2-hetarylthiazole-4-carboxamide derivatives, their preparation and use as pharmaceuticals

1. A compound of formula (I) with building blocks A, B, C and D:

in which

the building blocks B and D are in ortho position relative to one another, and

Q 1 is a pyridyl or pyrazinyl ring, and

R 1 and R 2 are independently of one another

(i) hydrogen, —NH 2 , hydroxy, halogen, —CF 3 , or

(ii) a C 1 -C 6 -alkoxy, C 1 -C 6 -fluoroalkyl or a C 1 -C 6 -fluoroalkoxy radical

Q 2 is a phenyl, pyrazolyl, thienyl, pyridinyl or 4,5,6,7-tetra-hydrothieno [2,3-c]pyridinyl ring, and

R 3 and R 4 are independently of one another hydrogen, halogen or C 1 -C 6 -alkyl, or a salt, enantiomer or diastereomer thereof.

2. A compound according to claim 1 which is selected from:

N-[2-(aminocarbonyl)phenyl]-2-(3-pyridinyl)-4-thiazolecarboxamide;

N-[5-(aminocarbonyl)-1-methyl-1H-pyrazol-4-yl]-2-(4-pyridinyl)-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)phenyl]-2-(4-pyridinyl)-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)-4-methylphenyl]-2-(3-pyridinyl)-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)-5-methylphenyl]-2-(3-pyridinyl)-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)-4-chlorophenyl]-2-(3-pyridinyl)-4-thiazolecarboxamide;

3-[(2-pyridin-3-ylthiazole-4-carbonyl)amino]pyridine-2-carboxamide;

N-[2-(aminocarbonyl)-5-methylphenyl]-2-(4-pyridinyl)-4-thiazolecarboxamide;

6-methyl-2-[(2-pyridin-4-ylthiazole-4-carbonyl)amino]-4,5,6,7-tetra-hydrothieno [2,3-c]pyridine-3-carboxamide; 2-pyridin-4-ylthiazole-4-(3-carbamoyl- 1-methyl- 1H-pyrazol-4-yl)carboxamide;

N-[2-(aminocarbonyl)-5-methylphenyl]-2-[4-(trifluoromethyl)-3-pyridinyl]-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)-5-methylphenyl]-2-[6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)-5-methylphenyl]-2-(6-methoxy-3-pyridinyl)-4-thiazolecarboxamide;

N-[3-(aminocarbonyl)- 1-methyl- 1H-pyrazol-4-yl]-2-(pyrazin-2-yl)-4-thiazolecarboxamide;

6-methyl-2-[(2-pyrazin-2-ylthiazole-4-carbonyl)amino]-4,5,6,7-tetra-hydrothieno [2,3-c]pyridine-3-carboxamide;

N-[5-(aminocarbonyl)- 1-methyl- 1H-pyrazol-4-yl]-2-(3-pyridinyl)-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)-5-(1,1-dimethylethyl)-3-thienyl]-2-(3-pyridinyl)-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)-4-fluorophenyl]-2-(3-pyridinyl)-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)-3-thienyl]-2-(3-pyridinyl)-4-thiazolecarboxamide;

N-[3-(aminocarbonyl)-4-methyl-2-thienyl]-2-(3-pyridinyl)-4-thiazole-carboxamide; 3-[(2-pyridin-4-ylthiazole-4-carbonyl)amino]pyridine-2-carboxamide; 3-[(2-pyridin-4-ylthiazole-4-carbonyl)amino]isonicotinamide;

N-[2-(aminocarbonyl)phenyl]-2-(6-methoxy-3-pyridinyl)-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)phenyl]-2-(2-methoxy-3-pyridinyl)-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)phenyl]-2-(5-chloro-3-pyridinyl)-4-thiazolecarboxamide;

N-[2-(aminocarbonyl)-5-methylphenyl]-2-(6-aminopyridin-3-yl)thiazole-4-carboxamide; or

N-[2-(aminocarbonyl)-5-methylphenyl]-2-(6-hydroxypyridin-3-yl)thiazole-4-carboxamide.

3. Process for preparing a compound according to claim 1 comprising the steps:

a) conversion of intermediates of the formula (V) into intermediates of the formula (IV) by reaction with ethyl bromopyruvate by heating in organic solvents

b) hydrolysis of the ethyl ester (IV) to obtain intermediates of the formula (III)

c) reaction of the intermediates of formula (III) with compounds of the formula (II) by an amide coupling reagent

where

Q 1 , Q 2 , R 1 , R 2 , R 3 and R 4 have the meanings indicated in claim 1 .

4. Process for preparing a compound according to claim 1 comprising the steps:

a) reaction of 2-bromothiazole-4-carboxylic acid with intermediates of the formula (II) by an amide coupling reagent

b) reaction of the intermediates of the formula (VI) with boronic acids or boronic acid pinacol esters in a Suzuki-Miyaura reaction to give compounds of the formula (I)

where

Q 1 , Q 2 , R 1 , R 2 , R 3 and R 4 have the meanings indicated in claim 1 .

5. Pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

6. A method comprising contacting human peripheral blood mononuclear cells with a compound of claim 1 to inhibit the release of TNF-alpha in the human peripheral blood mononuclear cells.