unless otherwise stated , the following terms used in the specification and claims have the meanings discussed below . “ alkyl ” refers to a saturated aliphatic hydrocarbon group including c 1 - c 20 straight chain and branched chain groups . preferably an alkyl group is an alkyl having 1 to 12 carbon atoms . representative examples include , but are not limited to methyl , ethyl , n - propyl , isopropyl , n - butyl , isobutyl , tert - butyl , sec - butyl , n - pentyl , 1 , 1 - dimethyl propyl , 1 , 2 - dimethyl propyl , 2 , 2 - dimethyl propyl , 1 - ethyl propyl , 2 - methylbutyl , 3 - methylbutyl , n - hexyl , 1 - ethyl - 2 - methylpropyl , 1 , 1 , 2 - trimethylpropyl , 1 , 1 - dimethylbutyl , 1 , 2 - dimethylbutyl , 2 , 2 - dimethylbutyl , 1 , 3 - dimethylbutyl , 2 - ethylbutyl , 2 - methylpentyl , 3 - methylpentyl , 4 - methylpentyl , 2 , 3 - dimethylbutyl , n - heptyl , 2 - methylhexyl , 3 - methylhexyl , 4 - methylhexyl , 5 - methylhexyl , 2 , 3 - dimethylpentyl , 2 , 4 - dimethylpentyl , 2 , 2 - dimethylpentyl , 3 , 3 - dimethylpentyl , 2 - ethylpentyl , 3 - ethylpentyl , n - octyl , 2 , 3 - dimethylhexyl , 2 , 4 - dimethylhexyl , 2 , 5 - dimethylhexyl , 2 , 2 - dimethylhexyl , 3 , 3 - dimethylhexyl , 4 , 4 - dimethylhexyl , 2 - ethylhexyl , 3 - ethylhexyl , 4 - ethylhexyl , 2 - methyl - 2 - ethylpentyl , 2 - methyl - 3 - ethylpentyl , n - nonyl , 2 - methyl - 2 - ethylhexyl , 2 - methyl - 3 - ethylhexyl , 2 , 2 - diethylpentyl , n - decyl , 3 , 3 - diethylhexyl , 2 , 2 - diethylhexyl , and the isomers of branched chain thereof . more preferably an alkyl group is a lower alkyl having 1 to 6 carbon atoms . representative examples include , but are not limited to methyl , ethyl , n - propyl , isopropyl , n - butyl , isobutyl , tert - butyl , sec - butyl , n - pentyl , 1 , 1 - dimethylpropyl , 1 , 2 - dimethylpropyl , 2 , 2 - dimethylpropyl , 1 - ethylpropyl , 2 - methylbutyl , 3 - methylbutyl , n - hexyl , 1 - ethyl - 2 - methylpropyl , 1 , 1 , 2 - trimethylpropyl , 1 , 1 - dimethylbutyl , 1 , 2 - dimethylbutyl , 2 , 2 - dimethylbutyl , 1 , 3 - dimethylbutyl , 2 - ethylbutyl , 2 - methylpentyl , 3 - methylpentyl , 4 - methylpentyl , 2 , 3 - dimethylbutyl and etc . the alkyl group may be substituted or unsubstituted . when substituted , the substituent group ( s ) is preferably one or more groups independently selected from the group consisting of alkyl , alkenyl , alkynyl , alkoxyl , alkylsulfo , alkylamino , halogen , thiol , hydroxyl , nitro , cyano , cycloalkyl , heterocyclic alkyl , aryl , heteroaryl , cycloalkoxyl , heterocylic alkoxyl , cycloalkylthio , heterocylic alkylthio , carbonyl , carboxy or carboxylic ester . “ cycloalkyl ” refers to saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group and have 3 to 20 carbon atoms . preferably a cycloalkyl group is a cycloalkyl having 3 to 12 carbon atoms . more preferably a cycloalkyl group is a cycloalkyl having 3 to 10 carbon atoms . representative examples of monocyclic cycloalkyl include , but are not limited to cyclopropyl , cyclobutyl , cyclopentyl , cyclopentenyl , cyclohexyl , cyclohexenyl , cyclohexadienyl , cycloheptyl , cycloheptatrienyl , cyclooctyl and etc . polycyclic cycloalkyl includes the cycloalkyl having spiro ring , fused ring and bridged ring . “ spiro cycloalkyl ” refers to 5 to 20 membered polycyclic hydrocarbon group with rings connected through one common carbon atom ( called as spiro atom ), wherein one or more rings may contain one or more double bonds , but none of the rings has a completely conjugated pi - electron system . preferably a spiro cycloalkyl is 6 to 14 membered , more preferably is 7 to 10 membered . according to the number of the common spiro atom , spiro cycloalkyl is divided into monocyclic spiro ring , bicyclic spiro ring or multicyclic spiro ring , preferably refers to monocyclic spiro ring or bicyclic spiro ring . more preferably spiro cycloalkyl is 4 - membered / 4 - membered , 4 - membered / 5 - membered , 4 - membered / 6 - membered , 5 - membered / 5 - membered , or 5 - membered / 6 - membered monocyclic spiro ring . representative examples of spiro cycloalkyl include , but are not limited to the following groups : “ fused cycloalkyl ” refers to 5 to 20 membered polycyclic hydrocarbon group , wherein each ring in the system shares an adjacent pair of carbon atoms with other ring , wherein one or more rings may contain one or more double bonds , but none of the rings has a completely conjugated pi - electron system . preferably a fused cycloalkyl group is 6 to 14 membered , more preferably is 7 to 10 membered . according to the number of membered ring , fused cycloalkyl is divided into fused bicyclic ring , tricyclic ring , tetracyclic ring or multicyclic ring , preferably refers to fused bicyclic ring or tricyclic ring . more preferably fused cycloalkyl is 5 - membered / 5 - membered , or 5 - membered / 6 - membered fused bicyclic ring . representative examples of fused cycloalkyl include , but are not limited to the following groups : “ bridged cycloalkyl ” refers to 5 to 20 membered polycyclic hydrocarbon group , wherein every two rings in the system share with two disconnected carbon atoms . the said rings could have one or more double bonds but have no completely conjugated pi - electron system . preferably a bridged cycloalkyl is 6 to 14 membered , more preferably is 7 to 10 membered . according to the number of membered ring , bridged cycloalkyl is divided into bridged bicyclic ring , tricyclic ring , tetracyclic ring or multicyclic ring , preferably refers to bicyclic ring , tricyclic ring or tetracyclic ring bridged cycloalkyl , more preferably refers to bicyclic ring or tricyclic ring bridged cycloalkyl . representative examples of bridged cycloalkyl include , but are not limited to the following groups : the said cycloalkyl can be fused to aryl , heteroaryl or heterocyclic alkyl , wherein the ring connected with parent structure is cycloalkyl . representative examples of bridged cycloalkyl include , but are not limited to indanylacetic , tetrahydronaphthalene , 6 , 7 , 8 , 9 - tetrahydro - 5h - benzo [ 7 ] annulene and so on . said cycloalkyl may be substituted or unsubstituted . when substituted , the substituent group ( s ) is preferably one or more groups independently selected from the group consisting of alkyl , alkenyl , alkynyl , alkoxyl , alkylsulfo , alkylamino , halogen , thiol , hydroxyl , nitro , cyano , cycloalkyl , heterocyclic alkyl , aryl , heteroaryl , cycloalkoxyl , heterocylic alkoxyl , cycloalkylthio , heterocylic alkylthio , carbonyl , carboxy or carboxylic ester . “ aryl ” refers to a 6 to 14 membered all - carbon monocyclic ring or a multicyclic fused ring ( a “ fused ” ring system means that each ring in the system shares an adjacent pair of carbon atoms with other ring in the system ) group , and has a completely conjugated pi - electron system . preferably aryl is 6 to 10 membered , such as phenyl and naphthyl . the said aryl can be fused to heteroaryl , heterocyclic alkyl or cycloalkyl , wherein the ring connected with parent structure is aryl . representative examples of aryl include , but are not limited to the following groups : said aryl may be substituted or unsubstituted . when substituted , the substituent group ( s ) is preferably one or more groups independently selected from the group consisting of alkyl , alkenyl , alkynyl , alkyxoyl , alkylsulfo , alkylamino , halogen , thiol , hydroxyl , nitro , cyano , cycloalkyl , heterocyclic alkyl , aryl , heteroaryl , cycloalkoxyl , heterocylic alkoxyl , cycloalkylthio , heterocylic alkylthio , carbonyl , carboxy or carboxylic ester . “ heteroaryl ” refers to an 5 - 14 membered aryl having 1 to 4 heteroatoms selected from the group consisting of o , s , and n as ring atoms , the remaining ring atoms being c . preferably , said ring is 6 or 10 membered ring . preferably , said heteroaryl is 5 or 6 membered ring . examples of heteroaryl groups are furan , thiophene , pyridine , pyrrole , n - alkyl pyrrole , pyrimidine , pyrazine , imidazole , tetrazolyl , and so on . the said heteroaryl can be fused to aryl , heterocyclic alkyl or cycloalkyl , wherein the ring connected with parent structure is heteroaryl . representative examples of bridged cycloalkyl include , but are not limited to the following groups : said heteroaryl may be substituted or unsubstituted . when substituted , the substituent group ( s ) is preferably one or more groups independently selected from the group consisting of alkyl , alkenyl , alkynyl , alkxoyl , alkylsulfo , alkylamino , halogen , thiol , hydroxyl , nitro , cyano , cycloalkyl , heterocyclic alkyl , aryl , heteroaryl , cycloalkoxyl , heterocylic alkoxyl , cycloalkylthio , heterocylic alkylthio , carbonyl , carboxy or carboxylic ester . “ heterocyclic alkyl ” refers to 3 to 20 membered saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more heteroatoms selected from the group consisting of n , o , or s ( o ) n ( wherein n is 0 , 1 or 2 ) as ring atoms , but excluding — o — o —, — o — s — or — s — s — in the ring , the remaining ring atoms being c . preferably , heterocyclic alkyl is 3 to 12 membered having 1 to 4 said heteroatoms ; more preferably , is 3 to 10 membered . representative examples of monocyclic heterocyclic alkyl include , but are not limited to pyrrolidyl , piperidyl , piperazinyl , morpholinyl , sulfo - morpholinyl , homopiperazinyl and so on . polycyclic heterocyclic alkyl includes the heterocyclic alkyl having spiro ring , fused ring and bridged ring . “ spiro heterocyclic alkyl ” refers to 5 to 20 membered polycyclic heterocyclic alkyl group with rings connected through one common carbon atom ( called as spiro atom ), wherein said rings have one or more heteroatoms selected from the group consisting of n , o , or s ( o ) p ( wherein p is 0 , 1 or 2 ) as ring atoms , the remaining ring atoms being c , wherein one or more rings may contain one or more double bonds , but none of the rings has a completely conjugated pi - electron system . preferably an spiro heterocyclic alkyl is 6 to 14 membered , more preferably is 7 to 10 membered . according to the number of common atom , spiro heterocyclic alkyl is divided into monocyclic spiro heterocyclic alkyl , bicyclic spiro heterocyclic alkyl or multicyclic spiro heterocyclic alkyl , preferably refers to monocyclic spiro heterocyclic alkyl or bicyclic spiro heterocyclic alkyl . more preferably spiro heterocyclic alkyl is 4 - membered / 4 - membered , 4 - membered / 5 - membered , 4 - membered / 6 - membered , 5 - membered / 5 - membered , or 5 - membered / 6 - membered monocyclic spiro heterocyclic alkyl . representative examples of spiro heterocyclic alkyl include , but are not limited to the following groups : “ fused heterocyclic alkyl ” refers to 5 to 20 membered polycyclic heterocyclic alkyl group , wherein each ring in the system shares an adjacent pair of carbon atoms with other ring , wherein one or more rings may contain one or more double bonds , but none of the rings has a completely conjugated pi - electron system , and wherein said rings have one or more heteroatoms selected from the group consisting of n , o , or s ( o ) p ( wherein p is 0 , 1 or 2 ) as ring atoms , the remaining ring atoms being c . preferably an fused heterocyclic alkyl is 6 to 14 membered , more preferably is 7 to 10 membered . according to the number of membered ring , fused heterocyclic alkyl is divided into fused bicyclic ring , tricyclic ring , tetracyclic ring or multicyclic ring , preferably refers to fused bicyclic ring or tricyclic ring . more preferably fused heterocyclic alkyl is 5 - membered / 5 - membered , or 5 - membered / 6 - membered fused bicyclic ring . representative examples of fused heterocyclic alkyl include , but are not limited to the following groups : “ bridged heterocyclic alkyl ” refers to 5 to 14 membered polycyclic heterocyclic alkyl group , wherein every two rings in the system share with two disconnected carbon atoms , said rings could have one or more double bonds but have no completely conjugated pi - electron system , said rings have one or more heteroatoms selected from the group consisting of n , o , and s ( o ) p ( wherein p is 0 , 1 or 2 ) as ring atoms , the remaining ring atoms being c . preferably an bridged heterocyclic alkyl is 6 to 14 membered , more preferably is 7 to 10 membered . according to the number of membered ring , bridged heterocyclic alkyl is divided into bridged bicyclic ring , tricyclic ring , tetracyclic ring or multicyclic ring , preferably refers to bicyclic ring , tricyclic ring or tetracyclic ring bridged heterocyclic alkyl , more preferably refers to bicyclic ring or tricyclic ring bridged heterocyclic alkyl . representative examples of bridged heterocyclic alkyl include , but are not limited to the following groups : the said heterocyclic alkyl can be fused to aryl , heterocyclic alkyl or cycloalkyl , wherein the ring connected with parent structure is heterocyclic alkyl . representative examples of heterocyclic alkyl include , but are not limited to the following groups : said heterocyclic alkyl may be substituted or unsubstituted . when substituted , the substituent group ( s ) is preferably one or more groups independently selected from the group consisting of alkyl , alkenyl , alkynyl , alkoxyl , alkylsulfo , alkylamino , halogen , thiol , hydroxyl , nitro , cyano , cycloalkyl , heterocyclic alkyl , aryl , heteroaryl , cycloalkoxyl , heterocylic alkoxyl , cycloalkylthio , heterocylic cycloalkylthio , carbonyl , carboxy or carboxylic ester . “ alkoxyl ” refers to both an — o -( alkyl ) and an — o -( unsubstituted cycloalkyl ) group , wherein alkyl as defined above . representative examples include , but are not limited to , methoxyl , ethoxyl , propoxyl , butoxyl , cyclopropoxyl , cyclobutoxyl , cyclopentyloxyl , cyclohexyloxyl , and the like . said alkoxyl may be substituted or unsubstituted . when substituted , the substituent group ( s ) is preferably one or more groups independently selected from the group consisting of alkyl , alkenyl , alkynyl , alkoxyl , alkylsulfo , alkylamino , halogen , thiol , hydroxyl , nitro , cyano , cycloalkyl , heterocyclic alkyl , aryl , heteroaryl , cycloalkoxyl , heterocylic alkoxyl , cycloalkylthio , heterocylic cycloalkylthio , carbonyl , carboxy or carboxylic ester . “ halo ” refers to fluoro , chloro , bromo , or iodo , preferably fluoro or chloro . “ optional ” or “ optionally ” means that the subsequently described event or circumstance may or may not occur , and that the description includes instances where the event or circumstance may or may not occur . for example , “ heterocycle group optionally further substituted by an alkyl group ” means that the alkyl may or may not be present , and the description includes situations where the heterocycle group is substituted by an alkyl group and situations where the heterocyclo group is not substituted by the alkyl group . a “ pharmaceutical composition ” refers to a mixture of one or more of the compounds described herein , or physiologically / pharmaceutically acceptable salts or prodrugs thereof , with other chemical components , such as physiologically / pharmaceutically acceptable carriers and excipients . the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism , benefit intaking of active ingredient more effectively . in order to complete the purpose of the invention , the invention applies the following technical solution : a preparation process of the compounds of formula ( i ) or pharmaceutically acceptable salts thereof according to this invention , comprising the following steps of : reacting the compounds of formula ( ia - 1 ) with diethylphosphonoacetic acid to obtain the compounds of formula ( ia ) in the presence of a condensation agent ; in a dry ice bath , reacting the compounds of formula ( ia ) with lithium bis ( trimethylsilyl ) amide , heating the reaction solution to room temperature and reacting it with the compounds of formula ( ib ) via witting reaction to obtain the compounds of formula ( i ); wherein a , b , n and r 1 to r 9 are as defined in formula ( i ). a preparation process of the compounds of formula ( ii ) or pharmaceutically acceptable salts thereof according to this invention , comprising the following steps of : reacting the compounds of the formula ( ia ) with lithium bis ( trimethylsilyl ) amide in a dry ice bath , then heating the reaction solution to room temperature and reacting it with the compounds of formula ( iib ) via witting reaction to obtain the compounds of formula ( ii ); wherein a , n , r 1 ˜ r 5 and r 8 ˜ r 9 are as defined in formula ( ii ). the present invention is further described by the following examples which are not intended to limit the scope of the invention . the structures of all compounds were identified by nuclear magnetic resonance ( 1 h nmr ) and / or mass spectrometry ( ms ). 1 h nmr chemical shifts were recorded as ppm ( 10 − 6 ). 1 h nmr was performed on a bruker avance - 400 spectrometer . the appropriate solvents included deuterated - methanol ( cd 3 od ), deuterated - chloroform ( cdcl 3 ) and deuterated - dimethyl sulfoxide ( dmso - d 6 ) with tetramethylsilane ( tms ) as the internal standard . ms was determined on a finnigan lcq ad ( esi ) mass spectrometer ( thermo , model : finnigan lcq advantage max ). hplc was determined on an agilent 1200dad high pressure liquid chromatography spectrometer ( sunfire c18 150 × 4 . 6 mm chromatographic column ) and a waters 2695 - 2996 high pressure liquid chromatography spectrometer ( gimini c18 150 × 4 . 6 mm chromatographic column ). ic 50 was determined on a novostar eliasa ( bmg co . german ). the thin - layer silica gel used yantai huanghai hsgf254 or qingdao gf254 silica gel plate . the dimension of the plates used in tlc was 0 . 15 mm to 0 . 2 mm , and the dimension of the plates used in product purification was 0 . 4 mm to 0 . 5 mm . column chromatography generally used yantai huanghai 200 to 300 mesh silica gel as carrier . alkaline alumina column chromatography generally used guoyao fcp200 to 300 mesh alkaline alumina as carrier . the starting materials of the present invention are known or purchased from abcr gmbh & amp ; co . kg , acros organics , aldrich chemical company , accela chembio inc , darui finechemical co ., ltd and so on , or they can be prepared by the conventional synthesis methods in the prior art . unless otherwise stated , the following reactions were placed under nitrogen atmosphere or argon atmosphere . the term “ argon atmosphere ” or “ nitrogen atmosphere ” refers to that a reaction flask is equipped with a balloon filled about 1 l nitrogen . the term “ hydrogen atmosphere ” refers to that a reaction flask is equipped with a balloon filled about 1 l hydrogen . pressured hydrogenation reactions were performed with a parr 3916ekx hydrogenation spectrometer and a ql - 500 hydrogen generator or a hc2 - ss hydrogenation spectrometer . in hydrogenation reactions , the reaction system was generally vacuumed and filled with hydrogen , repeat the above operation three times . unless otherwise stated , the solution used in examples refers to an aqueous solution . room temperature was the most ambient reaction temperature , which was 20 ° c .- 30 ° c . the reactions process of the examples was monitored by thin layer chromatography ( tlc ). the developing solvent system comprised dichloromethane and methanol system , hexane and ethyl acetate system , petroleum ether and ethyl acetate system , and acetone . the ratio of the volume of the solvent was adjusted according to the polarity of the compounds . the elution system of column chromatography and the developing solvent system of thin layer chromatography comprised : a : dichloromethane and methanol system , b : hexane and ethyl acetate system , c : dichloromethane and acetone system . the ratio of the volume of the solvent was adjusted according to the polarity of the compounds , and sometimes a basic agent such as triethylamine or an acidic agent such as acetic acid was also added . oxalyl chloride ( 1 . 1 ml , 13 . 02 mmol ) was dissolved in dimethylsulfoxide ( 1 . 9 ml , 26 . 04 mmol ) in a dry ice bath . after 30 minutes , a solution of [( 2s )- 1 - methylpyrrolidin - 2 - yl ] methanol 1a ( 1 g , 8 . 68 mmol ) in dichloromethane ( 25 ml ) was added dropwise . then the mixture was stirred at − 30 ° c . for 45 minutes , followed by dropwise addition of triethylamine ( 6 . 15 g , 60 . 77 mmol ). the mixture was warmed up to room temperature and stirred for 12 hours . the reaction mixture was added with 250 ml of dichloromethane , washed with saturated sodium bicarbonate ( 100 ml ), saturated ammonium chloride ( 100 ml ) and saturated brine ( 100 ml ) successively . the combined organic extracts were dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by alkaline alumina column chromatography with elution system a to obtain the title compound ( 2s )- 1 - methylpyrrolidine - 2 - carbaldehyde 1b ( 308 mg , yield 31 . 4 %) as a light yellow oil . n , n ′- carbonyldiimidazole ( 487 mg , 3 mmol ) was dissolved in 4 ml of tetrahydrofuran . the mixture was heated to 40 ° c . in an oil bath , a solution of diethylphosphonoacetic acid ( 588 mg , 3 mmol ) in tetrahydrofuran ( 4 ml ) was added dropwise to the mixture , and stirred for 30 minutes to the next step . 6 - amino - 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 7 - ethoxy - quinoline - 3 - carbonitrile 1c ( 446 mg , 1 mmol , prepared by the well - known method : patent application wo2005028443 ) was dissolved in 4 ml of tetrahydrofuran at 40 ° c ., followed by dropwise addition of the above reaction solution . after stirring for 12 hours , the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane ( 50 ml × 3 ). the combined organic extracts were washed with saturated brine ( 30 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 2 - diethoxyphosphoryl - acetamide 1d ( 624 mg , yield 99 . 9 %) as a light yellow solid . n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 2 - diethoxyphosphoryl - acetamide 1d ( 50 mg , 0 . 08 mmol ) was dissolved in 2 ml of tetrahydrofuran at − 78 ° c ., followed by dropwise addition of a solution of lithium bis ( trimethylsilyl ) amide ( 1 m ) in toluene ( 80 μl , 0 . 08 mmol ). after the mixture was stirred for 45 minutes , ( 2s )- 1 - methylpyrrolidine - 2 - carbaldehyde 1b ( 20 mg , 0 . 17 mmol ) was added . after stirring for another 1 hour , the reaction mixture was warmed up to room temperature and stirred for 12 hours . the reaction mixture was added with 1 ml of water and 1 ml of methanol , then the organic extracts were extracted with dichloromethane ( 50 ml × 3 ). the combined organic extracts were washed with saturated brine ( 30 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 3 -[( 2s )- 1 - methylpyrrolidin - 2 - yl ] prop - 2 - enamide 1 ( 25 mg , yield 53 . 5 %) as a yellow solid . 