3-([1,2,4]triazolo[4,3-a]pyridin-7-yl)benzamide derivatives
New inhibitors of the p38 mitogen-activated protein kinase having the general formula (I) are disclosed herein, as well as processes for their preparation, pharmaceutical compositions comprising them, and their use in therapy.
1. A compound of formula (I)
wherein
R 1 is chosen from C 1-4 alkyl, C 3-7 cycloalkyl, and —(CH 2 ) (1-3) —C 3-7 cycloalkyl;
R 2 is chosen from hydrogen and halogen atoms;
R 3 is chosen from methyl and halogen atoms;
L is a direct bond;
R 4 is chosen from C 1-4 alkyl, and C 3-6 cycloalkyl optionally substituted with methyl;
Y 1 and Y 2 are independently chosen from fluorine, and chlorine atoms;
or a pharmaceutically acceptable salt or a N-oxide thereof.
2. A compound according to claim 1 , wherein R 1 is chosen from C 3-6 cycloalkyl and —(CH 2 ) (1-3) —C 3-6 cycloalkyl.
3. A compound according to claim 2 , wherein R 1 is a C 3-4 cycloalkyl.
4. A compound according to claim 1 , wherein R 2 is chosen from hydrogen and fluorine.
5. A compound according to claim 1 , wherein R 3 is methyl.
6. A compound according to claim 1 , wherein R 4 is chosen from branched C 3-4 alkyl.
7. A compound according to claim 1 , wherein Y 1 and
Y 2 are each a fluorine atom.
8. A compound according to claim 1 , wherein R 1 is cyclopropyl, R 2 is chosen from hydrogen and fluorine, R 3 is methyl, L is a direct bond, R 4 is chosen from branched C 3-4 alkyl, and Y 1 and Y 2 are each a fluorine atom.
9. A compound chosen from:
N-Cyclopropyl-3-(3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-methylbenzamide;
N-Cyclopropyl-4-methyl-3-(3-(1-methylcyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzamide;
3-(3-Cyclobutyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-cyclopropyl-4-methylbenzamide;
3-(3-tert-Butyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-(cyclopropylmethyl)-4-methylbenzamide;
3-(3-tert-Butyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;
3-(3-tert-Butyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-chloro-N-cyclopropylbenzamide;
3-(3-tert-Butyl-6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-cyclopropyl-4-methylbenzamide;
3-(3-tert-Butyl-6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;
3-(3-tert-Butyl-6,8-difluoro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-cyclopropyl-4-methylbenzamide;
3-(3-tert-Butyl-6,8-difluoro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;
N-Cyclopropyl-3-(6,8-difluoro-3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)-5-fluoro-4-methylbenzamide;
N-cyclopropyl-3-(3-cyclopropyl-6,8-difluoro[1,2,4]triazolo[4,3-a]pyridin-7-yl)-5-fluoro-4-methylbenzamide;
N-cyclopropyl-3-(3-cyclopropyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)-5-fluoro-4-methylbenzamide;
N-cyclopropyl-3-fluoro-5-(3-isopropyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-methylbenzamide;
3-(3-Cyclobutyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;
3-(3-Cyclohexyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide; and
N-Cyclopropyl-3-fluoro-4-methyl-5-[3-(1-methylcyclopropyl)[1,2,4]triazolo[4,3-a]pyridin-7-yl]benzamide;
or a pharmaceutically acceptable salt or a N-oxide thereof.
10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable diluent or carrier.
11. A combination product comprising:
(i) a compound according to claim 1 ; and
(ii) another compound chosen from (1) antagonists of M3 muscarinic receptors, (2) β2-agonists, (3) PDE4 inhibitors, (4) cortiocosteroids, (5) leukotriene D4 antagonists, (6) inhibitors of egfr-kinase, (7) antagonists of the A2B adenosine receptor, (8) NK1 receptor agonists, (9) CRTh2 antagonists, (10) syk kinase inhibitors, (11) CCR3 antagonists, (12) VLA-4 antagonists, and (13) a DMARD (disease modifying antirheumatic drug)
for simultaneous, separate or sequential use in the treatment of the human or animal body.
12. A compound of formula (I)
wherein
R 1 is chosen from C 1-4 alkyl, C 3-7 cycloalkyl, and —(CH 2 ) (1-3) —C 3-7 cycloalkyl;
R 2 is chosen from hydrogen and halogen atoms;
R 3 is chosen from methyl and halogen atoms;
L is a direct bond;
R 4 is chosen from methyl, and C 3-6 cycloalkyl optionally substituted with methyl;
Y 1 and Y 2 are independently chosen from hydrogen, fluorine, and chlorine atoms;
or a pharmaceutically acceptable salt or a N-oxide thereof;
with the proviso that the compound of formula (I) is not N-Cyclopropyl-3-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-methylbenzamide.