Oxazino-quinazoline and oxazino-quinoline type compound, preparation method and uses thereof

Abstract

Provided are an oxazino-quinazoline and oxazino-quinoline type compound, a preparation method, and uses thereof. More particularly provided is a compound shown in formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt, a prodrug thereof, a preparation method, and uses thereof in preparing a drug acting as a kinase inhibitor. ##STR00001##

Claims

1. A compound of Formula (I), or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof: ##STR00315## in the formula (I), X is O, or NH; Y is N or C—Z, wherein Z is —H or —CN; R.sup.1 is ##STR00316## R.sup.3 is —H, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkyl substituted by halogen, or C.sub.1-C.sub.3 alkoxy substituted by halogen; L is ##STR00317## M is O or S; T is linear C.sub.1-C.sub.3 alkylene, or linear C.sub.1-C.sub.3 alkylene independently substituted by R.sup.5 and R.sup.6, respectively; R.sup.5 and R.sup.6 are independently —H, halogen, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkyl substituted by halogen; R.sup.4 is aryl, 5- to 6-membered heteroaryl, aryl substituted by 1-3 identical or different R.sup.7, or 5- to 6-membered heteroaryl substituted by 1-3 identical or different R.sup.7, wherein the heteroaryl group is a heteroaryl group containing 1-3 heteroatoms selected from N, O or S; R.sup.7 is —H, halogen, amino, hydroxy, cyano, C.sub.1-C.sub.3 alkylthio, amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, unsubstituted or substituted C.sub.1-C.sub.6 alkyl, or unsubstituted or substituted C.sub.1-C.sub.6 alkoxy, wherein the substituent of the substituted C.sub.1-C.sub.6 alkyl is halogen, hydroxy, amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkoxy, and wherein the substituent of the substituted C.sub.1-C.sub.6 alkoxy is halogen, C.sub.1-C.sub.3 alkoxy, or amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl; R.sup.2 is ##STR00318## L.sub.1 is selected from: ##STR00319## T.sub.1 is linear C.sub.1-C.sub.8 alkylene, linear C.sub.1-C.sub.8 alkylene independently substituted by R.sup.9 and R.sup.10, respectively; R.sup.9 and R.sup.10 are each independently —H, or C.sub.1-C.sub.3 alkyl; R.sup.8 is —H, hydroxy, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, 4- to 7-membered heterocyclyl or —NR.sup.11R.sup.12; R.sup.11 and R.sup.12 are each independently —H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkyl substituted by hydroxy, or C.sub.1-C.sub.6 alkyl substituted by C.sub.1-C.sub.3 alkoxy; the 4- to 7-membered heterocyclyl is a heterocyclyl containing 1-2 heteroatoms selected from N, O or S, the heterocyclyl is unsubstituted or substituted by one or two of the group consisting of: C.sub.1-C.sub.3 alkyl, aldehyde group, C.sub.1-C.sub.4 alkylacyl, aminoacyl, aminoacyl wherein the amino is substituted with mono- or di-C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkylsulfonyl, and C.sub.1-C.sub.3 alkylsulfinyl, or the sulfur in the heterocycle is oxidized by one to two oxygen atoms.

2. The compound, or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof according to claim 1, wherein: R.sup.1 is ##STR00320## R.sup.3 is —H, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy; L is ##STR00321## M is O or S, T is linear C.sub.1-C.sub.2 alkylene, or linear C.sub.1-C.sub.2 alkylene independently substituted by R.sup.5 and R.sup.6, respectively; R.sup.5 and R.sup.6 are independently —H, —F, methyl, ethyl or trifluoromethyl; R.sup.4 is aryl, 5- to 6-membered heteroaryl, aryl substituted by 1-2 identical or different R.sup.7, or 5- to 6-membered heteroaryl substituted by 1-2 identical or different R.sup.7, wherein the aryl or heteroaryl group is selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, pyrrolyl, thiadiazolyl, furyl, oxazolyl or isoxazolyl; R.sup.7 is —H, —F, —Cl, —Br, —CF.sub.3, —OCF.sub.3, amino, hydroxy, cyano, methylthio, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, dimethylamino, diethyl amino, cyclopropyl, cyclobutyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, methylaminomethyl, methylaminoethyl, methylaminopropyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, methoxyethoxy, methoxypropoxy, ethoxyethoxy, ethoxypropoxy, methylaminoethoxy, methylaminopropoxy, ethylaminoethoxy, ethylaminopropoxy, dimethylaminoethoxy, dimethylaminopropoxy, diethylaminoethoxy, or diethylaminopropoxy.

3. The compound, or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof according to claim 1, wherein: R.sup.2 is ##STR00322## L.sub.1 is selected from: ##STR00323## T.sub.1 is linear C.sub.1-C.sub.6 alkylene, or linear C.sub.1-C.sub.6 alkylene independently substituted by R.sup.9 and R.sup.10, respectively; R.sup.9 and R.sup.10 are independently —H or methyl; R.sup.8 is —H, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, 5- to 6-membered heterocyclyl or —NR.sup.11R.sup.12, R.sup.11 and R.sup.12 are each independently —H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, 1-ethylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, isopropoxyethyl, isopropoxypropyl, isopropoxybutyl, isopropoxypentyl or isopropoxyhexyl; the 5- to 6-membered heterocyclyl is a heterocyclyl containing 1-2 heteroatoms selected from N, O or S, the 5- to 6-membered heterocyclyl is unsubstituted or substituted by one or two of the group consisting of: methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, methyl aminoacyl, dimethylaminoacyl, methylsulfonyl, ethyl sulfonyl, isopropylsulfonyl, methylsulfinyl, ethylsulfinyl, or isopropylsulfinyl, or sulfur in the heterocycle is oxidized by one to two oxygen atoms.

4. The compound, or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof according to claim 3, wherein the 5- to 6-membered heterocyclyl is derived from the 5- to 6-membered heterocycle selected from the following: ##STR00324## and the 5- to 6-membered heterocyclyl is unsubstituted or substituted by one or two of the group consisting of: methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, methylaminoacyl, dimethylaminoacyl, methyl sulfonyl, ethyl sulfonyl, isopropylsulfonyl, methylsulfinyl, ethylsulfinyl, or isopropylsulfinyl, or sulfur in the heterocycle is oxidized by one to two oxygen atoms.

5. The compound, or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof according to claim 1, wherein: R.sup.2 is ##STR00325## L.sub.1 is selected from: ##STR00326## T.sub.1 is linear C.sub.1-C.sub.6 alkylene, or linear C.sub.1-C.sub.6 alkylene independently substituted by R.sup.9 and R.sup.10, respectively; R.sup.9 and R.sup.10 are each independently —H or methyl; R.sup.8 is —H, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5- to 6-membered heterocyclyl or —NR.sup.11R.sup.12, R.sup.11 and R.sup.12 are each independently —H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, 1-ethylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, isopropoxyethyl, isopropoxypropyl, isopropoxybutyl or isopropoxypentyl; the 5- to 6-membered heterocyclyl is selected from: ##STR00327## R.sup.13 is —H, methyl, ethyl, propyl, or isopropyl.

6. The compound, or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof according to claim 1, wherein: in the formula (I), X is NH; Y is N; R.sup.1 is ##STR00328## R.sup.3 is —H, halogen, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkyl substituted by halogen; L is ##STR00329## M is O or S; T is linear C.sub.1-C.sub.3 alkylene; R.sup.4 is aryl, 5- to 6-membered heteroaryl, or aryl substituted by 1-3 identical or different R.sup.7, wherein the heteroaryl group is a heteroaryl group containing 1-3 heteroatoms selected from N, O or S; R.sup.7 is —H, or halogen; R.sup.2 is ##STR00330## L.sub.1 is selected from: ##STR00331## T.sub.1 is linear C.sub.1-C.sub.8 alkylene; R.sup.8 is —NR.sup.11R.sup.12; R.sup.11 and R.sup.12 are each independently —H, C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.6 cycloalkyl.

7. The compound of Formula (I) according to claim 1, a pharmaceutically acceptable salt, diastereomer, enantiomer, hydrate, or solvate thereof, wherein the pharmaceutically acceptable salt is selected from one or more of the following salts of the said compound: hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, salicylate, hexonate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salt, magnesium salt, potassium salt, sodium salt and zinc salt.

8. The compound, or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of: 1-(10-((4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((3-chloro-4-((3-fluorobenzyloxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(m-tolyloxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(3-chlorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(3-fluorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(2-fluorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(4-fluorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(4-chlorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(2-methoxyphenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(pyridin-2-yloxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(pyridin-3-yloxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(3-methoxyphenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(thiazol-2-yloxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((3-fluoro-4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((3-chloro-4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-((4-fluorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-((3-fluorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-((3-trifluoromethylbenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(thiophen-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(thiazol-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(benzylthio)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-((3-fluorobenzyl)oxy)-3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-((3-fluorobenzyl)oxy)-3-(methoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-((3-fluorobenzyl)oxy)-3-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-((4-fluorophenyl)thio)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((2-fluoro-4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(2-(2-(dimethylamino)ethoxy)phenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(2-(3-(dimethylamino)propoxy)phenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-((4-(2-(2-methoxyethoxy)phenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-(4-phenoxyphenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-(3-chloro-4-(pyridin-2-ylmethoxy)phenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-(3-chloro-4-((3-fluorobenzyl)oxy)phenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-(4-(4-chlorophenoxy)phenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-(4-(4-fluorophenoxy)phenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-(4-(2,5-dichlorophenoxy)phenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-(4-(pyridin-2-ylmethoxy)phenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-(4-((2-fluorobenzyl)oxy)phenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-(4-((3-fluorobenzyl)oxy)phenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; 1-(10-(4-((4-fluorobenzyl)oxy)phenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-1-(10-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(dimethylamino)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(m-tolyloxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(3-chlorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(3-fluorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(2-fluorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(4-fluorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(4-chlorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(2-methoxyphenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(pyridin-2-yloxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(pyridin-3-yloxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(3-methoxyphenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(thiazol-2-yloxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((3-fluoro-4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((3-chloro-4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((4-fluorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((3-fluorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((3-(trifluoromethylbenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(thiophen-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(thiazol-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(benzylthio)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((3-fluorobenzyl)oxy-3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((3-fluorobenzyl)oxy)-3-methoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((3-fluorobenzyl)oxy)-3-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((4-fluorophenyl)thio)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(2-fluoro-5-methylphenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(5-chloro-2-fluorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(2,5-difluorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(1-(3-fluorophenyl)ethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(1-(pyridin-2-yl)ethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(pyridin-3-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-(pyridin-4-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-1-(10-((4-(benzyloxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(dimethylamino)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((2-fluorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((2-chlorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((2-methylbenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((2-methoxybenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-1-(10-((4-((3-chlorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(dimethylamino)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((3-methylbenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((3-cyanobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((3-methoxybenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((4-chlorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(dimethylamino)-1-(10-((4-((4-methylbenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-1-(10-((4-(2,5-difluorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(10-((4-((2-chloro-5-fluorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(10-((4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(pyrrolidin-1-yl)but-2-en-1-one; (E)-4-(diethylamino)-1-(10-((4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-1-(10-((4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(piperidin-1-yl)but-2-en-1-one; (E)-4-morpholino-1-(10-((4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-4-(4-methylpiperazin-1-yl)-1-(10-((4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-1-(10-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-morpholinobut-2-en-1-one; (E)-1-(10-((2-fluoro-4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(piperidin-1-yl)but-2-en-1-one; (E)-1-(10-((3-fluoro-4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(piperidin-1-yl)but-2-en-1-one; (E)-1-(10-((4-(2-fluorophenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((4-methoxybutyl)amino)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(cyclopropyl(methyl)amino)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(cyclopropylamino)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(isopropylamino)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-morpholinobut-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-methylpiperazin-1-yl)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(diethylamino)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(pyrrolidin-1-yl)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(piperidin-1-yl)but-2-en-1-one; (E)-4-(4-acetylpiperazin-1-yl)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(cyclobutylamino)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(isopropyl(methyl)amino)but-2-en-1-one; (S,E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one; 1-(10(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-yne-1-one; (R,E)-1-(10-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-hydroxypiperidin-1-yl)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-hydroxyl-4-methylpiperidin-1-yl)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-fluoropiperidin-1-yl)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((3-hydroxypropyl)(methyl)amino)but-2-en-1-one; (S,E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(2,4-dimethylpiperazin-1-yl)but-2-en-1-one; (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((2-hydroxyethyl)(methyl)amino)but-2-en-1-one; (R,E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(2,4-dimethylpiperazin-1-yl)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-methylpiperazin-1-yl)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(isopropyl(methyl)amino)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(piperidin-1-yl)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(diethylamino)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-methylpiperazin-1-yl)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(isopropyl(methyl)amino)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(piperidin-1-yl)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one; (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[ 1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one; and (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(diethylamino)but-2-en-1-one.

9. The compound according to claim 8 having the following structure: ##STR00332## or the pharmaceutically acceptable salt thereof.

10. The compound according to claim 8 having the following structure: ##STR00333## or the pharmaceutically acceptable salt thereof.

11. The compound according to claim 8 having the following structure: ##STR00334## or the pharmaceutically acceptable salt thereof.

12. The compound according to claim 8 having the following structure: ##STR00335## or the pharmaceutically acceptable salt thereof.

13. The compound according to claim 8 having the following structure: ##STR00336## or the pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition for treating diseases related to tyrosine kinases EGFR, HER2, HER3 or HER4, which consists of the compound of Formula (I) or a pharmaceutically acceptable salt, diastereomer, enantiomer, hydrate, or solvate thereof according to claim 1 and pharmaceutically acceptable carrier(s) or excipient(s).

15. A pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt, diastereomer, enantiomer, hydrate, or solvate thereof according to claim 1 as an active ingredient, one or more other therapeutic agents, and one or more pharmaceutically acceptable carriers or excipients.

16. A compound of Formula (I), or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof: ##STR00337## in the formula (I), X is O, or NH; Y is N or C—Z, wherein Z is —H or —CN; R.sup.1 is ##STR00338## R.sup.3 is —H, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkyl substituted by halogen or C.sub.1-C.sub.3 alkoxy substituted by halogen; L is ##STR00339## M is O or S; T is linear C.sub.1-C.sub.3 alkylene, or linear C.sub.1-C.sub.3 alkylene independently substituted by R.sup.5 and R.sup.6, respectively; R.sup.5 and R.sup.6 are each —H, halogen, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkyl substituted by halogen; R.sup.4 is substituted or unsubstituted fused heteroaryl, the substituted fused heteroaryl is substituted by 1-3 identical or different R.sup.7, the fused ring heteroaryl group is a heteroaryl group containing 1-3 heteroatoms selected from N, O or S; R.sup.7 is —H, halogen, amino, hydroxy, cyano, C.sub.1-C.sub.3 alkylthio, amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, unsubstituted or substituted C.sub.1-C.sub.6 alkyl, or unsubstituted or substituted C.sub.1-C.sub.6 alkoxy, wherein the substituent of the substituted C.sub.1-C.sub.6 alkyl is halogen, hydroxy, amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkoxy, and wherein the substituent of the substituted C.sub.1-C.sub.6 alkoxy is halogen, C.sub.1-C.sub.3 alkoxy, or amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl; R.sup.2 is ##STR00340## L.sub.1 is selected from: ##STR00341## T.sub.1 is linear C.sub.1-C.sub.8 alkylene, or linear C.sub.1-C.sub.8 alkylene independently substituted by R.sup.9 and R.sup.10, respectively; R.sup.9 and R.sup.10 are each independently —H, or C.sub.1-C.sub.3 alkyl; R.sup.8 is —H, hydroxy, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, 4- to 7-membered heterocyclyl or —NR.sup.11R.sup.12; R.sup.11 and R.sup.12 are each independently —H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkyl substituted by hydroxy or C.sub.1-C.sub.6 alkyl substituted by C.sub.1-C.sub.3 alkoxy; the 4- to 7-membered heterocyclyl is a heterocyclyl containing 1-2 heteroatoms selected from N, O or S, the heterocyclyl is unsubstituted or substituted by any one or two of the group consisting of: C.sub.1-C.sub.3 alkyl, aldehyde group, C.sub.1-C.sub.4 alkylacyl, aminoacyl, aminoacyl wherein the amino is substituted with mono- or di-C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkylsulfonyl, C.sub.1-C.sub.3 alkylsulfinyl, hydroxy, halogen, C.sub.1-C.sub.3 hydroxyalkyl, or C.sub.1-C.sub.3 haloalkyl, or the sulfur in the heterocycle is oxidized by one to two oxygen atoms.

17. The compound, or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof according to claim 16, wherein: R.sup.1 is ##STR00342## R.sup.3 is —H, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy; L is ##STR00343## M is O or S; T is linear C.sub.1-C.sub.2 alkylene, or linear C.sub.1-C.sub.2 alkylene independently substituted by R.sup.5 and R.sup.6, respectively; R.sup.5 and R.sup.6 are each independently —H, —F, methyl, ethyl or trifluoromethyl; R.sup.4 is unsubstituted or substituted ##STR00344##  the group is substituted by 1-3 identical or different R.sup.7, R.sup.7 is —H, —F, —Cl, —Br, —CF.sub.3, —OCF.sub.3, amino, hydroxy, cyano, methylthio, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, methylaminomethyl, methylaminoethyl, methylaminopropyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, methoxyethoxy, methoxypropoxy, ethoxyethoxy, ethoxypropoxy, methylaminoethoxy, methylaminopropoxy, ethylaminoethoxy, ethylaminopropoxy, dimethylaminoethoxy, dimethylaminopropoxy, diethylaminoethoxy, or diethylaminopropoxy.

18. The compound, or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof according to claim 5, wherein: in the formula (I), X is NH; Y is N; R.sup.1 is ##STR00345## R.sup.3 is —H, halogen, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkyl substituted by halogen; L is ##STR00346## M is O or S; T is linear C.sub.1-C.sub.3 alkylene; R.sup.4 is substituted or unsubstituted fused heteroaryl, wherein the fused ring heteroaryl group is a heteroaryl group containing 1-3 heteroatoms selected from N, O or S; R.sup.2 is ##STR00347## L.sub.1 is selected from: ##STR00348## T.sub.1 is linear C.sub.1-C.sub.8 alkylene; R.sup.8 is —NR.sup.11R.sup.12; R.sup.11 and R.sup.12 are each independently —H, or C.sub.1-C.sub.6 alkyl.

19. A compound of Formula (I), or a diastereomer, enantiomer, hydrate, solvate, or pharmaceutically acceptable salt thereof: ##STR00349## in the formula (I), X is O, or NH; Y is N or C—Z, wherein Z is —H or —CN; R.sup.1 is ##STR00350## R.sup.3 is —H, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkyl substituted by halogen or C.sub.1-C.sub.3 alkoxy substituted by halogen; L is ##STR00351## M is O or S; T is linear C.sub.1-C.sub.3 alkylene, or linear C.sub.1-C.sub.3 alkylene independently substituted by R.sup.5 and R.sup.6, respectively; R.sup.5 and R.sup.6 are each independently —H, halogen, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkyl substituted by halogen; R.sup.4 is aryl, 5- to 6-membered heteroaryl, aryl substituted by 1-3 identical or different R.sup.7, or 5- to 6-membered heteroaryl substituted by 1-3 identical or different R.sup.7, wherein the heteroaryl group is a heteroaryl group containing 1-3 heteroatoms selected from N, O or S; R.sup.7 is —H, halogen, amino, hydroxy, cyano, C.sub.1-C.sub.3 alkylthio, amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, unsubstituted or substituted C.sub.1-C.sub.6 alkyl, or unsubstituted or substituted C.sub.1-C.sub.6 alkoxy, wherein the substituent of the substituted C.sub.1-C.sub.6 alkyl is halogen, hydroxy, amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkoxy, and wherein the substituent of the substituted C.sub.1-C.sub.6 alkoxy is halogen, C.sub.1-C.sub.3 alkoxy, or amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl; R.sup.2 is ##STR00352## L.sub.1 is selected from ##STR00353## T.sub.1 is linear C.sub.1-C.sub.8 alkylene, or linear C.sub.1-C.sub.8 alkylene independently substituted by R.sup.9 and R.sup.10, respectively; R.sup.9 and R.sup.10 are each independently —H, or C.sub.1-C.sub.3 alkyl; R.sup.8 is —H, hydroxy, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, 4- to 7-membered heterocyclyl or —NR.sup.11R.sup.12; R.sup.11 and R.sup.12 are each independently —H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkyl substituted by hydroxyl or C.sub.1-C.sub.6 alkyl substituted by C.sub.1-C.sub.3 alkoxy; the 4- to 7-membered heterocyclyl is a heterocyclyl containing 1-2 heteroatoms selected from N, O or S, the heterocyclyl is unsubstituted or substituted by any one or two of the group consisting of: C.sub.1-C.sub.3 alkyl, hydroxy, halogen, C.sub.1-C.sub.3 hydroxyalkyl, or C.sub.1-C.sub.3 haloalkyl.

