Substituted quinolines and their use as medicaments

1. A compound of the formula 1

wherein

R 1 is a linear or branched C 1-6 -alkyl,

wherein R 1 is substituted by R 3 which is selected from the group consisting of a three-, four-, five-, six- or seven-membered cycloalkyl; a five-, six- or seven-membered, saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O; and a five- or six-membered heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O;

wherein the R 3 may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, —CO—NH 2 , —CO—NH(CH 3 ), —CO—N(CH 3 ) 2 , —C 1-5 -alkyl, —C 1-3 -alkylene-CO—NH 2 , —C 1-3 -alkylene-CO—NH(CH 3 ), —C 1-3 -alkylene-CO—N(CH 3 ) 2 , —C 1-3 -alkylene-CN and —CN, and wherein

R 2 is selected from the group consisting of halogen, phenyl, a five- or six-membered monocyclic heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O; a bicyclic nine-, ten- or eleven-membered, either aromatic or non-aromatic, but not fully saturated heterocycle comprising one, two, three or four heteroatoms each independently selected from the group consisting of N, S and O;

wherein the R 2 may optionally be substituted by one, two, three or four substituents R 4 which independently from one another are selected from the group consisting of linear or branched —O—C 1-5 -alkyl, —OH, oxo, halogen, —C 1-5 -haloalkyl, —SO 2 CH 3 , —C 1-3 -alkylene-SO 2 —C 1-3 -alkyl), —SO 2 —CF 3 , —CN, —C 3-6 -cycloalkyl, linear or branched —C 1-5 -alkyl, a four, five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group of N, S, —SO 2 and O;

—C 1-3 -alkylene-N(C 1-3 -alkyl)-CO—C 1-3 -alkyl, —NH—CO—C 1-3 -alkyl, —CO—NH(CH 3 ), —CO—NH 2 , —CO—N(CH 3 ) 2 , —O—R 5 , —CO—R 5 , —C 1-3 -alkylene-O—CO—C 1-3 -alkyl and

wherein the R 4 may optionally be substituted by one or two substituents R 5 ,

wherein each R 5 is independently from one another selected from the group consisting of linear or branched —C 1-4 -alkyl, oxo, —C 1-3 -haloalkyl, —OH, halogen, —C 1-2 -alkylene-C 1-3 -haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl, a five- or six-membered heteroaryl comprising one or two heteroatoms each independently selected from the group consisting of N, O and S,

wherein the R 5 may optionally be substituted by a group consisting of oxo, —C 1-3 -alkyl and —C 1-3 -haloalkyl,

or a pharmacologically acceptable salt thereof.

2. The compound of formula I according to claim 1 , wherein

R 1 is selected from the group consisting of —CH 3 and —CH 2 —(CH 3 ) which is substituted by R 3 which is selected from the group consisting of a three-, four-, five-, six- or seven-membered cycloalkl; a five-, six- or seven-membered, saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O; and a five- or six-membered heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O;

wherein the R 3 may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, —CO—NH 2 , —CO—NH(CH 3 ), —CO—N(CH 3 ) 2 , —C 1-5 -alkyl, —C 1-3 -alkylene-CO—NH 2 , —C 1-3 -alkylene-CO—NH(CH 3 ), —C 1-3 -alkylene-CO—N(CH 3 ) 2 , —C 1-3 -alkylene-CN and —CN,

or a pharmacologically acceptable salt thereof.

3. The compound of formula I according to claim 2 , wherein R 1 is substituted by R 3 which is selected from the group consisting of a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group consisting of N, S and O,

wherein the R 3 may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, —CO—NH 2 , —CO—NH(CH 3 ), —CO—N(CH 3 ) 2 , —C 1-5 -alkyl, —C 1-3 -alkylene-CO—NH 2 , —C 1-3 -alkylene-CO—NH(CH 3 ), —C 1-3 -alkylene-CO—N(CH 3 ) 2 , —C 1-3 -alkylene-CN and —CN,

or a pharmacologically acceptable salt thereof.

