 Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the product
专利摘要:
The present invention relates to a bicyclic heterocycle of formula (I), its teomers, stereoisomers and salts, especially pharmacologically acceptable salts with inorganic or organic acids or bases. Formula I In the above formula (I) R a , R b , R c , A, B, C, D, E and X are as defined in claim 1. The non-cyclic heterocycle of the present invention has useful pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases. The invention also relates to the use of the bicyclic heterocycle of the invention for the treatment of diseases, in particular of tumor diseases, lung and bronchial diseases, and to a process for the preparation of the compounds of the invention. 公开号:KR20020012290A 申请号:KR1020017016457 申请日:2000-06-16 公开日:2002-02-15 发明作者:힘멜즈바흐프랑크；랑콥프엘케；멧츠토마스；솔카플라비오；융비르기트；바움앙케 申请人:클래스 하인츠-게르트；베링거 잉겔하임 파르마 카게； IPC主号:
专利说明:
[0001] The present invention relates to bicyclic heterocycles, medicinal compositions containing them, their uses and methods for their preparation. [0001] The present invention relates to bicyclic heterocycles, medicaments containing these compounds, their uses and methods for the production thereof, [1] The present invention relates to non-cyclic heterocycles of formula (I) having useful pharmaceutical properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases, and their teomers, stereoisomers and salts, especially inorganic or organic acids or bases And the use thereof for the treatment of diseases, particularly tumor diseases, lungs and bronchial diseases, and a process for their preparation. [2] [3] In the above formula (I) [4] R a is a hydrogen atom or a C 1-4 -alkyl group, [5] R b is a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus can in each case be replaced by groups R 1 to R 3 , where R 1 and R 2 can be the same or different, , Hydrogen, fluorine, chlorine, bromine or iodine atoms; C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, C 3-6 -cycloalkyl, C 4-6 -cycloalkoxy, C 2-5 -alkenyl or C 2-5 -alkynyl group; Aryl, aryloxy, arylmethyl or arylmethoxy group; C 3-5 - alkenyloxy or C 3-5 - alkynyloxy group (this time, the art unsaturated moiety may not be bonded to an oxygen atom); C 1-4 - alkyl sulfonic phenyl, C 1-4 - alkyl, sulfinyl, C 1-4 - alkyl sulfonyl, C 1-4 - alkylsulfonyloxy, methyl sulfonyl group, methylsulfonyl, phenyl, trifluoromethyl trifluoromethyl sulfinyl or trifluoromethyl; A methyl or methoxy group substituted by one to three fluorine atoms; An ethyl or ethoxy group substituted with one to five fluorine atoms; Or a cyano or nitro group or an amino group unsubstituted or substituted by one or two C 1-4 -alkyl groups, wherein the substituents may be the same or different, or wherein R 1 and R 2 are adjacent carbon when coupled to the atom, they are together -CH = CH-CH = CH, -CH = CH-NH or -CH = forming an N-NH group, and R 3 is hydrogen, fluorine, chlorine or bromine atom; C 1-4 -alkyl, trifluoromethyl or C 1-4 -alkoxy group, [6] X is a cyano group or a methine group substituted by a nitrogen atom, [7] A is an imino group substituted or unsubstituted by a C 1-4 -alkyl group, [8] B is a carbonyl or sulfonyl group, [9] C is a 1,3-alenylene, 1,1- or 1,2-vinylene group which may in each case be substituted by one or two methyl groups or trifluoromethyl groups; An ethynylene group; Or 1,3-butadiene-1,4-ylene group which is unsubstituted or substituted by 1 to 4 methyl groups or by trifluoromethyl group, [10] D is alkylene, -CO- alkylene or -SO 2 - alkylene group (wherein, each case, the alkylene moiety is of 1 to 4 hydrogen atoms in the alkylene moiety in addition, contains from 1 to 8 carbon atoms must be bonded to the adjacent alkylene group through a carbonyl group or sulfonyl group, C) - is in each case may be replaced by fluorine atoms,, -CO- alkylene or -SO 2; -CO-O-alkylene, -CO-NR 4 -alkylene or -SO 2 -NR 4 -alkylene group, wherein the alkylene moiety in each case contains from 1 to 8 carbon atoms, , The bond to adjacent group C should only be via a carbonyl or sulfonyl group and R 4 is a hydrogen atom or a C 1-4 -alkyl group), or when D is bonded to the carbon atom of the group E, it is a direct bond , When D is bonded to the nitrogen atom of group E, it is a carbonyl or sulfonyl group, [11] E is amino, C 1-4 -alkylamino or di- (C 1-4 -alkyl) -amino group (wherein the alkyl residues may be the same or different); C 2-4 - alkylamino group [where the alkyl moiety is substituted by R 5 in the β-, γ- or δ- position relative to the nitrogen atom of the amino group, wherein R 5 is hydroxy, C 1-4 - Alkoxy, amino, C 1-4 -alkylamino or di- (C 1-4 -alkyl) -amino group; A 4 to 7 membered alkyleneimino group which is unsubstituted or substituted by one or two methyl groups; Or a 6 to 7 membered alkyleneimino group which is unsubstituted or substituted by one or two methyl groups, wherein in each case the methylene group at the 4-position is replaced by an oxygen or sulfur atom, or by sulfinyl, , Imino or N- (C 1-4 -alkyl) -imino group); N- (C 1-4 -alkyl) -N- (C 2-4 -alkyl) -amino group, wherein the C 2-4 -alkyl residue is optionally substituted with one or more groups selected from the group consisting of , It is substituted by R 5 in position, wherein R 5 is as defined above); Di- (C 2-4 -alkyl) -amino groups wherein two C 2-4 -alkyl moieties are substituted by R 5 at the -, - or - position for the nitrogen atom of the amino group, Wherein the substituents may be the same or different and R 5 is as defined above; C 3-7 -cycloalkylamino or a C 3-7 -cycloalkyl-C 1-3 -alkylamino group, wherein in each case the nitrogen atom may be further substituted by a C 1-4 -alkyl group ); Amino or a C 1-4 -alkylamino group, wherein the nitrogen atom is in each case optionally substituted by 1 to 3 C 1-4 -alkyl groups, tetrahydrofuran-3-yl, tetrahydropyranyl, Yl, tetrahydropyranylmethyl, 1- (tetrahydrofuran-3-yl) -piperidin-4-yl, 1- (tetrahydropyran- Piperidin-4-yl, 1- (tetrahydropyran-4-yl) -piperidin-4-yl, 3-pyrrolidinyl, 3- piperidinyl, 4- Hydroazepinyl or 4-hexahydroazepinyl group); A 4 to 7 membered alkyleneimino group which is unsubstituted or substituted by one to four C 1-2 -alkyl groups which may be substituted by R 5 , either a cyclic carbon atom or an alkyl group, , Wherein R < 5 > is as defined above; A piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranylmethyl group; A 6 to 7 membered alkyleneimino group optionally substituted by one or two C 1-2 -alkyl groups, wherein the methylene group in each case is an oxygen or sulfur atom at the 4-position, the group R 6 , Or a sulfinyl or sulfonyl group wherein R 6 is a hydrogen atom, a C 1-4 -alkyl, a 2-methoxy-ethyl, a 3-methoxy-propyl, a C 3-7 -Cycloalkyl , C 3-7 -cycloalkyl-C 1-4 -alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, , C 1-4 -alkyl-carbonyl, C 1-4 -alkylsulfonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl or di- (C 1-4 -alkyl) -aminocarbonyl group to be); An imidazolyl group which is unsubstituted or substituted by one to three methyl groups; Or a C 5-7 -cycloalkyl group, wherein the methylene group is replaced by an oxygen or sulfur atom, an imino group substituted by a group R 6 , a sulfinyl or a sulfonyl group, wherein R 6 is as defined above, Lt; / RTI & [12] D together with E represents a hydrogen, fluorine or chlorine atom; A C 1-4 -alkyl group which is unsubstituted or substituted with 1 to 5 fluorine atoms; C 3-6 -cycloalkyl group; Aryl, heteroaryl, C 1-4 -alkylcarbonyl or arylcarbonyl group; Carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylamino-carbonyl or di- (C 1-4 -alkyl) -aminocarbonyl group; Or a 4-to 7-membered alkyleneimino group, wherein the methylene group in each case is an oxygen or sulfur atom in the 6-membered to 7-membered alkyleneimino group, the group R 6 , Or a sulfinyl or sulfonyl group wherein R 6 is as defined above, [13] R c is C 4-7 - cycloalkoxy, or C 3-7 - cycloalkyl, -C 1-6 - alkoxy group [wherein, each case, the cycloalkyl moiety is C 1-3 - alkyl, hydroxy, C 1- 4 - alkoxy, amino, C 1-4 - alkylamino, di - (C 1-4-alkyl) -amino, pyrrolidino, piperidino, morpholino, piperazino, N- (C 1-2 Alkyl-piperazino, hydroxy-C 1-2 -alkyl, C 1-4 -alkoxy-C 1-2 -alkyl, amino-C 1-2 -alkyl, C 1-4 -alkylamino-C 1-2-alkyl, di - (C 1-4 -alkyl) -amino -C 1-2 -alkyl, -C 1-2 pyrrolidino-alkyl, piperidino -C 1-2 -alkyl, morpholinyl C 1-2 -alkyl, piperazino-C 1-2 -alkyl or N- (C 1-2 -alkyl) -piperazino-C 1-2 -alkyl group, The mono-substituted cycloalkyl moieties mentioned include C 1-3 -alkyl groups; Tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy; Tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group; C 2-4 -alkoxy substituted by an azetidin-1-yl, 4-methyl-homo-piperazino or 4-ethyl-homopiperazino group at the , Or group; Piperidinyloxy, 2-pyrrolidinyl-C 1-4 -alkyloxy, 3-pyrrolidinyl-C 1-4 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-pyrrolidinyloxy Piperidinyl-C 1-4 -alkyloxy, 3-piperidinyl-C 1-4 -alkyloxy, 4-piperidinyl-C 1-4 -alkyloxy, 3-hexahydroazepinyloxy, 4-hexahydroazepinyloxy, 2-hexahydroazepinyl-C 1-4 -alkyloxy, 3-hexahydroazepinyl-C 1-4 -alkyloxy or 4-hexahydroazepinyl-C 1-4 -alkyloxy group, wherein in each case the cyclic nitrogen atom may be replaced by a group R 6 , wherein R 6 is as defined above. [14] In particular, [15] R a , R b , A to C and X are as defined above, [16] E is amino, C 1-4 -alkylamino or di- (C 1-4 -alkyl) -amino group, wherein the alkyl residues may be the same or different; C 2-4 -alkylamino group wherein the alkyl moiety is substituted from the 2-position by R 5 , wherein R 5 is selected from the group consisting of hydroxy, C 1-4 -alkoxy, amino, C 1-4 -alkylamino or di- A 4- to 7-membered alkyleneimino group which is unsubstituted or substituted by a (C 1-4 -alkyl) -amino group, or a 6- to 7-membered alkylene group which is unsubstituted or substituted by one or two methyl groups, In each case the methylene group at the 4 position is replaced by an oxygen or sulfur atom or by a sulfinyl, sulfonyl, imino or N- (C 1-4 -alkyl) -imino group ); N- (C 1-4 - alkyl) -N- (C 2-4 - alkyl) amino group (wherein, C 2-4 - moiety is optionally substituted by R 5 at 2-position, wherein R 5 is from above Lt; / RTI > Di - (C 2-4 - alkyl) amino group (wherein the two C 2-4 - moiety is optionally substituted by R 5 In the second position, wherein the substituents may be the same or different and the above R 5 is Lt; / RTI > C 3-7 -cycloalkylamino or a C 3-7 -cycloalkyl-C 1-3 -alkylamino group, wherein in each case the nitrogen atom may be further substituted by a C 1-4 -alkyl group ); Amino or a C 1-4 -alkylamino group wherein the nitrogen atom is in each case optionally substituted by 1 to 3 C 1-4 -alkyl groups, 3-pyrrolidinyl, 3-piperidinyl , 4-piperidinyl, 3-hexahydroazepinyl or 4-hexahydroazepinyl group); A 4 to 7 membered alkyleneimino group which is unsubstituted or substituted by one to four C 1-2 -alkyl groups which may be substituted by R 5 , either a cyclic carbon atom or an alkyl group, , Wherein R < 5 > is as defined above; A 6 to 7 membered alkyleneimino group optionally substituted by one or two C 1-2 -alkyl groups, wherein the methylene group in each case is an oxygen or sulfur atom at the 4-position, the group R 6 already it is substituted with no group, or a sulfinyl or sulfonyl group substituted with, where R 6 is a hydrogen atom, C 1-4 - alkyl, C 3-7 - cycloalkyl, C 3-7 - cycloalkyl, -C 1 4 - alkyl, formyl, C 1-4 -alkyl-carbonyl, C 1-4-alkylsulfonyl, aminocarbonyl, C 1-4 -alkyl-aminocarbonyl or di - (C 1-4 -alkyl) - aminocarbonyl group); An imidazolyl group which is unsubstituted or substituted by one to three methyl groups; Or a C 5-7 -cycloalkyl group, wherein the methylene group is replaced by an oxygen or sulfur atom, an imino group substituted by a group R 6 , a sulfinyl or a sulfonyl group, wherein R 6 is as defined above, Lt; / RTI & [17] D is a hydrogen, fluorine or chlorine atom together with E; A C 1-4 -alkyl group which is unsubstituted or substituted with 1 to 5 fluorine atoms; C 3-6 -cycloalkyl group; Aryl, heteroaryl, C 1-4 -alkylcarbonyl or arylcarbonyl group; Carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylamino-carbonyl or di- (C 1-4 -alkyl) -aminocarbonyl group; Or a 4-to 7-membered alkyleneimino group, wherein the methylene group in each case is an oxygen or sulfur atom in the 6-membered to 7-membered alkyleneimino group, the group R 6 , Or a sulfinyl or sulfonyl group wherein R 6 is as defined above, [18] R c is C 4-7 - cycloalkoxy, or C 3-7 - cycloalkyl, -C 1-6 - alkoxy group [wherein, each case, the cycloalkyl moiety is C 1-3 - alkyl, hydroxy, C 1- 4 - alkoxy, amino, C 1-4 - alkylamino, di - (C 1-4-alkyl) -amino, pyrrolidino, piperidino, morpholino, piperazino, N- (C 1-2 Alkyl-piperazino, hydroxy-C 1-2 -alkyl, C 1-4 -alkoxy-C 1-2 -alkyl, amino-C 1-2 -alkyl, C 1-4 -alkylamino-C 1-2-alkyl, di - (C 1-4 -alkyl) -amino -C 1-2 -alkyl, -C 1-2 pyrrolidino-alkyl, piperidino -C 1-2 -alkyl, morpholinyl C 1-2 -alkyl, piperazino-C 1-2 -alkyl or N- (C 1-2 -alkyl) -piperazino-C 1-2 -alkyl group, The mono-substituted cycloalkyl moieties mentioned include C 1-3 -alkyl groups; Or 3-pyrrolidinyloxy, 2-pyrrolidinyl-C 1-4 -alkyloxy, 3-pyrrolidinyl-C 1-4 -alkyloxy, 3-piperidinyloxy, Piperidinyl-C 1-4 -alkyloxy, 3-piperidinyl-C 1-4 -alkyloxy, 4-piperidinyl-C 1-4 -alkyloxy, 3-hexahydroazepinyloxy , 4-hexahydroazepinyloxy, 2-hexahydroazepinyl-C 1-4 -alkyloxy, 3-hexahydroazepinyl-C 1-4 -alkyloxy or 4-hexahydroazepinyl- C 1-4 -alkyloxy group, wherein the cyclic nitrogen atom in each case may be substituted by a group R 6 , wherein R 6 is as defined above. I < / RTI > [19] Referred to as defining a group of the above mentioned moieties, in each case, R by the 7-substituted or substituted by R 8, disubstituted or trisubstituted, or R 7 is substituted by one by the addition of R 8 to A substituted or unsubstituted phenyl group wherein the substituents of the phenyl group may be the same or different and R 7 is cyano, carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkyl aminocarbonyl, di - (C 1-4-alkyl) aminocarbonyl, C 1-4 - alkyl sulfonic phenyl, C 1-4 - alkyl sulfinyl, C 1-4-alkylsulfonyl, hydroxy, C 1-4 - alkylsulfonyloxy, trifluoromethyl alkyloxy, nitro, amino, C 1-4 - alkylamino, di - (C 1-4 -alkyl) -amino, C 1-4 -alkyl-carbonyl-amino (C 1-4 -alkyl) -C 1-4 -alkylcarbonylamino, C 1-4 -alkylsulfonylamino, N- (C 1-4 -alkyl) -C 1-4 -alkylsulfonylamino, C 1-4 -alkylaminosulfonyl or di- (C 1-4 < RTI ID = 0.0 > -Alkyl) -aminosulfonyl group or a carbonyl group, which is substituted by a 5- to 7-membered alkyleneimino group, wherein the 6 to 7 membered alkyleneimino group, in each case the methylene group, (C 1-4 -alkyl) -imino group at the 4-position, and R 8 is a fluorine, chlorine, bromine or iodine atom (which may be substituted by an oxygen or sulfur atom, a sulfinyl, a sulfonyl, , C 1-4 -alkyl, trifluoromethyl or C 1-4 -alkoxy group, or when two groups R 8 are bonded to adjacent carbon atoms, these two groups R 8 together are C 3-5 -alkyl Methylenedioxy or 1,3-butadiene-1,4-ylene group). [20] The heteroaryl groups mentioned in defining the above-mentioned groups also include 5-membered heteroaromatic groups containing imino groups or containing oxygen or sulfur atoms or imino groups or containing oxygen or sulfur atoms and one or two nitrogen atoms group; Or a 6-membered heteroaromatic group containing one, two or three nitrogen atoms, wherein the 5-membered heteroaromatic group may in each case be substituted by one or two methyl or ethyl groups, The 6-membered heteroaromatic group may be substituted by one or two methyl or ethyl groups or by fluorine, chlorine, bromine or iodine atoms or by trifluoromethyl, hydroxy, methoxy or ethoxy groups . [21] Preferred compounds of formula (I) [22] R a is a hydrogen atom, [23] R b is a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus can in each case be replaced by a group R 1 to R 3 , where R 1 and R 2 can be the same or different, , Hydrogen, fluorine, chlorine, bromine or iodine atoms; C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, C 3-6 -cycloalkyl, C 4-6 -cycloalkoxy, C 2-5 -alkenyl or C 2-5 -alkynyl group; Aryl, aryloxy, arylmethyl or arylmethoxy group; A methyl or methoxy group substituted by one to three fluorine atoms; Or a cyano or nitro group, and R 3 is hydrogen, fluorine, chlorine or bromine atom, C 1-4 -alkyl, trifluoromethyl or C 1-4 -alkoxy group, [24] X is a cyano group or a methine group substituted