UA74614C2 - Quinazoline derivatives and medicament based thereon - Google Patents

Abstract

The invention relates to quinazoline derivatives of general formula (I), wherein Ra, Rb, and Rc have the meaning defined in claim 1, to their tautomers, their stereoisomers and their salts, especially their physiologically acceptable salts with inorganic or organic acids. Said compounds have valuable pharmacological properties, especially an inhibiting effect upon signal transduction caused by tyrosine kinase. The invention further relates to their utilization in the treatment of diseases, especially of tumoral diseases, diseases of the.

Description

Description of the invention

This invention relates to quinazoline derivatives of the general formula in () a -

M

M and:

E is M o

Kk their tautomers, their stereoisomers and their salts, primarily their physiologically acceptable salts with inorganic or organic acids, which have valuable pharmacological properties, primarily an inhibitory effect on tyrosine kinase-mediated signal transduction, and also relates to their use in the treatment of certain diseases, primarily tumor or cancer diseases and diseases of the lungs and respiratory tract, and the method of their reception.

In the above general formula | with

Ka means benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group, o

Where stands for dimethylamino-, M-methyl-M-ethylamino-, diethylamino-, M-methyl-M-isopropylamino-,

M-methyl-M-cyclopropylamino-, M-methyl-M-(2-methoxyethyl)amino-, M-ethyl-M-(2-methoxyethyl)amino-, bis(2-methoxyethyl)amino-, morpholino-, M -methyl-M-(tetrahydrofuran-z-yl)amino-,

M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino-, M-methyl-M-(tetrahydrofuran-3-ylmethyl)amino-, "

M-methyl-M-(tetrahydropyran-4-yl)amino-or M-methyl-M-tetrahydropyran-4-ylmethyl)amino group and "-

Co means cyclopropylmethoxy-, cyclobutyloxy-, cyclopentyloxy-, tetrahydrofuran-3-yloxy-, tetrahydrofuran-2-ylmethoxy-, tetrahydrofuran-3-ylmethoxy-, tetrahydropyran-4-yloxy- or "(0 tetrahydropyran-4-ylmethoxy-group, except the following compounds: - (in

3-chloro-4-fluorophenyl)amino1|-6-114-(M,M-diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, and - (2) 4-(3- chloro-4-fluorophenyl)amino|-6-(Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (3) « 4-(3-chloro- 4-fluorophenyl)amino!|-6-4-(dimethylamino)-1-oxo-2-buten-1-ylylamino)-7-cyclopropylmethoxyquinazoline, (43. 4-(3-chloro-4-fluorophenyl)amino|- 6-(4-(morpholin-4-yl)-1-oxo-2-buten-1-ylamino)-7-cyclobutyloxyquinazoline, and (5) from 4-(3-chloro-4-fluorophenyl)amino! |-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, " (6). 4-KZ-chloro-4-fluorophenyl)amino|-6-L14-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (7). 4-KZ-chloro-4-fluorophenyl)amino|-6-L14-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, (8). 4-KK)-(1-phenylethyl)amino1|-6-Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, - (9). 4-KK)-(1-phenylethyl)amino|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, iz (103. 4-KK) -(1-phenylethyl)amino|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, (11). 4-KK)-(1-phenylethyl)amino!|-6-Ch4-(diethylamino)-1-oxo-2-buten-1-yl|Iamino)-7-cyclobutyloxyquinazoline, b" (12). 4-KK)-(1-phenylethyl)amino!|-6-Ch4-(diethylamino)-1-oxo-2-buten-1-yl|Iamino)-7-cyclopentyloxyquinazoline, shu 70 (13). 4-KK)-(1-phenylethyl)amino1|-6-(Ch4-(diethylamino)-1-oxo-2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, (14) i» 4-(3-chloro -4-fluorophenyl)amino1-6-(14-Ibis(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylamino)-7-diclopropylmethoxy inazoline, (15)

A-(3-chloro-4-fluorophenyl)amino)|-6-(14-(M-ethyl-M-(2-methoxyethyl)amino)|-1-oxo-2-buten-1-ylamino)-7 -cyclopropylmethyl-N-(tetrahydropyran-4-yl)amino|-1-oxo- 2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, 60 (17) 4-(3-chloro-4-fluorophenyl)amino!|-6-C4-(diethylamino)-1-oxo-2-buten-1 -ilyamino)-7-Ktetrahydrofuran-2-yl)methoxy|) quinazoline, (18) 4-((3-chloro-4-fluorophenyl)amino)|-6-(4-(diethylamino)-1-oxo-2 -buten-1-ilyamino)-7-K5)-(tetrahydrofuran-3-yl)oxy 65 |Hquinazoline, (19)

4-(3-chloro-4-fluorophenyl)amino1|-6-C4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-tetrahydropyran-4-yl)oxy|quinazoline, 4- (3-chloro-4-fluorophenyl)amino1|-6-(14-(1M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino|-1-oxo-2-buten-1-yl)amino)-7 -cyclopropylmethoxyquinazoline and (21). 4-(3-chloro-4-fluorophenyl)amino)|-6-(34-(M-methyl-M-(tetrahydrofuran-3-yl)amino|-1-oxo-2-buten-1-yl)amino )-7-cyclopropylmethoxyquinazoline.

Preferred compounds of the above general formula I are those in which Ka, K, and Ko have the above 7/0 values, but with the exception of the following compounds: (0) 4-(3-chloro-4-fluorophenyl)amino1|-6- 1Ш4-(M,M-diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (2) 4-(3-chloro-4-fluorophenyl)amino|-6-(Ч4-( morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (3) 9 4-(3-chloro-4-fluorophenyl)amino!|-6-4-(dimethylamino) -1-oxo-2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, (4). 4-(Z-chloro-4-fluorophenyl)amino1|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (5) 4-(Z -chloro-4-fluorophenyl)amino!|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, (6). 4-KZ-chloro-4-fluorophenyl)amino|-6-L14-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (7). 4-KZ-chloro-4-fluorophenyl)amino|-6-L14-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, (8). 4-KK)-(1-phenylethyl)amino1|-6-Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (9). 4-KK)-(1-phenylethyl)amino|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, (10). 4-KK)-(1-phenylethyl)amino|-6-Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, sc (11). 4-K(K)-(1-phenylethyl)amino)|-6-14-(diethylamino)-1-oxo-2-buten-1-yl|amino)-7-cyclobutyloxyquinazoline, (12). 4-(K)-(1-phenylethyl)amino)|-6-14-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, and) (13). 4-KK)-(1-phenylethyl)amino1|-6-(Ch4-(diethylamino)-1-oxo-2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, (143. 4-((3-chloro- 4-Fluorophenyl)amino1-6-(14-Ibis(2-methoxyethyl)amino)|-1-oxo-2-buten-1-yl)amino)-7-cyclopropylmethoxyquinazoline, g zo (15). 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(M-ethyl-M-(2-methoxyethyl)amino)|-1-oxo-2-buten-1-yl)amino)- 7-cyclopropylmethoxyquinazoline, -- (16) te 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(1M-methyl-M-(tetrahydropyran-4-yl)amino|-1-oxo- 2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, "(7-4-(3-chloro-4-fluorophenyl)amino!|-6-C4-(diethylamino)-1-oxo-2-butene-1 -ilyamino)-7-tetrahydrofuran-2-yl)methoxy|)quinazoline, (18). 4-(3-chloro-4-fluorophenyl)amino|-6-14-(diethylamino)-1-oxo-2-buten-1-ylamino)-7-(5)-(tetrahydrofuran-3-yl)oxy ) quinazoline, « from 8) 2 s 4-(3-chloro-4-fluorophenyl)amino1|-6-C4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-Ctetrahydropyran-4- il)oxy|quin azoline, ;" (20) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(1M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino|-1-oxo-2-buten-1-yl) ) amino)-7-cyclopropylmethoxyquinazoline, - (27) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(IM-methyl-M-(tetrahydrofuran-3-yl)amino|-1-oxo -2-buten-1-yl)amino)-7-cyclo propylmethoxyquinazoline,

F (22) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-|(M-(2-methoxyethyl)-M-methylamino)|-1-oxo-2-buten-1-ylamino (23). 4-((3-chloro-4-fluorophenyl)amino1-6-(14-Ibis(2-methoxyethyl)amino)|-1-oxo-2-buten-1-yl)amino)-7-cyclobutyloxyquinazoline, (24 ) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(1N-methyl-N-(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylamino)-7-cyclobutyl syquinazoline,

F) (25). 4-KZ-chloro-4-fluorophenyl)amino1|-6-(14-((5)-M-methyl-M-(tetrahydrofuran-3-yl)amino)|-1-oxo-2-buten-1- yl ka)amino)-7-cyclobutyloxyquinazoline, (26). 4-(3-chloro-4-fluorophenyl)amino)|-6-(4-((K)-M-methyl-M-(tetrahydrofuran-3-yl)amino)|-1-oxo-2-butene-1 -yl in )amino)-7-cyclobutyloxyquinazoline, (27) 4-(3-chloro-4-fluorophenyl)amino-1|-6-(14-(1N-methyl-N-(tetrahydropyran-4-yl)amino)- 1-oxo-2-buten-1-ylamino)-7-cyclobutyloxyquinazoline, (28) 65 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-KK)-M-methyl-M- (tetrahydrofuran-2-ylmethyl)amino)|-1-oxo-2-buten-1-ylamino)-7-cyclobutyloxyquinazoline,

4-(3-chloro-4-fluorophenyl)amino1|-6-(14-((5)-M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino|-1-oxo-2-buten-1- yl)amino)-7-cyclobutyloxyquinazoline, (80) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-IM-methyl-N-(2-methoxyethyl)amino|-1-oxo-2 -buten-1-ylylamino)-7-(tetrahydrofuran-3-yloxy)quinazoline, (31) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(IM-methyl-M-(2 -methoxyethyl)amino|-1-oxo-2-buten-1-yl)amino)-7-(tetrahydrop 7/0. Iran-4-yloxy)quinazoline, (32) 4-(3-chloro-4-fluorophenyl )amino1|-6-(14-IM-methyl-N-(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylylamino)-7-(tetrahydrofuran-2-ylmethoxy)quinazoline and (33 ) 4-(3-chloro-4-fluorophenyl)amino|-6-Ch4-(M-cyclopropyl-M-methylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmetoksyquinazoline, their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of the general formula | there are those in which

Ka means 1-phenyl ethyl or 3-chloro-4-fluorophenyl group,

Where stands for dimethylamino-, M-methyl-M-ethylamino-, diethylamino-, M-methyl-M-isopropylamino-,

M-methyl-M-cyclopropylamino-, M-methyl-M-(2-methoxyethyl)amino-, M-ethyl-M-(2-methoxyethyl)amino-, bis(2-methoxyethyl)amino-, morpholino-, M -methyl-M-(tetrahydrofuran-z-yl)amino-,

M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino-, M-methyl-M-(tetrahydrofuran-3-ylmethyl)amino-,

M-methyl-M-(tetrahydropyran-4-yl)amino-or M-methyl-(tetrahydropyran-4-ylmethyl)amino group and