20. A method of treating cancer and autoimmune diseases associated with tyrosine kinases EGFR, HER2, HER3 or HER4 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, diastereomer, enantiomer, hydrate, or solvate thereof according to claim 1, wherein the cancer and autoimmune diseases include ocular fundus disease, xerophthalmia, psoriasis, leucoderma, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary cancer and sarcoma, and cholangiocarcinoma.

21. A compound represented by formula (VIII), ##STR00354## wherein X is O, or NH; Y is N or C—Z, wherein Z is —H or —CN; R.sup.1 is ##STR00355## R.sup.3 is —H, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkyl substituted by halogen, or C.sub.1-C.sub.3 alkoxy substituted by halogen; L is ##STR00356## M is O or S; T is linear C.sub.1-C.sub.3 alkylene, or linear C.sub.1-C.sub.3 alkylene independently substituted by R.sup.5 and R.sup.6, respectively; R.sup.5 and R.sup.6 are independently —H, halogen, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 substituted by halogen; R.sup.4 is aryl, 5- to 6-membered heteroaryl, aryl substituted by 1-3 identical or different R.sup.7, or 5- to 6-membered heteroaryl substituted by 1-3 identical or different R.sup.7, wherein the heteroaryl group is a heteroaryl group containing 1-3 heteroatoms selected from N, O or S; R.sup.7 is —H, halogen, amino, hydroxy, cyano, C.sub.1-C.sub.3 alkylthio, amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, unsubstituted or substituted C.sub.3-C.sub.6 alkyl, or unsubstituted or substituted C.sub.3-C.sub.6 alkoxy, wherein the substituent of the substituted C.sub.1-C.sub.6 alkyl is halogen, hydroxy, amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkoxy, and wherein the substituent of the substituted C.sub.3-C.sub.6 alkoxy is halogen, C.sub.1-C.sub.3 alkoxy, or amino substituted with mono- or di-C.sub.1-C.sub.3 alkyl.

22. A compound having the following structure: ##STR00357##

Description

DETAILED EMBODIMENTS

(1) Synthesis of the Compound Represented by Formula VIII (Intermediate of Compounds of the Present Disclosure)

Preparation of N-(4-phenoxyphenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (Intermediate No. VIII-1)

(2) ##STR00081##

Step 1) Preparation of 5-(2-hydroxyethoxy)-6-nitroquinazolin-4(3H)-one (II)

(3) ##STR00082##

(4) Ethylene glycol (352.7 g, 5.7 mol) was dissolved in 1 L of DMF, cooled in an ice bath, to which sodium hydride was added (68.2 g, 2.8 mol), and stirred for 0.5 h. 5-chloro-6-nitroquinazolin-4(3H)-one (128 g, 0.57 mol) was added, and the reaction was slowly warmed to room temperature and stirred until the reaction was completed. Ethyl acetate was added until a large amount of solid was precipitated out, which was filtered with suction, and the resulting solid was slurried with water. The slurry was adjusted to weak acidic with hydrochloric acid and filtered with suction to afford 129.7 g of a white solid with a yield of 91%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 12.55 (1H, s), 8.13-8.28 (2H, m), 7.52 (1H, d, J=8.9 Hz), 4.76 (1H, brs), 4.04-4.32 (2H, m), 3.60-3.84 (2H, m); MS: 252[M+H]+.

Step 2) Preparation of 5-(2-chloroethoxy)-6-nitro-N-(4-phenoxyphenyl)quinazolin-4-amine (VII-1)

(5) ##STR00083##

(6) 5-(2-hydroxyethoxy)-6-nitroquinazolin-4(3H)-one (3 g, 11.94 mmol) was added to a round-bottomed flask, to which thionyl chloride was added and stirred to dissolve it, catalytic amount of dimethylformamide was added dropwise, the reaction solution was heated to reflux until the raw materials were completely reacted, the reaction solution was evaporated to dryness under reduced pressure to afford a yellow solid, which was directly dissolved in dichloromethane, then 4-phenoxyaniline (2.2 g, 11.94 mmol) in ethanol was added and stirred until the reaction was completed. N-hexane was added and stirred until a large amount of solid was precipitated out, which was filtered with suction, washed with petroleum ether, and dried in air to afford 3.9 g of yellow solid with a yield of 88%. MS: 437[M+H].sup.+.

Step 3) Preparation of N-(4-phenoxyphenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (Intermediate No. VIII-1)

(7) 5-(2-chloroethoxy)-6-nitro-N-(4-phenoxyphenyl)quinazolin-4-amine (VII-1) (3.9 g, 8.7 mmol) was added to a round-bottomed flask, to which a mixed solvent of ethanol and water was added. Then iron powder (1.3 g, 22.7 mmol) and acetic acid (1.85 mL, 32.27 mmol) were added in sequence, and the reaction solution was heated and stirred until the reaction was completed. The solvent was distilled off, and extracted with ethyl acetate, concentrated, and subjected to column chromatography to afford 2.2 g of yellow solid with a yield of 65%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.92 (s, 1H), 8.47 (s, 1H), 7.79 (d, J=8.9 Hz, 2H), 7.44-7.37 (m, 3H), 7.35-7.28 (m, 1H), 7.16-7.13 (m, 1H), 7.09-7.06 (m, 2H), 7.04-7.00 (m, 2H), 6.82-6.74 (m, 1H), 4.71-4.66 (m, 2H), 4.13-4.08 (m, 2H); MS: 371[M+H].sup.+.

Preparation of Intermediate N-(4-(3-methylphenoxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (Intermediate No. VIII-2)

(8) ##STR00084##

(9) Step 1) is the same as the step 1) of the synthetic route of Intermediate No. VIII-1.

(10) Step 2) Preparation of 5-(2-chloroethoxy)-6-nitroquinazolin-4(3H)-one (III)

(11) ##STR00085##

(12) 5-(2-hydroxyethoxy)-6-nitroquinazolin-4(3H)-one (129.7 g, 0.52 mol) was placed in a flask, to which 200 ml of phosphorus oxychloride was added and heated to reflux until the reaction was completed. Phosphorus oxychloride was evaporated off, and slurried with water until a large amount of solid was precipitated out, which was filtered with suction to afford 120.8 g of white solid with a yield of 87%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.55 (s, 1H), 8.24-8.21 (m, 2H), 7.56 (d, J=9.0 Hz, 1H), 4.41 (t, J=5.4 Hz, 2H), 3.96 (t, J=5.4 Hz, 2H); MS: 270[M+H].sup.+.

Step 3) Preparation of 5-(2-chloroethoxy)-6-aminoquinazolin-4(3H)-one (IV)

(13) ##STR00086##

(14) 5-(2-chloroethoxy)-6-nitroquinazolin-4(3H)-one (120.8 g, 0.45 mol) was dissolved in a mixed solvent of methanol and tetrahydrofuran, to which 40 g raney nickel was added, and stirred at room temperature under hydrogen atmosphere until the reaction was completed. The reaction was filtered with suction, and concentrated to afford 107.4 g of a yellow solid with a yield of 100%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.76 (s, 1H), 7.74 (s, 1H), 7.24 (d, J=2.2 Hz, 2H), 5.32 (s, 2H), 4.15 (t, J=5.6 Hz, 2H), 3.97 (t, J=5.6 Hz, 2H); MS: 240[M+H].sup.+.

Step 4) Preparation of 2,3,4,9-tetrahydro-10H-[1,4]oxazino[2,3-f]quinazolin-10-one (V)

(15) ##STR00087##

(16) 5-(2-chloroethoxy)-6-aminoquinazolin-4(3H)-one (107.4 g, 0.45 mol) was dissolved in 1 L of DMF, to which triethylamine (94 mL, 0.68 mol) was added, heated until the reaction was completed, and then DMF was distilled off. Dichloromethane was added and stirred until a large amount of solid was precipitated out, which was filtered with suction to afford 80 g of a white solid with a yield of 88%. .sup.1H NMR (DMSO-d6, 300 MHz) δ 11.66 (1H, s), 7.67 (1H, s), 6.96-7.03 (2H, m), 6.11 (1H, s), 4.13-4.21 (2H, m), 3.25-3.33 (2H, m); MS: 204[M+H].sup.+.

Step 5) Preparation of N-(4-(3-methylphenoxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (Intermediate No. VIII-2)

(17) 2,3,4,9-tetrahydro-10H-[1,4]oxazino[2,3-f]quinazolin-10-one (0.5 g, 2.46 mmol), 4-(m-tolyloxy)aniline (979 mg, 4.92 mmol), (benzotriazol-1-oxy)tris(dimethylamino)phosphonium hexafluorphosphate (BOP)(1.4 g, 3.20 mmol) were placed in a round-bottomed flask, to which 5 ml of acetonitrile was added, and 1,8-diazabicycloundec-7-ene (DBU)(0.56 g, 3.69 mmol) was added after stirring well, and then was stirred under room temperature until the reaction was completed. The solvent was distilled off, and the resulting mixture was purified using silica gel column chromatography to afford 710 mg of brown solid with a yield of 75%. MS: 385[M+H].sup.+.

Preparation of Intermediate N-(3-trifluoromethyl-4-(3-fluorobenzyloxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (Intermediate No. VIII-3)

(18) ##STR00088##

(19) Step 1) to Step 4) are the same as Step 1) to Step 4) in the preparation method of Intermediate No. VIII-2.

Step 5) Preparation of 10-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazoline (VI)

(20) ##STR00089##

(21) 2,3,4,9-tetrahydro-10H-[1,4]oxazino[2,3-f]quinazolin-10-one (20.3 g, 100 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorphosphate (BOP) (44.2 g, 100 mmol) were placed in a round-bottomed flask, to which acetonitrile was added and stirred well, and 1,8-diazabicycloundec-7-ene (DBU)(15.2 g, 100 mmol) was then added, and stirred at room temperature until the reaction was completed. Water was added and stirred until a large amount of solid was precipitated out, which was filtered with suction to afford 28 g of yellow solid with a yield of 87%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.26 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.69-7.58 (m, 1H), 7.58-7.47 (m, 3H), 6.70 (s, 1H), 4.41 (t, J=4.2 Hz, 2H), 3.58-3.47 (m, 2H); MS: 321[M+H].sup.+.

Step 6) Preparation of N-(3-trifluoromethyl-4-(3-fluorobenzyloxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (Intermediate No. VIII-3)

(22) 10-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazoline (320 mg, 1 mmol) and 4-((3-fluorobenzyl)oxy)-3-(trifluoromethyl)aniline (285 mg, 1 mmol), p-toluenesulfonic acid monohydrate (17 mg, 0.1 mmol) were dissolved in isopropanol, and stirred at room temperature until the reaction was completed. Water was added and stirred, and filtered with suction to afford 424 mg of yellow solid product with a yield of 90%. MS: 471[M+H].sup.+.

Preparation of Intermediate No. VIII-4 to Intermediate No. VIII-63

(23) ##STR00090##

(24) Step 1) to Step 4) are the same as Step 1) to Step 4) in the synthetic method of Intermediate No. VIII-2.

(25) Step 5): See Step 5) in the synthetic route of Intermediate No. VIII-2, wherein the same operation was used, and the method was carried out using 2,3,4,9-tetrahydro-1H-[1,4]oxazino[2,3-f]quinazolin-10-one (V) as the starting material, and replacing 4-m-tolyloxyaniline with an equal molar equivalent of R.sup.1XH in the table below. Specific compounds are as follows:

(26) TABLE-US-00001 LCMS Intermediate m/z = No. R.sup.1X Compound name (M + H).sup.+ VIII-4 N-(3-chloro-4-(3- fluorobenzyloxy)phenyl)-3,4-dihydro- 2H-[1,4]oxazino[2,3-f]quinazolin-10- amine 437 VIII-5 N-(3-chloro-4-(pyridin-2- ylmethoxy)phenyl)-3,4-dihydro-2H- [1,4]oxazino[2,3-f]quinazolin-10- amine 420 VIII-6 N-(2-fluoro-4-phenoxyphenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 389 VIII-7 N-(3-fluoro-4-phenoxyphenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 389 VIII-8 N-(4-(2-fluorophenoxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 389 VIII-9 N-(4-(3- trifluoromethylphenoxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 439 VIII-10 N-(4-(3-chlorophenoxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 405 VIII-11 N-(4-(3-fluorophenoxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 389 VIII-12 N-(4-(4-fluorophenoxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 389 VIII-13 00 N-(4-(4-chlorophenoxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 405 VIII-14 01 N-(4-(2-methoxyphenoxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 401 VIII-15 02 N-(4-(2-pyridyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 372 VIII-16 03 N-(4-(3-pyridyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 372 VIII-17 04 N-(4-(3-methoxyphenoxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 401 VIII-18 05 N-(4-(thiazol-2-yloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 378 VIII-19 06 N-(3-chloro-4-phenoxyphenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 405 VIII-20 07 N-(4-(4-fluorobenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 403 VIII-21 08 N-(4-(3-fluorobenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 403 VIII-22 09 N-(4-(3- trifluoromethylbenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 453 VIII-23 0 N-(4-(pyridin-2-ylmethoxy)phenyl)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 386 VIII-24 N-(4-(thiophen-2-ylmethoxy)phenyl)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 391 VIII-25 N-(4-(thiazol-2-ylmethoxy)phenyl)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 392 VIII-26 N-(4-(benzylthio)phenyl)-3,4-dihydro- 2H-[1,4]oxazino[2,3-f]quinazolin-10- amine 401 VIII-27 N-(3-methoxy-4-(3- fluorobenzyloxy)phenyl)-3,4-dihydro- 2H-[1,4]oxazino[2,3-f]quinazolin-10- amine 433 VIII-28 N-(3-fluoro-4-(3- fluorobenzyloxy)phenyl)-3,4-dihydro- 2H-[1,4]oxazino[2,3-f]quinazolin-10- amine 421 VIII-29 N-(4-(4-fluorophenyl)thio)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 405 VIII-30 N-(4-(2-fluoro-5- methylphenoxy)phenyl)-3,4-dihydro- 2H-[1,4]oxazino[2,3-f]quinazolin-10- amine 403 VIII-31 N-(4-(2-fluoro-5-chloro- phenoxy)phenyl)-3,4-dihydro-2H- [1,4]oxazino[2,3-f]quinazolin-10- amine 423 VIII-32 N-(4-(2,5-difluorophenoxy)phenyl)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 407 VIII-33 0 N-(4-(1-(3- fluorophenyl)ethoxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 417 VIII-34 N-(4-(1-(pyridin-2-yl)-ethoxy)phenyl)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 400 VIII-35 N-(4-(pyridin-3-ylmethoxy)phenyl)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 386 VIII-36 N-(4-(pyridin-4-ylmethoxy)phenyl)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 386 VIII-37 N-(4-(2-(2- (dimethylamino)ethoxy)phenoxy) phenyl)-3,4-dihydro-2H-[1,4]oxazino [2,3-f]quinazolin-10-amine 458 VIII-38 N-(4-(2-(3- (dimethylamino)propoxy)phenoxy) phenyl)-3,4-dihydro-2H-[1,4]oxazino [2,3-f]quinazolin-10-amine 472 VIII-39 N-(4-(2-(2- methoxyethoxy)phenoxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 445 VIII-40 N-(4-phenoxyphenyl)-3,4-dihydro-2H- [1,4]oxazino[2,3-f]quinazolin-10- amine 371 VIII-41 N-(4-(benzyloxy)phenyl)-3,4-dihydro- 2H-[1,4]oxazino[2,3-f]quinazolin-10- amine 385 VIII-42 N-(4-(2-fluorobenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 403 VIII-43 0 N-(4-(2-chlorobenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 419 VIII-44 N-(4-(2-methylbenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 399 VIII-45 N-(4-(2-methoxybenzyloxy)phenyl)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 415 VIII-46 N-(4-(3-chlorobenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 419 VIII-47 N-(4-(3-methylbenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 399 VIII-48 N-(4-(3-cyanobenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 410 VIII-49 N-(4-(3-methoxybenzyloxy)phenyl)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 415 VIII-50 N-(4-(4-chlorobenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 419 VIII-51 N-(4-(4-methylbenzyloxy)phenyl)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 399 VIII-52 N-(4-(2,5-difluorobenzyloxy)phenyl)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazolin-10-amine 421 VIII-53 0 N-(4-(2-chloro-5- fluorobenzyloxy)phenyl)-3,4-dihydro- 2H-[1,4]oxazino[2,3-f]quinazolin-10- amine 437 VIII-54 10-(3-chloro-4-(pyridin-2- ylmethoxy)phenoxy)-3,4-dihydro-2H- [1,4]oxazino[2,3-f]quinazoline 421 VIII-55 10-(3-chloro-4-(3- fluorobenzyloxy)phenoxy)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazoline 438 VIII-56 10-(4-phenoxyphenoxy)-3,4-dihydro- 2H-[1,4]oxazino[2,3-f]quinazoline 372 VIII-57 10-(4-(4-chlorophenoxy)phenoxy)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazoline 406 VIII-58 10-(4-(4-fluorophenoxy)phenoxy)-3,4- dihydro-2H-[1,4]oxazino[2,3- f]quinazoline 390 VIII-59 10-(4-(2,5-dichlorophenoxy)phenoxy)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazoline 440 VIII-60 10-(4-(pyridin-2-ylmethoxy)phenoxy)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazoline 387 VIII-61 10-(4-(2-fluorobenzyloxy)phenoxy)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazoline 404 VIII-62 10-(4-(3-fluorobenzyloxy)phenoxy)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazoline 404 VIII-63 0 10-(4-(4-fluorobenzyloxy)phenoxy)- 3,4-dihydro-2H-[1,4]oxazino[2,3- f]quinazoline 404

PREPARATION OF EXAMPLE COMPOUNDS

Example 1

Preparation of 1-(10-((4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)prop-2-en-1-one

(27) ##STR00151##

(28) N-(4-(3-trifluoromethylphenoxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (Intermediate No. VIII-9)(219 mg, 0.5 mmol) was dissolved in tetrahydrofuran, to which acryloyl chloride (45.3 mg, 0.5 mmol) was added, and stirred at room temperature until the reaction was completed. The reaction was quenched by adding potassium carbonate aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel column chromatography to afford 196 mg of an off-white solid, with a yield of 80%. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) δ 9.92 (s, 1H), 8.47 (s, 1H), 8.03-7.71 (m, 3H), 7.69-7.58 (m, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.38-7.23 (m, 3H), 7.24-7.03 (m, 2H), 6.92-6.69 (m, 1H), 6.43-6.18 (m, 1H), 6.00-5.76 (m, 1H), 4.68 (t, J=4.5 Hz, 2H), 4.07 (t, J=4.5 Hz, 2H); .sup.13CNMR (101 MHz, DMSO-d.sub.6) δ 158.57, 157.66, 154.56, 151.72, 149.22, 144.48, 142.80, 135.76, 131.85, 130.33, 125.24, 123.57, 122.09, 121.93, 120.45, 119.89, 119.85, 119.21, 114.25, 114.21, 106.39, 68.71, 60.34, 45.62; MS: 493[M+H].sup.+.

