AU2003226705B2

AU2003226705B2 - 4-(N-phenylamino)-quinazolines / quinolines as tyrosine kinase inhibitors

Info

Publication number: AU2003226705B2
Application number: AU2003226705A
Authority: AU
Inventors: Frank Himmelsbach; Birgit Jung; Flavio Solca
Original assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2002-03-30
Filing date: 2003-03-25
Publication date: 2008-11-06
Anticipated expiration: 2023-03-25
Also published as: PE20040169A1; NO329271B1; PL371188A1; EP1492536A1; KR101064530B1; ATE557008T1; CN1642552A; NO20043997L; TWI331604B; EA200401191A1; EA200701302A1; AU2003226705A1; HK1079095A1; HRP20040898A2; IL164167A0; EA009300B1; WO2003082290A1; CA2476008C; JP4776882B2; NZ536114A

Description

WO 03/082290 1 PCT/EP03/03062 4-(N-Phenylamino) Quinazolines Quinolines as Tyrosine Kinase Inhibitors The present invention relates to bicyclic heterocyclic groups of general formula Ra Rb

N"

N

R(I),

the tautomers, the stereoisomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, as well as benign prostate hyperplasia (BPH), diseases of the lungs and respiratory tract, and the preparation thereof.

In the above general formula I

R

a denotes a hydrogen atom or a C1-4-alkyl group, Rb denotes a phenyl or 1-phenylethyl group, wherein the phenyl nucleus is substituted in each case by the groups R 1 to R 3 while

R

1 and R 2 which may be identical or different, in each case denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a C1- 4 -alkyl, hydroxy, C1-4-alkoxy, C 2 -3-alkenyl or C2-3-alkynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, WO 03/082290 2 PCT/EPO3/03062 a heteroaryl, heteroaryloxy, heteroaryl methyl or heteroarylmethoxy group, a methyl or methoxy group substituted by 1 to 3 fluorine atoms or a cyano, nitro or amino group, and R 3 denotes a hydrogen, fluorine, chlorine or bromine atom or a methyl or trifluoromethyl group, Rc denotes a cyclobutyl, cyclopentyl or cyclohexyl group which is substituted in each case by a group R 4

-N-R

5 while

R

4 denotes a hydrogen atom or a C 13 -alkyl group and

R

5 denotes a hydrogen atom or a 0 13 -alkyl group, an aminocarbonyl-Cl- 3 -alkyl, Cl 1 3 -alkylaminocarbonyl-C..

3 -alkyl, di- (C1.3-alkyl)aminocarbonyl-0 1 3 -alkyl, pyrrolidin-1 -ylcarbonyl-Cl- 3 -alkyl, piperidin-1 -ylcarbonyl-Ci..

3 -alkyl, homopiperidin-1 -ylcarbonyl-Cl 1 3 -alkyl, morpholin-4-ylcarbonyl-Cl- 3 -alkyl, homomorpholin-4-ylcarbonyl-

CI-

3 -alkyl, piperazin-1 -ylcarbonyl-C..

3 -alkyl, 4-Ci..

3 -alkyl-piperazin-1 ylcarbonyl-C..

3 -alkyl, homopiperazin-1 -ylcarbonyl-C..

3 -alkyl or a 4- C1..3-alkyl-homopiperazin-1 -ylcarbonyl-C..

3 -alkyl group, a hydroxy-0 2 -4-al kyl, C1..3-alkyloxy-0 2 -4-alkyl, Cl-4-al kyloxycarbonylamino-0 2 -4-alkyl, amino-C24-alkyl, C1..3-alkylamino-C 2 -4-alkyl, di-(Cl-.3-alkyl)amino-C 2 4-alkyl, C1l3-alkylcarbonylaminO-C 2 -4-alkyl, aminocarbonylamino-C 2 4 -alkyl, C1-3-alkylaminocarbonylamino- C2-4-alkyl, di-(C1.3-alkyl)amino-carbonylamino-0 2 -4-alkyl, pyrrolidin-1 ylcarbonylamino-C 2 4 -alkyl, piperidin-1 -ylcarbonylamino-0 2 -4-alkyl, 2 -4-alkyl, 01-3-alkylsulphonYl-C 2 4 -alkyl or WO 03/082290 WO 03/82290PCT/EP03/03062 a Cl 3 -alkylsulphonylamino-C 2 -4-alkyI group, a (2-oxo-pyrrolidin-1 -YI)-02-4-alkyl, (2-oxopipendin-1 -yi)-C2-4-alkyl, (3oxo-morpholin-4-y)-C 2 4-alkyI, (2-oxo-imidazolidin-1 -YI)-02-4-alkyl, (2oxo-3-Cl-.

3 -alkyl-imidazolid in-i -YI)-0 2 4 -aI kyl, (2-oxohexahydropyrimidin-1 -YI)-0 2 4 -alkyl or a (2-oxo-3-0 1 3 -alkylhexahydropyrimidin-1 -YI)-C 24 -alkyl group, a Cl-4-alkylsulphonyl, chloro-Cl-4-alkylsulphonyl, bromo- Cl-4-alkylsulphonyl, amino-Cl-4-alkylsulphonyl, 0 1 3 -alkylamino- Cl-4~-akysulphonyI, di-(Ci..

3 -alkyl)amino-C, 4 -alkylsulphonyl, (pyrrolidin- 1 -yI)-C,4-alkylsulphonyI, (piperidin-1 -yI)-CI..

4 -alkylsulphonyl, (homopiperidin-1 -YI)-Cl4-alkylsulphonyl, (morpholin-4-y)-Cl.

4 -alkyIsuiphonyl, (homomorpholin-4-yI)-Cl4-alkylsulphonyl, (piperazin-1 -yI)- Cl-4-alkylsulphonyI, (4-Ci..3-alkyl-piperazin-1 -YI)-Cl4-alkylsulphony, (homopiperazin-1 -YI)-C 1 4 -alkylsulphonyl or a (4-Ci 3 -alkylhomopiperazin-1 -yI)-Cl 4 -alkylsulphonyl group, a Cl4-alkyloxycarbonyI group, a formyl, C 14 -alkyl-carbonyl, Cv .3-alkyloxy-C,4-alkyl-carbonyl, tetra hyd rofura nylca rbonyl, tetra hyd ropyra nylca rbonyl, amino-C,4-alkylcarbonyl, Ci..3-alkylamino-Cl4-alkyl-carbonyl, di-(C 1 3 -alkyl)amino- C1A4-alkyl-carbonyl, pyrrolidin-1 -yi-C1A4-alkyl-carbonyl, piperidin-1 -yI- Cl-4-alkyl-carbonyl, (homopiperidin- 1 -Y)-Cl 4 -alkyl-carbonyl, morpholin- 4-yI-C1A4-aikyl-carbonyl, (homomorpholin-4-y)-C 1 -4-alkyI-carbony, (piperazin-1 -yI)-C 1 4 -alkyl-carbonyl, (4-C1-3-alkyl-piperazin-1 -yI)-

C

1 4-alkyI-carbonyI, (homopiperazin-1 -yI)-Cl-4-alkyi-carbonyl, (4-

C

1 3 -alkyl-homopiperazin-1 -Yi)-C 1 l 4 -aky-carbony or a C1-3-alkylsulphonyl-Cl-4-alkyl-carbony group, a cyano, aminocarbonyl, Cl13-alkyl-aminocarbonyl, di-(Cl- 3 -alkyl)aminocarbonyl, (Cl 3-alkylOXY-C 2 -4-alkyI)aminocarbony, N-(C 1 3 -alkyl 1 alkyloxy-C24-alkyl)aminocarbonyi, arylaminocarbonyl, pyrrolidin -1- WO 03/082290 WO 03/82290PCT/E P03/03062 ylcarbonyl, piperidin-1 -ylcarbonyl, homopiperidin-1 -ylcarbonyl, morphol in-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, bicyclol2 .2.1 ]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2.1 ]oct-8ylcarbonyl, 8-oxa-3-aza-bicyclo[3 .2.1 ]oct-3-ylcarbonyl, piperazin-1 ylcarbonyl, 4-01.3-al kyl-piperazin- 1-ylcarbonyl, homnopiperazin-1 ylcarbonyl, 4-0 1 3 -alkyl-homopiperazin-1 -ylcarbonyl, amninosulphonyl, Ci..

3 -alkyl-aminosulphonyl, di-(0 1 3 -alkyl)amino-sulphonyl, pyrrolidin-1 yI-sulphonyl, piperidin-1 -ylsulphonyl, homopiperidin-1 -ylsulphonyl, morpholin-4-ylsulphonyl, homomorpholin-4-ylsulphonyl, piperazin-1 ylsulphonyl, 4-C 1 3 -alkyl-piperazin-1 -ylsulphonyl, homnopiperazin-1 ylsulphonyl or a 4-Ci..3-alkyl-homopiperazin-1 -ylsLphonyl group, a cyclobutyl, cyclopentyl or cyclohexyl group which is substituted in each case by a group R'5, where

R

6 denotes a 2-oxo-pyrrolidin-1 -yl, 2-oxopiperidin-1 -yl, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1 -yl, 2-oxo-3-Ci..

3 -alkyl-imidazolidin- 1 -yI, 2-oxo-hexahydropyrimidin-1 -yI or a 2-oxo-3-0 1 3 -alkylhexahydropyrimidin-1 -yl group, an azetidin-3-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, a pyrrolidin-3-yl group which is substituted in the 1 position by the while R 5 is as hereinbefore defined, a piperidin-3-yl group which is substituted in the 1 position by the group R while R 5 is as hereinbefore defined, a piperidin-4-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, or a tetra hydrofura n-3-y, tetra hydropyran-3-y or tetra hyd ropyran-4 -yl group, WO 03/082290 WO 03/82290PCT/EPO3/03062 R d denotes a hydrogen atom or a fluorine, chlorine or bromine atom, a hydroxy group, a C 1 4-alkyloxy group, a methoxy group substituted by 1 to 3 fluorine atoms, an ethyloxy group substituted by 1 to 5 fluorine atoms, a C2-4-alkyloxy group which is substituted by a group R 6 or R while R 6 is as hereinbefore defined and R 7 denotes a hydroxy, C 1 .3-alkyloxy, C 36 -cycloal kyloxy, amino,

C

1 3 -alkylamino, di-(Ci..

3 -alkyl)amino, bis-(2-methoxyethyl)-amino, pyrrolidin-1 -yl, piperidin-1 -yi, homopiperidin-1 -yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyco[2 .2.1 ]hept-5-yI, 3-oxa-8-azabicycio[3 .2.1 ]oct-8-yI, 8-oxa-3-aza-bicyclo[3 .2.1 ]oct-3-yl, piperazi n-i -yl, 4-Ci..

3 -alkyl-piperazin-1 -yl, homopiperazin-1 -yI or C 13 -alkylhomopiperazin-1-yl group, or a formylamino, C14-alkylcarbonylamino, Cl.

3 -alkyloxy-C 1 3 -alkylcarbonylamino, Cl-4-alkyloxycarbonylamino, aminocarbonylamino, C1-3alkylaminocarbonylamino, di-(Cl..3-alkyl)aminocarbonylamino, pyrrolidin-1 -ylcarbonylamino, piperidin-1 -ylcarbonylamino, piperazin-1 ylcarbonylamino, 4-01-3-alkyl-piperazin-1 -ylcarbonylamino, morpholin- 4-ylcarbonylamino or a C14-alkyisulphonylamino group, a C3-7-cycloalkyloxy or C 3 7-cycloaikyl-C 1 4-alkyloxy group, a tetra h yd rofu ra n-3-yloxy, tetrahyd ropyra n-3-yI oxy or tetra hydropyra n-4 -yloxy group, WO 03/082290 PCT/EP03/03062 a tetrahydrofuranyl-Cl-4-alkyloxy or tetrahydropyranyl-C1-4-alkyloxy group, a C1-4-alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the group R 8 while

R

8 denotes a hydrogen atom or a C1-3-alkyl group, or a C1-4-alkoxy group which is substituted by a morpholinyl group substituted in the 4 position by the group R 8 while R 8 is as hereinbefore defined, and X denotes a methyne group substituted by a cyano group or a nitrogen atom, and by the aryl groups mentioned in the definition of the above groups is meant in each case a phenyl group which is mono- or disubstituted by R 9 while the substituents may be identical or different and

R

9 denotes a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a C-_ 3 -alkyl, hydroxy, C.-3-alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group, by the heteroaryl groups mentioned in the definition of the above groups is meant a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, while the abovementioned heteroaryl groups are each mono- or disubstituted by the group R 9 while the substituents may be identical or different and R 9 is as hereinbefore defined, and the abovementioned pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups may be substituted in each case by one or two C 1 -3-alkyl groups, and unless otherwise stated, the abovementioned alkyl groups may be straightchained or branched, with the proviso that the compound 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)- PI.OPER\PDB\Sp=N2OO0326705 Ip"dAXc2311WOOS 00 O -6A- O tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline is excluded, their tautomers, their stereoisomers, their mixtures and their salts.

The invention also relates to pharmaceutical compositions containing a compound c N according to the invention optionally together with one or more insert carriers C and/or diluents.

In a further aspect, the invention relates to use of a compound of formula for preparing a pharmaceutical composition which is suitable for treating benign or malignant tumours, for preventing and treating diseases of the airways and lungs and for treating diseases of the gastrointestinal tract, the bile duct and gall bladder.

The invention further relates to a method for treating benign or malignant tumours, for preventing and treating diseases of the airways and lungs and for treating diseases of the gastrointestinal tract, the bile duct and gall bladder, comprising administering to a subject in need thereof a compound of formula 00 S7 Preferred compounds of the above general formula I are those wherein

O

r R a denotes a hydrogen atom, In Rb denotes a phenyl group substituted by the groups R 1 to R 3 while

O

N R' denotes a hydrogen, fluorine, chlorine or bromine atom, Sa methyl, trifluoromethyl or ethynyl group, a phenyloxy or phenylmethoxy group, while the phenyl moiety of the abovementioned groups is optionally substituted by a fluorine or chlorine atom, or a pyridyloxy or pyridinylmethoxy group, while the pyridinyl moiety of the abovementioned groups is optionally substituted by a methyl or trifluoromethyl group,

R

2 denotes a hydrogen, fluorine or chlorine atom or a methyl group and

R

3 denotes a hydrogen atom, R" denotes a cyclopentyl group which is substituted in the 3 position by a group R 4

-N-R

5 while

R

4 denotes a hydrogen atom or a C1.

3 -alkyl group and

R

5 denotes a hydrogen atom or a C 1 3 -alkyl group, an aminocarbonyl-C1.

3 -alkyl, C1.3-alkylaminocarbonyl-C 1 -3-alkyl, di-

(C

1 -3-alkyl)aminocarbonyl-C 1 3 -alkyl, pyrrolidin-1-ylcarbonyl-C 1 3 -alkyl, piperidin-1-ylcarbonyl-C 1 -3-alkyl, piperazin-1-ylcarbonyl-C 1 -3-alkyl, WO 03/082290 WO 03/82290PCT/EP03/03062 4-C 1 3 -alkyl-piperazin-1 -yI-carbonyl-Cl- 3 -alkyl or morpholin-4-ylcarbonyl-

CI-

3 -alkyl group, a hydroxY-C.-t-alkyI, C 1 .3-al kyl oxy-C 2 4-aI kyl, Ci -4<-al kyloxycarbonylaminO-C 2 4-alkyI, amino-C24-alkyl, C 1 3 -alkylamino-C 24 -alkyl, di-(Cl- 3 -alkyl)amino-C 2 A-alkyl, Cl- 3 -alkylcarbonylamino-C 2 -4-alkyl, aminocarbonylamino-C 2 4 -alkyl, Cl 1 3 -alkylaminocarbonylamino-

C

2 -4-alkyI, di-(C 1 3 -alkyl)amino-carbonylamino-C 24 -alkyl, morpholin-4ylcarbonylamino-C 2 4 -alkyl, Cl 3 -aI kylsulphonyl-C 2 -4-alkyl or

C

1 3 -alkylsulphonylamino-C2- 4 -alky group, a (2-oxo-pyrrolidin-1 lI)-C 2 -4-alkyI, (2-oxopiperidin-1 -YI)-C 24 -alkyl, (3oxo-morpholin-4-yI )-C2-4-alkyl, (2-oxo-imidazolidin-1 -yI )-C2-4-alkyl, (2oxo-3-methyl-imidazolidin-1 -YI)-C2-4-alkyl, (2-oxo-hexahydropyrimidin- 1yI )-C2-4-alkyl or (2-oxo-3-methyl-hexahydropyrimidin-1 -yI)-C 2 4 -alkyl group, a Cl.

3 -alkylsulphonyl, chloro-C 2 -4-alkylsulphonyl, bromo-

C

2 -4-alkylsulphonyl, amino-C 2 -4-alkylsulphonyl, Cl.

3 -alkylamino-

C

2 -4-alkylsulphonyl, di-(C,..3-alkyl)amino-C 2 4-alkylsulphonyl, (pyrrolidin- I -yI)-C24-alkyisulphonyl, (piperidin-1 -YI)-C 2 4 -alkylsulphonyl or (morpholin-4-yi)-C 2 -4-alkylsulphonyI group, a Cl- 4 -alkyloxy-carbonyl group, a formyl, Cl 3 -alkyl-carbonyl, Ci..3-alkyloxy-Cl..

3 -alkyl-carbonyl, tetra hydrofura nylca rbonyl, tetra hyd ropyra nylca rbonyl, amino-Cl 1 3 -alkylcarbonyl, Ci..

3 -alkylamino-C 1 3 -alkyl-carbonyl, di-(Cl.

3 -alkyl)amino-

C

1 3 -alkyl-carbonyl, pyrrolidin-l 3 -alkyl-carbonyl, piperidin-l -yl- Cl, 3 -alkyl-carbonyl, piperazin-l -yI-C 1 3 -alkyl-carbonyl, 4-Cl- 3 -alkylpiperazin-l -y!-C 1 3 -alkyl-carbonyl, morphol in -4-yl-C 1 .3-alkyl-carbonyl or a Ci..3-alkylsulphonyl-Cl- 3 -alkyl-carbony group, a cyano, aminocarbonyl, Cl.

3 -alkyl-aminocarbonyl, di-(Cl- 3 -alkyl)amino- WO 03/082290 WO 03/82290PT/F P03/03062 carbonyl, (Cl..

3 -alkyloxy-C 2 A4-alkyl)aminocarbonyl, N-(0 1 3 -alkyl)-N- (Cl..

3 -alkyloxy-0 2 4-alkyl)aminocarbonyl, phenylamninocarbonyl, pyrrolidin-1 -ylcarbonyl, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl,

C

1 3 -alkyl-morpholin-4-ylcarbonyl, di-(Ci..

3 -alkyl)morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2 .2.1 ylcarbonyl, 3-oxa-8-aza-bicyclo[3 .2.1 ]oct-8-ylcarbonyl, 8-oxa-3-azabicyclo[3.2. 1 ]oct-3-ylcarbonyl, piperazin-1 -ylcarbonyl, 4-(Ci..

3 -alkyl)piperazin-1 -ylcarbonyl, amninosuiphonyl, Cl 13 -alkyl-aminosulphonyl, di- (Cl.

3 -alkyl)amino-sulphonyl, pyrrolidin-1 -yI-sulphonyl, piperidin-1 ylsulphonyl or a morphoiin-4-ylsulphonyl group, or a cyclopentyl group which is substituted in the 3 position by a group R while

R

6 denotes a 2-oxo-pyrrolidin-1 -yI, 2-oxopiperidin-1 -yI, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1 -yI, 2-oxo-3-methyl-imidazolidin-1 yl, 2-oxo-hexahydropyrimidin-1 -yl or a 2-oxo-3-methylhexahydropyrimidin-1 -yi group, a cyclohexyl group which is substituted in the 3 position or in the 4 position by a group R -N-R while W 4 and R 5 are as hereinbefore defined, a cyclohexyl group which is substituted in the 3 position or in the 4 position by a group R while R 6 is as hereinbefore defined, a pyrrolidin-3-yI group which is substituted in the 1 position by the group R while R 5 is as hereinbefore defined, a piperidin-3-yl group which is substituted in the 1 position by the groupR, while R 5 is as hereinbefore defined, a piperidin-4-yI group which is substituted in the 1 position by the groupR while R 5 is as hereinbefore defined, or a tetra hyd rofu ra n-3-yl, tetra hyd ropyra n -3-yI or tetra hyd ropyra n-4-yl group, WO 03/082290 10 PCT/EP03/03062 R d denotes a hydrogen atom, a Ci..

3 -alkyloxy group, a methoxy group which is substituted by one to three fluorine atoms, an ethyloxy group which is substituted in the 2 position by a group R 6 orR while R 6 is as hereinbefore defined and R 7 denotes a hydroxy, C 13 -alkyloxy, amino, Ci..

3 -alkylamino, di- (Cl 13 -alkyl)amino, bis-(2-methoxyethyl)-amino, pyrrolidin-1 -yI, piperidin- 1 -yl, morpholin-4-yl, homomorpholin-4-y, 2-oxa-5-aza bicyclo[2 .2.1 ]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1 ]oct-8-yI, 8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl, piperazin-1 -yl or a 4-0 1 3 -alkyl-piperazin-1 -yl group, or a formylamino, C14-alkylcarbonylamino, C 1 3 -alkyloxy-0 13 -alkylcarbonylamino, C14-alkyloxycarbonylamino, aminocarbonylamino, C 13 alkylaminocarbonylamino, di-(Ci..

3 -alkyl)aminocarbonylamino, pyrrolidin-1 -ylcarbonylamino, piperidin-1 -ylcarbonylamino, piperazin-1 ylcarbonylamino, 4-C 1 3 -alkyl-piperazin-1 -ylcarbonylamino- morpholin- 4-ylcarbonylamino or a Cl-4-alkylsulphonylamino group, a propyloxy group which is substituted in the 3 position by a group R 6 orR while R 6 and R 7 are as hereinbefore defined, or a butyloxy group which is substituted in the 4 position by a group R 6 orR while R 6 and R 7 are as hereinbefore defined, and X denotes a nitrogen atom, while, unless stated otherwise, the abovementioned alkyl groups may be straight-chained or branched, WO 03/082290 PTEO/36 PCT/EP03/03062 their tautomers, their stereoisomers, their mixtures and their salts.

