(1-azinone)-substituted pyridoindoles
View Patent ↗Substituted pyridoindoles for incorporation in pharmaceutical compositions employed in the treatment of various diseases correspond to formula (I) wherein R 1 is H or optionally substituted alkyl; R 2 , R 3 , R 4 are each independently selected from H, —O-alkyl, —S-alkyl, alkyl, halo, —CF 3 , and —CN; G is —CR 12 R 13 —NR 5 — or —NR 5 —CR 12 R 13 ; R 5 is H, optionally substituted alkyl, optionally substituted heterocycle, —C(═O)—R 6 , —C(═O)—O—R 7 , or —C(═O)—NR 19 R 20 ; R 6 and R 7 are each optionally substituted alkyl or optionally substituted heterocycle; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 19 and R 20 are each independently selected from H or optionally substituted alkyl; R 14 and R 15 are each independently H or halogen; L is —CH 2 —O—, —CH 2 CH 2 —, —CH═CH— or a bond; and B is aryl or heteroaryl or cycloalkyl; with the proviso that, when L is a direct bond, B cannot be unsubstituted heteroaryl or heteroaryl monosubstituted with fluorine.
1. A compound of formula I:
wherein
R 1 is H or optionally substituted alkyl;
R 2 , R 3 , R 4 are each independently selected from H, —O-alkyl, —S-alkyl, alkyl, halo, —CF 3 , and —CN;
G is —CR 12 R 13 —NR 5 — or —NR 5 —CR 12 R 13 ;
R 5 is H, optionally substituted alkyl, optionally substituted heterocycle, —C(═O)—R 6 , —C(═O)—O—R 7 , or —C(═O)—NR 19 R 20 ;
R 6 and R 7 are each optionally substituted alkyl or optionally substituted heterocycle;
R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 19 and R 20 are each independently selected from H or optionally substituted alkyl;
R 14 and R 15 are each independently H or halogen;
Y is N;
L is —CH 2 —O—, —CH 2 CH 2 —, —CH═CH— or a bond; and
B is aryl or heteroaryl or cycloalkyl;
with the proviso that, when L is a direct bond, B cannot be unsubstituted heteroaryl or heteroaryl monosubstituted with fluorine.
2. A compound according to claim 1 wherein G is —CH 2 —NR 5 —.
3. A compound according to claim 1 wherein G is —NR 5 —CH 2 —.
4. A compound according to claim 1 wherein R 5 is H.
5. A compound according to claim 1 wherein R 5 is optionally substituted alkyl.
6. A compound according to claim 5 wherein R 5 is selected from methyl, ethyl, 2-propyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 2-oxo-2-(pyrrolidin-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl and (S)-pyrrolidin-2-ylmethyl.
7. A compound according to claim 1 wherein R 5 is optionally substituted heterocycle.
8. A compound according to claim 7 wherein R 5 is selected from piperidin-4-yl and 1-methylpiperidin-4-yl.
9. A compound according to claim 1 wherein R 5 is —C(═O)—R 6 or —C(═O)—O—R 7 .
10. A compound according to claim 1 wherein R 5 is —C(═O)—NR 19 R 20 .
11. A compound according to claim 7 wherein R 6 and R 7 are each optionally substituted alkyl.
12. A compound according to claim 11 wherein R 6 and R 7 are selected from methyl, 2-pyrrolidin-1-ylmethyl and dimethylaminomethyl.
13. A compound according to claim 7 wherein R 6 and R 7 are each optionally substituted heterocycle.
14. A compound according to claim 13 wherein R 6 and R 7 are selected from pyrrolidin-3-yl, (R)-pyrrolidin-2-yl, (S)-pyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, (R)-1-methylpyrrolidin-2-yl and (S)-1-methylpyrrolidin-2-yl.