Examples 2-42

(29) ##STR00152##

(30) With reference to the preparation method of Example 1, wherein exactly the same operations were used, and N-(4-(3-trifluoromethylphenoxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine was replaced with the same molar equivalent of intermediate represented by formula (VIII) wherein R.sup.1X is the substituent in the table below. The specific example compounds are shown in the table below:

(31) TABLE-US-00002 Example compounds Example Starting LCMS No. Intermediate No. R.sup.1X Name m/z = (M + H).sup.+ HNMR  2 VIII-1  1-(10-((4- phenoxyphenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2, 3-f]quinazolin- 4-yl)prop-2-en- 1-one 425 (400 M, DMSO-d.sub.6) δ 9.88(s, 1H), 8.46(s, 1H), 7.81-7.79(m, 3H), 7.42-7.38(m, 2H), 7.32- 7.30(m, 1H), 7.15- 7.07(m, 5H), 7.03- 7.01(m, 1H), 6.35- 6.30(m, 1H), 5.90- 5.87(m, 1H), 4.68(m, 2H), 4.07(m, 2H).  3 VIII-4  1-(10-((3- chloro-4-((3- fluorobenzyloxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 491 (400 M, DMSO-d.sub.6) δ 9.83(s, 1H), 8.47(s, 1H), 7.99(s, 1H), 7.68- 7.66(m, 1H), 7.48- 7.45(m, 1H), 7.34- 7.25(m, 6H), 7.21- 7.17(m, 1H), 6.75- 6.70(m, 1H), 5.80- 5.76(m, 1H), 5.28(s, 2H), 4.74-4.66 (m, 2H), 4.06-3.96 (m, 2H).  4 VIII-5  1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 474 (400 M, DMSO-d.sub.6) δ 9.82(s, 1H), 8.61(s, 1H), 8.46(s, 1H), 8.01(s, 1H), 7.89-7.86(m, 1H), 7.68-7.57(m, 2H), 7.39- 7.36(m, 1H), 7.32- 7.25(m, 2H), 7.21- 7.17(m, 1H), 6.81- 6.75(m, 1H), 6.34- 6.30(m, 1H), 5.90- 5.87(m, 1H), 5.31(s, 2H), 4.74-4.66 (m, 2H), 4.06-3.96 (m, 2H).  5 VIII-2  1-(10-((4-(m- tolyloxy)phenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 439 (300 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 8.45 (s, 1H), 7.82-7.70 (m, 3H), 7.39-7.20 (m, 2H), 7.06 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 7.5 Hz, 1H), 6.87- 6.65 (m, 3H), 6.39- 1-one 6.22 (m, 1H), 6.05-5.69 (m, 1H), 4.67 (t, J = 4.6 Hz, 2H), 4.07 (t, J = 4.6 Hz, 2H), 2.29 (s, 3H).  6 VIII-10 1-(10-((4-(3- chlorophenoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 459 (300 MHz, DMSO-d.sub.6) δ 9.90 (s, 1H), 8.46 (s, 1H), 8.04-7.68 (m, 3H), 7.49-7.37 (m, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.24- 7.10 (m, 3H), 7.09- 6.93 (m, 2H), 6.88-6.62 (m, 1H), 6.49-6.14 (m, 1H), 5.96-5.75 (m, 1H), 4.68 (t, J = 4.6 Hz, 2H), 4.07 (t, J = 4.5 Hz, 2H).  7 VIII-11 1-(10-((4-(3- fluorophenoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 443 (300 MHz, DMSO-d.sub.6) δ 9.90 (s, 1H), 8.47 (s, 1H), 7.94-7.74 (m, 3H), 7.51-7.38 (m, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.04- 6.90 (m, 1H), 6.90- 6.71 (m, 3H), 6.38-6.24 (m, 1H), 6.01-5.73 (m, 1H), 4.75-4.60 (m, 2H), 4.14-4.00 (m, 2H).  8 VIII-8  1-(10-((4-(2- fluorophenoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2, 3-f]quinazolin- 4-yl)prop-2-en- 443 (300 MHz, DMSO-d.sub.6) δ 9.85 (s, 1H), 8.43 (s, 1H), 7.91-7.70 (m, 3H), 7.40 (s, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.27-7.11 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 6.87-6.69 1-one (m, 1H), 6.40-6.25 (m, 1H), 5.93-5.82 (m, 1H), 4.66 (t, J = 4.6 Hz, 2H), 4.06 (t, J = 4.6 Hz, 2H).  9 VIII-12 0 1-(10-((4-(4- fluorophenoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 443 (300 MHz, DMSO-d.sub.6) δ 9.85 (s, 1H), 8.44 (s, 1H), 7.82-7.73 (m, 3H), 7.35-7.16 (m, 3H), 7.14- 7.00 (m, 4H), 6.86- 6.71 (m, 1H), 6.38-6.25 (m, 1H), 5.93-5.82 (m, 1-one 1H), 4.67 (t, J = 4.6 Hz, 2H), 4.06 (t, J = 4.6 Hz, 2H). 10 VIII-13 1-(10-((4-(4- chlorophenoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 459 (300 MHz, DMSO-d.sub.6) δ 9.89 (s, 1H), 8.56-8.36 (m, 1H), 8.03-7.62 (m, 3H), 7.44 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.8 Hz, 1H), 7.16-6.97 (m, 4H), 6.78 (s, 1H), 6.32 (d, J = 1-one 16.7 Hz, 1H), 5.88 (d, J = 10.4 Hz, 1H), 4.77-4.57 (m, 2H), 4.17-3.95 (m, 2H). 11 VIII-14 1-(10-((4-(2- methoxyphenoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 455 (400 MHz, DMSO-d.sub.6) δ 9.79 (s, 1H), 8.41 (s, 1H), 7.82 (s, 1H), 7.73- 7.61 (m, 2H), 7.29 (d, J = 9.0 Hz, 1H), 7.24-7.16 (m, 2H), 7.10-6.97 (m, 2H), 6.93-6.87 (m, 2H), 1-one 6.86-6.71 (m, 1H), 6.39- 6.27 (m, 1H), 5.96- 5.83 (m, 1H), 4.66 (t, J = 4.6 Hz, 2H), 4.06 (t, J = 4.6 Hz, 2H), 3.77 (s, 3H). 12 VIII-15 1-(10-((4- (pyridin-2- yloxy)phenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 426 (300 MHz, DMSO-d.sub.6) δ 9.89 (s, 1H), 8.49-8.32 (m, 3H), 7.89-7.79 (m, 3H), 7.47-7.36 (m, 2H), 7.32 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.87-6.71 (m, 1H), 6.38- 4-yl)prop-2-en- 6.26 (m, 1H), 5.93- 1-one 5.83 (m, 1H), 4.68 (t, J = 4.6 Hz, 2H), 4.07 (t, J = 4.5 Hz, 2H). 13 VIII-16 1-(10-((4- (pyridin-3- yloxy)phenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 426 (300 MHz, DMSO-d.sub.6) δ 9.89 (s, 1H), 8.46 (s, 1H), 8.16 (d, J = 4.6 Hz, 1H), 7.94-7.71 (m, 4H), 7.32 (d, J = 9.1 Hz, 1H), 7.22-7.10 (m, 3H), 7.04 (d, J = 8.3 Hz, 1H), 6.91- 4-yl)prop-2-en- 6.62 (1H, m), 6.41- 1-one 6.26 (m, 1H), 5.94-5.82 (m, 1H), 4.74-4.61 (m, 2H), 4.13-4.01 (m, 2H). 14 VIII-17 1-(10-((4-(3- methoxyphenoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 455 (300 MHz, DMSO-d.sub.6) δ 9.88 (s, 1H), 8.45 (s, 1H), 7.99-7.69 (m, 3H), 7.41-7.19 (m, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.89- 6.67 (m, 2H), 6.65- 6.49 (m, 2H), 6.39-6.23 (m, 1H), 5.99-5.83 (m, 1-one 1H), 4.76-4.61 (m, 2H), 4.14-3.98 (m, 2H), 3.75-3.72 (m, 3H). 15 VIII-18 1-(10-((4- (thiazol-2- yloxy)phenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 432 (300 MHz, DMSO-d.sub.6) δ 9.95 (s, 1H), 8.49 (s, 1H), 8.03-7.72 (m, 3H), 7.47-7.28 (m, 4H), 7.22 (d, J = 3.8 Hz, 1H), 6.91- 6.65 (m, 1H), 6.40- 6.21 (m, 1H), 5.97-5.81 4-yl)prop-2-en- (m, 1H), 4.69 (t, J = 4.6 Hz, 1-one 2H), 4.07 (t, J = 4.6 Hz, 2H). 16 VIII-7  1-(10-((3- fluoro-4- phenoxyphenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 443 (400 MHz, DMSO-d.sub.6) δ 9.99 (s, 1H), 8.55 (s, 1H), 8.27-8.03 (m, 1H), 7.88 (s, 1H), 7.69-7.56 (m, 1H), 7.52-7.30 (m, 3H), 7.30-7.19 (m, 1H), 7.17-7.07 (m, 1H), 7.04- 4-yl)prop-2-en- 6.91 (m, 2H), 6.87- 1-one 6.68 (m, 1H), 6.50-6.24 (m, 1H), 6.02-5.81 (m, 1H), 4.75-4.57 (m, 2H), 4.08 (t, J = 4.7 Hz, 2H). 17 VIII-19 1-(10-((3- chloro-4- phenoxyphenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 459 (300 MHz, DMSO-d.sub.6) δ 9.96 (s, 1H), 8.50 (s, 1H), 8.06-7.69 (m, 3H), 7.51-7.31 (m, 5H), 7.29-7.18 (m, 2H), 6.78 (s, 1H), 6.32 (d, J = 16.8 Hz, 1H), 5.88 (d, J = 10.7 Hz, 1H), 4.77-4.59 (m, 2H), 4.18-4.00 (m, 2H). 18 VIII-20 1-(10-((4-((4- fluorobenzyl)oxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 457 (300 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.40 (s, 1H), 7.80 (s, 1H), 7.72- 7.61 (m, 2H), 7.59-7.46 (m, 2H), 7.36-7.15 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 6.88-6.69 (m, 1H), 6.41-6.24 (m, 1H), 5.98- 5.77 (m, 1H), 5.11 (s, 2H), 4.66 (t, J = 4.7 Hz, 2H), 4.06 (t, J = 4.6 Hz, 2H). 19 VIII-21 0 1-(10-((4-((3- fluorobenzyl)oxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 457 (300 MHz, DMSO-d.sub.6) δ 9.78 (s, 1H), 8.40 (s, 1H), 7.81 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.55- 7.40 (m, 1H), 7.38- 7.24 (m, 3H), 7.20-7.11 (m, 1H), 7.05 (d, J = 8.9 Hz, 2H), 6.78 (s, 1H), 6.41-6.23 (m, 1H), 5.95- 5.80 (m, 1H), 5.17 (s, 2H), 4.74-4.60 (m, 2H), 4.17-4.00 (m, 2H). 20 VIII-22 1-(10-((4-((3- trifluoromethyl benzyl)oxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 507 (300 MHz, DMSO-d.sub.6) δ 9.77 (s, 1H), 8.40 (s, 1H), 7.87-7.59 (m, 7H), 7.28 (d, J = 9.0 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.86-6.70 (m, 1H), 6.38- 6.25 (m, 1H), 5.93- 5.82 (m, 1H), 5.25 (s, 2H), 4.66 (t, J = 4.6 Hz, 2H), 4.06 (t, J = 4.7 Hz, 2H). 21 VIII-23 1-(10-((4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 440 (300 MHz, DMSO-d.sub.6) δ 9.78 (s, 1H), 8.59 (s, 1H), 7.91-7.79 (m, 2H), 7.65 (d, J = 9.9 Hz, 2H), 7.58-7.44 (m, 2H), 7.37- 7.25 (m, 2H), 7.08- 7.01 (m, 2H), 6.77 (s, 1H), 6.40-6.22 (m, 1H), 5.96-5.80 (m, 1H), 5.21 (s, 2H), 4.79-4.61 (m, 2H), 4.15-3.96 (m, 2H). 22 VIII-24 1-(10-((4- (thiophen-2- ylmethoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 445 (300 MHz, DMSO-d.sub.6) δ 9.77 (s, 1H), 8.40 (s, 1H), 7.80 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 5.2 Hz, 1H), 7.36- 7.18 (m, 2H), 7.13- 6.98 (m, 3H), 6.88-6.69 (m, 1H), 6.41-6.26 (m, 1H), 5.97-5.82 (m, 1H), 5.32 (s, 2H), 4.70-4.61 (m, 2H), 4.12-3.97 (m, 2H). 23 VIII-25 1-(10-((4- (thiazol-2- ylmethoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 446 (400 MHz, DMSO-d.sub.6) δ 9.78 (s, 1H), 8.41 (s, 1H), 7.87-7.79 (m, 3H), 7.73-7.65 (m, 2H), 7.29 (d, J = 9.0 Hz, 1H), 7.14- 7.07 (m, 2H), 6.85- 6.73 (m, 1H), 6.38-6.27 (m, 1H), 5.92-5.83 (m, 1H), 5.47 (s, 2H), 4.67 (t, J = 4.6 Hz, 2H), 4.06 (t, J = 4.7 Hz, 2H). 24 VIII-26 1-(10-((4- (benzylthio) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 455 (300 MHz, DMSO-d.sub.6) δ 9.89 (s, 1H), 8.48 (s, 1H), 7.87-7.74 (m, 3H), 7.37 (d, J = 2.7 Hz, 1H), 7.39-7.17 (m, 7H), 6.86- 6.70 (m, 1H), 6.38- 6.25 (m, 1H), 5.93-5.82 (m, 1H), 4.67 (t, J = 4.6 Hz, 2H), 4.22 (s, 2H), 4.06 (t, J = 4.7 Hz, 2H). 25 VIII-3  1-(10-((4-((3- fluorobenzyl) oxy)-3- (trifluoromethyl) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 525 (300 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 8.44 (s, 1H), 8.07 (d, J = 2.6 Hz, 1H), 8.02-7.91 (m, 1H), 7.84 (s, 1H), 7.55-7.41 (m, 1H), 7.37 (d, J = 9.1 Hz, 1H), 7.34-7.23 (m, 3H), 7.23-7.14 (m, 1H), 6.86-6.71 (m, 1H), 6.39- 6.26 (m, 1H), 5.94- 5.84 (m, 1H), 5.34 (s, 2H), 4.66 (t, J = 4.5 Hz, 2H), 4.06 (t, J = 4.5 Hz, 2H). 26 VIII-27 1-(10-((4-((3- fluorobenzyl) oxy)-3- (methoxy)phenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 487 (300 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.43 (s, 1H), 7.81-7.79 (m, 1H), 7.59-7.37 (m, 2H), 7.36- 7.25 (m, 4H), 7.16 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.78-6.75 (m, 1H), 6.32 (d, J = 16.7 Hz, 1H), 5.88 (d, J = 10.2 Hz, 1H), 5.14 (s, 2H), 4.74-4.59 (m, 2H), 4.11-3.99 (m, 2H), 3.82 (s, 3H). 27 VIII-28 1-(10-((4-((3- fluorobenzyl) oxy)-3- fluorophenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 475 (300 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 8.45 (s, 1H), 7.88-7.73 (m, 2H), 7.46-7.40 (m, 2H), 7.30- 7.26 (m, 4H), 7.16- 7.00 (m, 1H), 6.79-6.77 (m, 1H), 6.35-6.31 (m, 1H), 5.88-5.86 (m, 1H), 5.23 (s, 2H), 4.71-4.58 (m, 2H), 4.08-4.01 (m, 2H). 28 VIII-29 1-(10-((4-((4- fluorophenyl) thio)phenyl) amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 459 (300 MHz, DMSO-d.sub.6) δ 9.96 (s, 1H), 8.53 (s, 1H), 8.21 (d, J = 2.6 Hz, 1H), 7.96-7.77 (m, 2H), 7.45-7.30 (m, 3H), 7.20 (d, J = 8.8 Hz, 1H), 7.16- 7.09 (m, 1H), 7.01- 4-yl)prop-2-en- 6.91 (m, 2H), 6.87-6.70 1-one (m, 1H), 6.33 (d, J = 16.4 Hz, 1H), 5.89 (d, J = 10.7 Hz, 1H), 4.72-4.64 (m, 2H), 4.13-4.03 (m, 2H). 29 VIII-6  0 1-(10-((2- fluoro-4- phenoxyphenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2, 3-f]quinazolin- 4-yl)prop-2-en- 1-one 443 (400 MHz, DMSO-d.sub.6) δ 10.34 (s, 1H), 8.86- 8.71 (m, 1H), 8.60 (s, 1H), 7.88 (s, 1H), 7.52- 7.44 (m, 2H), 7.39 (d, J = 9.1 Hz, 1H), 7.28-7.16 (m, 4H), 7.00-6.93 (m, 1H), 6.84-6.72 (m, 1H), 6.40-6.28 (m, 1H), 5.95 5.87 (m, 1H), 4.43 (t, J = 4.7 Hz, 2H), 4.04 (t, J = 4.7 Hz, 2H). 30 VIII-37 1-(10-((4-(2-(2- (dimethylamino) ethoxy)phenoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 512 (400 MHz, Methanol-d.sub.4) δ 8.44-8.22 (m, 1H), 7.98-7.49 (m, 3H), 7.48- 7.21 (m, 2H), 7.19- 6.97 (m, 4H), 6.92-6.65 (m, 2H), 6.47-6.31 (m, 1H), 5.95-5.77 (m, 1H), 5.06-5.00 (m, 2H), 4.13- 4.02 (m, 2H), 3.30 (s, 6H), 2.35-2.19 (m, 4H). 31 VIII-38 1-(10-((4-(2-(3- (dimethylamino) propoxy)phenoxy) phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 526 (400 MHz, Methanol-d.sub.4) δ 8.44-8.28 (m, 1H), 7.89-7.57 (m, 3H), 7.27 (d, J = 9.1 Hz, 1H), 7.23- 7.11 (m, 2H), 7.08- 7.01 (m, 2H), 6.96 (d, J = 7.7 Hz, 1H), 6.90-6.80 (m, 2H), 6.79-6.69 (m, 1H), 6.46-6.30 (m, 1H), 5.98-5.78 (m, 1H), 4.15- 4.06 (m, 2H), 4.03- 3.91 (m, 2H), 3.31 (s, 6H), 2.55-2.45 (m, 2H), 2.36-2.28 (m, 4H). 32 VIII-39 1-(10-((4-(2-(2- methoxyethoxy) phenoxy)phenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 499 (400 MHz, DMSO-d.sub.6) δ 9.90-9.77 (m, 1H), 8.55- 8.31 (m, 1H), 7.86- 7.64 (m, 3H), 7.40-7.24 (m, 2H), 7.17 (d, J = 6.6 Hz, 2H), 7.03-6.95 (m, 2H), 6.93 (d, J = 8.5 Hz, 1H), 6.78 (s, 1H), 6.32 (d, J = 16.8 Hz, 1H), 5.88 (d, J = 10.8 Hz, 1H), 4.66 (t, J = 4.8 Hz, 2H), 4.12 (t, J = 4.8 Hz, 2H), 4.06 (t, J = 4.5 Hz, 2H), 3.56 (t, J = 4.7 Hz, 2H), 3.23 (s, 3H). 33 VIII-56 1-(10-(4- phenoxyphenoxy)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 426 (300 MHz, DMSO-d.sub.6) δ 8.60 (s, 1H), 8.03 (s, 1H), 7.53-7.39 (m, 3H), 7.28 (d, J = 8.6 Hz, 2H), 7.20-7.04 (m, 5H), 6.80 (s, 1H), 6.33 (d, J = 17.0 Hz, 1H), 5.89 (d, J = 10.7 Hz, 1H), 4.64-4.51 (m, 2H), 4.14-3.98 (m, 2H). 34 VIII-54 1-(10-(3- chloro-4- (pyridin-2- ylmethoxy) phenoxy)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 475 (400 MHz, DMSO-d.sub.6) δ 8.68-8.53 (m, 2H), 8.13- 7.95 (m, 1H), 7.94- 7.85 (m, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.57-7.45 (m, 2H), 7.43-7.35 (m, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.26-7.19 (m, 1H), 6.87-6.74 (m, 1H), 6.39- 6.28 (m, 1H), 5.93- 5.86 (m, 1H), 5.33 (s, 2H), 4.54 (t, J = 4.5 Hz, 2H), 4.05 (t, J = 4.5 Hz, 2H). 35 VIII-55 1-(10-(3- chloro-4-((3- fluorobenzyl) oxy)phenoxy)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 492 (400 MHz, DMSO-d.sub.6) δ 8.58 (s, 1H), 8.02 (s, 1H), 7.56-7.43 (m, 3H), 7.41-7.27 (m, 3H), 7.27- 7.14 (m, 2H), 6.84- 6.73 (m, 1H), 6.39-6.24 (m, 1H), 5.97-5.80 (m, 1H), 5.29 (s, 2H), 4.53 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H). 36 VIII-57 1-(10-(4-(4- chlorophenoxy) phenoxy)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 460 (400 MHz, DMSO-d.sub.6) δ 8.59 (s, 1H), 8.02 (s, 1H), 7.51-7.45 (m, 3H), 7.32-7.27 (m, 2H), 7.17- 7.12 (m, 2H), 7.11- 7.07 (m, 2H), 6.85-6.74 (m, 1H), 6.37-6.29 (m, 1H), 5.92-5.88 (m, 1H), 4.54 (t, J = 4.4 Hz, 2H), 4.05 (t, J = 4.4 Hz, 2H). 37 VIII-58 1-(10-(4-(4- fluorophenoxy) phenoxy)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 444 (400 MHz, DMSO-d.sub.6) δ 8.59 (s, 1H), 8.02 (s, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.43-7.19 (m, 4H), 7.19-7.01 (m, 4H), 6.85- 6.76 (m, 1H), 6.41- 6.26 (m, 1H), 5.95-5.81 (m, 1H), 4.54 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.7 Hz, 2H). 38 VIII-59 1-(10-(4-(2,5- dichlorophenoxy) phenoxy)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 494 (400 MHz, DMSO-d.sub.6) δ 8.59 (s, 1H), 8.01 (s, 1H), 7.82-7.78 (m, 1H), 7.51-7.46 (m, 2H), 7.31- 7.27 (m, 2H), 7.20- 7.16 (m, 1H), 7.11-7.07 (m, 2H), 6.84-6.75 (m, 1H), 6.36-6.29 (m, 1H), 5.92-5.86 (m, 1H), 4.54 (t, J = 4.4 Hz, 2H), 4.05 (t, J = 4.4 Hz, 2H). 39 VIII-60 0 1-(10-(4- (pyridin-2- ylmethoxy) phenoxy)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 441 (400 MHz, DMSO-d.sub.6) δ 8.61-8.59 (m, 1H), 8.55 (s, 1H), 8.08-7.93 (m, 1H), 7.89-7.84 (m, 1H), 7.58-7.54 (m, 1H), 7.50- 7.46 (m, 1H), 7.39- 7.34 (m, 1H), 7.19-7.16 (m, 2H), 7.13-7.08 (m, 2H), 6.85-6.74 (m, 1H), 6.33 (d, J = 16.4 Hz, 1H), 5.91-5.86 (m, 1H), 5.22 (s, 2H), 4.53 (t, J = 4.8 Hz, 2H), 4.05 (t, J = 4.8 Hz, 2H). 40 VIII-61 1-(10-(4-((2- fluorobenzyl) oxy)phenoxy)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 458 (400 MHz, DMSO-d.sub.6) δ 8.56 (s, 1H), 8.01 (s, 1H), 7.63-7.57 (m, 1H), 7.50-7.46 (m, 1H), 7.46- 7.41 (m, 1H), 7.31- 7.24 (m, 2H), 7.21-7.17 (m, 2H), 7.14-7.09 (m, 2H), 6.86-6.74 (m, 1H), 6.38-6.29 (m, 1H), 5.92- 5.86 (m, 1H), 5.18 (s, 2H), 4.58-4.51 (m, 2H), 4.09-4.01 (m, 2H). 41 VIII-62 1-(10-(4-((3- fluorobenzyl) oxy)phenoxy)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 458 (400 MHz, DMSO-d.sub.6) δ 8.55 (s, 1H), 7.99 (s, 1H), 7.50-7.42 (m, 2H), 7.35-7.29 (m, 2H), 7.20- 7.14 (m, 3H), 7.11- 7.07 (m, 2H), 6.86-6.71 (m, 1H), 6.37-6.27 (m, 1H), 5.92-5.84 (m, 1H), 5.18 (s, 2H), 4.56-4.49 (m, 2H), 4.08-4.00 (m, 2H). 42 VIII-63 1-(10-(4-((4- fluorobenzyl) oxy)phenoxy)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin- 4-yl)prop-2-en- 1-one 458 (400 MHz, DMSO-d.sub.6) δ 8.55 (s, 1H), 8.00 (s, 1H), 7.56-7.51 (m, 2H), 7.50-7.45 (m, 1H), 7.27- 7.20 (m, 2H), 7.19- 7.14 (m, 2H), 7.11-7.05 (m, 2H), 6.85-6.72 (m, 1H), 6.36-6.27 (m, 1H), 5.93-5.84 (m, 1H), 5.13 (s, 2H), 4.53 (t, J = 4.4 Hz, 2H), 4.05 (t, J = 4.4 Hz, 2H).