Particularly preferred compounds of the above general formula I are those wherein R a denotes a hydrogen atom, R b denotes a 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro- 4-fluoro-phenyl group, a 3-ch Ioro-4-benzyloxy-phenyl, 3-ch Ioro-4-[(3-fluoro-benzyl )oxy]-phenyl, 4- (pyrid in-3-yloxy)-phenyl, 4-[(6-methyl-pyridin-3-yI)oxy]-phenyl, 3-methyl-4- (pyridin-3-yloxy)-phenyl, 3-methyl-4-[(6-methyl-pyridin-3-yl )oxy]-phenyl, 3chloro-4-(pyridin-3-yloxy)-pheny or 3-chloro-4-[(6-methyl-pyridi n-3-yl )oxy]phenyl group, Rc denotes a cyclohexyl group which is substituted in the 3 position or in the 4 position by a group R 4 -N-R while

R

4 denotes a hydrogen atom, a methyl or ethyl group and

R

5 denotes a hydrogen atom, a methyl, aminocarbonylmethyl, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, pyrrolidin- 1 -ylcarbonylmethyl, piperidin-1 -ylcarbonylmethyl, piperazin-1 ylcarbonylmethyl, 4-methylpiperazin-1 -ylcarbonylmethyl, morpholin-4ylcarbonylmethyl, 2-(morpholin-4-yl-carbonyl)ethy or 3-(morpholin-4-ylcarbonyl)propyl group, an ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3methoxypropyl, 2-(butyloxycarbonylamino)-ethyl, 2-aminoethyl, 3aminopropyl, 2-(acetylamino)ethyl, 3-(acetylami no)propyl, 2- (ethylcarbonylamino)ethyl, 3-(ethylcarbonylamino)propyl, 2- (propylcarbonylamino)ethyl, 3-(propylcarbonylamino)propyl, 2- WO 03/082290 WO 03/82290PCT/EPO3/03062 (ethylaminocarbonylamino)ethyl, 3-(ethylaminocarbonylamino)propyl, 2-(dimethylaminocarbonylamino)ethyl, 3- (dimethylaminocarbonylamino)propyl, 2-(morpholin-4ylca rbonyla min o)ethyl, 3-(morpholin-4-ylcarbonylamino)propyl, 2- (methylsulphonyl)ethyl, 3-(methylsulphonyl)propyl, 2-(methylsulphonylamino)ethyl or a 3-(methylsulphonylamino)propyl group, a 2-(2-oxo-pyrrolidi n-I -yI )ethyl, 2-(2-oxopiperidin- 1 -yI)ethyl, 2 -(3-oxomorpholi n-4-yI)ethyl, 2-(2-oxo-imidazolidin-1 -yI )ethyl, 2-(2-oxo-3methyl-imidazolidin-1 -yI)ethyl, 2-(2-oxo-hexahydropyrimidin-1 -yI)ethyl or a 2-(2-oxo-3-methyi-h exahyd ropyri mid in 1 -yI )ethyl group, a 3-(2-oxo-pyrrolid in-i -yI )propyl, 3-(2-oxopiperidin-1 -yI )propyl, 3-(3-oxomorpholin-4-yI)propyi, 3-(2-oxo-imidazolidin-1 -yI)propyl, 3-(2-oxo-3methyl-imidazolidin-1 -yI)propyl, 3-(2-oxo-hexahydropyrimidin-1 yI)propyl or a 3-(2-oxo-3-methyl-hexahydropyri mid in- 1 -yI)propyl group, a methylsuiphonyl, ethylsuiphonyl, 3-chloropropylsulphonyl, 2- (morpholin-4-yi)-ethylsulphonyl or a 3-(morpholin-4-yI)-propylsulphony group, a propyloxycarbonyl or butyloxycarbonyl group, a formyl, acetyl, ethylcarbonyl, propylcarbonyl, methoxyacetyl, (2methoxyethy )carbonyl, (3-methoxypropyl)carbonyl, tetra hyd rofu ran-2 ylcarbonyl, tetra hyd ropyra n-4-yl ca rbonyl, aminoacetyl, methylaminoacetyl, dimethylaminoacetyl, morpholin-4-ylacetyl, [2- (morpholin-4-y )ethyl]carbonyl, [3-(morpholin-4-y )propyl]carbony or a methylsuiphonylacetyl group, a cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, (2methoxyethyi )aminocarbonyl, N-methyl-N-(2-methoxyethyl)aminocarbonyl, (3-methoxypropyl )aminocarbonyl, N-methyl-N-(3- WO 03/082290 WO 03/82290PCT/EP03/03062 methoxypropyl )-aminocarbonyl, phenylaminocarbonyl, pyrrolidin -1ylcarbonyi, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, 2methylmorphoiin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, homomorphol in-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2 .2.1 ylcarbonyl, 3-oxa-8-aza-bicyclo[3 .2.1 ]oct-8-ylcarbonyl, 8-oxa-3-azabicyclo[3.2.1 ]oct-3-ylcarbonyl, 4-methylpiperazin-1 -ylcarbonyl, aminosulphonyl, methylaminosuiphonyl, dimethylaminosulphonyl or a morpholin-4-ylsulphonyl group, a cyclohexyl group which is substituted in the 3 position or in the 4 position by a group R while R 6 denotes a 2-oxo-pyrrolidin-1 -yl, 2-oxopiperidin-1 -yl, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1 -yl, 2-oxo-3-methyl-imidazolidin-1 yl, 2-oxo-hexahydropyrimidin-1 -yI or a 2-oxo-3-methylhexahydropyrimidin-1 -yI group, a pyrrolidin-3-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, a piperidin-3-yI group which is substituted in the 1 position by the group R while R 5 is as hereinbefore defined, a piperidin-4-yl group which is substituted in the 1 position by the groupR while R 5 is as hereinbefore defined, a tetra hyd rofu ran tetra hyd ropyra n -3-yl or tetra hydropyra n-4-yI group, R d denotes a hydrogen atom, a methoxy, difluoromethoxy or ethyloxy group, an ethyloxy group which is substituted in the 2 position by a group R 6 orR while R 6 is as hereinbefore defined and r WO 03/082290 PCT/EP03/03062

R

7 denotes a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis-(2-methoxyethyl)-amino, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyclo[2.2.1 yl, 3-oxa-8-aza-bicyclo[3 .2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3yl, piperazin-1 -yl, 4-methylpiperazin-1 -yl or 4-ethylpiperazin-1 -yl group, or an acetylamino, ethylcarbonylamino, propylcarbonylamino, butylcarbonylamino, methoxyacetylamino, butyloxycarbonylamino, ethylaminocarbonylamino, dimethylaminocarbonylamino, pyrrolidin-1ylcarbonylamino, piperidin-1 -ylcarbonylamino, morpholin-4ylcarbonylamino, methylsulphonylamino, ethylsuiphonylamino or butylsulphonylamino group, a propyloxy group which is substituted in the 3 position by a group R 6 or R while R 6 and R 7 are as hereinbefore defined, or a butyloxy group which is substituted in the 4 position by a group R6 or R7 while R 6 and R 7 are as hereinbefore defined, and X denotes a nitrogen atom, while, unless stated otherwise, the abovementioned alkyl groups may be straight-chained or branched, their tautomers, their stereoisomers, their mixtures and their salts.

Most particularly preferred compounds of general formula I are those wherein Ra denotes a hydrogen atom, Rb denotes a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluoro-phenyl or a 3-ethynylphenyl group, or WO 03/082290 PTEO/36 PCT/EP03/03062 a 3-ch Ioro-4-benzyloxy-phenyl, 3-chloro-4-[(3-fluorbenzyl)oxy]-phenyl, 4- (pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridin-3-yI )oxy]-phenyl, 3-methyl-4- (pyridin-3-yloxy)-phenyl, 3-methyl-4-[(6-methyl-pyrid in-3-yI)oxy]-phenyl, 3chloro-4-(pyridin-3-yloxy)-pheny or 3-chloro-4-[(6-methyl-pyridin-3-y)oxy]phenyl group, Rc denotes a cyclohexyl group which is substituted in the 3 position by an amino, acetylamino, tert.-butyloxycarbonylamino or methylsuiphonylamino group, a cyclohexyl group which is substituted in the 4 position by an amino, methylamino, ethylamino, dimethylamino, aminocarbonylmethylamino, methylaminocarbonylmethylamino, dimethylaminocarbonylmethylamino, morpholin-4-ylcarbonylmethylamino, [3-(morpholin-4-ylcarbonyl)propyllamino, [2-(methylsulphonyl)ethyl]amino, [3-(methylsulphonyl)propyl]amino or [2- (methylsulphonylamino)ethyl]amino group, a cyclohexyl group which is substituted in the 4 position by a [2-(2-oxopyrrolidin-1 -yI)ethyl]amino, [2-(2-oxopiperidin-1 -yI)ethyl]amino, [2-(2-oxoimidazolidin-1 -yI)ethyl]amino, [2-(2-oxo-3-methyl-imidazolidin-1 -yI)ethyl]amino, [2-(2-oxo-hexahydropyrimidin-1 -yI )ethyl]amino or [2-(2-oxo-3-methylhexahydropyrimidin-1 -yI)ethyl]amino group, a cyclohexyl group which is substituted in the 4 position by a [3-(2-oxopyrrolidin-1 -yI )propyl]amino, [3-(2-oxopiperidin -1 -yI)propyl]amino, [3-(2-oxoimidazolidin-1 -yI)propyi]amino, [3-(2-oxo-3-methyl-imidazolidin-1 yI)propyl]amino, [3-(2-oxo-hexahydropyrimidin-1 -yI)propyllamino or [3-(2-oxo- 3-methyl-hexahydropyrimidin-1 -yI)propyl]amino group, a cyclohexyl group which is substituted in the 4 position by an acetylamino, N- (acetyl)-methylamino, aminomethylcarbonylamino, methylaminomethylcarbonylamino, dimethylaminomethylcarbonylamino, morpholin-4-ylmethylcarbonylami no, methoxyacetylamino, N -(methoxyacetyl)- WO 03/082290 WO 03/82290PCT/EPO3/03062 methylamino, tetra hydropyran-4 -yl ca rbonyla min o, N-(tetrahydropyran-4ylcarbonyl)-methylamino, tert.-butyloxycarbonylamino, N-(tert.butyloxycarbonyl)-methylamino, aminocarbonylamino, methylaminocarbonylamino, N-(ethylaminocarbonyl)-methylamino, dimethylaminocarbonylamino, N-(dimethylaminocarbonyl)-methylamino, N- (piperidin-1 -ylcarbonyl)-methylamino, morpholin-4-ylcarbonylamino, N- (morpholin-4-ylcarbonyl )-methylamino or N-(4-methylpiperazin-1 -ylcarbonyl methylamino group, a cyclohexyl group which is substituted in the 4 position by a 2-oxo-pyrrolidinl-yI, 2-oxopiperidin-1 -yI, 3-oxo-morpholin-4-y, 2-oxo-imidazolidin-1 -yI, 2-oxo- 3-methyl-imidazolidin-1 -yI, 2-oxo-hexahydropyrimidin-1 -yI or a 2-oxo-3methyl-hexahydropyrimidin-1 -yI group, a cyclohexyl group which is substituted in the 4 position by a methylsuiphonylamino, N-(methylsulphonyl)-methylamino, ethylsuiphonylamino, N-(ethylsulphonyl)-methylamino, dimethylaminosulphonylamino, N-(dimethylaminosulphonyl)-methylamino, morpholin-4-ylsulphonylamino, N-(morpholin-4-ylsulphonyl)-methylamino- 3chloropropylsulphonylamino, [2-(morpholin-4-yi)-ethyl]sulphonylamino or [3- (morpholin-4-yi)-propyl]sulphonylamino- group, a pyrrolidin-3-yI group, a pyrrolidin-3-yI group which is substituted in the 1 position by a methyl, acetyl, methoxyacetyl, tert.-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsuiphonyl group, a piperidin-3-yI group, a piperidin-3-yl group which is substituted in the 1 position by a methyl, acetyl, methoxyacetyl, tert.-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulphonyl group, WO 03/082290 WO 03/82290PCT/EPO3/03062 a piperidin-4-yl group which is substituted in the 1 position by a methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsuiphonyl )-ethyl, 3-(methylsulphonyl )-propyl, 2-(tert.butyloxycarbonyiamino)-ethyl, 2-aminoethyl, 2-(acetylamino)-ethyl, 2- (ethylcarbonylamino)-ethyl, 2-(propylcarbonylamino)-ethyl, 2- (ethylaminocarbonylamino)-ethyl, 2- (d imethyla mi noca rbonyla mino)- ethyl, 2- (morpholin-4-ylcarbonylamino)-ethyl, 3-(acetylamino)-propyl, 3- (ethylcarbonylamino)-propyl, 3-(propylcarbonylamino)-propyl, 3- (ethylaminocarbonylami no)-propyl, 3-(dimethylaminocarbonylami no)- propyl, 3-(morpholin-4-ylcarbonylamino)-propyl, 2-(methylsulphonylamino)-ethyl, 3- (methylsulIphonyla min o)-propyl, (aminocarbonyl)methyl, (methyiaminocarbonyl)methyl, (dimethylaminocarbonyl)methyl, (pyrrolidin-1 ylcarbonyl)methyl, (morpholin-4-ylcarbonyl )methyl, 2-(morpholin-4ylcarbonyl )-ethyl or 3-(morphol in-4-ylcarbonyl )-propyl group, a piperidin-4-yi group which is substituted in the 1 position by a 2-(2-oxopyrrolidin-1 -yI)-ethyi, 2-(2-oxopiperidin-1 -yI)-ethyl, 2-(3-oxomorpholin-4-y)ethyl, 2-(2-oxo-imidazolidin-1 -yl)-ethyl, 2-(2-oxo-3-methy-i midazolidin- 1-yI)ethyl, 2-(2-oxo-hexahydropyrimid in-I -yI)-ethyl or 2-(2-oxo-3-methylhexahydropyrimidin-1 -yl)-ethyl group, a piperidin-4-yl group which is substituted in the I position by a 3-(2-oxopyrrolid in-i -yl)-propyl, 3-(2-oxopi peridin-1 -yl )-propyl, 3-(3-oxomorpholin-4-yl)propyl, 3-(2-oxo-imidazolidin-1 -yI )-propyl, 3-(2-oxo-3-methyl-imidazolidin-1 -yI)propyl, 3-(2-oxo-hexahydropyrimidin-1 -yl )-propyl or 3-(2-oxo-3-methylhexahydropyrimidin-1 -yl)-propyl group, a piperidin-4-yl group which is substituted in the 1 position by a formyl, acetyl, methoxyacetyl, (2-methoxyethyl )carbonyl, (3-methoxypropyl )carbonyl, methylsulphonylacetyl, aminoacetyl, methylaminoacetyl, (dimethylamino)acetyl, (morpholin-4-yl)acetyl, [2-(morpholin-4-yl)ethylicarbonyl, [3-(morpholin-4-yl )-propyljcarbonyl, tetrahydrofuran -2ylcarbonyl or tetra hyd ropyran-4-ylca rbonyl group, WO 03/082290 WO 03/82290PCT/EPO3/03062 a piperidin-4-yI group which is substituted in the 1 position by a cyano, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, (2methoxyethyl)aminocarbonyl, N-methyl-N-(2-methoxyethyl)-aminocarbonyl, (3-methoxypropyl)aminocarbonyl, N -methyl-N-(3-methoxypropyl)aminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, pyrrolidin-1 -ylcarbonyl, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4 ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2 .2.1 ]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3 .2.1 ]oct-8ylcarbonyl, 8-oxa-3-aza-bicyclo[3.2. 1]oct-3-ylcarbonyl, 4-methylpiperazin-1 ylcarbonyl, isopropyloxycarbonyl or tert.-butyloxycarbonyl group, a piperidin-4-yI group which is substituted in the 1 position by a methylsuiphonyl, ethylsuiphonyl, [2-(morpholin-4-yI)-ethyl]sulphonyl, [3- (morpholin-4-yI)-propyl]sulphonyl, aminosuiphonyl, methylaminosuiphonyl, dimethylaminosuiphonyl or morpholin-4-ylsulphonyl group, or a tetra hyd rofu ra n-3-yl, tetra hyd ropyra n -3-yI or tetra hyd ropyra n-4-y group, R d denotes a hydrogen atom, a methoxy, difluoromethoxy or ethyloxy group, a 2-(morpholin-4-yI)ethyloxy, 3-(morpholin-4-yI)propyloxy or 4-(morpholin-4yI)butyloxy group, a 3-(dimethylamino)propyoxy, 3-(diethylamino)propyloxy, 3-[bis-(2 methoxyethyl )-amino]propyloxy, 3-(piperazin -1 -yI)propyloxy, 3-(4methyl piperazin-1 -yI )propyloxy or 3-(4-ethylpiperazi n-i -yI )propyloxy group, a 3-(homomorpholin-4 -yl)-propyloxy, 3-(2 -oxa-5-aza-bicyclo[2 .2.1 ]hept-5-yI propyloxy, 3-(3-oxa-8-aza-bicyclo[3.2.1 ]oct-8-yl )-propyloxy or 3-(8-oxa -3-azabicyclo[3.2.1] oct-3-yl)-propyioxy group, WO 03/082290 WO 03/82290PCT/EPO3/03062 a 2-(2-oxo-pyrrolidin-1 -yl )-ethyloxy, 2-(2-oxopiperidin-1 -yl )-ethyloxy, 2-(3oxomorpholin-4-yl )-ethyloxy, 2-(2-oxo-imidazolidin-1 -yI)-ethyloxy, 2-(2-oxo-3methyl-imidazolidi n-i -yl)-ethyloxy, 2-(2-oxo-hexahydropyrimidin-1 -yl )-ethyloxy or 2-(2-oxo-3-methyl-hexa hyd ropyri mid in 1 -yl )-ethyloxy group, a 3-(2-oxo-pyrrolidin-1 -yl )-propyloxy, 3-(2-oxopiperidin- l-yl )-propyloxy, 3-(3oxomorpholin-4-yI )-propyloxy, 3-(2-oxo-imidazolidin-i -yl )-propyloxy, 3-(2-oxo- 3-methyl-imidazolidin-1 -yl)-propyloxy, 3-(2-oxo-hexahyd ropyrimidin- 1-yl propyloxy or 3-(2-oxo-3-methyl-hexahydropyrimidin- 1 -yl)-propyloxy group, a 2-(methoxy)-ethyloxy, 2-(tert.-butyloxycarbonylamino)-ethyloxy, 2-(amino)ethyloxy, 2-(acetylamino)-ethyloxy, 2-(ethylcarbonylami no)-ethyloxy, 2- (propylcarbonylamino)-ethyloxy, 2-(isobutylcarbonylamino)-ethyloxy, 2- (methoxyacetylamino)-ethyloxy, 2-(ethylaminocarbonylamino)-ethyloxy, 2- (dimethylaminocarbonylamino)-ethyloxy, 2-(pyrrolidin-1 -ylcarbonylamino)ethyloxy, 2-(piperidin-1 -ylcarbonylamino)-ethyloxy, 2-(morpholin-4 ylcarbonylamino)-ethyloxy, 2-(methylsulphonylamino)-ethyloxy group, 2- (ethylsulphonylamino)-ethyloxy or 2-(butylsulphonylamino)-ethyloxy group, or a 3-(tert.-butyloxycarbonylamino)-propyloxy, 3-(amino)-propyloxy, 3- (acetylamino)-propyloxy or 3-(methylsulphonylamino)-propyloxy group, and X denotes a nitrogen atom, their tautomers, their stereolsomers, their mixtures and their salts.

Particularly preferred compounds of general formula I are those wherein Ra denotes a hydrogen atom, R b preferably denotes a 3-chloro-4-fluoro-phenyl group or also a 3ethynylphenyl group, WO 03/082290 WO 03/82290PCT/EP03/03062 R' denotes a cyclohexyl group which is substituted in the 3 position by an amino, acetylamino, tert.-butyloxycarbonylamino or methylsuiphonylamino group, a cyclohexyl group which is substituted in the 4 position by an amino, methylamino, dimethylamino, acetylamino, N-(acetyl)-methylamino, methoxyacetylamino, N-(methoxyacetyl)- methylamino, tetra hydropyra n-4 ylcarbonylamino, N-(tetrahydropyran-4-ylcarbonyl)-methylamino, tert.butyloxycarbonylamino, N-(tert.-butyloxycarbonyl)-methylamino, N- (ethylaminocarbonyl)-methylamino, dimethylaminocarbonylamino, N- (dimethylaminocarbonyl)-methylamino, N-(piperidin-1 -ylcarbonyl)methylamino, morpholin-4-ylcarbonylamino, N-(morpholin-4-ylcarbonyl)methylamino, N-(4-methylpiperazin-1 -ylcarbonyl )-methylamino, methylsuiphonylamino, N-(methylsulphonyl)-methylamino, ethylsuiphonylamino, N-(ethylsulphonyl)-methylamino, dimethylaminosulphonylamino, N-(dimethylaminosulphonyl)-methylamino, morpholin-4-ylsulphonylamino, N-(morpholin-4-ylsulphonyl)-methylamino, 3chloropropylsulphonylamino, or [3-(morpholin-4-yI)-propyl]sulphonylamino group, a pyrrolidin-3-yl group, a pyrrolidin-3-yl group which is substituted in the 1 position by a tert.butyloxycarbonyl or methylsuiphonyl group, a piperidin-3-yI group, a piperidin-3-yl group which is substituted in the 1 position by a tert.butyloxycarbonyl or methylsu Iphonyl group, a piperidin-4-yI group, a piperidin-4-yi group which is substituted in the 1 position by a methyl, WO 03/082290 WO 03/82290PCT/E P03/03062 (aminocarbonyl)methyl, (dimethylaminocarbonyl )methyl, (morpholin -4ylcarbonyl)methyl, 2-(tert.-butyloxycarbonylamino)ethyl, 2-ami noethyl, 2- (acetylamino)ethyl, 2-(methylsulphonylamino)ethyl, cyano, acetyl, methoxyacetyl, (dimethylamino)acetyl, (morpholin-4-yl)acetyl, tetra hydropyran -4 -yl ca rbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, pyrrolidin-1 -ylcarbonyl, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, 2methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 4-methylpiperazin-1 -yicarbonyl, isopropyloxycarbonyl, tert.-butyloxycarbonyl, methylsul phonyl, dimethylaminosulphonyl or morpholin-4-ylsulphonyl group, or a tetra hyd rofu ran-3-y, tetrahydropyran -3-yI or tetra hydropyra n-4-y group, R d denotes a hydrogen atom, a methoxy or ethyloxy group, a 2-(morpholin-4-yI)ethyloxy, 3-(morpholin-4-yI)propyloxy or 4-(morpholin-4yl)butyloxy group, a 2-(3-methyl-2-oxo-hexahydropyrimidin-1 -yI )-ethyloxy group, a 2-(methoxy)-ethyloxy, 2-(tert.-butyloxycarbonylamino)-ethyloxy, 2-aminoethyloxy, 2-(acetylamino)-ethyloxy or 2-(methylsu Iphonylamino)-ethyloxy group or a 3-(tert.-butyloxycarbonylamino)-propyloxy, 3-amino-propyloxy, 3- (acetylamino)-propyloxy or 3-(methylsulphonylamino)-propyloxy group, and X denotes a nitrogen atom, I 1 WO 03/082290 22 PCT/EP03/03062 their tautomers, their stereoisomers, their mixtures and their salts.