Ko means a cyclopropylmethoxy-, cyclobutyloxy-, cyclopentyloxy-, tetrahydrofuran-3-yloxy-, tetrahydrofuran-2-ylmethoxy-, tetrahydrofuran-3-ylmethoxy-, tetrahydropyran-4-yloxy- or tetrahydropyran-4-ylmethoxy group, and) by with the exception of the following compounds: cyclopropylmethoxyquinazoline, "g (2) 7 4-((3-chloro-4-fluorophenyl)amino)|-6-(4-(morpholin-4-yl)-1-oxo-2-buten-1-ylamino)- 7-cyclopropylmethoxyquinazoline, - (3) 4-((3-chloro-4-fluorophenyl)amino)|-6-(4-(dimethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, that (43. 4-(3-chloro-4-fluorophenyl)amino|-6-(4-(morpholin-4-yl)-1-oxo-2-buten-1-ylamino)-7-cyclobutyloxyquinazoline, - ( 5) and - 4-((3-chloro-4-fluorophenyl)amino|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, (6 ). 4-(3-chloro-4-fluorophenyl)amino)|-6-(4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (7). 4-K (3-chloro-4-fluorophenyl)amino)|-6-(4-(diethylamino )-1-oxo-2-butene-1-ilyamino)-7-cyclopentyloxyquinazoline, (8). 4-KK)-(1-phenylethyl)amino)|-6-(4-(morpholin-4-yl)-1-oxo-2-buten-1-yl|Iamino)-7-cyclobutyloxyquinazoline, « (8) А-КВ)-(1-phenyl 2s ethyl)amino)|-6-(4-(morpholin-4-yl)-1-oxo-2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, . (103. 4-KK)-(1-phenylethyl)amino|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, and (11). 4-KK)-(1-phenylethyl)amino!|-6-H4-(diethylamino)-1-oxo-2-buten-1-yl|Iamino)-7-cyclobutyloxyquinazoline, (12). 4-KK)-(1-phenylethyl)amino!|-6-H4-(diethylamino)-1-oxo-2-buten-1-yl|Iamino)-7-cyclopentyloxyquinazoline, (13). 4-KK)-(1-phenylethyl)amino|-6-C14-(diethylamino)-1-oxo-2-buten-1-yl|amino)-7-cyclopropylmethoxyquinazoline, (14) t 4-((Z- chloro-4-fluorophenyl)amino)|-6-(14-Ibis(2-methoxyethyl)amino|-1-oxo-2-buten-1-yl)amino)-7-cyclopropylmethoxy o inazolin, b (15) 4 -I(3-chloro-4-fluorophenyl)amino)-6-(14-|M-ethyl-m-(2-methoxyethyl)amino)|-1-oxo-2-buten-1-yl)amino)- 7-cyclopropylme - toxiquinazoline,

T» (16) 4-((3Z-chloro-4-fluorophenyl)amino)|-6-(14-(M-methyl-M-(tetrahydropyran-4-yl)amino|-1-oxo-2-butene) -1-yl)amino)-7-cyclopropylmethoxyquinazoline, (17) 4-(3-chloro-4-fluorophenyl)amino!|-6-C4-(diethylamino)-1-oxo-2-buten-1-ilyamino )-7-Ctetrahydrofuran-2-yl)methoxy|) (F) quinazoline,

According to (18) 4-(3-chloro-4-fluorophenyl)amino1|-6-C4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-5)-(tetrahydrofuran-3-yl) )oxybo/Yquinazoline, (19) 4-(3-chloro-4-fluorophenyl)amino1|-6-C4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-Ctetrahydropyran-4- yl)oxy|quin azoline, (20) 65 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(1M-methyl-M-(tetrahydrofuran-3-yl)amino|-1-oxo- 2-buten-1-yl)amino)-7-cyclopropylmethoxyquinazoline,

4-(3-chloro-4-fluorophenyl)amino1-6-(14-(M-(2-methoxyethyl)-M|-methylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropyl methoxyquinazoline , I (2) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-Ibis(2-methoxyethyl)amino)|-1-oxo-2-buten-1-yl)lamino)-7- cyclobutyloxykinase olin, (23) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(1M-methyl-M-(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylamino) )-7-cyclobutyl 70 syquinazoline, (24). 4-(3-chloro-4-fluorophenyl)amino)|-6-(34-(5)-M-methyl-M-(tetrahydrofuran-3-yl)amino |-1-oxo-2-buten-1-yl)amino)-7-cyclobutyloxyquinazoline, (25) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-((K)-M-methyl -M-(tetrahydrofuran-3-yl)amino|-1-oxo-2-buten-1-ilyamino)-7-C cyclobutyloxyquinazoline, (26) 4-(3-chloro-4-fluorophenyl)amino1|-6- (14-(1N-methyl-N-(tetrahydropyran-4-yl)amino|-1-oxo-2-buten-1-ylamino)-7-cyclobutyloxyquinazoline, (27) 4-(3-chloro-4- fluorophenyl)amino1|-6-(14-IM-methyl-N-(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylylamino)-7-(tetrahydrofuran-3-yloxy)quinazoline, ( 28) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(IM-methyl-M) -(2-Methoxyethyl)amino|-1-oxo-2-buten-1-yl)amino)-7-(tetrahydropyran-4-yloxy)quinazoline, compound (29) 4-(3-chloro-4-fluorophenyl )amino1|-6-(14-IM-methyl-N-(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylylamino)-7-(tetrahydrof)uran-2-ylmethoxy)quinazoline, (30) 4-(3-chloro-4-fluorophenyl)amino|-6-Ch4-(M-cyclopropyl-M-methylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoc syquinazoline, (31) - 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino)|-1-oxo-2-butene -1-yl)amino)-7-He cyclopropylmethoxyquinazoline, (32) h 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-KK)-M-methyl-M-(tetrahydrofuran-2- ylmethyl)amino)|-1-oxo-2-buten-1-ylamino )-7-cyclobutyloxyquinazoline and (33) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-((5 )-M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino|-1-oxo-2-buten-1-yl. ) amino)-7-cyclobutyloxyquinazoline, their tautomers, their stereoisomers and their salts. with c As an example of the most preferred compounds of the general formula | the following specific compounds can be named: (c) ; » 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(N,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7-cyclobutyloxyquinazoline, (6). 4-(3-chloro-4-fluorophenyl)amino)|-6-Ch14-("M,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7-cyclopentyloxyquinazoline, - and (in ) 4-KK)-(1-phenylethyl)amino!-6-(X4-(M,M-bis(2-methoxyethyl)amino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxy py quinazoline,

He» (3) 5o 0 4-KK)-(1-phenylethyl)amino)-6-((4-|(M-(2-methoxyethyl)-M-ethylamino)|-1-oxo-2-butene- 1-yl)amino)-7-cyclopropylmethok - syquinazoline, i" (e) 4-KK)-(1-phenylethyl)amino1-6-(14-(M-(2-methoxyethyl)-M-methylamino|-1 -oxo-2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, (e) 4-KK)-(1-phenylethyl)amino1-6-(14-(M-(tetrahydropyran-4-yl)-M- methylamino)|-1-oxo-2-buten-1-ylylamino)-7-cyclopro (F) pyrmethoxyquinazoline,

According to 4-KK)-(1-phenylethyl)amino1|-6-(14-(M-(tetrahydrofuran-3-yl)-M-methylamino)|-1-oxo-2-buten-1-ilyamino)- 7-cyclopropylmethoxyquinazoline, (c) 4-(3-chloro-4-fluorophenyl)amino1-6-K4-1h-(tetrahydrofuran-3-yl)umethyl|-M-methylamino)-1-oxo-2-butene -1-yl)amino|-7-cyclopropylmethoxyquinazoline, (y) 65 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(M,M-dimethylamino)-1-oxo-2-butene -1-ilyamino)-7-(K)-tetrahydrofuran-3-yloxy)quinazoline,

(ju. 4-(3-chloro-4-fluorophenyl)amino1|-6-14-(M,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7-((5)- Tetrahydrofuran-3-yloxy)quinazoline, (l) 4-(3-chloro-4-fluorophenyl)amino1|-6-X14-(M,M-dimethylamino)-1-oxo-2-buten-1-ylamino)- 7-(tetrahydropyran-4-yloxy) quinazoline, (m) 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(M,M-dimethylamino)-1-oxo-2-butene-1 -ilyamino)-7-tetrahydrofuran-2-yl)methoxyquinazoline, 70 (n) 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(M,M-dimethylamino)-1-oxo- 2-buten-1-ylamino)-7-tetrahydrofuran-3-yl)methoxyquinazoline, (o) 4-(3-chloro-4-fluorophenyl)amino1|-6-14-(M,M-diethylamino)-1 -oxo-2-buten-1-ilyamino)-7-tetrahydrofuran-3-yl)methoxy)quinazoline, (n) 4-(KK)-(1-phenylethyl)amino1|-6-114-(M,M -dimethylamine)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (p) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-IM,M-bis(2 -methoxyethyl)amino|-1-oxo-2-buten-1-ylamino)-7-tetrahydrofuran-2-yl)methoxy)quinazoline, (c) 4-((33-chloro-4-fluorophenyl)amino) |-6-(4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-tetrahydro ofuran-2-yl)methoxy quinazoline, (t) Ha 28 4-KZ-chloro-4-fluorophenyl)amino!|-6-Ch4-(M-cyclopropyl-M-methylamino)-1-oxo-2-butene- 1-yl)amino)-7-cyclopentyloxy inazoline and) (U) 4-((3-chloro-4-fluorophenyl)amino)|-6-(4-(M,M-dimethylamino)-1-oxo-2 -buten-1-yl|Iamino)-7-(5)-(tetrahydrofuran-2-yl)methoxy|)quinazoline, their tautomers, their stereoisomers and their salts.

Compounds of the general formula | can be obtained, for example, by the method described below. - a) In this variant, the compound of the general formula He eE (Z « in many

МН « 7 e

M - s and. (AND,

TS

I» M V. sh- in which Ka and Ko have the values indicated above, are subjected to interaction with a compound of the general formula и (1) and puttya (0 шу 70 and:

b i» o 59 in which K has the above values and 74 represents a leaving group such as a halogen atom, e.g.

HF) a chlorine or bromine atom, or a hydroxy group. 7 This 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, optionally in the presence of an inorganic or organic base and optionally in the presence of a dehydrating agent. preferably at a temperature from 50 to 1502C, preferably at a temperature from 20 to 8020.

The interaction with the compound of the general formula I, in which 74 is a leaving group, is carried out, if necessary, in a solvent or a mixture of solvents, for example, in methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, preferably in the presence of tertiary organic base such as triethylamine, pyridine or 4-dimethylaminopyridine in the presence

M-ethyldiisopropylamine (Hünig's bases), and such organic bases can simultaneously also serve as solvents, or in the presence of an inorganic base, such as sodium carbonate, potassium carbonate or caustic sodium solution, preferably at a temperature of -50 to 1502C, preferably at a temperature from -20 to 8020.

