IP Library Granted Patent US 8,003,658
Granted Patent B2
US 8,003,658 · App. 11/722,096 · Granted Aug 23, 2011

Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof

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Quick Facts
Patent No.
US 8,003,658
App. No.
11/722,096
Granted
Aug 23, 2011
Kind
B2
Abstract

The present invention relates to a novel quinazoline derivative and a pharmaceutically acceptable salt thereof for inhibiting the growth of cancer cells, a method for the preparation thereof and a pharmaceutical composition comprising same as an active ingredient.

Claims (262)

1. A quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof:

wherein,

R 1 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 alkylthio, 2 ((N-methyl-(2′hydroxyethyl)amino)methyilvinyl, phenoxy, phenyl, dimethylaminoethoxymethyl, methoxyethoxymethyl, 4-methylpiperazinylmethyl, ethoxycarbonyl, benzamino, cyclopentenyl, 2-(4-methylpiperazinylmethylvinyl, methanesulfonylethylaminomethyl, methoxyethylaminomethyl, 2-(methanesulfonylethylaminomethyl)vinyl, or 5-membered heteroaryl having 1-2 heteroatoms selected from N, O, or S which are optionally substituted with X;

R 2 is hydrogen, or C 1-6 alkyl;

R 3 is hydrogen, C 1-6 alkyl or C C 1-6 dialkylamino C 1-6 alkyl;

Y is —(CR 11 R 12 )—, phenyl or a 5-membered heteroaryl having 1 sulfur atom, R 11 and R 12 being each independently hydrogen, halogen, hydroxy, carboyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, phenyl, or optionally fused to each other to form a 3 membered non-aromatic ring, or R 11 or R 12 may be fused to R 2 to form together with the carbon and nitrogen they are attached to a 4 to 8-membered non-aromatic ring, optionally comprising additional heteroatom S;

R 4 is hydrogen, halogen, C 1-6 alkoxy, ethylsulfanyl, cyclopropylmethoxy, cyclopentyloxy or C 1-6 alkylamino optionally substituted with R 13 , R 13 being halogen, trifluoromethyl, C 1-6 alkoxy, 4-methylpiperidinylmethoxy, dimethylamino or a 6-membered heteroaryl having 1-2 heteroatoms selected from N and O;

R 5 is hydrogen or C 1-3 alkyl;

R 6 is phenyl, 1-phenyl-ethyl, 3-ethynyl-phenyl, 1-penta-2,4-dienyl-1H-indazol-5-yl, imidazole or a 9-membered heteroaryl having 1-2 nitrogen atoms, optionally substituted with R 15 , being hydrogen halogen, C 1-6 alkyl, or phenyl, benzyl, a 10-membered heteroaryl C 1-6 alkyl having 1 nitrogen atom, benzyloxy, a 6-membered heteroaryl C 1-6 alkoxy having 1 nitrogen atom, a 6-membered heteroaryloxy having a nitrogen atom, phenylcarbamoyl, optionally substituted with R 16 , wherein R 16 is halogen, nitro, C 1-6 alkyl, or C 1-6 alkoxy;

n is an integer in the range of 1 to 4;

p is 0 or 1;

X is a halogen, nitro, cyano, trifluoromethyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 dialkylamino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkanoyl, phenyl, or a 5- to 6-membered heteroaryl having 1-2 heteroatoms selected from N and O; wherein heteroaryl is a heteroaromatic or non-aromatic.

2. The compound of claim 1 , wherein R 1 is methyl, cyclopropyl, trifluoromethyl, cyanomethyl, chloromethyl, phenyl, methoxy, phenoxy, benzyloxy, methoxymethyl, acetoxymethyl, dimethylaminoethoxymethyl, methoxyethoxymethyl, methylthiomethyl, methanesulfinylmethyl, methanesulfonylmethyl, dimethylaminomethyl, morpholinomethyl, 4-methylpiperazinylmethyl, methanesulfonylethylaminomethyl, methoxyethylaminomethyl, ethoxycarbonyl, ethylamino, furan-3-yl, furan-2-yl-methylamino, benzamino, benzylamino, 1-buthoxy, 3-methyl-isoxazol-5-yl, 5-methyl-isoxazol-4-yl, 1H-pyrazol-4-yl, vinyl, penta-1,3-dienyl, cyclopentenyl, 2-phenylvinyl, 2-methylvinyl, 2,2-dimethylvinyl, 1-methylvinyl, 2-phenylethynyl, 2-methylethynyl, 2-(bromomethyl)vinyl, 2-(dimethylaminomethyl)vinyl, 2-(morpholinomethyl)vinyl, 2-(4-methylpiperazinylmethyl)vinyl, 2-((N-methyl-(2-hydroxyethyl)amino)methyl)vinyl or 2-(methanesulfonylethylaminomethyl)vinyl;

