-O-(CH 2) n-O-or
Figure BDA0000073876040000072
r 3be selected from F, Cl, Br, during I, with 2 amino-3,4-disubstituted benzenes formic acid or 2 amino-3,4-disubstituted benzenes manthanoate is raw material, through cyclization (1), prepares 6,7-disubstituted quinazoline ketone, 6,7-disubstituted quinazoline ketone is after sulfur oxychloride chlorination (2) and p-aminophenol sodium or potassium condensation (3), and last and corresponding isocyanic ester condensation (4) prepares target compound.Refer to following formula and embodiment.
Figure BDA0000073876040000073
Scheme two:
Work as substituent R 1be selected from-NH 2or CH 2=CH-CONH-, R 2be selected from CH 3-(CH2) m-O-(CH 2) n-O-or
Figure BDA0000073876040000081
r 3be selected from F, Cl, Br, during I, take 2-amino-4-halogenated benzoic acid or 2-amino-4-halogenated benzoic acid ester is raw material, through cyclization (1), prepare 7-halo quinazolinone, 7-halo quinazolinone obtains 6-nitro-7-halo quinazolinone through nitrated (2), 6-nitro-7-halo quinazolinone can first reduce (5) again with corresponding sodium alkoxide reagent react condensation (6) or first restore (4) with sodium alkoxide reagent react condensation (3) accordingly, obtain corresponding amino substituted quinazoline ketone, protection (7) is rear and p-aminophenol sodium or potassium condensation (9) by sulfur oxychloride chlorination (8), and with corresponding isocyanic ester condensation (10), hydrolysis deprotection (11 or 11+12) prepares target compound.Refer to following formula and embodiment.
Figure BDA0000073876040000082
Compound or pharmaceutically acceptable salt thereof of the present invention or solvate can be applicable to preparation treatment tumour or leukemia medicament, particularly preparation treatment lung cancer or liver-cancer medicine.
This compounds (experimental result of inside and outside shows): there is dual antitumor action, by suppressing RAF/MEK/ERK signal transduction pathway, directly suppress tumor growth on the one hand, by suppressing vascular endothelial growth factor (VEGF) and Thr6 PDGF BB (PDGF) acceptor, block tumor neovasculature formation on the other hand, cut off the nutrition supply of tumour cell and reach the object of inhibition tumor growth.The main molecules target spot of its antitumor action is the Raf-1 albumen in Raf signal transduction pathway, by suppressing its phosphorylation, suppress the phosphorylation of downstream associated protein, thereby blocking-up Raf signal transduction pathway is at tumour cell, abnormal activation in vascular endothelial cell, finally plays antitumous effect
This compounds has good anti-tumor activity, and its antitumor action shows and directly acts on tumour cell, suppresses its growth, migration; Act on tumour surrounding blood vessel endotheliocyte, suppress new vessel and generate; Thereby play the effect that suppresses tumour.
This compounds is many target spots inhibitor, itself and positive control drug carry out the experimental study of mouse S 180 sarcoma, human colon carcinoma HT-29 Nude Mice, people's lung cancer A549 Nude Mice, people's liver cancer Bel-7402 Nude Mice, its result demonstration, the new compound restraining effect of part is better than or is equivalent to positive control drug.
The invention provides and be applicable to the disease new compound that treatment is mediated by protein hydroxyphenylaminopropionic acid kinase activity, particularly include the new compound of anti-cancer properties.。The present invention further provides and be applicable to the disease that treatment is mediated by protein hydroxyphenylaminopropionic acid kinase activity, particularly include the new heterogeneous ring compound of anti-cancer properties, more specifically, new compound of the present invention is the strong inhibitor of protein tyrosine kinase, malignant tumour (human colon carcinoma with the treatment mankind, liver cancer, etc.).
Embodiment
Fusing point is measured at electric heating melting point apparatus, and thermometer is not calibrated; Elemental analyser is Foss-Heraeus type; Mass spectrum adopts electrospray ionization mass spectrum.
One. according to scheme one, prepare the cyclosubstituted sym-diphenylurea analog derivative of quinazoline of general formula [I]
Embodiment 1: the preparation of compound (56) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
By 2-amino-4,5-bis-(2-methoxy ethoxy) methyl benzoate 30g adds in 300ml glycol dimethyl ether together with FORMAMIDINE ACETATE 16g, reflux 20 hours, vacuum rotary steam removes 80% solvent, and residual solution cooling crystallization filters, a small amount of ice washing with alcohol obtains white solid, 6,7-bis-(2-methoxy ethoxy) quinazoline-4-one, dry weight 25.2g.
Upper step gained 6,7-bis-(2-methoxy ethoxy) quinazoline-4-one 20g adds in single port reaction flask, adds and heavily steams sulfur oxychloride 100g, dry DMF 0.2ml, back flow reaction is 10 hours together, has reacted and has boiled off unnecessary sulfur oxychloride, obtains faint yellow solid, be dissolved in methylene dichloride, washing, saturated sodium bicarbonate solution washing, dry, the faint yellow solid 4-of evaporate to dryness is chloro-6,7-bis-(2-methoxy ethoxy) quinazoline 20.2g.
4-chloro-6,7-bis-(2-methoxy ethoxy) quinazoline 20g is dissolved in 150mlDMF, add potassium tert.-butoxide 15g and 4-amino phenol 10g, 60 ℃ are reacted 12 hours, and reaction finishes rear reaction solution pours in 300ml water, and 300ml ethyl acetate is extracted, organic layer washing, dry, be evaporated to dry 4-p-aminophenyl oxygen base-6,7-bis-(2-methoxy ethoxy) quinazoline 16.8g.
4-p-aminophenyl oxygen base-6,7-bis-(2-methoxy ethoxy) quinazoline 10g is dissolved in 100ml methylene dichloride, add the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester 6.5g, stirring at room reaction 5 hours, crystallization, suction filtration, washed with dichloromethane, target compound (56) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea 12.8g.
