RU2000105243A

RU2000105243A - Derivatives of substituted quinazolines and their use as tyrosine kinase inhibitors

Info

Publication number: RU2000105243A
Application number: RU2000105243/04A
Authority: RU
Inventors: Аллан ВИССНЕР; Хвей-Ру ТСОУ; Бернард Дин ДЖОНСОН; Филип Росс ХАМАНН; Нан ЗАНГ
Original assignee: Американ Цианамид Компани
Priority date: 1997-08-01
Filing date: 1998-07-29
Publication date: 2002-01-10

Claims

1. The compound of formula 1, having the structure:

where X represents cycloalkyl containing from 3 to 7 carbon atoms, which may optionally be substituted with one or more alkyl groups containing from 1 to 6 carbon atoms; or a pyridinyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring may optionally be mono-, di- or tri-substituted with a substituent selected from the group consisting of halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2 -6 carbon atoms, alkynyl containing 2-6 carbon atoms, azido, hydroxyalkyl containing 1-6 carbon atoms, halogenmethyl, alkoxymethyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkoxy containing 1- 6 carbon atoms, alkylti containing 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino, containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, alkenoylamino containing 3-8 carbon atoms, alkynoylamino containing 3-8 carbon atoms, carboxyalkyl containing 2-7 carbon atoms, carboalkoxyalk sludge containing 3-8 carbon atoms, aminomethyl, N-alkylaminomethyl containing 2-7 carbon atoms, N, N-dialkylaminomethyl containing 3-7 carbon atoms, mercapto, methyl mercapto and benzoylamino;
Z is —NH, —O—, —S— or —NR—;
R represents alkyl containing 1-6 carbon atoms, or carboalkyl containing 2-7 carbon atoms;
R ₁ , R ₃ and R ₄ each independently represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, alkenyloxy containing 2- 6 carbon atoms, alkynyloxy containing 2-6 carbon atoms, hydroxymethyl, halogenomethyl, alkanoyloxy containing 1-6 carbon atoms, alkenoyloxy containing 3-8 carbon atoms, alkynyloxy containing 3-8 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkenoyloxymethyl containing 4-9 carbon atoms, alkynoyloxymethy l containing 4-9 carbon atoms, alkoxymethyl containing 2-7 carbon atoms, alkoxy containing 1-6 carbon atoms, alkylthio containing 1-6 carbon atoms, alkylsulfinyl containing 1-6 carbon atoms, alkylsulfonyl containing 1- 6 carbon atoms, alkylsulfonamido containing 1-6 carbon atoms, alkenylsulfonamido containing 2-6 carbon atoms, alkynylsulfonamido containing 2-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, phenok si, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino containing 1-4 carbon atoms, alkylamino containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N -alkyl-N-alkenylamino containing from 4 to 12 carbon atoms, N, N-dialkenylamino containing 6-12 carbon atoms, phenylamino, benzylamino, R ₇ - (C (R ₆ ) ₂ ) _g -Y-, R ₇ - (C (R ₆ ) ₂ ) _p- M- (C (R ₆ ) ₂ ) _k- Y-or Het-W- (C (R ₆ ) ₂ ) _k -Y-,
Y represents a divalent radical selected from the group consisting of:
- (CH ₂ ) _a -, -O- and -NR ₆ -;
R ₇ is —NR ₆ R ₆ or —OR ₆ ;
M represents> NR ₆ , —O—,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p —OR ₆ ;
W represents> NR ₆ , —O— or a bond;
Het is a heterocycle optionally mono- or disubstituted on carbon or nitrogen with R ₆ and optionally monosubstituted on carbon with a group —CH ₂ OR ₆ ; where the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, S, thiomorpholine S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran and tetrahydropyran;
R ₆ represents hydrogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, cycloalkyl containing 3-6 carbon atoms, carboalkyl containing 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more substituents from halogen, alkoxy containing 1-6 carbon atoms, trifluoromethyl, amino, alkylamino containing 1-3 carbon atoms, dialkylamino containing 2-6 carbon atoms, nitro, cyano, azido, halogenmethyl, alkoxy methyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkylthio containing 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, or alkyl containing 1-6 carbon atoms;
R ₂ selected from the group consisting of:

R ₅ represents, independently, hydrogen, alkyl containing 1-6 carbon atoms, carboxy, carboalkoxy containing 1-6 carbon atoms, phenyl, carboalkyl containing 2-7 carbon atoms,
R ₇ - (C (R ₆ ) ₂ ) _s -, R ₇ - (C (R ₆ ) ₂ ) _p -M- (C (R ₆ ) ₂ ) _r -,
R ₈ R ₉ -CH-M- (C (R ₆ ) ₂ ) _r - or Het-W- (C (R ₆ ) ₂ ) _r -;
R ₈ and R ₉ each independently represents —C (R ₆ ) ₂ ) _r NR ₆ R ₆ or - (C (R ₆ ) ₂ ) _r OR ₆ ;
J is independently hydrogen, chloro, fluoro or bromo;
Q represents alkyl containing 1-6 carbon atoms, or hydrogen;
a = 0 or 1;
g is 1-6;
k is 0-4;
n is 0-1;
p = 2-4;
q is 0-4;
r is 1-4;
s is 1-6;
u = 0-4 and v = 0-4, where the sum of u + v is 2-4
or a pharmaceutically acceptable salt thereof,
provided that when
Z represents NH;
n is 0
R ₂ selected from the group consisting of:

R ₅ represents, independently and exclusively, hydrogen, alkyl containing 1-6 carbon atoms, carboxy, carboalkoxy containing 1-6 carbon atoms, phenyl or carboalkyl containing 2-7 carbon atoms;
R ₁ represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, or alkoxy containing 1-6 carbon atoms;
R ₄ represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, or alkoxy containing 1-6 carbon atoms; and
R ₃ represents hydrogen, alkyl containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, hydroxy or trifluoromethyl;
X does not represent a phenyl ring exclusively substituted with one or more substituents selected from the group consisting of halogen, alkyl containing 1-6 carbon atoms, alkoxy containing 1-6 atoms
carbon, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, amino and alkanoylamino containing 1-6 carbon atoms;
further provided that when R ₂ represents

and R ₅ represents hydrogen or alkyl containing 1-6 carbon atoms,
R _{3 is} not halogen; and further provided that
when R ₆ is alkenyl containing 2-7 carbon atoms or alkynyl containing 2-7 carbon atoms, such an alkenyl or alkynyl group binds to a nitrogen or oxygen atom through a saturated carbon atom; and finally, provided that
when Y is —NR ₆ - or R ₇ is —NR ₆ R ₆ , then g = 2-6;
when M is —O— and R ₇ is —OR ₆ , then p is 1-4;
when Y is —NR ₆ -, then k = 2-4;
when Y represents —O— and M or W represents —O—, then k = 1-4,
and when W represents a bond with Het bonded through a nitrogen atom, and Y represents —O— or —NR ₆ -, then k = 2-4.

2. The compound of claim 1, wherein n = 0, Z is —NH—, and X is a phenyl ring unsubstituted or substituted with halogen or alkyl containing 1-6 carbon atoms, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein R ₁ , R _3, and R ₄ are hydrogen.

4. The compound according to claim 1, which is a 4-dimethylaminobut-2-enoic acid [4- (3-bromophenylamino) quinazolin-6-yl] amide or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, which is [4- (3-bromophenylamino) quinazolin-6-yl] 4-morpholin-4-ylbut-2-inic acid amide, [4- (3-bromophenylamino) quinazolin-6 4-dimethylaminobut-2-inic acid amide, [4- (3-bromophenylamino) quinazolin-6-yl] 4-diethylaminobut-2-inoic acid amide, [4- (3-bromophenylamino) quinazolin-6-yl ] 4- (4-ethylpiperazin-1-yl) but-2-inic acid amide, [4- (3-bromophenylamino) quinazolin-6-yl] 4- (4-methylpiperazin-1-yl) but-2- amide acid, [4- (3-bromophenylamino) quinazolin-6-yl] amide 4- [bis (2-methoxyethyl) amino] but-2-inic acid, [4- (3-bromophenylamino) quinazolin-6-yl](2-methoxyethyl) methylaminobut-2-inic acid amide, [4- (3-bromophenylamino) quinazolin-6-yl] isopropylmethylaminobut-2-inic acid amide, [4- (3-bromophenylamino) quinazolin-6-yl] amide diisopropylaminobut-2-inic acid, [4- (3-bromophenylamino) quinazolin-6-yl] allylmethylaminobut-2-inic acid amide or [4- (3-bromophenylamino) quinazolin-6-yl] but-2-inic acid amide or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, which is [4- (3-bromophenylamino) quinazolin-6-yl] amide of 4-methoxybut-2-inic acid, [4- (3-bromophenylamino) quinazolin-6-yl] amide 4- (2-methoxyethoxy) but-2-inic acid or [4- (3-bromophenylamino) quinazolin-6-yl] amide of 4-methoxymethoxybut-2-inic acid or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, which is 3- [4- (3-bromophenylamino) quinazolin-6-ylamino] -4-ethoxycyclobut-3-en-1,2-dione, 3- [4- (3- bromophenylamino) quinazolin-6-ylamino] -4-dimethylaminocyclobut-3-en-1,2-dione, 3- [4- (3-bromophenylamino) quinazolin-6-ylamino] -4-methylaminocyclobut-3-en-1, 2-dione, 3-amino-4- [4- (3-bromophenylamino) quinazolin-6-ylamino] cyclobut-3-en-1,2-dione or 3- [4- (3-bromophenylamino) quinazolin-6- ilamino] -4-morpholin-4-ylcyclobut-3-en-1,2-dione or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, which is [4- (3-bromophenylamino) quinazolin-6-yl] amide 4-methoxybut-2-enoic acid or [4- (3-bromophenylamino) quinazolin-6-yl] amide 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, which is N- [4- (3-bromophenylamino) quinazolin-6-yl] -2-morpholin-4-ylmethyl-acrylamide or [4- (3-bromophenylamino) quinazolin-6- yl] 4-diethylaminobut-2-enoic acid amide or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, which is N- [4- (3-bromophenylamino) quinazolin-6-yl] -2-methyldisulfanylpropionamide, N- [4- (3-bromophenylamino) quinazolin-6-yl] -3 -methyldisulfanylpropionamide, N- [4- (3-bromophenylamino) quinazolin-6-yl] -2-methyldisulfanylacetamide, N- [4- (3-bromophenylamino) quinazolin-6-yl] -2-tert-butyldisulfanylacetamide, N- [ 4- (3-bromophenylamino) quinazolin-6-yl] -2-isobutyl disulfanylacetamide or N- [4- (3-bromophenylamino) quinazolin-6-yl] -2-isopropyl disulfanylacetamide or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, which is a methyl ester of 2- {[4- (3-bromophenylamino) quinazolin-6-ylamino] methyl} acrylic acid or methyl ester (E) -4- [4- (3-bromophenylamino ) quinazolin-6-ylamino] methyl} but-2-enoic acid or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, which is [4- (3-bromophenylamino) quinazolin-6-yl] amide of 4-chlorobut-2-inic acid, [4- (3-bromophenylamino) quinazolin-6-yl] amide 4-hydroxybut-2-inic acid, N- [4 - [(3-bromophenyl) amino] -6-quinazolinyl] -3 (E) -chloro-2-propenamide, [4- (3-bromophenylamino) quinazolin-6 4-bromobut-2-enoic acid amide, [4- (3-bromophenylamino) quinazolin-6-yl] oxiran-2-carboxylic acid amide or [4- (3-bromophenylamino) quinazolin-6-yl] amide etensulfonic acid or a pharmaceutically acceptable salt thereof.