The interaction with the compound of the general formula I, in which 74 is a hydroxy group, is preferably carried out in the presence of a dehydrating agent, for example, in the presence of isobutyl ether of chloroformic acid, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane,

M,M'-dicyclohexylcarbodiimide, M,M'-dicyclohexylcarbodiimide/M-hydroxysuccinimide, 1-hydroxybenzotriazole, M,-M'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, preferably in a solvent such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene . ) In this variant, the compound of the general formula (M ach

MN

7 M Y 7 2 and (M), in o

M is c c (o) in which Ka and Co have the above values and 75 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a substituted hydroxy or sulfonyloxy group, a methanesulfonyloxy or p-toluenesulfonyloxy group, is subjected interactions with the compound of the general formula " "- n-t (Ce) in which Ku has the above values.

It is advisable to carry out this reaction in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, C

335 toluene, chlorobenzene, dimethylformamide, dimethyl sulfoxide, methylene chloride, ethylene glycol monomethyl ether, ethylene glycol diethyl ether, or sulfolane, or mixtures thereof, optionally in the presence of an inorganic or tertiary organic base, such as sodium carbonate or potassium hydroxide, a tertiary organic base, such as triethylamine or M-ethyldissopropylamine (Hünig's bases), and such organic bases can simultaneously also serve as solvents, and optionally in the presence of a reaction accelerator, such as an alkali metal halide, at a temperature from -20 to 1502C, preferably, however, at at a temperature from -10 - s to 10020. However, this reaction can also be carried out in the absence of a solvent or in an excess of the used "» compound of the general formula U. " In the reactions described above, the secondary amino group attached to the quinazoline of the general formula II or IM can be protected during the reaction by ordinary protecting groups, which are detached again after the completion of the reaction. As an example of such protective groups can be called formyl, acetyl, trifluoroacetyl, - ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl, or 2,4-dimethoxybenzyl group.

Necessary under certain conditions, the subsequent cleavage of the used protective group is carried out, for example, by hydrolytic means in an aqueous solvent, for example in water, isopropanol/water, acetic acid/water, --3 20 tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide, or by an aprotic route, for example in the presence of iodotrimethylsilane, at a temperature of from 0 to 1202C, preferably at a temperature of from 10 to 10090.

However, cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl group is carried out, for example, by hydrogenolysis, in particular using hydrogen in the presence of a catalyst such as palladium

HF) on charcoal, in a solvent such as methanol, ethanol, ethyl acetic acid or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at a temperature of 0 to 100 C, but preferably at room temperature from 20 to 602C, and at a hydrogen pressure from 1 to 7 bar, more preferably from 3 to 5 bar. The 2,4-dimethoxybenzyl group is preferably, however, cleaved in trifluoroacetic acid in the presence of anisole. tert-Butyl or tert-butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, or treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The trifluoroacetyl group is preferably cleaved by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid, at a temperature of 50 to 120°C or by treatment with caustic sodium, optionally in the presence of a solvent such as tetrahydrofuran, at a temperature from O to 5096.

In addition, compounds of the general formula | can, as already mentioned above, be divided into their enantiomers and/or diastereomers. For example, mixtures of cis-/trans-isomers can be divided into separate cis- and trans-isomers, and compounds with at least one optically active carbon atom into their enantiomers.

So, for example, the obtained mixtures of cis-/trans-isomers can be separated by chromatography into separate cis- and trans-isomers, the obtained compounds of the general formula I, which are formed in the form of racemates, can be separated by known methods | see AIPPdeg M... and EPei! E.G., "Torisv ip b(egeospeptivig", t.b., ed-vo UMiIeu 70 Ipiegvsiepse, 1971) into their optical antipodes, and compounds of the general formula I with at least 2 asymmetric carbon atoms can be separated on the basis of differences in their physical chemical properties according to known methods, for example, chromatography and/or fractional crystallization, into their diastereomers, which, when they are formed in racemic form, can then be separated, as described above, into enantiomers.

Separation into enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by interaction with an optically active substance that forms with a racemic compound salts or derivatives such as esters or amides, primarily with acids and their activated derivatives or alcohols, and separation of the resulting mixture of diastereomeric salts or derivatives, for example, on the basis of differences in their solubility, while free antipodes can be released from pure diastereomeric salts or derivatives under the influence of agents suitable for this purpose. As an example of the optically active acids most often used for the above purposes, we can name O- and Y-forms of tartaric or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. An example of an optically active alcohol is (g)- or (-)-menthol, and an example of an optically active acyl fragment in amides is (5)- or (-)-menthyloxycarbonyl. with

In addition, the obtained compounds of the formula | can be translated into their salts, primarily into their physiologically acceptable salts suitable for pharmaceutical use, with inorganic or organic acids. Examples of suitable acids for this purpose include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. "AND

Compounds of the general formulas 1II-M used as starting materials are partially known from the literature or are obtained by methods known from the literature. --

So, for example, the original compound of the general formula II is obtained by the interaction of an appropriately substituted 7-fluoro-b-nitro compound in the 4 position with the corresponding alcoholate followed by the reduction of the nitro compound obtained in this way, or the original compound of the general formula III is obtained, for example, by the interaction of an acceptable in

335 derivative of bromocrotonic acid with one of the amines of the general formula M known from the literature or the starting p compound of the general formula IM is obtained by acylation of the compound of the general formula II with a derivative of crotonic acid suitable for this purpose.

The compounds of the general formula !/ and their physiologically compatible salts proposed in the invention have, as already indicated above, valuable pharmacological properties, primarily an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (ESF-K), which can be caused, for example, by inhibition (such as binding of ligands, dimerization of receptors or tyrosine kinase itself. In addition, there is also the possibility of blocking signal transmission by components located at a deeper level. "» Biological properties of new compounds were studied according to the method described below.

Inhibition of human ESBE receptor kinase was determined using the cytoplasmic domain of tyrosine kinase, a fragment from methionine at position 664 to alanine at position 1186 based on the sequence, -i (published in Mayte 309 (1984), p.418)1. For this purpose, the protein in the form of a fusion with 57 (glutathione-5-transferase) protein was expressed in 5/9 insect cells using the baculovirus expression system.

Ge") Enzymatic activity was determined in the presence or absence of the tested compounds by the method of serial dilutions. Polymer pEM (4:1) from 5ISMA was used as a substrate. Biotinylated polymer pEM (bio-PECHU) was added as a labeled (indicator) substrate. Each 100 μl of reaction solution contained 1 μl of inhibitor

HT" in 5OH dmMeoo, 20 μl of substrate solution (200 millimolar NERE5 (M-2-hydroxyethylpiperazine-M'-2-ethanesulfonic acid) with pH7.4, 50 millimolar magnesium acetate, 2.5 mg/ml polymer pEM, Bmkg/ml of bio-pEM) and 20 μl of the enzymatic preparation. The enzymatic reaction was initiated by adding 50 μl of a 100 micromolar ATP solution in 10 millimolar magnesium chloride. The parameters of the process of diluting the enzymatic preparation were selected in such a way that the incorporation of phosphate into the bio-pEU and F) occurred in a linear dependence on time and enzyme consumption. The enzyme preparation was diluted in 20 millimolar NEREZ with pH7.4, 1 millimolar EDTC, 130 millimolar common salt solution, 0.0596 triton X-100, 1 millimolar dithiothreitol (DT) and 1095 glycerol. Experiments with enzymes were carried out at room temperature for 30 minutes, stopping the reaction by adding 5 µl of stop solution (250 millimolar EDTC in 20 millimolar HERE5 with pH7 4). A sample with a volume of 1000 μl was transferred to a streptavidin-coated titration microplate and incubated for 20 minutes. at room temperature. After that, the tablet was washed with 200 μl of washing solution (50 millimolar Tris, 0.0590 Tween 20). After adding 100 μl of horseradish peroxidase-labeled (NKRO) antibody to pRU (РУ2ОН 65 Api-RTukhNKR company Tgapzdysiop I arogaifogiev, 25 ng/ml) was incubated for 10 minutes. After that, the titration microplate was washed three times with a washing solution in portions of 200 μl. Then the samples were mixed with 10 μl of a solution containing TMB (3,3,5,5'-tetramethylbenzidine) and peroxidase (A:B -1:1, Kigkedaaga Regtu

Garogayugiyeez). After 10 minutes the reaction was stopped. The optical density of OGlvonm was measured using an EI IZA reader.

All values for the construction of the corresponding graphs were determined in three repetitions.

The data are aligned by iterative calculation using a sigmoidal curve analysis program (Sgarp Rai Rgizt program, version 3.0) with a variable hump slope. The correlation coefficient of all the allowed data obtained by iteration exceeded 0.9, and the upper and lower values of the curves differed by a factor equal to at least 5. Based on these curves, the concentration of the active substance at which the activity of the ECE receptor kinase was inhibited by 5095 (ISvo). 70 The following results were obtained: nisnnnnnnnnshshsh

It follows from the above results that the compounds of the general formula I! inhibit signal transduction mediated by tyrosine kinases, as illustrated by the example of the human EOPE receptor, and are therefore suitable for the treatment of pathophysiological processes caused by hyperfunction of tyrosine kinases. An example of such processes is the formation of benign and malignant tumors, primarily i) tumors of epithelial and neuroepithelial origin, metastasis, as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds proposed in the invention are also suitable for the prevention and treatment of diseases of the respiratory tract and lungs associated with excessive or altered mucus formation due to the stimulation of tyrosine kinases, for example, in inflammatory diseases of the respiratory tract, such as chronic bronchitis, chronic obstructive bronchitis, asthma , bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, A1-antitrypsin deficiency or cough, pulmonary emphysema, pulmonary fibrosis and increased airway reactivity. -

The compounds according to the invention are further suitable for the treatment of diseases of the gastrointestinal tract, as well as of the bile ducts and the gallbladder, associated with a violation of the activity of tyrosine kinases, as occurs, for example, in chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcer colitis and ulcers in the gastrointestinal tract, or as occurs in gastrointestinal diseases associated with hypersecretion, such as Menetriere's disease, adenoma of the secretory glands, and protein loss syndrome. "

Compounds of the general formula! and their physiologically compatible salts can be used, in addition, for the treatment of other diseases caused by the aberrant function of tyrosine kinases, such as, for example, epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation and hematopoietic cells, etc.

Due to their biological properties, the compounds proposed in the invention can be used individually or in combination with other pharmacologically active compounds, for example, for the therapeutic treatment of tumors in monotherapy or in combination with other antitumor therapeutic agents, for example, in combination with topoisomerase inhibitors (for example, etoposide), with antimitotic means (for example, vinblastine), with compounds that interact with nucleic acids (for example, cis-platinum,

He» cyclophosphamide, adriamycin), with hormone antagonists (for example, tamoxifen), with inhibitors of metabolic processes (for example, 5-RSh, etc.), with cytokines (for example, interferons), with antibodies, etc. - For the treatment of diseases of the respiratory tract, these compounds can be used individually or in combination with other drugs intended for the treatment of the respiratory tract, such as, for example, substances that have an expectorant, broncholytic effect and/or suppress the inflammatory process. For the treatment of diseases in the gastrointestinal tract, these compounds can also be prescribed individually or in combination with substances that affect peristalsis or secretion. In such combinations, the active substances can be administered either simultaneously or sequentially.

F) The compounds proposed in the invention individually or in combination with other active substances can be administered intravenously, subcutaneously, intramuscularly, intraperitoneally, nasally, by inhalation or transdermally or orally, and aerosol preparations are primarily suitable for inhalation. 60 In pharmaceutical application, the compounds proposed in the invention are administered, as a rule, to warm-blooded vertebrates, primarily to humans, in doses from 0.01 to 1O0Omg/kg of body weight, preferably from 0.1 to 15mg/kg.