4. The compound of formula 1 according to claim 2 , wherein R 1 is substituted by R 3 which is selected from the group consisting of a five- or six-membered heteroaryl comprising one or two heteroatoms each independently selected from the group consisting of N, S and O,

wherein the R 3 may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, —CO—NH 2 , —CO—NH(CH 3 ), —CO—N(CH 3 ) 2 , —C 1-5 -alkyl, —C 1-3 -alkylene-CO—NH 2 , —C 1-3 -alkylene-CO—NH(CH 3 ), —C 1-3 -alkylene-CO—N(CH 3 ) 2 , —C 1-3 -alkylene-CN and —CN,

or a pharmacologically acceptable salt thereof.

5. The compound of formula 1 according claim 4 , wherein

R 1 is a selected from the group consisting of —CH 3 or —CH 2 (CH 3 ),

wherein R 1 is substituted by R 3 which is selected from the group consisting of a three-, four-, five- or six-membered cycloalkl; a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group consisting of N, S and O; and a five- or six-membered heteroaryl comprising one or two heteroatoms each independently selected from the group consisting of N, S and O;

wherein the R 3 may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, —CO—NH 2 , —CH 2 —CO—NH 2 , methyl and —CH 2 —CN,

or a pharmacologically acceptable salt thereof.

6. The compound of formula 1 according to claim 5 , wherein

R 1 is selected from the group consisting of —CH 3 and —CH 2 —CH 3 ,

wherein R 1 is substituted by R 3 which is a five-membered saturated heterocycle comprising one nitrogen-atom,

wherein the R 3 is substituted by one oxo-group or a pharmacologically acceptable salt thereof.

7. The compound of formula 1 according to claim 5 , wherein

R 1 including its substitution with R 3 is the group

or a pharmacologically acceptable salt thereof.

8. The compound of formula 1 according to claim 5 , wherein

R 1 is selected from the group consisting of —CH 3 and —CH 2 —CH 3 ,

wherein R 1 is substituted by R 3 which is a six-membered heteroaryl comprising one nitrogen-atom,

wherein the R 3 is substituted by —CO—NH 2 ,

or a pharmacologically acceptable salt thereof.

9. The compound of formula 1 according to claim 5 , wherein

R 1 including its substitution with R 3 is the group

or a pharmacologically acceptable salt thereof.

10. The compound of formula 1 according to claim 9 , wherein

R 2 is selected from the group consisting of phenyl, a five- or six-membered monocyclic heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O; a bicyclic, nine- or ten-membered, either aromatic or non-aromatic, but not fully saturated heterocycle comprising one, two, three or four heteroatoms each independently selected from the group consisting of N, S and O;

wherein the R 2 may optionally be substituted by one, two, three or four substituents R 4 which independently from one another are selected from the group consisting of linear or branched —O—C 1-3 -alkyl, oxo, —OH, —F, —Cl, —CF 3 , —CHF 2 , —SO 2 CH 3 , —CH 2 —SO 2 —CH 3 , —SO 2 —CF 3 , —CH 3 , —CH 2 —CH 3 , propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group of N, S, SO 2 and O; —NH—CO—CH 3 , —C 1-3 -alkylene-N(C 1-3 -alkyl)-CO—C 1-3 -alkyl, —CO—NH(CH 3 ), —(C 1-3 -alkylene)-O—CO—CH 3 , —CO—NH 2 , —CO—N(CH 3 ) 2 , —O—R 5 , —CO—R 5 , —C 1-3 -alkylene-O—CO—C 1-3 -alkyl and

wherein the R 4 may optionally be substituted by one or two substituents R 5 ,

wherein each R 5 is independently from one another selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopropyl, n-butyl, isobutyl, tert-butyl, —C 1-3 -haloalkyl, oxo, —OH, halogen, —C 1-2 -alkylene-C 1-3 -haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl, a five- or six-membered heteroaryl comprising one or two heteroatoms each independently selected from the group consisting of N, S and O,

wherein the R 5 may optionally be substituted by a group consisting of oxo, methyl, ethyl, —CF 3 ,

or a pharmacologically acceptable salt thereof.