1 h nmr ( 400 mhz , dmso - d 6 ): δ 9 . 63 ( s , 2h ), 8 . 95 ( s , 1h ), 8 . 60 ( d , 1h ), 8 . 48 ( s , 1h ), 7 . 89 ( t , 1h ), 7 . 59 ( d , 1h ), 7 . 37 ( m , 3h ), 7 . 27 - 7 . 20 ( m , 2h ), 6 . 80 - 6 . 60 ( m , 2h ), 5 . 29 ( s , 2h ), 4 . 34 ( dd , 2h ), 2 . 33 - 2 . 24 ( m , 3h ), 2 . 23 - 2 . 15 ( m , 2h ), 1 . 99 - 1 . 88 ( m , 3h ), 1 . 80 - 1 . 78 ( m , 2h ), 1 . 49 ( t , 3h ) [( 2s )- pyrrolidin - 2 - yl ] methanol 2a ( 5 . 06 g , 0 . 05 mmol ) and triethylamine ( 10 . 12 g , 0 . 10 mmol ) were dissolved in 100 ml of dichloromethane in an ice - water bath . the reaction mixture was added with di - tert - butyl pyrocarbonate ( 16 . 37 g , 0 . 08 mmol ) in batches and stirred at room temperature for 12 hours . the reaction mixture was concentrated under reduced pressure , extracted with ethyl acetate ( 50 ml × 3 ). the combined organic extracts were washed with saturated brine ( 30 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure to obtain the title compound tert - butyl ( 2s )- 2 -( hydroxymethyl ) pyrrolidine - 1 - carboxylate 2b ( 10 g , yield 99 . 9 %) as a light yellow oil . oxalyl chloride ( 3 . 2 ml , 0 . 04 mol ) and dimethyl sulfoxide ( 4 . 3 ml , 0 . 06 mol ) were dissolved in 100 ml of dichloromethane in a dry ice bath . after stirring for 30 minutes , a solution of tert - butyl ( 2s )- 2 -( hydroxymethyl ) pyrrolidine - 1 - carboxylate 2b ( 2 g , 0 . 01 mol ) in 20 ml of dichloromethane was added dropwise . the reaction mixture was stirred for 45 minutes , and triethylamine ( 7 . 08 g , 0 . 07 mol ) was added dropwise . after stirring for another 1 hours at 0 ° c ., the reaction mixture was added with 500 ml of dichloromethane . the combined organic layers were washed with saturated brine ( 100 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound tert - butyl ( 2s )- 2 - formylpyrrolidine - 1 - carboxylate 2c ( 1 . 10 g , yield 55 . 4 %) as a light yellow oil . n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 2 - diethoxyphosphoryl - acetamide 1d ( 156 mg , 0 . 25 mmol ) was dissolved in 3 ml of tetrahydrofuran in a dry ice bath , followed by dropwise addition of a solution of lithium bis ( trimethylsilyl ) amide ( 1 m ) in toluene ( 375 μl , 0 . 38 mmol ). after the reaction mixture was stirred for 45 minutes , a solution of tert - butyl ( 2s )- 2 - formylpyrrolidine - 1 - carboxylate 2c ( 100 mg , 0 . 50 mmol ) in 2 ml of tetrahydrofuran was added . the reaction mixture was stirred for another 1 hour , then warmed up to room temperature and stirred for 12 hours . the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound tert - butyl ( 2s )- 2 -[( e )- 3 -[[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ] amino ]- 3 - oxo - prop - 1 - enyl ] pyrrolidine - 1 - carboxylate 2d ( 161 mg , yield 96 . 2 %) as a light yellow solid . tert - butyl ( 2s )- 2 -[( e )- 3 -[[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ] amino ]- 3 - oxo - prop - 1 - enyl ] pyrrolidine - 1 - carboxylate 2d ( 161 mg , 0 . 24 mmol ) was dissolved in a solution of hydrogen chloride ( 2m ) in 25 ml of 1 , 4 - dioxane . after stirring for 12 hours , the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane ( 50 ml × 3 ). the combined organic extracts were washed with saturated brine ( 30 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 3 -[( 2s )- pyrrolidin - 2 - yl ] prop - 2 - enamide 2 ( 20 mg , yield 14 . 6 %) as a yellow solid . 1 h nmr ( 400m hz , dmso - d 6 ): δ10 . 01 ( s , 1h ), 9 . 76 ( s , 1h ), 9 . 71 ( s , 2h ), 9 . 40 ( s , 1h ), 8 . 92 ( s , 1h ), 8 . 61 ( s , 1h ), 8 . 60 ( s , 1h ), 7 . 90 ( t , 1h ), 7 . 60 ( d , 1h ), 7 . 58 - 7 . 41 ( s , 2h ), 7 . 39 - 7 . 38 ( m , 2h ), 6 . 95 ( dd , 1h ), 6 . 79 ( d , 1h ), 5 . 29 ( s , 1h ), 4 . 35 ( t , 2h ), 4 . 21 - 4 . 20 ( m , 1h ), 3 . 23 - 3 . 22 ( m , 3h ), 2 . 21 - 2 . 20 ( m , 1h ), 2 . 039 - 1 . 94 ( m , 1h ), 1 . 84 - 1 . 76 ( m , 1h ), 1 . 49 ( t , 3h ) methyl ( 2s , 4r )- 4 - hydroxypyrrolidine - 2 - carboxylate 3a ( 5 . 53 g , 38 mmol ) was dissolved in 80 ml of methanol in an ice - water bath , followed by addition of 40 % formaldehyde solution ( 31 ml , 380 mmol ) and sodium cyanoborohydride ( 12 g , 190 mmol ) in batches . the reaction mixture was stirred for 0 . 5 hours , then warmed up to room temperature and stirred for 3 hours . the mixture was quenched with 40 ml of water , concentrated under reduced pressure and extracted with dichloromethane ( 80 ml × 3 ). the combined organic extracts were washed with saturated brine ( 30 ml × 2 ), dried over anhydrous sodium sulfate and filtered . the filtrate was concentrated under reduced pressure to obtain the title compound methyl ( 2s , 4r )- 4 - hydroxy - 1 - methyl - pyrrolidine - 2 - carboxylate 3b crude product as a colourless oil , which was directly used in the next step . methyl ( 2s , 4r )- 4 - hydroxy - 1 - methyl - pyrrolidine - 2 - carboxylate 3b ( 6 g , 37 mmol ) was dissolved in 100 ml of dichloromethane , followed by addition of imidazole ( 7 . 70 g , 113 mmol ) and tert - butyl dimethylchlorosilane ( 6 . 80 g , 45 mmol ) successively . after stirring for 12 hours , the reaction mixture was diluted with 100 ml of dichloromethane , washed with water ( 50 ml ) and saturated brine ( 50 ml ) successively , dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound methyl ( 2s , 4r )- 4 -( tert - butyl ( dimethyl ) silyl ) oxy - 1 - methyl - pyrrolidine - 2 - carboxylate 3c crude product as a colourless oi , which was directly used in the next step without purification . methyl ( 2s , 4r )- 4 -( tert - butyl ( dimethyl ) silyl ) oxy - 1 - methyl - pyrrolidine - 2 - carboxylate 3c ( 2 . 50 g , 9 . 10 mmol ) was dissolved in 50 ml of dichloromethane in an ice - water bath . diisobutyl aluminium hydride ( 18 ml , 18 mmol ) was added dropwise slowly , and the mixture was stirred for 6 hours . the reaction mixture was quenched with 1 ml of methanol , diluted with 200 ml of dichloromethane , added with anhydrous sodium sulfate , and stirred for 30 minutes . the reaction mixture was filtered and concentrated under reduced pressure and the resulting residue was purified by alkaline alumina column chromatography with elution system a to obtain the title compound [( 2s , 4r )- 4 -( tert - butyl ( dimethyesilyl ) oxy - 1 - methyl - pyrrolidin - 2 - yl ] methanol 3d ( 570 mg , yield 50 . 0 %) as a yellow oil . dimethyl sulfoxide ( 174 μl , 2 . 45 mmol ) was dissolved in 20 ml of dichloromethane in a dry ice bath . after the system temperature was stable , oxalyl chloride ( 156 μl , 1 . 80 mmol ) was added dropwise slowly . after stirring for 30 minutes , a solution of [( 2s , 4r )- 4 -( tert - butyl ( dimethyl ) silyl ) oxy - 1 - methyl - pyrrolidin - 2 - yl ] methanol 3d ( 300 mg , 1 . 20 mmol ) in 2 ml of dichloromethane was added dropwise . after stirring for 45 minutes , the reaction mixture was added with triethylamine ( 510 μl , 3 . 67 mmol ), and stirred for 10 minutes , then warmed up to room temperature and stirred for 1 hour . the reaction mixture was diluted with 100 ml of dichloromethane , washed with saturated sodium bicarbonate ( 20 ml ), saturated ammonium chloride ( 20 ml ) and saturated brine ( 20 ml ) successively , dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure to obtain the title compound ( 2s , 4r )- 4 -( tert - butyl ( dimethyl ) silyl ) oxy - 1 - methyl - pyrrolidine - 2 - carbaldehyde 3e ( 320 mg ) crude product as a yellow oil , which was directly used in the next step . n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 2 - diethoxyphosphoryl - acetamide 1d ( 418 mg , 0 . 67 mmol ) was dissolved in 2 . 