13. A method of inhibiting the biological effect of an upregulated protein tyrosine kinase in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula 1 having the structure

X represents cycloalkyl containing from 3 to 7 carbon atoms, which may optionally be substituted with one or more alkyl groups containing from 1 to 6 carbon atoms; or a pyridinyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring may optionally be mono-, di- or tri-substituted with a substituent selected from the group consisting of halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2 -6 carbon atoms, alkynyl containing 2-6 carbon atoms, azido, hydroxyalkyl containing 1-6 carbon atoms, halogenmethyl, alkoxymethyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkoxy containing 1- 6 carbon atoms, alkylti containing 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino, containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, alkenoylamino containing 3-8 carbon atoms, alkynoylamino containing 3-8 carbon atoms, carboxyalkyl containing 2-7 carbon atoms, carboalkoxyalk sludge containing 3-8 carbon atoms, aminomethyl, N-alkylaminomethyl containing 2-7 carbon atoms, N, N-dialkylaminomethyl containing 3-7 carbon atoms, mercapto, methyl mercapto and benzoylamino;
Z is —NH, —O—, —S— or —NR—;
R represents alkyl containing 1-6 carbon atoms, or carboalkyl containing 2-7 carbon atoms;
R ₁ , R ₃ and R ₄ each independently represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, alkenyloxy containing 2- 6 carbon atoms, alkynyloxy containing 2-6 carbon atoms, hydroxymethyl, halogenomethyl, alkanoyloxy containing 1-6 carbon atoms, alkenoyloxy containing 3-8 carbon atoms, alkynyloxy containing 3-8 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkenoyloxymethyl containing 4-9 carbon atoms, alkynoyloxymethy l containing 4-9 carbon atoms, alkoxymethyl containing 2-7 carbon atoms, alkoxy containing 1-6 carbon atoms, alkylthio containing 1-6 carbon atoms, alkylsulfinyl containing 1-6 carbon atoms, alkylsulfonyl containing 1- 6 carbon atoms, alkylsulfonamido containing 1-6 carbon atoms, alkenylsulfonamido containing 2-6 carbon atoms, alkynylsulfonamido containing 2-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, phenok si, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino containing 1-4 carbon atoms, alkylamino containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N -alkyl-N-alkenylamino containing from 4 to 12 carbon atoms, N, N-dialkenylamino containing 6-12 carbon atoms, phenylamino, benzylamino, R ₇ - (C (R ₆ ) ₂ ) _g -Y-, R ₇ - (C (R ₆ ) ₂ ) _p- M- (C (R ₆ ) ₂ ) _k- Y-or Het-W- (C (R ₆ ) ₂ ) _k -Y-,
Y represents a divalent radical selected from the group consisting of
- (CH ₂ ) _a -, -O- and -NR ₆ -;
R ₇ is —NR ₆ R ₆ or —OR ₆ ;
M represents> NR ₆ , —O—,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p —OR ₆ ;
W represents> NR ₆ , —O— or a bond;
Het is a heterocycle, optionally mono- or disubstituted on carbon or nitrogen, R ₆ and optionally monosubstituted on carbon, —CH ₂ OR ₆ , where the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, S, thiomorpholine S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran and tetrahydropyran;
R ₆ represents hydrogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, cycloalkyl containing 3-6 carbon atoms, carboalkyl containing 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more substituents from halogen, alkoxy containing 1-6 carbon atoms, trifluoromethyl, amino, alkylamino containing 1-3 carbon atoms, dialkylamino containing 2-6 carbon atoms, nitro, cyano, azido, halogenmethyl, alkoxy methyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkylthio containing 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, or alkyl containing 1-6 carbon atoms;
R ₂ selected from the group consisting of

,

R ₅ represents, independently, hydrogen, alkyl containing 1-6 carbon atoms, carboxy, carboalkoxy containing 1-6 carbon atoms, phenyl, carboalkyl containing 2-7 carbon atoms,
R ₇ - (C (R ₆ ) ₂ ) _s -, R ₇ - (C (R ₆ ) ₂ ) _p -M- (C (R ₆ ) ₂ ) _r -,
R ₈ R ₉ -CH-M- (C (R ₆ ) ₂ ) _r - or Het-W- (C (R ₆ ) ₂ ) _r -;
R ₈ and R ₉ each independently represent —C (R ₆ ) ₂ ) _r NR ₆ R ₆ or - (C (R ₆ ) ₂ ) _r OR ₆ ;
J is independently hydrogen, chloro, fluoro or bromo;
Q represents alkyl containing 1-6 carbon atoms, or hydrogen;
a = 0 or 1;
g is 1-6;
k is 0-4;
n is 0-1;
p = 2-4;
q is 0-4;
r is 1-4;
s is 1-6;
u = 0-4 and v = 0-4, where the sum of u + v is 2-4;
or a pharmaceutically acceptable salt thereof,
provided that when Z is NH;
n is equal to O
R ₂ selected from the group consisting of