Embodiment 2: the preparation of compound (1) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(2-methoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 3: the preparation of compound (2) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(2-methoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 4: the preparation of compound (3) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(2-methoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 5: the preparation of compound (4) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(3-methoxy propoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 6: the preparation of compound (5) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(3-methoxy propoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 7: the preparation of compound (6) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(3-methoxy propoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 8: the preparation of compound (7) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(2-ethoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 9: the preparation of compound (8) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(2-ethoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 10: the preparation of compound (9) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(2-ethoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 11: the preparation of compound (10) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(3-oxyethyl group propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 12: the preparation of compound (11) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(3-oxyethyl group propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 13: the preparation of compound (12) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(3-oxyethyl group propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 14: the preparation of compound (13) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(2-morpholino base oxethyl) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 15: the preparation of compound (14) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(2-morpholino base oxethyl) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 16: the preparation of compound (15) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(2-morpholino base oxethyl) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 17: the preparation of compound (16) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(3-morpholino base propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 18: the preparation of compound (17) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(3-morpholino base propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 19: the preparation of compound (18) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-7-(3-morpholino base propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 20: compound (55) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(2-methoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 21: compound (57) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(2-methoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 22: the preparation of compound (58) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(3-methoxy propoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 23: the preparation of compound (59) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(3-methoxy propoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 24: the preparation of compound (60) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(3-methoxy propoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 25: the preparation of compound (61) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(2-ethoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 26: the preparation of compound (62) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(2-ethoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 27: the preparation of compound (63) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(2-ethoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 28: the preparation of compound (64) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(3-oxyethyl group propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 29: the preparation of compound (65) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(3-oxyethyl group propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 30: the preparation of compound (66) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(3-oxyethyl group propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 31: the preparation of compound (67) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(2-morpholino base oxethyl) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 32: the preparation of compound (68) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(2-morpholino base oxethyl) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 33: the preparation of compound (69) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(2-morpholino base oxethyl) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 34: the preparation of compound (70) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(3-morpholino base propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 35: the preparation of compound (71) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(3-morpholino base propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 36: the preparation of compound (72) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-methoxy ethoxy)-7-(3-morpholino base propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 37: the preparation of compound (73) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(2-methoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 38: the preparation of compound (74) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(2-methoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 39: the preparation of compound (75) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(2-methoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 40: compound (76) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(3-methoxy propoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 41: compound (77) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(3-methoxy propoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 42: compound (78) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(3-methoxy propoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 43: the preparation of compound (79) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(2-ethoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 44: the preparation of compound (80) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(2-ethoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 45: the preparation of compound (81) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(2-ethoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 46: the preparation of compound (82) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(3-oxyethyl group propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 47: the preparation of compound (83) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(3-oxyethyl group propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 48: the preparation of compound (84) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(3-oxyethyl group propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 49: the preparation of compound (85) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(2-morpholino base oxethyl) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 50: the preparation of compound (86) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(2-morpholino base oxethyl) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 51: the preparation of compound (87) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(2-morpholino base oxethyl) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 52: the preparation of compound (88) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(3-morpholino base propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 53: the preparation of compound (89) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-methoxy propoxy)-7-(3-morpholino base propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 54: compound (90) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-6-(3-methoxy propoxy)-7-(3-morpholino base propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 55: the preparation of compound (91) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(2-methoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 56: the preparation of compound (92) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(2-methoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 57: the preparation of compound (93) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(2-methoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 58: the preparation of compound (94) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(3-methoxy propoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 59: the preparation of compound (95) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(3-methoxy propoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 60: the preparation of compound (96) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(3-methoxy propoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 61: compound (97) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(2-ethoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 62: compound (98) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(2-ethoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 63: compound (99) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(2-ethoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 64: the preparation of compound (100) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(3-oxyethyl group propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 65: the preparation of compound (101) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(3-oxyethyl group propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 66: the preparation of compound (102) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(3-oxyethyl group propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 67: the preparation of compound (103) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(2-morpholino base oxethyl) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 68: the preparation of compound (104) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(2-morpholino base oxethyl) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 69: the preparation of compound (105) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(2-morpholino base oxethyl) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 70: the preparation of compound (106) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(3-morpholino base propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 71: the preparation of compound (107) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(3-morpholino base propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 72: the preparation of compound (108) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-ethoxy ethoxy)-7-(3-morpholino base propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 73: the preparation of compound (109) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(2-methoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 74: the preparation of compound (110) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(2-methoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 75: the preparation of compound (111) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(2-methoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 76: the preparation of compound (112) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(3-methoxy propoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 77: the preparation of compound (113) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(3-methoxy propoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 78: the preparation of compound (114) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(3-methoxy propoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 79: the preparation of compound (115) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(2-ethoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 80: the preparation of compound (116) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(2-ethoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 81: the preparation of compound (117) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(2-ethoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 82: compound (118) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(3-oxyethyl group propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 83: compound (119) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(3-oxyethyl group propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 84: compound (120) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(3-oxyethyl group propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 85: compound (121) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group) the third amino-6-(3-oxyethyl group propoxy-)-7-(2-morpholino base oxethyl) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 86: the preparation of compound (122) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(2-morpholino base oxethyl) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 87: the preparation of compound (123) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(2-morpholino base oxethyl) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 88: the preparation of compound (124) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(3-morpholino base propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 89: the preparation of compound (125) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(3-morpholino base propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 90: the preparation of compound (126) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-oxyethyl group propoxy-)-7-(3-morpholino base propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 91: the preparation of compound (127) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(2-methoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 92: the preparation of compound (128) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(2-methoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 93: the preparation of compound (129) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(2-methoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 94: the preparation of compound (130) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(3-methoxy propoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 95: the preparation of compound (131) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(3-methoxy propoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 96: the preparation of compound (132) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(3-methoxy propoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 97: the preparation of compound (133) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(2-ethoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 98: the preparation of compound (134) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(2-ethoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 99: the preparation of compound (135) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(2-ethoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 100: the preparation of compound (136) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(3-oxyethyl group propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 101: the preparation of compound (137) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(3-oxyethyl group propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 102: the preparation of compound (138) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(3-oxyethyl group propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 103: compound (139) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(2-morpholino base oxethyl) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 104: compound (140) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(2-morpholino base oxethyl) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 105: compound (141) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(2-morpholino base oxethyl) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 106: the preparation of compound (142) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(3-morpholino base propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 107: the preparation of compound (143) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(3-morpholino base propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 108: the preparation of compound (144) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(2-morpholino base oxethyl)-7-(3-morpholino base propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 109: the preparation of compound (145) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(2-methoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 110: the preparation of compound (146) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(2-methoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 111: the preparation of compound (147) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(2-methoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 112: the preparation of compound (148) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(3-methoxy propoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 113: the preparation of compound (149) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(3-methoxy propoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 114: the preparation of compound (150) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(3-methoxy propoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 115: the preparation of compound (151) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(2-ethoxy ethoxy) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 116: the preparation of compound (152) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(2-ethoxy ethoxy) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 117: the preparation of compound (153) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(2-ethoxy ethoxy) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 118: the preparation of compound (154) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(3-oxyethyl group propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 119: the preparation of compound (155) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(3-oxyethyl group propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 120: the preparation of compound (156) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(3-oxyethyl group propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 121: the preparation of compound (157) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(2-morpholino base oxethyl) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 122: the preparation of compound (158) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(2-morpholino base oxethyl) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 123: the preparation of compound (159) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 1, take 2-amino-6-(3-morpholino base propoxy-)-7-(2-morpholino base oxethyl) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 124: compound (160) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(3-morpholino base propoxy-) methyl benzoate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 125: compound (161) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(3-morpholino base propoxy-) methyl benzoate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation;
Embodiment 126: compound (162) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } preparation of urea, with reference to embodiment 1, with 2-amino-6,7-bis-(3-morpholino base propoxy-) methyl benzoate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester are raw material preparation.
Two. according to scheme two, prepare the cyclosubstituted sym-diphenylurea analog derivative of quinazoline of general formula [I]
Embodiment 127: the preparation of the preparation of compound (19) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea and compound (37) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea
In 500ml reaction flask, add 2-amino-4-fluorophenyl carbamate 75g, acetic acid methyl ether 100g and ethylene glycol monomethyl ether 480ml, back flow reaction 20 hours, concentrated 80% the solvent that goes of filtrate, filter, washing with alcohol, obtains the fluoro-4-quinazolinone of the cotton-shaped solid 7-of white cotton 67.8g.