15. A compound according to claim 1 wherein R 1 is H.
16. A compound according to claim 1 wherein R 1 is alkyl.
17. A compound according to claim 16 wherein R 1 is selected from methyl and ethyl.
18. A compound according to claim 1 wherein the compound has the structure
19. A compound according to claim 1 wherein the compound has the structure
20. A compound according to claim 1 wherein L is a bond.
21. A compound according to claim 1 wherein L is —CH 2 —O—.
22. A compound according to claim 1 wherein L is —CH 2 CH 2 —.
23. A compound according to claim 1 wherein L is —CH═CH—.
24. A compound according to claim 1 wherein B is aryl.
25. A compound according to claim 24 wherein B is phenyl.
26. A compound according to claim 1 wherein B is heteroaryl.
27. A compound according to claim 26 wherein B is pyridinyl.
28. A compound according to claim 27 wherein B is pyridin-2-yl.
29. A compound according to claim 27 wherein B is pyridin-3-yl.
30. A compound according to claim 26 wherein B is pyridazinyl.
31. A compound according to claim 30 wherein B is pyridazin-3-yl.
32. A compound according to claim 26 wherein B is pyrimidinyl.
33. A compound according to claim 32 wherein B is pyrimidin-5-yl.
34. A compound according to claim 32 wherein B is pyrimidin-2-yl.
35. A compound according to claim 1 wherein B is cycloalkyl.
36. A compound according to claim 35 wherein B is cyclohexyl.
37. A compound according to claim 1 wherein R 2 , R 3 and R 4 are each H.
38. A compound according to claim 1 wherein two of R 2 , R 3 and R 4 are H, and the other of R 2 , R 3 and R 4 is selected from trifluoromethyl, chloro, fluoro, methyl, methoxy and methylthio.
39. A compound according to claim 1 wherein one of R 2 , R 3 and R 4 is H, another of R 2 , R 3 and R 4 is Cl, and the third of R 2 , R 3 and R 4 is F, Cl or methoxy.
40. A compound according to claim 1 wherein one of R 2 , R 3 and R 4 is H, another of R 2 , R 3 and R 4 is F, and the third of R 2 , R 3 and R 4 is methoxy.
41. A compound according to claim 1 wherein one of R 2 , R 3 and R 4 is H, another of R 2 , R 3 and R 4 is methoxy, and the third of R 2 , R 3 and R 4 is methyl.
42. A compound according to claim 1 wherein B, together with R 2 , R 3 and R 4 , is selected from phenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4-fluorophenyl, 4-chloro-2-fluorophenyl, 2-fluoro-4-methoxyphenyl, pyridin-2-yl, 5-chloropyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 5-fluoropyridin-2-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6-methylpyridazin-3-yl, 4-fluoro-2-methoxyphenyl, 6-(trifluoromethyl)pyridin-3-yl, 2-(trifluoromethyl)pyrimidin-5-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5-methylpyridin-2-yl, 6-methylpyridin-3-yl, cyclohexyl, 4-chloro-2-methoxyphenyl, pyrimidin-2-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-2-yl, 4-methoxyphenyl, 4-methanethiophenyl and 4-methoxy-2-methylphenyl.
43. A compound according to claim 1 wherein the compound is selected from
44. A compound according to claim 1 wherein R 1 is substituted alkyl.
45. A compound according to claim 44 wherein R 1 is selected from difluoromethyl and ethoxymethyl.
46. A compound according to claim 1 wherein at least one of R 8 and R 9 is H.
47. A compound according to claim 1 wherein at least one of R 8 and R 9 is alkyl.
48. A compound according to claim 47 wherein at least one of R 8 and R 9 is methyl.
49. A compound according to claim 1 wherein R 10 is alkyl.
50. A compound according to claim 49 wherein R 10 is methyl.
51. A compound according to claim 1 wherein R 10 is substituted alkyl.
52. A compound according to claim 51 wherein R 10 is hydroxymethyl.
53. A compound according to claim 1 wherein R 11 is alkyl.
54. A compound according to claim 53 wherein R 11 is methyl.
55. A compound according to claim 1 wherein R 12 is alkyl.
56. A compound according to claim 55 wherein R 12 is methyl.
57. A compound according to claim 1 wherein R 13 is alkyl.
58. A compound according to claim 57 wherein R 13 is methyl.
59. A compound according to claim 1 wherein R 10 , R 11 , R 12 and R 13 are each methyl.
60. A compound according to claim 1 wherein R 14 is H.
61. A compound according to claim 1 wherein R 14 is halogen.
62. A compound according to claim 1 wherein
G is —CH 2 —NR 5 — or —NR 5 —CH 2 —;
R 1 and R 5 are each independently H or methyl;
R 14 is H;
R 15 is H or halogen;
B is phenyl or heteroaryl; and
(a) when L is —CH 2 —O—, —CH 2 CH 2 —, or —CH═CH—; then R 2 , R 3 , R 4 are each independently selected from H, —O-alkyl, —S-alkyl, alkyl, halo, —CF 3 , and —CN; or
(b) when L is a direct bond, R 2 is selected from —O-alkyl, —S-alkyl, alkyl, Cl, Br, —CF 3 and —CN, and R 3 and R 4 are each independently selected from H, —O-alkyl, —S-alkyl, alkyl, halo, —CF 3 and —CN.
63. A compound according to claim 1 wherein the compound is in a pharmaceutically acceptable salt form.
64. A compound according to claim 63 wherein the salt is an HCl salt.
65. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent therefore.