R 2 is hydrogen, methyl, ethyl;

R 3 is methyl, ethyl or 3-(N,N-dimethylamino)propyl;

R 4 is hydrogen, fluoro, chloro, methoxy, ethoxy, methoxyethoxy, methoxypropoxy, ethylsulfanyl, cyclopropylmethoxy, cyclopentyloxy, 2,2,2-trifluoroethoxy, 2-fluoroethoxy, N,N-dimethylamino, morpholinopropoxy or 4-methylpiperadinylmethoxy;

R 5 is hydrogen;

R 6 is 1 phenyl-ethyl, 3-ethynyl-phenyl, biphenyl, 3-chloro-4-fluoro-phenyl, 3-chloro-4-(3-fluoro-benzyloxy)-phenyl, 3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl, 4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl, N-phenyl-benzamid-4-yl, 3-chloro-4-(pyridin-2-ylmethoxy)-phenyl, 3-chloro-4-(pyridin-3-ylmethoxy)-phenyl, 3-chloro-4-(6-methyl-pyridin-2-ylmethoxy)-phenyl, 3-chloro-4-(pyridin-4-ylmethoxy)-phenyl, 3-methyl-4-(pyridin-2-ylmethoxy)-phenyl, 1-pyridin-2-ylmethyl-1H-indazol-5-yl, 1-(3-fluoro-benzyl)-1H-indazol-5-yl, 1-penta-2,4-dienyl-1H-indazol-5-yl, 3-chloro-4-(2-fluoroethoxy)-phenyl, 2-methyl-1H-indol-5-yl or 1-benzyl-1H-indazol-5-yl;

Y is —(CR 11 R 12 )—, phenyl or thiophene, R 11 and R 12 being each independently hydrogen, hydroxyl, halogen, C 1-6 alkyl, carboxyC 1-3 alkyl, C 1-3 alkoxy, phenyl, or optionally, fused to each other to form a 3 membered non-aromatic ring, or R 11 or R 12 may be fused to R 2 to form together with the carbon and nitrogen they are attached to a 4 to 6-membered non-aromatic ring.

3. The compound of claim 1 , which is selected from the group consisting of:

({-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-methyl)-carbamic acid t-butylester;

N-({-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-methyl)-2-methoxy-acetamide;

N-({-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-methyl)-2-methanesulfonyl-acetamide;

N-({-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-methyl)-acrylamide;

(2S)—N-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-2-(2-methoxy-acetylamino)-3-phenyl-propionamide;

(1S)-(1-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-3-methanesulfanyl-propyl)-carbamic acid t-butylester;

(2S)—N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-2-(2-methoxy-acetylamino)-4-methanesulfanyl-butyramide;

(2S)—N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-2-(2-methanesulfonyl-acetamino)-4-methanesulfanyl-butyramide;

(2S)-2-acryloylamino-N-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-methanesulfanyl-butyramide;

(1-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-cyclopropyl)-carbamic acid t-butylester;

(2S)—N-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-2-(2-methoxy-acetylamino)-2-phenyl-acetamide;

(4S)-4-t-buthoxycarbonylamino-4-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-butyric acid methylester;

4-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-4-(2-methoxy-acetylamino)-butyric acid methylester;

4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-4-(2-methoxy-acetylamino)-butyric acid;

2-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-1-quinazolin-6-ylcarbamoyl}-pyrrolidine-1-carboxylic acid t-butylester;

1-(2-methoxy-acetyl)-pyrrolidine-2-carboxylic acid {-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-amide;

1-(2-methanesulfonyl-acetyl)-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-amide;

1-acryloyl-pyrrolidine-2-carboxylic acid {-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-amide;

(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-carbamic acid t-butylester;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2-methoxy-acetylamino)-propionamide;

N-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2-methanesulfonyl-acetylamino)-propionamide;