by a nitrogen atom, [25] A is an imino group, [26] B is a carbonyl or sulfonyl group, [27] C is a 1,3-alenylene, a 1,1- or 1,2-vinylene group, an ethynylene group, or a 1,3-butadiene-1,4- [28] D is alkylene, -CO- alkylene or -SO 2 - alkylene group (wherein, each case, the alkylene moiety is of 1 to 4 carbon atoms and 1 to contain in additional alkylene moiety of four hydrogen atoms must be bonded to the adjacent alkylene group through a carbonyl group or sulfonyl group, C) - is in each case may be replaced by fluorine atoms,, -CO- alkylene or -SO 2; -CO-O-alkylene, -CO-NR 4 -alkylene or -SO 2 -NR 4 -alkylene group, wherein the alkylene moiety in each case contains 1 to 4 carbon atoms, , They must be bonded to the adjacent group C via a carbonyl or sulfonyl group and R 4 is a hydrogen atom or a C 1-4 -alkyl group), or when D is bonded to the carbon atom of the group E, it is a direct bond , When D is bonded to the nitrogen atom of group E, it is a carbonyl or sulfonyl group, [29] E is a di- (C 1-4 -alkyl) -amino group, wherein the alkyl residues may be the same or different; (C 1-4 -alkyl) -N- (C 2-4 -alkyl) -amino group wherein the C 2-4 -alkyl residue is optionally substituted with one or more groups selected from the group consisting of , - or - It is substituted by R 5 in position, wherein R 5 is hydroxy, C 1-4 - alkoxy or di - (C 1-4-alkyl) -amino group; A 4 to 7 membered alkyleneimino group which is unsubstituted or substituted by one or two methyl groups; Or a six- to seven-membered alkyleneimino group which is unsubstituted or substituted by one or two methyl groups, wherein in each case the methylene group is replaced by an oxygen or sulfur atom at the 4-position or by sulfinyl, Substituted with an N- (C 1-4 -alkyl) -imino group; Di- (C 2-4 -alkyl) -amino group, wherein the two C 2-4 -alkyl residues are in each case bound to the nitrogen atom of the amino group by R 5 at the -, - or Wherein the substituents may be the same or different and R 5 is as defined above; C 3-7 -cycloalkylamino or a C 3-7 -cycloalkyl-C 1-3 -alkylamino group, wherein in each case the nitrogen atom may be further substituted by a C 1-4 -alkyl group ); C 1-4 -alkylamino group wherein the nitrogen atom is selected from the group consisting of tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, 1- (Tetrahydropyran-3-yl) -piperidin-4-yl, 1- (tetrahydropyran-3- yl) -piperidin- (C 1-2 -alkyl) -3-pyrrolidinyl, N- (C 1-2 -alkyl) -3-piperidinyl, N- (C 1-2- Alkyl) -4-piperidinyl, N- (C 1-2 -alkyl) -3-hexahydroazepinyl or N- (C 1-2 -alkyl) -4-hexahydroazepinyl group do); 1 to 4 methyl group, a substituted or a non-substituted 4-to 7-membered alkylene diamino group by (which is, and one of the cyclic carbon atom or a methyl group may be substituted by R 5, wherein R 5 is Lt; / RTI > A piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranylmethyl group; 1 or 2 for (where butylimino group 6-to 7-membered alkylene that is substituted or not substituted by two methyl groups, respectively, a methylene group, an imino substituted by oxygen or sulfur atom, a group R 6 eseo the 4-position It is replaced by a group, or a sulfinyl or sulfonyl group, wherein R 6 is C 1-4 - alkyl, 2-methoxyethyl, 3-methoxypropyl, C 3-7 - cycloalkyl, C 3-7 -cycloalkyl -C 1-4-alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-methyl, formyl, C 1-4 - alkyl carbonyl C 1-4 -alkyl-sulfonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl or di- (C 1-4 -alkyl) -aminocarbonyl group; Or a C 5-7 -cycloalkyl group, wherein the methylene group is replaced by an oxygen or sulfur atom, an imino group substituted by a group R 6 , a sulfinyl or a sulfonyl group, wherein R 6 is as defined above, Lt; / RTI & [30] D is a hydrogen, fluorine or chlorine atom together with E; A C 1-4 -alkyl group which is unsubstituted or substituted with 1 to 5 fluorine atoms; C 3-6 -cycloalkyl group; Aryl, C 1-4 -alkylcarbonyl or arylcarbonyl group; Carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylamino-carbonyl or di- (C 1-4 -alkyl) -aminocarbonyl group; Or a 4-to 7-membered alkyleneimino group, wherein the methylene group in each case is an oxygen or sulfur atom in the 6-membered to 7-membered alkyleneimino group, the group R 6 , Or a sulfinyl or sulfonyl group wherein R 6 is as defined above, [31] R c is C 4-7 - cycloalkoxy, or C 3-7 - cycloalkyl, -C 1-6 - alkoxy group [wherein, each case, the cycloalkyl moiety is C 1-3 - alkyl, hydroxy, C 1- 4-alkoxy, di - (C 1-4-alkyl) -amino, pyrrolidino, piperidino, morpholino, N- (C 1-2 - alkyl) - piperazino, hydroxy, -C 1- 2 -alkyl, C 1-4 - alkoxy -C 1-2 -alkyl, di - (C 1-4 -alkyl) -amino -C 1-2 -alkyl, pyrrolidino -C 1-2 -alkyl, P C 1-2 -alkyl, morpholino-C 1-2 -alkyl or N- (C 1-2 -alkyl) -piperazino-C 1-2 -alkyl group, The mono-substituted cycloalkyl moieties mentioned above include C 1-3 -alkyl groups; Tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy; Tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group; C 2-4 -alkoxy substituted by an azetidin-1-yl, 4-methyl-homo-piperazino or 4-ethyl-homopiperazino group at the , Or group; Piperidinyloxy, 2-pyrrolidinyl-C 1-4 -alkyloxy, 3-pyrrolidinyl-C 1-4 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-pyrrolidinyloxy Piperidinyl-C 1-4 -alkyloxy, 3-piperidinyl-C 1-4 -alkyloxy, 4-piperidinyl-C 1-4 -alkyloxy, 3-hexahydroazepinyloxy, 4-hexahydroazepinyloxy, 2-hexahydroazepinyl-C 1-4 -alkyloxy, 3-hexahydroazepinyl-C 1-4 -alkyloxy or 4-hexahydroazepinyl-C 1-4 -alkyloxy group, wherein in each case the cyclic nitrogen atom may be replaced by a group R 6 , wherein R 6 is as defined above, [32] The aryl moieties mentioned while defining the groups mentioned above, in each case, R by the 7-substituted or substituted by R 8, disubstituted or trisubstituted, or R 7 is substituted by one by the addition of R 8 to A phenyl group which may be substituted or disubstituted, wherein the substituents of the phenyl group may be the same or different and R 7 is cyano, carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkyl aminocarbonyl, di - (C 1-4-alkyl) aminocarbonyl, C 1-4 - alkyl sulfonic phenyl, C 1-4 - alkyl sulfinyl, C 1-4-alkylsulfonyl, hydroxy, C 1-4 - alkylsulfonyloxy, trifluoromethyl alkyloxy, nitro, amino, C 1-4 - alkylamino, di - (C 1-4 -alkyl) -amino, C 1-4 -alkyl-carbonyl-amino (C 1-4 -alkyl) -C 1-4 -alkylcarbonylamino, C 1-4 -alkylsulfonylamino, N- (C 1-4 -alkyl) -C 1-4 -alkylsulfonylamino, C 1-4 -alkylaminosulfonyl or di- (C 1-4 < RTI ID = 0.0 > -Alkyl) -aminosulfonyl group or a carbonyl group, which is substituted by a 5- to 7-membered alkyleneimino group, wherein the 6 to 7 membered alkyleneimino group, in each case the methylene group, (C 1-4 -alkyl) -imino group at the 4-position, and R 8 is a fluorine, chlorine, bromine or iodine atom , C 1-4 -alkyl, trifluoromethyl or C 1-4 -alkoxy group, or when two groups R 8 are bonded to adjacent carbon atoms, these two groups R 8 together are C 3-5 -alkyl Methylene dioxy or 1,3-butadiene-1,4-ylene group), and their terpolymers, stereoisomers and salts. [33] Particularly preferred compounds of formula (I) [34] R a is a hydrogen atom, [35] R b is a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus can in each case be replaced by groups R 1 and R 2 , where R 1 and R 2 can be the same or different, , Hydrogen, fluorine, chlorine or bromine atoms; Methyl, trifluoromethyl or methoxy group, [36] X is a nitrogen atom, [37] A is an imino group, [38] B is a carbonyl group, [39] C is a 1,2-vinylene group, an ethynylene group or a 1,3-butadiene-1,4-ylene group, [40] When D is a C 1-4 alkylene group or D is bonded to the carbon atom of the group E, it may be a direct bond, and when D is bonded to the nitrogen atom of the group E, it may be a carbonyl group, [41] E is a di- (C 1-4 -alkyl) -amino group, wherein the alkyl residues may be the same or different; (C 1-4 -alkyl) -N- (C 2-4 -alkyl) -amino group wherein the C 2-4 -alkyl residue is optionally substituted with one or more groups selected from the group consisting of , - or - It is substituted by R 5 in position, wherein the group R 5 is hydroxy, C 1-3 - alkoxy or di - (C 1-3-alkyl) -amino group; Pyrrolidino, piperidino or morpholino group; Di- (C 2-4 -alkyl) -amino group, wherein the two C 2-4 -alkyl residues are in each case bound to the nitrogen atom of the amino group by R 5 at the -, - or Wherein the substituents may be the same or different and R 5 is as defined above; (C 1-2 -alkyl) -pyrrolidin-3-yl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl, , 1- (C 1-2 -alkyl) -piperidin-3-yl, 1- (C 1-2 -alkyl) -piperidin-4-yl, 1- (tetrahydrofuran- (Piperidin-4-yl) -piperidin-4-yl, 1- (tetrahydropyran-3- yl) A C 1-4 -alkylamino group substituted by a C 1-4 -alkyl group; C 3-5 -cycloalkylamino or a C 3-5 -cycloalkyl-C 1-3 -alkylamino group, wherein in each case the nitrogen atom is further substituted with a C 1-3 -alkyl group; One or two (which is one methyl group, a substituted or a non-substituted 5-to 7-membered alkylene diamino group by, and one of the cyclic carbon atom or a methyl group may be substituted by R 5, wherein R 5 is Lt; / RTI > A piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranylmethyl group; It is substituted or not substituted by one or two methyl group, piperidino group (wherein, in each case, a methylene group, a nitrogen, oxygen or sulfur atom, a sulfinyl or sulfonyl group, or a group R 6 substituted at the 4-position It is already replaced by the no-group, wherein R 6 is C 1-3 - alkyl, 2-methoxyethyl, 3-methoxypropyl, C 3-6 - cycloalkyl, C 3-6 - cycloalkyl, -C 1 -3-alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-methyl, C 1-3 -alkyl-carbonyl, C 1-3 -alkyl C 1-3 -alkylaminocarbonyl or di- (C 1-3 -alkyl) -aminocarbonyl group, or is hydrogen, [42] D is together with E a hydrogen atom, a C 1-3 -alkyl group, an aryl or a C 1-4 -alkylcarbonyl group, or a C 1-4 -alkoxycarbonyl group, [43] Wherein R c is C 4-7 -cycloalkoxy or a C 3-7 -cycloalkyl-C 1-4 -alkoxy group, wherein in each case the cycloalkyl moiety is C 1-3 -alkyl or C 1-3 -alkoxy Lt; / RTI >group); Tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group; C 2-4 -alkoxy substituted by an azetidin-1-yl, 4-methyl-homo-piperazino or 4-ethyl-homopiperazino group at the , Or group; 3-pyrrolidinyloxy, 2-pyrrolidinyl-C 1-3 -alkyloxy, 3-pyrrolidinyl-C 1-3 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2 -piperidinyl -C 1-3-alkyloxy, 3-piperidinyl -C 1-3-alkyloxy, 4-piperidinyl -C 1-3-alkyloxy, 3-hexahydro-ah Jaffe carbonyl oxy, Hexahydroazepinyl-C 1-3 -alkyloxy, 3-hexahydroazepinyl-C 1-3 -alkyloxy or 4-hexahydroazepinyl-C 1-3 -alkyloxy group, wherein in each case the cyclic nitrogen atom may be substituted by methyl or ethyl groups, [44] A phenyl group, wherein the aryl moiety mentioned above may be mono-, di- or tri-substituted by R 8 , wherein the substituents of the phenyl group may be the same or different and R 8 is fluorine, chlorine , A bromine or iodine atom, a C 1-4 -alkyl, a trifluoromethyl or a C 1-4 -alkoxy group, and toomers, stereoisomers and salts thereof. [45] The most preferred compounds of formula (I) [46] R a is a hydrogen atom, [47] R b is a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus can in each case be replaced by groups R 1 and R 2 , where R 1 and R 2 can be the same or different, , Hydrogen, fluorine, chlorine or bromine atom, [48] X is a nitrogen atom, [49] A is an imino group, [50] B is a carbonyl group, [51] C is a 1,2-vinylene group, an ethynylene group or a 1,3-butadiene-1,4-ylene group, [52] D is a C 1-3 alkylene group, [53] E is a di- (C 1-4 -alkyl) -amino group, wherein the alkyl residues may be the same or different; Wherein the nitrogen atom is selected from the group consisting of 2-methoxyethyl, 1-methoxy-2-propyl, 2-methoxy-propyl, 3- methoxy-propyl, tetrahydrofuran- (Tetrahydrofuran-3-yl) -piperidin-4-yl, 1-methyl-piperidin- , A methylamino or ethylamino group substituted by a cyclopropyl or cyclopropylmethyl group; Bis- (2-methoxyethyl) -amino group; A pyrrolidino, piperidino or morpholino group, each of which is unsubstituted or substituted by one or two methyl groups; Methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2-methoxy-ethyl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl or tetrahydrofuran- A piperazino group; Thiomorpholino, S-oxido-thiomorpholino or S, S-dioxido-thio-morpholino group; Piperidino, 4-methoxy-piperidino, 4-ethoxy-piperidino, 4-methoxy-piperidino, , 4- (tetrahydrofuran-3-yl) -piperidino or 4-morpholino-piperidino group, [54] D is together with E a hydrogen atom, methyl, phenyl, methoxycarbonyl or ethoxycarbonyl group, [55] R c is cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy or cyclohexylmethoxy group; Cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group; Tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuran-2-ylmethoxy group; A straight chain C 2-4 -alkoxy group substituted at the end by a 4-methyl-homopiperazino or 4-ethyl-homopiperazino group; 1-methyl-piperidin-4-yloxy or 1-ethyl-piperidin-4-yloxy group; (1-methyl-piperidin-4-yl) -C 1-3 - alkyloxy or (1-ethyl-piperidin-4-yl) -C 1-3 - alkyl-oxy group in the compound, [56] Especially, [57] R a is a hydrogen atom, [58] R b is a 1-phenylethyl group or a phenyl group, wherein the phenyl nucleus may be substituted with groups R 1 to R 2 , where R 1 and R 2 may be the same or different and in each case hydrogen, fluorine, Chlorine or bromine atom, [59] X is a nitrogen atom, [60] A is an imino group, [61] B is a carbonyl group, [62] C is a 1,2-vinylene group, an ethynylene group or a 1,3-butadiene-1,4-ylene group, [63] D is a methylene group, [64] E is selected from the group consisting of dimethylamino, diethylamino, bis- (2-methoxy-ethyl) -amino, N-methyl-N- Amino, N-methyl-N-cyclopropylmethylamino, N-methyl-N- (1-methoxy- Methyl-N- (2-methoxy-propyl) -amino, N-methyl-N- (Tetrahydrofuran-4-yl) -amino, N-methyl-N- (tetrahydrofuran- Piperidin-4-yl) -amino group; A pyrrolidino, piperidino or morpholino group, each of which is unsubstituted or substituted by one or two methyl groups; A piperazino group substituted at the 4-position with methyl, ethyl, cyclopropylmethyl, 2-methoxy-ethyl group; S-oxido-thiomorpholino group; 2- (methoxymethyl) -pyrrolidino, 4-hydroxy-piperidino or 4-methoxy-piperidino group, [65] D is a hydrogen atom, methyl, phenyl or ethoxycarbonyl group together with E, [66] R c is cyclopropylmethoxy, cyclobutyloxy or cyclopentyloxy group; Tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuran-2-ylmethoxy group; A straight chain C 2-4 -alkoxy group substituted at the end by an azetidin-1-yl group or a 4-methyl-homopiperazino group; 1-methyl-piperidin-4-yloxy; (1-methyl-piperidin-4-yl) -C 1-3 -alkyloxy group, and the trimers, stereoisomers and salts thereof. [67] As the compounds particularly important among the compounds of formula I, the following compounds and their salts can be mentioned: [68] (a) 4- [3- (1-methyl-piperidin-4-yl) propyloxy] -6 - [(vinylcarbonyl) Amino] - < / RTI >quinazoline; [69] (b) from 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- } -7-cyclopropylmethoxy-quinazoline; And [70] (c) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin- 7-Cyclopropylmethoxy-quinazoline. [71] The compounds of formula (I) may be prepared, for example, by a process comprising the step (a) of reacting a compound of formula (II) with a compound of formula (III). [72] [73] [74] In the above formulas (II) and (III) [75] R a to R c , A, X, B, C, D and E are as defined above, [76] Z 1 is a leaving group such as a halogen atom (e.g., chlorine or bromine atom) or a hydroxy group. [77] The reaction may be carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / -tetrafuran or dioxane optionally in the presence of an inorganic or organic base optionally in the presence of a dehydrating agent , Conveniently at a temperature of from -50 to 150 캜, preferably from -20 to 80 캜. [78] The reaction is, Z 1 is leaving using the group of compounds of formula III, methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydro furan, or a solvent or solvent mixture in such as dioxane In the presence of N-ethyl-diisopropylamine (phonide base), conveniently in the presence of a tertiary organic base such as triethylamine, pyridine or 2-dimethylaminopyridine, Conveniently in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution, conveniently at a temperature of from -50 to 150 占 폚, preferably from -20 to 80 占 폚. [79] The reaction is preferably carried out