and R ₅ represents hydrogen or alkyl containing 1-6 carbon atoms,
R _{3 is} not halogen; and further provided that
when R ₆ is alkenyl containing 2-7 carbon atoms or alkynyl containing 2-7 carbon atoms, such an alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom; and finally, provided that
when Y is —NR ₆ - or R ₇ is —NR ₆ R ₆ , then g = 2-6;
when M is —O— and R ₇ is —OR ₆ , then p is 1-4;
when Y is —NR ₆ -, then k = 2-4;
when Y is —O— and M or W is —O—, then k = 1-4,
and when W represents a bond with Het bonded through a nitrogen atom, and Y represents —O— or —NR ₆ -, then k = 2-4.

14. A method of treating growth inhibition or elimination of tumors in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula 1 having the structure

X represents cycloalkyl containing from 3 to 7 carbon atoms, which may optionally be substituted with one or more alkyl groups containing from 1 to 6 carbon atoms; or a pyridinyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring may optionally be mono-, di- or tri-substituted with a substituent selected from the group consisting of halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2 -6 carbon atoms, alkynyl containing 2-6 carbon atoms, azido, hydroxyalkyl containing 1-6 carbon atoms, halogenmethyl, alkoxymethyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkoxy containing 1- 6 carbon atoms, alkylti containing 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino, containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, alkenoylamino containing 3-8 carbon atoms, alkynoylamino containing 3-8 carbon atoms, carboxyalkyl containing 2-7 carbon atoms, carboalkoxyalk sludge containing 3-8 carbon atoms, aminomethyl, N-alkylaminomethyl containing 2-7 carbon atoms, N, N-dialkylaminomethyl containing 3-7 carbon atoms, mercapto, methyl mercapto and benzoylamino;
Z is —NH, —O—, —S— or —NR—;
R represents alkyl containing 1-6 carbon atoms, or carboalkyl containing 2-7 carbon atoms;
R ₁ , R ₃ and R ₄ each independently represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, alkenyloxy containing 2- 6 carbon atoms, alkynyloxy containing 2-6 carbon atoms, hydroxymethyl, halogenomethyl, alkanoyloxy containing 1-6 carbon atoms, alkenoyloxy containing 3-8 carbon atoms, alkynyloxy containing 3-8 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkenoyloxymethyl containing 4-9 carbon atoms, alkynoyloxymethy l containing 4-9 carbon atoms, alkoxymethyl containing 2-7 carbon atoms, alkoxy containing 1-6 carbon atoms, alkylthio containing 1-6 carbon atoms, alkylsulfinyl containing 1-6 carbon atoms, alkylsulfonyl containing 1- 6 carbon atoms, alkylsulfonamido containing 1-6 carbon atoms, alkenylsulfonamido containing 2-6 carbon atoms, alkynylsulfonamido containing 2-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, phenok si, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino containing 1-4 carbon atoms, alkylamino containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N -alkyl-N-alkenylamino containing from 4 to 12 carbon atoms, N, N-dialkenylamino containing 6-12 carbon atoms, phenylamino, benzylamino, R ₇ - (C (R ₆ ) ₂ ) _g -Y-, R ₇ - (C (R ₆ ) ₂ ) _p- M- (C (R ₆ ) ₂ ) _k- Y- or Het-W- (C (R ₆ ) ₂ ) _k -Y-,
Y represents a divalent radical selected from the group consisting of
- (CH ₂ ) _a -, -O- and -NR ₆ -;
R ₇ is —NR ₆ R ₆ or —OR ₆ ;
M represents> NR ₆ , —O—,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p —OR ₆ ;
W represents> NR ₆ , —O— or a bond;
Het is a heterocycle optionally mono- or disubstituted on carbon or nitrogen R ₆ and optionally monosubstituted on carbon -CH ₂ OR ₆ , where the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, S, thiomorpholine S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran and tetrahydropyran;
R ₆ represents hydrogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, cycloalkyl containing 3-6 carbon atoms, carboalkyl containing 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more substituents from halogen, alkoxy containing 1-6 carbon atoms, trifluoromethyl, amino, alkylamino containing 1-3 carbon atoms, dialkylamino containing 2-6 carbon atoms, nitro, cyano, azido, halogenmethyl, alkoxy methyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkylthio containing 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, or alkyl containing 1-6 carbon atoms;
R ₂ selected from the group consisting of

R ₅ represents, independently, hydrogen, alkyl containing 1-6 carbon atoms, carboxy, carboalkoxy containing 1-6 carbon atoms, phenyl, carboalkyl containing 2-7 carbon atoms,
R ₇ - (C (R ₆ ) ₂ ) _s -, R ₇ - (C (R ₆ ) ₂ ) _p -M- (C (R ₆ ) ₂ ) _r -,
R ₈ R ₉ -CH-M- (C (R ₆ ) ₂ ) _r - or Het-W- (C (R ₆ ) ₂ ) _r -;
R ₈ and R ₉ each independently represent —C (R ₆ ) ₂ ) _r NR ₆ R ₆ or - (C (R ₆ ) ₂ ) _r OR ₆ ;
J is independently hydrogen, chloro, fluoro or bromo;
Q represents alkyl containing 1-6 carbon atoms, or hydrogen;
a = 0 or 1;
g is 1-6;
k is 0-4;
n is 0-1;
p = 2-4;
q is 0-4;
r is 1-4;
s is 1-6;
u = 0-4 and v = 0-4, where the sum of u + v is 2-4
or a pharmaceutically acceptable salt thereof,
provided that when
Z represents NH;
n is 0
R ₂ selected from the group consisting of