N-(2-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

3-phenyl-propionylic acid (2-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbarnoyl}-ethyl)-amide;

hexa-2,4-dienonylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

cyclopent-1-en carboxylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

N-(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-3-phenyl-acrylamide;

but-2-ynoylic acid(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

but-2-enonylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

3-methyl-but-2-enonylic acid, (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

N-(2-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-2-methyl-acrylamide;

N-(2-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-2-cyano-acetamide;

3-methyl-isoxazol-5-carboxylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

furan-3-carboxylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyp-amide;

1H-pyrazol-4-carboxylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyp-amide;

N-(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-benzamide;

N-(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-oxalamic acid ethylester;

cyclopropylcarboxylic acid (2-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

acetic acid 2-t-buthoxycarbonylamino-1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl carbamoyl}-ethylester;

acetic acid 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-2-(2-methoxy-acetylamino)-ethylester;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-2-hydroxyl-3-(2-methoxy-acetylamino)-propionamide;

(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-propyl)-carbamic acid t-butylester;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2-methoxy-acetylamino)-2-methyl-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2-methanesulfonyl-acetylamino)-2-methyl-propionamide;

N-(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-propyl)-acrylamide;

(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-1-phenyl-ethyl)-carbamic acid t-butylester;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2-methoxy-acetylamino)-3-phenyl-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2-methanesulfonyl-acetylamino)-3-phenyl-propionamide;

3-(2-methoxy-acetylamino)-thiophene-2-carboxylic acid {4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-amide;

(2-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-carbamic acid t-butylester;

3-(2-methanesulfonyl-acetylamino)-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl amino]-quinazolin-6-yl}-propionamide;

N-(2-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

{2-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-ylcarbamoyl]-ethyl}-carbamic acid t-butylester;

N-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-3-(2-methanesulfonyl-acetylamino)-propionamide;

N-{2-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-ylcarbamoyl]-ethyl}-acrylamide;

4-bromo-but-2-enonylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

4-dimethylamino-but-2-enonylic acid (2-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

4-morpholin-4-yl-but-2-enonylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

4-(4-methyl-piperazin-1-yl)-but-2-enonylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

4-[(2-hydroxyl-ethyl)-methyl-amino]-but-2-enonylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

4-(2-methanesulfonyl-ethylamino)-but-2-enonylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-amide;

3-(2-chloro-acetylamide)-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2-morpholin-4-yl-acetylamino)-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2-dimethylamino-acetylamino)-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-[2-(4-methyl-piperazin-1-yl)-acetylamino]-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-[2-(2-methoxy-ethylamino)-acetylamino]-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-[2-(2-methanesulfonyl-ethylamino)-acetylamino]-propionamide;

3-(2-chloro-acetylamino)-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamin]-quinazolin-6-yl}-propionamide;

N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-3-(2-morpholin-4-yl-acetylamino)-propionamide;

3-(2-dimethylamino-acetylamino)-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-propionamide;

N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-3-[2-(4-methyl-piperazin-1-yl)-acetylamino]-propionamide;

3-[2-(2-methoxy-ethylamino)-acetylamino]-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-methylamino]-quinazolin-6-yl}-propionamide;

3-[2-(2-methanesulfonyl-ethylamino)-acetylamino]-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop ionamide;

N-{2-[4-(2-methyl-1H-indol-5-ylamino)-quinazolin-6-ylcarbamoyl]ethyl}-acrylamide;

3-(2-methanesulfonyl-acetylamino)-N-[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-propionamide;

N-{2-[4-(1-phenyl-ethylamino)-quinazolin-6-ylcarbamoyl]-ethyl-acrylamide;

N-[2-(4-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenylamino}-quinazolin-6-ylcarbamoyl)-ethyl]-acrylamide;

{2-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-6-ylcarbamoyl]ethyl}-carbamic acid t-butylester;

N-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl]-3-(2-methanesulfonyl-acetylamino)-propionamide;

N-{2-[4-(1-benzyl-1H-imidazol-5-ylamino)-quinazolin-6-ylcarbamoyl]-ethyl}-acrylamide;

{2-[4-(4-phenylcarbamoyl-phenylamino)-quinazolin-6-ylcarbamoyl]-ethyl}-carbamic acid t-butylester;