Of the bicyclic heterocyclic groups of general formula I as described above as well as the sub-groups specified as being preferred, particularly preferred, most particularly preferred and especially preferred, special mention should be made of those compounds wherein Rc denotes a cyclohexyl group substituted in the 4 position, Rc denotes a pyrrolidin-3-yl group optionally substituted in the 1 position, Rc denotes a piperidin-3-yl group optionally substituted in the 1 position, RC denotes a piperidin-4-yl group optionally substituted in the 1 position, R' denotes a tetrahydrofuran-3-yl group, Rc denotes a tetrahydropyran-3-yl group, or Rc denotes a tetrahydropyran-4-yl group, while R a Rb, Rd and X in each case are as hereinbefore defined.

The following are mentioned as examples of particularly preferred compounds of general formula I: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((R)-tetrahydrofuran-3-yloxy)-7methoxy-quinazoline, WO 03/082290 WO 03/82290PCT/EPO3/03062 4-[(3-chloro-4-fluoro-phenyl)aminolj-6-(trans-4-amino-cyclohexane-1 yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylaminocyclohexane-1 -yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyq u inazol in e, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methanesulphonyl-piperidin-4yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin 4 -yI)propyl]sulphonylamino}-cyclohexan- I -yioxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7methoxy-quinazoline, 4-[3-ch Ioro-4-fluoro-ph enyl)a mi no] -6-(trans-4-{[3-(morphol in-4 -yI propyl]suiphonylamino}-cyclohexan-1 -yloxy)-7-methoxy-quinazol ine, (11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methyl-piperidin-4-yloxy)-7methoxy-quinazoline, (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(morpholin-4-yI)carbonyl]piperidin-4-yloxy}-7-methoxy-quinazoline, (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(methoxymethyl)carbonyl]p1 peridin-4-yloxy}-7-methoxy-quinazoline, (14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-( I -cyano-piperidin-4-yloxy)-7 methoxy-quinazoline, WO 03/082290 WO 03/82290PCT/EPO3/03062 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(morpholin-4-yl)sulphonyl]piperidin-4-yloxy}-7-methoxy-quinazoline, (16) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1 -(2-acetylami no-ethyl)piperidin-4-yloxy]-7-methoxy-quinazoline, (17) 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-{trans-4- [(dimethylamino)sulphonylamino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline, (18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4yI)carbonylamino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline, (19) 4-[(3-chloro-4-fluoro-phenyl)aminol-6-{trans-4-[(morpholin-4yl)sulphonylamino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-(tetrahydropyran-4-yloxy)-7-(2acetylamino-ethoxy)-quinazoline, (21) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2methanesulphonylamino-ethoxy)-quinazoline and (22) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2methoxy-ethoxy)-quinazoline, as well as their salts.

The compounds of general formula I may be prepared for example by the following methods: a) reacting a compound of general formula WO 03/082290 PCT/EP03/03062 i, ,(11) wherein

R

a Rb, Rd and X are as hereinbefore defined, with a compound of general formula

Z

1 RC wherein Rc is as hereinbefore defined and Z 1 denotes a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group.

With a compound of general formula III wherein Z 1 denotes a hydroxy group, the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of of a phosphine and an azodicarboxylic acid derivative such as e.g. triphenylphosphine/diethyl azodicarboxylate, conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or ethylenglycoldiethylether at temperatures between -50 and 150°C, but preferably at temperatures between -20 and 800C.

b) In order to prepare compounds of general formula I wherein Rd denotes one of the optionally substituted alkyloxy groups mentioned hereinbefore: reacting a compound of general formula WO 03/082290 PCT/EP03/03062 Ra Rb N O-H

(IV)

wherein Ra, R b RC and X are as hereinbefore defined, with a compound of general formula

Z

2

R

d wherein R d denotes a C1-4-alkyl group, a methyl group substituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorine atoms, a C2-4-alkyl group substituted by a group R 6 or R 7 where R 6 and R 7 are as hereinbefore defined, a C14-alkyl group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the group R 8 or a C14-alkyl group which is substituted by a morpholinyl group substituted in the 4 position by the group R 8 while R 8 in each case is as hereinbefore defined, and

Z

2 denotes a leaving group such as a halogen atom, an alkylsulphonyloxy, arylsulphonyloxy or a hydroxy group.

If the leaving group is a halogen atom such as a chlorine, bromine or iodine atom or an alkylsulphonyloxy or arylsulphonyloxy group such as the methanesulphonyloxy or p-toluenesulphonyloxy group, the reaction is preferably carried out in the presence of an organic or inorganic base such as potassium carbonate, sodium hydride or N-ethyl-diisopropylamine. If the leaving group is a hydroxy group, the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as e.g. triphenylphosphine/diethyl azodicarboxylate.

c) In order to prepare compounds of general formula I wherein Rd denotes WO 03/082290 PCT/EP03/03062 one of the abovementioned alkyloxy groups which is substituted by an optionally substituted amino, alkylamino or dialkylamino group or by an optionally substituted heterocyclic group bound via an iminonitrogen atom: reacting a compound of general formula Ra Rb

N

X Re N 0-(CH 2 2 -Z3 (VI), wherein R a Rb, Rc and X are as hereinbefore defined and Z 3 denotes a leaving group such as a halogen atom, e.g. a chlorine or bromine atom or a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group, with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or the suitable salts or derivatives thereof, such as morpholine, for example.

d) In order to prepare compounds of general formula I wherein Rd denotes a hydroxy group: Cleaving a protecting group from a compound of general formula Ra Rb

N

X R R N Rd"

(VII),

wherein Ra, Rb, RC and X are as hereinbefore defined and R d denotes a group which may be converted into a hydroxy group, for example an I I WVO 03/082290 PCT/EP03/03062 optionally substituted benzyloxy group, a trimethylsilyloxy, acetyloxy, benzoyloxy, methoxy, ethoxy, tert-butoxy or trityloxy group.

The protecting group is cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 1200C, preferably at temperatures between 10 and 1000C.

However, a benzyl or methoxybenzyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at ambient temperatures between 20 and 600C, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert.butyl or benzyl group is cleaved for example by treating with an acid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxan, methanol or diethyl ether.

e) In order to prepare compounds of general formula I wherein Rc contains a -NH- group: cleaving a protecting group from a compound of general formula Ra Rb

N

0 X R N Rd

(VIII),

WO 03/082290 PCT/EP03/03062 wherein R a

R

b Rd and X are as hereinbefore defined and RC has the meanings given for Rc hereinbefore, with the proviso that R c contains a protected nitrogen atom.

Conventional protecting groups for an amino, alkylamino or imino group are for example the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, while for the amino group the phthalyl group is an additional possibility.

The protecting group is cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 1000C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at ambient temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxan, methanol or diethyl ether.

1 WO 03/082290 PCT/EP03/03062 A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120°C or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 500C.

f) In order to prepare compounds of general formula I wherein Rc contains an alkyl group substituted by an optionally substituted amino, alkylamino or dialkyamino group or by an optionally substituted heterocyclic group bound via a nitrogen atom: reacting a compound of general formula Ra Rb

N

X Z3 N Rd

(IX),

wherein R a

R

b Rd and X are as hereinbefore defined, Z 3 denotes a leaving group, for example a halogen atom such as a chlorine or bromine atom, or a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group, and Rc" has the meanings given for R hereinbefore with the proviso that a hydrogen atom bound to an aliphatic carbon atom is replaced by the group Z 3 with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or the appropriate salts or derivatives thereof, such as morpholine, for example.

I I WO 03/082290 PCT/EP03/03062 If according to the invention a compound of general formula I is obtained which contains an amino, alkylamino or imino group, this may be converted by acylation, cyanation or sulphonylation into a corresponding acyl, cyano or sulphonyl compound of general formula I, the acylating agents being for example isocyanate, carbamoyl chloride, carboxylic acid halide, carboxylic acid anhydride and carboxylic acids with activating agents such as N,N'carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide or O-(benzotriazol-l-yl)- N,N,N'N'-tetramethyluronium-tetrafluoroborate, the sulphonylating agents being sulphonyl halides and the cyanating agents being chlorine or bromocyanogen, and/or if a compound of general formula I is obtained which contains an amino, alkylamino or imino group, this may be converted by alkylation or reductive alkylation into a corresponding alkyl compound of general formula I and/or if a compound of general formula I is obtained which contains a chloro-

C

1 4-alkylsulphonyl or bromo-C14-alkylsulphonyl group, this may be converted by reaction with an amine into a corresponding amino-C14-alkylsulphonyl compound and/or if a compound of general formula I is obtained which contains a tert.butyloxycarbonylamino, N-alkyl-N-(tert.-butyloxycarbonyl)amino or a N-tert.butyloxycarbonylimino group, this may be converted into a corresponding amino, alkylamino or imino compound of general formula I by treatment with an acid such as hydrochloric acid or trifluoroacetic acid.

In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

WO 03/082290 PCT/EP03/03062 Protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, for example.

Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between and 100°C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at ambient temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 1200C or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 500C.

I I WO 03/082290 PCT/EP03/03062 Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.

Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example or (-)-menthol and an optically active acyl group in amides, for example, may be a (-)-menthyloxycarbonyl.

Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable I WO 03/082290 PCT/EP03/03062 salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds of general formulae II to I used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (cf. Examples I to XXII) or the methods described hereinbefore, optionally with the additional use of protecting groups (e.g.

compounds of formula IV or VII and VIII).

As already mentioned hereinbefore, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R), whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerisation or tyrosine kinase itself. It is also possible that the transmission of signals to components located further down is blocked.

The biological properties of the new compounds were investigated as follows: The inhibition of human EGF-receptor kinase was determined using the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186 based on the sequence published in Nature 309 (1984), 418). For this the protein was expressed in Sf9 insect cells as GST fusion protein using the Baculovirus expression system.

The enzyme activity was measured in the presence or absence of the test compounds in serial dilutions. The polymer pEY obtained from SIGMA was used as the substrate. Biotinylated pEY (bio-pEY) was added as the tracer substrate. 100 ul of reaction solution contained 10 ul of the inhibitor in DMSO, 20 pl of the substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg/ml poly(EY), 5 pg/ml bio-pEY) and 20 pl of enzyme preparation. The enzyme reaction was started by the addition of 50 pl WO 03/082290 PCT/EP03/03062 of a 100 pM ATP solution in 10 mM of magnesium chloride. The dilution of the enzyme preparation was adjusted so that the incorporation of phosphate in the bio-pEY was linear in terms of time and quantity of enzyme. The enzyme preparation was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM common salt, 0.05% Triton X-100, 1 mM DTT and 10% glycerol.

The enzyme assays were carried out at ambient temperature over a period of minutes and ended by the addition of 50 pl of a stopping solution (250 mM EDTA in 20 mM HEPES pH 100 Il were placed on a streptavidinecoated microtitre plate and incubated for 60 minutes at ambient temperature.

Then the plate was washed with 200 pl of a wash solution (50 mM Tris, 0.05% Tween 20). After the addition of 100 pl of an HRPO-labelled anti-PY antibody Anti-PTyr:HRP made by Transduction Laboratories, 250 ng/ml) the preparation was incubated for 60 minutes. Then the microtitre plate was washed three times with 200 pl of wash solution. The samples were then combined with 100 pl of a TMB-peroxidase solution (A:B 1:1, Kirkegaard Perry Laboratories). After 10 minutes the reaction was stopped. The extinction was measured at OD450nm with an ELISA reader. All the results were measured three times.

The data were adapted by iterative calculation using an analytical pogramme for sigmoidal curves (Graph Pad Prism Version 3.0) with a variable Hill pitch.

All the iterative data produced had a correlation coefficient of more than 0.9 and the upper and lower values of the curves showed a spread of at least a factor of 5. The active substance concentration which inhibits the activity of EGF receptor kinase by 50% (ICso) was derived from the curves.

WO 03/082290 PCT/EP03/03062 The following results were obtained: Compound Inhibition of EGF- (Example Nr.) receptor kinase [nM] 1 0.13 1(1) 0.12 1(2) 2 1(3) 1.1 1(4) 0.6 0.6 1(6) 0.69 1(7) 1.6 2 2(1) 0.16 2(2) 0.22 3 0.9 3(1) 0.14 3(2) 0.22 3(7) 0.7 3(8) 0.6 3(9) 0.2 3(11) 0.1 3(15) 1 3(16) 1 3(17) 0.3 3(18) 0.4 3(20) 1 3(21) 0.4 4 0.41 4(1) 0.16 1

I

WO 03/082290 PCT/EP03/03062 The compounds of general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases.

These are e.g. benign or malignant tumours, particularly tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosine kinases, e.g. in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, al-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.

The compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Mnetrier's disease, secreting adenomas and protein loss syndrome.

In addition, the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat other diseases caused by abnormal function of tyrosine kinases, such as e.g. epidermal hyperproliferation (psoriasis), benign prostate hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of haematopoietic cells, the treatment of nasal polyps, etc.

I

WO 03/082290 PCT/EP03/03062 By reason of their biological properties the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors etoposide), mitosis inhibitors vinblastine), compounds which interact with nucleic acids (e.g.

cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g.

tamoxifen), inhibitors of metabolic processes 5-FU etc.), cytokines (e.g.

interferons), antibodies, etc. For treating respiratory tract diseases, these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic ambroxol, N-acetylcysteine), broncholytic tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and/or anti-inflammatory activity theophylline or glucocorticoids). For treating diseases in the region of the gastrointestinal tract, these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion. These combinations may be administered either simultaneously or sequentially.

These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation or transdermally or orally, whilst aerosol formulations are particularly suitable for inhalation.

For pharmaceutical use the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. For administration they are formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.

r WO 03/082290 PCT/EP03/03062 The following Examples are intended to illustrate the present invention without restricting it: Preparation of the starting compounds: Example I 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-benzyloxyquinazoline-hydrochloride A mixture of 10.84 g 4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxyquinazoline and 4.50 g 3-chloro-4-fluoranilin in 300 ml isopropanol is refluxed for four hours and then left to stand overnight at ambient temperature. The precipitate formed is suction filtered, washed with isopropanol and stirred with 150 ml of methanol. The suspension is stirred for another half hour at ambient temperature and then suction filtered. The filter cake is washed repeatedly with methanol and dried.

Yield: 9.07 g (60 of theory) Rf value: 0.27 (silica gel, cyclohexane/ethyl acetate 1:1) Mass spectrum (ESI): m/z 478, 480 The following compounds are obtained analogously to Example I: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7benzyloxy-quinazoline-hydrochloride Rf value: 0.34 (silica gel, cyclohexane/ethyl acetate 1:1) Mass spectrum m/z 466, 468 [M+H] 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)quinazoline-hydrochloride Rf value: 0.17 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 469, 471 [M+H] WO 03/082290 WO 03/82290PCT/EPO3/03062 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l1-trifluoroacetyl-piperid in-4-yloxy)- 7-acetoxy-quinazoline-hydrochloride Rf value: 0.70 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 527, 529 4-[(3-ethynyl-phenyl)amino]-6-acetoxy-7-methoxy-q ulnazol ine Rf value: 0.59 (silica gel, ethyl acetate) Mass spectrum m/z 334 Example 11 4-chloro-6-(tetrahydropyran-4-yloxy)-7 -benzyloxy-quinazoline Prepared by reacting 6- (tetra hyd ropyra n -4 -yl oxy)-7-benzyl oxy-3Hquinazoline-4-on with thionyl chloride in the presence of N,Ndimethylformamide in acetonitrile at reflux temperature.

Rf value: 0.90 (silica gel, ethyl acetate/methanol 9:1) The following compounds are obtained analogously to Example 11: 4-chloro-6-((S)-tetrahydrofuran -3-yloxy)-7-benzyloxy-quinazoline Rf value: 0.85 (silica gel, ethyl acetate/methanol 9:1) 4-chloro-6-(l1-trifluoroacetyl-piperidin -4-yloxy)-quinazoline Rf value: 0.92 (silica gel, ethyl acetate) 4-chloro-6-(l1-trifluoroacetyl-piperidin -4-yloxy)-7-acetoxy-quinazoline Example IIl 6-(tetra hydropyran-4-yloxy)-7-benzyloxy-3H-qu inazol ine-4-on

I

WO 03/082290 PCT/EP03/03062 A mixture of 15.08 g 2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)benzoic acid and 14.40 g formamidine acetate in 250 ml of absolute ethanol is refluxed overnight. The cooled reaction mixture is combined with 250 ml of water. The precipitate formed is suction filtered and dried at 700C in the drying cupboard.

Yield: 10.00 g (65 of theory) Rf value: 0.40 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 353 The following compounds are obtained analogously to Example III: 6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-3H-quinazolin-4-one Rf value: 0.60 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 339 6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-3H-quinazolin-4-one Rf value: 0.48 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 346 6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-hydroxy-3H-quinazolin- 4-one Rf value: 0.35 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 362 Example IV 2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid 16.40 g 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid are hydrogenated in the presence of 1.64 g Raney nickel in 800 ml of methanol at until the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate evaporated down, whereupon the desired I I WO 03/082290 PCT/EP03/03062 product crystallises out.

Yield: 15.08 g (100 of theory) Rf value: 0.60 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) The following compounds are obtained analogously to Example IV: benzyl 2-amino-4-benzyloxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoate Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate 1:1) Mass spectrum m/z 420 [M+H] 2-amino-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid Rf value: 0.43 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 337 [M+H] 2-amino-4-hydroxy-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]benzoic acid Rf value: 0.23 (silica gel, methylene chloride/methanol/acetic acid 90:10:1) Example V 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid Prepared by saponification of benzyl 2-nitro-4-benzyloxy-5-(tetrahydropyran- 4-yloxy)-benzoate with 1 N sodium hydroxide solution in methanol at ambient temperature.

Rf value: 0.20 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 374 [M+H] Example VI Benzyl 2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yloxy)-benzoate 42.60 g potassium-tert.-butoxide are added to 38 ml of tetrahydrofuran-4-ol in I 1 WO 03/082290 PCT/EP03/03062 228 ml N,N-dimethylformamide while cooling with an ice bath. The mixture is stirred for one hour at ambient temperature, then 22.90 g 6-nitrobenzo[1,3]dioxol-5-carboxylic acid are added. After 1.5 hours the reaction is complete according to thin layer chromatography and 28.94 ml of benzylbromide are added dropwise while cooling with an ice bath. The reaction mixture is stirred ovemight at ambient temperature, combined with 100 ml 10% citric acid and stirred for another day at ambient temperature.

Then the reaction mixture is evaporated down in vacuo at 60 oC and added to 800 ml ice water. The aqueous phase is extracted with ethyl acetate and the combined extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated.

The residue is stirred with diethyl ether, while 2-nitro-4-benzyloxy-5- (tetrahydropyran-4-yloxy)-benzoic acid crystallises out as a by-product. This is filtered off and the filtrate is evaporated down. The main product remaining is benzyl 2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yloxy)-benzoate, which is saponified without any further purification to form carboxylic acid (see Example V).

The following compounds are obtained analogously to Example VI: benzyl 2-nitro-4-benzyloxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoate Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate 1:1) Mass spectrum m/z 450 2-nitro-4-hydroxy-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid No reaction is carried out with benzyl bromide.

Rf value: 0.40 (silica gel, methylene chloride/methanol/acetic acid 90:10:1) Mass spectrum m/z 381 [M-H] Example VII 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.-butyloxycarbonylamino)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline WO 03/082290 PCT/EP03/03062 A mixture of 410 mg 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)- 7-methoxy-quinazoline-dihydrochloride, 240 mg N-(tert.-butyloxycarbonyl)-2bromo-ethylamine and 360 mg potassium carbonate in 5 ml N,Ndimethylformamide is stirred overnight at ambient temperature. Then a further mg of N-(tert.-butyloxycarbonyl)-2-bromo-ethylamine are added and the reaction mixture is stirred for a further four hours at ambient temperature. For working up it is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is chromatographed through a silica gel column with ethyl acetate/methanol (95:5 to 90:1) as eluant.

Yield: 370 mg (79 of theory) Rf value: 0.33 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 544, 546 [M-H] The following compound is obtained analogously to Example VII: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-quinazoline Rf value: 0.38 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 516, 518 Example VIII 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline-dihydrochloride Prepared by treating 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline with concentrated hydrochloric acid in dioxane at ambient temperature.