using a compound of formula (III) wherein Z < 1 > is a hydroxy group using a dehydrating agent such as iso-butyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole), optionally in the presence of a base such as N, N'-dicyclohexylcarbodiimide, (Such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl < RTI ID = 0.0 > (For example, 4-dimethylaminopyridine) at -50 to 150 ° C, preferably -20 to 150 ° C in the presence of a solvent such as tetrahydrofuran, tetrahydrofuran, tetrahydrofuran, tetrahydrofuran, Lt; 0 > C. [80] b) reacting a compound of formula (IV) with a compound of formula (V) to prepare a compound of formula (I) wherein E is bonded to group D via a nitrogen atom. [81] [82] [83] In the above formula (IV) and formula (V) [84] R a , R b , R c , A, B, C, D and X are as defined above, [85] Z 2 is a halogen atom, a substituted hydroxy or sulfonyloxy group, such as a chlorine or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group, [86] E 'is as defined above for E and is bonded to group D via a nitrogen atom. [87] The reaction is conveniently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, methylene chloride, ethylene glycol monomethyl ether, ethylene glycol diethyl ether, In the presence of an inorganic base (such as sodium carbonate or potassium hydroxide) or a tertiary organic base (e.g. triethylamine) or in the presence of N-ethyl-diisopropylamine (phosphine base) In the presence of a reaction accelerator such as an alkali metal halide, at a temperature of -20 to 150 占 폚, preferably -10 to 100 占 폚. However, the reaction may be carried out without solvent or with excessive use of the compound of formula (V). [88] When compounds of formula (I) containing amino, alkylamino or imino groups are obtained according to the invention, they can be converted into the corresponding acyl or sulfonyl compounds of formula (I) by acylation or sulfonylation, [89] When compounds of formula (I) containing amino, alkylamino or imino groups are obtained according to the present invention, said compounds are converted to the corresponding alkyl compounds of formula (I) by alkylation or reductive alkylation, [90] When a compound of formula (I) containing a carboxy or hydroxyphosphoryl according to the present invention is obtained, it can be converted into the corresponding ester of formula (I) by esterification, [91] When a compound of formula (I) containing a carboxy or ester group is obtained in accordance with the present invention, said compound can be converted to the corresponding amide of formula (I) by reaction with an amine. [92] The subsequent esterification reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, most advantageously in the corresponding alcohol (Such as isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N Dimethylamino-benzodiazepine, optionally in the presence of a base such as N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1- Conveniently in the presence of pyridine, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, conveniently at a temperature of from 0 to 150 ° C, preferably from 0 to 80 ° C. [93] Subsequent esterification reactions can also be performed by reacting a compound containing a carboxy or hydroxyphosphoryl group with the corresponding alkyl halide. [94] The subsequent acylation or sulfonylation reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, (E.g., isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trichlorosulfuric acid, phosphorus pentoxide, phosphorus pentachloride, etc.), optionally in the presence of an organic base, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole), optionally also 4-dimethyl Is conveniently carried out in the presence of an amino-pyridine, N, N'-carbonyldiimidazole or tri-phenylphosphine / carbon tetrachloride at a temperature of from 0 to 150 ° C, preferably from 0 to 80 ° C . [95] Subsequent alkylation may optionally be carried out in the presence of an alkylating agent such as a corresponding halide or sulfonate ester in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane Conveniently in the presence of a tertiary organic base or inorganic base, at a temperature of from 0 to 150 ° C, preferably from 0 to 100 ° C, using a suitable base (for example, methyl iodide, ethyl bromide, dimethyl sulfate or benzyl chloride) Lt; / RTI > [96] Subsequent reductive alkylation reactions can be carried out using the corresponding carbonyl compounds (e.g., formaldehyde, acetaldehyde, propionaldehyde, acetone or butyraldehyde) in the presence of complex metal hydrides such as borohydride, lithium borohydride, In the presence of palladium / charcoal, in the presence of palladium / charcoal, in the presence of palladium / charcoal, in the presence of palladium / charcoal, in the presence of palladium / charcoal, in the presence of palladium / 1 to 5 bar. The methylation reaction can also be carried out at elevated temperature, for example at temperatures between 60 and 120 < 0 > C, in the presence of formic acid as reducing agent. [97] Subsequent amide formation reactions can be carried out by reacting the corresponding reactive carboxylic acid derivative with a corresponding amine and optionally in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane In the presence of a tertiary organic base, or in the presence of an inorganic base, or using a corresponding carboxylic acid, in the presence of a dehydrating agent such as isobutyl chloroformate N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1- Hydroxy-benzotriazole), optionally in the presence of 4-dimethylamino-pyridine, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride To the presence, preferably conveniently from 0 to 150 ℃, it is carried out at a temperature of 0 to 80 ℃. [98] In the above-described reaction, any reactive groups present, such as hydroxy, carboxy, phosphono, O-alkyl-phosphono, amino, alkylamino or imino groups, may be protected by conventional protecting groups during the reaction, The protective group will be separated again after the reaction. [99] For example, the protecting group for the hydroxy group may be trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group, [100] The protecting group for the carboxy group may be trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, [101] The protecting group for the phosphono group may be an alkyl group such as a methyl, ethyl, isopropyl or n-butyl group, a phenyl or benzyl group, [102] The protecting group for the amino, alkylamino or imino group is formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4 -Dimethoxybenzyl group, and further the protecting group for the amino group may be a phthalyl group. [103] Any protecting group used may optionally be subsequently removed in the presence of an acid such as, for example, trifluoroacetic acid in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / In the presence of an alkali metal base (e.g. sodium hydroxide or potassium hydroxide) or in the presence of an aprotic solvent, for example in the presence of iodotrimethylsilane, preferably in the presence of a base such as hydrochloric acid or sulfuric acid Lt; RTI ID = 0.0 > 100 C < / RTI > [104] However, the benzyl, methoxybenzyl or benzyloxycarbonyl group can be hydrolyzed, for example, in a hydrolytic manner, for example at temperatures between 0 and 100 ° C, preferably between 20 and 60 ° C, optionally with addition of an acid such as hydrochloric acid Using hydrogen in the presence of a catalyst such as palladium / charcoal in a suitable solvent (e.g. methanol, ethanol, ethyl acetate or glacial acetic acid) at a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar. However, the 2,4-dimethoxybenzyl group is preferably isolated in trifluoroacetic acid in the presence of anisole. [105] The tert-butyl or tert-butyloxycarbonyl group is preferably treated with iodotrimethylsilane, optionally in a solvent such as methylene chloride, dioxane, methanol or diethyl ether, or with trifluoroacetic acid or hydrochloric acid . [106] The trifluoroacetyl group is preferably treated with an acid such as hydrochloric acid at 50-120 < 0 > C in the presence of a solvent such as acetic acid at 0-50 < 0 > C or optionally in the presence of a solvent such as tetrahydrofuran . [107] The phthalyl group is preferably present in the presence of a primary amine or hydrazine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at a temperature of from 20 to 50 & . [108] The single alkyl group is optionally protected with a protecting group such as O, O, O or S, using sodium iodide in a solvent such as, for example, acetone, methyl ethyl ketone, acetonitrile or dimethylformamide at a temperature of from 40 to 150 캜, preferably from 60 to 100 캜. '- dialkylphosphono group. [109] Both of the alkyl groups can be reacted at a temperature between 0 ° C and the boiling point of the reaction mixture, preferably at 20 to 60 ° C, for example in a solvent such as methyl chloride, chloroform or acetonitrile, iodotrimethylsilane, Can be separated from the O, O'-dialkyl-phosphono group using trimethylsilane or chlorotrimethylsilane / sodium iodide. [110] Furthermore, the compounds of formula (I) obtained can be resolved into their optical isomers and / or diastereomers as mentioned above. Thus, for example, the cis / trans mixture can be decomposed into their cis and trans isomers, and one or more optically active carbons can be separated into their enantiomers. [111] Thus, for example, the cis / trans mixture can be resolved into its cis and trans isomers by chromatography, and the resulting compound of formula (I), which appears as racemate, can be isolated by known methods Can be separated into their optical isomers by Eliel EL in " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971. Compounds of formula (I) having two or more asymmetric carbon atoms can be separated by known methods, For example, they can be resolved into their diastereomers based on physical-chemical differences by chromatography and / or fractional crystallization, and when these compounds are obtained in racemic form, they are subsequently converted to enantiomers It can be decomposed into an isomer. [112] The enantiomers are preferably optically active compounds which form the chiral phase by column separation or by recrystallization from an optically active solvent or with salts or derivatives thereof such as esters or amides with racemic compounds, And separating the mixture of diastereomeric isomers of the salt or derivative thus obtained is carried out, for example, on the basis of the difference in solubility thereof, and the free coliform is separated from the solution of a suitable preparation Can be separated from the pure diastereomeric salt or derivative. Commonly used optically active acids include, for example, D-and L-form of tartaric acid or dibenzoyl tartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or queenic acid Lt; RTI ID = 0.0 > diastereomeric < / RTI > salts or derivatives. The optically active alcohol may be, for example, (+) or (-) - menthol, and the optically active acyl group in the amide may be, for example, (+) - or (-) - menthyloxycarbonyl. [113] In addition, the compounds of formula (I) can be converted into their salts, in particular pharmacologically acceptable salts with inorganic or organic acids, for pharmaceutical use. Acids that may be used for such purposes include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. [114] In addition, when the novel compounds of formula I thus obtained contain carboxy, hydroxyporphoryl, sulfo or 5-tetrazolyl groups, they can subsequently be reacted with an inorganic or organic base In particular for pharmacological use, in the form of their pharmaceutically acceptable salts. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexyl-amine, ethanolamine, diethanolamine and triethanolamine. [115] The compounds of formulas (II) to (V) used as starting materials are known in some cases from the literature and can be obtained by methods known from the literature (see Examples I to VII). [116] For example, the starting compounds of formula (I) may be obtained by reacting a correspondingly substituted 7-fluoro-6-nitro compound at the 4-position with the corresponding alkoxide and then reducing the nitro compound thus obtained, [117] The starting compound of formula (IV) is obtained by reacting the correspondingly substituted 7-fluoro-6-nitro compound with the corresponding alkoxide at the 4-position, then reducing the thus obtained nitro compound and then acylating the corresponding compound . [118] As already mentioned above, the compounds of formula (I) according to the invention and their pharmacologically acceptable salts have valuable pharmaceutical properties and are especially suitable for the inhibition of signal transduction mediated by epithelial growth factor receptor (EGF-R) While it may be achieved, for example, by inhibiting ligand binding, receptor dimerization or tyrosine kinase itself. It may also block the transmission of signals to the components located below. [119] The biological properties of the novel compounds were studied as follows: [120] Inhibition of EGF-R-mediated signaling is indicated, for example, using cells expressing human EGF-R and dependent on stimulation by EGF or TGF-alpha dependent on survival and proliferation. Here, interleukin-3 (IL-3) dependent cell lines obtained from mice and genetically modified to express functional human EGF-R are used. Therefore, proliferation of these cells known as F / L-HERC can be stimulated by murine IR-3 or EGF (see von Ruden, T. et al. in EMBO J. 7 , 2749-2756 (1988) and Pierce, JH et al. in Scien-ce 239 , 628-631 (1988)]. [121] The starting material used for F / L-HERc cells is the cell line FDC-P 1 , the preparation of which is described in the literature (Dexter, TM et al. in J. Exp. Med. 152, 1036-1047 (1980). However, other growth factor dependent cells may also be used instead [Pierce, JH et al. in Science 239 , 628-631 (1988), Shibuya, H. et al. in Cell 70 , 57-67 (1992) and Alexander, WS et al. in EMBO J. 10 , 3683-3691 (1991)]. To express human EGF-R cDNA [Ull-rich, A. et al. in Nature 309 , 418-425 (1984)], recombinant retroviruses were used as described in von Ruden, T. et al., EMBO J. 7 , 2749-2756 (1988) The viral vector LXSN (Miller, AD et al. in BioTechniques 7 , 980-990 (1989)) was used for the expression of EGF-R cDNA and the cell line GP + E86 (Markowitz, D. et al. in J. Virol. 62 , 1120-1124 (1988)] is used as a packaging cell. [122] The test is performed as follows: [123] F / L-HERc cells were cultured in RPMI / 1640 medium (Bio-Whittaker) and cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng / ml human EGF Promega) to be supplied at 37 ℃ and 5% CO 2. To investigate the inhibitory activity of the compounds according to the invention, 1.5 x 10 4 cells per well were cultured in triplicate in 96-well dishes in the medium (200 μl) and cell proliferation was induced by EGF (20 ng / ml) Stimulate with IL-3. The IL-3 used is obtained from the supernatant of the culture of cell line X63 / 0 mIL-3 (see Karasuyama, H. et al. In Eur. J. Immunol. 