Example 43

Preparation of (E)-4-(dimethylamino)-1-(10-((4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-en-1-one

(32) ##STR00194##

(33) N-(4-(3-trifluoromethylphenoxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-9)(219 mg, 0.5 mmol) was dissolved in a mixed solvent of tetrahydrofuran and dimethylformamide, and trans-4-dimethylaminocrotonic acid hydrochloride (92 mg, 0.5 mmol) was added, and stirred at room temperature until the reaction was completed. The reaction was quenched by adding potassium carbonate aqueous solution, extracted with ethyl acetate, the organic phase was concentrated and purified by silica gel column chromatography to afford 208 mg of an off-white solid with a yield of 76%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.92 (s, 1H), 8.48 (s, 1H), 7.93-7.84 (m, 3H), 7.66-7.58 (m, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.35-7.25 (m, 3H), 7.23-7.14 (m, 2H), 6.88-6.76 (m, 1H), 6.58 (d, J=15.2 Hz, 1H), 4.68 (t, J=4.6 Hz, 2H), 4.06 (t, J=4.6 Hz, 2H), 3.12-3.05 (m, 2H), 2.18 (s, 6H); .sup.13CNMR (101 MHz, DMSO-d6) δ 158.57, 157.66, 154.56, 151.72, 149.22, 144.48, 142.80, 135.76, 131.85, 130.33, 125.24, 123.57, 122.09, 121.93, 120.45, 119.89, 119.85, 119.21, 114.25, 114.21, 106.39, 68.71, 60.34, 45.62; MS: 550[M+H].sup.+.

Examples 44-90

(34) ##STR00195##

(35) With reference to the preparation method of Example 43, wherein exactly the same operations were used, and N-(4-(3-trifluoromethylphenoxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-9) was replaced with the same molar equivalent of intermediate represented by formula (VIII) wherein R.sup.1X is the substituent in the table below. The specific example compounds are shown in the table below:

(36) TABLE-US-00003 Example compounds Example Starting LCMS No. Intermediate No. R.sup.1X Name m/z = (M + H).sup.+ HNMR 44 VIII-1  (E)-4-(dimethylamino)- 1-(10-((4- phenoxyphenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 482 (400 M, CDCl.sub.3) δ9.56(s, 1H), 8.62(s, 1H), 7.71- 7.68(m, 2H), 7.61(brs, 1H), 7.47-7.45(m, 1H), 7.38-7.34(m, 2H), 7.14-7.05(m, 6H), 6.72-6.64(m, 1H), 4.72-4.66(m, 2H), 4.24-4.18(m, 2H), 3.38-3.31(m, 2H), 2.46(s, 6H) 45 VIII-4  (E)-1-(10-((3-chloro-4- ((3- fluorobenzyl)oxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)-4- (dimethylamino)but-2- en-1-one 548 (400 MHz, DMSO-d.sub.6) δ 9.82 (s, 1H), 8.46 (s, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.83 (s, 1H), 7.71-7.63 (m, 1H), 7.53- 7.43 (m, 1H), 7.37- 7.22 (m, 4H), 7.21-7.12 (m, 1H), 6.89-6.74 (m, 1H), 6.58 (d, J = 15.3 Hz, 1H), 5.27 (s, 2H), 4.66 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.10 (d, J = 5.8 Hz, 2H), 2.19 (s, 6H). 46 VIII-5  (E)-1-(10-((3-chloro-4- (pyridin-2- ylmethoxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)-4- (dimethylamino)but-2- en-1-one 531 (400 MHz, DMSO-d.sub.6) δ 9.81 (s, 1H), 8.64-8.58 (m, 1H), 8.46 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.92- 7.75 (m, 2H), 7.71- 7.63 (m, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.42-7.34 (m, 1H), 7.34- 7.22 (m, 2H), 6.87- 6.76 (m, 1H), 6.58 (d, J = 15.2 Hz, 1H), 5.31 (s, 2H), 4.66 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.09 (d, J = 5.8 Hz, 2H), 2.19 (s, 6H). 47 VIII-2  (E)-4-(dimethylamino)- 1-(10-((4-(m- tolyloxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 496 (400 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 8.45 (s, 1H), 7.89-7.76 (m, 3H), 7.34- 7.23 (m, 2H), 7.11- 7.04 (m, 2H), 6.98-6.92 (m, 1H), 6.86-6.77 (m, 3H), 6.58 (d, J = 15.4 Hz, 1H), 4.72-4.66 (m, 2H), 4.12-4.02 (m, 2H), 3.12- 3.04 (m, 2H), 2.30 (s, 3H), 2.18 (s, 6H). 48 VIII-10 00 (E)-4-(dimethylamino)- 1-(10-((4-(3- chlorophenoxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 516 (400 MHz, DMSO-d.sub.6) δ 9.90 (s, 1H), 8.47 (s, 1H), 7.90-7.82 (m, 3H), 7.42 (t, J = 8.1 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.22-7.11 (m, 3H), 7.07-6.94 (m, 2H), 6.88- 6.76 (m, 1H), 6.59 (d, J = 15.3 Hz, 1H), 4.67 (t, J = 4.6 Hz, 2H), 4.06 (t, J = 4.6 Hz, 2H), 3.11 (d, J = 5.7 Hz, 2H), 2.20 (s, 6H). 49 VIII-11 01 (E)-4-(dimethylamino)- 1-(10-((4-(3- fluorophenoxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 500 (400 MHz, DMSO-d.sub.6) δ 9.90 (s, 1H), 8.47 (s, 1H), 7.93-7.74 (m, 3H), 7.46- 7.38 (m, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.18-7.12 (m, 2H), 6.99-6.93 (m, 1H), 6.89- 6.77 (m, 3H), 6.59 (d, J = 15.3 Hz, 1H), 4.72-4.64 (m, 2H), 4.06 (t, J = 4.7 Hz, 2H), 3.13- 3.05 (m, 2H), 2.18 (s, 6H). 50 VIII-8  02 (E)-4-(dimethylamino)- 1-(10-((4-(2- fluorophenoxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 500 (400 MHz, DMSO-d.sub.6) δ 9.85 (s, 1H), 8.44 (s, 1H), 7.77 (d, J = 8.9 Hz, 3H), 7.46- 7.36 (m, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.27-7.21 (m, 2H), 7.20-7.13 (m, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.87- 6.77 (m, 1H), 6.58 (d, J = 15.3 Hz, 1H), 4.66 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.10-3.04 (m, 2H), 2.17 (s, 6H). 51 VIII-12 03 (E)-4-(dimethylamino)- 1-(10-((4-(4- fluorophenoxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 500 (400 MHz, DMSO-d.sub.6) δ 9.86 (s, 1H), 8.45 (s, 1H), 7.89-7.76 (m, 3H), 7.30 (d, J = 9.0 Hz, 1H), 7.28- 7.19 (m, 2H), 7.13-7.01 (m, 4H), 6.89-6.77 (m, 1H), 6.58 (d, J = 15.3 Hz, 1H), 4.67 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.08 (d, J = 5.8 Hz, 2H), 2.18 (s, 6H). 52 VIII-13 04 (E)-4-(dimethylamino)- 1-(10-((4-(4- chlorophenoxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 516 (400 MHz, DMSO-d.sub.6) δ 9.88 (s, 1H), 8.46 (s, 1H), 7.89-7.77 (m, 3H), 7.48- 7.40 (m, 2H), 7.31 (d, J = 9.0 Hz, 1H), 7.15-7.08 (m, 2H), 7.08-7.01 (m, 2H), 6.86- 6.77 (m, 1H), 6.58 (d, J = 15.2 Hz, 1H), 4.67 (t, J = 4.6 Hz, 2H), 4.06 (t, J = 4.7 Hz, 2H), 3.12-3.04 (m, 2H), 2.18 (s, 6H). 53 VIII-14 05 (E)-4-(dimethylamino)- 1-(10-((4-(2- methoxyphenoxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 512 (400 MHz, DMSO-d.sub.6) δ 9.79 (s, 1H), 8.41 (s, 1H), 7.83 (s, 1H), 7.72-7.63 (m, 2H), 7.29 (d, J = 9.0 Hz, 1H), 7.25- 7.16 (m, 2H), 7.08- 7.03 (m, 1H), 7.03-6.95 (m, 1H), 6.95-6.87 (m, 2H), 6.87- 6.76 (m, 1H), 6.57 (d, J = 15.3 Hz, 1H), 4.69-4.61 (m, 2H), 4.05 (t, J = 4.7 Hz, 2H), 3.77 (s, 3H), 3.11-3.04 (m, 2H), 2.17 (s, 6H). 54 VIII-15 06 (E)-4-(dimethylamino)- 1-(10-((4-(pyridin-2- yloxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 483 (400 MHz, DMSO-d.sub.6) δ 9.90 (s, 1H), 8.47 (s, 1H), 8.45 (t, J = 1.8 Hz, 1H), 8.36 (t, J = 3.0 Hz, 1H), 7.85 (d, J = 8.8 Hz, 3H), 7.43 (t, J = 2.3 Hz, 2H), 7.31 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.88-6.76 (m, 1H), 6.58 (d, J = 15.3 Hz, 1H), 4.67 (t, J = 4.7 Hz, 2H), 4.06 (t, J = 4.7 Hz, 2H), 3.08 (d, J = 5.9 Hz, 2H), 2.18 (s, 6H). 55 VIII-16 07 (E)-4-(dimethylamino)- 1-(10-((4-(pyridin-3- yloxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 483 (400 MHz, DMSO-d.sub.6) δ 9.89 (s, 1H), 8.47 (s, 1H), 8.19-8.13 (m, 1H), 7.90- 7.83 (m, 2H), 7.83- 7.78 (m, 2H), 7.31 (d, J = 9.0 Hz, 1H), 7.19-7.15 (m, 2H), 7.15- 7.11 (m, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.86-6.78 (m, 1H), 6.58 (d, J = 15.3 Hz, 1H), 4.68 (t, J = 4.6 Hz, 2H), 4.06 (t, J = 4.6 Hz, 2H), 3.08 (d, J = 5.8 Hz, 2H), 2.18 (s, 6H). 56 VIII-17 08 (E)-4-(dimethylamino)- 1-(10-((4-(3- methoxyphenoxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 512 (400 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 8.46 (s, 1H), 7.96-7.74 (m, 3H), 7.35- 7.24 (m, 2H), 7.15- 7.03 (m, 2H), 6.89-6.75 (m, 1H), 6.74-6.69 (m, 1H), 6.63- 6.52 (m, 3H), 4.72- 4.66 (m, 2H), 4.06 (t, J = 4.6 Hz, 2H), 3.75 (s, 3H), 3.12-3.04 (m, 2H), 2.18 (s, 6H). 57 VIII-18 09 (E)-4-(dimethylamino)- 1-(10-((4-(thiazol-2- yloxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 489 (400 MHz, DMSO-d.sub.6) δ 9.95 (s, 1H), 8.49 (s, 1H), 7.96-7.82 (m, 3H), 7.40 (d, J = 8.9 Hz, 2H), 7.36- 7.28 (m, 2H), 7.23 (d, J = 3.8 Hz, 1H), 6.88-6.76 (m, 1H), 6.64- 6.54 (m, 1H), 4.68 (t, J = 4.6 Hz, 2H), 4.06 (t, J = 4.6 Hz, 2H), 3.08 (d, J = 5.8 Hz, 2H), 2.18 (s, 6H). 58 VIII-7  0 (E)-4-(dimethylamino)- 1-(10-((3-fluoro-4- phenoxyphenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 500 (400 MHz, Methanol-d.sub.4) δ 8.51 (s, 1H), 8.32 (s, 1H), 8.05-8.01 (m, 1H), 7.88- 7.82 (m, 1H), 7.75- 7.72 (m, 1H), 7.51-7.45 (m, 1H), 7.27-7.21 (m, 2H), 7.18- 7.14 (m, 2H), 6.94- 6.87 (m, 2H), 6.70-6.64 (m, 1H), 4.74 (d, J = 4.8 Hz, 2H), 4.17 (t, J = 4.8 Hz, 2H), 3.23-3.19 (m, 2H), 2.33 (s, 6H). 59 VIII-19 (E)-4-(dimethylamino)- 1-(10-((3-chloro-4- phenoxyphenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 516 (400 MHz, DMSO-d.sub.6) δ 9.95 (s, 1H), 8.53 (s, 1H), 8.21 (d, J = 2.6 Hz, 1H), 7.94- 7.76 (m, 2H), 7.45- 7.36 (m, 2H), 7.33 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.00-6.91 (m, 2H), 6.86-6.80 (m, 1H), 6.62- 6.56 (m, 1H), 4.68 (t, J = 4.5 Hz, 2H), 4.06 (t, J = 4.6 Hz, 2H), 3.14-3.06 (m, 2H), 2.18 (s, 6H). 60 VIII-20 (E)-4-(dimethylamino)- 1-(10-((4-((4- fluorobenzyl)oxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 514 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.41 (s, 1H), 7.90-7.72 (m, 1H), 7.70- 7.62 (m, 2H), 7.57- 7.49 (m, 2H), 7.32-7.20 (m, 3H), 7.10-7.02 (m, 2H), 6.87- 6.76 (m, 1H), 6.57 (d, J = 15.3 Hz, 1H), 5.12 (s, 2H), 4.66 (t, J = 4.7 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.11- 3.04 (m, 2H), 2.18 (s, 6H). 61 VIII-21 (E)-4-(dimethylamino)- 1-(10-((4-((3- fluorobenzyl)oxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 514 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.40 (s, 1H), 7.80 (s, 1H), 7.70-7.63 (m, 2H), 7.51-7.40 (m, 1H), 7.35- 7.24 (m, 3H), 7.22- 7.12 (m, 1H), 7.06 (d, J = 8.9 Hz, 2H), 6.87-6.75 (m, 1H), 6.57 (d, J = 15.2 Hz, 1H), 5.17 (s, 2H), 4.65 (t, J = 4.6 Hz, 2H), 4.04 (t, J = 4.6 Hz, 2H), 3.11-3.04 (m, 2H), 2.17 (s, 6H). 62 VIII-22 (E)-4-(dimethylamino)- 1-(10-((4-((3- (trifluoromethylbenzyl) oxy)phenyl)amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 564 (400 MHz, DMSO-d.sub.6) δ 9.77 (s, 1H), 8.41 (s, 1H), 7.86-7.76 (m, 3H), 7.75- 7.61 (m, 4H), 7.28 (d, J = 9.0 Hz, 1H), 7.08 (d, J = 8.9 Hz, 2H), 6.87-6.75 (m, 1H), 6.57 (d, J = 15.3 Hz, 1H), 5.25 (s, 2H), 4.65 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.08 (d, J = 5.8 Hz, 2H), 2.18 (s, 6H). 63 VIII-23 (E)-4-(dimethylamino)- 1-(10-((4-(pyridin-2- ylmethoxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 497 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.63-8.56 (m, 1H), 8.40 (s, 1H), 7.90-7.80 (m, 1H), 7.80 (s, 1H), 7.66 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 7.9 Hz, 1H), 7.40-7.32 (m, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.07 (d, J = 8.9 Hz, 2H), 6.87-6.75 (m, 1H), 6.57 (d, J = 15.3 Hz, 1H), 5.21 (s, 2H), 4.65 (t, J = 4.7 Hz, 2H), 4.04 (t, J = 4.6 Hz, 2H), 3.08 (d, J = 5.8 Hz, 2H), 2.17 (s, 6H). 64 VIII-24 (E)-4-(dimethylamino)- 1-(10-((4-(thiophen-2- ylmethoxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 502 (400 MHz, DMSO-d.sub.6) δ 9.77 (s, 1H), 8.41 (s, 1H), 7.80 (s, 1H), 7.72-7.64 (m, 2H), 7.59-7.53 (m, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.26- 7.21 (m, 1H), 7.11-7.01 (m, 3H), 6.86-6.76 (m, 1H), 6.57 (d, J = 15.1 Hz, 1H), 5.32 (s, 2H), 4.69- 4.62 (m, 2H), 4.09- 4.02 (m, 2H), 3.11-3.04 (m, 2H), 2.17 (s, 6H). 65 VIII-25 (E)-4-(dimethylamino)- 1-(10-((4-(thiazol-2- ylmethoxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 503 (400 MHz, DMSO-d.sub.6) δ 9.78 (s, 1H), 8.41 (s, 1H), 7.86-7.79 (m, 3H), 7.74- 7.65 (m, 2H), 7.28 (d, J = 9.0 Hz, 1H), 7.14-7.07 (m, 2H), 6.87-6.75 (m, 1H), 6.57 (d, J = 15.3 Hz, 1H), 5.47 (s, 2H), 4.66 (t, J = 4.7 Hz, 2H), 4.05 (t, J = 4.7 Hz, 2H), 3.07 (d, J = 5.5 Hz, 2H), 2.17 (s, 6H). 66 VIII-26 (E)-4-(dimethylamino)- 1-(10-((4- (benzylthio)phenyl) amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 512 (400 MHz, DMSO-d.sub.6) δ 9.89 (s, 1H), 8.48 (s, 1H), 7.91-7.76 (m, 3H), 7.42- 7.20 (m, 8H), 6.89- 6.75 (m, 1H), 6.58 (d, J = 15.3 Hz, 1H), 4.67 (t, J = 4.6 Hz, 2H), 4.23 (s, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.12- 3.00 (m, 2H), 2.18 (s, 6H). 67 VIII-3  (E)-4-(dimethylamino)- 1-(10-((4-((3- fluorobenzyl)oxy-3- (trifluoromethyl)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 582 (400 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 8.44 (s, 1H), 8.08 (d, J = 2.6 Hz, 1H), 7.99- 7.93 (m, 1H), 7.84 (s, 1H), 7.54-7.45 (m, 1H), 7.37 (d, J = 9.1 Hz, 1H), 7.34- 7.24 (m, 3H), 7.22-7.15 (m, 1H), 6.86-6.78 (m, 1H), 6.58 (d, J = 15.2 Hz, 1H), 5.34 (s, 2H), 4.69- 4.62 (m, 2H), 4.09- 4.02 (m, 2H), 3.13-3.04 (m, 2H), 2.18 (s, 6H). 68 VIII-27 0 (E)-4-(dimethylamino)- 1-(10-((4-((3- fluorobenzyl)oxy)-3- methoxyphenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 544 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.43 (s, 1H), 7.81 (s, 1H), 7.50-7.40 (m, 2H), 7.35-7.25 (m, 4H), 7.21- 7.11 (m, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.87-6.77 (m, 1H), 6.58 (d, J = 15.3 Hz, 1H), 5.14 (s, 2H), 4.67 (t, J = 4.5 Hz, 2H), 4.09- 4.02 (m, 2H), 3.83 (s, 3H), 3.15-3.03 (m, 2H), 2.18 (s, 6H). 69 VIII-28 (E)-4-(dimethylamino)- 1-(10-((4-((3- fluorobenzyl)oxy)-3- fluorophenyl)amino)-2,3- dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 532 (400 MHz, DMSO-d.sub.6) δ 9.83 (s, 1H), 8.48 (s, 1H), 7.96-7.77 (m, 2H), 7.54- 7.40 (m, 2H), 7.37- 7.15 (m, 5H), 6.89-6.77 (m, 1H), 6.58 (d, J = 15.4 Hz, 1H), 5.23 (s, 2H), 4.73-4.61 (m, 2H), 4.10- 4.00 (m, 2H), 3.14- 3.00 (m, 2H), 2.17 (s, 6H). 70 VIII-29 (E)-4-(dimethylamino)- 1-(10-((4-((4- fluorophenyl)thio)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 516 (400 MHz, DMSO-d.sub.6) δ 9.97 (s, 1H), 8.51 (s, 1H), 7.96-7.82 (m, 3H), 7.43- 7.32 (m, 5H), 7.27- 7.20 (m, 2H), 6.86-6.78 (m, 1H), 6.58 (d, J = 15.2 Hz, 1H), 4.71- 4.64 (m, 2H), 4.09-4.04 (m, 2H), 3.12-3.06 (m, 2H), 2.18 (s, 6H). 71 VIII-30 (E)-4-(dimethylamino)- 1-(10-((4-(2-fluoro-5- methylphenoxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 514 (400 MHz, DMSO-d.sub.6) δ 9.96- 9.72 (m, 1H), 8.43 (s, 1H), 7.98-7.63 (m, 3H), 7.37- 7.15 (m, 2H), 7.10- 6.92 (m, 4H), 6.88-6.70 (m, 1H), 6.67-6.47 (m, 1H), 4.83- 4.47 (m, 2H), 4.14- 3.87 (m, 2H), 3.15-2.94 (m, 2H), 2.35-2.24 (m, 3H), 2.22- 2.00 (s, 6H). 72 VIII-31 (E)-4-(dimethylamino)- 1-(10-((4-(5-chloro-2- fluorophenoxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 534 (400 MHz, DMSO-d.sub.6) δ 9.88 (s, 1H), 8.45 (s, 1H), 7.96-7.67 (m, 3H), 7.47 (dd, J = 10.8, 8.8 Hz, 1H), 7.33-7.24 (m, 2H), 7.22- 7.05 (m, 3H), 6.87- 6.73 (m, 1H), 6.58 (d, J = 15.2 Hz, 1H), 4.66 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.9 Hz, 2H), 3.07 (d, J = 5.8 Hz, 2H), 2.17 (s, 6H). 73 VIII-32 (E)-4-(dimethylamino)- 1-(10-((4-(2,5- difluorophenoxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 518 (400 MHz, DMSO-d.sub.6) δ 9.83 (s, 1H), 8.43 (s, 1H), 8.02-7.61 (m, 3H), 7.57- 7.41 (m, 1H), 7.38- 7.21 (m, 2H), 7.18-7.08 (m, 1H), 7.02 (d, J = 8.6 Hz, 2H), 6.87- 6.72 (m, 1H), 6.57 (d, J = 15.4 Hz, 1H), 4.65 (t, J = 4.6 Hz, 2H), 4.04 (t, J = 4.7 Hz, 2H), 3.07 (d, J = 5.8 Hz, 2H), 2.17 (s, 6H). 74 VIII-33 (E)-4-(dimethylamino)- 1-(10-((4-(1-(3- fluorophenyl)ethoxy) phenyl)amino)-2,3-dihydro- 4H-[1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 528 (400 MHz, DMSO-d.sub.6) δ 9.70 (s, 1H), 8.37 (s, 1H), 7.77 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.47-7.34 (m, 1H), 7.30- 7.14 (m, 3H), 7.14- 7.00 (m, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.85-6.71 (m, 1H), 6.56 (d, J = 15.4 Hz, 1H), 5.61-5.39 (m, 1H), 4.62 (t, J = 4.7 Hz, 2H), 4.02 (t, J = 4.7 Hz, 2H), 3.07 (d, J = 5.8 Hz, 2H), 2.16 (s, 6H), 1.56 (d, J = 6.3 Hz, 3H). 75 VIII-34 (E)-4-(dimethylamino)- 1-(10-((4-(1-(pyridin-2- yl)ethoxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 511 (400 MHz, DMSO-d.sub.6) δ 9.73 (d, J = 19.8 Hz, 1H), 8.66-8.51 (m, 1H), 8.44- 8.29 (m, 1H), 7.88- 7.74 (m, 2H), 7.63-7.51 (m, 2H), 7.45 (d, J = 7.4 Hz, 1H), 7.40- 7.22 (m, 2H), 7.01- 6.88 (m, 2H), 6.88-6.70 (m, 1H), 6.55 (d, J = 18.1 Hz, 1H), 5.62- 5.35 (m, 1H), 4.73-4.54 (m, 2H), 4.11-3.92 (m, 2H), 3.41- 3.33 (m, 3H), 3.06 (d, J = 5.8 Hz, 2H), 2.16 (s, 6H). 76 VIII-35 (E)-4-(dimethylamino)- 1-(10-((4-(pyridin-3- ylmethoxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 497 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.59- 8.51 (m, 1H), 8.40 (s, 1H), 7.93-7.86 (m, 1H), 7.84- 7.70 (m, 1H), 7.70- 7.60 (m, 2H), 7.47-7.38 (m, 1H), 7.32-7.22 (m, 1H), 7.10- 7.00 (m, 2H), 6.84- 6.74 (m, 1H), 6.57 (d, J = 15.2 Hz, 1H), 5.18 (s, 2H), 4.90-4.42 (m, 2H), 4.04 (t, J = 4.7 Hz, 2H), 3.09 (d, J = 5.8 Hz, 2H), 2.23-2.02 (s, 6H). 77 VIII-36 (E)-4-(dimethylamino)- 1-(10-((4-(pyridin-4- ylmethoxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 497 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.59 (d, J = 5.1 Hz, 2H), 8.40 (s, 1H), 7.80 (s, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 5.0 Hz, 2H), 7.27 (d, J = 9.0 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.90- 6.73 (m, 1H), 6.57 (d, J = 15.3 Hz, 1H), 5.22 (s, 2H), 4.65 (t, J = 4.6 Hz, 2H), 4.04 (t, J = 4.6 Hz, 2H), 3.08 (d, J = 6.1 Hz, 2H), 2.17 (s, 6H). 78 VIII-41 0 (E)-1-(10-((4- (benzyloxy)phenyl)amino)- 2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)-4- (dimethylamino)but-2- en-1-one 496 (400 MHz, DMSO-d.sub.6) δ 9.75 (s, 1H), 8.40 (s, 1H), 7.80 (s, 1H), 7.67-7.63 (m, 2H), 7.49-7.45 (m, 2H), 7.43- 7.38 (m, 2H), 7.36- 7.33 (m, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.07-7.03 (m, 2H), 6.84- 6.77 (m, 1H), 6.62- 6.53 (m, 1H), 5.13 (s, 2H), 4.65 (t, J = 4.4 Hz, 2H), 4.04 (t, J = 4.4 Hz, 2H), 3.09 (d, J = 5.6 Hz, 2H), 2.18 (s, 6H). 79 VIII-42 (E)-4-(dimethylamino)- 1-(10-((4-((2- fluorobenzyl)oxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 514 (400 MHz, DMSO-d.sub.6) δ 9.77 (s, 1H), 8.40 (s, 1H), 7.80 (s, 1H), 7.69-7.65 (m, 2H), 7.60-7.56 (m, 1H), 7.46- 7.40 (m, 1H), 7.29- 7.26 (m, 2H), 7.25-7.23 (m, 1H), 7.08-7.05 (m, 2H), 6.85- 6.77 (m, 1H), 6.60- 6.53 (m, 1H), 5.17 (s, 2H), 4.65 (t, J = 4.4 Hz, 2H), 4.04 (t, J = 4.4 Hz, 2H), 3.07 (dd, J = 6.0, 1.6 Hz, 2H), 2.17 (s, 6H). 80 VIII-43 (E)-4-(dimethylamino)- 1-(10-((4-((2- chlorobenzyl)oxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 530 (400 MHz, DMSO-d.sub.6) δ 9.77 (s, 1H), 8.40 (s, 1H), 7.80 (s, 1H), 7.68-7.66 (m, 2H), 7.64-7.60 (m, 1H), 7.54- 7.51 (m, 1H), 7.42- 7.39 (m, 2H), 7.28 (d, J = 9.0 Hz, 1H), 7.08-7.05 (m, 2H), 6.85- 6.77 (m, 1H), 6.57 (d, J = 15.2 Hz, 1H), 5.19 (s, 2H), 4.65 (t, J = 4.6 Hz, 2H), 4.04 (t, J = 4.6 Hz, 2H), 3.07 (dd, J = 6.0, 1.6 Hz, 2H), 2.17 (s, 6H). 81 VIII-44 (E)-4-(dimethylamino)- 1-(10-((4-((2- methylbenzyl)oxy)phenyl) amino)-2,3-dihydro- 4H-[1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 510 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.40 (s, 1H), 7.79 (s, 1H), 7.67-7.63 (m, 2H), 7.43 (d, J = 7.2 Hz, 1H), 7.29- 7.21 (m, 4H), 7.09- 7.05 (m, 2H), 6.84-6.77 (m, 1H), 6.57 (d, J = 15.2 Hz, 1H), 5.11 (s, 2H), 4.65 (t, J = 4.4 Hz, 2H), 4.04 (t, J = 4.4 Hz, 2H), 3.07 (dd, J = 6.0, 1.6 Hz, 2H), 2.35 (s, 3H), 2.17 (s, 6H). 82 VIII-45 (E)-4-(dimethylamino)- 1-(10-((4-((2- methoxybenzyl)oxy) phenyl)amino)-2,3-dihydro- 4H-[1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 526 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.40 (s, 1H), 7.80 (s, 1H), 7.66-7.63 (m, 2H), 7.41 (dd, J = 7.2, 1.6 Hz, 1H), 7.37-7.32 (m, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.08- 7.05 (m, 1H), 7.04- 7.01 (m, 2H), 7.00-6.95 (m, 1H), 6.85-6.77 (m, 1H), 6.57 (d, J = 15.2 Hz, 1H), 5.08 (s, 2H), 4.65 (t, J = 4.6 Hz, 2H), 4.04 (t, J = 4.6 Hz, 2H), 3.84 (s, 3H), 3.07 (dd, J = 6.0, 1.6 Hz, 2H), 2.17 (s, 6H). 83 VIII-46 (E)-1-(10-((4-((3- chlorobenzyl)oxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)-4- (dimethylamino)but-2- en-1-one 530 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.40 (s, 1H), 7.79 (s, 1H), 7.66 (d, J = 9.0 Hz, 2H), 7.57-7.48 (m, 1H), 7.48- 7.34 (m, 3H), 7.27 (d, J = 9.0 Hz, 1H), 7.07-6.99 (m, 2H), 6.88-6.70 (m, 1H), 6.57 (d, J = 15.2 Hz, 1H), 5.16 (s, 2H), 4.65 (t, J = 4.7 Hz, 2H), 4.04 (t, J = 4.6 Hz, 2H), 3.14-2.97 (m, 2H), 2.17 (s, 6H). 84 VIII-47 (E)-4-(dimethylamino)- 1-(10-((4-((3- methylbenzyl)oxy)phenyl) amino)-2,3-dihydro- 4H-[1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 510 (400 MHz, DMSO-d.sub.6) δ 9.75 (s, 1H), 8.40 (s, 1H), 7.80 (s, 1H), 7.66-7.63 (m, 2H), 7.29-7.25 (m, 4H), 7.16- 7.13 (m, 1H), 7.05- 7.02 (m, 2H), 6.84-6.77 (m, 1H), 6.57 (d, J = 15.2 Hz, 1H), 5.09 (s, 2H), 4.65 (t, J = 4.4 Hz, 2H), 4.04 (t, J = 4.4 Hz, 2H), 3.07 (dd, J = 6.0, 1.6 Hz, 2H), 2.33 (s, 3H), 2.17 (s, 6H). 85 VIII-48 (E)-4-(dimethylamino)- 1-(10-((4-((3- cyanobenzyl)oxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 521 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.40 (s, 1H), 7.94-7.92 (m, 1H), 7.86- 7.78 (m, 3H), 7.68- 7.65 (m, 2H), 7.65-7.61 (m, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.08- 7.05 (m, 2H), 6.85- 6.78 (m, 1H), 6.57 (d, J = 15.2 Hz, 1H), 5.20 (s, 2H), 4.65 (t, J = 4.6 Hz, 2H), 4.04 (t, J = 4.6 Hz, 2H), 3.07 (dd, J = 6.0, 1.6 Hz, 2H), 2.17 (s, 6H). 86 VIII-49 (E)-4-(dimethylamino)- 1-(10-((4-((3- methoxybenzyl)oxy) phenyl) amino)-2,3-dihydro- 4H-[1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 526 (400 MHz, DMSO-d.sub.6) δ 9.75 (s, 1H), 8.40 (s, 1H), 7.79 (s, 1H), 7.67-7.57 (m, 2H), 7.38-7.19 (m, 2H), 7.10- 6.95 (m, 4H), 6.94- 6.74 (m, 2H), 6.57 (d, J = 15.3 Hz, 1H), 5.11 (s, 2H), 4.68-4.57 (m, 2H), 4.04 (t, J = 4.7 Hz, 2H), 3.77 (s, 3H), 3.10-2.99 (m, 2H), 2.17 (s, 6H). 87 VIII-50 (E)-4-(dimethylamino)- 1-(10-((4-((4- chlorobenzyl)oxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 530 (400 MHz, DMSO-d.sub.6) δ 9.76 (s, 1H), 8.40 (s, 1H), 7.80 (s, 1H), 7.67-7.64 (m, 2H), 7.51-7.49 (m, 2H), 7.47- 7.45 (m, 2H), 7.27 (d, J = 9.0 Hz, 1H), 7.06-7.02 (m, 2H), 6.84-6.77 (m, 1H), 6.57 (d, J = 15.2 Hz, 1H), 5.14 (s, 2H), 4.65 (t, J = 4.6 Hz, 2H), 4.04 (t, J = 4.6 Hz, 2H), 3.07 (dd, J = 6.0, 1.6 Hz, 2H), 2.17 (s, 6H). 88 VIII-51 0 (E)-4-(dimethylamino)- 1-(10-((4-((4- methylbenzyl)oxy)phenyl) amino)-2,3-dihydro- 4H-[1,4]oxazino[2,3- f]quinazolin-4-yl)but-2- en-1-one 510 (400 MHz, DMSO-d.sub.6) δ 9.75 (s, 1H), 8.39 (s, 1H), 7.79 (s, 1H), 7.65-7.62 (m, 2H), 7.35 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 7.6 Hz, 2H), 7.04-7.01 (m, 2H), 6.84- 6.77 (m. 1H), 6.57 (d, J = 15.2 Hz, 1H), 5.08 (s, 2H), 4.65 (t, J = 4.4 Hz, 2H), 4.04 (t, J = 4.4 Hz, 2H), 3.07 (dd, J = 6.0, 1.6 Hz, 2H), 2.31 (s, 3H), 2.17 (s, 6H). 89 VIII-52 (E)-1-(10-((4-((2,5- difluorobenzyl)oxy)phenyl) amino)-2,3-dihydro- 4H-[1,4]oxazino[2,3- f]quinazolin-4-yl)-4- (dimethylamino)but-2- en-1-one 532 (400 MHz, DMSO-d.sub.6) δ 9.78 (s, 1H), 8.41 (s, 1H), 7.80 (s, 1H), 7.72-7.64 (m, 2H), 7.47-7.37 (m, 1H), 7.38- 7.20 (m, 3H), 7.12- 7.02 (m, 2H), 6.88-6.75 (m, 1H), 6.57 (d, J = 15.3 Hz, 1H), 5.16 (s, 2H), 4.65 (t, J = 4.7 Hz, 2H), 4.04 (t, J = 4.7 Hz, 2H), 3.13-3.02 (m, 2H), 2.17 (s, 6H). 90 VIII-53 (E)-1-(10-((4-((2-chloro- 5- fluorobenzyl)oxy)phenyl) amino)-2,3-dihydro-4H- [1,4]oxazino[2,3- f]quinazolin-4-yl)-4- (dimethylamino)but-2- en-1-one 548 (400 MHz, DMSO-d.sub.6) δ 9.78 (s, 1H), 8.41 (s, 1H), 7.80 (s, 1H), 7.73-7.62 (m, 2H), 7.63-7.53 (m, 1H), 7.53- 7.41 (m, 1H), 7.36- 7.17 (m, 2H), 7.14-7.02 (m, 2H), 6.88-6.73 (m, 1H), 6.57 (d, J = 15.3 Hz, 1H), 5.18 (s, 2H), 4.65 (t, J = 4.7 Hz, 2H), 4.04 (t, J = 4.7 Hz, 2H), 3.13-3.00 (m, 2H), 2.18 (s, 6H).