Rf value: 0.53 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) WO 03/082290 PCT/EP03/03062 Mass spectrum m/z 403, 405 The following compounds are obtained analogously to Analog Example VIII: 6-(piperidin-4-yloxy)-3H-quinazolin-4-one x 2 trifluoroacetic acid Carried out with trifluoroacetic acid in methylene chloride.

Mass spectrum m/z 246 [M+H] 6-(piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-one Carried out with trifluoroacetic acid in methylene chloride.

Rf value: 0.60 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 262 Example IX 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1 -(tert.-butyloxycarbonyl)-piperidin-4yloxy]-7-methoxy-quinazoline A solution of 7.80 ml diethyl azodicarboxylate in 100 ml methylene chloride is added dropwise to a mixture of 10.00 g 4-[(3-chloro-4-fluoro-phenyl)amino]-6hydroxy-7-methoxy-quinazoline and 9.40 g 1-(tert.-butyloxycarbonyl)-4hydroxy-piperidine and 12.40 g triphenylphosphine in 400 ml methylene chloride at ambient temperature. The suspension is stirred for three days at ambient temperature and then suction filtered. The filtrate is evaporated and chromatographed through a silica gel column with methylene chloride/methanol (98:2 auf 95:5) as eluant. The crude product obtained is combined with diisopropylether, stirred overnight therein, suction filtered and dried.

Yield: 5.34 g (34 of theory) Rf value: 0.46 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 503, 505 [M+H] Example X 1 WO 03/082290 PCT/EP03/03062 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(4-bromobutyloxy)-quinazoline A mixture of 500 mg 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4yloxy)-7-hydroxy-quinazoline, 165 pl 1-bromo-4-chloro-propane and 360 mg potassium carbonate in 5 ml N,N-dimethylformamide is stirred overnight at For working up the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated.

The crude product is further reacted without any more purification.

Yield: 650 mg (97 of theory) The following compounds are obtained analogously to Example X: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-(4bromo-butyloxy)-quinazoline Rf value: 0.84 (silica gel, ethyl acetate/methanol 9:1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)- 7-ethoxy-quinazoline Mass spectrum m/z 513, 515 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)- 7-(2-methoxy-ethoxy)-quinazoline Rf value: 0.38 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 543, 545 Example XI 1 -(2-hydroxy-ethyl)-3-methyl-tetrahyd ropyrimidin-2-on Prepared by hydrogenolytically cleaving 1-(2-benzyloxy-ethyl)-3-methyltetrahydropyrimidin-2-one in the presence of palladium on activated charcoal in methanol at ambient temperature.

WO 03/082290 PCT/EP03/03062 Rf value: 0.23 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 159 [M+H] Example XII 1-(2-benzyloxy-ethyl)-3-methyl-tetrahydropyrimidin-2-on Prepared by reacting 1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-one with methyl iodide in the presence of potassium-tert.-butoxide in N,Ndimethylformamide at ambient temperature.

Rf value: 0.62 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum (ESI m/z 249 [M+H] Example XIII 1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-on Prepared by treating 1-(2-benzyloxy-ethyl)-3-(3-chloro-propyl)-urea with potassium-tert.-butoxide in N,N-dimethylformamide at ambient temperature.

Rf value: 0.42 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 235 [M+H] Example XIV 1 -(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-one Prepared by reacting 2-benzyloxy-ethylamine with 3-chloro-propyl-isocyanate in tetrahydrofuran.

Rf value: 0.73 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 271, 273 [M+H] Example XV I 1 WO 03/082290 PCT/EPO3/03062 3-(tert.-butyloxycarbonylamino)-cyclohexanol Prepared by reacting 3-amino-cyclohexanol with di-tert.butyl pyrocarbonate in the presence of triethylamine in a mixture of dioxan/water at 500C.

Rf value: 0.34 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 214 The following compounds are obtained analogously to Example XV: cis-4-[N-(tert.-butyloxycarbonyl)-N-methyl-amino]-cyclohexanol The reaction takes place in methanol.

Rf value: 0.70 (silica gel, ethyl acetate) Mass spectrum m/z 230 Example XVI 6-(1 -trifluoroacetyl-piperidin-4-yloxy)-3H-quinazolin-4-one Prepared by reacting 6-(piperidin-4-yloxy)-3H-quinazolin-4-one x 2 trifluoroacetic acid with trifluoroacetic acid anhydride in the presence of triethylamine in tetrahydrofuran.

Rf value: 0.48 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 342 [M+H] The following compounds are obtained analogously to Example XVI: 6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-one Carried out with methyl trifluoroacetate in the presence of Hunig base in methanol.

Rf value: 0.80 (silica gel, methylene chloride/methanol 4:1) Mass spectrum m/z 358 Example XVII

I

WO 03/082290 PCT/EP03/03062 2-nitro-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid 21.00 g potassium-tert.-butoxide are added batchwise to 25.14 g 1-(tert.butyloxycarbonyl)-piperidin-4-ol in 120 ml N,N-dimethylformamide while cooling with an ice bath, while the temperature is kept below 10°C. The mixture is stirred for a further 30 minutes while cooling with an ice bath, then 11.60 g of 5-fluoro-2-nitro-benzoic acid are added. After another three hours the reaction mixture is poured onto water, adjusted to pH 1 with conc.

hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with dilute citric acid solution, dried over magnesium sulphate and evaporated. The residue is triturated with diethyl ether, suction filtered and dried. More product crystallises out of the filtrate after standing for some time, and this is also suction filtered and dried.

Yield: 9.58 g (42 of theory) Rf value: 0.43 (silica gel, methylene chloride/methanol/acetic acid 90:10:1) Mass spectrum m/z 367[M+H]' Example XVIII 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -bromacetyl-piperidin-4-yloxy)quinazoline and 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -chloracetyl-piperidin- 4-yloxy)-quinazoline Prepared by reacting 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)quinazoline with bromoacetic acid chloride in the presence of HUnig base in tetrahydrofuran at ambient temperature. A mixture of the bromine and chlorine compounds is obtained.

Rf value: 0.43 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 493, 495, 497 and 449, 451, 453 [M2+H] The following compounds are obtained analogously to Example XVIII: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-chloracetyl-piperidin-4-yloxy)-7- WO 03/082290 PCT/EP03/03062 methoxy-quinazoline The reaction takes place with chloroacetyl chloride.

Rf value: 0.59 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 477, 479, 481 Example XIX 1 -methyl-3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazol-1 -ium-iodide Prepared by reacting 3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazole with methyl iodide in acetonitrile at ambient temperature. The crude product is reacted further without any more purification.

The following compounds are obtained analogously to Example XIX: 1-methyl-3-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-3H-imidazol-1ium-iodide Rf value: 0.12 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) 1-methyl-3-[(2-methyl-morpholin-4-yl)carbonyl]-3H-imidazol-1-ium-iodide Rf value: 0.02 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Example XX 3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazole Prepared by reacting [1,4]oxazepan with N,N'-carbonyldiimidazole in the presence of triethylamine in tetrahydrofuran at ambient temperature.

Rf value: 0.30 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 196 WO 03/082290 51 PCT/EP03/03062 The following compounds are obtained analogously to Example XX: 3-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-3H-imidazole Rf value: 0.46 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) 3-[(2-methyl-morpholin-4-yl)carbonyl]-3H-imidazole Rf value: 0.43 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Example XXI 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -trifluoroacetyl-piperidin-4-yloxy)-7hydroxy-quinazoline Prepared by treating 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetylpiperidin-4-yloxy)-7-acetoxy-quinazoline-hydrochloride with saturated sodium hydrogen carbonate solution in methanol at ambient temperature. In addition to the desired product, some 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin- 4-yloxy)-7-hydroxy-quinazoline is also isolated as a by-product.

Rf value: 0.20 (silica gel, methylene chloride/methanol 20:1) Mass spectrum m/z 483, 485 The following compounds are obtained analogously to Example XXI: 4-[(3-ethynyl-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline Carried out with 40 sodium hydroxide solution in ethanol.

Rf value: 0.32 (silica gel, ethyl acetate) Mass spectrum m/z 292 Example XXII 6-(1 -trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-3H-quinazolin-4-one Prepared by reacting 6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-3H- 1 WO 03/082290 52 PCT/EP03/03062 quinazolin-4-one with acetic anhydride in pyridine at 80 0

C.

Rf value: 0.60 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 400 Preparation of the end compounds: Example 1 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7methoxy-quinazoline ci

NH

N 0 N 0

CH

3 300 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxyquinazoline in 6 ml acetonitrile are combined with 114 pl (R)-3-hydroxytetrahydrofuran and 370 mg triphenylphosphine. Then 234 pl diethyl azodicarboxylate are added and the reaction mixture is stirred overnight at ambient temperature. For working up the reaction mixture is filtered and the filtrate evaporated down in vacuo. The crude product is purified by chromatography over a silica gel column with ethyl acetate/methanol (95:5) as eluant.

Yield: 53 mg (15 of theory) melting point: 1780C Mass spectrum m/z 390, 392 [M+H] The following compounds are obtained analogously to Example 1: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7- WO 03/082290 PCT/EP03/03062 methoxy-quinazoline ci F I~t

NH

N 0

CH

3 Rf value: 0.54 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 404, 406 [M-IH]+ 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(tert.butyloxycarbonylami no)-cyclohexan- 1-yloxy]-7-methoxy-quinazoli ne ci F

NH

0 0NN

H

3

C

H 3 c CH 3 Rf value: 0.70 (silica gel, ethyl acetate/methanol =9:1) Mass spectrum m/z 517, 519 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-((R)-tetrahydrofuran-3-yloxy)-7methoxy-quinazoline WO 03/082290 WO 03/82290PCT/E P03/03062 Rf value: 0.64 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 390, 392 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-[trans-4-(tert.butyloxycarbonylamino)-cyclohexan-1 -yloxy]-7-methoxy-quinazoline c1

F

NH

N ao

N

N) 0 N

CH

3 0 0 H 3 c>K

H

3 c CH 3 Rf value: 0.65 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 517, 519 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-[1 -(tert.-butyloxycarbonyl piperidin-4-yloxy]-7-methoxy-quinazoline ci F '&H0

-O

NH

N Y H3 c

H

3 melting point: 18400 Mass spectrum m/z 503, 505 IM+H]+ 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-(tetrahyd ropyran-3-yloxy)-7methoxy-quinazoline WO 03/082290PC/P0036 PCT/EP03/03062 Fj:

'NH

N' 0

OH

3 Rf value: 0.52 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 404, 406 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methyl-piperidin-4-yloxy)-7methoxy-quinazoline

F

Cl:) NH N 0 kNa o 0 OH 3

OH

3 melting point: 218 0

C

Mass spectrum m/z 417, 419 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)-1 -(tert.-butyloxycarbonyl)pyrrolidin-3-yloxy]-7-methoxy-quinazol ine Carried out with diisopropyl azodicarboxylate in methylene chloride.

Rf value: 0.51 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 489, 491 4-[(3-chioro-4-fluoro-phenyl)amino]-6-[1 -(tert.-butyloxycarbonyl)piperidin-3-yloxy]-7-methoxy-quinazoline Carried out with diisopropyl azodicarboxylate in methylene chloride.

Rf value: 0.56 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 501, 503 WO 03/082290 WO 03/82290PCT/E P03/03062 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[2- (3-methyl-2-oxo-hexahydropyrimidin-1 -yl )-ethoxy]-quinazoline Carried out with dilsopropyl azodicarboxylate in methylene chloride.

melting point: 235 0

C

Mass spectrum m/z 516, 518 (11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(tert.-butyloxycarbonylamino)cyclohexan-1 -yloxy]-7-methoxy-quinazoline Carried out with diisopropyl azodicarboxylate in methylene chloride.

Rf value: 0.68 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 515, 517 (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(tert.-butyloxycarbonyl)- N-methyl-amino]-cyclohexan-1 -yloxy}-7-methoxy-q u inazoline Carried out with diisopropyl azodicarboxylate in methylene chloride.

Rf value: 0.37 (silica gel, methylene chloride/methanol 9:1) Mass spectrum (ES m/z 531, 533 (13) 4-[(3-chloro-4-fluoro-phenyl)aminol-6-{trans-4-[N-(tert.butyloxycarbonyl)-N-methyl-amino]-cyclohexan-1 -yloxy}-7-methoxyq u inazol in e Carried out with diisopropyl azodicarboxylate in methylene chloride.

melting point: 231 0

C

Mass spectrum m/z 531, 533 [M+HI' Example 2 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-amino-cyclohexan-1 -yloxy)-7methoxy-quinazoline x trifluoroacetic acid WO 03/082290 PCT/E P03/03062

F

CI aNH NkN0a o NH 2

LOH

3 Prepared by treating 4-[(3-chloro-4-fluoro-phenyl )amino]-6-[cis-4-(tert.butyloxycarbonylamino)-cyclohexan- 1 -yloxy]-7-methoxy-quinazoline with trifluoroacetic acid in methylene chloride at ambient temperature.

melting point: 221 0

C

Mass spectrum m/z 417, 419 The following compounds are obtained analogously to Example 2: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1 yloxy)-7-methoxy-q ulnazoline

F

CI aNH N 0' kN 0 NH 2

UH

3 Mass spectrum m/z 417, 419 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yioxy)-7-methoxyquinazoline x trifluoroacetic acid

F

CI a NH 0

N

NN

kN) 0

UH

3 melting point: 232 0

C

WO 03/082290 WO 03/82290PCT/EP03/03062 Mass spectrum m/z 403, 405 Example 3 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methanesulphonylaminocyclohexan-1 -yloxy)-7-methoxy-quinazoline

F

ci NH N 0 kN' aO N\ CH I HO0

OH

3 Prepared by reacting 4-[(3-chloro-4-fluoro-phenyl)a mi no]-6-(cis-4-aminocyclohexan-1 -yloxy)-7-methoxy-q u inazoline x trifluoroacetic acid with methanesuiphonic acid chloride in the presence of H~inig base in tetrahydrofuran at ambient temperature.

Rf value: 0.77 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 40:10:1) Mass spectrum m/z 495, 497 [M+Hf+ The following compounds are obtained analogously to Example 3: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylaminocyclohexan-1 -yloxy)-7-methoxy-quinazoline

F

CI aNH N 0 1 HO

CH

3 Rf value: 0.20 (silica gel, ethyl acetate) Mass spectrum m/z 495, 497 WO 03/082290 PCT/E P03/03062 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methanesulphonyl-piperidin-4yloxy)-7-methoxy-quinazoline

F

CI NH N

Z

N 0 OH 3 CH 3 Rf value: 0.59 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia= 90:10:1) Mass spectrum mlz 481, 483 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(3-chloropropyl)sulphonylamino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline

F

Ci aNH N I HO0

UH

3 The reaction takes place with 3-chloropropansulphonyl chloride.

Rf value: 0.79 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 555, 557, 559 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-{trans-4-[(3-chloropropyl)sulphonylamino]-cyclohexan-1 -yloxy)-7-methoxy-quinazoline

F

CI

NH

N 0 I HO

OH

3 WO 03/082290 WO 03/82290PCT/E P03/03062 The reaction takes place with 3-chioropropanesuiphonyl chloride.

Rf value: 0.42 (silica gel, ethyl acetate) Mass spectrum m/z 557, 559, 561 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methylcarbonyl-piperidin-4yloxy)-7-methoxy-q ulnazoline

F

CI: a NH 0

UH

3

CH

3 The reaction takes place with acetic anhydride.

melting point: 21600 Mass spectrum m/z 445, 447 [M+H]f 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(dimethylamino)carbonyl]piperidin-4-yloxy}-7-methoxy-quinazoli ne

F

N a U3H 3 C ON1 H 3 The reaction takes place with N,N-dimethylcarbamoylchloride.

Rf value: 0.28 (Reversed phase ready-made TLC plate Merck), acetonitrile/water! trifluoroacetic acid 50:50:1) Mass spectrum m/z 474, 476 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(morphol in-4-yl)carbonyl]piperidi n-4-yloxy}-7-methoxy-quinazol ine WO 03/082290 PCT/EPO3/03062

F

N N 0 The reaction takes place with (morpholin-4-yl)carbonylchloride in acetonitrile.

Rf value: 0.37 (Reversed phase ready-made TLC plate Merck), acetonitrile/water! trifluoroacetic acid 50:50:1) Mass spectrum m/z 516, 518 4-[(3-ch Ioro-4-fluoro-phenyl)amino]-6-{lI-[(methoxymethyl)carbonyllpiperidi n-4-yloxy}-7-methoxy-quinazolime

F

N

_O

N 0

OH

3 K 0 cH 3 The reaction takes place with methoxyacetic acid chloride.

Rf value: 0.80 (silica gel, methylene chloride/methanol 9:1) Mass spectrum mlz 475, 477 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l1-cyano-piperidin-4-yloxy)-7 methoxy-quinazoline

F

Cl: NH WO 03/082290 WO 03/82290PCT/EPO3/03062 The reaction takes place with bromocyanogen in methylene chloride.

Rf value: 0.40 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 428, 430 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(dimethylamino)sulphonyl]piperidin-4-yloxy}-7-methoxy-quinazoline

F

ci NH

N~-

N0 3H 3 c N cH 3 The reaction takes place with N,N-dimethylsulphamoylchloride in acetonitrile.

Rf value: 0.24 (Reversed phase ready-made TLC plate Merck), acetonitrile/water! trifluoroacetic acid 50:50:1) Mass spectrum m/z 510, 512 (11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(morpholin-4-yl)sulphonyl]piperidin-4-yloxy}-7-methoxy-quinazol ine

F

ci: NH N 0 N 0 cH 3

N

0) The reaction takes place with (morpholin-4-yl)sulphonyl chloride in acetonitrile.

Rf value: 0.29 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) WO 03/082290 WO 03/82290PCT/E P03/03062 Mass spectrum m/z 552, 554 (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methanesulphonyl-piperidin-3yloxy)-7-methoxy-qu inazoline Rf value: 0.33 (Reversed phase ready-made TLC plate Merck), acetonitrile/water! trifluoroacetic acid 50:50:1) Mass spectrum m/z 481, 483 (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-1 -methanesulphonylpyrrol idin-3-yloxy)-7-methoxy-quinazoli ne melting point: 249C Mass spectrum m/z 467, 469 (14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1 -(2-methanesulphonylaminoethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline Rf value: 0.49 (Reversed phase ready-made TLC plate Merck), acetonitrile/water! trifluoroacetic acid 50:50:1) Mass spectrum (ES m/z 524, 526 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1 -(2-acetylamino-ethyl)-piperidin- 4-yloxy]-7-methoxy-q uinazoline The reaction takes place with acetic anhydride.

Rf value: 0.51 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum mlz 488, 490 (16) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4- [(dimethylamino)sulphonylamino]-cyclohexan-1 -yloxy}-7-methoxyquinazoline The reaction takes place with N,N-dimethylsulphamoylchloride in acetonitrile.

Rf value: 0.69 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 524, 526 WO 03/082290 WO 03/82290PT/EPO3/03062 (17) 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-{trans-4-[(morpholin-4yl )carbonylami no]-cyclohexan- I -yloxy}-7-methoxy-quinazoli ne The reaction takes place with (morpholin-4-yl)carbonylchloride in acetonitrile.

Rf value: 0.38 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 530, 532 (18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4yl)sulphonylamino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline The reaction takes place with (morpholin-4-yl)sulphonyl chloride in acetonitrile.

melting point: 23700 Mass spectrum mlz 564, 566 (19) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-methanesulphonylaminocyclohexan-1 -yloxy)-7-methoxy-quinazoline Rf value: 0.66 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 493, 495 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2acetylamino-ethoxy)-quinazoline The reaction takes place with acetylchloride in acetonitrile.

melting point: 2240C Mass spectrum m/z 475, 477 [M+H]f (21) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahyd ropyran-4-yloxy)-7-(2methanesulphonylamino-ethoxy)-quinazoline melting point: 2270C Mass spectrum (ES m/z 511, 513 (22) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-3-acetylamino-cyclohexan-1 yloxy)-7-methoxy-q uinazoline The reaction takes place with acetylchloride in acetonitrile. Cis- and transisomer are separated by chromatography over a silica gel column.

Rf value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueous WO 03/082290 WO 03/82290PCT/E P03/03062 ammonia 90:10:1) Mass spectrum m/z 459, 461 (23) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-3-acetylamino-cyclohexan- 1 -yloxy)-7-methoxy-quinazoline The reaction takes place with acetyichioride in acetonitrile. Cis- and transisomer are separated by chromatography over a silica gel column.

Rf value: 0.49 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 459, 461 (24) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahyd ropyran-4-yloxy)-7-(3acetylamino-propyloxy)-quinazoline The reaction takes place with acetylchloride.

melting point: 2250C Mass spectrum m/z 489, 491 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-(tetrahydropyran-4-yloxy)-7-(3methanesulphonylamino-propyloxy)-quinazoline melting point: 2220C Mass spectrum m/z 525, 527 (26) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(l -methanesulphony-piperidin-4yloxy)-quinazoline Rf value: 0.44 (silica gel, methylene chloride /methanol 9:1) Mass spectrum m/z 451, 453 (27) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l -[(morpholin-4-yl)carbonyl]piperid in-4-yloxy}-quinazoline The reaction takes place with (morpholin-4-yl)carbonylchloride in acetonitrile.

Rf value: 0.40 (silica gel, methylene chloride /methanol 9:1) Mass spectrum mlz 486, 488 [M+HJ+ (28) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-( 1 -acetyl-piperidin-4-yloxy)- WO 03/082290 WO 03/82290PCT/E P03/03062 q u inazol ine The reaction takes place with acetic anhydride.

Rf value: 0.50 (silica gel, methylene chloride /methanol 9:1) Mass spectrum m/z 415, 417 (29) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(dimethylamino)carbonyl]piperidin-4-yloxy}-quinazoline The reaction takes place with N,N-dimethylcarbamoylchloride.