For the preparation of medicinal products, such compounds are processed together with one or more common inert carriers and/or diluents, such as corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylrolidone, citric acid, tartaric acid, 65 WATER, water/ethanol , water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose, or fat-containing substances such as solidified fat, or acceptable mixtures thereof, into conventional galenic forms such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

Below, the invention is illustrated by non-limiting examples.

Preparation of starting compounds

Example I

Z-methyl aminotetrahydrofuran

3.43 g of lithium aluminum hydride is added in portions to 5 Oml of tetrahydrofuran while cooling in an ice bath.

Next, a solution of 5.00 g of 3-((benzyloxycarbonyl)amino)tetrahydrofuran in 20 Oml of 7/0 tetrahydrofuran is added dropwise, while maintaining the temperature below 1022. After 10 minutes, the cooling bath is removed and the reaction mixture is refluxed for about three hours refrigerator. For processing, the reaction mixture, while cooling in an ice bath, is carefully mixed dropwise with 3.7 ml of water, 3.7 ml of 15956 caustic sodium solution and again with 3 ml of water. After that, a small amount of tetrahydrofuran is added and then stirred for 15 minutes. Aluminum hydroxide , which has precipitated, is separated by vacuum filtration and then 75 is washed with tetrahydrofuran in a total amount of 150 ml. The filtrate is concentrated on a rotary evaporator. As a result, a colorless oil is obtained as a residue, which is used in the next reaction without additional purification.

Mass spectrum (EBI"): t/2-102|MANI".

K value: 0.20 (silica gel, methylene chloride/methanol in a ratio of 9:1).

Example II 3-Kbenzyloxycarbonyl)amino|tetrahydrofuran 12.36 ml of tetrahydrofuran-3-carboxylic acid and 27.84 ml of diphenylphosphoryl azide in 500 ml of dioxane are mixed with 41.91 g of benzyl alcohol and 35.81 ml of triethylamine. The reaction mixture is heated to 1002C and kept at this temperature for about seven hours. After cooling to room temperature, the He reaction mixture is concentrated on a rotary evaporator. The residue is dissolved in 500 ml of methylene chloride and washed twice with In. (5) caustic sodium in portions of 100 ml. The organic phase is dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography using cyclohexane/ethyl acetate (3:1 to 1:2) as eluent.

Yield: 15.60g (5595 from theory). AND

Mass spectrum (EI): t/2-220 |M-NO. "-

K value: 0.78 (silica gel, methylene chloride/methanol in a ratio of 9:1).

Example I (Ce) b-amino-4-(3-chloro-4-fluorophenyl)amino)|-7-(K)-tetrahydrofuran-3-yloxy)quinazoline

A mixture of 12.80 g of 4-((3-chloro-4-fluorophenyl)amino|-6-nitro-7-(K)-tetrahydrofuran-3-yloxy)quinazoline, 200 ml

From ethanol, 10 ml of water and 17.20 ml of glacial acetic acid are heated to the boiling point with reflux. refrigerator Next, iron powder is added in portions in a total amount of 7.00 g. The reaction mixture is refluxed for about four hours and then left overnight to cool to room temperature. For processing, the reaction mixture is concentrated on a rotary evaporator. The residue is dissolved in methylene chloride/methanol (9:1), mixed with 20 ml of concentrated ammonia solution and filtered

Through a layer of silica gel. Next, the reaction mixture is intensively washed with methylene chloride/methanol (9:1) and the combined filtrates are concentrated. The residue is mixed with diethyl ether and separated by vacuum filtration. Yield: 8.59 g (7390 from theory).

Mass spectrum (EI): t/2-373, 375 |M-NO,

Kvalue: 0.27 (silica gel, ethyl acetate/methanol in a ratio of 9:1). - Similarly to example I, the following compounds are obtained: iz (1). b-amino-4-((3-chloro-4-fluorophenyl)amino|-7-(5)-tetrahydrofuran-3-yloxy)quinazoline: mass spectrum (EBIU: m/2-373, 375 | M-NO , b Ke value: 0.27 (silica gel, ethyl acetate/methanol in a ratio of 9:1); - 70 (2). b-amino-4-((3-chloro-4-fluorophenyl)amino|-7-(tetrahydropyran- 4-yloxy) quinazoline:

GT" mass spectrum (EB5IU: t/2-387, 389 |M-NI,

Ke value: 0.20 (silica gel, ethyl acetate); (3). b-amino-4-((3-chloro-4-fluorophenyl)amino|-7-(tetrahydrofuran-2-yl)methoxy|)quinazoline: mass spectrum (EB5IU: m/2-387, 389 |M-NO ,

Kvalue: 0.55 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (F) (4) b-amino-4-((3-chloro-4-fluorophenyl)amino|-7-tetrahydrofuran-3-yl)methoxy)quinazole in: ka mass spectrum (E5IU): t/2- 387, 389 |M-NO,

K value: 0.40 (silica gel, ethyl acetate/methanol in a ratio of 9:1). 60 Example IM 4-(3-chloro-4-fluorophenyl)amino)|-b-nitro-7-(K)-tetrahydrofuran-3-yloxy)quinazoline

To a solution of 10.80 g of (K)-3-hydroxytetrahydrofuran in 1000 ml of M,M-dimethylformamide, while cooling in an ice bath, add 13.80 g of potassium tert-butylate in portions. The reaction mixture is stirred for about one hour, after which 10.40 g of 4-((3-chloro-4-fluorophenyl)amino|-6b-nitro-7-fluoroquinazoline is added in portions. 65 Then the cooling bath is removed, and the reaction mixture of dark red colors are stirred for two hours at room temperature. For processing, the reaction mixture is poured into approximately 500 ml of water and neutralized

2n. hydrochloric acid. The yellowish precipitate that fell out was separated by vacuum filtration and dried in an oven with air circulation at 7020.

Output: 12.80 g.

Melting point: 244960.

Mass spectrum (E5IU: t/2-403, 405 |M-NO.

Analogously to the IM example, the following compounds are obtained: (1). 4-(3-chloro-4-fluorophenyl)amino|-6-nitro-7-(5)-tetrahydrofuran-3-yloxy)quinazoline: mass spectrum (EBIU): m/2-403, 405 IM-NI,

Ke value: 0.45 (silica gel, ethyl acetate); (2). 4-(3-chloro-4-fluorophenyl)amino|-6-nitro-7-(tetrahydropyran-4-yloxy)quinazoline: mass spectrum (EB5IU: m/2-417, 419 IM-NI,

Ke value: 0.42 (silica gel, ethyl acetate); (3). 4-(3-chloro-4-fluorophenyl)amino|-b-nitro-7-K(tetrahydrofuran-2-yl)methoxy|)quinazoline: mass spectrum (EI): t/2-417,419 |M-NG,

Ke value: 0.47 (silica gel, ethyl acetate); (4). 4-(3-chloro-4-fluorophenyl)amino|-b-nitro-7-K(tetrahydrofuran-3-yl)methoxy|)quinazoline: mass spectrum (EB5IU: t/2-417, 419 IM-NI,

Ke value: 0.41 (silica gel, ethyl acetate); (5). 4-(3-chloro-4-fluorophenyl)amino)-b-nitro-7-((tetrahydropyran-4-yl)methoxy|)quinazoline: mass spectrum (ESI"): m/2-433, 435 MANI" ,

Ke value: 0.79 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (6). 4-(3-chloro-4-fluorophenyl)amino|-6-nitro-7-(K)-(tetrahydrofuran-2-yl)methoxy)quinazoline: ch mass spectrum (E5I"): m/2-419, 421 IMANI",

Ke value: 0.44 (silica gel, ethyl acetate); i) (7). 4-(Z-chloro-4-fluorophenyl)amino|-b-nitro-7-(Z)-(tetrahydrofuran-2-yl)methoxy|)quinazoline: mass spectrum (ESI"): m/2-419,421 MANI ,

Ke value: 0.44 (silica gel, ethyl acetate). "AND

Example M (k)-M-Ktetrahydrofuran-2-yl)methyl|-M-methylamine -- 21.10 g of (K)-M-Ktetrahydrofuran-2-yl)methyl|-M-benzyl-M-methylamine (crude product from example MI) "0 is dissolved in 200 ml of methanol and hydrogenated in the presence of 4.00 g of palladium on activated carbon (1096 Pa) at room temperature until hydrogen absorption stops. For recycling, the catalyst is filtered off the filtrate is concentrated on a rotary evaporator. As a residue, a liquid yellowish oil is obtained, which after additional purification is used in the next reaction.

Output: 8.6Ω (7390 from theory).

Mass spectrum (EBI"): t/2-116 (MANI. "

Similarly to example M, the following compounds are obtained: (1) (5)-M-Ktetrahydrofuran-2-yl)methyl/|-M-methylamine: - mass spectrum (E5I"): t/2-116 MANI"; "» (2) M-Ktetrahydropyran-4-yl)umethyl|-M-methylamine " mass spectrum (EBI"): t/2-130 MANI.

Example MI (kO-M-Ktetrahydrofuran-2-yl)methyl|-M-benzyl-M-methylamine - A solution of 24.60 g of M-benzyl-M-methylamide (K )-tetrahydrofuran-2-carboxylic acid in 9Oml of tetrahydrofuran. The reaction mixture is refluxed for two hours. For processing, the reaction mixture is cooled to

In an ice bath to 02C, mix with 20 ml of water and 1 ml of 15N. caustic sodium and then stir for 20 minutes. After -k 70 it is filtered through a layer of magnesium sulfate and then washed with tetrahydrofuran in a total amount of approximately 500 ml. The filtrate is concentrated in a vacuum, while obtaining as a residue a yellowish oil, which without

T" of additional purification is used in the next reaction.

Yield: 21.10g (9295 from theory)

Mass spectrum (EBI"): t/2-206 (MANI. 59 Similarly to the MI example, the following compounds are obtained:

HF) (1) (5)-N-tetrahydrofuran-2-yl)methyl|-N-benzyl-N-methylamine: 7 K value: 0.20 (silica gel, ethyl acetate/methanol in the ratio 9:1); (2) M-Ctetrahydropyran-4-yl)umethyl|-M-benzyl-M-methylamine: mass spectrum (ESI"): t/2-220 MANI. 60

Example of MINE

M-benzyl-M-methylamide (K)-tetrahydrofuran-2-carboxylic acid

To a solution of 20.00 ml of (K)-tetrahydrofuran-2-carboxylic acid in 200 ml of tetrahydrofuran, add 25.30 g

M-benzyl-M-methylamine. Then, during cooling in an ice bath, tetrafluoroborate and O-(benzotriazol-1-yl)-M,M,M',M'-tetramethyluronium in a total amount of 67.10 g are added in portions, and the reaction mixture is then stirred at room temperature for about 48 hours. The precipitate formed is separated by vacuum filtration, the filtrate is concentrated, mixed with water and filtered again. The pH value of the obtained filtrate is set to alkaline with the help of sodium bicarbonate solution and extracted with ethyl acetate.

The combined ethyl acetate extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. As a result, a yellowish oil is obtained as a residue, which is used in the next reaction without further purification.