Under ice bath, 75ml nitrosonitric acid is added dropwise in the 75ml vitriol oil, maintains ice bath and stir after 10min, 15 ℃ of disposable step product 36g that add once, after stirring at room 20min, add 100 ℃ of reaction 3h, reaction solution is directly poured in 500g ice, stirs, there are a large amount of faint yellow particulate solid to separate out, add 500ml water, stir together 10min, filter, be washed to neutrality, the 32g of drying, glacial acetic acid recrystallization, obtains the yellow macrobead solid of the fluoro-4-quinazolinone of 6-nitro-7-21.61g.
12g biscuit metal sodium is added in 280ml ethylene glycol monomethyl ether in batches, slowly heating reflux reaction is entirely molten to sodium piece, complete molten rear reaction solution is cooled to 5 ℃, add the fluoro-4-quinazolinone of 6-nitro-7-21g, heating reflux reaction 15 hours slowly again, after having reacted, be cooled to room temperature, reaction solution is poured into water, and concentrated hydrochloric acid regulates PH to 4, a large amount of solids are separated out, filter a small amount of ethylene glycol monomethyl ether washing of filter cake, washing, 40 ℃ of vacuum-dryings obtain faint yellow solid 24.12g, i.e. 6-nitro-7-(2-methoxy ethoxy)-4-quinazolinone.
In 250ml reaction flask, add 6-nitro-7-(2-methoxy ethoxy)-4-quinazolinone 14g, ethanol 140ml, water 70ml, glacial acetic acid 8ml, be heated to micro-boiling, add the iron powder 8g of activation, high degree of agitation back flow reaction 1 hour, cooling, regulate PH to 9, filter, washing with alcohol is to colourless, filtrate boils off organic phase, add ethyl acetate 500ml to dissolve together, washing 200ml * 3, dry, the blackish green solid 11.6g of evaporate to dryness, i.e. 6-amino-7-(2-methoxy ethoxy)-4-quinazolinone.
In 250ml reaction flask, add 6-amino-7-(2-methoxy ethoxy)-4-quinazolinone 10g, triethylamine 6.5g, tetrahydrofuran (THF) 100ml, (Boc) 2o 7.5g, back flow reaction is 6 hours together, cooling, evaporate to dryness, adds 200ml ethyl acetate and 200ml water dissolution, separates organic layer, saturated sodium bicarbonate washing, dry, pale powder shape 6-t-butoxycarbonyl amino-7-(2-the methoxy ethoxy)-4-quinazolinone 12.1g of evaporate to dryness.
In 250ml single port bottle, add 6-t-butoxycarbonyl amino-7-(2-methoxy ethoxy)-4-quinazolinone 12g, heavily steam sulfur oxychloride 100ml, DMF0.2ml, back flow reaction is 10 hours together, has reacted rear reaction solution evaporate to dryness, methylene dichloride dissolves, washing, saturated sodium bicarbonate washing, dry, evaporate to dryness obtains faint yellow solid 12.6g, i.e. the chloro-6-t-butoxycarbonyl amino-7-of 4-(2-methoxy ethoxy) quinazoline.
The chloro-6-t-butoxycarbonyl amino-7-of 4-(2-methoxy ethoxy) quinazoline 10g is dissolved in 150mlDMF, add potassium tert.-butoxide 7.6g and 4-amino phenol 5.2g, 60 ℃ are reacted 12 hours, reaction finishes rear reaction solution and pours in 300ml water, 300ml ethyl acetate is extracted, organic layer washing, dry, be evaporated to dry brown ceramic powder shape solid 4-p-aminophenyl oxygen base-6-t-butoxycarbonyl amino-7-(2-methoxy ethoxy) quinazoline 6.8g.
4-p-aminophenyl oxygen base-6-t-butoxycarbonyl amino-7-(2-methoxy ethoxy) quinazoline 5g is dissolved in 50ml methylene dichloride, add the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester 2.2g, stirring at room reaction 5 hours, crystallization, suction filtration, washed with dichloromethane, obtains N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-t-butoxycarbonyl amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea 6.3g.
N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-t-butoxycarbonyl amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea 6g stirring at room reaction 6 hours together with 10% hydrogen chloride methanol solution 300ml, filter, cold methanol washing, obtains compound (19) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea 3.12g.
N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-and 4-[(6-amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea 3g, triethylamine 1.2g, tetrahydrofuran (THF) 20ml together ice bath is cooled to 0 ℃, drip the mixing solutions of 0.9g acrylate chloride and 5ml tetrahydrofuran (THF), drip off room temperature reaction 2 hours, in reaction solution, drip water 3ml, stir 10min, be spin-dried for, add 30ml acetic acid ethyl dissolution, washing, saturated sodium bicarbonate washing, dry, evaporate to dryness obtains khaki color solid, and 60% ethyl alcohol recrystallization obtains white solid 2.1g.Be target compound (37) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea.
Embodiment 128: the preparation of compound (20) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 129: the preparation of compound (21) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 130: the preparation of compound (22) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 131: the preparation of compound (23) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 132: the preparation of compound (24) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 133: the preparation of compound (25) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 134: the preparation of compound (26) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 135: the preparation of compound (27) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 136: the preparation of compound (28) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 137: the preparation of compound (29) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 138: the preparation of compound (30) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 139: the preparation of compound (31) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 140: the preparation of compound (32) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 141: the preparation of compound (33) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 142: the preparation of compound (34) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 143: the preparation of compound (35) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 144: the preparation of compound (36) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 145: the preparation of compound (38) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 146: the preparation of compound (39) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 147: the preparation of compound (40) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 148: the preparation of compound (41) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 149: the preparation of compound (42) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 150: the preparation of compound (43) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 151: the preparation of compound (44) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 152: the preparation of compound (45) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 153: the preparation of compound (46) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 154: the preparation of compound (47) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 155: the preparation of compound (48) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 156: the preparation of compound (49) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 157: the preparation of compound (50) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 158: the preparation of compound (51) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 159: the preparation of compound (52) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the fluoro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 160: the preparation of compound (53) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the chloro-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation;
Embodiment 161: the preparation of compound (54) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea, with reference to embodiment 127, take 2-amino-4-fluorophenyl carbamate and the bromo-3-of isocyanic acid 4-(trifluoromethyl) phenyl ester as raw material preparation.