Rf value: 0.47 (silica gel, methylene chloride /methanol 9:1) Mass spectrum (ES m/z 444, 446 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-acetylamino-cyclohexan- 1 -yloxy}-7-methoxy-quinazoline The reaction takes place with acetic anhydride.

Rf value: 0.50 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 459, 461 (31) 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-{trans-4- [(dimethylamino)carbonylamino] -cyclohexan-1 -yloxy}-7-methoxyq u inazol ine The reaction takes place with N, N-dimethylcarbamoylchloride.

Rf value: 0.40 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 488, 490 (32) 4-[(3-ch loro-4-fluoro-phenyl)amino]-6-[trans-4-(2-methoxy-acetylamino)cyclohexan-1 -yloxy]-7-methoxy-quinazoline The reaction takes place with methoxyacetic acid chloride.

Rf value: 0.35 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 489, 491 (33) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1 -(2-methoxy-acetyl)-piperidin-4yloxy]-quinazoline The reaction takes place with methoxyacetic acid chloride.

Rf value: 0.41 (silica gel, methylene chloride/methanol 9:1) WO 03/082290 WO 03/82290PCT/EPO3/03062 Mass spectrum mlz 445, 447 (34) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -isopropyloxycarbonyl-piperidin- 4-yloxy)-7-methoxy-quinazoline The reaction takes place with isopropyl chioroformate.

Rf value: 0.67 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia= 98:2:1) Mass spectrum m/z 489, 491 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(lI-cyano-piperid in-4-yloxy)quinazoline The reaction takes place with bromocyanogen in methylene chloride.

Rf value: 0.49 (silica gel, methylene chloride/methanol 9:1) Mass spectrum mlz 396, 398 (36) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(dimethylamino)sulphonyl]piperidin-4-yloxy}-quinazoline The reaction takes place with N,N-dimethylsulphamoylchloride in acetonitrile.

Rf value: 0.34 (silica gel, methylene chloride/methanol 9:1) Mass spectrum (ES m/z 480, 482 (37) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(morpholin-4-yl)sulphonyl]piperidin-4-yloxy}-quinazoline The reaction takes place with (morpholin-4-yl)sulphonyl chloride in acetonitrile.

Rf value: 0.15 (silica gel, cyclohexane/ethyl acetate 1:1) Mass spectrum m/z 522, 524 (38) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1 -(2-acetylamino-ethyl)-piperidin- 4-yloxy]-quinazoline The reaction takes place with acetic anhydride in acetonitrile.

melting point: 221 0

C

Mass spectrum m/z 458, 460 [M-iH]+ WO 03/082290 WO 03/82290PCT/EP03/03062 (39) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(diethylamino)carbonyl] piperidin-4-yloxy}-7-methoxy-quinazoli ne The reaction takes place with N,N-diethylcarbamoylchloride.

Rf value: 0.40 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 95:5:1) Mass spectrum m/z 502, 504 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(piperidin-1 -yl)carbonyllpiperidin-4-yloxy}-7-methoxy-quinazoline The reaction takes place with (piperidin-1-yl)carbonylchloride.

Rf value: 0.51 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 95:5:1) Mass spectrum m/z 512, 514 (41) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(pyrrolidin-1 -yl)carbonyl]piperidin-4-yloxy}-7-methoxy-quinazoline The reaction takes place with (pyrrolidin-1-yl)carbonylchloride.

melting point: 23700 Mass spectrum m/z 500, 502 (42) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(4-methyl-piperazin-1 yl )carbonyl]-piperidin-4-yloxy}-7-methoxy-qu inazol ine The reaction takes place with (4-methyl-piperazin-1 -yl)carbonylchloridehydrochloride.

Rf value: 0.28 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 527, 529 (43) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-Nmethyl-amino)-cyclohexan-1 -yloxy]-7-methoxy-quinazoline The reaction takes place in methylene chloride.

Rf value: 0.71 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum (ES m/z 509, 511 WO 03/082290 WO 03/82290PCT/E P03/03062 (44) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)cyclohexan- 1 -yloxy]-7-methoxy-q uinazoline The reaction takes place with acetic anhydride.

melting point: 23400 Mass spectrum m/z 473, 475 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-Nmethyl-amino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline The reaction takes place with methoxyacetic acid chloride.

Rf value: 0.40 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 503, 505 (46) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminocarbonyl- N-methyl-amino)-cyclohexan-1 -yloxy]-7-methoxy-quinazoline The reaction takes place with N,N-dimethylcarbamoylchloride.

Rf value: 0.51 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum (ES m/z 502, 504 (47) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin -4yl)carbonyl]-N-methyl-amino}-cyclohexan-1 -yloxy)-7-methoxyq u inazol ine The reaction takes place with (morpholin-4-yl)carbonylchloride.

Rf value. 0.50 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 544, 546 (48) 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-(cis-4-{N-[(morpholin -4yl)sulphonyl]-N-methyl-amino}-cyclohexan -1 -yloxy)-7-methoxyq ui nazol ine The reaction takes place with (morpholin-4-yl)sulphonyl chloride in acetonitrile.

Rf value: 0.24 (Reversed phase ready-made TLC plate Merck), aceton itrile/water! trifluoroacetic acid 50:50:1) Mass spectrum m/z 580, 582 [M-IH]+ WO 03/082290 WO 03/82290PCT/E P03/03062 (49) 4-[(3-ch loro-4-fluoro-phenyl)ami no]-6-[cis-4-(N-dimethylaminosulphonyl- N-methyl-amino)-cyclohexan-1 -yloxy]-7-methoxy-quinazoline The reaction takes place with N,N-dimethylsulphamoylchloride in acetonitrile.

Rf value: 0.53 (silica gel, ethyl acetate) Mass spectrum m/z 538, 540 4-[(3-ch loro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylaminocyclohexan- 1 -yloxy)-7-methoxy-qu inazoline The reaction takes place with ethanesulphonic acid chloride in methylene chloride.

Rf value: 0.41 (silica gel, ethyl acetate) Mass spectrum m/z 509, 511 (51) 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-{1 -[(morphol in-4-yl)carbonyl]piperidin-4-yloxy}-7-ethoxy-qu inazoline The reaction takes place with (morpholin-4-yl)carbonylchloride.

Rf value: 0.48 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 530, 532 (52) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methanesulphonyl-piperidin-4yloxy)-7-ethoxy-quinazoline Rf value: 0.50 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 495, 497 (53) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1 -(2-methoxy-acetyl)-piperidin-4yloxy]-7-ethoxy-qu inazoline The reaction takes place with methoxyacetic acid chloride.

Rf value: 0.40 (silica gel, methylene chloride/methanol 20:1) Mass spectrum m/z 489, 491 (54) 4-[(3-chloro-4-fluoro-phenyl)amino-6-(1 -methanesulphonyl-piperidin-4yloxy)-7-(2-methoxy-ethoxy)-qu inazoline Rf value: 0.47 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 525, 527 WO 03/082290 WO 03/82290PCT/E P03/03062 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{lI-[(morpholin-4-yl)carbonyljpiperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline The reaction takes place with (morpholin-4-yl)carbonylchloride.

Rf value: 0.48 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 560, 562 (56) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1 -(2-methoxy-acetyl)-piperidin-4yloxy]-7-(2-methoxy-ethoxy)-qu inazoline The reaction takes place with methoxyacetic acid chloride.

Rf value: 0.48 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 519, 521 (57) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1 yloxy)-7-methoxy-quinazol ine The reaction takes place with acetic anhydride.

melting point: 28100C Mass spectrum (ES m/z 459, 461 (58) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(2-methoxy-acetylamino)cyclohexan-1 -yloxy]-7-methoxy-quinazoline The reaction takes place with methoxyacetic acid chloride.

melting point: 264 0

C

Mass spectrum m/z 489, 491 (59) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1 -yl)carbonyl]- N-methyl-amino}-cyclohexan-1 -yloxy)-7-methoxy-quinazolime The reaction takes place with (piperidin-1 -yl)carbonylchloride.

melting point: 25300 Mass spectrum (ES m/z 542, 544 [M-4H]+ 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1 yl )carbonyl]-N-methyl-amino}-cyclohexan-1 -yloxy)-7-methoxyquinazoline WO 03/082290 WO 03/82290PCT/EP03/03062 The reaction takes place with (4-methyl-piperazin-1 -yl)carbonylchloridehydrochloride.

melting point: 262 0

C

Mass spectrum m/z 557, 559 (61) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-ethanesulphonyl-Nmethyl-amino)-cyclohexan-1 -yloxy]-7-methoxy-quinazoline The reaction takes place with ethanesuiphonic acid chloride in methylene chloride.

Rf value: 0. 19 (Reversed phase ready-made TLC plate Merck), acetonitrile/water! trifluoroacetic acid 50:50:1) Mass spectrum m/z 523, 525 (62) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4yl )carbonylamino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline The reaction takes place with (morpholin-4-yl)carbonylchloride.

Rf value: 0.33 (Reversed phase ready-made TLC plate Merck), aceton itrile/water! trifluoroacetic acid 50:50:1) Mass spectrum m/z 530, 532 (63) 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-{cis-4-[(morpholin-4yl)sulphonylamino]-cyclohexan-1 -yloxy-7-methoxy-quinazoline The reaction takes place with (morpholin-4-yl)sulphonyl chloride in acetonitrile.

Rf value: 0.81 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 566, 568 (64) 4-[(3-ethynyl-phenyl)amino]-6-(l1-acetyl-piperidin-4-yloxy)-7-methoxyquinazoline The reaction takes place with acetic anhydride.

Rf value: 0.30 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia= 90:10:1) Mass spectrum m/z 417 [M+HI+ WO 03/082290 WO 03/82290PCT/EPO3/03062 4-I(3-ethynyl-phenyl)amino]-6-[l1-(2-methoxy-acetyl )-pi peridin-4-yloxy]-7methoxy-quinazoline The reaction takes place with methoxyacetic acid chloride.

Rf value: 0.37 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum (ES m/z 447 (66) 4-[(3-ethynyl-phenyl)amino]-6-(1 -methanesulphonyl-piperidin-4-yloxy)-7methoxy-quinazoline Rf value: 0.59 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia= 90:10:1) Mass spectrum mlz 453 (67) 4-[(3-ethynyl-phenyl)amino]-6-{1 -[(morpholin-4-yl)carbonyl]-piperidin-4yloxy}-7-methoxy-quinazoline The reaction takes place with (morpholin-4-yl)carbonylchloride.

Rf value: 0.43 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 488 (68) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-Nmethyl-amino)-cyclohexan-1 -yloxy]-7-methoxy-quinazoline Rf value: 0.50 (silica gel, methylene chloride /methanol 9:1) Mass spectrum m/z 509, 511 (69) 4-[(3-chloro-4-fluoro-phenyl)amino-6-(trans-4-N-[(morpholin-4yl )carbonyl]-N-methyl-amino}-cyclohexan-1 -yloxy)-7-methoxyquinazoline The reaction takes place with (morpholin-4-yl)carbonylchloride.

Rf value: 0.54 (silica gel, methylene chloride /methanol 9:1) Mass spectrum m/z 544, 546 I 1 WO 03/082290 PCT/E P03/03062 Example 4 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)propyl]sulphonylamino}-cyclohexan-1 -yloxy)-7-methoxy-quinazoline

F

CI NH 0 r0 N 0 o I H O

CH

3 23 pl of morpholine are added to 60 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-{cis-4-[(3-chloro-propyl)sulphonylamino]-cyclohexan-1 yloxy}-7-methoxy-quinazoline in 2 ml acetonitrile and the reaction mixture is refluxed overnight. For working up the mixture is taken up in ethyl acetate and washed with water. The organic phase is dried over magnesium sulphate and evaporated down. The crude product is purified through a silica gel column with methylene chloride/methanol as eluant.

Yield: 18 mg (27% of theory) Rf value: 0.36 (silica gel, methylene chloride /methanol 9:1) Mass spectrum m/z 608, 610 The following compounds are obtained analogously to Example 4: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-(morpholin-4-yl)propyl]sulphonylamino}-cyclohexan-1 -yloxy)-7-methoxy-quinazoline

F

CI NH 0 ro\~\/I N 010 N 0 N O I HO

CH

3 Rf value: 0.16 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia WO 03/082290 75 PCT/EP03/03062 90:1 0:1) Mass spectrum mlz 608, 610 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[4- (morpholin-4-yl)-butyloxy]-quinazoline Carried out in the presence of sodium carbonate and sodium iodide in Nmethylpyrrolidone at 1 0000.

Rf value: 0. 18 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 40:10:0.5) Mass spectrum mlz 531, 533 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[4- (morpholin-4-yl)-butyloxy]-quinazoline Carried out in the presence of sodium carbonate and sodium iodide in Nmethylpyrrolidone at 10000C.

Rf value: 0.32 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 80:20:1) Mass spectrum m/z 517, 519 4-[(3-ch loro-4-fluoro-phenyl)amino]-6-{l1-[(morpholin-4-yI)acetyl] piperidin-4-yloxy}-quinazoline Carried out in the presence of HOnig base in tetrahydrofuran at ambient temperature.

Rf value: 0.30 (silica gel, methylene chloride /methanol 9:1) Mass spectrum mlz 500, 502 [M+HJ+ 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -dimethylaminoacetyl-piperid in- 4-yloxy)-quinazoline Carried out in the presence of Hiinig base in tetrahydrofuran at ambient temperature.

Rf value: 0.11 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 458, 460 WO 03/082290 PCT/EP03/03062 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-dimethylaminoacetyl-piperidin- 4-yloxy)-7-methoxy-quinazoline Carried out in the presence of Hunig base in tetrahydrofuran at ambient temperature.

Rf value: 0.19 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 488, 490 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)acetyl]piperidin-4-yloxy}-7-methoxy-quinazoline Carried out in the presence of Hunig base in tetrahydrofuran at ambient temperature.

Mass spectrum m/z 530, 532 Example 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-pyrrolidin-3-yloxy)-7-methoxyquinazoline-dihydrochloride A solution of 370 mg 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)-1-(tert.butyloxy-carbonyl)-pyrrolidin-3-yloxy]-7-methoxy-quinazoline in 5 ml dioxane is combined with 0.32 ml concentrated hydrochloric acid and stirred overnight at ambient temperature. The precipitate formed is suction filtered and washed with copious amounts of dioxane. The crude product is dissolved in a little methanol and re-precipitated by the addition of the same amount of ethyl acetate. The white solid thus obtained is suction filtered and dried.

Yield: 200 mg (57 of theory) melting point: 281°C Mass spectrum m/z 389, 391 [M+H] The following compounds are obtained analogously to Example 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxyquinazoline-dihydrochloride WO 03/082290 WO 03/82290PCT/EP03/03062 melting point: 26300 Mass spectrum (ES m/z 403, 505 [M-eH]+ 4-[(3-ch Ioro-4-fluoro-phenyl)amino]-6-[l1-(2-amino-ethyl )-piperidin-4yloxy]-7-methoxy-quinazoline-dihydrochloride melting point: 2770C Mass spectrum m/z 446, 448 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-amino-cyclohexan-1 -yloxy)-7methoxy-quinazoline-dihydrochloride Mass spectrum m/z 417, 419 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2amino-ethoxy)-quinazoline-d ihydrochloride Carried out with isopropanolic hydrochloric acid (5-6 M) in methylene chloride.

Rf value: 0.58 (Reversed phase ready-made TLC plate Merck), acetonitrile/water! trifluoroacetic acid 50:50:1) Mass spectrum m/z 433, 435 [M+H]f 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3amino-propyloxy)-quinazoline-dihydrochloride Carried out with isopropanolic hydrochloric acid (5-6 M) in methylene chloride.

Rf value: 0.44 (Reversed phase ready-made TLC plate Merck), aqueous sodium chloride solution 7:3) Mass spectrum m/z 447, 449 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1 -(2-amino-ethyl )-piperidin-4yloxy]-quinazoline-dihydrochloride Rf value: 0.50 (Reversed phase ready-made TLC plate Merck), acetonitrile/water! trifluoroacetic acid 50:50:1) Mass spectrum m/z 416, 418 [M+HI+ 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1 yloxy)-7-methoxy-quinazoli ne-dihydrochlbride I 1 WO 03/082290 PCT/EP03/03062 Carried out with isopropanolic hydrochloric acid (5-6 M) in methylene chloride.

Rf value: 0.35 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 431, 433 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazolinedihydrochloride Carried out with isopropanolic hydrochloric acid (5-6 M) in methylene chloride.

Rf value: 0.50 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 375 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan- 1-yloxy)-7-methoxy-quinazoline-dihydrochloride melting point: 251°C Mass spectrum m/z 431, 433 Example 6 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxyquinazoline A mixture of 9.00 g 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4yloxy)-7-benzyloxy-quinazoline-hydrochloride and 50 ml trifluoroacetic acid is heated to 100°C for 1.5 hours. Then the reaction mixture is evaporated and the residue is taken up in 10 ml acetonitrile. This solution is added dropwise to 100 ml saturated sodium hydrogen carbonate solution with vigorous stirring.

After 1.5 hours the precipitate formed is suction filtered and washed several times with water. The crude product is stirred with diethyl ether, suction filtered and dried.

Yield: 5.90 g (87 of theory) Rf value: 0.21 (silica gel, ethyl acetate) Mass spectrum m/z 390, 392 [M+H] WO 03/082290 79 PCT/EP03/03062 The following compounds are obtained analogously to Example 6: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7hydroxy-quinazoline Rf value: 0.44 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 376, 378 Example 7 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[3- (morpholin-4-yl)-propyloxy]-quinazoline A mixture of 300 mg 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4yloxy)-7-hydroxy-quinazoline, 130 mg 3-(morpholin-4-yl)-propylchloride and 530 mg potassium carbonate in 5 ml N,N-dimethylformamide is stirred overnight at 80°C. For working up the reaction mixture is diluted with 25 ml of water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is stirred with diethyl ether, suction filtered and dried.

Yield: 250 mg (63 of theory) melting point: 2050C Mass spectrum m/z 517, 519 The following compounds are obtained analogously to Example 7: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[2- (morpholin-4-yl)-ethoxy]-quinazoline Rf value: 0.33 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 40:10:0.5) Mass spectrum m/z 503, 505 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7ethoxy-quinazoline WO 03/082290 WO 03/82290PCT/EPO3/03062 Rf value: 0.76 (silica gel, ethyl acetate/methanol/cono. aqueous ammonia 90:1 0:1) Mass spectrum m/z 418, 420 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[3- (morpholin-4-yl )-propyloxy]-q uinazoline Rf value: 0.20 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia= 90:10:1) Mass spectrum (ESIL): m/z 501, 503[M-H]- 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-((S)-tetrahydrofuran-3-yloxy)-7-[2- (morpholin-4-yl )-ethoxy]-quinazol ine Rf value: 0. 19 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia= 90:10:1) Mass spectrum m/z 489, 491 4-[(3-ch loro-4-flu oro-ph enyl)a mi no]-6- (tetra hyd ropyran-4-yl oxy)-7-(2methoxy-ethoxy)-quinazoline Rf value: 0.57 (silica gel, methylene chloride /methanol 9:1) Mass spectrum m/z 448, 450 4-[(3-ch loro-4-fl uoro-ph enyl)a min o] (tetra hyd ropyran-4-yl oxy)-7-[2- (tert.-butyloxycarbonylamino)-ethoxy]-quinazoline Rf value: 0.64 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 95:5:0.1) Mass spectrum m/z 533, 535 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahyd ropyran-4-yloxy)-7-[3- (tert.-butyloxycarbonylamino)-propyloxy]-quinazoline Rf value: 0.74 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 95:5:0.1) Mass spectrum m/z 547, 549 Example 8 WO 03/082290 PCT/EP03/03062 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazoline A solution of 4.55 g 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetylpiperidin-4-yloxy)-quinazoline-hydrochloride in 35 ml methanol is combined with 13 ml (3 N) sodium hydroxide solution and stirred for about half an hour at ambient temperature. For working up the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is stirred with diethyl ether, suction filtered and dried.

Yield: 3.00 g (89 of theory) Rf value: 0.48 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 373, 375 [M+H] The following compounds are obtained analogously to Example 8: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-ethoxyquinazoline Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 417, 419 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-(2-methoxyethoxy)-quinazoline Rf value: 0.10 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 447, 449 Example 9 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(ethylamino)carbonyl]-piperidin-4yloxy}-7-methoxy-quinazoline WO 03/082290 WO 03/82290PCT/EP03/03062 Prepared by reacting 4-[(3-chloro-4-fluoro-phenyl )amino]-6-(piperid in-4-yloxy)- 7-methoxy-quinazoline with ethyl isocyanate in tetrahydrofuran at ambient temperature.

Rf value: 0.53 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 474, 476 The following compounds are obtained analogously to Example 9: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(isopropylamino)carbonyl]piperidin-4-yloxy}-7-methoxy-q uinazoline melting point: 236 0

C

Mass spectrum mlz 486, 488 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(phenylamino)carbonyl]piperidin-4-yloxy}-7-methoxy-quinazoline Rf value: 0.70 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 95:5:0.1) Mass spectrum m/z 522, 524 4-[(3-chloro-4-fluoro-pheny)amino-6-(cis-4-{N-[(ethylamino)carbonyl]-Nmethyl-amino}-cyclohexan-1 -yloxy)-7-methoxy-quinazoline Rf value: 0.38 (silica gel, methylene chloride/methanol 9:1) Mass spectrum m/z 502, 504 Example 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(dimethylamino)carbonylmethyl]piperidin-4-yloxy}-quinazoline Prepared by reacting 4-[(3-chloro-4-fiuoro-phenyl)amino]-6-(piperidi n-4-yloxy)quinazoline with 2-chloro-N,N-dimethylacetamide in the presence of potassium carbonate in N,N-dimethylformamide at ambient temperature.