4-{6-[3-(2-methanesulfonyl-acetylamino)-propionylamino]-quinazolin-4-ylamino}-N-phenyl-benzamide;

4-[6-(3-acryloylamino-propionylamino)-quinazolin-4-ylamino]-N-phenyl-benzamide;

N-[4-(biphenyl-4-ylamino)-quinazolin-6-yl]-3-(2-methanesulfonyl-acetylamino)-propionamide;

N-{2-[4-(biphenyl-4-ylamino)-quinazolin-6-ylcarbamoyl]-ethyl}-acrylamide;

N-{2-[4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-ylcarbamoyl]-ethyl}-acrylamide;

(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-propyl)-carbamic acid t-butylester;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-methoxy-acetylamino)-butyramide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-methanesulfonyl-acetylamino)-butyramide;

4-acryloylamino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-butyramide;

N-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-propyl)-benzamide;

N-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-propyl)-oxalamic acid ethylester;

cyclopropylcarboxylic acid (3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-propyl)-amide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-cyano-acetyl amino)-butyramide;

furan-3-carboxylic acid (3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-propyl)-amide;

1H-pyrazol-4-carboxylic acid (3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-propyl)-amide;

{3-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-ylcarbamoyl]-propyl}-carbamic acid t-butylester;

N-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-4-(2-methanesulfonyl-acetylamino)-butyramide;

4-acryloylamino-N-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-butyramide;

(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylcarbonyl}-propyl)-carbamic acid t-butylester;

4-(2-methanesulfonyl-acetylamino)-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl amino]-quinazolin-6-yl}-butyramide;

4-acryloylamino-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-butyramide;

4-(2-chloro-acetylamino)-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-butyramide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-morpholin-4-yl-acetylamino)-butyramide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-dimethylamino-acetylamino)-butyramide;

N-{-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-[2-(4-methyl-piperazin-1-yl)-acetylamino]-butyramide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-[2-(2-methoxy-ethylamino)-acetylamino]-butyramide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-[2-(2-methanesulfonyl-ethylamino)-acetylamino]-butyramide;

4-(2-chloro-acetylamino)-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-butyramide;

N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-4-(2-morpholin-4-yl-acetylamino)-butyramide;

4-(2-dimethylamino-acetylamino)-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-butyramide;

N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl]-4-[2-(4-methyl-piperazin-1-yl)-acetylamino]-butyramide;

4-[2-(2-methanesulfonyl-ethylamino)-acetylamino]-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-butyramide;

4-[2-(2-methoxy-ethylamino)-acetylamino]-N-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-butyramide;

(4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-butyl)-carbamic acid t-butylester;

5-(2-methoxy-acetylamino)-pentanoic acid {4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-amide;

5-(2-methanesulfonyl-acetylamino)-pentanoic acid {4-[3-chloro-4-(3-fluoro-benzyloxy)-pentylamino]-quinazolin-6-yl}-amide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2-methanesulfanyl-acetylamino)-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2-methanesulfinyl-acetylamino)-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(2,2,2-trifluoro-acetylamino)-propionamide;

3-acetylamino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-propionamide;

acetic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethylcarbamoyl)-methylester;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-[2-(2-dimethylamino-ethoxy)-acetylamino]-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(3-ethyl-ureido)-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(3-phenyl-ureido)-propionamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-(3-furan-2-ylmethyl-ureido)-propionamide;

(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-carbamic acid methylester;

(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-carbamic acid phenylester;

(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-carbamic acid benzylester;

N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-3-(2-methoxy-acetylamino)-propionamide;

N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-3-(2-methanesulfonyl-acetylamino)-propionamide;

N-(2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

N-{4-[3-chloro-4-(pyridin-3-ylmethoxy)-phenylamino]-quinazolin-6-yl}-3-(2-methoxy-acetylamino)-propionamide;

N-{4-[3-chloro-4-(pyridin-3-ylmethoxy)-phenylamino]-quinazolin-6-yl}-3-(2-methanesulfonyl-acetylamino)-propionamide;

N-(2-{4-[3-chloro-4-(pyridin-3-ylmethoxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-3-[2-(2-methoxy-ethoxy)-acetylamino]-propionamide;

5-methyl-isoxazol-4-carboxylic acid (2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazol in-6-ylcarbamoyl}-ethyl)-amide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-methanesulfanyl-acetylamino)-butyramide;