The compound characteristic parameter of recording in embodiment is as shown in the table:
Table 1:6 position is without substituted quinazoline ring derivatives
Figure BDA0000073876040000311
Figure BDA0000073876040000321
Table 2:6 position is amino substituted quinazoline ring derivatives
Figure BDA0000073876040000322
Figure BDA0000073876040000331
Figure BDA0000073876040000341
Table 3:6 position is acrylamido substituted quinazoline ring derivatives
Figure BDA0000073876040000342
Figure BDA0000073876040000351
Table 4:6 position is (2-methoxy ethoxy) substituted quinazoline ring derivatives
Figure BDA0000073876040000361
Figure BDA0000073876040000371
Table 5:6 position is (3-methoxy propoxy) substituted quinazoline ring derivatives
Figure BDA0000073876040000372
Figure BDA0000073876040000391
Table 6:6 position is (2-ethoxy ethoxy) substituted quinazoline ring derivatives
Figure BDA0000073876040000401
Table 7:6 position is (3-oxyethyl group propoxy-) substituted quinazoline ring derivatives
Figure BDA0000073876040000402
Figure BDA0000073876040000421
Table 8:6 position is (2-morpholino base oxethyl) substituted quinazoline ring derivatives
Figure BDA0000073876040000422
Table 9:6 position is (3-morpholino base propoxy-) substituted quinazoline ring derivatives
Figure BDA0000073876040000432
Figure BDA0000073876040000441
Figure BDA0000073876040000451
The mensuration of the compound antitumor activity of recording in embodiment
1. compound of the present invention is active to the kinase whose inhibition of Raf
[instrument]
Bole Westernblot electrophoresis apparatus shaking table
[test materials]
[main agents]
Raf kinase inhibitor screening reagent box is purchased from upstate company
Raf-1(truncated)
MEK1 unactive
Assay Dilution Buffer1
Magnesium/ATP Cocktail
Anti-phospho-MEK1(Ser218/222)/MEK2
Goat anti-rabbit HRP conjugated lgG
Acrylamide, sigma
The two acrylamides of methene, sigma
Ammonium Persulfate 98.5, Amresco
Beta-mercaptoethanol, Amresco
TEMED，Amresco
Cocktail，Roche
Glycine, SDS, the import packing of Shanghai chemical reagents corporation of traditional Chinese medicines group
NC film, Poll company
ECL chemical illuminating reagent, PIERCE
DAB colouring reagents box, 0.01M citrate buffer, Beijing Zhong Shan Golden Bridge
[key instrument]
Half dry type transferring film groove, Bio-Rad
Mini-Protean 3 electrophoresis chambers, Bio-Rad
Power PacTM Basic fundamental power supply, Bio-Rad
The desk-top constant temperature oscillator of THZ-312 type, smart grand equipment
DGX-9003 type air dry oven, good fortune agate equipment
Thermostatical circulating water bath cabinet, Fisher
BIO-RAD gel imaging instrument, Tecan
[given the test agent]
Compound 1-162
[positive control drug]
Positive control 1 is Xarelto
Positive control 2 is N-(4-fluorophenyl)-N '-{ 4-[(6,7-dimethoxy-4 '-quinazolyl) oxygen] phenyl } urea
Positive control 3 is N-(3-trifluoromethyl)-N '-{ 4-[(6,7-dimethoxy-4 '-quinolyl) oxygen] phenyl } urea
Positive control 4 is N-(2,4 difluorobenzene base)-N '-(the chloro-4-{[6-methoxyl group-7-of 2-(2-morpholino base oxethyl)-4-quinolyl] oxygen } phenyl) urea
Positive control 5 is N-(2,4 difluorobenzene base)-N '-(the chloro-4-{[6-methoxyl group-7-of 2-(2-methoxy ethoxy)-4-quinolyl] oxygen } phenyl) urea
[test method]
1. get 500ulEP pipe, add 20ul Magnesium/ATP Cocktail
2. add 1ul Raf-1 (truncated)
3. add 4ul medicine (1.0*10 to be sieved -4mol/ml)
4. add 0.84ul MEK1 unactive, then add 14.16ul Assay Dilution Buffer1
Microcentrifuge centrifugal after, 30 degrees Celsius of 30min on shaking table
6. add again 40ulsample buffer, boiling water boiling 5min
7. every hole 10ul, SDS-PAGE electrophoresis, transferring film, tri-distilled water is washed film twice
8. containing the TBST sealing of 5% skim-milk, on room temperature shaking table, shake gently 30min
9. incubate primary antibodie Anti-phospho-MEK1 (Ser218/222)/MEK2,4 degrees Celsius are spent the night
10. tri-distilled water is washed film twice
11. incubate Goat anti-rabbit HRP conjugated lgG bis-resists
12. tri-distilled waters are washed film twice
13. use .TBS-0.05%Tween-20 wash film 3-5min
14. tri-distilled water rinsing films 4-5 time
15.westernblot chemiluminescence detection (1.0*10 -5mol/ml)
Figure BDA0000073876040000471
[test-results]
Table 10: compound 1-162 and positive control drug are to the kinase whose inhibiting rate of Raf
Figure BDA0000073876040000472
Figure BDA0000073876040000481
Figure BDA0000073876040000491
Figure BDA0000073876040000501
Compound shows the kinase whose inhibition active testing of Raf result: the compounds of this invention is better than or is equivalent to positive control drug 1 Xarelto, positive control drug 2 or positive control drug 3 to the kinase whose inhibition activity of Raf.Test-results shows, this compounds can be by suppressing Raf kinases, and the ras protein signal that interrupts tumour cell transmits cascade, affects survival, increment and the progression of disease of tumour cell.Therefore compound or pharmaceutically acceptable salt thereof or solvate have the potentiality of the tumour of being applied to and leukemia treating.
2. the experimental therapy effect of compound of the present invention to mouse S 180 sarcoma
[test materials]
Experimental animal: age in days 7-11 days, the female ICR mouse of body weight 18-25g, is provided by animal housing of China Medicine University,
Conformity certification number: kinoplaszm SCXK (Soviet Union) 2009--0011 of Soviet Union
Test knurl kind: mouse S 180 sarcoma (institute of materia medica provides by Chinese Academy of Sciences Shanghai)
[given the test agent]
Compound 1-162 (white solid)
[positive control drug]
Positive control 1 is Xarelto
Positive control 2 is N-(4-fluorophenyl)-N '-{ 4-[(6,7-dimethoxy-4 '-quinazolyl) oxygen] phenyl } urea
Positive control 3 is N-(3-trifluoromethyl)-N '-{ 4-[(6,7-dimethoxy-4 '-quinolyl) oxygen] phenyl } urea
Positive control 4 is N-(2,4 difluorobenzene base)-N '-(the chloro-4-{[6-methoxyl group-7-of 2-(2-morpholino base oxethyl)-4-quinolyl] oxygen } phenyl) urea
Positive control 5 is N-(2,4 difluorobenzene base)-N '-(the chloro-4-{[6-methoxyl group-7-of 2-(2-methoxy ethoxy)-4-quinolyl] oxygen } phenyl) urea
[test method]
Compound method:
Take given the test agent or positive control drug 120mg and add the vibration of 2.5ml anhydrous alcohol solution completely, add again 2.5ml polyethylene Viscotrol C and dissolve vibration completely, obtain and when concentration is the each administration of 24mg/ml., draw 1ml stoste and add 3ml tri-distilled water and dissolve vibration completely;
Medication and the course for the treatment of
The murine sarcoma S180 knurl kind of selecting the female ICR mouse of 18-25g and well-grown 7-11 days, is inoculated in ICR right side of mice armpit subcutaneous, about 4.5-5 * 10 6individual cell/only, inoculate random minute cage after 24 hours, oral administration 60mg/kg, administration 9 days.Within the tenth day, put to death mouse, weigh, knurl weight, calculate and respectively organize average knurl weight, by formula given below, obtain tumor control rate and carry out T check.