Rf value: 0.24 (silica gel, methylene chloride/methanol 9:1) WO 03/082290 WO 03/82290PCT/EPO3/03062 Mass spectrum m/z 458, 460 The following compounds are obtained analogously to Example 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(morpholin-4yl)carbonylmethyl]-piperidin-4-yloxy}-quinazoline Rf value: 0.42 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 500, 502 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -aminocarbonylmethyl-piperid in- 4-yloxy)-7-methoxy-q ulnazoline melting point: 251 0

C

Mass spectrum m/z 460, 462 4-[(3-chloro-4-fluoro-phenyl)ami no]-6-{1 imethylamino)carbonylmethyl] -piperidin-4-yloxy}-7-methoxyquinazoline melting point: 233 0

C

Mass spectrum mlz 488, 490 [M+HI+ 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(morpholin-4yl)carbonylmethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline melting point: 2145 0

C

Mass spectrum m/z 530, 532 Example 11 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 +[tetra hyd ropyra n-4-yl)carbonyl] piperidin-4-yloxy}-7-methoxy-quinazoline mg 1-hydrox y- 1H-benzotriazole and 250 mg 2-(1 H-benzotriazol- 1-yl)- 1,1 ,3,3-tetramethyluronium-tetrafluoroborate are added to a mixture of 300 mg 4-[(3-ch loro-4-fluoro-phenyl )amino]-6-(piperidin-4-yloxy)-7-methoxyr WO 03/082290 PCT/EP03/03062 quinazoline-dihydrochloride, 82 mg tetrahydropyran-4-carboxylic acid and 0.54 ml Hunig base in 5 ml N,N-dimethylformamide. The reaction mixture is stirred overnight at ambient temperature. For working up it is combined with ml ethyl acetate and washed with water, 10% potassium carbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and evaporated. The residue is stirred with a little ethyl acetate, suction filtered and dried.

Yield: 250 mg (77 of theory) Rf value: 0.43 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 515, 517 The following compounds are obtained analogously to Example 11: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(tetrahydropyran-4yl)carbonylamino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline Rf value: 0.44 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 529, 531 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4yl)carbonyl]-N-methyl-amino}-cyclohexan-1 -yloxy)-7-methoxyquinazoline Rf value: 0.31 (silica gel, ethyl acetate/methanol 9:1) Mass spectrum m/z 543, 545 Example 12 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[([1,4]oxazepan-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxy-quinazoline 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline-dihydrochloride and 1.05 ml triethylamine are added to 900 mg of 1-methyl-3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazol-1-ium-iodide in 10 ml WO 03/082290 PCT/EP03/03062 methylene chloride. The yellowish suspension is stirred for about 24 hours at ambient temperature. For working up the reaction mixture is combined with ml methylene chloride and extracted with water as well as 10% citric acid. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The residue is chromatographed through a silica gel column with methylene chloride/methanol/conc. ammonia as eluant. The desired product is stirred with diethyl ether, suction filtered and dried.

Yield: 800 mg (80 of theory) Rf value: 0.30 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 530, 532 The following compounds are obtained analogously to Example 12: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline Rf value: 0.41 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum (ESI m/z 544, 546 [M+H] 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline Rf value: 0.50 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 530, 532 [M+H] Example 13 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methyl-piperidin-4-yloxy)-7-ethoxyquinazoline pl 37 aqueous formalin solution and 110 mg of sodium triacetoxyborohydride are added to 175 mg 4-[(3-chloro-4-fluoro- WO 03/082290 PCT/EP03/03062 phenyl)amino]-6-(piperidin-4-yloxy)-7-ethoxy-quinazoline in 1 ml of tetrahydrofuran. The reaction mixture is stirred for about four hours at ambient temperature. For working up 5 ml saturated sodium hydrogen carbonate solution are added and the mixture is stirred thoroughly. Then 20 ml ethyl acetate are added and the aqueous phase is separated off. The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is stirred with diisopropylether, suction filtered and dried.

Yield: 144 mg (80 of theory) Rf value: 0.80 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 60:10:1) Mass spectrum m/z 431, 433 The following compounds are obtained analogously to Example 13: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2methoxy-ethoxy)-quinazoline Rf value: 0.85 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 60:10:1) Mass spectrum m/z 461, 463 [M+H] 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxyquinazoline-hydrochloride Rf value: 0.26 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 389 [M+H] 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylaminocyclohexan-1 -yloxy)-7-methoxy-quinazoline Rf value: 0.80 (aluminium oxide, methylene chloride/methanol 9:1) Mass spectrum m/z 445, 447 [M+H] r WO 03/082290 PCT/EP03/03062 Example 14 4-[(3-ethynyl-phenyl)amino]-6-[1 -(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7methoxy-quinazoline A mixture of 3.00 g 4-[(3-ethynyl-phenyl)amino]-6-hydroxy-7-methoxyquinazoline, 4.50 g 1-(tert.-butyloxycarbonyl)-4-(p-toluolsulphonyloxy)piperidin and 2.90 g potassium carbonate in 30 ml N,N-dimethylformamide is stirred for two days at 60 oC. For working up the mixture is combined with 200 ml ethyl acetate and extracted with water. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is purified over a silica gel column with methylene chloride/methanol/conc. ammonia as eluant.

Yield: 3.25 g (67 of theory) Rf value: 0.25 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 95:5:1) Mass spectrum m/z 475 The following compounds are obtained analogously to Example 14: 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxyquinazoline Rf value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1) Mass spectrum m/z 376 Example 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[2-(tert.-butyloxycarbonylamino)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline A mixture of 410 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4yloxy)-7-methoxy-quinazoline-dihydrochloride, 240 mg of N-(tert.butyloxycarbonyl)-2-bromo-ethylamine and 360 mg of potassium carbonate in ml N,N-dimethylformamide is stirred overnight at ambient temperature. Then

I

WO 03/082290 PCT/EP03/03062 another 80 mg N-(tert.-butyloxycarbonyl)-2-bromo-ethylamine are added and the reaction mixture is stirred for a further four hours at ambient temperature.

For working up it is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is chromatographed through a silica gel column with ethyl acetate/methanol (95:5 to 90:1) as eluant.

Yield: 370 mg (79 of theory) Rf value: 0.33 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum (ESI): m/z 544, 546 The following compound is obtained analogously to Example 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-quinazoline Rf value: 0.38 (Reversed phase ready-made TLC plate Merck), acetonitrile/water/ trifluoroacetic acid 50:50:1) Mass spectrum m/z 516, 518 [M+H] The following compounds may also be prepared analogously to the foregoing Examples and other methods known from the literature: WO 03/082290 PCT/EP03/03062 Example No. Structure F 'LZ N y C c, a N 0 0 0 ao N 0 F 0 )aN

C)

0C

N

7 )F (C8a C~a

N

WO 03/082290 PCT/EP03/03062 Example No. Structure (12) F q NI N 4z 0

NN

0

N

(17) FIX0aN CI'0

N

(18) y N0

N

(1 6) F) WO 03/082290 PCT/EP03/03062 Example No. Structure (19) CIXN

Q

0 0 CIXN 9 N' 0

N?

0 (21) F~L p 0

N

(2 2 )F0

K)

(23) F q 0 N0 (24)N 0 F IOaN y Cl'd 0 N0 (26) FI 0 W N WO 03/082290 PCT/EPO3/03062 Example No. Structure (28)F C~a0

N

NN

N (33)

FI~X

CaN N 'C Q, N0 WO 03/082290 PCT/EP03/03062 Example No. Structure (36) F (37) CI aN

N

(38) F C' CI N (39) NI N i, 0-0~ a>2QNJN 3 9) F a (41) CI' N (42) CI N 0~0 N6 I WO 03/082290 PCT/EP03/03062 Example No. Structure (43)

N

(44)

C~N

CI N (46) F N N0

KNN

(47) F, X

X

0 Y h C' N I K) (48) CI K) (49) N 0 F112.

CaN WO 03/082290 PCT/E P03/03062 Example No. Structure (51) F ICN N N (52)F CI aN N 0K~S 0 (54)F CI N N 0 N~N F: N

N

0 (57) F: N N N N 0 N NK<- N WO 03/082290 PCT/EP03/03062 Example No. Structure (59) F N z O' ON 0

N

(61) F (62) CaN o N (63) N 0 (64)

N

-0 0K~ N 0K2NNI (66) F C~aN 0Yh N64 FKN WO 03/082290 PCT/EP03/03062 Example No. Structure (67) 'a

N

(68) F N 0 N (69) CI a) (71)

CI')

N

(72) F CI N N OK.- N N (73) N OK-KNA (74) F C~aa N'ao N (I WO 03/082290 PCT/EP03/03062 Example No. Structure

CN

N OK-N-- (76) F (77)F N OKaNN, (78) N 0O N-

C~

00 N79 Frr (81) ~cI NP c

N

NN

N I r-O WO 03/082290 PCT/EP03/03062 Example No. Structure (83) FI2IaN

W

(84)F

N

QI N (86) F~c CI a N

NN

(87) FI'2~ 0>~

N

i' O siI- 0

C~N

N N 0 a

N

0 (89)F a CI N N N 0 0 N

N

0 0" O'Q I'a oo> WO 03/082290 100 PCT/EP03/03062 Example No. Structure (91) 0N (92) F N 0 (93)

F

CI N N N (94)

K)

F

(96) CI i N- (97) 0 (98)

N

aN 1 WO 03/082290 PCT/EPO3/03062 Example No. Structure (99) Br caN 9 0 N 0 (100) (101) "10 N N N 0 (102) "o e (103) 0 (104) 0 9 (105) >9 0 0 C O Ni WO 03/082290 102 PCT/EP03/03062 Example No. Structure (106)

FO

N

(107) (108)F 0

N

(113)F N, N, WO 03/082290 103 PCT/EP03/03062 Example No. Structure (114) FIII~h~

C~N

N 0 "a (117)

F

C~N

N0 0 ~N 1 N0 (119)

F

N0.- N 0 -ON (120)

F

N

NI 0 N 0 0~N~

CI~K)

WO 03/082290 PCT/EPO3/03062 Example No. Structure (121)

F

N~a N I'l rN N 0 (122)

F

Nl N 0 (123)

F

NIa NI N N 0 (124) F0 0 N 0 (125)

F

N N O N 0 KN 0 (126)

F-

CI X N) 0 (127)

F

C: N N

NN

N~ 0 1 0 WO 03/082290 105 PCT/EP03/03062 Example No. Structure (128)

F

CI a N N

O'C

N 0 (129)

F

N)

0 N IN.Na0 N 0 N "-N 0 00 (130)

F

CI aN 0 (131)

F

N 0I N (132)

F

C~N

a N O NN0 KN 0 (133)

F

CI aN 0 WO 03/082290 106 PCT/EPO3/03062 Example No. Structure (135) Fn N( (136)

F

WN

I0 N

N

0 N 0 0 (13) F :a CI N N -O N N 0 N 0 Nyr (138)

F

N 0 (139)

F

Cl: N N 0 1 F WO 03/082290 107 PCT/EP03/03062 Example No. Structure (141)

F

CI aN N( C 0 N",aN 0 (142)

F

CI aN 0 CN N N O N 0 (143)

F

C~N

0I N"

O

CI~aN N: 0 (144)

F

N 0

N

(145)

F

CI aN 00 N 0 WO 03/082290 108 PCT/EP03/03062 Example No. Structure (148)

F

CI a N N N N 0 0 (149)

F

N~a N N 0 N: 0 N' 0 (150)

F

N

CI N 00 N_ N

N

KN" -_0 00 (151) F a CI' N N 0 N-~ 0 (152)

F

NVa N N N 0 I 0 (153)

F

N( N 0 WO 03/082290 109 PCT/E P03/03062 Example No. Structure (156)

F

C~N

-N N NJ0 0 (157) F CI aNH N 0 NNN 0 (158) F )N CI N NCN) N

NN

N 0 0 (159) F CI aNH K -O N 0

N

0 (160) F a CI N 0o- N N N 0 (161) Cl 0 F

N

N 'a CI N WO 03/082290 110 PCT/EPO3/03062 Example No. Structure (162) 0 N (163) 0 Na N N -N N14 0 (164) N~ CIN

N

0 0 N 0-

-'O

(165) F I

N('NH

N)'a N (166)

F

CIaN N KN 0 (167)

F

CIaN 0 NK 0- CIN 0 01 WO 03/082290 ill PCT/EP03/03062 Example No. Structure (169)

F

NN

CI N 0 N 0 0 (170) F0 CI N 0 (171) F 0 N N N 0P (172) F 0a C1 N N N11 00 0 (173) F0

CN

NI N KN N 0 (174) F 0 a CI N N 0 L0 WO 03/082290 PCT/EPO3/03062 Example No. Structure (175) F0 N 0 KN ~N N 0 (176) F0 CI aN N 0

N

0 (178) F0 CI N N 0 N -Tr y 0 (179) F 0 CI~a N 0 NUa- (180)CNa N0 00 N

N.

LI 0

N

0 (181) F 0 CN 9 N N 0 0 (182) F0 Ni N N 0 WO 03/082290 113 PCT/E P03/03062 Example No. Structure (183) F0 CI

N:

N 0 0 (184) F0 CI aN N 0

N

N N (185) F 0 N 0 No 0 (186) F0 CI aNH 0 r 1 WO 03/082290 114 PCT/EP03/03062 Example 16 Coated tablets containing 75 mg of active substance 1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mg Preparation: The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks 13 mm in diameter are produced in a tabletmaking machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape.

Weight of core: 230 mg die: 9 mm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.

Weight of coated tablet: 245 mg.

WO 03/082290 115 PCT/EP03/03062 Example 17 Tablets containing 100 mg of active substance Composition: 1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg Method of Preparation: The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.

Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.

Example 18 Tablets containing 150 mg of active substance Composition: 1 tablet contains: active substance 50.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg WO 03/082290 116 PCT/EP03/03062 Preparation: The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.

Weight of tablet: 300 mg die: 10 mm, flat Example 19 Hard gelatine capsules containing 150 mg of active substance 1 capsule contains: active substance corn starch (dried) lactose (powdered) magnesium stearate 50.0 mg approx. 80.0 mg approx. 87.0 mg 3.0 mg approx. 420.0 mg Preparation: The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules.

Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.

WO 03/082290 117 PCT/EP03/03062 Example Suppositories containing 150 mg of active substance 1 suppository contains: active substance polyethyleneglycol 1500 polyethyleneglycol 6000 polyoxyethylene sorbitan monostearate 150.0 mg 550.0 mg 460.0 mg 840.0 mg 2000.0 mg Preparation: After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.

Example 21 Suspension containing 50 mg of active substance 100 ml of suspension contain: active substance carboxymethylcellulose-Na-salt methyl p-hydroxybenzoate propyl p-hydroxybenzoate glucose glycerol sorbitol solution flavouring dist. water 1.00 g 0.10 g 0.05 g 0.01 g 10.00 g 5.00 g 20.00 g 0.30 g 100 ml Preparation: WO 03/082290 118 PCT/EP03/03062 The distilled water is heated to 70 0 C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air.

ml of suspension contain 50 mg of active substance.

Example 22 Ampoules containing 10 mg active substance Composition: active substance 10.0 mg 0.01 N hydrochloric acid q.s.

double-distilled water 2.0 ml Preparation: The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.

Example 23 Ampoules containing 50 mg of active substance Composition: active substance 50.0 mg 0.01 N hydrochloric acid q.s.

double-distilled water 10.0 ml WO 03/082290 119 PCT/EP03/03062 Preparation: The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.

Example 24 Capsules for powder inhalation containing 5 mg of active substance 1 capsule contains: active substance lactose for inhalation 5.0 mg 15.0 mg 20.0 mg Preparation: The active substance is mixed with lactose for inhalation. The mixture is packed into capsules in a capsule-making machine (weight of the empty capsule approx. 50 mg).

weight of capsule: 70.0 mg size of capsule 3 Example Inhalable solution for hand-held nebulisers containing 2.5 mg active substance 1 spray contains: active substance benzalkonium chloride 1N hydrochloric acid q.s.

2.500 mg 0.001 mg P:\OPER\PDB\Spwcl2(U322670 Ispa doc.21/10/2008 00 -120- O ethanol/water (50/50) 15.000 mg Preparation: n The active substance and benzalkonium chloride are dissolved in ethanol/water (50/50). The pH of the solution is adjusted with 1N hydrochloric acid. The N resulting solution is filtered and transferred into suitable containers for use in m' hand-held nebulisers (cartridges).

Contents of the container: 4.5 g Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