Example 91: Preparation of (E)-1-(10-((4-phenoxyphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(pyrrolidin-1-yl)but-2-en-1-one

(37) ##STR00243##

(38) N-(4-phenoxyphenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-1) (185 mg, 0.5 mmol) was dissolved in a mixed solvent of dichloromethane and dimethylformamide, to which 4-bromocrotonyl chloride (91 mg, 0.5 mmol) was added, and stirred at room temperature until the reaction was completed. The reaction was quenched with water, extracted with ethyl acetate, the organic phase was concentrated and directly dissolved in acetonitrile, to which diisopropylethylamine (129 mg, 1 mmol) and pyrrolidine (67 mg, 1 mmol) were added, and stirred at room temperature until the reaction was completed. The reaction was quenched by adding water, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel column chromatography to afford 63 mg of a off-white solid with a yield of 25%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 8.46 (s, 1H), 7.84-7.78 (m, 3H), 7.44-7.37 (m, 2H), 7.32-7.28 (m, 1H), 7.16-7.11 (m, 1H), 7.10-7.06 (m, 2H), 7.05-7.00 (m, 2H), 6.90-6.82 (m, 1H), 6.62-6.55 (m, 1H), 4.67 (t, J=4.4 Hz, 2H), 4.05 (t, J=4.4 Hz, 2H), 3.27-3.23 (m, 2H), 2.49-2.45 (m, 4H), 1.72-1.67 (m, 4H); MS: 508[M+H].sup.+.

Examples 92-111

(39) ##STR00244##

(40) With reference to the preparation method of Example 91, wherein exactly the same operations were used, and N-(4-phenoxyphenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-1) was replaced with the same molar equivalent of intermediate represented by formula (VIII) wherein R.sup.1X is the substituent in the table below and pyrrolidine was replaced with equivalent molar equivalent of

(41) ##STR00245##
The specific example compounds are shown in the table below:

(42) TABLE-US-00004 Example compound Example No. Starting Intermediate No. R.sup.1X Name LCMS m/z = (M + H).sup.+ HNMR 92 VIII-1 (E)-4- (diethylamino)- 1-(10-((4- phenoxyphenyl) amino)-2,3- dihydro-4H- 510 (400 M, CDCl.sub.3) δ 9.55 (s, 1H), 8.62 (s, 1H), 7.70- 7.68 (m, 2H), 7.61 (brs, 1H), 7.47-7.45 (m, 1H), [1,4]oxazino[2, 7.38-7.35 (m, 2H), 3-f]quinazolin- 7.15-7.05 (m, 6H), 4-yl)but-2-en- 6.72-6.64 (m, 1H), 1-one 4.70 (s, 2H), 4.22 (s, 2H), 3.64 (br, 2H), 3.02-2.98 (m, 2H), 1.66 (br, 2H), 1.31- 1.27 (m, 6H) 93 VIII-1 0 (E)-1-(10-((4- phenoxyphenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2, 3-f]quinazolin- 4-yl)-4- 522 (400 M, DMSO- d.sub.6) δ 9.87 (s, 1H), 8.45 (s, 1H), 7.81- 7.79 (m, 3H), 7.42- 7.38 (m, 2H), 7.30- 7.28 (m, 1H), 7.15- 7.01 (m, 5H), 6.84- (piperidin-1- 6.80 (m, 1H), 6.60- yl)but-2-en-1- 6.56 (m, 1H), 4.69- one 4.63 (m, 2H), 4.09- 4.03 (m, 2H), 3.14- 3.08 (m, 2H), 2.39- 2.33 (m, 4H), 1.49- 1.47 (m, 4H), 1.42- 1.36 (m, 2H) 94 VIII-1 (E)-4- morpholino-1- (10-((4- phenoxyphenyl) amino)-2,3- dihydro-4H- 524 (300 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 8.45 (s, 1H), 7.88-7.73 (m, 3H), 7.44- 7.36 (m, 2H), 7.30 [1,4]oxazino[2, (d, J = 9.0 Hz, 1H), 3-f]quinazolin- 7.16-7.00 (m, 4-yl)but-2-en- 5H), 6.79 (s, 1H), 1-one 6.68-6.53 (m, 1H), 4.71-4.58 (m, 2H), 4.09- 4.03 (m, 2H), 3.57 (t, J = 4.6 Hz, 4H), 3.14 (d, J = 5.5 Hz, 2H), 2.43-2.34 (m, 4H). 95 VIII-1 (E)-4-(4- methylpiperazin- 1-yl)-1-(10- ((4- phenoxyphenyl) amino)-2,3- dihydro-4H- 537 (400 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 8.46 (s, 1H), 7.86-7.72 (m, 3H), 7.42- 7.38 (m, 2H), 7.30 (d, J = 8.9 Hz, 1H), [1,4]oxazino[2, 7.13 (t, J = 7.4 Hz, 3-f]quinazolin- 1H), 7.10-7.06 4-yl)but-2-en- (m, 2H), 7.05- 1-one 7.00 (m, 2H), 6.85- 6.76 (m, 1H), 6.59 (d, J = 15.2 Hz, 1H), 4.67 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.14 (d, J = 5.7 Hz, 2H), 2.49-2.22 (m, 8H), 2.17 (s, 3H). 96 VIII-4 (E)-1-(10-((3- chloro-4-((3- fluorobenzyl) oxy)phenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2, 3-f]quinazolin- 4-yl)-4- morpholinobut- 590 (400 MHz, DMSO-d.sub.6) δ 9.82 (s, 1H), 8.47 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.90- 7.74 (m, 1H), 7.70- 7.65 (m, 1H), 7.52-7.44 (m, 1H), 7.35-7.24 (m, 4H), 7.22- 2-en-1-one 7.15 (m, 1H), 6.85- 6.77 (m, 1H), 6.66-6.56 (m, 1H), 5.27 (s, 2H), 4.66 (t, J = 4.4 Hz, 2H), 4.04 (t, J = 4.4 Hz, 2H), 3.61- 3.55 (m, 4H), 3.17- 3.11 (m, 2H), 2.44-2.36 (m, 4H) 97 VIII-6 (E)-1-(10-((2- fluoro-4- phenoxyphenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2, 540 (400 MHz, Methanol-d.sub.4) δ 8.77-8.65 (m, 1H), 8.48-8.41 (m, 1H), 7.69- 7.47 (m, 1H), 7.38- 3-f]quinazolin- 7.29 (m, 2H), 4-yl)-4- 7.28-7.13 (m, (piperidin-1- 2H), 7.06-6.95 yl)but-2-en-1- (m, 2H), 6.94- one 6.86 (m, 1H), 6.86- 6.71 (m, 2H), 6.68-6.61 (m, 1H), 5.39 (s, 2H), 4.38-4.25 (m, 2H), 3.76-3.67 (m, 2H), 3.08- 2.91 (m, 4H), 1.64- 1.45 (m, 6H). 98 VIII-7 0 (E)-1-(10-((3- fluoro-4- phenoxyphenyl) amino)-2,3- dihydro-4H- [1,4]oxazino[2, 540 (400 MHz, Methanol-d.sub.4) δ 8.51 (s, 1H), 8.08- 7.99 (m, 1H), 7.93- 7.79 (m, 1H), 7.51-7.45 (m, 3-f]quinazolin- 1H), 7.40-7.30 4-yl)-4- (m, 3H), 7.17- (piperidin-1- 6.97 (m, 4H), 6.94- yl)but-2-en-1- 6.87 (m, 1H), one 6.66 (d, J = 15.2 4.65 (m, 2H), 4.21- 4.13 (m, 2H), 3.25-3.19 (m, 2H), 2.58-2.42 (m, 4H), 1.68- 1.60 (m, 4H), 1.55- 1.47 (m, 2H). 99 VIII-8 (E)-1-(10-((4- (2- fluorophenoxy) phenyl)amino)- 2,3-dihydro- 4H- 558 (400 MHz, Methanol-d.sub.4) δ 8.45-8.40 (m, 1H), 7.77-7.69 (m, 3H), 7.40- 7.34 (m, 2H), 7.30- [1,4]oxazino[2, 7.26 (m, 1H), 3-f]quinazolin- 7.23-7.19 (m, 4-yl)-4-((4- 2H), 7.07-7.02 methoxybutyl) (m, 2H), 7.02- amino)but-2- 6.94 (m, 1H), 6.82- en-1-one 6.74 (m, 1H), 4.84-4.69 (m, 2H), 4.19-4.14 (m, 2H), 3.70 (s, 3H), 3.19-3.12 (m, 2H), 2.94- 2.83 (m, 2H), 2.32- 2.14 (m, 2H), 1.69-1.66 (m, 4H). 100 VIII-5 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 557 (400 MHz, DMSO-d.sub.6) δ 9.82 (s, 1H), 8.64-8.55 (m, 1H), 8.46 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.95- 7.73 (m, 2H), 7.70- 7.62 (m, 1H), 3-f]quinazolin- 7.58 (d, J = 7.8 Hz, 4-yl)-4- 1H), 7.42-7.34 (cyclopropyl (m, 1H), 7.32- (methyl)amino) 7.16 (m, 2H), 6.89- but-2-en-1-one 6.78 (m, 1H), 6.55 (d, J = 15.2 Hz, 1H), 5.31 (s, 2H), 4.65 (t, J = 4.6 Hz, 2H), 4.04 (t, J = 4.7 Hz, 2H), 3.32- 3.29 (m, 2H), 2.27 (s, 3H), 1.78- 1.72 (m, 1H), 0.49- 0.23 (m, 4H). 101 VIII-5 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 543 (400 MHz, DMSO-d.sub.6) δ 9.82 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.90- 7.87 (m, 1H), 7.66 (d, J = 6.2 Hz, 1H), 3-f]quinazolin- 7.58 (d, J = 7.8 Hz, 4-yl)-4- 1H), 7.50-7.48 (cyclopropylamino) (m, 1H), 7.39- but-2-en- 7.36 (m, 1H), 7.31- 1-one 7.28 (m, 1H), 7.27-7.25 (m, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.57 (d, J = 14.8 Hz, 1H), 5.31 (s, 2H), 4.64 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.1 Hz, 2H), 3.51- 3.50 (m, 1H), 3.42- 3.41 (m, 2H), 2.68-2.66 (m, 1H), 0.41-0.37 (m, 2H), 0.27- 0.23 (m, 2H). 102 VIII-5 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 545 (400 MHz, DMSO-d.sub.6) δ 9.83 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.47 (s, 1H), 8.01 (d, J = 2.8 Hz, 1H), 7.92- 7.80 (m, 2H), 7.67 (dd, J = 8.8, 2.8 Hz, 3-f]quinazolin- 1H), 7.58 (d, J = 4-yl)-4- 7.8 Hz, 1H), 7.39- (isopropylamino) 7.35 (m, 1H), 7.33- but-2-en-1- 7.25 (m, 2H), one 6.89-6.80 (m, 1H), 6.80-6.68 (m, 1H), 5.31 (s, 2H), 4.67 (t, J = 4.6 Hz, 2H), 4.07 (t, J = 4.6 Hz, 2H), 3.68- 3.62 (m, 2H), 3.31-3.31 (m, 1H), 2.68-2.66 (m, 1H), 1.14 (d, J = 6.4 Hz, 6H). 103 VIII-5 0 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 573 (400 MHz, DMSO-d.sub.6) δ 9.83 (s, 1H), 8.62-8.58 (m, 1H), 8.47 (s, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.93- 7.78 (m, 2H), 7.68- 7.63 (m, 1H), 3-f]quinazolin- 7.61-7.56 (m, 4-yl)-4- 1H), 7.41-7.35 morpholinobut- (m, 1H), 7.33- 2-en-1-one 7.24 (m, 2H), 6.86- 6.77 (m, 1H), 6.72-6.60 (m, 1H), 5.31 (s, 2H), 4.66 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.70- 3.60 (m, 4H), 3.18- 3.12 (m, 2H), 2.66-2.51 (m, 4H). 104 VIII-5 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 586 (400 MHz, DMSO-d.sub.6) δ 9.82 (s, 1H), 8.64-8.56 (m, 1H), 8.46 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.93- 7.86 (m, 1H), 7.86- 7.68 (m, 1H), 3-f]quinazolin- 7.68-7.63 (m, 4-yl)-4-(4- 1H), 7.58 (d, J = methylpiperazin- 7.8 Hz, 1H), 7.43- 1-yl)but-2- 7.33 (m, 1H), 7.33- en-1-one 7.23 (m, 2H), 6.87-6.75 (m, 1H), 6.70-6.52 (m, 1H), 5.31 (s, 2H), 4.66 (t, J = 4.5 Hz, 2H), 4.04 (t, J = 4.6 Hz, 2H), 3.14 (d, J = 5.7 Hz, 2H), 2.52-2.30 (m, 8H), 2.22 (s, 3H). 105 VIII-5 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 559 (400 MHz, DMSO-d.sub.6) δ 9.84 (s, 1H), 8.63-8.59 (m, 1H), 8.47 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.93- 7.86 (m, 1H), 7.79- 7.61 (m, 2H), 3-f]quinazolin- 7.58 (d, J = 7.8 Hz, 4-yl)-4- 1H), 7.41-7.35 (diethylamino) (m, 1H), 7.34- but-2-en-1-one 7.24 (m, 2H), 6.90- 6.61 (m, 2H), 5.32 (s, 2H), 4.68 (t, J = 4.7 Hz, 2H), 4.06 (t, J = 4.7 Hz, 2H), 3.39-3.31 (m, 6H), 1.18- 0.97 (m, 6H). 106 VIII-5 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 557 (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.61 (d, J = 4.8 Hz, 1H), 8.47 (s, 1H), 8.03-8.00 (m, 1H), 7.92- 7.84 (m, 2H), 7.69- 7.65 (m, 1H), 3-f]quinazolin- 7.60-7.57 (m, 4-yl)-4- 1H), 7.39-7.35 (pyrrolidin-1- (m, 1H), 7.32- yl)but-2-en-1- 7.25 (m, 2H), 6.88- one 6.82 (m, 1H), 6.61-6.56 (m, 1H), 5.32 (s, 2H), 4.66 (t, J = 4.7 Hz, 2H), 4.05 (t, 2H), 3.36-3.30 (m, 2H), 2.61-2.53 (m, 4H), 1.78- 1.68 (m, 4H). 107 VIII-5 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 571 (400 MHz, DMSO-d.sub.6) δ 9.83 (s, 1H), 8.63-8.56 (m, 1H), 8.47 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.92- 7.71 (m, 2H), 7.72- 7.65 (m, 1H), 3-f]quinazolin- 7.59 (d, J = 7.8 Hz, 4-yl)-4- 1H), 7.42-7.34 (piperidin-1- (m, 1H), 7.34- yl)but-2-en-1- 7.23 (m, 2H), 6.92- one 6.61 (m, 2H), 5.31 (s, 2H), 4.68 (t, J = 4.7 Hz, 2H), 4.07 (t, J = 4.6 Hz, 2H), 3.36-3.30 (m, 4H), 1.86- 1.30 (m, 8H). 108 VIII-5 0 (E)-4-(4- acetylpiperazin- 1-yl)-1-(10- ((3-chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 614 (400 MHz, DMSO-d.sub.6) δ 9.86 (s, 1H), 8.65-8.56 (m, 1H), 8.47 (s, 1H), 8.00 (s, 1H), 7.96-7.72 (m, 2H), 7.71-7.63 (m, 1H), 7.58 (d, J = 4H- 7.8 Hz, 1H), 7.41- [1,4]oxazino[2, 7.35 (m, 1H), 3-f]quinazolin- 7.35-7.23 (m, 4-yl)but-2-en- 2H), 6.88-6.77 1-one (m, 1H), 6.75- 6.58 (m, 1H), 5.31 (s, 2H), 4.67 (t, J = 4.7 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.52-3.35 (m, 6H), 2.79-2.51 (m, 4H), 2.00 (s, 3H). 109 VIII-5 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 557 (400 MHz, DMSO-d.sub.6) δ 9.83 (s, 1H), 8.63-8.59 (m, 1H), 8.50- 8.45 (m, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.93-7.82 (m, 2H), 7.71-7.65 3-f]quinazolin- (m, 1H), 7.58 (d, J = 4-yl)-4- 7.8 Hz, 1H), 7.41- (cyclobutylamino) 7.35 (m, 1H), but-2-en-1- 7.33-7.24 (m, one 2H), 6.91-6.83 (m, 1H), 6.59 (d, J = 13.9 Hz, 1H), 5.32 (s, 2H), 4.65 (t, J = 4.6 Hz, 2H), 4.10-4.00 (m, 2H), 3.35-3.34 (m, 1H), 3.32 (d, J = 6.3 Hz, 2H), 3.24- 3.20 (m, 1H), 2.13-2.04 (m, 2H), 1.70 (d, J = 9.1 Hz, 2H), 1.65- 1.55 (m, 2H). 110 VIII-5 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 571 (400 MHz, DMSO-d.sub.6) δ 9.83 (s, 1H), 8.64-8.59 (m, 1H), 8.46 (s, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.94- 7.77 (m, 2H), 7.70- 7.63 (m, 1H), 3-f]quinazolin- 7.58 (d, J = 7.8 Hz, 4-yl)-4- 1H), 7.41-7.34 (cyclobutyl (m, 1H), 7.31- (methyl)amino) 7.24 (m, 2H), 6.87- but-2-en-1-one 6.77 (m, 1H), 6.62-6.52 (m, 1H), 5.31 (s, 2H), 4.66 (t, J = 4.6 Hz, 2H), 4.04 (t, J = 4.6 Hz, 2H), 3.03 (d, J = 5.9 Hz, 2H), 2.90- 2.80 (m, 1H), 2.04 (s, 3H), 2.01- 1.92 (m, 2H), 1.82- 1.71 (m, 2H), 1.64-1.53 (m, 2H). 111 VIII-5 (E)-1-(10-((3- chloro-4- (pyridin-2- ylmethoxy) phenyl)amino)- 2,3-dihydro- 4H- [1,4]oxazino[2, 559 (400 MHz, DMSO-d.sub.6) δ 9.83 (s, 1H), 8.63-8.58 (m, 1H), 8.46 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.92- 7.86 (m, 1H), 7.80 (s, 1H), 7.69-7.64 3-f]quinazolin- (m, 1H), 7.58 (d, J = 4-yl)-4- 7.8 Hz, 1H), 7.41- (isopropyl 7.35 (m, 1H), (methyl)amino)but- 7.31-7.25 (m, 2-en-1-one 2H), 6.86-6.77 (m, 1H), 6.64- 6.55 (m, 1H), 5.31 (s, 2H), 4.66 (t, J = 4.6 Hz, 2H), 4.04 (t, J = 4.7 Hz, 2H), 3.22-3.18 (m, 2H), 2.87-2.76 (m, 1H), 2.13 (s, 3H), 0.96 (d, J = 6.5 Hz, 6H).