5 ml of tetrahydrofuran in a dry ice bath , followed by dropwise addition of a solution of lithium bis ( trimethylsilyl ) amide ( 1 m ) in toluene ( 1 ml , 1 mmol ). after the mixture was stirred for 45 minutes , a solution of ( 2s , 4r )- 4 -( tert - butyl ( dimethyl ) silyl ) oxy - 1 - methyl - pyrrolidine - 2 - carbaldehyde 3e ( 326 mg , 1 . 34 mmol ) in 2 . 5 ml of tetrahydrofuran was added , and stirred for another 1 hour , then warmed up to room temperature and stirred for 12 hours . the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- 3 -[( 2s , 4r )- 4 -( tert - butyl ( dimethyl ) silyl ) oxy - 1 - methyl - pyrrolidin - 2 - yl ]- n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ] prop - 2 - enamide 3f ( 292 mg , yield 61 . 2 %) as a yellow solid . ( e )- 3 -[( 2s , 4r )- 4 -( tert - butyl ( dimethyl ) silyl ) oxy - 1 - methyl - pyrrolidin - 2 - yl ]- n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ] prop - 2 - enamide 3f ( 50 mg , 0 . 07 mmol ) and tetrabutyl ammonium fluoride ( 51 mg , 0 . 21 mmol ) were dissolved in 5 ml of tetrahydrofuran , and the mixture was stirred for 12 hours . the reaction mixture was added with 1 ml of water , concentrated under reduced pressure and extracted with dichloromethane ( 50 ml × 3 ). the combined organic extracts were washed with saturated brine ( 30 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 3 -[( 2s , 4r )- 4 - hydroxy - 1 - methyl - pyrrolidin - 2 - yl ] prop - 2 - enamide 3 ( 17 mg , yield 40 . 4 %) as a yellow solid . 1 h nmr ( 400m hz , dmso - d 6 ): δ 9 . 63 ( s , 1h ), 9 . 52 ( s , 1h ), 8 . 97 ( s , 1h ), 8 . 61 - 8 . 60 ( m , 1h ), 8 . 48 ( s , 1h ), 7 . 904 - 7 . 862 ( m , 1h ), 7 . 60 ( d , 1h ), 7 . 41 - 7 . 36 ( m , 3h ), 7 . 28 - 7 . 20 ( m , 2h ), 6 . 76 ( dd , 1h ), 6 . 61 ( d , 1h ), 5 . 29 ( s , 2h ), 4 . 82 ( s , 1h ), 4 . 35 - 4 . 29 ( m , 2h ), 4 . 21 ( d , 1h ), 3 . 42 - 3 . 38 ( m , 2h ), 3 . 36 - 3 . 33 ( m , 3h ), 2 . 93 ( d , 1h ), 2 . 41 - 2 . 37 ( m , 1h ), 2 . 20 - 2 . 18 ( m , 1h ), 1 . 49 ( t , 3h ) 6 - nitro - 3h - quinazolin - 4 - one 4a ( 18 . 88 g , 99 . 40 mmol ) was dissolved in phosphoricchloride ( 31 . 03 g , 149 mmol ). the mixture was warmed up to 160 ° c ., and stirred for 3 hours . the reaction mixture was added to 250 ml of n - hexane while hot , stirred and a lot of the solid was precipitated from the solution , filtered , the filter cake was washed with n - hexane , dried under vacuum to obtain the title compound 4 - chloro - 6 - nitro - quinazoline 4b ( 18 . 14 g , yield 87 . 2 %) as a yellow solid . 4 - chloro - 6 - nitro - quinazoline 4b crude product ( 6 . 06 g , 28 . 90 mmol ) was dissolved in 100 ml of isopropanol , followed by addition of 3 - chloro - 4 -( 2 - pyridylmethoxy ) aniline 4c ( 7 . 47 g , 31 . 8 mmol ). the reaction mixture was heated to reflux for 5 hours . the mixture was cooled to room temperature , the solid was precipitated , filtered and the filter cake was washed with ethyl acetate , saturated brine ( 50 ml ) and water ( 150 ml ) successively , dried under vacuum to obtain the title compound n -[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ]- 6 - nitro - quinazolin - 4 - amine 4d ( 8 . 38 g , yield 74 . 8 %) as a yellow solid . n -[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ]- 6 - nitro - quinazolin - 4 - amine 4d ( 4 . 07 g , 10 mmol ) and concentrated hydrochloric acid ( 2 ml , 24 mmol ) were dissolved in 130 ml of the solvent mixture of 95 % ethanol and water ( v / v = 10 / 3 ), followed by addition of iron powder ( 11 . 17 g , 200 mmol ). the reaction mixture was heated to reflux for 2 hours , filtered while hot and the filtrate was concentrated under reduced pressure to remove ethanol . the resulting residue was adjusted to ph & gt ; 7 with ammonium hydroxide , filtered and the filter cake was dried under vacuum , purified by silica gel column chromatography with elution system a to obtain the title compound n4 -[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] quinazoline - 4 , 6 - diamine 4e ( 2 . 04 g , yield 54 . 1 %) as a white solid . diethylphosphonoacetic acid ( 1 . 04 g , 5 . 30 mmol ) was dissolved in 10 ml of dichloromethane in an ice - water bath , followed by addition of oxalyl chloride ( 1 . 34 g , 10 mmol ) and 1 drop of n , n - dimethylformamide . after stirring for 1 hour , the mixture was warmed up to room temperature and stirred for another 1 hour , concentrated under reduced pressure , and added with 10 ml of tetrahydrofuran to the next step . n4 -[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] quinazoline - 4 , 6 - diamine 4e ( 1 g , 2 . 65 mmol ) was dissolved in n , n - diisopropylethylamine ( 1 . 03 g , 7 . 94 mmol ), followed by dropwise addition of the above reaction solution . the mixture was warmed up to room temperature and stirred for 1 hour . the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane ( 50 ml × 3 ). the combined organic extracts were washed with saturated brine ( 30 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ] quinazolin - 6 - yl ]- 2 - diethoxyphosphoryl - acetamide 4f ( 671 mg , yield 45 . 7 %) as a brown solid . n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ] quinazolin - 6 - yl ]- 2 - diethoxyphosphoryl - acetamide 4f ( 277 mg , 0 . 50 mmol ) was dissolved in 2 . 5 ml of tetrahydrofuran in a dry ice bath , followed by dropwise addition of a solution of lithium bis ( trimethylsilyl ) amide ( 1 m ) in toluene ( 750 μl , 0 . 75 mmol ). after stirring for 45 minutes , the reaction mixture was added with ( 2s )- 1 - methylpyrrolidine - 2 - carbaldehyde 1b ( 113 mg , 2 mmol ), and stirred for 1 hour , then warmed up to room temperature and stirred for 12 hours . the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ] quinazolin - 6 - yl ]- 3 -[( 2s )- 1 - methylpyrrolidin - 2 - yl ] prop - 2 - enamide 4 ( 85 mg , yield 33 . 0 %) as a yellow solid . 1 h nmr ( 400 mhz , dmso - d 6 ): δ 10 . 47 ( s , 1h ), 9 . 82 ( s , 1h ), 8 . 79 ( s , 1h ), 8 . 61 ( d , 1h ), 8 . 52 ( s , 1h ), 8 . 00 ( s , 1h ), 7 . 91 - 7 . 89 ( m , 2h ), 7 . 78 - 7 . 69 ( m , 2h ), 7 . 61 ( d , 1h ), 7 . 38 ( d , 1h ), 7 . 28 ( d , 1h ), 6 . 78 - 6 . 72 ( m , 1h ), 6 . 47 ( d , 1h ), 5 . 30 ( s , 2h ), 3 . 14 - 3 . 00 ( m , 2h ), 3 . 001 ( s , 1h ), 2 . 31 ( m , 4h ), 2 . 10 - 2 . 07 ( m , 1h ), 1 . 81 ( m , 2h ), 1 . 63 ( m , 1h ) lithium aluminium hydride ( 230 mg , 6 mmol ) and n - tert - butoxycarbonyl - l - prolinol 5a ( 400 mg , 2 mmol ) were dissolved in 10 ml of dry tetrahydrofuran in an ice - water bath in batches . after no gas was released obviously , the reaction mixture was heated to reflux for 2 hours . the reaction mixture was added dropwise with 5 ml of methanol in an ice - water bath , followed by addition of 5 ml of water , dried over anhydrous magnesium sulfate , filtered and concentrated under reduced pressure to obtain the title compound [( 2r )- 1 - methylpyrrolidin - 2 - yl ] methanol 5b ( 221 mg , yield 77 . 0 %) as a colourless oil . dimethyl sulfoxide ( 820 μl , 11 . 46 mmol ) was dissolved in 5 ml of dichloromethane in a dry ice bath , followed by dropwise slowly addition of oxalyl chloride ( 968 mg , 7 . 64 mmol ). after stirring for 45 minutes , a solution of [( 2r )- 1 - methylpyrrolidin - 2 - yl ] methanol 5b ( 220 mg , 1 . 91 mmol ) in 2 ml of dichloromethane was added to the solution . the reaction mixture was stirred for 45 minutes , and triethylamine ( 1 . 9 ml , 13 . 