4-a Ikyloxy- carbonylamino-C 2 4-alkyl, aminO-C 2 4-alkyl, C 1 3 -alkylamino-C 24 -alkyl, di-(CI..3-alkyl)amino-C 2 -4-alkyl, C1.3-alkylcarbonylamino-C 2 4-alkyl, aminocarbonylamino-C 2 4 -alkyl, C1-3-alkylaminocarbonylamino- C2-4-alkyl, di-(C1..3-aky)amino-carbonylamino-C 2 4-alky, pyrrolidin-1 ylcarbonylamino-C 24 -alkyl, piperidin-1 -ylcarbonylamino-C 2 -4-alkyl, morpholin-4-ylcarbonylamino-C 24 -akyl, Cli 3 -alkylsulphonYl-C 2 4 -alkyl or a Cl .3-alkylsulphonylamino-C 2 -4-alkyl group, a (2-oxo-pyrrolidin-1 -yI)-C 24 -alkyl, (2-oxopipendin-1 -yI)-C2-4-alkyl, (3- oxo-morpholin-4-yi)-C 2 -4-alkyl, (2-oxo-imidazolidin-1 -Yl)-C 2 -4-alkyl, (2- oxo-3-C, 3 -alkyl-imidazolidin-1 -yI)-C 2 4 -alkyl, (2-oxo- hexahydropyrimidin-1 -yI)-C 2 4 -alkyl or a (2-oxo-3-C.. 3 -alkyl- hexahydropyrimidin-1 -Yl)-C 2 4 -alkyl group, a C 14 -alkylsulphonyl, chloro-C 14 -alkylsulphonyl, bromo- C14-alkylsulphonyl, amino-C,4-alkylsulphony, CI.. 3 -alkylamino- C14-alkylsulphonyl, di-(C1..3-alkyl)amino-Cl-4-alkylsulphonyl, (pyrrolidin- WO 03/082290 WO 03/82290PCT/EPO3/03062 1 -yI)-Cl 4 -alkylsulphonyl, (piperidin-1 -yI)-CI- 4 -alkylsulphonyl, (homopiperidin-1 -YI)-C1A-alkylsulphonyl, (morpholin-4-y)-C.. 4 -alkyl- suiphonyl, (homomorpholin-4-yI)-C, A-alkylsulphonyl, (piperazin-1 -yI)- C14-alkylsulphonyl, (4-C 1 3 -alkyl-piperazin-1 -yI)-CI-4-alkylsulphonyl, (homopiperazin-1 -yI)-C 1 4 -alkylsulphonyl or a (4-CI.. 3 -alkyl- homopiperazin-1 -yI)-C 14 -alkylsulphonyl group, a Cl-4-alkyloxycarbonyl group, a formyl, C 1 4 -alkyl-carbonyl, Ci. 3 -alkyloxy-C,4-alkyI-carbony, tetra hydrofu ran ylca rbon yl, tetra hydropyra nylcarbonyl, amnoCl 4 -alkyl- carbonyl, C1.3-alkylamino-C,4-alkyl-carbonyl, 3 -alkyl)amino- C 1 4-alkyI-carbonyI, pyrrolidin-1 -yi-CI-4~-aky-carbonyI, piperidin- l-yI- Ci 4-aky-carbonyI, (homopiperidin- 1-yI)-C 1 -4-alkyI-carbony, morpholin- 4 -yi-Ci 4 -alkyl-carbonyl, (homomorpholin -4-yI)-Ci-4-alkyI-carbony, (piperazin-1 -yI)-CI.. 4 -alkyl-carbonyl, (4-Ci.. 3 -alkyl-piperazin-1 -yI)- C 1 A-alkyl-carbonyl, (homopiperazin-1 -yI)-C,4-aI kyl-carbonyl, (4- C 1 3 -alkyl-homopiperazin-1 -YI)-Cl 4 -alkyl-carbonyl or a Cl..3-alkylsulphonyl-CIA4-alkyl-carbony group, a cyano, aminocarbonyl, Cli3-alkyl-aminocarbonyl, di-(C 1 3 -alkyl)amino- carbonyl, (Cv .3-alkyloxy-C 2 -4-alkyl)aminocarbonyl, N-(Ci.. 3 -alkyl)-N-(Cl-.3- alkyloxy-C 2 -4-alkyl)aminocarbonyl, arylaminocarbonyl, pyrrolidin-1 ylcarbonyl, piperidin-1 -ylcarbonyl, homopiperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, bicyclo[2 .2.1 ]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2.1 ]oct-8- ylcarbonyl, 8-oxa-3-aza-bicyclo[3.2.1I]oct-3-ylcarbonyl, piperazin-1 ylcarbonyl, 4-C 1 3 -alkyl-piperazin-1 -ylcarbonyl, homopiperazin- 1- ylcarbonyl, 4-C1..3-alkyl-homopiperazin-1 -ylcarbonyl, aminosuiphonyl, CI. 3 -alkyl-aminosulphonyl, di-(C 1 3 -alkyl)amino-sulphonyl, pyrrolidin-1 yI-sulphonyl, piperidin-1 -ylsulphonyl, homopiperidin-1 -ylsulphonyl, morpholin-4-ylsulphonyl, homomorpholin-4-ylsulphonyl, piperazin-1 ylsulphonyl, 4-CI.. 3 -alkyl-piperazin-1 -ylsulphonyl, homopiperazin-1 ylsulphonyl or a 4-CI.. 3 -alkyl-homopiperazin-1 -ylsulphonyl group, r WO 03/082290 PCT/EP03/03062 a cyclobutyl, cyclopentyl or cyclohexyl group which is substituted in each case by a group R 6 where R 6 denotes a 2-oxo-pyrrolidin-l-yl, 2-oxopiperidin-l-yl, 3-oxo- morpholin-4-yl, 2-oxo-imidazolidin-1 -yl, 2-oxo-3-C-. 3 -alkyl-imidazolidin- 1-yl, 2-oxo-hexahydropyrimidin-l-yl or a 2-oxo-3-C1- 3 -alkyl- hexahydropyrimidin-1-yl group, an azetidin-3-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, a pyrrolidin-3-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, a piperidin-3-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, a piperidin-4-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, Rd denotes a hydrogen atom or a fluorine, chlorine or bromine atom, a hydroxy group, a C1- 4 -alkyloxy group, a methoxy group substituted by 1 to 3 fluorine atoms, an ethyloxy group substituted by 1 to 5 fluorine atoms, a C 2 4 -alkyloxy group which is substituted by a group R 6 or R 7 while WO 03/082290 WO 03/82290PCT/EPO3/03062 R 6 is as hereinbefore defined and R 7 denotes a hydroxy, 3 -alkyloxy, C3--cycloalkyloxy, amino, CI-3-alkylamino, di-(Cl-. 3 -alkyl)amino, bis-(2-methoxyethyl)-amino, pyrrolidin-1 -yI, piperidin-1 -yI, homopiperidin-1 -yl, morpholin-4-yl, homomorpholin-4-y, 2-oxa-5-aza-bicyclo[2 .2.1 ]hept-5-yI, 3-oxa-8-aza- bicyclo[3.2.1 ]oct-8-yI, 8-oxa-3-aza-bicyclo[3.2.1 ]oct-3-yI, piperazin-1 -yI, 4-C 1 alkyl-piperazin-1 -yI, homopiperazin-1 -yI or C 1 3 -alkyl- homopiperazin-1 -yi group, or a formylamino, Cl-4-alkylcarbonylamino, Cl 13 -alkyloxy-Cl- 3 -alkyl- carbonylamino, Cl-4-alkyloxycarbonylamino, aminocarbonylamino, C 1 3 alkylaminocarbonylamino, di-(C 1 3 -alkyl)aminocarbonylamino, pyrrolidin-1 -ylcarbonylamino, piperidin-1I-ylcarbonylamino, piperazin-1 ylcarbonylamino, 4-Cv 3 -alkyl-piperazin-1 -ylcarbonylamino, morpholin- 4-ylcarbonylamino or a C1-4-alkylsulphonylamino group, a C 3 7 -CYCloalIkyloxy or 0 3
7-CYCloalIkyl-C 1 4 -alkyloxy group, a tetra hyd rofu ran-3-yloxy, tetrahyd ropyra n-3-yloxy or tetra hydropyra n-4 -yl oxy group, a tetrahydrofuranYl-C14-alkyloxy or tetrahydropyrany-C 1 4-alkyloxy group, a C14-alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the group R 8 while R 8 denotes a hydrogen atom or a 3 -alkyl group, or a C14-alkoxy group which is substituted by a morpholinyl group substituted in the 4 position by the group R while R 8 is as hereinbefore defined, and X denotes a methyne group substituted by a cyano group or a nitrogen atom, WO 03/082290 126 PCT/EP03/03062 and by the aryl groups mentioned in the definition of the above groups is meant in each case a phenyl group which is mono- or disubstituted by R 9 while the substituents may be identical or different and R 9 denotes a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a C 1 -3-alkyl, hydroxy, Ci-3-alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group, by the heteroaryl groups mentioned in the definition of the above groups is meant a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, while the abovementioned heteroaryl groups are each mono- or disubstituted by the group R 9 while the substituents may be identical or different and R 9 is as hereinbefore defined, and the abovementioned pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups may be substituted in each case by one or two C-_ 3 -alkyl groups, and unless otherwise stated, the abovementioned alkyl groups may be straight- chained or branched, with the proviso that the compound 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)- tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline is excluded, their tautomers, their stereoisomers, their mixtures and their salts. 2. Bicyclic heterocyclic groups of general formula I according to claim 1, wherein R a denotes a hydrogen atom, Rb denotes a phenyl group substituted by the groups R 1 to R 3 while WO 03/082290 WO 03/82290PCT/E P03/03062 R 1 denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl or ethynyl group, a phenyloxy or phenylmethoxy group, while the phenyl moiety of the abovementioned groups is optionally substituted by a fluorine or chlorine atom, or a pyridyloxy or pyridinylmethoxy group, while the pynidinyl moiety of the abovementioned groups is optionally substituted by a methyl or trifluoromethyl group, R 2 denotes a hydrogen, fluorine or chlorine atom or a methyl group and R 3 denotes a hydrogen atom, Rc denotes a cyclopentyl group which is substituted in the 3 position by a group R 4 -N-R while R 4 denotes a hydrogen atom or a C1. 3 -alkyl group and R 5 denotes a hydrogen atom or a C 1 3 -alkyl group, an aminocarbonyl-C.- 3 -alkyl, CI..3-alkylaminocarbonyl-Cl. 3 -alkyl, di- (C1.3-alky aminocarbony-Cl-. 3 -alkyl, pyrrolidin-1 -ylcarbonyl-C.. 3 -alkyl, piperidin-1 -ylcarbonyl-0 1 3 -alkyl, piperazin-1 -ylcarbonyl-C.. 3 -alkyl, 4-CI.. 3 -alkyl-piperazin-1 -yl-carbonyl-C.. 3 -alkyl or morpholin-4-ylcarbonyl- C 1 3 -alkyl group, a hydroxy-C 2 4-alkyl, Cl13-alkyloxy-C 2 4-alkyl, C14-alkyloxy- carbonylamino-C 24 -alkyl, amino-C 2 4-alkyl, C1..3-alkylamino-C 2 4 -alkyl, di-(C1..3-alkyl)aminO-C 2 4-alkyl, C1..3-alkylcarbonylamino-C 24 -alkyl, aminocarbonylamino-C 2 4 -alkyl, CI-.3-alkylaminocarbonylamino- C24-alkyl, di-(CI-.3-alkyl)amino-carbonylamino-C 2 4-alkyl, morpholin-4- WO 03/082290 128 WO 0308229 128PCT/EPO3/03062 ylcarbonylamino-C 2 4 -alkyl, C 1 3 -alkylsulphonYl-C 24 -alkyl or C 1 3 -alkylsulphonylamino-C2- 4 -alky group, a (2-oxo-pyrrolidin- 1-yI)-C2A4-alkyl, (2-oxopiperidin-1 -YI)-C2-4-alkyl, (3- oxo-morpholin-4-yI )-C2-4-alkyl, (2-oxo-imidazolidin-1 -YI)-C 24 -alkyl, (2- oxo-3-methyl-imidazolidin-1 -yI)-C2-4-alkyl, (2-oxo-hexahydropyrimidin- 1- yI )-C 2 -4-alkyI or (2-oxo-3-methyl-hexahydropyrimidin-1 -YI)-C 2 4 -alkyl group, a C 1 3 -alkylsulphonyl, chloro-C 24 -alkylsulphonyl, bromo- C 24 -alkylsulphonyl, aminO-C 2 -4-alkylsulphony, C 1 3 -alkylamino- C 24 -alkylsulphonyl, di-(Cl-. 3 -alkyl )aminO-C 2 -4-alkylsulphonyI, (pyrrolidin- 1 -yI)-C 2 -4-alkylsulphonyl, (piperidin-1 -yI)-C 2 4 -alkylsulphonyl or (morpholin-4-yI)-C 2 -4-alkylsulphony group, a C 1 4 -alkyloxy-carbonyl group, a formyl, C 1 .3-alkyl-carbonyl, C1..3-alkyloxy-Cl.. 3 -alkyl-carbonyl, tetra hydrofu ran ylca rbonyl, tetra hydropyra nyl ca rbonyl, amino-C 13 -alkyl- carbonyl, CI-3-alkylamino-CI.. 3 -alkyl-carbonyl, di-(CI.. 3 -alkyl)amino- CI.. 3 -alkyl-carbonyl, pyrrolidin-1 -yI-C 1 3 -alkyl-carbonyl, piperidin-1 -yI- CI-. 3 -alky-carbonyl, piperazin-1 -YI-C1..3-alkyl-carbonyl, 4-Cl. 3 -alkyl- piperazin-1 -YI-C 1 3 -alkyl-carbonyl, morpholin-4-yI-C 1 3 -alkyl-carbonyI or a C 1 .3-alkylsulphonyl-Cl.. 3 -alkyl-carbony group, a cyano, aminocarbonyl, C 1 3 -alkyl-aminocarbonyl, di-(C 1 3 -alkyl)amino- carbonyl, (C 1 .3-alkyloxy-C 2 4-alkyl)aminocarbonyl, N-(C 1 3 -alkyl)-N- (C1.3-alkyloxy-C 24 -alkyl)aminocarbonyl, phenylaminocarbonyl, pyrrolidin-1 -ylcarbonyl, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, Ci..3-alkyl-morpholin-4-ylcarbonyl, di-(C1.3-alkyl)morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2 .2.1 ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2.1 ]oct-8-ylcarbonyl, 8-oxa-3-aza- bicyclo[3.2.1 ]oct-3-ylcarbonyl, piperazin-1 -ylcarbonyl, 4-(C 1 3 -alkyl)- piperazin-1 -ylcarbonyl, aminosuiphonyl, Cl13-alkyl-aminosulphonyl, di- WO 03/082290 129 PCT/EP03/03062 (C1- 3 -alkyl)amino-sulphonyl, pyrrolidin-1-yl-sulphonyl, piperidin-1- ylsulphonyl or a morpholin-4-ylsulphonyl group, or a cyclopentyl group which is substituted in the 3 position by a group R 6 while R 6 denotes a 2-oxo-pyrrolidin-l-yl, 2-oxopiperidin-l-yl, 3-oxo- morpholin-4-yl, 2-oxo-imidazolidin-l -yl, 2-oxo-3-methyl-imidazolidin-1 yl, 2-oxo-hexahydropyrimidin-l-yl or a 2-oxo-3-methyl- hexahydropyrimidin-1-yl group, a cyclohexyl group which is substituted in the 3 position or in the 4 position by a group R 4 -N-R 5 while R 4 and R 5 are as hereinbefore defined, a cyclohexyl group which is substituted in the 3 position or in the 4 position by a group R 6 while R 6 is as hereinbefore defined, a pyrrolidin-3-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, a piperidin-3-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, a piperidin-4-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, Rd denotes a hydrogen atom, a C_-3-alkyloxy group, a methoxy group which is substituted by one to three fluorine atoms, an ethyloxy group which is substituted in the 2 position by a group R 6 or R 7 WO 03/082290 130 PCT/EPO3/03062 while R 6 is as hereinbefore defined and R 7 denotes a hydroxy, C 1 3 -alkyloxy, amino, Ci.. 3 -alkylamino, di- (Ci.. 3 -alkyl)amino, bis-(2-methoxyethyl)-amino, pyrrolidin-1 -yl, piperidin- l-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza bicyclo[2 .2.1 ]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1 ]oct-8-yl, 8-oxa-3-aza- bicyclo[3.2 .1 loct-3-yI, piperazin-1 -yI or a 4-C 1 3 -alkyl-piperazin-1 -yl group, or a formylamino, Cl-4-alkylcarbonylamino, 3 -alkyloxy-C,.. 3 -alkyl- carbonylamino, Cl-4-alkyloxycarbonylamino, aminocarbonylamino, C 1 3 alkylaminocarbonylamino, di-(CI.. 3 -alkyl)aminocarbonylamino, pyrrolidin-1 -ylcarbonylamino, piperidin-1 -ylcarbonylamino, piperazin-1 ylcarbonylamino, 4-Ci .3-alkyl-piperazin-1 -ylcarbonylamino- morpholin- 4-ylcarbonylamino or a C 14 -alkylsulphonylamino group, a propyloxy group which is substituted in the 3 position by a group RorR while R 6 and R 7 are as hereinbefore defined, or a butyloxy group which is substituted in the 4 position by a group R 6 orR while R 6 and R 7 are as hereinbefore defined, and X denotes a nitrogen atom, while, unless stated otherwise, the abovementioned alkyl groups may be straight-chained or branched, their tautomers, their stereoisomers, their mixtures and their salts. 3. Bicyclic heterocyclic groups of general formula 1 according to claim 1, wherein R a denotes a hydrogen atom, WO 03/082290 WO 03/82290PCT/E P03/030 62 R b denotes a 3-ethynyiphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chioro- 4-fluoro-phenyl group, a 3-chloro-4-benzyloxy-phenyl, 3-chloro-4-[(3-fluoro-benzyl)oxyj-phenyl, 4- (pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridin-3-yl )oxyl-phenyl, 3-methyl-4- (pyridin-3-yloxy)-phenyl, 3-methyl-4-[(6-methyl-pyndin-3-yl)oxy]-phenyl, 3- chloro-4-(pyridin-3-yloxy)-pheny or 3-chloro-4-[(6-methyl-pyridin-3-yl)oxyj- phenyl group, Rc denotes a cyclohexyl group which is substituted in the 3 position or in the 4 position by a group R 4 -N-R while R 4 denotes a hydrogen atom, a methyl or ethyl group and R 5 denotes a hydrogen atom, a methyl, aminocarbonylmethyl, methylaminocarbonymethyl, dimethylaminocarbonylmethyl, pyrrolidin- I -ylcarbonylmethyl, piperidin-1 -ylcarbonylmethyl, piperazin-1 ylcarbonylmethyl, 4-methylpiperazin-1 -ylcarbonylmethyl, morpholin-4- ylcarbonylmethyl, 2-(morpholin-4-yl-carbonyl )ethyl or 3-(morpholin-4-y- carbonyl)propyl group, an ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3- methoxypropyl, 2-(butyloxycarbonylamino)-ethyl, 2-aminoethyl, 3- aminopropyl, 2-(acetylamino)ethyl, 3-(acetylamino)propyl, 2- (ethyl ca rbon yla mi no)ethyl, 3-(ethylcarbonylamino)propyl, 2- (propylcarbonylamino)ethyl, 3-(propylcarbonylamino)propyl, 2- (ethylaminocarbonylamino)ethyl, 3-(ethylaminocarbonylamino)propyl, 2-(dimethylaminocarbonylamino)ethyl, 3- (dimethylaminocarbonylamino)propyl, 2-(morpholin-4- ylcarbonylamino)ethyl, 3-(morpholin-4-ylcarbonylamino)propyl, 2- (methylsulphonyl)ethyl, 3-(methylsulphonyl)propyl, 2-(methylsulphonyl- amino)ethyl or a 3-(methylsulphonylamino)propyl group, a 2-(2-oxo-pyrrolidin-1 -yl)ethyl, 2-(2-oxopiperidin- 1 -yI)ethyl, 2 -(3-oxo- WO 03/082290 132 WO 0308229 132PCT/EPO3/03062 morpholin-4-yI)ethyl, 2-(2-oxo-imidazolidin-1 -yI)ethyl, 2-(2-oxo-3- methyl-imidazolidin-1 -yI)ethyl, 2-(2-oxo-hexahydropyrimidin-1 -yI)ethyl or a 2-(2-oxo-3-meth yl-h exah yd ropyri mid in 1 -yI)ethyl group, a 3-(2-oxo-pyrrolidin-1 -yl)propyl, 3-(2-oxopiperidin-1 -yI)propyl, 3-(3-oxo- morpholin-4-yI)propyl, 3-(2-oxo-imidazolidin-1 -yl)propyl, 3-(2-oxo-3- methyl-imidazolidin-1 -yI)propyl, 3-(2-oxo-hexahydropyimidin-1 yI )propyl or a 3-(2-oxo-3-methyl-hexahydropyrimidin-1 -yI)propyl group, a methylsuiphonyl, ethylsuiphonyl, 3-chloropropylsulphonyl, 2- (morpholin-4-yI )-ethylsulphonyl or a 3-(morpholin-4-yI )-propylsulphonyl group, a propyloxycarbonyl or butyloxycarbonyl group, a formyl, acetyl, ethylca rbonyl, propylca rbonyl, methoxyacetyl, (2- methoxyethyl)carbonyl, (3-methoxypropyl )carbonyl, tetra hydrofu ran-2 ylcarbonyl, tetra hydropyran-4-ylcarbonyl, aminoacetyl, methylaminoacetyl, dimethylaminoacetyl, morpholin-4-ylacetyl, [2- (morpholin-4-yI)ethyl]carbonyl, [3-(morpholin-4-yI)propyl]carbony or a methylsulphonylacetyl group, a cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, (2- methoxyethyl)aminocarbonyl, N-methyl-N-(2-methoxyethyl)- aminocarbonyl, (3-methoxypropyl)aminocarbonyl, N-methyl-N-(3- methoxypropyl)-aminocarbonyl, phenylaminocarbonyl, pyrrolidin -1- ylcarbonyl, pipeddin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, 2- meth yl morphol in-4-yl carbon yl, 2,6-dimethylmorpholin-4 -ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1 ylca rbonyl, 3-oxa-8-aza-bicyclo[3.2.1 ]oct-8-ylcarbonyl, 8-oxa-3-aza- bicyclo[3.2.1 Joct-3-ylcarbonyl, 4-methylpiperazin-1 -ylcarbonyl, aminosuiphonyl, methytaminosuiphonyl, dimethylaminosulphonyl or a morpholin-4-ylsulphonyl group, WO 03/082290 133 WO 0308229 133PCTIEPO3IO3062 a cyclohexyl group which is substituted in the 3 position or in the 4 position by a group R while R 6 denotes a 2-oxo-pyrrolidin-1 -yl, 2-oxopiperidin-1 -yl, 3-oxo- morpholin-4-yl, 2-oxo-imidazolidin-1 -yl, 2-oxo-3-methyl-imidazolidin-1 yI, 2-oxo-hexahydropyrimidin-1 -yl or a 2-oxo-3-methyl- hexahydropyrimidin-1 -yI group, a pyrrolidin-3-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, a piperidin-3-yI group which is substituted in the 1 position by the while R 5 is as hereinbefore defined, a piperidin-4-yl group which is substituted in the 1 position by the group R 5 while R 5 is as hereinbefore defined, a tetra hydrofu ran -3-yI, tetra hyd ropyra n-3-y or tetra hyd ropyra n-4-yl group, R d denotes a hydrogen atom, a methoxy, difluoromethoxy or ethyloxy group, an ethyloxy group which is substituted in the 2 position by a group R 6 orR while R 6 is as hereinbefore defined and R 7 denotes a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis-(2-methoxyethyl)-amino, pyrrolidin-1 -yI, piperidin-1 -yl, morpholin-4-yl, homomorpholin-4-y, 2-oxa-5-aza-bicyclo[2 .2.1 yI, 3-oxa-8-aza-bicyclo[3.2.1I]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1 Joct-3- yI, piperazin-1 -yI, 4-methylpiperazin-1 -yl or 4-ethylpiperazin-1 -yl group, or WO 03/082290 134 WO 0308229 134PCT/EPO3/03062 an acetylamino, ethylcarbonylamino, propylcarbonylamino, butylcarbonylamino, methoxyacetylamino, butyloxycarbonylamino, ethylaminocarbonylamino, dimethylaminocarbonylamino, pyrrolidin-1 ylcarbonylamino, piperidin-1 -ylca rbonylamino, morpholin-4- ylcarbonylamino, methylsulphonylamino, ethylsulphonylamino or butylsulphonylamino group, a propyloxy group which is substituted in the 3 position by a group R 6 orR7 while R 6 and R 7 are as hereinbefore defined, or a butyloxy group which is substituted in the 4 position by a group R 6 orR while R 6 and R 7 are as hereinbefore defined, and X denotes a nitrogen atom, while, unless stated otherwise, the abovementioned alkyl groups may be straight-chained or branched, their tautomers, their stereoisomers, their mixtures and their salts. 4. Bicyclic heterocyclic groups of general formula I according to claim 1, wherein R a denotes a hydrogen atom, Rb denotes a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluoro-phenyl or a 3-ethynylphenyl group, or a 3-chloro-4-benzyloxy-phenyl, 3-ch loro-4-[(3-fl uorb enzyl)oxy]-ph enyl, 4- (pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridin-3-yl)oxy]-phenyl, 3-methyl-4- (pyridin-3-yloxy)-phenyl, 3-methyl-4-[(6-methyl-pyridin-3-y)oxy]-phenyl, 3- chloro-4-(pyridin-3-yloxy)-pheny or 3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]- phenyl group, WO 03/082290 15PTEP0/36 135 PCT/EP03/03062 RC denotes a cyclohexyl group which is substituted in the 3 position by an amino, acetylamino, tert.