R ₅ represents, independently and exclusively, hydrogen, alkyl containing 1-6 carbon atoms, carboxy, carboalkoxy containing 1-6 carbon atoms, phenyl or carboalkyl containing 2-7 carbon atoms;
R ₁ represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, or alkoxy containing 1-6 carbon atoms;
R ₄ represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, or alkoxy containing 1-6 carbon atoms; and
R ₃ represents hydrogen, alkyl containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, hydroxy or trifluoromethyl;
X is not a phenyl ring exclusively substituted with one or more substituents selected from the group consisting of halogen, alkyl containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, amino and alkanoylamino containing 1-6 carbon atoms;
further provided that when R ₂ represents

and R ₅ represents hydrogen or alkyl containing 1-6 carbon atoms,
R _{3 is} not halogen; and further provided that
when R ₆ is alkenyl containing 2-7 carbon atoms or alkynyl containing 2-7 carbon atoms, such an alkenyl or alkynyl moiety is bonded to a nitrogen or oxygen atom through a saturated carbon atom; and finally, provided that
when Y is —NR ₆ - or R ₇ is —NR ₆ R ₆ , then g = 2-6;
when M is —O— and R ₇ ; represents -OR ₆ , then p = 1-4;
when Y is —NR ₆ -, then k = 2-4;
when Y represents —O— and M or W represents —O—, then k = 1-4,
and when W represents a bond with Het bonded through a nitrogen atom, and Y represents —O— or —NR ₆ -, then k = 2-4.

15. The method of claim 14, wherein the tumor expresses EGFR or erbB2 (Her2).

16. The method according to p. 14, where the tumor is selected from the group consisting of tumors of the mammary gland, kidney, bladder, oral cavity, larynx, esophagus, stomach, rectum, ovaries and lungs.

17. A method of treating, inhibiting the development or elimination of polycystic kidney disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula 1 having the structure

where X represents cycloalkyl containing from 3 to 7 carbon atoms, which may optionally be substituted with one or more alkyl groups containing from 1 to 6 carbon atoms; or a pyridinyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring may optionally be mono-, di- or tri-substituted with a substituent selected from the group consisting of halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2 -6 carbon atoms, alkynyl containing 2-6 carbon atoms, azido, hydroxyalkyl containing 1-6 carbon atoms, halogenmethyl, alkoxymethyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkoxy containing 1- 6 carbon atoms, alkylti containing 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino, containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, alkenoylamino containing 3-8 carbon atoms, alkynoylamino containing 3-8 carbon atoms, carboxyalkyl containing 2-7 carbon atoms, carboalkoxyalk sludge containing 3-8 carbon atoms, aminomethyl, N-alkylaminomethyl containing 2-7 carbon atoms, N, N-dialkylaminomethyl containing 3-7 carbon atoms, mercapto, methyl mercapto and benzoylamino;
Z is —NH, —O—, —S— or —NR—;
R represents alkyl containing 1-6 carbon atoms, or carboalkyl containing 2-7 carbon atoms;
R ₁ , R ₃ and R ₄ each independently represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, alkenyloxy containing 2- 6 carbon atoms, alkynyloxy containing 2-6 carbon atoms, hydroxymethyl, halogenomethyl, alkanoyloxy containing 1-6 carbon atoms, alkenoyloxy containing 3-8 carbon atoms, alkynyloxy containing 3-8 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkenoyloxymethyl containing 4-9 carbon atoms, alkynoyloxymethy l containing 4-9 carbon atoms, alkoxymethyl containing 2-7 carbon atoms, alkoxy containing 1-6 carbon atoms, alkylthio containing 1-6 carbon atoms, alkylsulfinyl containing 1-6 carbon atoms, alkylsulfonyl containing 1- 6 carbon atoms, alkylsulfonamido containing 1-6 carbon atoms, alkenylsulfonamido containing 2-6 carbon atoms, alkynylsulfonamido containing 2-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, phenok si, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino containing 1-4 carbon atoms, alkylamino containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N -alkyl-N-alkenylamino containing from 4 to 12 carbon atoms, N, N-dialkenylamino containing 6-12 carbon atoms, phenylamino, benzylamino, R ₇ - (C (R ₆ ) ₂ ) _g -Y-, R ₇ - (C (R ₆ ) ₂ ) _p- M- (C (R ₆ ) ₂ ) _k- Y- or Het-W- (C (R ₆ ) ₂ ) _k -Y-,
Y represents a divalent radical selected from the group consisting of
- (CH ₂ ) _a -, -O- and -NR ₆ -;
R ₇ is —NR ₆ R ₆ or —OR ₆ ;
M represents> NR ₆ , —O—,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p —OR ₆ ;
W represents> NR ₆ , —O— or a bond;
Het is a heterocycle optionally mono- or disubstituted on carbon or nitrogen R ₆ and optionally monosubstituted on carbon —CH ₂ OR ₆ ; where the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, S, thiomorpholine S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran and tetrahydropyran;
R ₆ represents hydrogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, cycloalkyl containing 3-6 carbon atoms, carboalkyl containing 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more substituents from halogen, alkoxy containing 1-6 carbon atoms, trifluoromethyl, amino, alkylamino containing 1-3 carbon atoms, dialkylamino containing 2-6 carbon atoms, nitro, cyano, azido, halogenmethyl, alkoxy methyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkylthio containing 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, or alkyl containing 1-6 carbon atoms;
R ₂ selected from the group consisting of