11. The compound of formula 1 according to claim 10 , wherein

R 2 is phenyl,

wherein the R 2 may optionally be substituted by one, two, three or four substituents R 4 which independently from one another are selected from the group consisting of linear or branched —O—C 1-3 -alkyl, oxo, —OH, —F, —Cl, —CF 3 , —CHF 2 , —SO 2 CH 3 , —CH 2 —SO 2 —CH 3 , —SO 2 —CF 3 , —CH 3 , —CH 2 —CH 3 , propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group of N, S and O; —NH—CO—CH 3 , —C 1-3 -alkylene-N(C 1-3 -alkyl)-CO—C 1-3 -alkyl, —CO—NH(CH 3 ), —(C 1-3 -alkylene)-O—CO—CH 3 , —CO—NH 2 , —CO—N(CH 3 ) 2 , —O—R 5 , —CO—R 5 , —C 1-3 -alkylene-O—CO—C 1-3 -alkyl and

wherein the R 4 may optionally be substituted by one or two substituents R 5 ,

wherein each R 5 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, oxo, —C 1-3 -haloalkyl, —OH, halogen, —C 1-2 -alkylene-C 1-3 -haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl, a five- or six-membered heteroaryl comprising one or two heteroatoms each independently selected from the group consisting of N, S and O, wherein the R 5 may optionally be substituted by a group consisting of oxo, methyl,

or a pharmacologically acceptable salt thereof.

12. The compound of formula 1 according to claim 11 , wherein

R 2 is phenyl,

and wherein the R 2 may optionally be substituted by one, two, three or four substituents R 4 which independently from one another are selected from the group consisting of —OCH 3 , oxo, —OH, —F, Cl, —CF 3 , —CHF 2 , —SO 2 CH 3 , —SO 2 —CF 3 , —CH 3 , —CH 2 —CH 3 , propyl, isopropyl; —NH—CO—CH 3 , —C 1-3 -alkylene-N(C 1-3 -alkyl)-CO—CH 3 , —CO—NH(CH 3 ), —(C 1-3 -alkylene)-O—CO—CH 3 , —CO—NH 2 , —CO—N(CH 3 ) 2 , —O—R 5 , —CO—R 5 , —C 1-3 -alkylene-O—CO—C 1-3 -alkyl and

wherein the R 4 may optionally be substituted by one or two substituents R 5 ,

wherein each R 5 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopropyl, n-butyl, isobutyl, tert-butyl, —C 1-3 -haloalkyl, —OH, halogen, —C 1-2 -alkylene-C 1-3 -haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl,

wherein the R 5 may optionally be substituted by a group consisting of oxo, methyl, or a pharmacologically acceptable salt thereof.

13. The compound of formula 1 according to claim 10 , wherein

R 2 is a five- or six-membered monocyclic heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O;

wherein the R 2 may optionally be substituted by one, two, three or four substituents R 4 which independently from one another are selected from the group consisting of —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, oxo, —OH, —F, —CF 3 , —CHF 2 , —SO 2 CH 3 , —CH 2 —SO 2 —CH 3 , —SO 2 —CF 3 , —CH 3 , —CH 2 —CH 3 , propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group of N, S and O; —NH—CO—CH 3 , —C 1-3 -alkylene-N(C 1-3 -alkyl)-CO—C 1-3 -alkyl, —CO—NH(CH 3 ), —(C 1-3 -alkylene)-O—CO—CH 3 , —CO—NH 2 , —CO—N(CH 3 ) 2 , —O—R 5 , —CO—R 5 , —C 1-3 -alkylene-O—CO—C 1-3 -alkyl and

wherein the R 4 may optionally be substituted by one or two substituents R 5 ,

wherein each R 5 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —C 1-3 -haloalkyl, —OH, halogen, —C 1-2 -alkylene-C 1-3 -haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl,

wherein the R 5 may optionally be substituted by a group consisting of oxo, methyl and —CF 3 ,

or a pharmacologically acceptable salt thereof.