Yield: 24.60g (5495 from theory).

Mass spectrum (EBI"): t/2-220 (MANI.

Ke value: 0.62 (silica gel, ethyl acetate). 70 Similarly to the MI example, the following compounds are obtained: (1) M-benzyl-M-methylamide (5)-tetrahydrofuran-2-carboxylic acid: mass spectrum (ESI"): t/2-242 |Me-Mai/",

Ke value: 0.62 (silica gel, ethyl acetate); (2) M-benzyl-M-methylamine of tetrahydropyran-4-carboxylic acid (amide coupling with 75. 1,1-carbonyldiimidazole is carried out in tetrahydrofuran): mass spectrum (ESI"): t/2-256 |Me-Mai ,

Ke value: 0.45 (silica gel, ethyl acetate).

Example of MIA b-amino-4-((3-chloro-4-fluorophenyl)amino|-7-Ktetrahydropyran-4-yl)methoxy|)quinazoline 20 22.80g 4-(3-chloro-4-fluorophenyl)amino) |-b-nitro-7-(tetrahydropyran-4-yl)umethoxy)quinazoline at room temperature is hydrogenated in ZOO ml of tetrahydrofuran in the presence of 3.50 g of platinum dioxide until the calculated amount of hydrogen is absorbed. Then the catalyst is filtered off, and the filtrate is concentrated to dryness on a rotary evaporator. The residue is mixed with diethyl ether, separated by vacuum filtration, then washed with diethyl ether and dried at room temperature. p 25 Yield: 19.95 g (9395 from theory). at

Mass spectrum (EBI"): t/2-403, 405 MANI.

Melting point: 22196.

Similarly to the example of MIII, the following compounds are obtained: (1). b-amino-4-((3-chloro-4-fluorophenyl)amino|-7-KK)-(tetrahydrofuran-2-yl)methoxy)quinazoline: C 30 mass spectrum (EVI7): m/2-389, 391 MANI", -

Ke value: 0.11 (silica gel, ethyl acetate); (2). b-amino-4-((3-chloro-4-fluorophenyl)amino|-7-(5)-(tetrahydrofuran-2-yl)methoxy|)quinazoline: mass spectrum (ESI"): m/ 2-389, 391 MANI", "I with Ke value: 0.33 (silica gel, ethyl acetate/methanol in the ratio 9:1). M

Preparation of final compounds

Example 1 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(M-(2-methoxyethyl)-M-methylamino)|-1-oxo-2-buten-1-ylamino)-7- cyclopropylmethoxyquinazoline « 20 To a solution of 4.50 g of bromocrotonic acid in bOml of methylene chloride, 4.7Oml of oxalyl chloride is added dropwise. Then add one drop of M,M-dimethylformamide. After approximately ЗОхв. the evolution of gas is completed, and the reaction mixture is concentrated on a rotary evaporator. Crude bromocrotonic acid chloride is dissolved in 30 ml of methylene chloride and, upon cooling in an ice bath, 7.00 g is added dropwise to the solution. 4-(3-chloro-4-fluorophenyl)amino|-6-amino-7-cyclopropylmethoxyquinazoline and 10.20 ml of Hunig's base in 1500 ml of tetrahydrofuran. The reaction mixture is stirred for approximately 1.5 hours while cooling in an ice-1 bath, and then for another two hours at room temperature. After that, 5.20 g are added

M-(2-methoxyethyl)-M-methylamine and the reaction mixture is stirred overnight at room temperature. For its processing, the reaction mixture is diluted with methylene chloride and thoroughly washed with water. Organic phase

Fu is dried over magnesium sulfate and concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate followed by ethyl acetate/methanol (19:1) as eluent. - Yield: 5.07g (51905 from theory).

T» Mass spectrum (EviIU): t/2-512, 514 M-NI.

K value: 0.25 (silica gel, ethyl acetate/methanol in a ratio of 9:1).

Similarly to example 1, the following compounds are obtained: vv (O 4-((3Z-chloro-4-fluorophenyl)amino)|-6-(4-(M,M-dimethylamino)-1-oxo-2-buten-1- ilyamino)-7-cyclobutyloxyquinazoline: iF) mass spectrum (EI: t/2-468, 470 |M-NI, co K value: 0.09 (silica gel, ethyl acetate/methanol in the ratio 9:1); (2) in 4-I(3-chloro-4-fluorophenyl)amino)|-6-14-(M,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7-cyclopentyloxyquinazoline: mass spectrum (EBIU : t/2-482,484 IM-NO,

Ke value: 0.11 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (3) 4-KK)-(1-phenylethyl)amino!-6-(Х4-(M,M-bis(2-methoxyethyl)amino)-1-oxo-2-buten-1-ilyamino)-7- cyclopropylmethoxy 65 Quinazoline: mass spectrum (EBIU: t/2-532 |M-NI,

K value: 0.40 (silica gel, ethyl acetate/methanol in a ratio of 9:1); 4-KK)-(1-phenylethyl)amino1-6-(14-(M-(2-methoxyethyl)-M-ethylamino|-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoc syquinazoline: mass -spectrum (EBIU: t/2-502 |M-NI,

K value: 0.20 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (5) 4-KK)-(1-phenylethyl)amino1|-6-(14-M-(2-methoxyethyl)-M-methylamino|-1-oxo-2-buten-1-yl)iamino)-7 -cyclopropylmetok 70 syquinazoline: mass spectrum (EBIU: t/2-488 |M-NI,

K value: 0.25 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (6) 4-KK)-(1-phenylethyl)amino1-6-(14-(M-(tetrahydropyran-4-yl)-M-methylamino)|-1-oxo-2-buten-1-ylylamino)- 7-cyclopro 75 pyrmethoxyquinazoline: mass spectrum (E5IU: t/2-514 |M-NI,

K value: 0.15 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (7). 4-KK)-(1-phenylethyl)amino1|-6-(14-(M-(tetrahydrofuran-3-yl)-M-methylamino)-1-oxo-2-buten-1-yl)amino)-7 -cyclopropylmethoxyquinazoline: mass spectrum (EBIU: t/2-500 |M-NGI,

Ke value: 0.18 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (8) 4-(3-chloro-4-fluorophenyl)amino1-6-K4-1h-(tetrahydrofuran-3-yl)umethyl|-M-methylamino)-1-oxo-2-buten-1-yl)amino |- 7-cyclopropylmethoxyquinazoline: c mass spectrum (EVIU: t/2-538, 540 |M-NG, o

Ke value: 0.27 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (9) 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(M,M-dimethylamino)-1-oxo-2-buten-1-ilyamino)-7-(K)-tetrahydrofuran -3-yloxy)quinazoline: C 3o mass spectrum (EBI7): m/2-486,488 MEI"; - (10) 4-(3-chloro-4-fluorophenyl)amino1|-6-1Х14-(M, M-Dimethylamino)-1-oxo-2-buten-1-ylamino)-7-(5)-tetrahydrofuran-3-yloxy)quinazoline: ChI mass spectrum (ESI"): m/2-486 , 488 MANI", m

Ke value: 0.45 (silica gel, methylene chloride/methanol in a ratio of 5:1); (11) 4-(3-chloro-4-fluorophenyl)amino1|-6-X14-(M,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7-(tetrahydropyran-4-yloxy ) quinazoline: "20 mass spectrum (EBI"): t/2-500, 502 MANI", - s Ke value: 0.55 (silica gel, methylene chloride/methanol in a ratio of 5:1); (12) » 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(N,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7-tetrahydrofuran-2-yl)meth oxyquinazoline: -mass spectrum (EBI"): t/2-500, 502 MANI", -I K value: 0.60 (silica gel, methylene chloride/methanol in a ratio of 5:1); (13) e 4-(3-chloro-4-fluorophenyl)amino! il) met

He») oxyquinazoline: tsu 5 mass spectrum (EBI"): t/2-500, 502 MANI",

K value: 0.50 (silica gel, methylene chloride/methanol in a ratio of 5:1); t" (14) 4-(3-chloro-4-fluorophenyl)amino1|-6-14-(M,M-diethylamino)-1-oxo-2-buten-1-ilyamino)-7-Ctetrahydrofuran-3- yl)metho xy)quinazoline: mass spectrum (EBI"): t/2-528, 530 MANI",

Gee! Ke value: 0.31 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (15) where 4-KK)-(1-phenylethyl)amino1|-6-Ch4-(M,M-dimethylamino)-1-oxo-2-buten-1-yl|amino)-7-cyclopropylmethoxyquinazoline: mass spectrum (E5BI"): t/2-446 MANI, 60 K value: 0.11 (silica gel, ethyl acetate/methanol in the ratio 9:1); (16) 4-(3-chloro-4-fluorophenyl)amino1|-6 -(14-IM,M-bis(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylamino)-7-tetrahydrofuran-2-yl)umethoxy)quinazoline: mass spectrum (EBI") : t/2-588, 590 MANI", because Ke value: 0.55 (silica gel, methylene chloride/methanol in a ratio of 9:1);

4-(3-chloro-4-fluorophenyl)amino|-6-(Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-tetrahydrofuran-2-yl)methoxy quinazoline : mass spectrum (E5BI"): t/2-542, 544 MANI",

K value: 0.55 (silica gel, methylene chloride/methanol in a ratio of 9:1); (18) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(M-(2-methoxyethyl)-M-1-methylamino|-1-oxo-2-buten-1-yl)iamino )-7-cyclopentyloxyquinazoline: 70 mass spectrum (EBI"): t/2-528, 530 MANI",

K value: 0.25 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (19) 4-(3-chloro-4-fluorophenyl)amino1-6-K4-(K)-M-(tetrahydrofuran-2-yl)methyl|-M-methylamino)-1-oxo-2-buten-1 -yl)amino|-7-cyclopropylmethoxyquinazoline: mass spectrum (EBI"): m/2-540, 542 MANI", melting point: 149-15390; (20) 4-(3-chloro-4-fluorophenyl)amino!-6-K4-4(5)-M-tetrahydrofuran-2-yl)umethyl|-M-methylamino)-1-oxo-2-butene- 1-yl)amino|-7-cyclopropylmethoxyquinazoline: mass spectrum (EVI7): m/2-540, 542 MANI",

Ke value: 0.29 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (21). 4-KK)-(1-phenylethyl)amino)|-6-Ch4-(M,M-dimethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline: mass spectrum (EBI" ): t/2-560 MANI, p. 29 Ke value: 0.17 (silica gel, ethyl acetate/methanol in a ratio of 9:1); Ge) (22) 4-(3-chloro-4-fluorophenyl)amino1|-6- Х14-(M-cyclopropyl-M-methylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxy inazoline: « mass spectrum (EI: t/2-508, 510 |M-NI, temperature melting point: 1409С; - (23) c 4-(3-chloro-4-fluorophenyl)amino|-6-Х4-(-diclopropyl-M-methylamino)-1-oxo-2-buten-1-ylidamino)-7 -cyclopropylmethox iquinazoline: "I mass spectrum (Evi"7): t/2-496,498 MANI, im-