R ₅ represents, independently, hydrogen, alkyl containing 1-6 carbon atoms, carboxy, carboalkoxy containing 1-6 carbon atoms, phenyl, carboalkyl containing 2-7 carbon atoms,
R ₇ - (C (R ₆ ) ₂ ) _s -, R ₇ - (C (R ₆ ) ₂ ) _p -M- (C (R ₆ ) ₂ ) _r -,
R ₈ R ₉ -CH-M- (C (R ₆ ) ₂ ) _r - or Het-W- (C (R ₆ ) ₂ ) _r -;
R ₈ and R ₉ each independently represents —C (R ₆ ) ₂ ) _r NR ₆ R ₆ or - (C (R ₆ ) ₂ ) _r OR ₆ ;
J is independently hydrogen, chloro, fluoro or bromo;
Q represents alkyl containing 1-6 carbon atoms, or hydrogen;
a = 0 or 1;
g is 1-6;
k is 0-4;
n is 0-1;
p = 2-4;
q is 0-4;
r is 1-4;
s is 1-6;
u = 0-4 and v = 0-4, where the sum of u + v is 2-4
or a pharmaceutically acceptable salt thereof, provided that when
Z represents NH;
n is 0
R ₂ selected from the group consisting of

R ₅ represents, independently and exclusively, hydrogen, alkyl containing 1-6 carbon atoms, carboxy, carboalkoxy containing 1-6 carbon atoms, phenyl or carboalkyl containing 2-7 carbon atoms;
R ₁ represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, or alkoxy containing 1-6 carbon atoms;
R ₄ represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, or alkoxy containing 1-6 carbon atoms; and
R ₃ represents hydrogen, alkyl containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, hydroxy or trifluoromethyl;
X does not represent a phenyl ring exclusively substituted with one or more substituents selected from the group consisting of halogen, alkyl, containing 1-6
carbon atoms, alkoxy containing 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, amino and alkanoylamino containing 1-6 carbon atoms ;
further provided that when R ₂ represents

18. The pharmaceutical composition, which includes a compound of formula 1, having the structure:

where X is cycloalkyl containing from 3 to 7 carbon atoms, which may optionally be substituted with one or more alkyl groups containing from 1 to 6 carbon atoms; or a pyridinyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring may optionally be mono-, di- or tri-substituted with a substituent selected from the group consisting of halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2 -6 carbon atoms, alkynyl containing 2-6 carbon atoms, azido, hydroxyalkyl containing 1-6 carbon atoms, halogenmethyl, alkoxymethyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkoxy containing 1- 6 carbon atoms, alkylti containing 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino, containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, alkenoylamino containing 3-8 carbon atoms, alkynoylamino containing 3-8 carbon atoms, carboxyalkyl containing 2-7 carbon atoms, carboalkoxyalk sludge containing 3-8 carbon atoms, aminomethyl, N-alkylaminomethyl containing 2-7 carbon atoms, N, N-dialkylaminomethyl containing 3-7 carbon atoms, mercapto, methyl mercapto and benzoylamino;
Z is —NH, —O—, —S— or —NR—;
R represents alkyl containing 1-6 carbon atoms, or carboalkyl containing 2-7 carbon atoms;
R ₁ , R ₃ and R ₄ each independently represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, alkenyloxy containing 2- 6 carbon atoms, alkynyloxy containing 2-6 carbon atoms, hydroxymethyl, halogenomethyl, alkanoyloxy containing 1-6 carbon atoms, alkenoyloxy containing 3-8 carbon atoms, alkynyloxy containing 3-8 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkenoyloxymethyl containing 4-9 carbon atoms, alkynoyloxymethy l containing 4-9 carbon atoms, alkoxymethyl containing 2-7 carbon atoms, alkoxy containing 1-6 carbon atoms, alkylthio containing 1-6 carbon atoms, alkylsulfinyl containing 1-6 carbon atoms, alkylsulfonyl containing 1- 6 carbon atoms, alkylsulfonamido containing 1-6 carbon atoms, alkenylsulfonamido containing 2-6 carbon atoms, alkynylsulfonamido containing 2-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 atoms carbon, carboalkyl containing 2-7 carbon atoms, pheno si, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino containing 1-4 carbon atoms, alkylamino containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N -alkyl-N-alkenylamino containing from 4 to 12 carbon atoms, N, N-dialkenylamino containing 6-12 carbon atoms, phenylamino, benzylamino, R ₇ - (C (R ₆ ) ₂ ) _g -Y-, R ₇ - (C (R ₆ ) ₂ ) _p- M- (C (R ₆ ) ₂ ) _k -Y- or Het-W- (C (R ₆ ) ₂ ) _k -Y-,
Y represents a divalent radical selected from the group consisting of
- (CH ₂ ) _a -, -O- and -NR ₆ -;
R ₇ is —NR ₆ R ₆ or —OR ₆ ;
M represents> NR ₆ , —O—,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p —OR ₆ ;
W represents> NR ₆ , —O— or a bond;
Het is a heterocycle optionally mono- or disubstituted on carbon or nitrogen R ₆ and optionally monosubstituted on carbon —CH ₂ OR ₆ ; where the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, S, thiomorpholine S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran and tetrahydropyran;
R ₆ represents hydrogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, cycloalkyl containing 3-6 carbon atoms, carboalkyl containing 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more substituents from halogen, alkoxy containing 1-6 carbon atoms, trifluoromethyl, amino, alkylamino containing 1-3 carbon atoms, dialkylamino containing 2-6 carbon atoms, nitro, cyano, azido, halogenmethyl, alkoxy methyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkylthio containing 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, or alkyl containing 1-6 carbon atoms;
R ₂ selected from the group consisting of