[test-results]
Table 11: compound 1-2 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Figure BDA0000073876040000512
Figure BDA0000073876040000521
Table 12: compound 3-12 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 3 4 5 6 7 8 9 10 11 12
Inhibiting rate (%) 52.5 41.1 53.6 33.1 59.6 44.5 55.4 41.8 64.8 51.6
Table 13: compound 13-22 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 13 14 15 16 17 18 19 20 21 22
Inhibiting rate (%) 61.4 55.0 62.9 46.7 61.3 59.2 51.6 58.2 68.5 53.9
Table 14: compound 23-32 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 23 24 25 26 27 28 29 30 31 32
Inhibiting rate (%) 56.5 65.4 61.6 52.5 48.7 53.6 55.1 62.6 59.4 48.2
Table 15: compound 33-42 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 33 34 35 36 37 38 39 40 41 42
Inhibiting rate (%) 44.6 62.2 51.3 44.9 61.5 61.8 50.1 54.6 54.8 49.8
Table 16: compound 43-52 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 43 44 45 46 47 48 49 50 51 52
Inhibiting rate (%) 43.6 61.2 55.6 59.8 57.2 42.9 60.0 48.1 56.8 57.3
Table 17: compound 53-62 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 53 54 55 56 57 58 59 60 61 62
Inhibiting rate (%) 58.5 61.1 59.4 60.8 47.9 50.1 59.7 52.9 55.6 68.1
Table 18: compound 63-72 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 63 64 65 66 67 68 69 70 71 72
Inhibiting rate (%) 52.2 46.3 59.5 35.2 51.2 67.6 58.8 36.2 54.2 48.1
Table 19: compound 73-82 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 73 74 75 76 77 78 79 80 81 82
Inhibiting rate (%) 68.2 53.3 47.1 59.2 51.1 38.5 56.8 53.9 52.8 59.1
Table 20: compound 83-92 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 83 84 85 86 87 88 89 90 91 92
Inhibiting rate (%) 69.6 42.5 61.3 46.2 53.3 59.2 40.9 58.1 57.5 61.0
Table 21: compound 93-102 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 93 94 95 96 97 98 99 100 101 102
Inhibiting rate (%) 57.5 50.3 58.3 51.1 43.1 61.6 59.4 58.3 51.9 58.5
Table 22: compound 103-112 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 103 104 105 106 107 108 109 110 111 112
Inhibiting rate (%) 63.2 56.5 64.9 52.6 62.6 51.8 60.2 52.9 64.6 59.1
Table 23: compound 113-122 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 113 114 115 116 117 118 119 120 121 122
Inhibiting rate (%) 37.2 51.6 45.1 48.3 50.2 39.9 33.5 41.0 52.5 49.6
Table 24: compound 123-132 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 123 124 125 126 127 128 129 130 131 132
Inhibiting rate (%) 47.5 52.6 49.8 32.6 49.3 41.8 39.5 55.8 56.4 59.5
Table 25: compound 133-142 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 133 134 135 136 137 138 139 140 141 142
Inhibiting rate (%) 53.6 62.1 39.5 53.6 57.5 46.0 49.1 30.8 49.5 53.4
Table 26: compound 143-152 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 143 144 145 146 147 148 149 150 151 152
Inhibiting rate (%) 46.5 53.8 47.6 52.3 39.5 42.5 53.6 47.4 51.9 49.5
Table 27: compound 153-162 and the positive control drug growth inhibition ratio to mouse S 180 sarcoma
Group 153 154 155 156 157 158 159 160 161 162
Inhibiting rate (%) 56.5 54.1 49.8 40.8 57.9 59.4 51.5 40.6 48.8 56.7
3. the experimental therapy effect of compound of the present invention to human colon carcinoma HT-29 Nude Mice
[test materials]
Experimental animal: age in days 35-40 days, the female BALB/cA mouse of body weight 18-22g, is provided conformity certification number by Shanghai Slac Experimental Animal Co., Ltd.: SCXK (Shanghai) 2007--0005
Test knurl kind: human colon carcinoma HT-29 Nude Mice, is inoculated in nude mouse in human colon carcinoma HT-29 cell strain subcutaneous and set up
[given the test agent]
Compound 1-162 (white solid)
[positive control drug]
Positive control 1 is Xarelto
Positive control 2 is N-(4-fluorophenyl)-N '-{ 4-[(6,7-dimethoxy-4 '-quinazolyl) oxygen] phenyl } urea
Positive control 3 is N-(3-trifluoromethyl)-N '-{ 4-[(6,7-dimethoxy-4 '-quinolyl) oxygen] phenyl } urea
Positive control 4 is N-(2,4 difluorobenzene base)-N '-(the chloro-4-{[6-methoxyl group-7-of 2-(2-morpholino base oxethyl)-4-quinolyl] oxygen } phenyl) urea
Positive control 5 is N-(2,4 difluorobenzene base)-N '-(the chloro-4-{[6-methoxyl group-7-of 2-(2-methoxy ethoxy)-4-quinolyl] oxygen } phenyl) urea
[test method]
Compound method:
Take given the test agent or positive control drug 120mg and add the vibration of 2.5ml anhydrous alcohol solution completely, add again 2.5ml polyethylene Viscotrol C and dissolve vibration completely, obtain and when concentration is the each administration of 24mg/ml., draw 1ml stoste and add 3ml tri-distilled water and dissolve vibration completely;
Medication and the course for the treatment of:
The tumor tissue of getting growth animated period cuts into 1.5mm 3left and right, under aseptic condition, is inoculated in nude mouse right side armpit subcutaneous.Nude Mice has vernier caliper measurement transplanted tumor diameter, treats that tumor growth is to 100-300mm 3after by animal random packet.Use the method for measuring knurl footpath, dynamically observe the antineoplastic effect of tested thing.The measurement number of times of diameter of tumor is 3 times weekly, and each measurement also needs to claim mouse heavy simultaneously.Positive control drug and tested medicine gastric infusion 60mg/kg, continuous 9 times.Solvent control gastric infusion, continuous 9 times.Negative control group is given equivalent CONTROL simultaneously.
Gross tumor volume (tumor volume, TV), calculation formula is:
TV＝1/2×a×b 2
Wherein a, b represent respectively length and width
Relative tumour volume (relative tumor volume, RTV), calculation formula is:
RTV＝TV T/TV O。
TV wherein o(d while representing to divide cage administration 0) gross tumor volume
TV tgross tumor volume while representing each measurement
Relative tumour appreciation rate T/C (%), calculation formula is:
Figure BDA0000073876040000551
T wherein rTVrepresent treatment group RTV
C rTVrepresent negative control group RTV
[test evaluation standard]
Test-results is usingd the evaluation index of relative tumour appreciation rate T/C (%) as anti-tumor activity.