18 , 97-104 (1988)]. The compounds according to the invention are dissolved in 100% dimethylsulfoxide (DMSO) and added to variously diluted cultures, with a maximum DMSO concentration of 1%. The cultures are incubated at 37 ° C for 48 hours. [124] To measure the inhibitory activity of the compounds according to the invention, the relative cell number is determined in OD units using a cell titrator (Cell Titer 96 TM ) aqueous radioactive inactivation cell proliferation assay ((Promega) (Inhibitor free F / LHERc cells), from which the concentration of active substance (IC 50 ) inhibiting cell proliferation by 50% is derived. The following results are obtained: [125] The compound (Example No.)Inhibition of EGF-dependent proliferation IC 50 [nMm] One<0.35 2 (3)0.35 1 (7)<0.5 35 3 (1)0.2 [126] Thus, the compounds of formula (I) according to the invention inhibit signal transduction by tyrosine kinases as described by way of example of human EGF receptors and are therefore useful for the treatment of pathophysiologic progression caused by the hyperactivity of tyrosine kinases . These include, for example, benign or malignant tumors, especially tumors originating from the epithelium and neuroepithelium, metastasis and abnormal proliferation of vascular endothelial cells (neovascularization). [127] The compounds according to the present invention are useful in the treatment of diseases of the airways and lungs which are accompanied by proliferation or transformation of mucous membranes induced by stimulation of tyrosine kinases such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchial, allergic or non- Rhinitis or sinusitis, cystic fibrosis, α1-antitrypsin deficiency, or inflammatory diseases of the airways such as cough, lung-evading species, pulmonary fibrosis and hyperactive respiratory tract. [128] The compounds may also be used for the treatment of diseases which may be found in chronic inflammatory disorders such as gastrointestinal, biliary and gallicular diseases associated with the activity of tyrosine kinases such as, for example, cholecystitis, Crohn's disease, ulcerative colitis and ulcers in the gastrointestinal tract, For example, in diseases of the gastrointestinal tract associated with increased secretion, such as erosion, erosion, and protein loss. [129] In addition, the compounds of formula (I) and their pharmacologically acceptable salts can be used for the treatment of other diseases caused by the abnormal action of tyrosine kinases such as, for example, epithelial hyperproliferation (psoriasis), inflammation, immune system diseases, ≪ / RTI > [130] Due to their biological properties, the compounds according to the invention may be administered alone or in combination with other pharmaceutically active compounds, e. G. Compounds which are active in tumor therapy, in monotherapy or with other antitumor agents, A compound that interacts with a nucleic acid (e.g., cis-platin, cyclopurfamide, adriamycin), a hormone antagonist (e.g., tamoxifen, such as tamoxifen), a mitotic inhibitor (e.g., etoposide), a mitotic inhibitor ), Metabolic inhibitors (such as 5-FU), cytokines (such as interferon), antibodies, and the like. To treat airway diseases, the compounds may be used alone or in combination with other airway therapeutics, such as active substances. To treat diseases in the gastrointestinal tract, these compounds may also be administered alone or in combination with substances that affect exercise or secretion. These combinations may be administered simultaneously or sequentially. [131] These compounds may be administered intravenously, subcutaneously, intramuscularly, intranasally or alone, or in combination with other active substances, for inhalation, transdermal or oral administration, but aerosol formulations are particularly suitable for inhalation. [132] For use as a medicament, the compounds according to the invention are usually used in a dose of 0.01 to 100 mg / kg, preferably 0.1 to 15 mg / kg, per kg of body weight in warm-blooded animals, especially humans. In order to administer these compounds, they may be formulated with one or more conventional inert carriers and / or diluents, for example, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, Such as tablets, coated tablets, capsules or tablets with water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances , Powders, suspensions, solutions, sprays or suppositories. [133] The following examples are provided to illustrate the present invention, but the present invention is not limited thereto. [134] Preparation of starting compounds: [135] Example I [136] Amino-7- [3- (1-methyl-piperidin-4-yl) propyloxy] - quinazoline [137] 1.00 g of 4 - [(3-bromophenyl) amino] -7- [3- (1 -methyl-piperidin-4-yl) propyloxy] -6-nitro- quinazoline were dissolved in 16 ml of water, Dissolved in 1.3 ml of glacial acetic acid and heated to boiling. 540 mg of iron powder is added with stirring. The reaction mixture is refluxed for about 35 minutes. During the post-treatment, the cooled reaction mixture is diluted with 15 ml of ethanol, alkalized using 15 N sodium hydroxide solution and combined with 20 g of Extrelute for about 20 minutes. The precipitate formed is filtered off with suction and washed with 200 ml of warm ethanol. The filtrate is concentrated by evaporation, mixed with about 30 ml of water and extracted three times with 70 ml of methylene chloride / methanol (9: 1) each time. The combined extracts are dried over sodium sulfate and concentrated by evaporation to give a beige solid. [138] Yield: 716 mg (76% of theory). [139] Melting point: 191-198 占 폚. [140] Mass spectrum (ESI + ) + 470, 472 [M + H] < + >. [141] The following compounds are similarly obtained according to Example I: [142] (1) 6-Amino-4 - [(3-bromophenyl) amino] -7- [2- (1- methyl- piperidin- 4- yl) ethoxy] -quinazoline [143] Melting point: 197 캜. [144] Mass spectrum (ESI + ): m / z = 456, 458 [M + H] < + & [145] (2) 6-Amino-4 - [(3-bromophenyl) amino] -7 - [(1- methyl- piperidin- 4- yl) methoxy] -quinazoline [146] Melting point: 207-208 ° C [147] Mass spectrum (ESI + ): m / z = 442, 444 [M + H] < + & [148] (3) Synthesis of 6-amino-4 - [(3-bromophenyl) amino] -7 - [(1- methyl- piperidin- 4- yl) oxy] -quinazoline [149] Melting point: 170 DEG C [150] Mass spectrum (ESI + ): m / z = 428, 430 [M + H] < + & [151] (4) Synthesis of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopropyl-methoxy-quinazoline [152] Melting point: 209 DEG C [153] Rf value: 0.68 (silica gel, ethyl acetate) [154] (5) 6-Amino-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyl-oxy-quinazoline [155] Rf value: 0.32 (silica gel, cyclohexane / ethyl acetate = 3: 4) [156] Mass spectrum (ESI + ): m / z = 359, 361 [M + H] < + & [157] (6) Synthesis of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopentyloxy-quinazoline [158] Rf value: 0.33 (silica gel, cyclohexane / ethyl acetate = 1: 1) [159] Mass spectrum (ESI + ): m / z = 373, 375 [M + H] < + & [160] (7) 6-Amino-4 - [(R) - (1-phenyl- ethyl) amino] -7- cyclobutyloxyquinazoline [161] Rf value: 0.28 (silica gel, ethyl acetate) [162] Mass spectrum (ESI + ): m / z = 335 [M + H] < + & [163] (8) Synthesis of 6-amino-4 - [( R ) - (1-phenyl- ethyl) amino] -7-cyclopropylmethoxyquinazoline [164] Rf value: 0.54 (silica gel, ethyl acetate) [165] Mass spectrum (ESI + ): m / z = 335 [M + H] < + & [166] (9) Synthesis of 6-amino-4 - [( R ) - (1-phenyl- ethyl) amino] -7-cyclopentyloxyquinazoline [167] Rf value: 0.20 (silica gel, ethyl acetate) [168] Mass spectrum (ESI + ): m / z = 349 [M + H] < + & [169] (10) Synthesis of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (1 -methyl-piperidin- 4- yl) propyloxy] -quinazoline [170] R f value: 0.12 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [171] Mass spectrum (ESI + ): m / z = 444, 446 [M + H] < + & [172] (11) Synthesis of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(tetrahydrofuran-2-yl) methoxy] [173] Melting point: 162-164 DEG C [174] Rf value: 0.55 (silica gel, ethyl acetate / methanol = 9: 1) [175] Mass spectrum (ESI -): m / z = 387, 389 [MH] - [176] (12) Synthesis of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [( S ) - (tetrahydrofuran-3-yl) oxy] [177] Rf value: 0.27 (silica gel, ethyl acetate / methanol = 9: 1) [178] Mass spectrum (ESI -): m / z = 373, 375 [MH] - [179] (13) Synthesis of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(tetrahydropyran-4-yl) oxy] [180] Rf value: 0.41 (silica gel, ethyl acetate / methanol = 9: 1) [181] Mass spectrum (ESI -): m / z = 387, 389 [MH] - [182] (14) Synthesis of 6-amino-4 - [( R ) - (1-phenyl- ethyl) amino] -7- [2- (azetidin- l-yl) -ethoxy] -quinazoline [183] R f value: 0.37 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [184] Mass spectrum (ESI + ): m / z = 364 [M + H] < + & [185] (15) To a solution of 6-amino-4 - [( R ) - (1-phenyl- ethyl) amino] -7- [2- (4-methyl-perhydro- Lt; / RTI > [186] R f value: 0.10 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 1) [187] Mass spectrum (ESI + ): m / z = 421 [M + H] < + & [188] (16) Synthesis of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (4-methyl-perhydro- Oxy] -quinazoline [189] R f value: 0.09 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [190] Mass spectrum (ESI + ): m / z = 459, 461 [M + H] < + & [191] (17) Synthesis of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (azetidin- l-yl) -propyloxy] -quinazoline [192] R f value: 0.11 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [193] Mass spectrum (ESI + ): m / z = 402, 404 [M + H] < + > [194] Example II [195] Amino] -7- [3- (1 -methyl-piperidin-4-yl) propyl-oxy] -6-nitro-quinazoline [196] To a solution of 3- (1-methyl-piperidin-4-yl) -propan-1-ol in 40 ml of tetrahydrofuran is added 360 mg of sodium hydride. The resulting white suspension was stirred at 65 < 0 > C for 15 minutes, cooled and then mixed with 4 - [(3-bromophenyl) -amino] -7-fluoro-6-nitro- quinazoline, . The reaction mixture is first stirred at ambient temperature for 10 minutes and then at 65 < 0 > C for 45 minutes. As the reaction is not yet complete, 150 mg of additional sodium hydride are added and the mixture is stirred for an additional 45 minutes at 65 < 0 > C. The solvent was distilled off using a rotary evaporator, and the brown residue was stirred with 50 ml of ice water. The aqueous phase is extracted with methylene chloride. The combined extracts are washed with water, dried with sodium sulfate and concentrated by evaporation. The crude product is purified by chromatography on a silica gel column using a methylene chloride / methanol / concentrated ammonia solution (90: 10: 0.05). [197] Yield: 1.30 g (65% of theory), [198] Rf value: 0.28 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [199] Mass spectrum (ESI + ): m / z = 500, 502 [M + H] < + & [200] The following compounds are prepared in a manner analogous to Example II: [201] (1) 4- [(3-bromophenyl) amino] -7- [2- (1 -methyl- piperidin- 4- yl) -ethoxy] -6-nitro- quinazoline [202] Melting point: 152 캜 [203] Mass spectrum (ESI + ): m / z = 486, 488 [M + H] < + & [204] (2) Synthesis of 4 - [(3-bromophenyl) amino] -7 - [(1 -methyl- piperidin- 4- yl) -methoxy] -6-nitro-quinazoline [205] Melting point: 205-207 ° C [206] Mass spectrum (ESI + ): m / z = 472, 474 [M + H] < + & [207] (3) Synthesis of 4 - [(3-bromophenyl) amino] -7 - [(1 -methyl- piperidin- 4- yl) oxy] -6- [208] Melting point: 219 DEG C [209] Mass spectrum (ESI + ): m / z = 458, 460 [M + H] < + & [210] (4) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6-nitro- quinazoline (using potassium tert-butoxide as the base in dimethylformamide ) [211] Melting point: 211-213 DEG C [212] Mass spectrum (ESI + ): m / z = 389, 391 [M + H] < + & [213] (5) 4 - [(3-Chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6-nitro-quinazoline (carried out in dimethylformamide using potassium tert- do) [214] Melting point: 235 DEG C [215] Rf value: 0.65 (silica gel, cyclohexane / ethyl acetate = 3: 4) [216] (6) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopentyloxy-6-nitro- quinazoline (carried out in dimethylformamide using potassium tert- do) [217] Melting point: 230 캜 [218] Mass spectrum (ESI + ): m / z = 403, 405 [M + H] < + & [219] (7) Preparation of 4 - [( R ) - (1-phenyl-ethyl) amino] -7-cyclobutyloxy-6-nitro- quinazoline (carried out in dimethylformamide using potassium tert- do) [220] Melting point: 108-110 DEG C [221] Rf value: 0.54 (silica gel, ethyl acetate) [222] (8) Synthesis of 4 - [( R ) - (1-phenyl-ethyl) amino] -7-cyclopropylmethoxy-6-nitro- quinazoline (using potassium tert-butoxide as the base in dimethylformamide ) [223] Melting point: 155 캜 [224] Rf value: 0.24 (silica gel, cyclohexane / ethyl acetate = 1: 1) [225] (9) A mixture of 4 - [( R ) - (1-phenyl- ethyl) amino] -7-cyclopentyloxy-6-nitro-quinazoline (carried out in dimethylformamide using potassium tert- do) [226] Rf value: 0.24 (silica gel, petroleum ether / ethyl acetate = 1: 1) [227] Mass spectrum (ESI + ): m / z = 379 [M + H] < + & [228] (10) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7- [3- (1-methyl- piperidin- 4- yl) propyloxy] -quinazoline [229] R f value: 0.30 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [230] Mass spectrum (ESI + ): m / z = 474, 476 [M + H] < + & [231] (11) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(tetrahydrofuran-2-yl) methoxy] -6-nitro- quinazoline Side < / RTI > in dimethylformamide) [232] Rf value: 0.47 (silica gel, ethyl acetate) [233] Mass spectrum (ESI -): m / z = 417, 419 [MH] - [234] (12) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [( S ) - (tetrahydrofuran-3-yl) oxy] -6-nitro- quinazoline Lt; / RTI > is carried out in dimethylformamide using < RTI ID = 0.0 > [235] Rf value: 0.45 (silica gel, ethyl acetate) [236] Mass spectrum (ESI -): m / z = 403, 405 [MH] - [237] (13) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7 - [(tetrahydropyran-4-yl) oxy] -6-nitro- quinazoline (potassium tert- Lt; / RTI > in dimethylformamide) [238] Rf value: 0.41 (silica gel, ethyl acetate) [239] Mass spectrum (ESI -): m / z = 417, 419 [MH] - [240] (14) Synthesis of 4 - [( R ) - (1-phenyl-ethyl) amino] -7- [2- (tetrahydropyran- 2- yloxy) -ethoxy] -6-nitro-quinazoline [241] Rf value: 0.12 (silica gel, cyclohexane / ethyl acetate = 1: 1) [242] Mass spectrum (ESI + ): m / z = 439 [M + H] < + & [243] (15) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7- {3 - [(tert- butyldimethylsilyl) oxy] -propyloxy} -6-nitro- quinazoline Is carried out in dimethylformamide using potassium tert-butoxide as potassium tert-butoxide) [244] R f value: 0.87 silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [245] Mass spectrum (ESI + ): m / z = 507, 509 [M + H] < + & [246] Example III [247] 4 - [(R) - (1-phenyl-ethyl) amino] -6-nitro-7-fluoro- quinazoline [248] Chloro-6-nitro-7-fluoro-quinazoline in 800 ml of methylene chloride is added dropwise to a solution of 74 ml of ( R ) -1-phenyl- ethylamine in 100 ml of dioxane. The reaction mixture is stirred at room temperature overnight, then washed with water, the organic phase is separated off, dried and evaporated. The obtained residue is purified by chromatography on a silica gel column (petroleum ether / ethyl acetate = 1: 1). [249] Yield: 52.9 g (35% of theory), [250] Melting point: 203 DEG C [251] Mass spectrum (ESI + ): m / z = 313 [M + H] < + & [252] Example IV [253] 4-[( R) - (l-phenyl-ethyl) amino] -7- [2- (azetidin- l-yl) -ethoxy] -6-nitro- quinazoline [254] 221 mg of dried potassium carbonate and 50 mg of sodium iodide are added to a solution of 4 - [( R ) - (1-phenyl- ethyl) amino] -7- [2-methanesulfonyloxy-ethoxy] 600 mg of quinazoline and 0.34 ml of azetidine. The reaction mixture is heated to 70 < 0 > C with stirring. Subsequently, 3 ml of acetonitrile are added after 1 hour, and the mixture is stirred for another 40 minutes at 70 < 0 > C. The solvent is removed in vacuo and the residue obtained is mixed with ice water. The precipitate is filtered by suction and dried. The aqueous phase is extracted with methylene chloride and evaporated. The combined precipitates are dissolved in ethyl acetate and further precipitated by stirring with a small amount of silica gel and 120 mg of charcoal. The resulting suspension is filtered and evaporated to give a yellow resin. [255] Yield: 518 mg (95% of theory), [256] R f value: 0.40 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [257] Mass spectrum (ESI + ): m / z = 394 [M + H] < + & [258] The following compounds are obtained analogously to Example IV: [259] (1) Synthesis of 4 - [( R ) - (1-phenyl-ethyl) amino] -7- [2- (4-methyl-perhydro- - Nitro-quinazoline [260] R f value: 0.30 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [261] Mass spectrum (ESI + ): m / z = 451 [M + H] < + & [262] (2) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (4-methyl- perhydro- 1, 4-diazepin- - Nitro-quinazoline [263] R f value: 0.34 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 80: 20: 0.1) [264] Mass spectrum (ESI + ): m / z = 489, 491 [M + H] < + & [265] (3) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (azetidin- 1 -yl) -propyloxy] -6-nitro-quinazoline [266] R f value: 0.23 silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [267] Mass spectrum (ESI + ): m / z = 432, 434 [M + H] < + & [268] Example V [269] 4-[( R) - (l-phenyl-ethyl) amino] -7- [2- (methanesulfonyloxy) -ethoxy] -6-nitro- quinazoline [270] A solution of 1.79 ml of methanesulfonic acid chloride in 10 ml of methylene chloride is added to a solution of 4 - [( R ) - (1-phenyl- ethyl) amino] -7- (2- hydroxy- Quinazoline and 4.53 ml of ethyl diisopropylamine in an ice bath. The reaction mixture is stirred at room temperature for about 1 hour, and further 0.4 ml of methanesulfonic acid chloride and 0.5 ml of ethyldiisopropylamine are added to terminate the reaction. Subsequently, the reaction mixture is mixed with ice water, and a saturated