R ₅ represents, independently, hydrogen, alkyl containing 1-6 carbon atoms, carboxy, carboalkoxy containing 1-6 carbon atoms, phenyl, carboalkyl containing 2-7 carbon atoms,
R ₇ - (C (R ₆ ) ₂ ) _s -, R ₇ - (C (R ₆ ) ₂ ) _p -M- (C (R ₆ ) ₂ ) _r -,
R ₈ R ₉ -CH-M- (C (R ₆ ) ₂ ) _r - or Het-W- (C (R ₆ ) ₂ ) _r -;
R ₈ and R ₉ each independently represents —C (R ₆ ) ₂ ) _r NR ₆ R ₆ or - (C (R ₆ ) ₂ ) _r OR ₆ ;
J is independently hydrogen, chloro, fluoro or bromo;
Q represents alkyl containing 1-6 carbon atoms, or hydrogen;
a = 0 or 1;
g is 1-6;
k is 0-4;
n is 0-1;
p = 2-4;
q is 0-4;
r is 1-4;
s is 1-6;
u = 0-4 and v = 0-4, where the sum of u + v is 2-4;
or a pharmaceutically acceptable salt thereof, provided that when
Z represents NH;
n is 0
R ₂ selected from the group consisting of

and R ₅ represents hydrogen or alkyl containing 1-6 carbon atoms,
R _{3 is} not halogen; and further provided that
when R ₆ is alkenyl containing 2-7 carbon atoms or alkynyl containing 2-7 carbon atoms, such an alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom; and finally, provided that
when Y is —NR ₆ - or R ₇ is —NR ₆ R ₆ , then g = 2-6;
when M is —O— and R ₇ is —OR ₆ , then p is 1-4;
when Y is —NR ₆ -, then k = 2-4;
when Y is —O— and M or W is —O—, then k = 1-4,
and when W represents a bond with Het bonded through a nitrogen atom and Y represents —O— or —NR ₆ -, then k = 2-4,
and a pharmaceutical carrier.

19. The compound of formula 1 according to any one of paragraphs. 1-12 for use as a pharmaceutical or therapeutic substance.

20. The compound of claim 19 for use in inhibiting the biological effect of an upregulated protein tyrosine kinase in a mammal in need thereof.

21. The compound of claim 19 for use in the treatment, inhibition of growth, or elimination of tumors in a mammal in need thereof.

22. The compound of claim 21 for use in treating growth inhibition or eliminating tumors, wherein the tumor expresses EGFR or erbR2 (Her2).

23. The compound of claim 21 for use in treating, inhibiting the growth or elimination of tumors, wherein the tumor is selected from the group consisting of tumors of the breast, kidney, bladder, oral cavity, larynx, esophagus, stomach, rectum, ovaries and lungs .

24. The compound of claim 19 for use in treating, inhibiting the development or elimination of polycystic kidney disease in a mammal in need thereof.