Anti-tumor in vivo activity rating
Figure BDA0000073876040000552
[test-results]
Table 28: compound 1-2 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Figure BDA0000073876040000562
Table 29: compound 3-12 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 3 4 5 6 7 8 9 10 11 12
T/C(％) 43.6 32.6 34.2 39.2 21.6 40.6 38.2 28.5 36.2 57.6
Table 30: compound 13-22 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 13 14 15 16 17 18 19 20 21 22
T/C(％) 38.8 34.3 36.2 49.6 39.2 41.5 35.2 40.3 72.9 34.3
Table 31: compound 23-32 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 23 24 25 26 27 28 29 30 31 32
T/C(％) 43.5 39.5 31.6 71.5 35.3 39.1 32.3 34.0 36.1 40.1
Table 32: compound 33-42 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 33 34 35 36 37 38 39 40 41 42
T/C(％) 32.6 46.2 33.1 39.8 36.3 32.3 46.6 32.1 31.9 28.6
Table 33: compound 43-52 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 43 44 45 46 47 48 49 50 51 52
T/C(％) 21.2 36.5 39.2 38.6 25.2 30.6 45.1 36.8 42.1 48.5
Table 34: compound 53-62 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 53 54 55 56 57 58 59 60 61 62
T/C(％) 33.5 39.0 45.3 21.6 40.4 36.2 44.8 39.5 36.6 32.5
Table 35: compound 63-72 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 63 64 65 66 67 68 69 70 71 72
T/C(％) 35.5 40.3 31.6 28.2 45.5 31.5 48.6 33.2 31.6 39.5
Table 36: compound 73-82 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 73 74 75 76 77 78 79 80 81 82
T/C(％) 32.7 42.6 29.8 41.9 34.6 38.1 35.2 32.5 34.3 28.8
Table 37: compound 83-92 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 83 84 85 86 87 88 89 90 91 92
T/C(％) 32.6 35.8 39.6 22.5 35.8 41.9 36.2 53.4 37.6 38.1
Table 38: compound 93-102 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 93 94 95 96 97 98 99 100 101 102
T/C(％) 31.1 46.5 39.2 43.6 32.8 21.3 36.7 45.1 41.0 39.2
Table 39: compound 103-112 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 103 104 105 106 107 108 109 110 111 112
T/C(％) 37.2 36.5 21.3 36.1 39.2 29.9 39.0 35.2 28.5 31.6
Table 40: compound 113-122 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 113 114 115 116 117 118 119 120 121 122
T/C(％) 32.6 36.5 38.8 22.3 41.6 50.3 44.6 46.9 39.2 46.6
Table 41: compound 123-132 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 123 124 125 126 127 128 129 130 131 132
T/C(％) 77.2 49.1 37.9 49.8 41.6 35.3 39.4 46.2 39.3 34.1
Table 42: compound 133-142 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 133 134 135 136 137 138 139 140 141 142
T/C(％) 38.5 22.9 43.5 39.1 38.1 42.9 26.8 31.9 41.5 49.1
Table 43: compound 143-152 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 143 144 145 146 147 148 149 150 151 152
T/C(％) 39.2 45.5 36.7 31.3 42.6 47.3 39.7 31.6 60.7 29.4
Table 44: compound 153-162 and the positive control drug relative tumour appreciation rate T/C (%) to human colon carcinoma HT-29 Nude Mice
Group 153 154 155 156 157 158 159 160 161 162
T/C(％) 42.1 32.9 36.8 34.3 49.5 36.1 40.2 29.4 39.2 34.3
4. the experimental therapy effect of compound of the present invention to people's lung cancer A549 Nude Mice
[test materials]
Experimental animal: age in days 35-40 days, the female BALB/cA mouse of body weight 18-22g, is provided conformity certification number by Shanghai Slac Experimental Animal Co., Ltd.: SCXK (Shanghai) 2007--0005
Test knurl kind: people's lung cancer A549 Nude Mice, is inoculated in nude mouse in the strain of people's lung cancer A549 cell subcutaneous and set up
[given the test agent]
Compound 1-162 (white solid)
[positive control drug]
Positive control 1 is Xarelto
Positive control 2 is N-(4-fluorophenyl)-N '-{ 4-[(6,7-dimethoxy-4 '-quinazolyl) oxygen] phenyl } urea
Positive control 3 is N-(3-trifluoromethyl)-N '-{ 4-[(6,7-dimethoxy-4 '-quinolyl) oxygen] phenyl } urea
Positive control 4 is N-(2,4 difluorobenzene base)-N '-(the chloro-4-{[6-methoxyl group-7-of 2-(2-morpholino base oxethyl)-4-quinolyl] oxygen } phenyl) urea
Positive control 5 is N-(2,4 difluorobenzene base)-N '-(the chloro-4-{[6-methoxyl group-7-of 2-(2-methoxy ethoxy)-4-quinolyl] oxygen } phenyl) urea
[test method]
Compound method:
Take given the test agent or positive control drug 120mg and add the vibration of 2.5ml anhydrous alcohol solution completely, add again 2.5ml polyethylene Viscotrol C and dissolve vibration completely, obtain and when concentration is the each administration of 24mg/ml., draw 1ml stoste and add 3ml tri-distilled water and dissolve vibration completely;
Medication and the course for the treatment of:
The tumor tissue of getting growth animated period cuts into 1.5mm 3left and right, under aseptic condition, is inoculated in nude mouse right side armpit subcutaneous.Nude Mice has vernier caliper measurement transplanted tumor diameter, treats that tumor growth is to 100-300mm 3after by animal random packet.Use the method for measuring knurl footpath, dynamically observe the antineoplastic effect of tested thing.The measurement number of times of diameter of tumor is 3 times weekly, and each measurement also needs to claim mouse heavy simultaneously.Positive control drug and tested medicine gastric infusion 60mg/kg, continuous 9 times.Solvent control gastric infusion, continuous 9 times.Negative control group is given equivalent CONTROL simultaneously.
Gross tumor volume (tumor volume, TV), calculation formula is:
TV＝1/2×a×b 2
Wherein a, b represent respectively length and width
Relative tumour volume (relative tumor volume, RTV), calculation formula is:
RTV＝TV T/TV O。
TV wherein o(d while representing to divide cage administration 0) gross tumor volume
TV tgross tumor volume while representing each measurement
Relative tumour appreciation rate T/C (%), calculation formula is:
T wherein rTVrepresent treatment group RTV
C rTVrepresent negative control group RTV
[test evaluation standard]
Test-results is usingd the evaluation index of relative tumour appreciation rate T/C (%) as anti-tumor activity.