K value: 0.42 (silica gel, ethyl acetate/methanol in a ratio of 9:1); (24) 4-(3-chloro-4-fluorophenyl)amino!-6-K4-1Mh-((tetrahydropyran-4-yl)umethyl|-M-methylamino)-1-oxo-2-buten-1-yl )amino|- 7-cyclopropylmethoxyquinazoline: "mass spectrum (EBI"): t/2-554, 556 MANI", - s melting point: 14190; . 25 )amino|-7-c cyclopropylmethoxyquinazoline: mass spectrum (ESI"): t/2-530 MANI, - and Ke value: 0.32 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia in the ratio 90:10:0, 5); (25) 4-(3-chloro-4-fluorophenyl)amino1-6-K4-(K)-M-(tetrahydrofuran-2-yl)methyl|-M-methylamino)-1-oxo-2-butene- 1-yl)ami(o)no|-7-cyclopentyloxyquinazoline: -oUu 70 mass spectrum (EBI"): m/2-554, 556 MANI", melting point: 117-12190; t" (t) 4-(3-chloro-4-fluorophenyl)amino!-6-K4-4(5)-M-tetrahydrofuran-2-yl)umethyl|-M-methylamino)-1-oxo-2- buten-1-yl)amino|-7-cyclopentyloxyquinazoline: 99 mass spectrum (EVI7): m/2-554, 556 MANI",

HF) K value: 0.32 (silica gel, ethyl acetate/methanol/concentrated aqueous ammonia in the ratio 90:10:0.5); t (28) 4-(3-chloro-4-fluorophenyl)amino1|-6-N4-(N,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7-tetrahydropyran-4-yl )methoxyquinazoline: 60. mass spectrum (EBI7): t/2-514, 516 (MENI,

Ke value: 0.19 (silica gel, methylene chloride/methanol/aqueous ammonia conc. ratio 95:5:0.05); (29) 4-(3-chloro-4-fluorophenyl)amino!|-6-(4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-Ctetrahydropyran-4- il)umethox b iquinazoline: mass spectrum (EB5IU: t/2-554, 556 |M-NI,

melting point: 1749; 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-IM,M-bis(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylylamino)-7-(Ktetrahydropyran -4-yl)umethoxy|)quinazoline: mass spectrum (E5I"): m/2-602, 604 MANI", melting point: 100-10290; (31) 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(M,M-dimethylamino)-1-oxo-2-buten-1-ilyamino)-7-KK)-(tetrahydrofuran -2-yl 70 )methoxy|)quinazoline: mass spectrum (ESI"): m/2-500, 502 MANI", melting point: 110-11290; (32) 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(N,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7-(5)-( tetrahydrofuran-2-yl 75 U"methoxy)quinazoline: mass spectrum (E5I"): t/2-500, 502 MANI",

Ke value: 0.23 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia in the ratio 90:10:01); (33). 4-I(3-chloro-4-fluorophenyl)amino1|-6-14-(M-ethyl-M-methylamino)-1-oxo-2-buten-1-ylamino)-7-(5)-( tetrahydrofuran-Z-yl)oxy|quinazoline: mass spectrum (EBI"): t/2-500, 502 MANI", melting point: 154-15790; (34) 4-(3-chloro-4-fluorophenyl)amino1|-6-1Х4-(M-isopropyl-M-methylamino)-1-oxo-2-buten-1-ylamino)-7-(5)- (tetrahydrofuran-Z-yl)oxy)quinazoline: cm mass spectrum (EBI"): m/2-514, 516 MANI", o)

Ke value: 0.34 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia in the ratio 90:10:1); (35). 4-((3-chloro-4-fluorophenyl)amino|-6-44-(morpholin-4-yl)-1-oxo-2-buten-1-yl amino)-7-(5)-(tetrahydrofuran- Z-yl)oxy|quinazoline: "mass spectrum (ESI"): m/2-528, 530 |MANI", melting point: 184-1852С; (36) t 4-(3-chloro-4-fluorophenyl)amino1|-6-X4-(K-isopropyl-M-methylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquine (Te ) azoline: mass spectrum (E5BI"): t/2-512, 514 IMANI", Z

Ke value: 0.53 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia in the ratio 90:10:0.5); - (37) 4-(3-chloro-4-fluorophenyl)amino1|-6-14-(M-ethyl-M-methylamino)-1-oxo-2-buten-1-ilyamino)-7-(5) -(tetrahydrofuran-2-ylmethoxy)quinazoline: mass spectrum (E5IU: t/2-512, 514 IM-NI,

K value: 0.15 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia in the ratio 90:10:1); - c (38) h 4-(3-chloro-4-fluorophenyl)amino!|-6-Х4-(M-diethylamino)-1-oxo-2-buten-1-ilyamino)-7-((5) -(tetrahydrofuran-2-yl)me » toxy)quinazoline: mass spectrum (EBIU: t/2-526, 528 |M-NI,

Ke value: 0.27 (silica gel, methylene chloride/methanol in a ratio of 9:1); them (39) their 4-(3-chloro-4-fluorophenyl)amino1|-6-1Х4-(M-isopropyl-M-methylamino)-1-oxo-2-buten-1-ylamino)-7-(5 )-(tetrahydrofuran-2-yl)methoxy|)quinazoline: b mass spectrum (ESI"): m/2-528, 530 MANI", - 70 Ke value: 0.31 (silica gel, methylene chloride/methanol in the ratio of 9 :1).

Similarly to the above examples and other methods known from the literature, it is also possible to obtain

T" the following compounds: (1). 4-benzylamino-6-14-(M,M-diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (2) 4-(3-chloro-4-fluorophenyl)amino!- 6-K4-1Mch-((tetrahydropyran-4-yl)umethyl|-M-methylamino)-1-oxo-2-buten-1-yl)amino|-

HF) 7-cyclopropylmethoxyquinazoline, q (3) 4-(3-chloro-4-fluorophenyl)amino1|-6-X4-(M,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7 -Ktetrahydropyran-4-yl)methoxyquinazoline, 4-KK)-(1-phenylethyl)amino|-6-К4-1хЧ-(Ktetrahydrofuran-2-yl)methyl|-M-methylamino)-1-oxo-2- buten-1-yl)amino!-7-cyclopropylmethoxyquinazoline, (5) 4-KK)-(1-phenylethyl)amino!-6-H4-(M,M-dimethylamino)-1-oxo-2-butene -1-ilamino)-7-tetrahydrofuran-2-yl)methoxybenzoylquinazoline,

4-KK)-(1-phenylethyl)amino1|-6-(14-(M,M-bis(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylamino)-7-Ktetrahydrofuran-2 -yl)methoxy)quinazoline, I FO 4-KK)-(1-phenylethyl)amino!|-6-Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7- Tetrahydrofuran-2-yl) methoxy) x inazoline.

Example 2

Dragee with the content of the active substance 75mg 70 Composition based on 1 core of the dragee: active substance 75.0mg calcium phosphate 93.Omg corn starch 35.Bmg polyvinylpyrrolidone 10.Omg hydroxypropylmethylcellulose 15.O0mg

Obtaining:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the specified amount of magnesium stearate. Pressed products with a diameter of approximately 13 mm are obtained from the resulting mixture on a tabletting machine, which are rubbed on a suitable machine through a sieve with a cell size of 1.5 mm and mixed with the remaining amount of magnesium stearate. From this granulate, tablets of a given shape are pressed on a tableting machine.

Core weight: 23Omg.

Punch: Omm diameter, with a concave working surface. high school

A film coating is applied to the dragee cores obtained in this way, which consists mainly of (o) hydroxypropylmethylcellulose. Finished coated dragees are polished with beeswax.

Dragee mass: 245 mg.

Example C

Tablets with the active substance content of 100 mg Z

Composition based on 1 tablet: -

F

"zv t 11111 royumy"

Obtaining:

The active ingredient is mixed with lactose and starch and evenly moistened with an aqueous solution of polyvinylpyrrolidone. After pressing the wet mass through a sieve (cell size 2.0 mm) and drying in a lattice drying cabinet at 502C, the product is again sieved through a sieve (with a cell size of 1.5 mm) and a lubricant is mixed in. The mixture ready for pressing is processed into tablets.

Tablet weight: 220 mg.

Tablet diameter: 1 Ohm, double-flat with a double-sided facet and a dividing notch on one side. 7 Example 4 tablets with the content of the active substance 150 mg

Composition based on 1 tablet: (22) z » t (F) vom o Obtaining:

The mixture of the active substance with lactose, corn starch and silicic acid is moistened with a 2095-niM 60 aqueous solution of polyvinylpyrrolidone and pressed through a sieve with a cell size of 1.5 mm. The granulate dried at 452C is once again rubbed through the same sieve and mixed with the specified amount of magnesium stearate. Tablets are pressed from this mixture.

Weight of tablets: ZOOmg.

Punch: diameter 10 mm, with a flat working surface. because Example 5

Hard gelatin capsules containing 150 mg of active substance

Composition based on 1 capsule: and 1111100 approx.

The active substance is mixed with auxiliary substances, sifted through a sieve with a cell size of 0.75 mm and mixed until homogeneity in the appropriate apparatus. The resulting mixture is packaged in hard gelatin capsules of size 1.

The mass of the contents of the capsule: approximately 32Omg. t Capsule shell: hard gelatin capsule size 1.

Example 6

Suppositories with the active substance content of 150 mg

Composition based on 1 candle: zv 111 rooooo cm

Obtaining: shchi

After melting the mass for suppositories, the active substance is homogeneously dispersed in it and the molten mass is poured into pre-cooled forms.

Example 7 -

Suspension with the content of the active substance 50 mg "-

Composition based on 100 ml of suspension: (Se) active substance 1.00 g "E

Carboxymethylcellulose oil O1og 3 methyl ether of p-hydroxybenzoic acid O,oBg c. propyl ether of p-hydroxybenzoic acid b, О1g cane sugar 10.00g glycerin God « sorbitol solution, 7095th 20.0ог flavoring О,Зог З с water, distilled to 10О0ml . » Obtaining:

Distilled water is heated to 702C. Further, methyl and propyl ethers of p-hydroxybenzoic acid, as well as glycerin and sodium salt of carboxymethylcellulose are dissolved in it with stirring. The solution is cooled to room temperature, the active substance is added while stirring and dispersed until they are homogenous. After adding and dissolving sugar, sorbitol solution, and flavoring, the suspension is vacuumed while stirring to remove air from it.

Me. In 5 ml of suspension, the content of the active substance is 500 mg. -oUu 70 Example 8

Ampoules with the content of the active substance 1Omg. Composition: active substance 10.Omg

O, O1n. hydrochloric acid 8.4.

HF) double distilled water up to 2.00 ml of water. Preparation:

The active substance is dissolved in the required amount of 0.01n. NSI, the solution is brought to isotonic by adding 60 table salt, sterilized by filtration and packaged in 2-milliliter ampoules.

Example 9

Ampoules with the content of the active substance 5Omg

Composition: 65 active substance BO Omg

O, O1n. hydrochloric acid in.4.

twice distilled water up to 10.Oml

Obtaining:

The active substance is dissolved in the required amount of О,О01n. NS, the solution is brought to isotonic by adding table salt, sterilized by filtration and packaged in 10-milliliter ampoules.

Example 10

Capsules for powder inhalation with the active substance content of 5 mg

Composition based on 1 capsule: in fractions

Obtaining:

The active substance is mixed with lactose for inhalation. The resulting mixture is packed into capsules (the weight of an empty capsule is about 5 Ω) in a machine for filling capsules.