25. A method of obtaining a compound of formula 1 having the structure

X represents cycloalkyl containing from 3 to 7 carbon atoms, which may optionally be substituted with one or more alkyl groups containing from 1 to 6 carbon atoms; or a pyridinyl, pyrimidinyl or phenyl ring, wherein the pyridinyl, pyrimidinyl or phenyl ring may optionally be mono-, di- or tri-substituted with a substituent selected from the group consisting of halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2 -6 carbon atoms, alkynyl containing 2-6 carbon atoms, azido, hydroxyalkyl containing 1-6 carbon atoms, halogenmethyl, alkoxymethyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkoxy containing 1- 6 carbon atoms, alkylti containing 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino, containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, alkenoylamino containing 3-8 carbon atoms, alkynoylamino containing 3-8 carbon atoms, carboxyalkyl containing 2-7 carbon atoms, carboalkoxyalk sludge containing 3-8 carbon atoms, aminomethyl, N-alkylaminomethyl containing 2-7 carbon atoms, N, N-dialkylaminomethyl containing 3-7 carbon atoms, mercapto, methyl mercapto and benzoylamino;
Z is —NH, —O—, —S— or —NR—;
R represents alkyl containing 1-6 carbon atoms, or carboalkyl containing 2-7 carbon atoms;
R ₁ , R ₃ and R ₄ each independently represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, alkenyloxy containing 2 -6 carbon atoms, alkynyloxy containing 2-6 carbon atoms, hydroxymethyl, halogenomethyl, alkanoyloxy containing 1-6 carbon atoms, alkenoyloxy containing 3-8 carbon atoms, alkynyloxy containing 3-8 carbon atoms, alkanoyloxymethyl containing 2- 7 carbon atoms, alkenoyloxymethyl containing 4-9 carbon atoms, alkynoyloxymeth l containing 4-9 carbon atoms, alkoxymethyl containing 2-7 carbon atoms, alkoxy containing 1-6 carbon atoms, alkylthio containing 1-6 carbon atoms, alkylsulfinyl containing 1-6 carbon atoms, alkylsulfonyl containing 1- 6 carbon atoms, alkylsulfonamido containing 1-6 carbon atoms, alkenylsulfonamido containing 2-6 carbon atoms, alkynylsulfonamido containing 2-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, pheno si, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino containing 1-4 carbon atoms, alkylamino containing 1-6 carbon atoms, dialkylamino containing 2-12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N -alkyl-N-alkenylamino containing from 4 to 12 carbon atoms, N, N-dialkenylamino containing 6-12 carbon atoms, phenylamino, benzylamino, R ₇ - (C (R ₆ ) ₂ ) _g -Y-, R ₇ - (C (R ₆ ) ₂ ) _p- M- (C (R ₆ ) ₂ ) _k- Y- or Het-W- (C (R ₆ ) ₂ ) _k -Y-,
Y represents a divalent radical selected from the group consisting of
- (CH ₂ ) _a -, -O- and -NR ₆ -;
R ₇ is —NR ₆ R ₆ or —OR ₆ ;
M represents> NR ₆ , —O—,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p —OR ₆ ;
W represents> NR ₆ , —O— or a bond;
Het is a heterocycle optionally mono- or disubstituted on carbon or nitrogen R ₆ and optionally monosubstituted on carbon —CH ₂ OR ₆ ; where the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, S, thiomorpholine S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran and tetrahydropyran; represents hydrogen, alkyl containing 1-6 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, cycloalkyl containing 3-6 carbon atoms, carboalkyl containing 2-7 carbon atoms, carboxyalkyl ( 2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more substituents of halogen, alkoxy containing 1-6 carbon atoms, trifluoromethyl, amino, alkylamino containing 1-3 carbon atoms, dialkylamino containing 2-6 carbon atoms , nitro, cyano, azido, halogenmethyl, alkoxime tyl containing 2-7 carbon atoms, alkanoyloxymethyl containing 2-7 carbon atoms, alkylthio containing 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy containing 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino containing 1-6 carbon atoms, or alkyl containing 1-6 carbon atoms;
R ₂ selected from the group consisting of

R ₅ represents, independently and exclusively, hydrogen, alkyl containing 1-6 carbon atoms, carboxy, carboalkoxy containing 1-6 carbon atoms, phenyl or carboalkyl containing 2-7 carbon atoms;
R ₁ represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, or alkoxy containing 1-6 carbon atoms;
R ₄ represents hydrogen, halogen, alkyl containing 1-6 carbon atoms, or alkoxy containing 1-6 carbon atoms; and
R ₃ represents hydrogen, alkyl containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, hydroxy or trifluoromethyl;
X does not represent a phenyl ring exclusively substituted by one or more substituents selected from the group consisting of halogen, alkyl containing 1-6 carbon atoms, alkoxy containing 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy containing 2-7 carbon atoms, carboalkyl containing 2-7 carbon atoms, amino and alkanoylamino containing 1-6 carbon atoms;
further provided that when R ₂ represents

and R ₅ represents hydrogen or alkyl containing 1-6 carbon atoms,
R _{3 is} not halogen; and further provided that
when R ₆ is alkenyl containing 2-7 carbon atoms or alkynyl containing 2-7 carbon atoms, such an alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom; and finally, provided that
when Y is —NR ₆ - or R ₇ is —NR ₆ R ₆ , then g = 2-6;
when M is —O— and R ₇ is —OR ₆ , then p is 1-4;
when Y is —NR ₆ -, then k = 2-4;
when Y is —O— and M or W is —O—, then k = 1-4,
and when W represents a bond with Het bonded through a nitrogen atom and Y represents —O— or —NR ₆ -, then k = 2-4; which includes a reaction of a compound of the formula

where R ₁ , R ₃ , R ₄ X and n are as defined above, with a compound of the formula

where R ₅ is as defined above, R ₁₀ represents alkyl containing 1-6 carbon atoms, and R ' ₂ represent

where R ₅ , R ₆ , J, s, r, u and v are as defined above, in an inert solvent and in the presence of an organic base and further reaction of a compound of the formula

with a compound of the formula
H ₂ N- (CH ₂ ) _n -X
in the presence of an inert solvent and, optionally, the formation of a pharmaceutically acceptable salt of the resulting compound of formula 1.

26. The method according to p. 25, where the compound of the formula

where R ₁ , R ₃ , R ₄ X and n are as defined in claim 25, obtained by reacting the corresponding compound of the formula:

with a reducing agent.

27. The method according to p. 26, where the compound of the formula

where R ₁ , R ₃ , R ₄ , X and n are as defined in claim 26, obtained by reacting the corresponding compound of the formula

with dimethylacetal and then reacting the resulting compound of the formula

with aniline of the formula X-NH ₂ where X is as defined in paragraph 26.

28. The method according to p. 26, in which the compound of the formula

with a compound of the formula
H ₂ N- (CH ₂ ) _n -X or HS- (CH ₂ ) _n -X, or HO- (CH ₂ ) _n -X,
where X and n are as defined in paragraph 26.

29. The method according to any one of paragraphs. 25-28, in which any of the groups R ' ₂ , X, R ₁ , R ₃ or R ₄ represents a primary or secondary amino or hydroxyl group, which includes protecting these groups with a protecting group before carrying out the reaction sequence and then removing the protecting group.