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-methanesulfinyl-acetylamino)-butyramide;

N-[2-({4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-methyl-carbamoyl)-ethyl]-acrylamide;

N-[2-({4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-ethyl-carbamoyl)-ethyl]-acrylamide;

N-{2-[{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-(3-dimethylamino-propyl)-carbamoyl]-ethyl}-acrylamide;

N-(2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-N-methyl-acrylamide;

N-(2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-N-methyl-acrylamide;

N-(2-{4-[3-chloro-4-(6-methyl-pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

(2S)-1-acryloyl-pyrrolidin-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

(2S)-1-(1-oxo-butyn-2-yl)-pyrrolidin-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(6-methyl-pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

(3R,5S)-acetic acid 1-acryloyl-5-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-pyrrolidin-3-ylester;

(2S,4R)-1-acryloyl-4-hydroxyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl)-amide;

(2S,4R)-1-acryloyl-4-ethylsulfanyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

(2S,4R)-1-acryloyl-4-dimethylamino-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-3-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-4-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

2-(1-acryloyl-pyrrolidin-2-yl)-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-acetamide;

1-acryloyl-pyrrolidine-3-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

1-acryloyl-piperidine-4-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid [4-(3-ethynyl-phenylamino)-quinazolin-6-yl]-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid [4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]amide;

(2S,4R)-1-acryloyl-4-ethanesulfonyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

(2S,4R)-1-acryloyl-4-methoxy-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

1-acryloyl-piperidine-3-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

1-acryloyl-azetidine-3-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

1-acryloyl-piperidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-fluoro-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

N-(2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

(2S)-1-acryloyl-pyrrolidin-2-carboxylic acid {7-methoxy-4-[3-methyl-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

2-(1-acryloyl-pyrrolidin-2-yl)-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-acetamide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-ethoxy-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-ethylsulfanyl-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-cyclopropylmethoxy-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-cyclopentyloxy-quinazolin-6-yl}-amide;

N-(2-{4-[3-chloro-4-(pyridin-4-ylmethoxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

(2S)-1-(4-dimethylamino-buten-2-oyl)-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {7-chloro-4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {7-fluoro-4-[3-methyl-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

N-(2-{7-fluoro-4-[3-methyl-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

(2S)-1-acryloyl-2,5-dihydro-1H-pyrrol-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

(4R)-3-acryloyl-thiazolidin-4-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

1-acryloyl-azetidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide;

1-acryloyl-azetidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid [4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2,2,2-trifluoro-ethoxy)-quinazolin-6-yl]-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-dimethylamino-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid [7-methoxy-4-(1-pyridin-2-ylmethyl-1H-indazol-5-ylamino)-quinazolin-6-yl]-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-methyl-4-(pyridin-2-ylmethoxy)-phenylamino]-7-ethoxy-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid [4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2-fluoro-ethoxy)-quinazolin-6-yl]-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-7-methoxy-quinazolin-6-yl}-amide;

(1R)—N-(1-{4-[3chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

(1S)—N-(1-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

(1S)—N-(1-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ylcarbamoyl}ethyl)-N-methyl-acrylamide;

N-(2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-fluoro-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid [7-methoxy-4-(1-penta-2,4-dienyl-1H-indazol-5-ylamino)-quinazolin-6-yl]-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(6-methyl-pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

1-acryloyl-azetidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-fluoro-quinazolin-6-yl}-amide;

1-acryloyl-piperidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

1-acryloyl-piperidine-4-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

1-acryloyl-pyrrolidine-3-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

1-acryloyl-azetidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-ethoxy-quinazolin-6-yl}-amide;

1-acryloyl-azetidine-3-carboxylic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

(3S)-1-acryloyl-piperidine-3-carboxylic acid

{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

N-((1S)-1-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ylcarbamoyl}-ethyl)-N-ethyl-acrylamide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(2-fluoro-ethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-3-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-amide;

(2S)-2-acryloylamino-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-butyramide;

N-(2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ylcarbamoyl}-2-fluoro-ethyl)-acrylamide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-3-ylmethoxy)-phenylamino]-7-(1-methyl-piperidin-4-ylmethoxy)-quinazolin-6-yl}-amide;