Example 112

Preparation of (S,E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one

(43) ##STR00287##

Step 1) Preparation of diethyl (2-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-2-oxoethyl)phosphate

(44) ##STR00288##

(45) N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-5)(210 mg, 0.5 mmol), 2-(diethoxyphosphoryl)acetic acid (0.5 mmol) were dissolved in tetrahydrofuran, to which N,N′-carbonyldiimidazole (81 mg, 0.5 mmol) was added, stirred at room temperature until the reaction was completed. Water and ethyl acetate were added for extraction, the organic phase was concentrated and purified using column chromatography to afford 253 mg of yellow solid with a yield of 85%. MS: 598[M+H].sup.+.

Step 2) Preparation of (S,E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one

(46) diethyl (2-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-2-oxoethyl)phosphate (253 mg, 0.43 mmol) was dissolved in tetrahydrofuran, which was cooled to −78° C., and 1 mol/1 of toluene solution of bistrimethylsilylamide lithium (0.83 mL, 0.83 mmol) was added dropwise, and stirred until the all of the materials were disappeared. (S)-1-methylpyrrolidinyl-2-carbaldehyde (48.6 mg, 0.43 mmol) was added, the reaction was warmed to room temperature and stirred until the reaction was completed. Water and ethyl acetate were added for extraction, the organic phase was concentrated and purified using column chromatography to afford 167 mg of off-white solid with a yield of 70%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.82 (s, 1H), 8.65-8.56 (m, 1H), 8.46 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.95-7.72 (m, 2H), 7.71-7.61 (m, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.40-7.32 (m, 1H), 7.32-7.26 (m, 2H), 6.77-6.64 (m, 1H), 6.64-6.48 (m, 1H), 5.31 (s, 2H), 4.66 (s, 2H), 4.16-3.92 (m, 2H), 3.09-2.94 (m, 1H), 2.91-2.74 (m, 1H), 2.29-2.11 (m, 4H), 2.06-1.91 (m, 1H), 1.82-1.64 (m, 2H), 1.62-1.44 (m, 1H); MS: 557[M+H].sup.+.

Example 113

Preparation of 1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)but-2-yne-1-one

(47) ##STR00289##

(48) But-2-ynoic acid (42 mg, 0.5 mmol) was dissolved in dichloromethane, and 0.05 mL of dimethylformamide was added dropwise, which was cooled in an ice bath and then oxalyl chloride (32 mg, 0.25 mmol) was added. After stirring for 0.5 h, N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-5)(210 mg, 0.5 mmol) was added, and the reaction was warmed to room temperature and stirred until the reaction was completed. The reaction was quenched by potassium carbonate aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated and purified using column chromatography to afford 75 mg of off-white solid product, with a yield of 31%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.82 (s, 1H), 8.63-8.59 (m, 1H), 8.46 (s, 1H), 8.40-8.34 (m, 1H), 8.01-7.97 (m, 1H), 7.92-7.86 (m, 1H), 7.69-7.63 (m, 1H), 7.60-7.57 (m, 1H), 7.40-7.36 (m, 1H), 7.33-7.25 (m, 2H), 5.34-5.28 (m, 2H), 4.76-4.68 (m, 2H), 4.28 (s, 2H), 2.14 (s, 3H). MS: 486[M+H].sup.+.

Example 114: Preparation of (R,E)-1-(10-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one

Step 1): Preparation of diethyl (2-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-2-oxoethyl)phosphonate

(49) ##STR00290##

(50) N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (210 mg, 0.5 mmol), 2-(diethoxyphosphoryl)acetic acid (98 mg, 0.5 mmol) were dissolved in tetrahydrofuran, to which N,N′-carbonyldiimidazole (81 mg, 0.5 mmol) was added, the solution was stirred in a 40° C. oil bath until the reaction was completed. Water and ethyl acetate were added for extraction, the organic phase was concentrated and purified using column chromatography to afford 254 mg of yellow solid with a yield of 85%. MS: 598[M+H].sup.+.

Step 2) Preparation of (R,E)-1-(10-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-3-(1-methylpyrrolidinyl-2-yl)prop-2-en-1-one

(51) ##STR00291##

(52) diethyl (2-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-2-oxoethyl)phosphonate (254 mg, 0.43 mmol) was dissolved in tetrahydrofuran, cooled to −78° C., and 1 mol/1 of toluene solution of bistrimethylsilylamide lithium (0.65 mL, 0.65 mmol) was added dropwise, which was stirred until the all of the materials were disappeared. (R)-1-methylpyrrolidinyl-2-carbaldehyde (48.6 mg, 0.43 mmol) was added, and the reaction was warmed to room temperature and stirred until the reaction was completed. Water and ethyl acetate were added for extraction, the organic phase was concentrated and separated by high performance liquid chromatography to afford 154 mg of white solid with a yield of 65%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.82 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.92-7.74 (m, 2H), 7.69-7.64 (m, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.40-7.34 (m, 1H), 7.31-7.24 (m, 2H), 6.73-6.66 (m, 1H), 6.55 (d, J=15.4 Hz, 1H), 5.31 (s, 2H), 4.70-4.63 (m, 2H), 4.11-3.97 (m, 2H), 2.99 (d, J=8.2 Hz, 1H), 2.82-2.74 (m, 1H), 2.20 (s, 3H), 2.16 (d, J=8.7 Hz, 1H), 2.06-1.92 (m, 1H), 1.71 (d, J=9.4 Hz, 2H), 1.63-1.49 (m, 1H); MS: 557[M+H].sup.+.

Example 115: Preparation of (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-hydroxypiperidin-1-yl)but-2-en-1-one

(53) ##STR00292##

(54) N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (210 mg, 0.5 mmol) was dissolved in dimethylformamide, to which 4-bromocrotonyl chloride (91 mg, 0.5 mmol) was added, and stirred at room temperature until the reaction was completed. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was concentrated and directly dissolved in acetonitrile, to which diisopropylethylamine (129 mg, 1 mmol) and piperidin-4-ol (101 mg, 1 mmol) were added, and stirred at room temperature until the reaction was completed. The reaction was quenched by the addition of water, extracted with ethyl acetate, and the organic phase was concentrated and purified by high performance liquid chromatography to afford 97 mg of white solid with a yield of 33%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.81 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.92-7.85 (m, 1H), 7.81 (s, 1H), 7.71-7.63 (m, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.41-7.33 (m, 1H), 7.28 (t, J=9.4 Hz, 2H), 6.86-6.76 (m, 1H), 6.57 (d, J=15.4 Hz, 1H), 5.31 (s, 2H), 4.66 (t, J=4.6 Hz, 2H), 4.50 (d, J=4.1 Hz, 1H), 4.04 (t, J=4.7 Hz, 2H), 3.44 (s, 1H), 3.11 (d, J=5.6 Hz, 2H), 2.69 (d, J=12.0 Hz, 2H), 2.07 (t, J=10.7 Hz, 2H), 1.70 (d, J=12.4 Hz, 2H), 1.37 (d, J=11.1 Hz, 2H); MS: 587[M+H].sup.+.

Example 116: Preparation of (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-hydroxyl-4-methylpiperidin-1-yl)but-2-en-1-one

(55) ##STR00293##

(56) It was prepared by a method similar to that of Example 115, except that piperidin-4-ol was replaced by the same molar equivalent of 4-methylpiperidin-4-ol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.81 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.45 (s, 1H), 8.00 (s, 1H), 7.94-7.72 (m, 2H), 7.69-7.61 (m, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.41-7.32 (m, 1H), 7.26 (t, J=8.7 Hz, 2H), 6.86-6.74 (m, 1H), 6.62-6.46 (m, 1H), 5.30 (s, 2H), 4.65 (t, J=4.7 Hz, 2H), 4.10 (s, 1H), 4.03 (t, J=4.8 Hz, 2H), 3.19-3.06 (m, 2H), 2.46-2.28 (m, 4H), 1.51-1.26 (m, 4H), 1.08 (s, 3H); MS: 601[M+H].sup.+.

Example 117: Preparation of (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)but-2-en-1-one

(57) ##STR00294##

(58) It was prepared by a method similar to that of Example 115, except that piperidin-4-ol was replaced by the same molar equivalent of piperidin-4-ylmethanol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.81 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.88 (t, J=8.0 Hz, 2H), 7.70-7.62 (m, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.40-7.33 (m, 1H), 7.28 (t, J=9.4 Hz, 2H), 6.87-6.75 (m, 1H), 6.57 (d, J=15.3 Hz, 1H), 5.31 (s, 2H), 4.66 (d, J=5.0 Hz, 2H), 4.37 (t, J=5.3 Hz, 1H), 4.04 (s, 2H), 3.23 (t, J=5.9 Hz, 2H), 3.12 (d, J=5.7 Hz, 2H), 2.83 (d, J=11.1 Hz, 2H), 1.92 (t, J=11.4 Hz, 2H), 1.63 (d, J=12.6 Hz, 2H), 1.37-1.25 (m, 1H), 1.18-1.04 (m, 2H); MS: 601[M+H].sup.+.

Example 118: Preparation of (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-fluoropiperidin-1-yl)but-2-en-1-one

(59) ##STR00295##

(60) It was prepared by a method similar to that of Example 115, except that piperidin-4-ol was replaced by the same molar equivalent of 4-fluoropiperidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.81 (s, 1H), 8.63-8.57 (m, 1H), 8.46 (s, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.93-7.76 (m, 2H), 7.70-7.62 (m, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.40-7.34 (m, 1H), 7.32-7.22 (m, 2H), 6.87-6.77 (m, 1H), 6.59 (d, J=15.2 Hz, 1H), 5.31 (s, 2H), 4.66 (t, J=4.7 Hz, 3H), 4.04 (t, J=4.4 Hz, 2H), 3.15 (d, J=5.6 Hz, 2H), 2.55 (d, J=6.9 Hz, 2H), 2.34 (s, 2H), 1.91-1.77 (m, 2H), 1.70 (s, 2H); MS: 589[M+H].sup.+.

Example 119: Preparation of (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one

(61) ##STR00296##

(62) It was prepared by a method similar to that of Example 115, except that piperidin-4-ol was replaced by the same molar equivalent of N-(2-methoxyethyl)methylamine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.81 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.93-7.73 (m, 2H), 7.70-7.61 (m, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.42-7.31 (m, 1H), 7.31-7.18 (m, 2H), 6.87-6.73 (m, 1H), 6.64-6.51 (m, 1H), 5.30 (s, 2H), 4.65 (t, J=4.7 Hz, 2H), 4.04 (t, J=4.7 Hz, 2H), 3.40 (t, J=5.8 Hz, 2H), 3.24-3.14 (m, 5H), 2.55-2.51 (m, 2H), 2.21 (s, 3H); MS: 575[M+H].sup.+.

Example 120: Preparation of (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((3-hydroxypropyl)(methyl)amino)but-2-en-1-one

(63) ##STR00297##

(64) It was prepared by a method similar to that of Example 115, except that piperidin-4-ol was replaced by the same molar equivalent of 3-(methylamino)-1-propanol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.81 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.92-7.76 (m, 2H), 7.71-7.63 (m, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.37 (t, J=6.3 Hz, 1H), 7.32-7.23 (m, 2H), 6.88-6.77 (m, 1H), 6.58 (d, J=15.2 Hz, 1H), 5.31 (s, 2H), 4.65 (d, J=4.8 Hz, 2H), 4.39 (s, 1H), 4.04 (t, J=4.6 Hz, 2H), 3.44 (d, J=5.8 Hz, 2H), 3.15 (d, J=5.7 Hz, 2H), 2.39 (t, J=7.3 Hz, 2H), 2.17 (s, 3H), 1.62-1.52 (m, 2H); MS: 575[M+H].sup.+.

Example 121: Preparation of (S,E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(2,4-dimethylpiperazin-1-yl)but-2-en-1-one

(65) ##STR00298##

(66) It was prepared by a method similar to that of Example 115, except that piperidin-4-ol was replaced by the same molar equivalent of (S)-1,3-dimethylpiperazine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.80 (s, 1H), 8.59 (d, J=4.7 Hz, 1H), 8.45 (s, 1H), 8.00 (d, J=2.6 Hz, 1H), 7.87 (t, J=7.7, 1.9 Hz, 1H), 7.84-7.69 (m, 1H), 7.69-7.62 (m, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.41-7.32 (m, 1H), 7.26 (t, J=9.3 Hz, 2H), 6.89-6.78 (m, 1H), 6.65-6.51 (m, 1H), 5.29 (s, 2H), 4.72-4.56 (m, 2H), 4.13-3.90 (m, 2H), 3.55-3.41 (m, 1H), 3.05-2.94 (m, 1H), 2.72-2.62 (m, 1H), 2.58-2.52 (m, 1H), 2.47-2.30 (m, 2H), 2.28-2.20 (m, 1H), 2.10 (s, 3H), 2.04-1.96 (m, 1H), 1.74 (t, J=10.1 Hz, 1H), 0.96 (d, J=6.2 Hz, 3H); MS: 600[M+H].sup.+.

Example 122: Preparation of (E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((2-hydroxyethyl)(methyl)amino)but-2-en-1-one

(67) ##STR00299##

(68) It was prepared by a method similar to that of Example 115, except that piperidin-4-ol was replaced by the same molar equivalent of 2-methylaminoethanol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.81 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.91-7.79 (m, 2H), 7.70-7.63 (m, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.37 (t, J=6.3 Hz, 1H), 7.34-7.23 (m, 2H), 6.89-6.78 (m, 1H), 6.61 (d, J=15.5 Hz, 1H), 5.31 (s, 2H), 4.66 (t, J=4.5 Hz, 2H), 4.38 (t, J=5.4 Hz, 1H), 4.05 (t, J=4.7 Hz, 2H), 3.52-3.44 (m, 2H), 3.20 (d, J=5.7 Hz, 2H), 2.44 (t, J=6.3 Hz, 2H), 2.22 (s, 3H); MS: 561[M+H].sup.+.

Example 123: Preparation of (R,E)-1-(10-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(2,4-dimethylpiperazin-1-yl)but-2-en-1-one

(69) ##STR00300##

(70) It was prepared by a method similar to that of Example 115, except that piperidin-4-ol was replaced by the same molar equivalent of (R)-1,3-dimethylpiperazine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.82 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.46 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.92-7.72 (m, 2H), 7.71-7.63 (m, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.37 (t, J=6.3 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 6.90-6.80 (m, 1H), 6.66-6.51 (m, 1H), 5.31 (s, 2H), 4.72-4.59 (m, 2H), 4.13-3.95 (m, 2H), 3.50 (d, J=15.7 Hz, 1H), 3.13-2.96 (m, 2H), 2.70 (d, J=13.2 Hz, 1H), 2.54 (s, 1H), 2.41 (s, 1H), 2.26 (t, J=10.6 Hz, 1H), 2.11 (s, 3H), 2.04 (d, J=11.1 Hz, 1H), 1.76 (s, 1H), 0.97 (d, J=6.2 Hz, 3H); MS: 600[M+H].sup.+.

Example 124: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(dimethylamino)but-2-en-1-one

(71) ##STR00301##

(72) N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (213 mg, 0.5 mmol) was dissolved in dimethylformamide, to which (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (137 mg, 0.75 mmol) was added at room temperature, and stirred at room temperature until the reaction was completed. The reaction was quenched by the addition of potassium carbonate aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated and purified by high performance liquid chromatography to afford 200 mg of white solid with a yield of 75%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.93 (s, 1H), 8.94 (d, J=7.5 Hz, 1H), 8.50 (s, 1H), 8.38 (s, 1H), 7.97-7.69 (m, 3H), 7.32 (d, J=9.0 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.08-6.98 (m, 1H), 6.87-6.72 (m, 2H), 6.64-6.52 (m, 1H), 4.69 (t, J=4.6 Hz, 2H), 4.06 (t, J=4.5 Hz, 2H), 3.14-3.01 (m, 2H), 2.33-2.03 (m, 9H); MS: 537[M+H]*.

Example 125: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(dimethylamino)but-2-en-1-one

(73) ##STR00302##

(74) N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (223 mg, 0.5 mmol) was dissolved in dimethylformamide, to which (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (137 mg, 0.75 mmol) was added at room temperature, and stirred at room temperature until the reaction was completed. The reaction was quenched by the addition of potassium carbonate aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated and purified by high performance liquid chromatography to afford 195 mg of white solid with a yield of 70%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.03 (s, 1H), 8.97 (d, J=7.3 Hz, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 8.32 (d, J=2.5 Hz, 1H), 7.98-7.93 (m, 1H), 7.93-7.73 (m, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.34 (d, J=9.1 Hz, 1H), 7.11-7.02 (m, 1H), 6.92 (d, J=2.6 Hz, 1H), 6.87-6.77 (m, 1H), 6.65-6.52 (m, 1H), 4.69 (t, 2H), 4.06 (t, J=4.7 Hz, 2H), 3.11-3.02 (m, 2H), 2.17 (s, 6H); MS: 557[M+H].sup.+.

Example 126: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-methylpiperazin-1-yl)but-2-en-1-one

(75) ##STR00303##

(76) N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (223 mg, 0.5 mmol) was dissolved in dimethylformamide, to which 4-bromocrotonyl chloride (91 mg, 0.5 mmol) was added, and stirred at room temperature until the reaction was completed. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was concentrated and directly dissolved in acetonitrile, to which diisopropylethylamine (129 mg, 1 mmol) and 1-methylpiperazine (100 mg, 1 mmol) were added, and stirred at room temperature until the reaction was completed. The reaction was quenched by the addition of water, extracted with ethyl acetate, the organic phase was concentrated and purified by high-performance liquid chromatography to afford a white solid 125 mg with a yield of 41%. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.66 (d, J=7.5 Hz, 1H), 8.46-8.38 (m, 2H), 8.21-8.18 (m, 2H), 7.73 (d, J=2.6 Hz, 1H), 7.71 (d, J=2.6 Hz, 1H), 7.29-7.24 (m, 2H), 7.00-6.96 (m, 1H), 6.91-6.83 (m, 1H), 6.74 (d, J=2.5 Hz, 1H), 6.58 (d, J=15.3 Hz, 1H), 4.64 (t, J=4.7 Hz, 2H), 4.06 (t, 2H), 3.18 (dd, J=6.1, 1.6 Hz, 2H), 2.76-2.62 (m, 4H), 2.61-2.45 (m, 4H), 2.40 (s, 3H); MS: 612[M+H].sup.+.

Example 127: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(isopropyl(methyl)amino)but-2-en-1-one

(77) ##STR00304##

(78) It was prepared by a method similar to that of Example 126, except that 1-methylpiperazine was replaced by the same molar equivalent of N-isopropylmethylamine. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.65 (d, J=7.5 Hz, 1H), 8.40 (d, J=1.7 Hz, 2H), 8.22-8.16 (m, 2H), 7.79-7.68 (m, 2H), 7.29-7.22 (m, 2H), 6.99-6.95 (m, 1H), 6.92-6.85 (m, 1H), 6.73 (d, J=2.6 Hz, 1H), 6.68-6.62 (m, 1H), 4.64 (t, J=4.7 Hz, 2H), 4.06 (t, J=4.7 Hz, 2H), 3.41 (dd, J=6.6, 1.4 Hz, 2H), 3.06-2.98 (m, 1H), 2.30 (s, 3H), 1.06 (d, J=6.6 Hz, 6H); MS: 585[M+H].sup.+.