aqueous solution of sodium carbonate is added thereto, followed by stirring. The organic phase is separated and washed with water, dried over magnesium sulfate and evaporated. The resulting dark colored resin residue is crystallized by stirring with a very small amount of tert-butyl methyl ether, filtered by suction and dried in a drier. [271] Yield: 9,72 g (99% of theory), [272] Melting point: 128-134 DEG C [273] Mass spectrum (ESI -): m / z = 431 [MH] - [274] The following compounds are obtained analogously to Example V: [275] (1) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (methanesulfonyloxy) -propyloxy] -6-nitro-quinazoline [276] R f value: 0.75 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [277] Mass spectrum (ESI + ): m / z = 471, 473 [M + H] < + & [278] Example VI [279] 4-[( R) - (l -phenyl-ethyl) amino] -7- (2-hydroxy-ethoxy) -6-nitro-quinazoline [280] 120 ml of methanol and 2 ml of concentrated hydrochloric acid are added to a solution of 4 - [( R ) - (1-phenyl-ethyl) amino] -7- [2- (tetrahydropyran- 2- yloxy) -ethoxy] . After stirring at 50 < 0 > C for 1.5 hours, the reaction mixture is neutralized using a concentrated aqueous sodium carbonate solution and evaporated. The solid residue is dissolved in ethyl acetate and the resulting solution is washed with water, washed with a concentrated aqueous sodium chloride solution, dried over magnesium sulfate solution and evaporated. The resulting yellow residue was stirred with 20 ml of tert-butyl methyl ether, filtered by suction, and then dried in a drier. [281] Yield: 4.53 g (91% of theory), [282] Melting point: 192-194 DEG C [283] Mass spectrum (ESI -): m / z = 353 [MH] - [284] Example VII [285] 4- [(3-chloro-4-fluorophenyl) amino] -7- (3-hydroxy- propyloxy) -6- [286] (3-chloro-4-fluorophenyl) amino] -7- {3 - [(tert-butyldimethylsilyloxy) ethyl] ethyl chloride was obtained by separating the protecting silyl group using tetrabutylammonium fluoride in tetrahydrofuran. Silyl) oxy] -propyloxy} -6-nitro-quinazoline. [287] Yield: 94% of theory, [288] R f value: 0.61 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [289] Mass spectrum (ESI -): m / z = 391, 393 [MH] - [290] Preparation of the final product: [291] Example 1 [292] 4 - [(3-bromophenyl) amino] -7- [3- (1 -methyl- piperidin-4- yl) propyl- oxy] -6 - [(vinylcarbonyl) amino] -quinazoline [293] To a solution of 300 mg of 6-amino-4 - [(3-bromophenyl) amino] -7- [3- (1-methyl- piperidin- 4- yl) propyloxy] -quinazoline in 7 ml of dichloromethane 0.28 ml of triethylamine is added. The reaction mixture is cooled in ice / sodium chloride cold bath to about -10 < 0 > C. Then a solution of 59 [mu] l of acrylic acid chloride in 1 ml of tetrahydrofuran is added dropwise within 10 min. The cold bath is removed and the mixture is stirred at ambient temperature for an additional 15 minutes. During the post-treatment, the reaction mixture is poured into 20 ml of ice water and mixed with 2 to 3 ml of 2N sodium hydroxide solution to form a bright colored precipitate. The precipitate is filtered off with suction, washed with ice water, and then dissolved in dichloromethane. The solution is dried with sodium sulfate and concentrated by evaporation. The resinous crude product is purified by chromatography on silica gel using methylene chloride / methanol / concentrated ammonia solution (90: 10: 0.5). [294] Yield: 118 mg (35% of theory) [295] R f value: 0.35 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [296] Mass spectrum (ESI + ): m / z = 524, 526 [M + H] < + & [297] The following compounds are obtained analogously to Example 1: [298] (1-methyl-piperidin-4-yl) -ethoxy] -6 - [(vinylcarbonyl) amino] - Quinazoline [299] Melting point: 129 占 폚 [300] Mass spectrum (ESI + ): m / z = 510, 512 [M + H] < + > [301] (2-methyl-piperidin-4-yl) methoxy] -6 - [(vinylcarbonyl) amino] [302] Melting point: 174 DEG C [303] Mass spectrum (ESI + ): m / z = 496, 498 [M + H] < + & [304] (3) Synthesis of 4 - [(3-bromophenyl) amino] -7 - [(1 -methyl- piperidin-4- yl) oxy] -6 - [(vinylcarbonyl) amino] -quinazoline [305] Melting point: 166 DEG C [306] Mass spectrum (ESI + ): m / z = 482, 484 [M + H] < + & [307] (4-methyl-piperidin-4-yl) oxy] -6 - [(1-oxo-2-buten- ) Amino] -quinazoline [308] R f value: 0.67 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 40: 10: 0.5) [309] Mass spectrum (ESI + ): m / z = 496, 498 [M + H] < + & [310] (5-methyl-piperidin-4-yl) methoxy] -6 - [(1-oxo-2-butene- Yl) amino] - quinazoline [311] R f value: 0.45 (aluminum oxide, activity III; ethyl acetate / methanol = 4: 1) [312] Mass spectrum (EI): m / z = 509, 511 [M] < + & [313] 6- (3-ethoxycarbonyl-amino) -7- [3- (1-methyl-piperidin- 1-oxo-2-propen-1-yl) amino] - quinazoline [314] Rf value: 0.28 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [315] Mass spectrum (ESI + ): m / z = 596, 598 [M + H] < + & [316] (7) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (1- methylpiperidin- Amino] -quinazoline [317] Rf value: 0.33 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [318] Mass spectrum (ESI + ): m / z = 498, 500 [M + H] < + & [319] (8) Synthesis of 4 - [( R ) - (1-phenylethyl) amino] -7- [2- (azetidin- 1 -yl) -ethoxy] -6 - [(vinylcarbonyl) amino] Sleepy [320] R f value: 0.60 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [321] Mass spectrum (ESI -): m / z = 416 [MH] - [322] (9) Synthesis of 4 - [( R ) - (1-phenyl- ethyl) amino] -7- [2- (4-methyl-perhydro- 1, 4-diazepin- - [(vinylcarbonyl) amino] -quinazoline [323] R f value: 0.37 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [324] Mass spectrum (ESI -): m / z = 473 [MH] - [325] (10) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (4-methyl- perhydro- - [(vinylcarbonyl) -amino] -quinazoline [326] R f value: 0.29 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [327] Mass spectrum (ESI + ): m / z = 513, 515 [M + H] < + & [328] (11) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (azetidin- 1 -yl) -propyloxy] -6 - [(vinylcarbonyl) amino] Sleepy [329] R f value: 0.39 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 90: 10: 0.1) [330] Mass spectrum (ESI -): m / z = 454, 456 [MH] - [331] Example 2 [332] 4 - [(3-bromophenyl) amino] -7- [3- (1 -methyl-piperidin- Yl) amino] - < / RTI > quinazoline [333] To 31 mg of sorbic acid in 1 ml of tetrahydrofuran is added 40 μl of isobutyl chloroformate followed by 45 μl of N-methylmorpholine, followed by cooling with an ice bath. The white suspension was stirred for 1 min and then a solution of 6-amino-4 - [(3-bromophenyl) amino] -7- [3- (1-methyl-piperidin- Oxy] - < / RTI > quinazoline. The ice bath is removed and the reaction mixture is stirred overnight. During the post-treatment, 20 ml of ice water are poured, stirred for 30 minutes and then adjusted to pH 9-10 using a few drops of 2N sodium hydroxide solution. The aqueous phase is extracted with methylene chloride and the combined organic phases are dried over sodium sulfate and concentrated by evaporation. The resinous crude product is purified by chromatography on an aluminum oxide column (activity III) using methylene chloride / methanol (99.5: 0.5). [334] Yield: 62 mg (52% of theory), [335] R f value: 0.29 (aluminum oxide, activity III; methylene chloride / methanol = 98: 2) [336] Mass spectrum (EI): m / z = 563, 565 [M] < + & [337] The following compounds are obtained analogously to Example 2: [338] (1-methyl-piperidin-4-yl) -propyloxy] -6 - [(1-oxo-2-butene) Yl) amino] - < / RTI > quinazoline [339] R f value: 0.26 (aluminum oxide, activity III; methylene chloride / methanol = 98: 2) [340] Mass spectrum (ESI + ): m / z = 538, 540 [M + H] < + & [341] (2-methyl-piperidin-4-yl) -propyloxy] -6 - [(3-phenyl- Yl) amino] - < / RTI > quinazoline [342] R f value: 0.26 (aluminum oxide, activity III; methylene chloride / methanol = 98: 2) [343] Mass spectrum (EI): m / z = 599, 601 [M] < + & [344] (3-methyl-piperidin-4-yl) -propyloxy] -6 - [(1-oxo-2-butyne) Yl) amino] - < / RTI > quinazoline [345] R f value: 0.40 (aluminum oxide, activity III; methylene chloride / methanol = 98: 2) [346] Mass spectrum (ESI + ): m / z = 536, 538 [M + H] < + & [347] Example 3 [348] Amino] -6- {[4- (N, N-diethylamino) -1-oxo-2-buten- Cyclopropylmethoxy-quinazoline [349] To a solution of 640 mg of 4-bromo-2-butenoic acid in 10 ml of methylene chloride is added 0.67 ml of oxalyl chloride and one drop of dimethylformamide at ambient temperature. The reaction mixture is stirred at ambient temperature for about 30 minutes until gas evolution ceases. The formed acid chloride is treated in a rotary evaporator under vacuum to substantially remove the solvent. The crude product was then dissolved in 10 ml of methylene chloride and added dropwise to a solution of 6-amino-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy- Is added dropwise to a mixture of 1.00 g of quinazoline and 1.60 ml of Fynidine base. The reaction mixture is stirred for 1.5 hours in an ice bath and at ambient temperature for a further 2 hours. Then 2.90 ml of diethylamine are added and the mixture is stirred at ambient temperature for 2.5 days. For work-up, the reaction mixture is filtered and the filtrate is concentrated by evaporation. The filtrate residue is purified by chromatography on silica gel using ethyl acetate / methanol (19: 1). [350] Yield: 550 mg (40% of theory), [351] Melting point: 114 占 폚 [352] Mass spectrum (ESI + ): m / z = 498, 500 [M + H] < + & [353] The following compounds are obtained analogously to Example 3: [354] (1) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin- 7-Cyclopropylmethoxy-quinazoline [355] Rf value: 0.53 (silica gel, ethyl acetate / methanol = 9: 1) [356] Mass spectrum (ESI -): m / z = 510, 512 [MH] - [357] (2) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (4-ethyl-piperazin- ] Amino} -7-cyclopropylmethoxy-quinazoline [358] Rf value: 0.44 (silica gel, ethyl acetate / methanol / aqueous concentrated ammonia solution = 9: 1: 0.1) [359] Mass spectrum (EI): m / z = 538, 540 [M] < + & [360] (3) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (2,6- -Yl] amino} -7-cyclopropylmethoxy-quinazoline [361] Melting point: 160 캜 [362] Mass spectrum (ESI + ): m / z = 540, 542 [M + H] < + & [363] (4) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (dimethylamino) -1- Methoxy-quinazoline [364] Melting point: 137 캜 [365] Mass spectrum (ESI + ): m / z = 470, 472 [M + H] < + & [366] (5) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (1-oxydido-thiomorpholin- -Yl] amino} -7-cyclopropylmethoxy-quinazoline [367] Melting point: 239 DEG C [368] Mass spectrum (ESI + ): m / z = 544, 546 [M + H] < + & [369] (6) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin- 7-Cyclobutyloxy-quinazoline [370] R f value: 0.45 (silica gel, ethyl acetate / methanol = 9: 1) [371] Mass spectrum (ESI + ): m / z = 512, 514 [M + H] < + & [372] (7) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin- 7-Cyclopentyloxy-quinazoline [373] Melting point: 143 캜 [374] R f value: 0.45 (silica gel, ethyl acetate / methanol = 9: 1) [375] (8) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) Butyloxy-quinazoline [376] Melting point: 111 DEG C [377] Rf value: 0.21 (silica gel, ethyl acetate / methanol = 9: 1) [378] (9) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) Pentyloxy-quinazoline [379] Melting point: 105 DEG C [380] Rf value: 0.23 (silica gel, ethyl acetate / methanol = 9: 1) [381] (10) 4 - [( R ) - (1-phenyl-ethyl) amino] -6 - {[4- (morpholin- 7-Cyclobutyloxy-quinazoline [382] Rf value: 0.33 (silica gel, ethyl acetate / methanol = 9: 1) [383] Mass spectrum (ESI + ): m / z = 488 [M + H] < + & [384] (11) 4 - [(R ) - (1- phenyl-ethyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} - 7-Cyclopropylmethoxy-quinazoline [385] Rf value: 0.37 (silica gel, ethyl acetate / methanol = 9: 1) [386] Mass spectrum (ESI + ): m / z = 488 [M + H] < + & [387] (12) 4 - [(R ) - (1- phenyl-ethyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} - 7-Cyclopentyloxy-quinazoline [388] Rf value: 0.35 (silica gel, ethyl acetate / methanol = 9: 1) [389] Mass spectrum (ESI + ): m / z = 502 [M + H] < + & [390] (13) Synthesis of 4 - [( R ) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) Butyloxy-quinazoline [391] Rf value: 0.26 (silica gel, ethyl acetate / methanol = 4: 1) [392] Mass spectrum (ESI + ): m / z = 474 [M + H] < + & [393] (14) Synthesis of 4 - [( R ) - (1-phenyl-ethyl) amino] -6 - {[4- (diethylamino) Pentyloxy-quinazoline [394] Rf value: 0.31 (silica gel, ethyl acetate / methanol = 4: 1) [395] Mass spectrum (ESI + ): m / z = 488 [M + H] < + & [396] (15) Synthesis of 4 - [( R ) - (1-phenylethyl) amino] -6 - {[4- (diethylamino) Propylmethoxy-quinazoline [397] Rf value: 0.15 (silica gel, ethyl acetate / methanol = 9: 1) [398] Mass spectrum (ESI + ): m / z = 474 [M + H] < + & [399] (16) 4 - [(3-chloro-4-fluorophenyl) amino] -6- Oxo-2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline [400] Rf value: 0.28 (silica gel, ethyl acetate / methanol / aqueous concentrated ammonia solution = 80: 20: 2) [401] Mass spectrum (ESI + ): m / z = 553, 555 [M + H] < + & [402] (17) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [( R ) -2- methoxy- methyl- pyrrolidin- 1 -yl] Yl} amino) -7-cyclopropylmethoxy-quinazoline < / RTI > [403] Rf value: 0.33 (silica gel, ethyl acetate / methanol = 9: 1) [404] Mass spectrum (ESI + ): m / z = 540, 542 [M + H] < + & [405] (18) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4 - [( S ) -2-methoxy- methyl-pyrrolidin- 1 -yl] Yl} amino) -7-cyclopropylmethoxy-quinazoline < / RTI > [406] Melting point: 120 占 폚 [407] Mass spectrum (ESI + ): m / z = 540, 542 [M + H] < + & [408] (19) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [bis- (2-methoxy- -Yl} amino) -7-cyclopropylmethoxy-quinazoline < / RTI > [409] Rf value: 0.51 (silica gel, ethyl acetate / methanol = 9: 1) [410] Mass spectrum (ESI + ): m / z = 558, 560 [M + H] < + & [411] (20) 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N- ethyl- N- (2- methoxyethyl) Yl} amino) -7-cyclopropylmethoxy-quinazoline < / RTI > [412] Rf value: 0.33 (silica gel, ethyl acetate / methanol = 9: 1) [413] Mass spectrum (ESI + ): m / z = 528, 530 [M + H] < + & [414] Amino] -6- {[4- (piperidin-1-yl) -1-oxo-2-buten- -7-cyclopropylmethoxy-quinazoline < / RTI > [415] Rf value: 0.22 (silica gel, ethyl acetate / methanol = 9: 1) [416] Mass spectrum (ESI + ): m / z = 510, 512 [M + H] < + > [417] (22) 4- [(3-chloro-4-fluorophenyl) amino] -6- { Lt; RTI ID = 0.0 > amino} -7-cyclopropylmethoxy-quinazoline [418] Rf value: 0.21 (silica gel, ethyl acetate / methanol = 9: 1) [419] Mass spectrum (ESI + ): m / z = 524, 526 [M + H] < + & [420] Amino] -6- {[4- (pyrrolidin-1-yl) -1-oxo-2-buten- -7-cyclopropylmethoxy-quinazoline < / RTI > [421] Rf value: 0.10 (silica gel, ethyl acetate / methanol = 9: 1) [422] Mass spectrum (ESI + ): m / z = 496, 498 [M + H] < + & [423] (24) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- { 1-yl] amino} -7-cyclopropylmethoxy-quinazoline [424] Melting point: 117 DEG C [425] Mass spectrum (ESI + ): m / z = 565, 567 [M + H] < + & [426] (25) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- Lt; RTI ID = 0.0 > amino} -7-cyclopropylmethoxy-quinazoline [427] Melting point: 108-110 DEG C [428] Rf value: 0.27 (silica gel, ethyl acetate / methanol = 9: 1) [429] (26) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (tetrahydropyran- 2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline [430] Rf value: 0.29 (silica gel, ethyl acetate / methanol = 9: 1) [431] Mass spectrum (ESI -): m / z = 538, 540 [MH] - [432] (27) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (cis-2,6-dimethyl- piperidin- 1 -yl) But-1-yl] amino} -7-cyclopropylmethoxy-quinazoline [433] Rf value: 0.27 (silica gel, ethyl acetate / methanol = 9: 1) [434] Mass spectrum (ESI -): m / z = 536, 538 [MH] - [435] (28) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (2,5- 1-yl] amino} -7-cyclopropyl-methoxy-quinazoline [436] R f value: 0.36 (silica gel, ethyl acetate / methanol = 9: 1) [437] Mass spectrum (ESI -): m / z = 522, 524 [MH] - [438] (29) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) (Tetrahydrofuran-2-yl) methoxy] -quinazoline [439] R f value: 0.35 (silica gel, ethyl acetate / methanol / aqueous concentrated ammonia solution = 9: 1: 0.1) [440] Mass spectrum (ESI -): m / z = 526, 528 [MH] - [441] Amino] -6- {[4- (diethylamino) -1-oxo-2-buten- 1 -yl] amino} -7- [ ( S ) - (tetrahydrofuran-3-yl) oxy] - quinazoline [442] Melting point: 119 캜 [443] Mass spectrum (ESI -): m / z = 512, 514 [MH] - [444] (3-chloro-4-fluorophenyl) amino] -6- {[4- (4-diethylamino- methyl-piperidin- 1 -yl) But-1-yl] amino} -7-cyclopropylmethoxy-quinazoline [445] Rf value: 0.20 (silica gel, methylene chloride / methanol = 9: 1) [446] Mass spectrum (ESI -): m / z = 593, 595 [MH] - [447] (32) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- { -Yl] amino} -7-cyclopropylmethoxy-quinazoline [448] Rf value: 0.73 (silica gel, methylene chloride / methanol = 9: 1) [449] Mass spectrum (ESI + ): m / z = 510, 512 [M + H] < + > [450] (33) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (2- methoxypropyl) Yl) amino) -7-cyclopropylmethoxy-quinazoline (N-methyl-N- (2-methoxypropyl) -amine used is obtained by reacting 2-methoxypropionic acid chloride with methylamine , ≪ / RTI > lithium ammonium hydride) [451] Melting point: 123-125 DEG C [452] R f value: 0.66 (silica gel, methylene chloride / methanol = 9: 1) [453] (34) 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (3- methoxypropyl) But-1-yl} amino) -7-cyclopropylmethoxy-quinazoline [454] R f value: 0.66 (silica gel, methylene chloride / methanol = 9: 1) [455] Mass spectrum (ESI + ): m / z = 528, 530 [M + H] < + & [456] (3-chloro-4-fluorophenyl) amino] -6 - {[4- (4- methoxy- -Yl] amino} -7-cyclopropyl-methoxy-quinazoline [457] Melting point: 129-130 DEG C [458] Rf value: 0.20 (silica gel, ethyl acetate / methanol = 9: 1) [459] Mass spectrum (ESI -): m / z = 538, 540 [MH] - [460] (36) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- -Yl] amino} -7-cyclopropyl-methoxy-quinazoline [461] R f value: 0.30 (silica gel, methylene chloride / methanol / aqueous concentrated ammonia solution = 9: 1: 0.1) [462] Mass spectrum (ESI -): m / z = 524, 526 [MH] - [463] (37) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (diethylamino) (Tetrahydropyran-4-yl) oxy] - quinazoline [464] R f value: 0.47 (silica gel, methylene chloride / methanol = 9: 1) [465] Mass spectrum (ESI -): m / z = 528, 530 [MH] - [466] (38) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (tetrahydrofuran- Oxo-2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline [467] Melting point: about 145 캜 (decomposition) [468] Rf value: 0.23 (silica gel, methylene chloride / methanol = 15: 1) [469] Mass spectrum (ESI + ): m / z = 540, 542 [M + H] < + & [470] (39) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (tetrahydrofuran- (Starting material N-methyl-N- (3-tetrahydrofuranyl) -amine was prepared by reacting tetrahydrofuran-3-carboxylic acid with benzyl Is reacted with diphenylphosphonate azide in alcohol and then the obtained 3- (benzyloxycarbonylamino) -tetrahydrofuran is reduced with lithium aluminum hydride. [471] Melting point: 157-159 DEG C [472] Rf value: 0.23 (silica gel, methylene chloride / methanol = 15: 1) [473] Mass spectrum (ESI + ): m / z = 526, 528 [M + H] < + & [474] (40) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- Yl} amino) -7-cyclopropylmethoxy-quinazoline (starting material N-methyl-N- (1-methoxy-2- propyl) -amine was prepared by reacting methoxyacetone with methylamine hydrochloride Chloride and sodium triacetoxyborohydride in the presence of sodium acetate. This reaction is carried out in tetrahydrofuran) [475] Rf value: 0.38 (silica gel, ethyl acetate / methanol = 9: 1) [476] Mass spectrum (ESI + ): m / z = 528, 530 [M + H] < + & [477] The following compounds can also be obtained in analogy to the above examples and other methods known from the literature: [478] (1) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- -7-cyclopropylmethoxy-quinazoline; [479] (2) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dibutyl- } -7-cyclopropylmethoxy-quinazoline; [480] (3) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (piperidin- 1 -yl) -7-cyclopropylmethoxy-quinazoline; [481] (4) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (2,6- -Yl] amino} -7-cyclopropylmethoxy-quinazoline; [482] (5) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- ] Amino} -7-cyclopropylmethoxy-quinazoline < / RTI > [483] (6) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (4-cyclopropylmethyl-piperazin- -Yl] amino} -7-cyclopropyl-methoxy-quinazoline; [484] (7) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- Lt; / RTI > amino} -7-cyclopropylmethoxy-quinazoline; [485] (8) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (4-methylsulfonyl-piperazin- -Yl] amino} -7-cyclopropyl-methoxy-quinazoline; [486] (9) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (4-acetyl-piperazin- ] Amino} -7-cyclopropylmethoxy-quinazoline < / RTI > [487] (10) 4 - [(N, N-dimethylamino) carbonyl] -piperazin-1-yl} - Oxo-2-buten-l-yl) -amino] -7-cyclopropylmethoxy-quinazoline; [488] Amino] -6- {[4- (pyrrolidin- 1 -yl) -1-oxo-2-buten- 1 -yl] amino} -7-cyclopropylmethoxy-quinazoline; [489] (12) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl- Amino} -7-cyclopropylmethoxy-quinazoline < / RTI > [490] (13) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl- Lt; / RTI > amino} -7-cyclopropyl-methoxy-quinazoline; [491] (14) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- -7-cyclopropylmethoxy-quinazoline; [492] (15) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethyl- } -7-cyclopropylmethoxy-quinazoline; [493] (4-fluorophenyl) amino] -6 - {[4- (piperidin-1-yl) -7-cyclopropylmethoxy-quinazoline; [494] (17) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin- 7-Cyclopropylmethoxy-quinazoline; [495] (18) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- ] Amino} -7-cyclopropylmethoxy-quinazoline < / RTI > [496] (19) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (4-methylsulfonyl-piperazin- -Yl] amino} -7-cyclopropyl-methoxy-quinazoline; [497] (20) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin- Amino} -7-cyclopropylmethoxy-quinazoline < / RTI > [498] (21) 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- -Dioxo-2-buten-l-yl} amino] -7-cyclopropylmethoxy-quinazoline; [499] (22) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({2- -Yl} amino] -7-cyclopropylmethoxy-quinazoline < / RTI > [500] (23) A process for the preparation of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (2-methoxymethyl-pyrrolidin- 1 -yl) 1-yl] amino} -7-cyclopropylmethoxy-quinazoline; [501] (24) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N, N-bis (2- methoxyethyl) amino] 1 -yl} amino) -7-cyclopropylmethoxy-quinazoline; [502] (25) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N- (2-methoxy- But-1-yl} amino) -7-cyclopropylmethoxy-quinazoline; [503] (26) 4 - [(3-chloro-4-fluorophenyl) amino] -6- { -7-cyclobutylmethoxy-quinazoline; [504] Amino] -6-methyl-4- {N, N-dimethyl-amino) -7-cyclopentylmethoxy-quinazoline; [505] Amino] -6-methyl-4- {N, N-dimethyl-amino) -7-cyclohexylmethoxy-quinazoline; [506] (3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N- dimethyl- -7- (2-Cyclopropyl-ethoxy) -quinazoline; [507] (30) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- -7- (3-cyclopropyl-propyloxy) -quinazoline; [508] (31) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [4- (tetrahydrofuran- 3- yl) -piperidin- Oxo-2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline; [509] (32) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [4- (morpholin-4-yl) -piperidin- -2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline; [510] (33) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [4- (tetrahydrofuran- 3- yl) -piperazin- -2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline; [511] (34) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [4- (tetrahydrofuran- -Oxo-2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline; [512] (35) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - [(4- {N- methyl- N- [1- (tetrahydrofuran- 4-yl] -amino} -1-oxo-2-buten-l-yl) amino] -7-cyclopropylmethoxy-quinazoline; [513] (36) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4 - [( S ) -2- methoxymethyl-pyrrolidin- 1 -yl] 2-buten-l-yl} amino) -7-cyclobutyl-oxy-quinazoline; [514] (37) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4 - [( R ) -2- methoxymethyl-pyrrolidin- 2-buten-l-yl} amino) -7-cyclobutyl-oxy-quinazoline; [515] (38) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [bis- (2-methoxy- -Yl} amino) -7-cyclobutyloxy-quinazoline; [516] (39) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (2- methoxyethyl) But-1-yl} amino) -7-cyclo-butyloxy-quinazoline; [517] 40 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(S) -N- methyl -N- (1- methoxy-2-propyl) amino] -1-oxo-2-buten-l-yl} amino) -7-cyclobutyloxy-quinazoline; [518] 41 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(R) -N- methyl -N- (1- methoxy-2-propyl) amino] -1-oxo-2-buten-l-yl} amino) -7-cyclobutyloxy-quinazoline; [519] (42) A process for the preparation of 4 - [(3-chloro-4-fluorophenyl) amino] -6- -2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline; [520] (43) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (2- methoxypropyl) But-1-yl} amino) -7-cyclopropylmethoxy-quinazoline; [521] (44) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (3- methoxypropyl) But-1-yl} amino) -7-cyclopropylmethoxy-quinazoline; [522] (45) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (tetrahydrofuran- 2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline; [523] 46 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(S) -N- methyl -N- (tetrahydrofuran-3-yl) amino] - 1-oxo-2-buten-l-yl} amino) -7-cyclobutyloxy-quinazoline; [524] 47 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(R) -N- methyl -N- (tetrahydrofuran-3-yl) amino] - 1-oxo-2-buten-l-yl} amino) -7-cyclobutyloxy-quinazoline; [525] (48) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (tetrahydropyran- 2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline; [526] (49) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (tetrahydropyran- 2-buten-1-yl} amino) -7-cyclo-butyloxy-quinazoline; [527] (50) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- Lt; / RTI > amino} -7-cyclobutyloxy-quinazoline; [528] (51) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- -Yl] amino} -7-cyclobutyl-oxy-quinazoline; [529] (52) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl- ] Amino} -7-cyclobutyloxy-quinazoline < / RTI > [530] (53) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropylmethyl- Lt; / RTI > amino} -7-cyclobutyl-oxy-quinazoline; [531] (54) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (tetrahydrofuran- -2-buten-l-yl} amino) -7-cyclopropylmethoxy-quinazoline; [532] 55 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(R) -N- methyl -N- (tetrahydrofuran-2-ylmethyl) -amino] -1-oxo-2-buten-l-yl} -amino) -7-cyclobutyloxy-quinazoline; [533] 56 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4 - [(S) -N- methyl -N- (tetrahydrofuran-2-ylmethyl) -amino] -1-oxo-2-buten-l-yl} -amino) -7-cyclobutyloxy-quinazoline; [534] Amino] -6- {[4- (pyrrolidin- 1 -yl) -1-oxo-2-buten- 1 -yl] amino} -7-cyclobutyloxy-quinazoline; [535] (58) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- Lt; / RTI > amino} -7-cyclobutyloxy-quinazoline; [536] (59) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (2,5- dimethyl- pyrrolidin- 1 -yl) 1 -yl] amino} -7-cyclobutyloxy-quinazoline; [537] (60) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (piperidin- 1 -yl) -7-cyclobutyloxy-quinazoline; [538] (61) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- Lt; / RTI > amino} -7-cyclobutyloxy-quinazoline; [539] (62) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (2,6-dimethyl- piperidin- 1 -yl) 1 -yl] amino} -7-cyclobutyloxy-quinazoline; [540] (63) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (4-hydroxy- piperidin- 1 -yl) -Yl] amino} -7-cyclobutyloxy-quinazoline; [541] (64) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (4-methoxypiperidin- 1 -yl) -Yl] amino} -7-cyclobutyloxy-quinazoline; [542] (65) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [4- (2-methoxy- ethyl) -piperazin- 2-buten-l-yl} amino) -7-cyclobutyloxy-quinazoline; [543] (66) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- ] Amino} -7-cyclobutyloxy-quinazoline < / RTI > [544] -6- {[4- (3,5-dimethyl-morpholin-4-yl) -1-oxo-2-butene- -Yl] amino} -7-cyclobutyloxy-quinazoline; [545] (68) A mixture of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (2- methoxyethyl) But-1-yl} amino) -7- (tetrahydrofuran-3-yl-oxy) - quinazoline; [546] (69) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N- methyl- N- (2- methoxyethyl) amino] -1-yl} amino) -7- (tetrahydropyran-4-yl-oxy) - quinazoline; [547] (70) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N-methyl- N- (2- methoxyethyl) amino] -1-yl} amino) -7- (tetrahydrofuran-2-yl-methoxy) - quinazoline; [548] (71) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (azetidin- l-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] Sleepy; [549] (72) Synthesis of 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (4-methyl-homopiperazin- 1- yl) propyloxy] -6 - [(vinylcarbonyl) Amino] - < / RTI >quinazoline; [550] Example 4 [551] A coated tablet containing 75 mg of active substance [552] Tablets One core contains the following ingredients: [553] Active substance 75.0 mg [554] Calcium phosphate 93.0 mg [555] Corn starch 35.5 mg [556] 10.0 mg of polyvinylpyrrolidone [557] 15.0 mg of hydroxypropyl methylcellulose [558] Magnesium stearate 1.5 mg [559] 230.0 mg [560] Manufacturing method: [561] The active substance is mixed with calcium phosphate, corn starch polyvinylpyrrolididone, hydroxypropyl methylcellulose and a predetermined amount of magnesium stearate. Blank diameters of 13 mm are prepared in a tablet machine and then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and then mixed with the remaining magnesium stearate. The resulting granules are compressed in a tablet machine to form tablets of the desired shape. [562] Core weight: 230 mg [563] Die: 9 mm, convex side [564] The tabular core thus prepared is coated with a film essentially consisting of hydroxypropyl methylcellulose. Grind the finished coated tablets with beeswax. [565] Defined weight: 245 mg. [566] Example 5 [567] Tablets containing 100 mg of active substance [568] Furtherance: [569] One tablet contains the following ingredients: [570] Active substance 100.0 mg [571] Lactose 80.0 mg [572] Corn starch 34.0 mg [573] 4.0 mg of polyvinylpyrrolidone [574] Magnesium stearate 2.5 mg [575] 220.0 mg [576] Manufacturing method: [577] The active substance, lactose and starch are mixed together and uniformly wetted with an aqueous solution of polyvinylpyrrolidone. The wet composition is screened (mesh size 2.0 mm), dried in a lathe dryer at 50 ° C, screened again (mesh size 1.5 mm) and lubricant is added. The processed mixture is compressed to form tablets. [578] Tablet weight: 220 mg [579] Diameter: 10mm, double-sided type with both sides shaved and one side notched. [580] Example 6 [581] Tablets containing 150 mg of active substance [582] Furtherance: [583] One tablet contains the following ingredients: [584] Active substance 50.0 mg [585] Powdered lactose 89.0 mg [586] Corn starch 40.0 mg [587] Colloidal silica 10.0 mg [588] 10.0 mg of polyvinylpyrrolidone [589] Magnesium stearate 1.0 mg [590] 300.0 mg [591] Manufacturing method: [592] The active material mixed with lactose, corn starch and silica is wetted with 20% aqueous solution of polyvinylpyrrolidone and passed through a screen having a mesh size of 1.5 mm. The resulting granules are dried at 45 占 폚, passed through the same screen again, and mixed with a predetermined amount of magnesium stearate. The resulting mixture is compressed to produce tablets. [593] Tablet weight: 300 mg [594] Die: 10mm, flat. [595] Example 7 [596] Hard gelatin capsules containing 150 mg of the active substance [597] The first capsule contains the following ingredients: [598] Active substance 50.0 mg [599] Corn starch (dry) about 80.0 mg [600] Lactose (powder) Approximately 87.0 mg [601] Magnesium stearate 3.0 mg [602] About 420.0 mg [603] Manufacturing method: [604] The active material is mixed with excipients, passed through a screen having a mesh size of 0.75 mm, and mixed homogeneously using suitable equipment. The processed mixture is filled into size 1 hard gelatine capsules. [605] Capsule filling weight: about 320 mg [606] Capsule skin: Size 1 hard gelatine capsules [607] Example 8 [608] Suppositories containing 150 mg of active substance [609] One suppository contains the following ingredients: [610] Active substance 150.0 mg [611] Polyethylene glycol 1500 550.0 mg [612] Polyethylene