(1R)—N-(1-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2-methoxy-ethoxy)-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(pyridin-3-ylmethoxy)-phenylamino]-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl}-amide;

N-({4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ylcarbamoyl}-methyl)-acrylamide

N-({4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-methoxy-quinazolin-6-ylcarbamoyl}-methyl)-acrylamide;

(3S)-3-acryloylamino-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-butyramide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid [4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl]-amide;

(1S)—N-{1-[4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

(2S)-1-acryloyl-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-amide;

(1S)—N-(1-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

N-{[4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-ylcarbamoyl]-methyl}-acrylamide;

N-({4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-ylcarbamoyl}-methyl]-acrylamide;

(1S)—N-(1-{4-[3-chloro-4-(pyridin-2-ylemthoxy)-phenylamino]-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-ylcarbamoyl}-ethyl-acrylamide;

(1S)—N-(1-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(3-methoxypropoxy)-quinazolin-6-ylcarbamoyl}-ethyl)-acrylamide;

(2S)-2-acryloylamino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-4-methylsulfanyl-butyramide;

(2S)-2-acryloylamino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-4-methylsulfanyl-butyramide;

(2S)-2-acryloylamino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-methoxy-quinazolin-6-yl}-4-methylsulfanyl-butyramide;

(2S)-2-acryloylamino-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazol in-6-yl}-3-methyl-butyramide; and

(2S)-2-acryloylamino-4-methyl-pentanoic acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-yl}-amide.

4. A process for preparing the quinazoline derivative of claim 1 , which comprises the step of subjecting a compound of formula (IV) to a condensation reaction with a compound of formula (V):

wherein,

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y, n and p have same meanings as defined in claim 1 .

5. A process for preparing the quinazoline derivative of claim 1 , which comprises the step of subjecting a compound of formula (II) to a condensation reaction with a compound of formula (IX):

wherein,

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y, n and p have same meanings as defined in claim 1 , and G′ is halogen, hydroxy or C 1-6 alkanoyloxy.

6. The process of claim 4 , wherein the condensation reaction is carried out in the presence of a condensation reagent selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N,N-dicyclohexyldiimide, C1-6alkylchloroformate, carbonyldiimidazole and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate.

7. The process of claim 4 , wherein the condensation reaction is carried out in a solvent selected form the group consisting of methylene chloride, chloroform, N,N-dimethylformamide, THF, 1,4-dioxane, acetonitrile and a mixture thereof at a temperature ranging from −20° C. to the boiling point of the solvent.

8. The process of claim 5 , wherein the compound of formula (II) is prepared by subjecting a compound of formula (IV) to a condensation reaction with a compound of formula (VIII) to obtain a compound of formula (III), followed by removing the amine protecting group P from the compound of formula (III):

wherein,

R 2 , R 3 , R 4 , R 5 , R 6 , Y, n and p have same meanings as defined in claim 1 , P is an amine protecting group, and G is halogen, hydroxy or C 1-6 alkanoyloxy.

9. The process of claim 4 , wherein the compound of formula (IV) is prepared by reacting a compound of formula (XVII) with a compound of formula (XX) to obtain a compound of formula (XVI), followed by reducing the compound of formula (XVI):

wherein,

R 4 , R 5 , R 6 and p have same meanings as defined in claim 1 .

10. A pharmaceutical composition comprising the compound or salt defined in claim 1 as an active ingredient and a pharmaceutically acceptable carrier.

11. The composition of claim 10 , which is administered in combination with an anticancer agent selected from the group consisting of cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents and antiandrogen.

Assignments (3)
CHANGE OF NAME Recorded Aug 3, 2012
From: HANMI HOLDINGS CO., LTD.
To: HANMI SCIENCE CO., LTD.
Reel/Frame 028722/0332 →
CHANGE OF NAME Recorded Jan 7, 2011
From: HANMI PHARM. CO., LTD.
To: HANMI HOLDINGS CO., LTD.
Reel/Frame 025599/0842 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 19, 2007
From: HAM, YOUNG JIN; GONG, JI HYEON; CHA, MI YOUNG; KIM, JONG WOO; KIM, MAENG SUP; KIM, EUN YOUNG; SONG, JI YEON; KIM, CHANG IN; KIM, SE YOUNG; LEE, GWAN SUN
To: HANMI PHARM. CO., LTD
Reel/Frame 019446/0640 →