14. The compound of formula 1 according to claim 13 , wherein

R 2 is a five- or six-membered monocyclic heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O;

wherein the R 2 may optionally be substituted by one, two, three or four substituents R 4 which independently from one another are selected from the group consisting of —O—CH 3 , oxo, —OH, —F, —CF 3 , —CHF 2 , —SO 2 CH 3 , —CH 2 —SO 2 —CH 3 , —SO 2 —CF 3 , —CH 3 , —CH 2 —CH 3 , propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently from one another selected from the group of N, S and O; —NH—CO—CH 3 , —C 1-3 -alkylene-N(C 1-3 -alkyl)-CO—C 1-3 -alkyl, —CO—NH(CH 3 ), —(C 1-3 -alkylene)-O—CO—CH 3 , —CO—NH 2 , —CO—N(CH 3 ) 2 , —O—R 5 , —CO—R 5 ,

wherein the R 4 may optionally be substituted by one or two substituents R 59

wherein each R 5 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —CF 3 , —CH 2 —CF 3 , —CHF 2 , CH 2 F, —CF 2 —CF 3 , —OH, halogen, -ethylen-CF 3 , a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl,

wherein the R 5 may optionally be substituted by a group consisting of oxo, methyl and —CF 3 ,

or a pharmacologically acceptable salt thereof.

15. The compound of formula 1 according to claim 14 , wherein

R 2 is a five-membered monocyclic heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O;

whereby this five-membered monocyclic heteroaryl is linked to the quinoline core structure via a carbon atom and wherein this five-membered monocyclic heteroaryl optionally may be further substituted as identified in claim 14 ,

or a pharmacologically acceptable salt thereof.

16. The compound of formula 1 according to claim 14 , wherein

R 2 is a five-membered monocyclic heteroaryl comprising at least one nitrogen atom and optionally one or two further heteroatoms each independently selected from the group consisting of N, S and O;

whereby this five-membered monocyclic heteroaryl is linked to the quinoline core structure via a nitrogen atom,

and wherein this five-membered monocyclic heteroaryl optionally may be further substituted as identified in claim 14 ,

or a pharmacologically acceptable salt thereof.

17. The compound of formula 1 according to claim 10 , wherein

R 2 is a bicyclic, nine- or ten-membered, either aromatic or non-aromatic, but not fully saturated heterocycle comprising one, two, three or four heteroatoms each independently selected from the group consisting of N, S and O;

wherein the R 2 may optionally be substituted by one, two, three or four substituents R 4 which independently from one another are selected from the group consisting of linear or branched —O—C 1-3 -alkyl, oxo, —OH, —F, —CF 3 , —CHF 2 , —SO 2 CH 3 , —CH 2 —SO 2 —CH 3 , —SO 2 —CF 3 , —CH 3 , —CH 2 —CH 3 , propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently from one another selected from the group of N, S and O; —NH—CO—CH 3 , —C 1-3 -alkylene-N(C 1-3 -alkyl)-CO—C 1-3 -alkyl, —CO—NH(CH 3 ), —(C 1-3 -alkylene)-O—CO—CH 3 , —CO—NH 2 , —CO—N(CH 3 ) 2 , —O—R 5 , —CO—R 5 , —C 1-3 -alkylene-O—CO—C 1-3 -alkyl and

wherein the R 4 may optionally be substituted by one or two substituents R 5 ,

wherein each R 5 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, —C 1-3 -haloalkyl, —OH, halogen, —C 1-2 -alkylene-C 1-3 -haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl,

wherein the R 5 may optionally be substituted by a group consisting of oxo, methyl and —CF 3 ,

or a pharmacologically acceptable salt thereof.

18. The compound of formula 1 according to one of claims 17 , wherein

R 2 is a bicyclic, nine- or ten-membered, either aromatic or non-aromatic, but not fully saturated heterocycle comprising one, two, three or four heteroatoms each independently selected from the group consisting of N, S and O;

wherein the R 2 may optionally be substituted by one, two, three or four substituents R 4 which independently from one another are selected from the group consisting of —O—CH 3 , —O-ethyl, —O-propyl, —O-isopropyl, oxo, —OH, —F, —CF 3 , methyl, ethyl, propyl and isopropyl,

or a pharmacologically acceptable salt thereof.