glycol 6000 460.0 mg [613] Polyoxyethylene sorbitan [614] 840.0 mg monostearate [615] 2,000.0 mg [616] Manufacturing method: [617] After the suppository mass is melted, the active material is homogeneously distributed therein and the melt is poured into the cooled mold. [618] Example 9 [619] A suspension containing 50 mg of the active substance [620] 100 ml of suspension contains the following ingredients: [621] Active substance 1.00 g [622] Carboxymethylcellulose Na salt 0.10 g [623] 0.05 g of methyl p-hydroxybenzoate [624] 0.01 g of propyl p-hydroxybenzoate [625] Glucose 10.00 g [626] Glycerol 5.00 g [627] 70% sorbitol solution 20.00 g [628] Spices 0.30 g [629] The amount to make 100 ml deionized water [630] Manufacturing method: [631] The distilled water is heated to 70 占 폚. Methyl and propyl p-hydroxybenzoates are dissolved in distilled water with stirring with glycerol and carboxymethylcellulose sodium salt. The solution is cooled to ambient temperature and the active substance is homogeneously dispersed in the solution while stirring with stirring. Sugar, sorbitol solution and perfume are added and dissolved, and the suspension is evacuated with stirring to remove air. [632] A suspension of 5 ml contains 50 mg of the active substance. [633] Example 10 [634] Ampoule containing 10 mg of active substance [635] Furtherance: [636] Active substance 10.0 mg [637] 0.01 N hydrochloric acid suitable amount [638] The amount of double distilled water combined to 2.0 ml [639] Manufacturing method: [640] The active substance is dissolved in the required amount of 0.01 N HCl and made into isotonic solution using conventional salts, sterile filtered and transferred into a 2 ml ampoule. [641] Example 11 [642] Ampoule containing 50 mg of active substance [643] Furtherance: [644] Active substance 50.0 mg [645] 0.01 N hydrochloric acid Appropriate amount [646] The amount of double distilled water combined to 10.0 ml [647] Manufacturing method: [648] The active substance is dissolved in the required volume of 0.01 N HCl and made into isotonic solution using conventional salts, sterile filtered and transferred into 10 ml ampoules. [649] Example 12 [650] A powder inhalation capsule containing 5 mg of the active substance [651] One capsule contains the following ingredients: [652] Active substance 5.0 mg [653] Lactose for inhalation 15.0mg [654] 20.0 mg [655] Manufacturing method: [656] The active substance is mixed with lactose for inhalation. The mixture is filled into capsules in a capsule maker (empty capsule weight: about 50 mg) [657] Weight of capsule: 70.0 mg [658] Capsule size: 3 [659] Example 13 [660] Hand-held nebulized low-dose inhalation solution containing 2.5 mg of active substance [661] One spray contains the following ingredients: [662] Active substance 2.500 mg [663] Benzalkonium chloride 0.001 mg [664] 1N hydrochloric acid suitable amount [665] Ethanol / water (50/50) Total amount of 15.000mg [666] Manufacturing method: [667] The active substance and benzalkonium chloride are dissolved in ethanol / water (50/50). The pH of the solution is adjusted using 1N hydrochloric acid. The resulting solution is filtered and transferred into a suitable container for use in hand-held nebulizers (cartridges). [668] Container contents: 4.5 g
权利要求:
Claims (11) [1" claim-type="Currently amended] A bicyclic heterocycle of formula (I), and its tautomers, stereoisomers and salts. Formula I In the above formula (I) R a is a hydrogen atom or a C 1-4 -alkyl group, R b is a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus can in each case be replaced by groups R 1 to R 3 , where R 1 and R 2 can be the same or different, , Hydrogen, fluorine, chlorine, bromine or iodine atoms; C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, C 3-6 -cycloalkyl, C 4-6 -cycloalkoxy, C 2-5 -alkenyl or C 2-5 -alkynyl group; Aryl, aryloxy, arylmethyl or arylmethoxy group; C 3-5 - alkenyloxy or C 3-5 - alkynyloxy group (this time, the art unsaturated moiety may not be bonded to an oxygen atom); C 1-4 - alkyl sulfonic phenyl, C 1-4 - alkyl, sulfinyl, C 1-4 - alkyl sulfonyl, C 1-4 - alkylsulfonyloxy, methyl sulfonyl group, methylsulfonyl, phenyl, trifluoromethyl trifluoromethyl sulfinyl or trifluoromethyl; A methyl or methoxy group substituted by one to three fluorine atoms; An ethyl or ethoxy group substituted with one to five fluorine atoms; Or a cyano or nitro group or an amino group unsubstituted or substituted by one or two C 1-4 -alkyl groups, wherein the substituents may be the same or different, or wherein R 1 and R 2 are adjacent carbon when coupled to the atom, they are together -CH = CH-CH = CH, -CH = CH-NH or -CH = forming an N-NH group, and R 3 is hydrogen, fluorine, chlorine or bromine atom; C 1-4 -alkyl, trifluoromethyl or C 1-4 -alkoxy group, X is a cyano group or a methine group substituted by a nitrogen atom, A is an imino group substituted or unsubstituted by a C 1-4 -alkyl group, B is a carbonyl or sulfonyl group, C is a 1,3-alenylene, 1,1- or 1,2-vinylene group which may in each case be substituted by one or two methyl groups or trifluoromethyl groups; An ethynylene group; Or 1,3-butadiene-1,4-ylene group which is unsubstituted or substituted by 1 to 4 methyl groups or by trifluoromethyl group, D is alkylene, -CO- alkylene or -SO 2 - alkylene group (wherein, each case, the alkylene moiety is of 1 to 4 hydrogen atoms in the alkylene moiety in addition, contains from 1 to 8 carbon atoms must be bonded to the adjacent alkylene group through a carbonyl group or sulfonyl group, C) - is in each case may be replaced by fluorine atoms,, -CO- alkylene or -SO 2; -CO-O-alkylene, -CO-NR 4 -alkylene or -SO 2 -NR 4 -alkylene group, wherein the alkylene moiety in each case contains from 1 to 8 carbon atoms, , The bond to adjacent group C should only be via a carbonyl or sulfonyl group and R 4 is a hydrogen atom or a C 1-4 -alkyl group), or when D is bonded to the carbon atom of the group E, it is a direct bond , When D is bonded to the nitrogen atom of group E, it is a carbonyl or sulfonyl group, E is amino, C 1-4 -alkylamino or di- (C 1-4 -alkyl) -amino group (wherein the alkyl residues may be the same or different); C 2-4 - alkylamino group [where the alkyl moiety is substituted by R 5 in the β-, γ- or δ- position relative to the nitrogen atom of the amino group, wherein R 5 is hydroxy, C 1-4 - Alkoxy, amino, C 1-4 -alkylamino or di- (C 1-4 -alkyl) -amino group; A 4 to 7 membered alkyleneimino group which is unsubstituted or substituted by one or two methyl groups; Or a 6 to 7 membered alkyleneimino group which is unsubstituted or substituted by one or two methyl groups, wherein in each case the methylene group at the 4-position is replaced by an oxygen or sulfur atom, or by sulfinyl, , Imino or N- (C 1-4 -alkyl) -imino group); N- (C 1-4 -alkyl) -N- (C 2-4 -alkyl) -amino group, wherein the C 2-4 -alkyl residue is optionally substituted with one or more groups selected from the group consisting of , It is substituted by R 5 in position, wherein R 5 is as defined above); Di- (C 2-4 -alkyl) -amino groups wherein two C 2-4 -alkyl moieties are substituted by R 5 at the -, - or - position for the nitrogen atom of the amino group, Wherein the substituents may be the same or different and R 5 is as defined above; C 3-7 -cycloalkylamino or a C 3-7 -cycloalkyl-C 1-3 -alkylamino group, wherein in each case the nitrogen atom may be further substituted by a C 1-4 -alkyl group ); Amino or a C 1-4 -alkylamino group, wherein the nitrogen atom is in each case optionally substituted by 1 to 3 C 1-4 -alkyl groups, tetrahydrofuran-3-yl, tetrahydropyranyl, Yl, tetrahydropyranylmethyl, 1- (tetrahydrofuran-3-yl) -piperidin-4-yl, 1- (tetrahydropyran- Piperidin-4-yl, 1- (tetrahydropyran-4-yl) -piperidin-4-yl, 3-pyrrolidinyl, 3- piperidinyl, 4- Hydroazepinyl or 4-hexahydroazepinyl group); A 4 to 7 membered alkyleneimino group which is unsubstituted or substituted by one to four C 1-2 -alkyl groups which may be substituted by R 5 , either a cyclic carbon atom or an alkyl group, , Wherein R < 5 > is as defined above; A piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranylmethyl group; A 6 to 7 membered alkyleneimino group optionally substituted by one or two C 1-2 -alkyl groups, wherein the methylene group in each case is an oxygen or sulfur atom at the 4-position, the group R 6 , Or a sulfinyl or sulfonyl group wherein R 6 is a hydrogen atom, a C 1-4 -alkyl, a 2-methoxy-ethyl, a 3-methoxy-propyl, a C 3-7 -Cycloalkyl , C 3-7 -cycloalkyl-C 1-4 -alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, , C 1-4 -alkyl-carbonyl, C 1-4 -alkylsulfonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl or di- (C 1-4 -alkyl) -aminocarbonyl group to be); An imidazolyl group which is unsubstituted or substituted by one to three methyl groups; Or a C 5-7 -cycloalkyl group, wherein the methylene group is replaced by an oxygen or sulfur atom, an imino group substituted by a group R 6 , a sulfinyl or a sulfonyl group, wherein R 6 is as defined above, Lt; / RTI & D together with E represents a hydrogen, fluorine or chlorine atom; A C 1-4 -alkyl group which is unsubstituted or substituted with 1 to 5 fluorine atoms; C 3-6 -cycloalkyl group; Aryl, heteroaryl, C 1-4 -alkylcarbonyl or arylcarbonyl group; Carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylamino-carbonyl or di- (C 1-4 -alkyl) -aminocarbonyl group; Or a 4-to 7-membered alkyleneimino group, wherein the methylene group in each case is an oxygen or sulfur atom in the 6-membered to 7-membered alkyleneimino group, the group R 6 , Or a sulfinyl or sulfonyl group wherein R 6 is as defined above, R c is C 4-7 - cycloalkoxy, or C 3-7 - cycloalkyl, -C 1-6 - alkoxy group [wherein, each case, the cycloalkyl moiety is C 1-3 - alkyl, hydroxy, C 1- 4 - alkoxy, amino, C 1-4 - alkylamino, di - (C 1-4-alkyl) -amino, pyrrolidino, piperidino, morpholino, piperazino, N- (C 1-2 Alkyl-piperazino, hydroxy-C 1-2 -alkyl, C 1-4 -alkoxy-C 1-2 -alkyl, amino-C 1-2 -alkyl, C 1-4 -alkylamino-C 1-2-alkyl, di - (C 1-4 -alkyl) -amino -C 1-2 -alkyl, -C 1-2 pyrrolidino-alkyl, piperidino -C 1-2 -alkyl, morpholinyl C 1-2 -alkyl, piperazino-C 1-2 -alkyl or N- (C 1-2 -alkyl) -piperazino-C 1-2 -alkyl group, The mono-substituted cycloalkyl moieties mentioned include C 1-3 -alkyl groups; Tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy; Tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group; C 2-4 -alkoxy substituted by an azetidin-1-yl, 4-methyl-homo-piperazino or 4-ethyl-homopiperazino group at the , Or group; Piperidinyloxy, 2-pyrrolidinyl-C 1-4 -alkyloxy, 3-pyrrolidinyl-C 1-4 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-pyrrolidinyloxy Piperidinyl-C 1-4 -alkyloxy, 3-piperidinyl-C 1-4 -alkyloxy, 4-piperidinyl-C 1-4 -alkyloxy, 3-hexahydroazepinyloxy, 4-hexahydroazepinyloxy, 2-hexahydroazepinyl-C 1-4 -alkyloxy, 3-hexahydroazepinyl-C 1-4 -alkyloxy or 4-hexahydroazepinyl-C 1-4 -alkyloxy group, wherein in each case the cyclic nitrogen atom may be replaced by a group R 6 , wherein R 6 is as defined above, Referred to as defining a group of the above mentioned moieties, in each case, R by the 7-substituted or substituted by R 8, disubstituted or trisubstituted, or R 7 is substituted by one by the addition of R 8 to A substituted or unsubstituted phenyl group wherein the substituents of the phenyl group may be the same or different and R 7 is cyano, carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkoxycarbonyl, alkylamino-carbonyl, di - (C 1-4-alkyl) aminocarbonyl, C 1-4 - alkyl sulfonic phenyl, C 1-4 - alkyl sulfinyl, C 1-4-alkylsulfonyl, hydroxy, C 1-4 - alkylsulfonyloxy, trifluoromethyl alkyloxy, nitro, amino, C 1-4 - alkylamino, di - (C 1-4 - alkyl) amino, C 1-4 - alkyl-carbonyl Amino, N- (C 1-4 -alkyl) -C 1-4 -alkylcarbonylamino, C 1-4 -alkylsulfonylamino, N- (C 1-4 -alkyl) -C 1-4 -alkyl Sulfonylamino, aminosulfonyl, C 1-4 -alkylaminosulfonyl or di - (C 1-4 -alkyl) -aminosulfonyl group or a carbonyl group, which is substituted by a 5- to 7-membered alkyleneimino group, wherein the 6- to 7-membered alkyleneimino group is substituted by , The methylene group may be replaced by an oxygen or sulfur atom, a sulfinyl, a sulfonyl, an imino or an N- (C 1-4 -alkyl) -imino group at the 4-position, and R 8 is fluorine, chlorine, bromine or iodine atom, a C 1-4 - alkyl, trifluoromethyl or C 1-4 - alkoxy group or, when two groups R 8 bonded to adjacent carbon atoms, the two groups R 8 are together C 3-5 -alkylene, methylenedioxy or 1,3-butadiene-1,4-ylene group, The heteroaryl groups mentioned in defining the above-mentioned groups also include 5-membered heteroaromatic groups containing imino groups or containing oxygen or sulfur atoms or imino groups or containing oxygen or sulfur atoms and one or two nitrogen atoms group; Or a 6-membered heteroaromatic group containing 1, 2 or 3 nitrogen atoms, wherein the 5-membered heteroaromatic group may in each case be substituted by 1 or 2 methyl or ethyl groups, The aromatic group may be substituted by one or two methyl or ethyl groups or by fluorine, chlorine, bromine or iodine atoms or by trifluoromethyl, hydroxy, methoxy or ethoxy groups . [2" claim-type="Currently amended] The method according to claim 1, R a is a hydrogen atom, R b is a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus can in each case be replaced by a group R 1 to R 3 , where R 1 and R 2 can be the same or different, , Hydrogen, fluorine, chlorine, bromine or iodine atoms; C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, C 3-6 -cycloalkyl, C 4-6 -cycloalkoxy, C 2-5 -alkenyl or C 2-5 -alkynyl group; Aryl, aryloxy, arylmethyl or arylmethoxy group; A methyl or methoxy group substituted by one to three fluorine atoms; Or a cyano or nitro group, and R 3 is hydrogen, fluorine, chlorine or bromine atom, C 1-4 -alkyl, trifluoromethyl or C 1-4 -alkoxy group, X is a cyano group or a methine group substituted by a nitrogen atom, A is an imino group, B is a carbonyl or sulfonyl group, C is a 1,3-alenylene, a 1,1- or 1,2-vinylene group, an ethynylene group, or a 1,3-butadiene-1,4- D is alkylene, -CO- alkylene or -SO 2 - alkylene group (wherein, each case, the alkylene moiety is of 1 to 4 carbon atoms and 1 to contain in additional alkylene moiety of four hydrogen atoms must be bonded to the adjacent alkylene group through a carbonyl group or sulfonyl group, C) - is in each case may be replaced by fluorine atoms,, -CO- alkylene or -SO 2; -CO-O-alkylene, -CO-NR 4 -alkylene or -SO 2 -NR 4 -alkylene group, wherein the alkylene moiety in each case contains 1 to 4 carbon atoms, , They must be bonded to the adjacent group C via a carbonyl or sulfonyl group and R 4 is a hydrogen atom or a C 1-4 -alkyl group), or when D is bonded to the carbon atom of the group E, it is a direct bond , When D is bonded to the nitrogen atom of group E, it is a carbonyl or sulfonyl group, E is a di- (C 1-4 -alkyl) -amino group, wherein the alkyl residues may be the same or different; (C 1-4 -alkyl) -N- (C 2-4 -alkyl) -amino group wherein the C 2-4 -alkyl residue is optionally substituted with one or more groups selected from the group consisting of , - or - It is substituted by R 5 in position, wherein R 5 is hydroxy, C 1-4 - alkoxy or di - (C 1-4-alkyl) -amino group; A 4 to 7 membered alkyleneimino group which is unsubstituted or substituted by one or two methyl groups; Or a six- to seven-membered alkyleneimino group which is unsubstituted or substituted by one or two methyl groups, wherein in each case the methylene group is replaced by an oxygen or sulfur atom at the 4-position or by sulfinyl, Substituted with an N- (C 1-4 -alkyl) -imino group; Di- (C 2-4 -alkyl) -amino group, wherein the two C 2-4 -alkyl residues are in each case bound to the nitrogen atom of the amino group by R 5 at the -, - or Wherein the substituents may be the same or different and R 5 is as defined above; C 3-7 -cycloalkylamino or a C 3-7 -cycloalkyl-C 1-3 -alkylamino group, wherein in each case the nitrogen atom may be further substituted by a C 1-4 -alkyl group ); C 1-4 -alkylamino group wherein the nitrogen atom is selected from the group consisting of tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl, 1- (Tetrahydropyran-3-yl) -piperidin-4-yl, 1- (tetrahydropyran-3- yl) -piperidin- (C 1-2 -alkyl) -3-pyrrolidinyl, N- (C 1-2 -alkyl) -3-piperidinyl, N- (C 1-2- Alkyl) -4-piperidinyl, N- (C 1-2 -alkyl) -3-hexahydroazepinyl or N- (C 1-2 -alkyl) -4-hexahydroazepinyl group do); 1 to 4 methyl group, a substituted