-butyloxycarbonylamino or methylsuiphonylamino group, a cyclohexyl group which is substituted in the 4 position by an amino, methylamino, ethylamino, dimethylamino, aminocarbonylmethylamino, methylaminocarbonylmethylamino, dimethylaminocarbonylmethylamino, morpholin-4-ylcarbonylmethylamino, [3-(morpholin-4-ylcarbonyl)propyl]amino, [2-(methylsulphonyl )ethyl]amino, [3-(methylsulphonyl )propyl]amino or [2- (methylsulphonylamino)ethyl]amino group, a cyclohexyl group which is substituted in the 4 position by a [2-(2-oxo- pyrrolidin-1 -yI)ethyllamino, [2-(2-oxopiperidin-1 -yI)ethyljamino, [2-(2-oxo- imidazolidin-1 -yI)ethyllamino, [2-(2-oxo-3-methyl-imidazolidin-1 -yI)ethyl]amino, [2-(2-oxo-hexahydropyrimidin-1 -yI)ethyl]amino or [2-(2-oxo-3-methyl- hexahydropyimidin-1 -yI)ethyllamino group, a cyclohexyl group which is substituted in the 4 position by a [3-(2-oxo- pyrrolidin-1 -yI )propyl]amino, [3-(2-oxopiperidin -1 -yI)propyl]amino, [3-(2-oxo- imidazolidin-1 -yI)propyllamino, [3-(2-oxo-3-methyl-imidazolidin-1 yI)propyl]amino, [3-(2-oxo-hexahydropyrimidin-1 -yI)propyl]amino or [3-(2-oxo- 3-methyl-hexahydropyrimidin-1 -yI )propyl]amino group, a cyclohexyl group which is substituted in the 4 position by an acetylamino, N- (acetyl )-methylamino, aminomethylcarbonylamino, methylaminomethylcarbonylamino, dimethylaminomethylcarbonylamino, morpholin-4-ylmethylcarbonylamino, methoxyacetylamino, N -(methoxyacetyl)- methylamino, tetra hydropyran-4 -ylca rbonylamino, N -(tetra hydropyra n -4- ylcarbonyl )-methylamino, tert.-butyloxycarbonylamino, N-(tert.- butyloxycarbonyl)-methylamino, aminocarbonylamino, methylaminocarbonylamino, N-(ethylaminocarbonyl)- methylamino, dimethylaminocarbonylamino, N-(d imeth yla min oca rbonyl )-methyla min o, N- (piperidin-1I-ylcarbonyl)-methylamino, morpholin-4-ylcarbonylamino, N- (morpholin-4-ylcarbonyl)-methylamino or N-(4-methylpiperazin-1 -ylcarbonyl)- WO 03/082290 136 WO 0308229 136PCT/E P03/03062 methylamnino group, a cyclohexyl group which is substituted in the 4 position by a 2-oxo-pyrrolidin- 1 -yl, 2-oxopiperidin-1 -yI, 3-oxo-morpholin-4-yi, 2-oxo-imidazolidin-1 -yl, 2-oxo- 3-methyl-imidazolidin-1 -yI, 2-oxo-hexahydropyrimidin-1 -yI or a 2-oxo-3- methyl-hexahydropyrimidin-1 -yI group, a cyclohexyl group which is substituted in the 4 position by a methylsuiphonylamnino, N-(methylsulphonyl)-methylamino, ethylsuiphonylamnino, N-(ethylsulphonyl )-methylamino, dimethylaminosuiphonylamino, N-(dimethylaminosulphonyl)-methylamino, morpholin-4-ylsulphonylamino, N-(morpholin-4-ylsulphonyl)-methylamino- 3- chioropropylsuiphonylamnino, [2-(morpholin-4-yI)-ethyljsulphonylamino or [3- (morpholin-4-yI)-propyl]sulphonylamino- group, a pyrrolidin-3-y group, a pyrrolidin-3-yl group which is substituted in the 1 position by a methyl, acetyl, methoxyacetyl, tert.-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsuiphonyl group, a piperidin-3-yI group, a piperidin-3-y group which is substituted in the 1 position by a methyl, acetyl, methoxyacetyl, tert.-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsuiphonyl group, a piperidin-4-yl group which is substituted in the 1 position by a methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulphonyl)-ethyl, 3-(methylsulphonyl)-propyl, 2-(tert.- butyloxycarbonylamino)-ethyl, 2-aminoethyl, 2-(acetylamino)-ethyl, 2- (ethylcarbonylamino)-ethyl, 2-(propylcarbonylamino)-ethyl, 2- (ethylaminocarbonylamino)-ethyl, 2-(dimethylaminocarbonylamino)-ethyl, 2- (morpholin-4-ylcarbonylamino)-ethyl, 3-(acetylamino)-propyl, 3- WO 03/082290 137 WO 0308229 137PCT/EP03/03062 (ethylcarbonylamino)-propyl, 3-(propylcarbonylamino)-propyl, 3- (ethylaminocarbonylamino)-propyl, 3-(dimethylaminocarbonylamino)-propyl, 3-(morpholin-4-ylcarbonylamino)-propyl, 2-(methylsulphonylamino)-ethyl, 3- (methylsulphonylamino)-propyl, (aminocarbonyl)methyl, (methylaminocarbonyl)methyl, (dimethylaminocarbonyl)methyl, (pyrrolidin-1 ylcarbonyl )methyl, (morpholin-4-ylcarbonyl)methyl, 2-(morpholin-4- ylcarbonyl )-ethyl or 3-(morpholin-4-ylcarbonyl)-propyl group, a piperidin-4-yI group which- is substituted in the 1 position by a 2-(2-oxo- pyrrolidin-1 -yi)-ethyl, 2-(2-oxopiperidin-1 -yI)-ethyl, 2-(3-oxomorpholin-4-yl)- ethyl, 2-(2-oxo-imidazolidin-1 -yI)-ethyl, 2-(2-oxo-3-methyl-imidazolidin- 1-yl)- ethyl, 2-(2-oxo-hexahydropyrimidin-1 -yI)-ethyl or 2-(2-oxo-3-methyl- hexahydropyimidin-1-yi)-ethyl group, a piperidin-4-yI group which is substituted in the 1 position by a 3-(2-oxo- pyrrolidin-1 -yI)-propyl, 3-(2-oxopiperidin-1 -yI)-propyl, 3-(3-oxomorpholin-4-y)- propyl, 3-(2-oxo-imidazolidin-1 -yI )-propyl, 3-(2-oxo-3-methyl-imidazolidin-1 -yl)- propyl, 3-(2-oxo-hexahydropyimidin-1 -yi )-propyl or 3-(2-oxo-3-methyl- hexahydropyimidin-1 -yi)-propyl group, a piperidin-4-yI group which is substituted in the 1 position by a formyl, acetyl, methoxyacetyl, (2-methoxyethyl )ca rbonyl, (3-methoxypropyl )carbonyl, methylsuiphonylacetyl, amninoacetyl, methylaminoacetyl, (dimethylamino)acetyl, (morpholin-4 -yI)acetyl, [2-(morpholin-4-yl)- ethyl]carbonyl, [3-(morpholin-4-yl)-propyl]carbonyl, tetrahydrofuran-2- ylcarbonyl or tetra hydropyran-4-ylcarbonyl group, a piperidin-4-yI group which is substituted in the 1 position by a cyano, aminocarbonyl, methylaminocarbonyl, ethylamninocarbonyl, (2- methoxyethyl)a minocarbonyl, N-methyl-N-(2-methoxyethyl)-aminocarbonyl, (3-methoxypropyl)aminocarbonyl, N -methyl-N-(3-methoxypropyl)- amninocarbonyl, isopropylamninocarbonyl, phenylaminocarbonyl, dimethylaminocarbonyl, diethylamninocarbonyl, pyrrolidin -I-ylcarbonyl, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4 WO 03/082290 WO 03/82290PCT/EPO3/03062 ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.lI hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2.1 ]oct-8- ylcarbonyl, 8-oxa-3-aza-bicyclo[3.2.1 ]oct-3-ylcarbonyl, 4-methylpiperazin-1 ylcarbonyl, isopropyloxycarbonyl or tert.-butyloxycarbonyl group, a piperidin-4-yI group which is substituted in the 1 position by a methylsuiphonyl, ethylsuiphonyl, [2-(morpholin-4-yi)-ethyllsulphonyl, [3- (morpholin-4-yI)-propyl]sulphonyl, aminosuiphonyl, methylaminosuiphonyl, dimethylaminiosuiphonyl or morpholin-4-yisulphonyl group, or a tetra hyd rofu ran-3-y, tetrahydropyran-3-yI or tetra hyd ropyra n-4-y group, R d denotes a hydrogen atom, a methoxy, difluoromethoxy or ethyloxy group, a 2-(morpholin-4-yI)ethyloxy, 3-(morpholin-4-yI)propyloxy or 4-(morpholin-4- yI)butyloxy group, a 3-(dimethylamino)propyloxy, 3-(diethylamino)propyloxy, 3-[bis-(2 methoxyethyl )-ami no] propyloxy, 3-(piperazin -1 -yI)propyloxy, 3-(4- methylpiperazin-1 -yI)propyloxy or 3-(4-ethylpiperazin-1 -yI)propyloxy group, a 3-(homomorpholin-4-yI)-propyloxy, 3-(2-oxa-5-aza-bicyclo[2.2.1 propyloxy, 3-(3-oxa-8-aza-bicyclo[3 .2.1 ]oct-8-yi )-propyloxy or 3-(8-oxa -3-aza- bicyclo[3.2.1 ]oct-3-yI)-propyloxy group, a 2-(2-oxo-pyrrolidin-1 -yI)-ethyloxy, 2-(2-oxopiperidin-1 -yi)-ethyloxy, 2-(3- oxomorpholin-4-y)-ethyloxy, 2-(2-oxo-imidazolidin-1 -yI)-ethyloxy, 2-(2-oxo-3- methyl-imidazolidin-I -yI)-ethyloxy, 2-(2-oxo-hexahydropyrimidin-1 -yI)-ethyloxy or 2-(2-oxo-3-met hyl-h exa hyd ropyri mid in- 1 -yI)-ethyloxy group, a 3-(2-oxo-pyrrolidin-1 -yI )-propyloxy, 3-(2-oxopipend in-I -yI )-propyloxy, 3-(3- oxomorpholin-4-yi)-propyloxy, 3-(2-oxo-imidazolidin-1 -yI)-propyloxy, 3-(2-oxo- WO 03/082290 139 WO 0308229 139PCT/E P03/03062 3-methyl-imidazolidin-1 -yl)-propyloxy, 3-(2-oxo-hexahydropyrimidin- 1-yl)- propyloxy or 3-(2-oxo-3-methyl-hexahydropyrimidin-1 -yI)-propyloxy group, a 2-(methoxy)-ethyloxy, 2-(tert.-butyloxycarbonylamino)-ethyloxy, 2-(amino)- ethyloxy, 2-(acetylamino)-ethyloxy, 2-(ethylcarbonylamino)-ethyloxy, 2- (propylcarbonylamino)-ethyloxy, 2-(isobutylcarbonylamino)-ethyloxy, 2- (methoxyacetylamino)-ethyloxy, 2-(ethylaminocarbonylamino)-ethyloxy, 2- (dimethylaminocarbonylamino)-ethyloxy, 2-(pyrrolidin-1 -ylcarbonylamino)- ethyloxy, 2-(piperidin-1 -ylcarbonylamino)-ethyloxy, 2-(morpholin-4 ylcarbonylamino)-ethyloxy, 2-(methylsulphonylamino)-ethyloxy group, 2- (ethylsulphonylamino)-ethyloxy or 2-(butylsulphonylamino)-ethyloxy group, or a 3-(tert.-butyloxycarbonylamino)-propyloxy, 3-(amino)-propyloxy, 3- (acetylamino)-propyloxy or 3-(methylsulphonylamino)-propyloxy group, and X denotes a nitrogen atom, their tautomers, their stereoisomers, their mixtures and their salts. Bicyclic heterocyclic groups of general formula I according to claim 1, wherein R a denotes a hydrogen atom, R b denotes a 3-chloro-4-fluoro-phenyl group or a 3-ethynylphenyl group, Rc denotes a cyclohexyl group which is substituted in the 3 position by an amino, acetylamino, tert.-butyloxycarbonylamino or methylsulphonylamino group, a cyclohexyl group which is substituted in the 4 position by an amino, methylamino, dimethylamino, acetylamino, N-(acetyl)-methylamino, WO 03/082290 WO 03/82290PCT/E P03/03062 methoxyacetylamino, N-(methoxyacetyl)-methylamino, tetra hydropyra n-4 ylcarbonylamino, N-(tetrahydropyran-4-ylcarbonyl)-methylamino, tert.- butyloxycarbonylamino, N-(tert.-butyloxycarbonyl)-methylamino, N- (ethylaminocarbonyl )-methylamino, dimethylaminocarbonylamino, N- (dimethylaminocarbonyl )-methylamino, N-(piperidin-1 -ylcarbonyl)- methylamino, morpholin-4-ylcarbonylamino, N-(morpholin-4-ylcarbonyl)- methylamino, N-(4-methylpiperazin-1 -ylcarbonyl)-methylamino, methylsuiphonylamino, N-(methylsulphonyl)-methylamino, ethylsulphonylamino, N-(ethylsulphonyl)-methylamino, dimethylaminosulphonylamino, N-(dimethylaminosulphonyl )-methylamino, morpholin-4-ylsulphonylamino, N-(morpholin-4-ylsulphonyl)-methylamino, 3- chioropropylsuiphonylamino, or [3-(morpholin-4-yI)-propyl]sulphonylamino group, a pyrrolidin-3-yl group, a pyrrolidin-3-y group which is substituted in the 1 position by a tert.- butyloxycarbonyl or methylsulphonyl group, a piperidin-3-yl group, a piperidin-3-yl group which is substituted in the 1 position by a tert.- butyloxycarbonyl or methylsuiphonyl group, a piperidin-4-yI group, a piperidin-4-yI group which is substituted in the 1 position by a methyl, (a min ocarbon yl)m ethyl, (dimethylaminocarbonyl)methyl, (morpholin -4- ylcarbonyl)methyl, 2-(tert.-butyloxycarbonylamino)ethyl, 2-aminoethyl, 2- (acetylamino)ethyl, 2-(methylsulphonylamino)ethyl, cyano, acetyl, methoxyacetyl, (dimethylamino)acetyl, (morpholin-4-yl)acetyl, tetra hydropyra n-4 -ylca rbon yl, ethylaminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, pyrrolidin-1 -ylcarbonyl, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, 2- WO 03/082290 WO 03/82290PCT/EPO3/03062 methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4 -ylcarbonyl, homomorpholin-4-ylcarbonyl, 4-methylpiperazin-1 -ylcarbonyl, isopropyloxycarbonyl, tert.-butyloxycarbonyl, methylsuiphonyl, dimethylaminosulphonyl or morpholin-4-ylsulphonyl group, or a tetra hydrofura n-3-y, tetra hydropyra n-3-yl or tetrahydropyran-4-yl group, R d denotes a hydrogen atom, a methoxy or ethyloxy group, a 2-(morpholin-4-yI)ethyloxy, 3-(morpholin-4-yI)propyloxy or 4-(morpholin-4- yI)butyloxy group, a 2-(3-methyl-2-oxo-hexahydropyrimidin-1 -yl)-ethyloxy group, a 2-(methoxy)-ethyloxy, 2-(tert.-butyloxycarbonylamino)-ethyloxy, 2-amino- ethyloxy, 2-(acetylamino)-ethyloxy or 2-(methylsulphonylamino)-ethyloxy group or a 3-(tert.-butyloxycarbonylamino)-propyloxy, 3-amino-propyloxy, 3- (acetylamino)-propyloxy or 3-(methylsulphonylamino)-propyloxy group, and X denotes a nitrogen atom, their tautomers, their stereoisomers, their mixtures and their salts. 6. The following compounds of general formula I according to claim 1: 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7- methoxy-quinazoline, WO 03/082290 142 PCT/EPO3/03062 4-I(3-chlIoro-4-fl uoro-ph enyl)a min (tetra hyd ropyral-4 -yoxy)-7- methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((R)-tetrahydrofuran-3-yloxy)-7- methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1 yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)aminol-6-(trans-4-methanesulphonylamino- cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy- q uinazoli ne, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methanesulphonyl-piperidin-4- yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino-6-(cis-4-[3-(morpholin-4-yi)- propyl]sulphonylamino}-cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3-chlIoro-4-fl uoro-ph en yl)a min (tetra hyd ropyra n-3 -yl oxy)-7- methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-(morpholin-4-y propyl]sulphonylamino}-cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -methyl-piperidin-4-yloxy)-7- methoxy-quinazoline, (in) 4-[(3-chloro-4-fluoro-phenyl)amino-6-{1 -[(morpholin-4-yI)carbonyl]- piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(methoxymethyl)carbonyl]- WO 03/082290 143 WO 0308229 143PCT/EP03/03062 piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-( 1 -cyano-pipeddin-4-yloxy)-7 methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino-6-{1 -[(morpholin-4-yl)sulphonylj- piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino-6-[1 -(2-acetylamino-ethyl)-piperidin- 4-yloxyJ-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4- [(dimethylamino)sulphonylamino]-cyclohexan-1 -yloxy}-7-methoxy- qu inazoline, 4-[(3-chloro-4-fluoro-phenyl)amino-6-{trans-4-I(morpholin-4- yI)carbonylamino]-cyclohexan-1 -yloxy-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4- yl)sulphonylamino]-cyclohexan-1 -yloxy}-7-methoxy-quinazoline, 4-[3-chlIoro-4-fl uoro-ph enyl)a m ino]j-6- (tetra hyd ropyra n-4 -yl oxy)-7-(2- acetylamino-ethoxy)-quinazoline, 4-[3-chlIoro-4-fl uoro-ph enyl)a min o] (tetra hyd ropyran-4 -yloxy)-7-(2- methanesulphonylamino-ethoxy)-quinazoline and 4-[3-chlIoro-4-fl uoro-ph enyl)a min o] (tetra hyd ropyran-4 -yl oxy)-7-(2- methoxy-ethoxy)-quinazoline, and the salts thereof. 7. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 6 with inorganic or organic acids or bases. WO 03/082290 144 PCT/EP03/03062
8. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 6 or a physiologically acceptable salt according to claim 7 optionally together with one or more inert carriers and/or diluents.
9. Use of a compound according to at least one of claims 1 to 7 for preparing a pharmaceutical composition which is suitable for treating benign or malignant tumours, for preventing and treating diseases of the airways and lungs and for treating diseases of the gastrointestinal tract, the bile duct and gall bladder. Process for preparing a pharmaceutical composition according to claim 8, characterised in that a compound according to at least one of claims 1 to 7 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
11. Process for preparing the compounds of general formula I according to claims 1 to 6, characterised in that a) a compound of general formula R .NRb R a N Rb 0-H dd N R,(ll) wherein R a Rb, Rd and X are defined as in claims 1 to 6, is reacted with a compound of general formula Z Rc ,(III) WO 03/082290 145 PCTEP03/03062 wherein R is defined as in claims 1 to 6 and Z 1 denotes a leaving group, or b) in order to prepare compounds of general formula I wherein Rd denotes one of the optionally substituted alkyloxy groups mentioned in claims 1 to 6, a compound of general formula R a Rb X O'R c N O-H (I) wherein R a R b Rc and X are defined as in claims 1 to 6, is reacted with a compound of general formula Z 2 R d wherein R d denotes a C14-alkyl group, a methyl group substituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorine atoms, a C 24 -alkyl group substituted by a group R 6 or R 7 while R 6 and R 7 are defined as in claims 1 to 6, a C1-4-alkyl group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the group R 8 or a C1- 4 -alkyl group which is substituted by a morpholinyl group substituted in the 4 position by the group R 8 while R 8 in each case is defined as in claims 1 to 6, and Z 2 denotes a leaving group, or c) in order to prepare compounds of general formula I wherein Rd denotes one of the alkyloxy groups mentioned in claims 1 to 6, which is substituted by an optionally substituted amino, alkylamino or dialkylamino group or by an WO 03/082290 146 PCT/EP0 3/0 30 62 optionally substituted heterocyclic group bound via an iminonitrogen atom, a compound of general formula Ra N Rb N x0 Rc N 0-(CH 2 2 4 -Z3 (VI), wherein R a Rb, RC and X are defined as in claims 1 to 6 and Z 3 denotes a leaving group, is reacted with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or the appropriate salts or derivatives thereof, or d) in order to prepare compounds of general formula I wherein Rd denotes a hydroxy group, a protecting group is cleaved from a compound of general formula Ra Rb N 0 X N Re N R (VI), wherein Ra, Rb, RC and X are defined as in claims 1 to 6 and R d denotes a group which can be converted into a hydroxy group, or e) in order to prepare compounds of general formula I wherein Re contains a -NH- group, WO 03/082290 147 PCT/EP03/03062 a protecting group is cleaved from a compound of general formula Ra Rb N 0 X Re' N R (VIII), wherein R a Rb, Rd and X are defined as in claims 1 to 6 and Rchas the meanings given for Rc in claims 1 to 6, with the proviso that Rc contains a protecoted nitrogen atom, or f) in order to prepare compounds of general formula I wherein RC contains an alkyl group substituted by an optionally substituted amino, alkylamino or dialkyamino group or by an optionally substituted heterocyclic group bound via a nitrogen atom, a compound of general formula Ra Rb N N Rd (IX), wherein R a R b Rd and X are defined as in claims 1 to 6, Z 3 denotes a leaving group and R c has the meanings given for Rc in claims 1 to 6, with the proviso that a hydrogen atom bound to an aliphatic carbon atom is replaced by the group Z 3 is reacted with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or the appropriate salts or derivatives thereof and if desired a compound of general formula I thus obtained which contains an WO 03/082290 148 PCT/EP03/03062 amino, alkylamino or imino group is converted by acylation, cyanation or sulphonylation into a corresponding acyl, cyano or sulphonyl compound of general formula I and/or a compound of general formula I thus obtained which contains an amino, alkylamino or imino group is converted by alkylation or reductive alkylation into a corresponding alkyl compound of general formula I and/or a compound of general formula I thus obtained which contains a chloro- C 1 -4-alkylsulphonyl or a bromo-C 14 -alkylsulphonyl group is converted by reaction with an amine into a corresponding amino-C.- 4 -alkylsulphonyl compound and/or a a compound of general formula I thus obtained which contains a tert.- butyloxycarbonylamino, N-alkyl-N-(tert.-butyloxycarbonyl)amino or a N-tert.- butyloxycarbonylimino group is converted by treatment with an acid into a corresponding amino, alkylamino or imino compound of general formula I, and/or if necessary any protecting group used in the reactions described above is cleaved again and/or if desired a compound of general formula I thus obtained is resolved into the stereoisomers thereof and/or a compound of general formula I thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof. POPER\PMBSpm.\2XI3226705 Ispadoc2I/IW2(O 00 o O
149- O 12. A method for treating benign or malignant tumours, for preventing and c treating diseases of the airways and lungs and for treating diseases of the gastrointestinal tract, the bile duct and gall bladder, comprising administering to a in subject in need thereof a compound according to one of claims 1 to 7. r- cN 13. A compound prepared by the process of claim 11. 0 14. A compound according to claim 1 or 13; or a use according to claim 9; or a process according to claim 10 or 11; or a method according to claim 12, substantially as hereinbefore described and/or exemplified.