37 mmol ) were added . the reaction mixture was stirred for 10 minutes , then warmed up to room temperature and stirred for 1 hour . the reaction mixture was washed with water ( 20 ml ) and saturated brine ( 10 ml ) successively . the combined organic extracts were dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by alkaline alumina column chromatography with elution system a to obtain the title compound ( 2r )- 1 - methylpyrrolidine - 2 - carbaldehyde 5c ( 300 mg ) as a yellow solid , which was directly used in the next step without purification . n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 2 - diethoxyphosphoryl - acetamide 1d ( 250 mg , 0 . 40 mmol ) was dissolved in 10 ml of dry tetrahydrofuran in a dry ice bath , followed by dropwise addition of a solution of lithium bis ( trimethylsilyl ) amide ( 1 m ) in toluene ( 440 μl , 0 . 44 mmol ). the reaction mixture was stirred for 30 minutes , added dropwise with a solution of ( 2r )- 1 - methylpyrrolidine - 2 - carbaldehyde 5c ( 90 mg , 0 . 80 mmol ) in 5 ml of tetrahydrofuran , and stirred for 30 minutes , then warmed up to room temperature and stirred for 12 hours . the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 3 -[( 2r )- 1 - methylpyrrolidin - 2 - yl ] prop - 2 - enamide 5 ( 46 mg , yield 19 . 7 %) as a yellow solid . 1 h nmr ( 400 mhz , dmso - d 6 ): δ 9 . 16 ( s , 1h ), 8 . 63 ( d , 1h ), 8 . 56 ( s , 1h ), 8 . 26 ( s , 1h ), 7 . 83 - 7 . 80 ( dd , 1h ), 7 . 76 - 7 . 50 ( m , 2h ), 7 . 57 - 7 . 56 ( m , 1h ), 7 . 40 ( s , 1h ), 7 . 38 ( s , 1h ), 7 . 19 ( d , 1h ), 7 . 06 - 7 . 03 ( m , 2h ), 6 . 34 - 6 . 31 ( d , 1h ), 5 . 35 ( s , 2h ), 4 . 39 ( m , 2h ), 4 . 27 - 4 . 26 ( m , 1h ), 3 . 32 ( m , 1h ), 3 . 10 ( m , 1h ), 2 . 73 ( s , 3h ), 2 . 37 - 2 . 36 ( m , 2h ), 2 . 07 - 2 . 01 ( m , 2h ), 1 . 64 ( t , 3h ) dimethyl sulfoxide ( 3 . 3 ml , 46 mmol ) was dissolved in 15 ml of dichloromethane in a dry ice bath , followed by dropwise slowly addition of oxalyl chloride ( 2 . 6 ml , 31 mmol ). after stirring for 45 minutes , a solution of ( 1 - methyl - 2 - piperidyl ) methanol 6a ( 1 g , 7 . 74 mmol ) in 5 ml of dichloromethane was added dropwise to the solution . the reaction mixture was stirred for 45 minutes , then added with triethylamine ( 7 . 2 ml , 52 mmol ), and stirred for 10 minutes , then warmed up to room temperature and stirred for 1 hour . the reaction mixture was washed with water ( 20 ml ) and saturated brine ( 20 ml ) successively . the combined organic extracts were dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure then the resulting residue was purified by alkaline alumina column chromatography with elution system a to obtain the title compound 1 - methylpiperidine - 2 - carbaldehyde 6b ( 300 mg , yield 31 . 0 %) as a brown oil , which was directly used in the next step without purification . n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 2 - diethoxyphosphoryl - acetamide 1d ( 300 mg , 0 . 48 mmol ) was dissolved in 10 ml of tetrahydrofuran in a dry ice bath , followed by dropwise addition of a solution of lithium bis ( trimethylsilyl ) amide ( 1 m ) in toluene ( 530 μl , 0 . 53 mmol ). after stirring for 30 minutes , a solution of 1 - methylpiperidine - 2 - carbaldehyde 6b ( 120 mg , 0 . 96 mmol ) in 5 ml of tetrahydrofuran was added dropwise . the reaction mixture was stirred for another 30 minutes , then warmed up to room temperature and stirred for 12 hours . the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 3 -( 1 - methyl - 2 - piperidyl ) prop - 2 - enamide 6 ( 14 mg , yield 4 . 9 %) as a yellow solid . 1 h nmr ( 400 mhz , dmso - d 6 ): δ 9 . 09 ( s , 1h ), 8 . 63 ( d , 1h ), 8 . 51 ( s , 1h ), 7 . 83 - 7 . 79 ( m , 2h ), 7 . 58 - 7 . 56 ( m , 1h ), 7 . 30 - 7 . 27 ( m , 3h ), 7 . 14 - 7 . 12 ( m , 2h ), 7 . 04 ( d , 1h ), 6 . 69 - 6 . 66 ( m , 1h ), 5 . 32 ( s , 2h ), 4 . 32 - 4 . 29 ( m , 2h ), 4 . 27 - 4 . 24 ( m , 2h ), 3 . 60 - 3 . 40 ( m , 2h ), 2 . 71 ( s , 3h ), 2 . 05 - 1 . 72 ( m , 6h ), 1 . 62 ( t , 3h ) n , n ′- carbonyldiimidazole ( 292 mg , 1 . 80 mmol ) was dissolved in 4 ml of tetrahydrofuran . the mixture was heated to 50 ° c . in an oil bath , a solution of diethylphosphonoacetic acid ( 353 mg , 1 . 8 mmol ) in 3 ml of tetrahydrofuran was added dropwise , and stirred for 1 . 5 hours to the next step . n4 -( 3 - chloro - 4 - fluoro - phenyl )- 7 - ethoxy - quinazoline - 4 , 6 - diamine 7a ( 200 mg , 0 . 60 mmol , prepared by the well - known method : patent application wo2005028443 ) was dissolved in 10 ml of tetrahydrofuran , followed by dropwise addition of the above reaction solution at 50 ° c . after stirring for 3 hours at 40 ° c ., the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane ( 50 ml × 3 ). the combined organic extracts were washed with saturated brine ( 50 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound n -[ 4 -[( 3 - chloro - 4 - fluoro - phenyl ) amino ]- 7 - ethoxy - quinazolin - 6 - yl ]- 2 - diethoxyphosphoryl - acetamide 7b ( 100 mg , yield 33 . 3 %) as a light yellow solid . n -[ 4 -[( 3 - chloro - 4 - fluoro - phenyl ) amino ]- 7 - ethoxy - quinazolin - 6 - yl ]- 2 - diethoxyphosphoryl - acetamide 7b ( 100 mg , 0 . 20 mmol ) was dissolved in 10 ml of tetrahydrofuran . the mixture was cooled to − 78 ° c . in a dry ice bath , followed by dropwise addition of a solution of lithium bis ( trimethylsilyl ) amide ( 1 m ) in toluene ( 400 μl , 0 . 40 mmol ), and the mixture was stirred for 45 minutes , added with ( 2s )- 1 - methylpyrrolidine - 2 - carbaldehyde 1b ( 100 mg , 0 . 85 mmol ). after stirring for another 1 hour , the reaction mixture was warmed up to room temperature and stirred for 12 hours . the reaction mixture was added with water ( 1 ml ) and methanol ( 1 ml ), extracted with dichloromethane ( 100 ml × 3 ). the combined organic extracts were washed with saturated brine ( 30 ml × 2 ), dried over anhydrous sodium sulfate , filtered and the filtrate was concentrated under reduced pressure , then the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- n -[ 4 -[( 3 - chloro - 4 - fluoro - phenyl ) amino ]- 7 - ethoxy - quinazolin - 6 - yl ]- 3 -[( 2s )- 1 - methylpyrrolidin - 2 - yl ] prop - 2 - enamide 7 ( 60 mg , yield 65 . 2 %) as a yellow solid . 1 h nmr ( 400 mhz , dmso - d 6 ): δ 9 . 78 ( s , 1h ), 9 . 53 ( s , 1h ), 8 . 91 ( s , 1h ), 8 . 52 ( s , 1h ), 8 . 13 - 8 . 15 ( m , 1h ), 7 . 79 - 7 . 81 ( m , 1h ), 7 . 39 - 7 . 43 ( m , 1h ), 7 . 26 ( s , 1h ), 6 . 67 - 6 . 69 ( m , 2h ), 4 . 26 - 4 . 31 ( m , 2h ), 4 . 09 - 4 . 10 ( m , 1h ), 3 . 17 - 3 . 15 ( m , 2h ), 3 . 08 - 3 . 04 ( m , 1h ), 2 . 77 - 2 . 79 ( m , 1h ), 2 . 87 - 2 . 82 ( m , 1h ), 2 . 23 ( s , 3h ), 1 . 74 - 1 . 76 ( m , 1h ), 1 . 47 ( m , 3h ) 2 - methoxyethanol ( 152 mg , 2 mmol ) was dissolved in 30 ml of dimethyl sulfoxide in an ice - water bath , followed by addition of 60 % sodium hydride ( 80 mg , 2 mmol ). the mixture was warmed up to 40 ° c . and stirred for 2 hours , then n -( 3 - chloro - 4 - fluoro - phenyl )- 7 - fluoro - 6 - nitro - quinazolin - 4 - amine 8a ( 336 mg , 1 mmol ) was added . the reaction mixture was stirred for 4 hours at 40 ° c ., then warmed up to 50 ° c . and stirred for 12 hours . the reaction mixture was added with water ( 20 ml ), filtered and the filter cake was washed with water ( 50 ml ), dried under vacuum to obtain the title compound n -( 3 - chloro - 4 - fluoro - phenyl )- 7 -( 2 - methoxyethoxy )- 6 - nitro - quinazolin - 4 - amine 8b ( 392 mg , yield 100 %) as a yellow solid , which was directly used in the next step . n -( 3 - chloro - 4 - fluoro - phenyl )- 7 -( 2 - methoxyethoxy )- 6 - nitro - quinazolin - 4 - amine 8b ( 392 mg , 1 mmol ) and iron powder ( 392 mg , 7 mmol ) were dissolved in 20 ml of acetic acid . the reaction mixture was heated to reflux for 4 hours , concentrated under reduced pressure . the residue was added with 100 ml of saturated sodium bicarbonate , extracted with dichloromethane ( 100 ml × 3 ). the combined organic extracts were washed with saturated brine ( 50 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure to obtain the title compound n4 -( 3 - chloro - 4 - fluoro - phenyl )- 7 -( 2 - methoxyethoxy ) quinazoline - 4 , 6 - diamine 8c ( 200 mg , yield 55 . 