Anti-tumor in vivo activity rating
[test-results]
Table 45: compound 1-2 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Figure BDA0000073876040000613
Figure BDA0000073876040000621
Table 46: compound 3-12 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 3 4 5 6 7 8 9 10 11 12
T/C(％) 48.9 35.2 39.1 42.6 35.6 49.1 38.3 47.9 40.5 68.1
Table 47: compound 13-22 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 13 14 15 16 17 18 19 20 21 22
T/C(％) 39.6 31.6 29.1 35.6 40.5 52.1 32.3 29.5 32.6 41.9
Table 48: compound 23-32 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 23 24 25 26 27 28 29 30 31 32
T/C(％) 35.2 39.1 40.9 37.2 46.3 41.2 34.6 46.2 49.1 48.3
Table 49: compound 33-42 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 33 34 35 36 37 38 39 40 41 42
T/C(％) 42.3 31.6 46.3 42.1 39.5 43.6 44.8 38.4 31.2 39.6
Table 50: compound 43-52 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 43 44 45 46 47 48 49 50 51 52
T/C(％) 37.3 41.2 50.3 35.9 41.9 40.6 34.1 41.6 45.3 33.1
Table 51: compound 53-62 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 53 54 55 56 57 58 59 60 61 62
T/C(％) 39.6 40.9 31.6 29.2 41.5 44.6 38.1 41.9 50.8 38.2
Table 52: compound 63-72 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 63 64 65 66 67 68 69 70 71 72
T/C(％) 37.6 41.3 38.6 35.6 41.6 25.5 49.1 38.8 30.6 46.1
Table 53: compound 73-82 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 73 74 75 76 77 78 79 80 81 82
T/C(％) 39.4 50.6 39.8 45.9 42.1 38.6 40.5 42.1 39.9 45.6
Table 54: compound 83-92 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 83 84 85 86 87 88 89 90 91 92
T/C(％) 36.8 38.9 34.6 42.1 40.9 44.2 48.0 39.4 41.1 36.2
Table 55: compound 93-102 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 93 94 95 96 97 98 99 100 101 102
T/C(％) 50.2 35.1 39.4 46.5 50.0 33.6 39.2 40.5 35.2 41.6
Table 56: compound 103-112 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 103 104 105 106 107 108 109 110 111 112
T/C(％) 35.1 42.6 38.5 32.6 34.1 48.2 30.9 39.2 34.6 40.1
Table 57: compound 113-122 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 113 114 115 116 117 118 119 120 121 122
T/C(％) 42.9 44.1 38.9 54.0 40.9 41.8 44.6 39.2 41.6 35.5
Table 58: compound 123-132 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 123 124 125 126 127 128 129 130 131 132
T/C(％) 38.2 40.1 38.7 37.3 45.1 36.7 32.9 39.5 54.3 39.9
Table 59: compound 133-142 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 133 134 135 136 137 138 139 140 141 142
T/C(％) 42.6 39.4 51.6 40.6 36.8 49.5 32.5 51.9 39.4 39.8
Table 60: compound 143-152 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 143 144 145 146 147 148 149 150 151 152
T/C(％) 37.8 41.6 40.9 45.2 39.1 46.0 37.7 41.8 45.1 30.8
Table 61: compound 153-162 and the positive control drug relative tumour appreciation rate T/C (%) to people's lung cancer A549 Nude Mice
Group 153 154 155 156 157 158 159 160 161 162
T/C(％) 37.9 42.3 33.4 41.9 38.5 43.6 35.9 35.7 42.9 32.8
5. the experimental therapy effect of compound of the present invention to people's liver cancer Bel-7402 Nude Mice
[test materials]
Experimental animal: age in days 35-40 days, the female BALB/cA mouse of body weight 18-25g, is provided conformity certification number by Shanghai Slac Experimental Animal Co., Ltd.: SCXK (Shanghai) 2007--0005
Test knurl kind: people's lung cancer A549 Nude Mice, is inoculated in nude mouse in Human hepatocarcinoma Bel-7402 cell strain subcutaneous and set up
[given the test agent]
Compound 1-162 (white solid)
[positive control drug]
Positive control 1 is Xarelto
Positive control 2 is N-(4-fluorophenyl)-N '-{ 4-[(6,7-dimethoxy-4 '-quinazolyl) oxygen] phenyl } urea
Positive control 3 is N-(3-trifluoromethyl)-N '-{ 4-[(6,7-dimethoxy-4 '-quinolyl) oxygen] phenyl } urea
Positive control 4 is N-(2,4 difluorobenzene base)-N '-(the chloro-4-{[6-methoxyl group-7-of 2-(2-morpholino base oxethyl)-4-quinolyl] oxygen } phenyl) urea
Positive control 5 is N-(2,4 difluorobenzene base)-N '-(the chloro-4-{[6-methoxyl group-7-of 2-(2-methoxy ethoxy)-4-quinolyl] oxygen } phenyl) urea
[test method]
Compound method:
Take given the test agent or positive control drug 120mg and add the vibration of 2.5ml anhydrous alcohol solution completely, add again 2.5ml polyethylene Viscotrol C and dissolve vibration completely, obtain and when concentration is the each administration of 24mg/ml., draw 1ml stoste and add 3ml tri-distilled water and dissolve vibration completely;
Medication and the course for the treatment of:
The tumor tissue of getting growth animated period cuts into 1.5mm 3left and right, under aseptic condition, is inoculated in nude mouse right side armpit subcutaneous.Nude Mice has vernier caliper measurement transplanted tumor diameter, treats that tumor growth is to 100-300mm 3after by animal random packet.Use the method for measuring knurl footpath, dynamically observe the antineoplastic effect of tested thing.The measurement number of times of diameter of tumor is 3 times weekly, and each measurement also needs to claim mouse heavy simultaneously.Positive control drug and tested medicine gastric infusion 60mg/kg, continuous 9 times.Solvent control gastric infusion, continuous 9 times.Negative control group is given equivalent CONTROL simultaneously.
Gross tumor volume (tumor volume, TV), calculation formula is:
TV＝1/2×a×b 2
Wherein a, b represent respectively length and width
Relative tumour volume (relative tumor volume, RTV), calculation formula is:
RTV＝TV T/TV O。
TV wherein o(d while representing to divide cage administration 0) gross tumor volume
TV tgross tumor volume while representing each measurement
Relative tumour appreciation rate T/C (%), calculation formula is:
Figure BDA0000073876040000661
T wherein rTVrepresent treatment group RTV
C rTVrepresent negative control group RTV
[test evaluation standard]
Test-results is usingd the evaluation index of relative tumour appreciation rate T/C (%) as anti-tumor activity.