Capsule weight: 70.Omg.

Capsule size: 3.

Example 11

Solution for inhalation, which contains 2.5 mg of the active substance, for a manual inhaler

The composition based on one portion, which is released with a single click on the head of the inhaler: active substance 2,500 mg benzalkonium chloride b, 001 mg Ge etc. hydrochloric acid 4.5. Ge) ethanol/water (50:50) up to 15,000 mg

Obtaining:

The active ingredient and benzalkonium chloride are dissolved in ethanol/water (50:50). The pH value of the solution is set to the required value by adding In. hydrochloric acid. The resulting solution is filtered and packaged in replaceable canisters - (cartridges) intended for a manual inhaler.

The mass of the contents of the can: 4.5 g. (se)

Claims (1)

"The formula of the invention of M 1. Quinazoline derivatives of the general formula E MN h N a av av Z s I. | t ke also by :» m that (Fi sh- NK in which t- Ka means benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group, Ge") K means dimethylamino-, M-methyl-M-ethylamino- , diethylamino-, M-methyl-M-isopropylamino-, 5p / M-methyl-M-cyclopropylamino-, M-methyl-M-(2-methoxyethyl)amino-, M-ethyl-M-(2-methoxyethyl)amino -, - bis(2-methoxyethyl)amino-, morpholino-, M-methyl-M-(tetrahydrofuran-z-yl)amino-, Ta» M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino-, M -methyl-M-(tetrahydrofuran-3-ylmethyl)amino-, M-methyl-M-(tetrahydropyran-4-yl)amino- or M-methyl-M-(tetrahydropyran-4-ylmethyl)amino group and Ko means cyclopropylmethoxy- , cyclobutyloxy-, cyclopentyloxy-, tetrahydrofuran-3-yloxy-, tetrahydrofuran-2-ylmethoxy-, tetrahydrofuran-3-ylmethoxy-, tetrahydropyran-4-yloxy- or tetrahydropyran-4-ylmethoxy group, iF) with the exception of the following compounds: o ( in 4-((3Z-chloro-4-fluorophenyl)amino)|-6-44-(M,M-diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, 60 (2) 4-(3-chloro-4-fluorophenyl)amino!|-6-4-(morpholin-4-yl)-1-o xo-2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, (3) 4-(3-chloro-4-fluorophenyl)amino!|-6-4-(dimethylamino)-1-oxo-2-buten-1 -iliamino)-7-cyclopropylmethoxyquinazoline, (4). 4-(3-chloro-4-fluorophenyl)amino)|-6-Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ylamino)-7-cyclobutyloxyquinazoline, 65 (53. 4- (3-chloro-4-fluorophenyl)amino)|-6-H4-(morpholin-4-yl)-1-oxo-2-buten-1-ylamino)-7-cyclopentyloxyquinazoline, (6). 4-KZ-chloro-4-fluorophenyl)amino|-6-L14-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (7). 4-K(3-chloro-4-fluorophenyl)amino1|-6-(4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, (8). 4-KK)-(1-phenylethyl)amino)|-6-(4-(morpholin-4-yl)-1-oxo-2-buten-1-yl|Iamino)-7-cyclobutyloxyquinazoline, (9). 4-KK)-(1-phenylethyl)amino|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (10). 4-(K)-(1-phenylethyl)amino!|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-yl|Iamino)-7-cyclopentyloxyquinazoline, (11). 4-KK)-(1-phenylethyl)amino)-6-(4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (12). 4-KK)-(1-phenylethyl)amino)-6-(4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, (13). 4-KK)-(1-phenylethyl)amino)|-6-14-(diethylamino)-1-oxo-2-buten-1-yl|amino)-7-cyclopropylmethoxyquinazoline, (14) 70 4-(Z- chloro-4-fluorophenyl)amino1-6-(14-Ibis(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylamino)-7-diclopropylmethoxy inazoline, (15). 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(M-ethyl-M-(2-methoxyethyl)amino)|-1-oxo-2-buten-1-yl)amino)- 7-cyclopropylmethoxyquinazoline, (16) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-M-methyl-M-(tetrahydropyran-4-yl)amino|-1-oxo-2-buten- 1-yl)amino)-7-cyclopropylmethoxyquinazoline, 17 4-(3-chloro-4-fluorophenyl)amino!|-6-C4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7 -Ktetrahydrofuran-2-yl)methoxy|)quinazoline, (18). 4-(3-chloro-4-fluorophenyl)amino|-6-D4-(diethylamino)-1-oxo-2-buten-1-yl|iamino)-7-((5)-(tetrahydrofuran-z-yl) )oxy|)quinazoline, (19) 4-(3-chloro-4-fluorophenyl)amino1|-6-C4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-Ctetrahydropyran-4- yl)oxy|quin azoline, sc (20) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino)|-1- oxo-2-buten-1-yl)amino)-7- i) cyclopropylmethoxyquinazoline and (21). 4-(3-chloro-4-fluorophenyl)amino)|-6-(54-M-methyl-M-(tetrahydrofuran-3-yl)amino|-1-oxo-2-buten-1-yl)amino) -7-cyclopropylmethoxyquinazoline, their tautomers, their stereoisomers and their salts. 2. Compounds of the general formula I according to claim 1, in which Ka, Ky and Kos have the values specified in claim 1, but with the exception of the following compounds: "o (1) 4-KZ-chloro-4-fluorophenyl)amino|- 6- D4-(M,M-diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, « (2) - 4-(3-chloro-4-fluorophenyl)amino!|-6 -4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (3) 4-(3-chloro-4-fluorophenyl)amino!|-6-4- (dimethylamino)-1-oxo-2-butene-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (4). 4-(3-chloro-4-fluorophenyl)amino)|-6-Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ylamino)-7-cyclobutyloxyquinazoline, " (5). 4-(3-chloro-4-fluorophenyl)amino)|-6-(4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-dcyclopentyloxyquinazoline, pe) c (6 ). 4-KZ-chloro-4-fluorophenyl)amino|-6-L14-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, . (7). 4-KZ-chloro-4-fluorophenyl)amino|-6-L14-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, and? (8). 4-KK)-(1-phenylethyl)amino1|-6-Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (9). 4-KK)-(1-phenylethyl)amino|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (10). 4-KK)-(1-phenylethyl)amino1|-6-Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, -I (11). 4-KK)-(1-phenylethyl)amino)|-6-Ch4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (123. 4-KK)-(1- phenylethyl)amino)|-6-Ch4-(diethylamino)-1-oxo-2-buten-1-ylamino)-7-cyclopentyloxyquinazoline, ve (13). 4-KK)-(1-phenylethyl)amino1|-6-(4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, Ge" (143. 4-((Z- chloro-4-fluorophenyl)amino1-6-(14-Ibis(2-methoxyethyl)amino)|-1-oxo-2-buten-1-yl)5or amino)-7-cyclopropylmethoxyquinazoline, t (15) i» 4 -(3-chloro-4-fluorophenyl)amino1|-6-(14-I(1N-ethyl-M-(2-methoxyethyl)amino|-1-oxo-2-buten-1-yl)iamino)-7 -cyclopropyl toxiquinazoline, (16). 4-KZ-chloro-4-fluorophenyl)amino1|-6-(14-M-methyl-M-(tetrahydropyran-4-yl)amino|-1-oxo-2-buten-1-yl) diamino)- 7-cyclopropylmethoxyquinazoline, 17F) 4-(3-chloro-4-fluorophenyl)amino!|-6-C4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-tetrahydrofuran-2-yl )methoxy|)ca quinazoline, (18) bo 4-KZ-chloro-4-fluorophenyl)amino)|-6-CH4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-(( 5)-(tetrahydrofuran-3-yl)oxy)1-quinazoline, (19) 4-(3-chloro-4-fluorophenyl)amino1|-6-C4-(diethylamino)-1-oxo-2-buten-1-ilyamino )-7-Ctetrahydropyran-4-yl)oxy|quinazoline, vv (0) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(M-methyl-M-(tetrahydrofuran-2- ylmethyl)amino)|-1-oxo-2-buten-1-yl)amino)-7- cyclopropylmethoxyquinazoline, (21). 4-(3-chloro-4-fluorophenyl)amino)|-6-(34-(M-methyl-M-(tetrahydrofuran-3-yl)amino|-1-oxo-2-buten-1-yl)amino )-7-cyclopropylmethoxyquinazoline, I (2 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-|(M-(2-methoxyethyl)-M-methylamino)|-1-oxo-2- buten-1-ylamino)-7-cyclopropyl ethoxyquinazoline, (23) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-Ibis(2-methoxyethyl)amino)|-1-oxo-2-butene -1-yl)amino)-7-cyclobutyloxykinase 70 olin, (24) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(1N-methyl-N-(2-methoxyethyl)amino|- 1-oxo-2-buten-1-ylamino)-7-cyclobutyl syquinazoline, (25). 4-(3-chloro-4-fluorophenyl)amino)|-6-(34-(5)-M-methyl- M-(tetrahydrofuran-3-yl)amino|-1-oxo-2-buten-1-yl)amino)-7-cyclobutyloxyquinazoline, (26). 4-(3-chloro-4-fluorophenyl)amino1-6-(14-KK)-M-methyl-M-(tetrahydrofuran-3-yl)amino|-1-oxo-2-buten-1-yl)amino )-7-cyclobutyloxyquinazoline, (27). 4-KZ-chloro-4-fluorophenyl)amino1|-6-(14-M-methyl-M-(tetrahydropyran-4-yl)amino|-1-oxo-2-buten-1-yl)amino)-7 -cyclobutyloxyquinazoline, (28) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-KK)-M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino|-1-oxo-2- buten-1-yl)amino)-7-cyclobutyloxyquinazoline, (29) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-((5)-M-methyl-M-(tetrahydrofuran-2 -ylmethyl)amino|-1-oxo-2-buten-1-yl)amino )-7-cyclobutyloxyquinazoline, (30). 