2 %) as a light yellow solid . n , n ′- carbonyldiimidazole ( 292 mg , 1 . 80 mmol ) was dissolved in 4 ml of tetrahydrofuran . the mixture was heated to 50 ° c . in an oil bath , a solution of diethylphosphonoacetic acid ( 353 mg , 1 . 8 mmol ) in 3 ml of tetrahydrofuran was added dropwise , and stirred for 1 . 5 hours to the next step . n4 -( 3 - chloro - 4 - fluoro - phenyl )- 7 -( 2 - methoxyethoxy ) quinazoline - 4 , 6 - diamine 8c ( 200 mg , 0 . 55 mmol ) was dissolved in 10 ml of tetrahydrofuran , followed by dropwise addition of the above reaction solution at 50 ° c . after stirring for 3 hours at 40 ° c ., the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane ( 50 ml × 3 ). the combined organic extracts were washed with saturated brine ( 50 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound n -[ 4 -[( 3 - chloro - 4 - fluoro - phenyl ) amino ]- 7 -( 2 - methoxyethoxy ) quinazolin - 6 - yl ]- 2 - diethoxyphosphoryl - acetamide 8d ( 150 mg , yield 50 . 5 %) as a light yellow solid . n -[ 4 -[( 3 - chloro - 4 - fluoro - phenyl ) amino ]- 7 -( 2 - methoxyethoxy ) quinazolin - 6 - yl ]- 2 - diethoxyphosphoryl - acetamide 8d ( 200 mg , 0 . 37 mmol ) was dissolved in 10 ml of tetrahydrofuran . the mixture was cooled to − 78 ° c . in a dry ice bath . under argon , a solution of lithium bis ( trimethylsilyl ) amide ( 1 m ) in toluene ( 740 μl , 0 . 74 mmol ) was added dropwise . after stirring for 30 minutes , ( 2r )- 1 - methylpyrrolidine - 2 - carbaldehyde 5c ( 84 mg , 0 . 74 mmol ) was added to the reaction solution . the reaction mixture was stirred for another 1 hour , then warmed up to room temperature and stirred for 12 hours . the reaction mixture was concentrated , added with 10 ml of water , extracted with dichloromethane ( 25 ml × 3 ). the combined organic extracts were washed with saturated brine ( 30 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- n -[ 4 -[( 3 - chloro - 4 - fluoro - phenyl ) amino ]- 7 -( 2 - methoxyethoxy ) quinazolin - 6 - yl ]- 3 -[( 2r )- 1 - methylpyrrolidin - 2 - yl ] prop - 2 - enamide 8 ( 100 mg , yield 54 . 2 %) as a yellow solid . 1 h nmr ( 400 mhz , dmso - d 6 ): δ 9 . 82 ( s , 1h ), 9 . 58 ( s , 1h ), 8 . 89 ( s , 1h ), 8 . 53 ( s , 1h ), 8 . 12 - 8 . 13 ( m , 1h ), 7 . 79 - 7 . 81 ( m , 1h ), 7 . 40 - 7 . 44 ( m , 1h ), 7 . 32 ( s , 1h ), 6 . 57 - 6 . 75 ( m , 2h ), 4 . 36 - 4 . 37 ( m , 2h ), 3 . 80 - 3 . 81 ( m , 2h ), 3 . 35 - 3 . 32 ( m , 4h ), 3 . 15 - 3 . 13 ( m , 1h ), 2 . 5 ( s , 3h ), 2 . 40 - 2 . 31 ( m , 2h ), 2 . 08 ( m , 1h ), 1 . 90 - 1 . 81 ( m , 1h ), 1 . 70 - 1 . 64 ( m , 1h ) n -[ 4 -[( 3 - chloro - 4 - fluoro - phenyl ) amino ]- 7 - ethoxy - quinazolin - 6 - yl ]- 2 - diethoxyphosphoryl - acetamide 7b ( 300 mg , 0 . 59 mmol ) was dissolved in 10 ml of tetrahydrofuran . the mixture was cooled to − 78 ° c . in a dry ice bath . under argon , a solution of lithium bis ( trimethylsilyl ) amide ( 1 m ) in toluene ( 1 . 2 ml , 1 . 18 mmol ) was added dropwise . after the mixture was stirred for 30 minutes , ( 2r )- 1 - methylpyrrolidine - 2 - carbaldehyde 5c ( 133 mg , 1 . 18 mmol ) was added , and the mixture was stirred for another 1 hour , then warm up to room temperature and stirred for 12 hours . the reaction mixture was concentrated , added with 10 ml of water , extracted with dichloromethane ( 25 ml × 3 ). the combined organic extracts were washed with saturated brine ( 30 ml × 2 ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- n -[ 4 -[( 3 - chloro - 4 - fluoro - phenyl ) amino ]- 7 - ethoxy - quinazolin - 6 - yl ]- 3 -[( 2r )- 1 - methylpyrrodin - 2 - yl ] prop - 2 - enamide 9 ( 130 mg , yield 47 . 3 %) as a yellow solid . 1 h nmr ( 400 mhz , dmso - d 6 ): δ 9 . 79 ( s , 1h ), 9 . 53 ( s , 1h ), 8 . 93 ( s , 1h ), 8 . 53 ( s , 1h ), 8 . 12 - 8 . 15 ( m , 1h ), 7 . 79 - 7 . 83 ( m , 1h ), 7 . 40 - 7 . 45 ( m , 1h ), 7 . 27 ( s , 1h ), 6 . 67 - 6 . 73 ( m , 1h ), 6 . 56 - 6 . 60 ( m , 1h ), 4 . 27 - 4 . 32 ( m , 2h ), 4 . 09 - 4 . 10 ( m , 1h ), 3 . 17 ( m , 2h ), 3 . 04 ( m , 1h ), 2 . 77 - 2 . 79 ( m , 1h ), 2 . 18 - 2 . 16 ( m , 1h ), 2 . 21 ( s , 3h ), 1 . 74 - 1 . 76 ( m , 1h ), 1 . 47 ( t , 3h ) 7 ml of thionyl chloride was dissolved in 50 ml of methanol in an ice - water bath , followed by addition of pyrrolidine - 2 - carboxylic acid 10a ( 5 g , 43 . 40 mmol ). the mixture was warmed up to room temperature and stirred for 24 hours . the mixture was concentrated under reduced pressure to obtain methylpyrrolidine - 2 - carboxylate 10b ( 10 g ) crude product as a white solid , which was directly used in the next step without purification . methyl pyrrolidine - 2 - carboxylate 10b crude product ( 5 g ) was dissolved in 100 ml of methanol . the solution was cooled to 0 ˜ 5 ° c . in an ice - water bath , followed by addition of 13 ml of 40 % formaldehyde . the reaction mixture was warmed up to room temperature and stirred for 2 hours , then cooled to 0 ˜ 5 ° c . in an ice - water bath , and sodium cyanoborohydride ( 5 . 45 g , 87 . 20 mmol ) was added in batches . the reaction mixture was warmed up to room temperature and stirred for 24 hours . the mixture was concentrated under reduced pressure and added with 5 ml of water , extracted with dichloromethane ( 5 ml × 3 ). the combined organic extracts were dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure to obtain methyl 1 - methylpyrrolidine - 2 - carboxylate 10c ( 4 . 7 g , yield 70 . 1 ) crude product as a brown oil . diisobutyl aluminium hydride ( 60 ml , 66 mmol ) was added dropwise to a solution of methyl 1 - methylpyrrolidine - 2 - carboxylate 10c ( 4 . 7 g , 33 mmol ) in 50 ml of dichloromethane . the reaction mixture was stirred for 6 hours in an ice - water bath , followed by addition of 10 ml of methanol . the reaction mixture was concentrated under reduced pressure to obtain the title compound ( 1 - methylpyrrolidin - 2 - yl ) methanol 10d ( 1 . 8 g , yield 47 . 4 %) as a brown oil . dimethyl sulfoxide ( 2 . 2 ml , 31 . 20 mmol ) was dissolved in 20 ml of dichloromethane in a dry ice - acetone bath , followed by addition of oxalyl chloride ( 2 ml , 23 . 40 mmol ). after stirring for 45 minutes at − 18 ° c ., ( 1 - methylpyrrolidin - 2 - yl ) methanol 10d ( 1 . 8 g , 15 . 60 mmol ) was added . after stirring for another 45 minutes , triethylamine ( 6 . 5 ml , 46 . 80 mmol ) was added . the reaction mixture was warmed up to room temperature and stirred for 1 hour . the reaction mixture was washed with saturated brine ( 50 ml ), dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure and the resulting residue was purified by alkaline alumina column chromatography with elution system a to obtain 1 - methylpyrrolidine - 2 - carbaldehyde 10e ( 1 g , yield 56 . 8 %) as a brown oil . n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 2 - diethoxyphosphoryl - acetamide 1d ( 3 g , 4 . 40 mmol ) was dissolved in 30 ml of tetrahydrofuran in a dry ice bath , followed by dropwise addition of a solution of lithium bis ( trimethylsilyl ) amide ( 1 m ) in toluene ( 9 . 6 ml , 8 . 80 mmol ). after the mixture was stirred for 30 minutes , a solution of 1 - methylpyrrolidine - 2 - carbaldehyde 10e ( 1 g , 8 . 80 mmol ) in 5 ml of tetrahydrofuran was added dropwise . the reaction mixture was stirred for another 30 minutes , then warmed up to room temperature and stirred for 24 hours . the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system a to obtain the title compound ( e )- n -[ 4 -[[ 3 - chloro - 4 -( 2 - pyridylmethoxy ) phenyl ] amino ]- 3 - cyano - 7 - ethoxy - 6 - quinolyl ]- 3 -( 1 - methylpyrrolidin - 2 - yl ) prop - 2 - enamide 10 ( 500 mg , yield 20 . 