Anti-tumor in vivo activity rating
Figure BDA0000073876040000662
Figure BDA0000073876040000671
[test-results]
Table 62: compound 1-2 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Figure BDA0000073876040000672
Table 63: compound 3-12 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 3 4 5 6 7 8 9 10 11 12
T/C(％) 15.8 25.3 29.8 30.6 34.9 30.9 42.1 19.8 27.9 22.8
Table 64: compound 13-22 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 13 14 15 16 17 18 19 20 21 22
T/C(％) 15.6 22.8 21.9 30.7 23.9 25.8 37.6 22.7 23.3 37.9
Table 65: compound 23-32 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 23 24 25 26 27 28 29 30 31 32
T/C(％) 22.8 39.6 38.4 21.0 30.5 28.2 23.9 31.8 27.6 38.2
Table 66: compound 33-42 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 33 34 35 36 37 38 39 40 41 42
T/C(％) 18.5 30.9 22.6 25.4 31.8 39.7 38.5 21.8 21.2 19.6
Table 67: compound 43-52 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 43 44 45 46 47 48 49 50 51 52
T/C(％) 25.6 22.1 31.8 16.1 23.9 17.1 40.5 38.3 27.1 21.5
Table 68: compound 53-62 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 53 54 55 56 57 58 59 60 61 62
T/C(％) 26.8 34.6 22.1 23.6 28.1 29.2 35.4 28.5 26.7 39.5
Table 69: compound 63-72 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 63 64 65 66 67 68 69 70 71 72
T/C(％) 21.2 19.0 25.7 24.9 22.5 33.3 21.6 30.8 31.9 41.5
Table 70: compound 73-82 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 73 74 75 76 77 78 79 80 81 82
T/C(％) 34.6 21.2 29.8 36.5 27.7 20.3 38.4 21.0 38.2 40.7
Table 71: compound 83-92 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 83 84 85 86 87 88 89 90 91 92
T/C(％) 26.2 21.5 23.9 38.4 41.9 37.5 26.2 23.8 21.9 20.4
Table 72: compound 93-102 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 93 94 95 96 97 98 99 100 101 102
T/C(％) 24.2 35.8 22.6 17.1 23.7 38.5 39.1 24.1 49.3 29.2
Table 73: compound 103-112 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 103 104 105 106 107 108 109 110 111 112
T/C(％) 38.5 20.2 39.4 22.6 48.5 27.3 26.9 39.9 42.5 20.6
Table 74: compound 113-122 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 113 114 115 116 117 118 119 120 121 122
T/C(％) 17.6 31.6 25.5 38.7 22.9 30.7 26.4 23.9 48.8 22.6
Table 75: compound 123-132 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 123 124 125 126 127 128 129 130 131 132
T/C(％) 26.5 23.1 30.6 22.4 29.3 21.6 39.4 33.5 42.8 45.2
Table 76: compound 133-142 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 133 134 135 136 137 138 139 140 141 142
T/C(％) 28.2 43.9 22.1 35.6 36.8 47.5 39.4 22.6 41.1 34.2
Table 77: compound 143-152 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 143 144 145 146 147 148 149 150 151 152
T/C(％) 22.8 35.3 41.9 22.4 38.7 41.8 30.4 19.9 22.0 38.5
Table 78: compound 153-162 and the positive control drug relative tumour appreciation rate T/C (%) to people's liver cancer Bel-7402 Nude Mice
Group 153 154 155 156 157 158 159 160 161 162
T/C(％) 36.8 25.9 22.7 38.6 21.9 35.3 20.6 45.8 31.6 33.7
The test-results of inside and outside shows, the mechanism of action of this compounds is by suppressing raf kinases, interrupt the ras protein signaling cascade of tumour cell, affect survival, increment and the progression of disease of tumour cell, thereby suppressed the growth such as achiblastomas such as malignant tumour (such as bladder cancer, lung cancer, carcinoma of the pancreas), myelopathy (such as myelogenous leukemia) or adenomas (such as villous adenoma of colon).
The cancer test-results that presses down of inside and outside shows, this compounds is better than or is equivalent to positive control drug to the restraining effect of mouse S 180 sarcoma, human colon carcinoma HT-29 Nude Mice, people's lung cancer A549 Nude Mice, people's liver cancer Bel-7402 Nude Mice.
Above-mentioned test-results shows, the compound or pharmaceutically acceptable salt thereof of general formula of the present invention [I] or solvate can be used as the application of preparation treatment tumour or leukemia medicament.

Claims (9)

1. the compound or pharmaceutically acceptable salt thereof of general formula [I],
Wherein,
Figure FDA0000410721920000011
R 1for-H ,-NH 2, CH 2=CH-CONH-, CH 3-(CH 2) m-O-(CH 2) n-O-or
Figure FDA0000410721920000012
m is 0～3 integer, the integer that n is 1～3, the integer that x is 1～5;
R 2for CH 3-(CH 2) m'-O-(CH 2) n'-O-or
Figure FDA0000410721920000013
m ' is 0～3 integer, the integer that n ' is 1～3, the integer that y is 1～5;
R 3for halogen.
2. compound according to claim 1, wherein,
R 1for-H ,-NH 2, CH 2=CH-CONH-, CH 3-(CH 2) m-O-(CH 2) n-O-or
Figure FDA0000410721920000014
m be 0,1 or 2, n be 1,2 or 3, x be 1,2 or 3.
3. compound according to claim 2, wherein,
R 1for-H ,-NH 2, CH 2=CH-CONH-, CH 3-(CH 2) m-O-(CH 2) n-O-or m be 0 or 1, n be 2 or 3, x be 2 or 3.
4. compound according to claim 1, wherein,
R 2for CH 3-(CH 2) m'-O-(CH 2) n'-O-or
Figure FDA0000410721920000016
m ' be 0,1 or 2, n ' be 1,2 or 3, y be 1,2 or 3.
5. compound according to claim 1, wherein,
R 3for F, Cl or Br.
6. according to the compound or pharmaceutically acceptable salt thereof described in any one in claim 1～5, wherein said compound is selected from:
(1) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(2) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(3) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(4) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(5) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(6) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(7) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(8) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(9) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(10) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(11) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(12) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(13) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(14) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(15) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(16) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(17) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(18) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(19) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(20) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(21) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(22) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(23) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(24) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(25) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(26) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(27) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(28) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(29) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(30) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(31) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(32) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(33) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(34) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(35) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(36) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-amino-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(37) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(38) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(39) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(40) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(41) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(42) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(43) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(44) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(45) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(46) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(47) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(48) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(49) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(50) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(51) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(52) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(53) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(54) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-acrylamido-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(55) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(56) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(57) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(58) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(59) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(60) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(61) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(62) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(63) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(64) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(65) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(66) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(67) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(68) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(69) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(70) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(71) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(72) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-methoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(73) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(74) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(75) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(76) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(77) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(78) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(79) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(80) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(81) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(82) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(83) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(84) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(85) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(86) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(87) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(88) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(89) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(90) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-methoxy propoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(91) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(92) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(93) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(94) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(95) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(96) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(97) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(98) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(99) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(100) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(101) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(102) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(103) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(104) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(105) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(106) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(107) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(108) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-ethoxy ethoxy)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(109) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(110) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(111) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(112) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(113) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(114) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(115) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(116) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(117) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(118) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(119) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(120) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(121) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(122) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(123) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(124) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(125) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(126) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-oxyethyl group propoxy-)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(127) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(128) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(129) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(130) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(131) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(132) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(133) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(134) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(135) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(136) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(137) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(138) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(139) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(140) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(141) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(142) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(143) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(144) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(2-morpholino base oxethyl)-7-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(145) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(146) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(147) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-methoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(148) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(149) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(150) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-methoxy propoxy)-4-quinazolyl) oxygen] phenyl } urea,
(151) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(152) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(153) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-ethoxy ethoxy)-4-quinazolyl) oxygen] phenyl } urea,
(154) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(155) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(156) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(3-oxyethyl group propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(157) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(158) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(159) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6-(3-morpholino base propoxy-)-7-(2-morpholino base oxethyl)-4-quinazolyl) oxygen] phenyl } urea,
(160) N-(the fluoro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(161) N-(the chloro-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea,
(162) N-(the bromo-3-trifluoromethyl of 4-) phenyl-N '-{ 4-[(6,7-bis-(3-morpholino base propoxy-)-4-quinazolyl) oxygen] phenyl } urea.
In claim 1～5 compound or pharmaceutically acceptable salt thereof described in any one in the application of preparing medicine for treating tumor object space face.
8. the application of the compound or pharmaceutically acceptable salt thereof described in any one aspect preparation treatment leukemia medicament in claim 1～5.
9. the application of the compound or pharmaceutically acceptable salt thereof described in any one aspect preparation treatment lung cancer or liver-cancer medicine in claim 1～5.
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