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(M-methyl-M-(2-methoxyethyl)amino|-1-oxo-2-buten-1-yl) and) amino) -7-(tetrahydrofuran-3-yloxy)quinazoline, (31) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(1M-methyl-M-(2-methoxyethyl)amino|-1- oxo-2-buten-1-yl)amino)-7-(tetrahydropyran-4-yloxy)quinazoline, (32) - 4-(3-chloro-4-fluorophenyl)amino1|-6-(14 -IM-methyl-N-(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylylamino)-7-(tetrahydrogeuran-2-ylmethoxy)quinazoline and (33) h 4-(Z- chloro-4-fluorophenyl)amino|-6-Ch4-(M-cyclopropyl-M-methylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmetoc and syquinazoline, their tautomers, their stereoisomers and their salt C. Compounds of the general formula I according to claim 1, in which Ka means 1-phenylethyl or 3-chloro-4-fluorophenyl group, "K means dimethylamino-, M-methyl-M-ethylamino-, diethylamino-, M-methyl-M -isopropylamino-, nta) with M-methyl-M-cyclopropylamino-, M-methyl-M-(2-methoxyethyl)amino-, M-ethyl-M-(2-methoxyethyl)amino-, . bis(2-methoxyethyl)amino-, morpholino-, M-methyl-M-(tetrahydrofuran-z-yl)amino-, and? M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino-, M-methyl-M-(tetrahydrofuran-3-ylmethyl)amino-, M-methyl-M-(tetrahydropyran-4-yl)amino- or M- methyl-M-(tetrahydropyran-4-ylmethyl)amino group and Co means cyclopropylmethoxy-, cyclobutyloxy-, cyclopentyloxy-, tetrahydrofuran-3-yloxy-, -I tetrahydrofuran-2-ylmethoxy-, tetrahydrofuran-3-ylmethoxy-, tetrahydropyran-4 -yloxy- or tetrahydropyran-4-ylmethoxy group, with the exception of the following compounds: -oxo-2-buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, (2) 4-(3-chloro-4-fluorophenyl)amino!|-6-4-(morpholin-4-yl)-1- oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (3) 4-((33-chloro-4-fluorophenyl)amino)|-6-(4-(dimethylamino)-1-oxo-2-butene -1-ilyamino)-7-cyclopropylmethoxyquinazoline, (4). 4-K(3-chloro-4-fluorophenyl)amino|-6-Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (5). 4-(3-chloro-4-fluorophenyl)amino|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, (F, (6). 4-(3-chloro-4-fluorophenyl)amino)|-6-(4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, ka (7). 4-K(3-chloro-4-fluorophenyl)amino1|-6-(4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, (8). 4-KK)-(1-phenylethyl)amino)|-6-(4-(morpholin-4-yl)-1-oxo-2-buten-1-yl|Iamino)-7-cyclobutyloxyquinazoline, in (9) . 4-KK)-(1-phenylethyl)amino|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (103. 4-KK)- (1-phenylethyl)amino|-6-14-(morpholin-4-yl)-1-oxo-2-buten-1-yl)iamino)-7-cyclopentyloxyquinazoline, (11). 4-KK)-(1-phenylethyl)amino)-6-(4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclobutyloxyquinazoline, (12). 4-KK)-(1-phenylethyl)amino)-6-(4-(diethylamino)-1-oxo-2-buten-1-ilyamino)-7-cyclopentyloxyquinazoline, (13). 4-KK)-(1-phenylethyl)amino)|-6-14-(diethylamino)-1-oxo-2-buten-1-yl|amino)-7-cyclopropylmethoxyquinazoline, b 4-((3-chloro- 4-fluorophenyl)amino)|-6-(14-Ibis(2-methoxyethyl)amino|-1-oxo-2-buten-1-yl)amino)-7-cyclopropylmethoxy inazoline, 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-I(1N-ethyl-M-(2-methoxyethyl)amino|-1-oxo-2-buten-1-yl)iamino)- 7-cyclopropylmethoxyquinazoline, (16) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(1M-methyl-M-(tetrahydropyran-4-yl)amino|-1-oxo-2- buten-1-ylamino)-7-cyclopropylmethoxyquinazoline, 17 70 4-(3-chloro-4-fluorophenyl)amino!|-6-C4-(diethylamino)-1-oxo-2-buten-1-ylamino)- 7-Ctetrahydrofuran-2-yl)methoxy)quinazoline, (18) 4-(3-chloro-4-fluorophenyl)amino-1-6-C4-(diethylamino)-1-oxo-2-buten-1-ylamino) -7-5)-(tetrahydrofuran-3-yl)oxy)1quinazoline, (18) 4-(3-chloro-4-fluorophenyl)amino1|-6-C4-(diethylamino)-1-oxo-2-butene- 1-Ilyamino)-7-Ktetrahydropyran-4-yl)oxy|quinazoline, (20) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(IM-methyl-M-(tetrahydrofuran-3 -yl)amino|-1-oxo-2-buten-1-yl)iamino)-7-cyclopropylmethoxyquinazoline, (21) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-|( M-(2-methoxyethyl)-M-methylamino)|-1-oxo-2-buten-1-ylamino)-7-cyclopropyl ethoxyquinazoline, (22) ch 4-(3-chloro-4-fluorophenyl)amino1-6 -(14-Ibis(2-methoxyethyl)amino)|-1-oxo-2 -buten-1-yl)lamino)-7-cyclobutyloxyquinase olin, (8) (23) 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(1M-methyl-M-(2-methoxyethyl) )amino|-1-oxo-2-buten-1-ylamino)-7-cyclobutyl cyquinazoline, "g zo (24) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-((5 )-M-methyl-M-(tetrahydrofuran-Z-yl)amino)|-1-oxo-2-buten-1-ilyamino)-7-C -- cyclobutyloxyquinazoline, Ge (25) 4-(Z-chloro- 4-fluorophenyl)amino1-6-(14-((K)-M-methyl-M-(tetrahydrofuran-3-yl)amino|-1-oxo-2-buten-1-ilyamino)-7-C" cyclobutyloxyquinazoline , i- (26) 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(1M-methyl-N-(tetrahydropyran-4-yl)amino|-1-oxo-2-buten- 1-ylamino)-7-cyclobutyloxyquinazoline, (t) "4-(3-chloro-4-fluorophenyl)amino-1-6-(14-N-methyl-N-(2-methoxyethyl)amino-1-oxo -2-buten-1-ylylamino)-7-(tetrahydrof with uran-3-yloxy)quinazoline, . (28) and?" 4-(3-chloro-4-fluorophenyl)amino1-6-(14-(1M-methyl-M-(2-methoxyethyl)amino|-1-oxo-2-buten-1-yl)amino)-7- (tetrahydrop iran-4-yloxy)quinazoline, (29). 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(M-methyl-M-(2-methoxyethyl)amino|-1-oxo-2-buten-1-yl)-I amino) -7-(tetrahydrofuran-2-ylmethoxy)quinazoline, (30) and 4-(3-chloro-4-fluorophenyl)amino|-6-Ch4-(M-cyclopropyl-M-methylamino)-1-oxo-2- buten-1-ilyamino)-7-cyclopropylmethoc He»syquinazoline, (31) - 4-(3-chloro-4-fluorophenyl)amino1|-6-(14-(M-methyl-M-(tetrahydrofuran-2-ylmethyl) )amino)|-1-oxo-2-buten-1-yl)amino)-7-th» cyclopropylmethoxyquinazoline, (32) 4-(3-chloro-4-fluorophenyl)amino 1|-6-(14-KK) -M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino|-1-oxo-2-buten-1-yl)amino)-7-cyclobutyloxyquinazoline and (33) F) 4-(3-chloro-4- fluorophenyl)amino1|-6-(14-((5)-M-methyl-M-(tetrahydrofuran-2-ylmethyl)amino|-1-oxo-2-buten-1-yl)amino ka )-7-cyclobutyloxyquinazoline , their tautomers, their stereoisomers and their salts. in 4. Compounds of the general formula | according to claim 1 from the group that includes: (c) 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(M,M-dimethylamino)-1-oxo-2-buten-1-ylamino )-7-cyclobutyloxyquinazoline, (6) 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(M,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7 -cyclopentyloxyquinazoline, (c) that 4-KK)-(1-phenylethyl)amino!-6-(Х4-(M,M-bis(2-methoxyethyl)amino)-1-oxo-2-buten-1-ilyamino )-7-cyclopropylmethoxy quinazoline, 4-KK)-(1-phenylethyl)amino1-6-(14-(M-(2-methoxyethyl)-M-ethylamino|-1-oxo-2-buten-1-ilyamino) -7-cyclopropylmethoc syquinazoline, (d) 4-KK)-(1-phenylethyl)amino1-6-(14-(M-(2-methoxyethyl)-M-methylamino|-1-oxo-2-buten-1- illamino)-7-cyclopropylmetho xyquinazoline, (e) 70 4-KK)-(1-phenylethyl)amino1|-6-(14-(M-(tetrahydrofuran-4-yl)-M-methylamino)|-1-oxo -2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (g) 4-KK)-(1-phenylethyl)amino1|-6-(14-(M-(tetrahydrofuran-3-yl)-M-methylamino) )|-1-oxo-2-buten-1-ilyamino)-7-cyclopropylmethoxyquinazoline, (c) 4-(3-chloro-4-fluorophenyl)amino1-6-K4-1h-(tetrahydrofuran-3-yl) umethyl|-M-methylamino)- 1-oxo-2-buten-1-yl)amino|-7-cyclopropylmethoxyquinazoline, (y) 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(M,M-dimethylamino)-1 -oxo-2-buten-1-ylamino)-7-(K)-tetrahydrofuran-3-yloxy)quinazoline, (u 4-((3Z-chloro-4-fluorophenyl)amino)|-6-14-( M,M-dimethylamino)-1-oxo-2-buten-1-ilyamino)-7-(5)-tetrahydrofuran-3-yloxy)quinazoline, (l) Ha 4-(3-chloro-4-fluorophenyl) amino1|-6-X14-(M,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7-(tetrahydropyran-4-yloxy)quinazoline, (8) (m) 4-(Z- chloro-4-fluorophenyl)amino!|-6-X4-(M,M-dimethylamino)-1-oxo-2-buten-1-ilyamino)-7-tetrahydrofuran-2-yl)methoxyquinazoline, "g (n ) 4-(3-chloro-4-fluorophenyl)amino!|-6-X4-(N,M-dimethylamino)-1-oxo-2-buten-1-ylamino)-7-tetrahydrofuran-3-yl)meth -- oxyquinazoline, Ge (o) 4-(3-chloro-4-fluorophenyl)amino1|-6-14-(M,M-diethylamino)-1-oxo-2-buten-1-ilyamino)-7-tetrahydrofuran -3-yl)metho "xy)quinazoline, y- (n) 4-KK)-(1-phenylethyl)amino1|-6-Ch4-(M,M-dimethylamino)-1-oxo-2-buten-1 -yl|iamino)-7-cyclopropylmethoxyquinazoline, (p) 4-(3-chloro-4-fluorophenyl)amino1|-6-( 14-IM,M-bis(2-methoxyethyl)amino|-1-oxo-2-buten-1-ylamino)-7-tetrahydrofuran-2-yl)methoxy)quinazoline, with c (c) . 4-(3-chloro-4-fluorophenyl)amino|-6-(Ch4-(morpholin-4-yl)-1-oxo-2-buten-1-ylamino)-7-tetrahydrofuran-2-yl)methoxy ? quinazoline, (7) 4-(3-chloro-4-fluorophenyl)amino1|-6-X14-(M-cyclopropyl-M-methylamino)-1-oxo-2-buten-1-ylamino)-7-cyclopentyloxy - I inazolin and (U) o 4-((3-chloro-4-fluorophenyl)amino)|-6-(4-(M,M-dimethylamino)-1-oxo-2-buten-1-yl|Iamino) -7-(5)-(tetrahydrofuran-2-yl Ge)methoxy|)quinazoline, their tautomers, their stereoisomers and their salts. - 5. Compounds according to any of claims 1-4, which are physiologically acceptable salts with inorganic or organic acids or bases. 6. Medicinal product intended for the treatment of benign or malignant tumors, for the prevention and treatment of diseases of the respiratory tract and lungs, as well as for the treatment of diseases of the gastrointestinal tract and bile ducts and gall bladder, which contains a compound according to any of claims 1 -5, optionally in combination with one or more inert carriers and/or diluents. F) name) 60 b5