Example 128: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(piperidin-1-yl)but-2-en-1-one

(79) ##STR00305##

(80) It was prepared by a method similar to that of Example 126, except that 1-methylpiperazine was replaced by the same molar equivalent of piperidine. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.67 (d, J=7.5 Hz, 1H), 8.43 (s, 2H), 8.23-8.18 (m, 2H), 7.73 (dd, J=8.8, 2.6 Hz, 2H), 7.30-7.25 (m, 2H), 6.99 (dd, J=7.5, 2.6 Hz, 1H), 6.93-6.84 (m, 1H), 6.75 (d, J=2.6 Hz, 1H), 6.63 (d, J=15.3 Hz, 1H), 4.65 (t, J=4.7 Hz, 2H), 4.07 (t, J=4.7 Hz, 2H), 3.38-3.31 (m, 2H), 2.62 (s, 4H), 1.64-1.57 (m, 4H), 1.48-1.40 (m, 2H); MS: 597[M+H].sup.+.

Example 129: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one

(81) ##STR00306##

(82) It was prepared by a method similar to that of Example 126, except that 1-methylpiperazine was replaced by the same molar equivalent of N-methylcyclobutylamine hydrochloride. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.66 (dd, J=7.4, 0.6 Hz, 1H), 8.42 (s, 1H), 8.40 (s, 1H), 8.24-8.17 (m, 2H), 7.72 (dd, J=8.8, 2.6 Hz, 2H), 7.30-7.24 (m, 2H), 7.00-6.96 (m, 1H), 6.93-6.85 (m, 1H), 6.74 (d, J=2.6 Hz, 1H), 6.58 (d, J=15.2 Hz, 1H), 4.65 (t, J=4.6 Hz, 2H), 4.06 (t, 2H), 3.16 (dd, J=6.7, 1.4 Hz, 2H), 3.00-2.91 (m, 1H), 2.14 (s, 3H), 2.06-1.98 (m, 2H), 1.90-1.79 (m, 2H), 1.69-1.57 (m, 2H); MS: 597[M+H].sup.+.

Example 130: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one

(83) ##STR00307##

(84) It was prepared by a method similar to that of Example 126, except that 1-methylpiperazine was replaced by the same molar equivalent of N-(2-methoxyethyl)methylamine. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.79 (dd, J=7.5, 0.7 Hz, 1H), 8.56 (s, 1H), 8.34-8.32 (m, 2H), 7.94-7.89 (m, 1H), 7.88-7.87 (m, 1H), 7.86-7.85 (m, 1H), 7.41 (dd, J=8.9, 4.0 Hz, 2H), 7.12 (dd, J=7.5, 2.6 Hz, 1H), 7.07-6.99 (m, 1H), 6.89-6.87 (m, 1H), 6.71 (d, J=15.3 Hz, 1H), 4.77 (t, J=4.8 Hz, 2H), 4.19 (t, J=4.7 Hz, 2H), 3.55 (t, J=5.5 Hz, 2H), 3.35 (t, 2H), 3.35 (s, 3H), 2.68 (t, J=5.5 Hz, 2H), 2.37 (s, 3H); MS: 601 [M+H].sup.+.

Example 131: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chlorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(diethylamino)but-2-en-1-one

(85) ##STR00308##

(86) It was prepared by a method similar to that of Example 126, except that 1-methylpiperazine was replaced by the same molar equivalent of diethylamine. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.79 (dd, J=7.5, 0.7 Hz, 1H), 8.56 (s, 1H), 8.33 (s, 1H), 8.32 (d, J=2.5 Hz, 1H), 7.91-7.88 (m, 1H), 7.88-7.86 (m, 1H), 7.86 (d, J=2.6 Hz, 1H), 7.43-7.39 (m, 2H), 7.13-7.10 (m, 1H), 7.09-7.01 (m, 1H), 6.88-6.87 (m, 1H), 6.70 (d, J=15.3 Hz, 1H), 4.77 (t, J=4.7 Hz, 2H), 4.20-4.16 (m, 2H), 3.39 (dd, J=6.3, 1.5 Hz, 2H), 2.64 (q, J=7.2 Hz, 4H), 1.12 (t, J=7.2 Hz, 6H); MS: 585 [M+H].sup.+.

Example 132: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(4-methylpiperazin-1-yl)but-2-en-1-one

(87) ##STR00309##

(88) N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (212 mg, 0.5 mmol) was dissolved in dimethylformamide, to which 4-bromocrotonyl chloride (91 mg, 0.5 mmol) was added, and stirred at room temperature until the reaction was completed. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was concentrated and directly dissolved in acetonitrile, to which diisopropylethylamine (129 mg, 1 mmol) and 1-methylpiperazine (100 mg, 1 mmol) were added, and stirred at room temperature until the reaction was completed. The reaction was quenched by the addition of water, extracted with ethyl acetate, and the organic phase was concentrated and purified by high performance liquid chromatography to afford 110 mg of a white solid with a yield of 37%. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.77 (d, J=7.5 Hz, 1H), 8.49 (s, 1H), 8.31 (s, 1H), 7.88-7.83 (m, 1H), 7.83-7.80 (m, 2H), 7.79-7.77 (m, 1H), 7.38 (d, J=9.1 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.12-7.09 (m, 1H), 7.03-6.96 (m, 1H), 6.84 (d, J=2.5 Hz, 1H), 6.70 (d, J=15.3 Hz, 1H), 4.76 (t, J=4.7 Hz, 2H), 4.18 (t, J=4.7 Hz, 2H), 3.30-3.28 (m, 2H), 2.78-2.55 (m, 8H), 2.45 (s, 3H), 2.27 (s, 3H); MS: 592 [M+H].sup.+.

Example 133: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(isopropyl(methyl)amino)but-2-en-1-one

(89) ##STR00310##

(90) It was prepared by a method similar to that of Example 132, except that 1-methylpiperazine was replaced by the same molar equivalent of N-isopropylmethylamine. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.76 (d, J=7.5 Hz, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.89-7.83 (m, 1H), 7.81 (t, J=2.4 Hz, 2H), 7.78 (d, J=2.7 Hz, 1H), 7.40-7.36 (m, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.12-7.08 (m, 1H), 7.06-6.98 (m, 1H), 6.84 (d, J=2.6 Hz, 1H), 6.71 (d, J=15.2 Hz, 1H), 4.76 (t, J=4.7 Hz, 2H), 4.18 (t, J=4.7 Hz, 2H), 3.41-3.39 (m, 2H), 3.03-2.96 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 1.13 (s, 3H), 1.12 (s, 3H); MS: 565 [M+H].sup.+.

Example 134: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(piperidin-1-yl)but-2-en-1-one

(91) ##STR00311##

(92) It was prepared by a method similar to that of Example 132, except that 1-methylpiperazine was replaced by the same molar equivalent of piperidine. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.64 (d, J=7.5 Hz, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.79-7.75 (m, 1H), 7.70-7.67 (m, 2H), 7.66 (d, J=2.7 Hz, 1H), 7.26 (d, J=9.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.00-6.96 (m, 1H), 6.89-6.82 (m, 1H), 6.75 (s, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.66 (d, J=4.7 Hz, 2H), 4.10-4.05 (m, 2H), 3.63 (d, J=6.6 Hz, 2H), 2.97-2.86 (m, 4H), 2.15 (s, 3H), 1.75-1.67 (m, 4H), 1.57-1.50 (m, 2H); MS: 577 [M+H].sup.+.

Example 135: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one

(93) ##STR00312##

(94) It was prepared by a method similar to that of Example 132, except that 1-methylpiperazine was replaced by the same molar equivalent of N-methylcyclobutylamine hydrochloride. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.74 (d, J=7.5 Hz, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 7.88-7.81 (m, 1H), 7.80-7.75 (m, 2H), 7.34 (d, J=9.1 Hz, 1H), 7.19-7.16 (m, 1H), 7.09-7.05 (m, 1H), 7.02-6.94 (m, 1H), 6.84-6.75 (m, 2H), 4.75 (t, J=4.6 Hz, 2H), 4.18 (t, J=4.6 Hz, 2H), 3.56 (d, J=6.8 Hz, 2H), 3.42-3.37 (m, 1H), 2.66 (d, J=9.4 Hz, 2H), 2.49 (s, 3H), 2.24 (s, 3H), 2.17-2.09 (m, 2H), 1.85-1.75 (m, 2H); MS: 577 [M+H].sup.+.

Example 136: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one

(95) ##STR00313##

(96) It was prepared by a method similar to that of Example 132, except that 1-methylpiperazine was replaced by the same molar equivalent of N-(2-methoxyethyl)methylamine. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.76 (dd, J=7.6, 0.7 Hz, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.93-7.83 (m, 1H), 7.83-7.80 (m, 2H), 7.79-7.77 (m, 1H), 7.38 (d, J=9.1 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.12-7.08 (m, 1H), 7.07-6.99 (m, 1H), 6.85-6.83 (m, 1H), 6.70 (d, J=15.3 Hz, 1H), 4.76 (t, J=4.7 Hz, 2H), 4.18 (t, 2H), 3.57-3.52 (m, 2H), 3.35-3.34 (m, 5H), 2.67 (t, J=5.5 Hz, 2H), 2.35 (s, 3H), 2.27 (s, 3H); MS: 581 [M+H].sup.+.

Example 137: Preparation of (E)-1-(10-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-4-(diethylamino)but-2-en-1-one

(97) ##STR00314##

(98) It was prepared by a method similar to that of Example 132, except that 1-methylpiperazine was replaced by the same molar equivalent of diethylamine. .sup.1H NMR (400 MHz, MeOH-d.sub.4) δ 8.76 (dd, J=7.5, 0.7 Hz, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.84-7.80 (m, 2H), 7.78 (d, J=2.7 Hz, 1H), 7.38 (d, J=9.1 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.12-7.10 (m, 1H), 7.10-7.08 (m, 1H), 7.07-7.01 (m, 1H), 6.84 (dd, J=2.7, 0.7 Hz, 1H), 6.70 (d, J=15.3 Hz, 1H), 4.77 (t, J=4.7 Hz, 2H), 4.19 (d, J=4.7 Hz, 2H), 3.41-3.39 (m, 2H), 2.67-2.63 (m, 4H), 2.27 (s, 3H), 1.12 (t, J=7.1 Hz, 6H); MS: 565 [M+H].sup.+.

Assay Example 1

(99) The assay for the inhibition of EGFR and HER2 kinase activity by small molecular compounds was carried out using the method as follows:

(100) 1) Dilution of the compounds

(101) In a 96-well plate a, the compounds were diluted with DMSO using a 3-fold gradient dilution to form 11 concentrations, the 12th concentration is pure DMSO (as a positive control); and in a new 96-well plate b the above solutions were diluted 25 times with ultrapure water (DMSO concentration is 4%).

(102) 2) Transferring the compounds to 384-well plate

(103) The compound solutions diluted with ultrapure water in the 96-well plate b above was transferred to the corresponding wells of a 384-well plate in duplicate.

(104) 3) Addition of 4×kinase solution: 2.5 μl of the above 4× kinase solution was taken using multichannel pipette and added to the corresponding reaction wells of the 384-well plate, mixed well and pre-reacted at room temperature for 5 minutes.

(105) 4) Addition of 2×substrate/ATP mixed solution: 5 μl of the above 2×substrate/ATP mixed solution was taken using multichannel pipette and added to the corresponding reaction wells of the 384-well plate.

(106) 5) Negative control: negative control wells were set in the 384-well plate, and 2.5 μl 4×substrate, 2.5 μl 4×enzyme solution, 2.5 μl 1×Kinase Assay Buffer and 2.5 μl ultrapure water containing 4% DMSO were added to each well.

(107) 6) Mixed by centrifugation and kept at room temperature for 2 hours in the dark.

(108) 7) Termination of the enzymatic reaction:

(109) 5 μl of the above 4× stop solution was pipetted to the corresponding wells of the 384-well plate, centrifuged and mixed, and reacted at room temperature for 5 minutes.

(110) 8) Development reaction:

(111) 5 μl of the above 4× detection solution was pipetted into the corresponding wells of the 384-well plate, centrifuged and mixed, and reacted at room temperature for 1 hour.

(112) 9) The 384-well plate was placed into a microplate reader and the signal was detected using the corresponding program.

(113) 10) IC.sub.50 analysis:
Well reading value=10000*EU665 value/EU615 value
Inhibition rate=(reading value of positive control well−reading value of experimental well)/(reading value of positive control well−reading value of negative control well)*100%
Corresponding IC.sub.50s can be calculated by entering the drug concentrations and the corresponding inhibition rates into GraphPad Prism 5.

(114) Conditions of experiment for screening EGFR kinase inhibitory molecules:

(115) The final concentration of EGFR kinase in the reaction system is 0.35 nM, and the final concentration of ATP is 150 μM, the final concentration of substrate ULight™-labeled JAK-1 (Tyr1023) Peptide is 100 nM, and the enzymatic reaction time is 2 hours.

(116) The maximum final concentration of the compound in the reaction system is 2.5 μM, 11 concentrations were made with a 3-fold gradient dilution, and the minimal final concentration is 0.042 nM. The final concentration of DMSO is 1%.

(117) Conditions of experiment for screening HER2 kinase inhibitory molecules:

(118) The final concentration of HER2 kinase in the reaction system is 10 nM, the final concentration of ATP is 10 μM, the final concentration of substrate ULight™-labeled PolyGT is 100 nM, and the enzymatic reaction time is 2 hours.

(119) The maximum final concentration of the compound in the reaction system is 2.5 μM, 11 concentrations were made with a 3-fold gradient dilution, and the minimal final concentration is 0.042 nM. The final concentration of DMSO is 1%.

(120) Assay results of the inhibitory activity of some compounds disclosed herein on tyrosine kinases were listed in Table (1), wherein A means IC.sub.50 is less than or equal to 50 nM, B means IC.sub.50 is greater than 50 nM but less than or equal to 500 nM, C means IC.sub.50 is greater than 500 nM but less than or equal to 5000 nM, D means IC.sub.50 is greater than 5000 nM, and NT means that the compound was not tested for the corresponding kinase.

(121) Table (1), assay results of the inhibitory activity of the compounds disclosed herein on EGFR and HER2 kinases

(122) TABLE-US-00005 Example No. HER2 IC.sub.50 nM EGFR IC.sub.50 nM 1 A NT 2 A A 3 A A 4 A A 5 A NT 6 A NT 7 A NT 8 A NT 9 A NT 10 A NT 11 A NT 12 A NT 13 A NT 14 A NT 15 A NT 16 A NT 17 A NT 18 A NT 19 A NT 20 A NT 21 A NT 22 A NT 23 A NT 24 A NT 25 A NT 26 A NT 27 A NT 28 A NT 29 A NT 30 A NT 31 B NT 32 A NT 33 A A 34 A A 35 A A 36 A NT 37 A A 38 A NT 39 A A 40 A A 41 A A 42 A A 43 A A 44 A A 45 A A 46 A A 47 A A 48 A A 49 A A 50 A A 51 A A 52 A A 53 A A 54 A C 55 A C 56 A A 57 A B 58 A NT 59 A A 60 A A 61 A A 62 A A 63 A B 64 A B 65 A A 66 A A 67 A A 68 A A 69 A A 70 A A 71 A A 72 A A 73 A B 74 A B 75 A B 76 A C 77 A C 78 A NT 79 A NT 80 A NT 81 A NT 82 A NT 83 A A 84 A NT 85 A NT 86 A NT 87 A NT 88 A NT 89 A NT 90 A NT 91 A A 92 A A 93 A A 94 A A 95 A A 96 A A 97 A NT 98 A NT 99 A B 100 A NT 101 B NT 102 A NT 103 A NT 104 A A 105 A A 106 A A 107 A A 108 A A 109 A NT 110 A A 111 A A 112 A NT 113 A NT 114 A NT 115 A NT 116 A NT 117 A NT 118 A NT 119 A NT 120 A NT 121 A NT 122 A NT 123 A NT 124 A B 125 A B 126 A A 127 A B 128 A B 129 A B 130 A B 131 A B 132 A B 133 A C 134 A B 135 A B 136 A B 137 A C

Assay Example 2

(123) The assay for the inhibition of cell proliferation by small molecular compounds was carried out using the method as follows:

(124) 1. 600 μL pancreatin was added to a T75 cell culture flask, which was digested in a 37° C. incubator for about 1 min before 5 mL of DMEM complete culture solution was added, blew evenly, transferred to a 15 mL centrifuge tube, and centrifuged at 1000 rpm for 4 min;

(125) 2. The supernatant was removed and 5 mL DMEM complete culture solution was added, blew evenly, and 10 μL cell suspension was taken and mixed with 10 μL 0.4% Trypan Blue, and counted using a cell counter;

(126) 3. BT474 and HCC827 cell lines were seeded in 96-well plates at a cell density of 10,000 and 3000 cells/well/80 μL, respectively, and cultured overnight. Only sterile water was added to the 36 wells on the periphery of the 96-well plate without adding cells, and only the 60 wells in the center of the 96-well plate were used for cell assays and controls;

(127) 4. Dilution of compounds: the compounds were diluted with a 3-fold dilution to make 10 concentrations in total with an initial concentration of 10 mM;

(128) 5. 20 μL of different compounds with different concentrations were added to each well, and 20 μL of complete culture solution was added to the remaining wells. The final concentration of DMSO in each well is 0.25%;

(129) 6. After 72 h of incubation, 10 μL CCK-8 reagent was added to each well, and incubated at 37° C. for 1-2 h; and the OD value was read at 450 nm;

(130) 7. Cell survival rate (%)=[(As−Ab)/(Ac−Ab)]*100%

(131) As: Assay well (medium containing cell, CCK-8, compound)

(132) Ac: Control well (medium containing cell, CCK-8)

(133) Ab: Blank well (CCK-8, medium without cell and compound)

(134) 8. The value was imported into Graphpad Prism5 software for the calculation of IC.sub.50s (compound concentration at which 50% maximum survival rate is observed).

(135) Table (2) lists the assay results of representative compounds disclosed herein on the viability of BT474 and HCC827 cancer cells. Wherein A means IC.sub.50 is less than or equal to 50 nM, B means IC.sub.50 is greater than 50 nM but less than or equal to 500 nM, C means IC.sub.50 is greater than 500 nM but less than or equal to 5000 nM, D means IC.sub.50 is greater than 5000 nM, and NT means that the compound was not tested for the corresponding cell.

(136) TABLE-US-00006 TABLE 2 Assay results of representative compounds disclosed herein on cell viability Example No. BT474 IC.sub.50 HCC827 IC.sub.50 44 A C 46 A B 47 A C 48 B C 49 A B 50 A C 51 A C 53 A C 54 A C 55 A C 56 A C 57 A C 58 A B 59 A C 60 A C 61 A D 62 B D 63 A C 64 A B 65 A B 66 A C 68 A C 69 A C 70 A NT 71 A C 72 A B 73 A C 74 A C 76 A B 78 A C 79 A C 80 A C 81 A C 82 A C 83 A C 84 A B 85 A C 86 A C 87 B C 88 A C 89 A C 90 A C 91 A C 92 A C 93 A B 94 A C 95 A B 96 A B 100 A B 101 NT C 102 A B 103 A B 104 A B 105 A B 106 A B 107 A C 108 A B 109 A B 110 A B 111 A C 112 A B 113 B C 114 A NT 115 A NT 116 A B 117 A NT 118 A NT 119 A B 120 A NT 121 A NT 122 A NT 123 A NT 124 A NT 125 A NT 126 A NT 127 A NT 128 A NT 129 A NT 130 A NT 131 A NT 132 A NT 133 A NT 134 A NT 135 A NT 136 A NT 137 A NT

(137) The biological data provided by the present disclosure indicates that the compounds of the present disclosure have extremely strong inhibitory ability on HER2 kinase and HER2 expressing cells, which are beneficial to the treatment or prevention of diseases caused by abnormality of HER2 kinase. Another feature of the compound of the present disclosure is that its ability to inhibit cells with EGFR expression is relatively weak, thereby greatly reducing side effects caused by excessive inhibition of EGFR.

(138) The above is a preferred embodiment of the present disclosure, and it should be noted that those skilled in the art can make various improvements and modifications to the embodiments of the present disclosure without departing from the principles of the present disclosure. These improvements and modifications are also considered to be within the scope of the disclosure.