19. The compound of formula 1 according to claim 14 , wherein

R 2 is pyridine,

wherein the R 2 may optionally be substituted by one, two, three or four substituents R 4 which independently from one another are selected from the group consisting of —O—CH 3 , oxo, —OH, —F, —CF 3 , —CHF 2 , —SO 2 CH 3 , —CH 2 —SO 2 —CH 3 , —SO 2 —CF 3 , —CH 3 , —CH 2 —CH 3 , propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group of N, S and O; —NH—CO—CH 3 , —C 1-3 -alkylene-N(C 1-3 -alkyl)-CO—C 1-3 -alkyl, —CO—NH(CH 3 ), —(C 1-3 -alkylene)-O—CO—CH 3 , —CO—NH 2 , —CO—N(CH 3 ) 2 , —O—R 5 , —CO—R 5 ,

wherein the R 4 may optionally be substituted by one or two substituents R 5 ,

wherein each R 5 is independently from one another selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, —CF 3 , —CH 2 —CF 3 , —CHF 2 , CH 2 F, —CF 2 —CF 3 , —OH, halogen, —C 1-2 -alkylene-CF 3 , a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl,

wherein the R 5 may optionally be substituted by a group consisting of oxo, methyl and —CF 3

or a pharmacologically acceptable salt thereof.

20. The compound of formula 1 according to claim 19 , wherein

R 2 is pyridine,

wherein the R 2 is substituted by one or two R 4 which independently from one another are selected from the group consisting of —O—CH 3 , —OH, —F, —CF 3 , —CHF 2 , —CH 3 , —CH 2 —CH 3 , propyl, isopropyl and —O—R 5 ,

wherein R 5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, —CF 3 , —CHF 2 , CH 2 F, —CH 2 —CF 3 , —CF 2 —CF 3

or a pharmacologically acceptable salt thereof.

21. The compound according to formula 1 according to claim 1 , wherein

R 1 including its substitution with R 3 is selected from the group consisting of

and wherein

R 2 is selected from the group consisting of

or a pharmacologically acceptable salt thereof.

22. The compound according to formula 1 according to claim 1 selected from the group consisting of

or a pharmacologically acceptable salt thereof.

23. A pharmaceutical formulation comprising a therapeutically affective amount of a compound of formula 1 according to claim 1 and one or more pharmaceutically acceptable carriers and/or adjuvants.

24. The pharmaceutical formulation according to claim 23 in combination with an active substance selected from the group consisting of anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors, CRTH2-antagonists, CCR1-antagonists, NSAIDS, COX 2-inhibitors (Coxibe), iNOS-inhibitors, HMG-CoA reductase inhibitors and folic acid antagonists.

25. A compounds selected from formula 7

from formula A

from formula B

and from formula C

wherein R 1 and R 2 are defined as in one of claim 1 .

26. A compound of formula 1 selected from a group consisting of:

27. The compound according to claim 26 wherein the compound is:

28. The compound according to claim 26 wherein the compound is:

29. The compound according to claim 26 wherein the compound is:

30. The compound according to claim 26 wherein the compound is:

31. The compound according to claim 26 wherein the compound is:

32. The compound according to claim 26 wherein the compound is:

33. The compound according to claim 26 wherein the compound is:

34. A pharmaceutical formulation comprising a therapeutically affective amount of a compound of formula 1 according to claim 26 and one or more pharmaceutically acceptable carriers and/or adjuvants.

35. The pharmaceutical formulation according to claim 34 in combination with an active substance selected from the group consisting of anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors, CRTH2-antagonists, CCR1-antagonists, NSAIDS, COX 2-inhibitors (Coxibe), iNOS-inhibitors, HMG-CoA reductase inhibitors and folic acid antagonists.