or a non-substituted 4-to 7-membered alkylene diamino group by (which is, and one of the cyclic carbon atom or a methyl group may be substituted by R 5, wherein R 5 is Lt; / RTI > A piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranylmethyl group; 1 or 2 for (where butylimino group 6-to 7-membered alkylene that is substituted or not substituted by two methyl groups, respectively, a methylene group, an imino substituted by oxygen or sulfur atom, a group R 6 eseo the 4-position It is replaced by a group, or a sulfinyl or sulfonyl group, wherein R 6 is C 1-4 - alkyl, 2-methoxyethyl, 3-methoxypropyl, C 3-7 - cycloalkyl, C 3-7 -cycloalkyl -C 1-4-alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-methyl, formyl, C 1-4 - alkyl carbonyl C 1-4 -alkyl-sulfonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl or di- (C 1-4 -alkyl) -aminocarbonyl group; Or a C 5-7 -cycloalkyl group, wherein the methylene group is replaced by an oxygen or sulfur atom, an imino group substituted by a group R 6 , a sulfinyl or a sulfonyl group, wherein R 6 is as defined above, Lt; / RTI & D is a hydrogen, fluorine or chlorine atom together with E; A C 1-4 -alkyl group which is unsubstituted or substituted with 1 to 5 fluorine atoms; C 3-6 -cycloalkyl group; Aryl, C 1-4 -alkylcarbonyl or arylcarbonyl group; Carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylamino-carbonyl or di- (C 1-4 -alkyl) -aminocarbonyl group; Or a 4-to 7-membered alkyleneimino group, wherein the methylene group in each case is an oxygen or sulfur atom in the 6-membered to 7-membered alkyleneimino group, the group R 6 , Or a sulfinyl or sulfonyl group wherein R 6 is as defined above, R c is C 4-7 - cycloalkoxy, or C 3-7 - cycloalkyl, -C 1-6 - alkoxy group [wherein, each case, the cycloalkyl moiety is C 1-3 - alkyl, hydroxy, C 1- 4-alkoxy, di - (C 1-4-alkyl) -amino, pyrrolidino, piperidino, morpholino, N- (C 1-2 - alkyl) - piperazino, hydroxy, -C 1- 2 -alkyl, C 1-4 - alkoxy -C 1-2 -alkyl, di - (C 1-4 -alkyl) -amino -C 1-2 -alkyl, pyrrolidino -C 1-2 -alkyl, P C 1-2 -alkyl, morpholino-C 1-2 -alkyl or N- (C 1-2 -alkyl) -piperazino-C 1-2 -alkyl group, The mono-substituted cycloalkyl moieties mentioned above include C 1-3 -alkyl groups; Tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy; Tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group; C 2-4 -alkoxy substituted by an azetidin-1-yl, 4-methyl-homo-piperazino or 4-ethyl-homopiperazino group at the , Or group; Piperidinyloxy, 2-pyrrolidinyl-C 1-4 -alkyloxy, 3-pyrrolidinyl-C 1-4 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2-pyrrolidinyloxy Piperidinyl-C 1-4 -alkyloxy, 3-piperidinyl-C 1-4 -alkyloxy, 4-piperidinyl-C 1-4 -alkyloxy, 3-hexahydroazepinyloxy, 4-hexahydroazepinyloxy, 2-hexahydroazepinyl-C 1-4 -alkyloxy, 3-hexahydroazepinyl-C 1-4 -alkyloxy or 4-hexahydroazepinyl-C 1-4 -alkyloxy group, wherein in each case the cyclic nitrogen atom may be replaced by a group R 6 , wherein R 6 is as defined above, The aryl moieties mentioned while defining the groups mentioned above, in each case, R by the 7-substituted or substituted by R 8, disubstituted or trisubstituted, or R 7 is substituted by one by the addition of R 8 to A phenyl group which may be substituted or disubstituted, wherein the substituents of the phenyl group may be the same or different and R 7 is cyano, carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkyl aminocarbonyl, di - (C 1-4-alkyl) aminocarbonyl, C 1-4 - alkyl sulfonic phenyl, C 1-4 - alkyl sulfinyl, C 1-4-alkylsulfonyl, hydroxy, C 1-4 - alkylsulfonyloxy, trifluoromethyl alkyloxy, nitro, amino, C 1-4 - alkylamino, di - (C 1-4 -alkyl) -amino, C 1-4 -alkyl-carbonyl-amino (C 1-4 -alkyl) -C 1-4 -alkylcarbonylamino, C 1-4 -alkylsulfonylamino, N- (C 1-4 -alkyl) -C 1-4 -alkylsulfonylamino, C 1-4 -alkylaminosulfonyl or di- (C 1-4 < RTI ID = 0.0 > -Alkyl) -aminosulfonyl group or a carbonyl group, which is substituted by a 5- to 7-membered alkyleneimino group, wherein the 6 to 7 membered alkyleneimino group, in each case the methylene group, (C 1-4 -alkyl) -imino group at the 4-position, and R 8 is a fluorine, chlorine, bromine or iodine atom , C 1-4 -alkyl, trifluoromethyl or C 1-4 -alkoxy group, or when two groups R 8 are bonded to adjacent carbon atoms, these two groups R 8 together are C 3-5 -alkyl Methylene dioxy, or 1,3-butadiene-1,4-ylene group, and the thermomers, stereoisomers and salts thereof. [3" claim-type="Currently amended] The method according to claim 1, R a is a hydrogen atom, R b is a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus can in each case be replaced by groups R 1 and R 2 , where R 1 and R 2 can be the same or different, , Hydrogen, fluorine, chlorine or bromine atoms; Methyl, trifluoromethyl or methoxy group, X is a nitrogen atom, A is an imino group, B is a carbonyl group, C is a 1,2-vinylene group, an ethynylene group or a 1,3-butadiene-1,4-ylene group, When D is a C 1-4 alkylene group or D is bonded to the carbon atom of the group E, it may be a direct bond, and when D is bonded to the nitrogen atom of the group E, it may be a carbonyl group, E is a di- (C 1-4 -alkyl) -amino group, wherein the alkyl residues may be the same or different; (C 1-4 -alkyl) -N- (C 2-4 -alkyl) -amino group wherein the C 2-4 -alkyl residue is optionally substituted with one or more groups selected from the group consisting of , - or - It is substituted by the group R 5 at the location, wherein R 5 is hydroxy, C 1-3 - alkoxy or di - (C 1-3-alkyl) -amino group; Pyrrolidino, piperidino or morpholino group; Di- (C 2-4 -alkyl) -amino group, wherein the two C 2-4 -alkyl residues are in each case bound to the nitrogen atom of the amino group by R 5 at the -, - or Wherein the substituents may be the same or different and R 5 is as defined above; (C 1-2 -alkyl) -pyrrolidin-3-yl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl, , 1- (C 1-2 -alkyl) -piperidin-3-yl, 1- (C 1-2 -alkyl) -piperidin-4-yl, 1- (tetrahydrofuran- (Piperidin-4-yl) -piperidin-4-yl, 1- (tetrahydropyran-3- yl) A C 1-4 -alkylamino group substituted by a C 1-4 -alkyl group; C 3-5 -cycloalkylamino or a C 3-5 -cycloalkyl-C 1-3 -alkylamino group, wherein in each case the nitrogen atom is further substituted with a C 1-3 -alkyl group; One or two (which is one methyl group, a substituted or a non-substituted 5-to 7-membered alkylene diamino group by, and one of the cyclic carbon atom or a methyl group may be substituted by R 5, wherein R 5 is Lt; / RTI > A piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranylmethyl group; It is substituted or not substituted by one or two methyl group, piperidino group (wherein, in each case, a methylene group, a nitrogen, oxygen or sulfur atom, a sulfinyl or sulfonyl group, or a group R 6 substituted at the 4-position It is already replaced by the no-group, wherein R 6 is C 1-3 - alkyl, 2-methoxyethyl, 3-methoxypropyl, C 3-6 - cycloalkyl, C 3-6 - cycloalkyl, -C 1 -3-alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-methyl, C 1-3 -alkyl-carbonyl, C 1-3 -alkyl C 1-3 -alkylaminocarbonyl or di- (C 1-3 -alkyl) -aminocarbonyl group, or is hydrogen, D is together with E a hydrogen atom, a C 1-3 -alkyl group, an aryl or a C 1-4 -alkylcarbonyl group, or a C 1-4 -alkoxycarbonyl group, Wherein R c is C 4-7 -cycloalkoxy or a C 3-7 -cycloalkyl-C 1-4 -alkoxy group, wherein in each case the cycloalkyl moiety is C 1-3 -alkyl or C 1-3 -alkoxy Lt; / RTI >group); Tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group; C 2-4 -alkoxy substituted by an azetidin-1-yl, 4-methyl-homo-piperazino or 4-ethyl-homopiperazino group at the , Or group; 3-pyrrolidinyloxy, 2-pyrrolidinyl-C 1-3 -alkyloxy, 3-pyrrolidinyl-C 1-3 -alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy, 2 -piperidinyl -C 1-3-alkyloxy, 3-piperidinyl -C 1-3-alkyloxy, 4-piperidinyl -C 1-3-alkyloxy, 3-hexahydro-ah Jaffe carbonyl oxy, Hexahydroazepinyl-C 1-3 -alkyloxy, 3-hexahydroazepinyl-C 1-3 -alkyloxy or 4-hexahydroazepinyl-C 1-3 -alkyloxy group, wherein in each case the cyclic nitrogen atom may be substituted by methyl or ethyl groups, The aryl moiety mentioned hereinbefore defining the groups mentioned above is a phenyl group which may be mono-, di- or tri-substituted by R 8 , wherein the substituents may be the same or different and R 8 is fluorine, chlorine, bromine or iodine An iodine atom, a C 1-4 -alkyl, a trifluoromethyl or a C 1-4 -alkoxy group, and toomers, stereoisomers and salts thereof. [4" claim-type="Currently amended] The method according to claim 1, R a is a hydrogen atom, R b is a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus can in each case be replaced by groups R 1 and R 2 , where R 1 and R 2 can be the same or different, , Hydrogen, fluorine, chlorine or bromine atom, X is a nitrogen atom, A is an imino group, B is a carbonyl group, C is a 1,2-vinylene group, an ethynylene group or a 1,3-butadiene-1,4-ylene group, D is a C 1-3 alkylene group, E is a di- (C 1-4 -alkyl) -amino group, wherein the alkyl residues may be the same or different; Wherein the nitrogen atom is selected from the group consisting of 2-methoxyethyl, 1-methoxy-2-propyl, 2-methoxy-propyl, 3- methoxy-propyl, tetrahydrofuran- (Tetrahydrofuran-3-yl) -piperidin-4-yl, 1-methyl-piperidin- , A methylamino or ethylamino group substituted by a cyclopropyl or cyclopropylmethyl group; Bis- (2-methoxyethyl) -amino group; A pyrrolidino, piperidino or morpholino group, each of which is unsubstituted or substituted by one or two methyl groups; Methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2-methoxy-ethyl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl or tetrahydrofuran- A piperazino group; Thiomorpholino, S-oxido-thiomorpholino or S, S-dioxido-thio-morpholino group; Piperidino, 4-methoxy-piperidino, 4-ethoxy-piperidino, 4-methoxy-piperidino, , 4- (tetrahydrofuran-3-yl) -piperidino or 4-morpholino-piperidino group, D is together with E a hydrogen atom, methyl, phenyl, methoxycarbonyl or ethoxycarbonyl group, R c is cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy or cyclohexylmethoxy group; Cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group; Tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuran-2-ylmethoxy group; A straight chain C 2-4 -alkoxy group substituted at the end by a 4-methyl-homopiperazino or 4-ethyl-homopiperazino group; 1-methyl-piperidin-4-yloxy or 1-ethyl-piperidin-4-yloxy group; (1-methyl-piperidin-4-yl) -C 1-3 -alkyloxy or (1-ethyl-piperidin-4-yl) -C 1-3 -alkyloxy group Click heterocycle, and its tartar, stereoisomer and salt. [5" claim-type="Currently amended] The method according to claim 1, R a is a hydrogen atom, R b is a 1-phenylethyl group or a phenyl group, wherein the phenyl nucleus may be substituted with groups R 1 to R 2 , where R 1 and R 2 may be the same or different and in each case hydrogen, fluorine, Chlorine or bromine atom, X is a nitrogen atom, A is an imino group, B is a carbonyl group, C is a 1,2-vinylene group, an ethynylene group or a 1,3-butadiene-1,4-ylene group, D is a methylene group, E is selected from the group consisting of dimethylamino, diethylamino, bis- (2-methoxy-ethyl) -amino, N-methyl-N- Amino, N-methyl-N-cyclopropylmethylamino, N-methyl-N- (1-methoxy- Methyl-N- (2-methoxy-propyl) -amino, N-methyl-N- (Tetrahydrofuran-4-yl) -amino, N-methyl-N- (tetrahydrofuran- Piperidin-4-yl) -amino group; A pyrrolidino, piperidino or morpholino group, each of which is unsubstituted or substituted by one or two methyl groups; A piperazino group substituted at the 4-position with methyl, ethyl, cyclopropylmethyl, 2-methoxy-ethyl group; S-oxido-thiomorpholino group; 2- (methoxymethyl) -pyrrolidino, 4-hydroxy-piperidino or 4-methoxy-piperidino group, D is a hydrogen atom, methyl, phenyl or ethoxycarbonyl group together with E, R c is cyclopropylmethoxy, cyclobutyloxy or cyclopentyloxy group, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuran-2-ylmethoxy group; A straight chain C 2-4 -alkoxy group substituted at the end by an azetidin-1-yl group or a 4-methyl-homopiperazino group; 1-methyl-piperidin-4-yloxy; (1-methyl-piperidin-4-yl) - C 1-3 -alkyloxy group, and the trimers, stereoisomers and salts thereof. [6" claim-type="Currently amended] The method according to claim 1, (a) 4- [3- (1-methyl-piperidin-4-yl) propyloxy] -6 - [(vinylcarbonyl) Amino] -quinazoline, (b) from 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- } -7-cyclopropylmethoxy-quinazoline, (c) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin- 7-cyclopropylmethoxy-quinazoline, and salts thereof. [7" claim-type="Currently amended] 7. A pharmacologically acceptable salt of a compound according to any one of claims 1 to 6 with an inorganic or organic acid or base. [8" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt according to claim 7 together with any one or more inert carriers and / or diluents. [9" claim-type="Currently amended] The use of any one of claims 1 to 7 for the manufacture of a pharmaceutical composition suitable for the treatment of benign or malignant tumors, for the prevention and treatment of diseases of the airways and respiratory tracts and for the treatment of diseases of the gastrointestinal tract, Use of compounds. [10" claim-type="Currently amended] 9. A process for the preparation of a pharmaceutical composition according to claim 8, characterized in that the compound according to any one of claims 1 to 7 is incorporated into the at least one inert carrier and / or diluent by a non-chemical method. [11" claim-type="Currently amended] a) reacting a compound of formula (II) with a compound of formula (III) b) reacting a compound of formula (IV) with a compound of formula (V) to prepare a compound of formula (I) wherein E is bonded to group D via a nitrogen atom, Optionally, the thus obtained compound of formula (I) containing an amino, alkylamino or imino group is converted to the corresponding acyl or sulfonyl compound of formula (I) by acylation or by sulfonylation, The thus obtained compound of formula (I) containing an amino, alkylamino or imino group is converted to the corresponding alkyl compound of formula (I) by alkylation or reductive alkylation and / The thus obtained compound of formula (I) containing a carboxy or hydroxyphosphoryl group is converted into the corresponding ester of formula (I) by esterification and / The thus obtained compound of formula (I) containing a carboxy or ester group can be converted to the corresponding amide of formula (I) by reacting with the corresponding amine and / In some cases, any protecting groups used during the above reaction may be resealed and / If desired, the compounds of formula I thus obtained may be resolved into their stereoisomers and / A compound according to any one of claims 1 to 7, characterized in that the compound of formula (I) thus obtained is converted into its salt or, more particularly, is converted into its pharmacologically acceptable salts for use in pharmaceutical applications Lt; RTI ID = 0.0 > (I) < / RTI > (II) (III) Formula IV Formula V In the above formulas (II), (III), (IV) and (V) Wherein R a , R b , R c , A, B, C, D, E and X are as defined in any one of claims 1 to 6, Z 1 and Z 2 are each a leaving group, E 'is as defined for E in any one of claims 1 to 6 and is bonded to group D via a nitrogen atom.
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引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
1999-06-21|Priority to DE19928281.1 1999-06-21|Priority to DE1999128281 1999-07-30|Priority to US14664499P 1999-07-30|Priority to US60/146,644 2000-05-11|Priority to DE10023085.7 2000-05-11|Priority to DE2000123085 2000-06-16|Application filed by 클래스 하인츠-게르트, 베링거 잉겔하임 파르마 카게 2002-02-15|Publication of KR20020012290A 2007-04-24|Application granted 2007-04-24|Publication of KR100709909B1
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申请号 | 申请日 | 专利标题 DE19928281.1|1999-06-21| DE1999128281|DE19928281A1|1999-06-21|1999-06-21|Arylamino and aralkylamino substituted quinoline and quinazoline derivatives, useful for the treatment of e.g. tumors, pulmonary, respiratory and gastrointestinal disorders and psoriasis| US14664499P| true| 1999-07-30|1999-07-30| US60/146,644|1999-07-30| DE10023085.7|2000-05-11| DE2000123085|DE10023085A1|2000-05-11|2000-05-11|Arylamino and aralkylamino substituted quinoline and quinazoline derivatives, useful for the treatment of e.g. tumors, pulmonary, respiratory and gastrointestinal disorders and psoriasis| 相关专利
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