8 %) as a yellow solid . 1 h nmr ( 400 mhz , dmso - d 6 ): δ 11 . 59 ( s , 1h ), 11 . 28 ( s , 1h ), 9 . 19 ( s , 1h ), 9 . 05 ( s , 1h ), 8 . 71 ( d , 1h ), 8 . 09 - 8 . 07 ( m , 1h ), 7 . 74 - 7 . 68 ( m , 3h ), 7 . 56 - 7 . 55 ( m , 1h ), 7 . 45 - 7 . 37 ( m , 2h ), 7 . 04 - 7 . 00 ( m , 1h ), 6 . 88 - 6 . 84 ( m , 1h ), 5 . 43 ( s , 2h ), 4 . 38 ( dd , 2h ), 4 . 10 ( m , 2h ), 3 . 63 - 3 . 60 ( m , 1h ), 3 . 13 - 3 . 08 ( m , 1h ), 2 . 73 - 2 . 72 ( m , 3h ), 2 . 31 - 2 . 29 ( m , 1h ), 2 . 08 - 2 . 02 ( m , 2h ), 1 . 53 ( t , 3h ) the following in vitro assay is to determine the activity of the compounds of the invention for inhibiting the proliferation of human epidermoid carcinoma a431 cells , which has high expression of egfr . the following in vitro assay is to determine the activity of the tested compounds for inhibiting the proliferation of cancer cells , which has high expression of egfr . the activity is represented by the ic 50 value . the general procedures of the assay are given as follows : the cancer cells a431 that highly expressing egfr ( institute of biochemistry and cell biology ) were chosen and seeded to 96 - well cell culture plate at a suitable concentration ( e . g ., 5000 cells / ml medium ). the cells then were incubated in carbon dioxide ( co 2 ) incubator until they reached 85 % confluency . then , the cell culture medium was replaced by fresh one with tested compounds added in it at serial concentrations ( general 6 to 7 concentrations ). then the cells were put back to the incubator and cultured continuously . 72 hours later , the activity of the tested compounds for inhibiting the cell proliferation was determined by using sulforhodamine b ( srb ) method . ic 50 value on tested cells are calculated by the data of inhibition rates of serial concentrations of the tested compounds . the biological activity of the compounds of the invention was tested by using the assay described above . the ic 50 values were measured and showed in table below : conclusion : the compounds of the present invention had obvious activity for inhibiting the proliferation of a431 cell . the in vitro egfr kinase activity was tested by the following assay . the following assay may be used to determine the activity of the compounds of the invention for inhibiting egfr kinase activity . the half maximal inhibitory concentration ic 50 ( the concentration of the tested compound showing 50 % inhibition of the enzyme activity ) of each compound was determined by incubating several different concentrations of the tested compounds with a specific enzyme and substrate . egfr kinase used in this assay is a human - derived recombinant protein ( cell signaling technology , # 7908 ), which was reacted with peptide substrate and different concentrations of tested compounds in a buffer solution containing 60 mm hepes ( ph7 . 5 ), 5 mm mgcl 2 , 5 mm mncl 2 , 3 μm na 3 vo 4 , 1 . 25 m dtt ( 1000 ×) and 20 μm atp at 25 ° c ., for 45 minutes . the egfr kinase activity was determined by using a time - resolved fluorescence method . the biological activity of the compounds of the invention was tested by using the assay described above . the ic 50 values were measured and showed in table below : conclusion : the compounds of the present invention had obvious activity for inhibiting the proliferation of egfr kinase . the pharmacokinetics assay of the compounds of example 1 and example 5 of the present invention the compounds of example 1 and example 5 of the present invention were administrated intragastrically to rats to determine the drug concentration in plasma at different time points by lc / ms / ms method . the pharmacokinetic behavior of the compounds of the present invention was studied and evaluated in rats . 8 healthy adult sd rats , male and female in half , were purchased from sino - britsh sippr / bk lab . animal ltd ., co , license number : scxk ( shanghai ) 2003 - 0002 the right amount of compounds were weighted and grinded with 0 . 5 % sodium carboxymethyl cellulose uniformly , suspended them with 1 % tween 80 to 2 . 5 mg / ml of suspension before use . 8 healthy adult adult sd rats , male and female in half , after an overnight fast , were administered intragastrically at a dose of 25 . 0 mg / kg , at a volume of 10 ml / kg . 8 healthy adult adult sd rats , male and female in half , were divided into 2 groups . after an overnight fast , the rats were administered intragastrically at a dose of 25 . 0 mg / kg . blood samples ( 0 . 2 ml ) were taken from orbital sinus at pre administration and at 0 . 5 , 1 . 0 , 2 . 0 , 3 . 0 , 4 . 0 , 5 . 0 , 7 . 0 , 9 . 0 , 12 . 0 , 24 . 0 and 30 . 0 hours post administration , which were stored in heparinized tubes and centrifuged for 10 minutes at 3 , 500 rpm . the plasma samples were stored at − 20 ° c . until analysis . the rats were fed 2 hours after administration . 50 μl of rat plasmas taken at various time points after administration were mixed with 50 μl of standard series solution to obtain plasma concentration of 50 . 0 , 100 , 200 , 500 , 1000 , 2000 , 5000 ng / ml . 150 μl methanol was added and then the mixture was mixed for 3 minute using a vortexer and centrifuged for 10 minutes at 13 , 500 rpm . 10 μl of the supernatant was analyzed by lc - ms / ms . the main pharmacokinetic parameters were caculated by das 2 . 0 software . pharmacokinetic parameters of the compounds of the present invention were shown as follows : conclusion : the compounds of the present invention had good absorption in pharmacokinetics and the pharmacokinetic characteristics improved obviously . the therapeutic effects against xenografts of calu - 3 human lung cancer in nude mice the therapeutic effect of the compound of example 1 against xenografts of calu - 3 human lung cancer in nude mice was estimated . the compound of example 1 markedly inhibited the growth of calu - 3 human lung cancer , and the tested mice were well tolerant . the therapeutic effects of the compounds of example 1 and example 5 against xenografts of calu - 3 human lung cancer in nude mice was estimated and compared . drugs name and batch of drugs : the compounds of example 1 and example 5 preparation method : the compounds of example 1 and example 5 were prepared to corresponding concentration by using distilled water containing 0 . 1 % tween - 80 . balb / ca - nude mice , 6 to 7 weeks old , ♀, purchased from slaccas experimental animal ltd ., co . nude mice were hypodermic inoculated calu - 3 human lung cancer cell . after tumors grew to 150 - 250 mm 3 , mice were randomly divided into teams ( d0 ). the volume of tumors and the weigh of the mice were measured and recorded for 2 - 3 times per week . the calculation formula of the volume of tumor ( v ) is : v = ½ × a × b 2 , a : length of tumor , b : width of tumor . the compound of example 1 markedly inhibited the growth of calu - 3 human lung cancer . low dose ( 100 mg / kg ) of the compound of example 1 reduced 2 / 6 of the tumor volume , high dose ( 200 mg / kg ) of the compound of example 1 reduced 1 / 6 of the tumor volume and completely degrade other 1 / 6 of the tumor . low dose ( 100 mg / kg ) of the compound of example 5 reduced 3 / 6 of the tumor volume , high dose ( 200 mg / kg ) of the compound of example 5 reduced 4 / 6 of the tumor volume . moreover , the mice were well tolerant to the compounds of example 1 and example 5 according to the present administration protocol .