Pyridone derivatives for the treatment of viral infections and further diseases
View Patent ↗This invention relates to pyridone derivatives, processes for their preparation, phamaceutical compositions, and their use in therapy.
1. A compound of formula (I)
or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein
R 1 is C 1-6 alkyl, optionally substituted by one or more substituents independently selected from the group consisting of aryl, halogen, OH, NH 2 , CO 2 H, CO 2 C 1-3 alkyl, C(O)NHC 1-3 alkyl, C(O)NHSO 2 C 1-3 alkyl, C 1-3 alkyl, C 3-6 cycloalkyl, SO 2 C 1-3 alkyl, S(O)C 1-3 alkyl, SO 2 NHC 1-3 alkyl, heterocyclyl and CN; and
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, aryl, —CF 3 and heterocyclyl;
or wherein
R 2 and R 3 form a 5-7 membered saturated or partially saturated monocyclic moiety optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,
R 3 and R 4 form a 5-7 membered saturated or partially saturated monocyclic moiety optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or
R 4 and R 5 form a 5-7 membered saturated or partially saturated monocyclic moiety optionally comprising one or more heteroatoms selected from nitrogen, oxygen or sulfur.
2. A compound of formula (I) according to claim 1 wherein R 1 is n-butyl and wherein R 2 , R 3 , R 4 , and R 5 are hydrogen.
3. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof, together with one or more pharmaceutically acceptable excipients, diluents or carriers.
4. A method of treating a disorder in which the modulation activating TLR 7 and/or TLR 8 in a cell, comprising contacting said cell with a therapeutically effective amount of at least one compound of claim 1 .
5. A method of inducing interferon production in a cell, comprising contacting said cell with a therapeutically effective amount of at least one compound of claim 1 .
6. A compound of formula (I) according to claim 1 , wherein R 1 is C 4-6 alkyl.
7. A compound of formula (I) according to claim 1 , wherein R 2 , R 3 , R 4 and R 5 are each hydrogen.
8. A compound of formula (I) according to claim 1 , wherein R 2 and R 3 are each independently hydrogen or CH 3 .
9. A compound of formula (I) according to claim 1 , wherein R 4 is CF 3 or CH 3 .
10. A compound of formula (I) according to claim 1 , wherein R 5 is F or hydrogen.
11. A compound of formula (I) according to claim 1 , wherein R 1 is C 4-6 alkyl; and R 2 , R 3 , R 4 and R 5 are each hydrogen.
12. A compound of formula (I) according to claim 1 , wherein R 2 is CH 3 ; and R 3 , R 4 and R 5 are each hydrogen.
13. A compound of formula (I) according to claim 1 , wherein R 2 , R 4 and R 5 are each hydrogen; and R 3 is CH 3 .
14. A compound of formula (I) according to claim 1 , wherein R 2 , R 3 and R 5 are each hydrogen; and R 4 is CF 3 or CH 3 .
15. A compound of formula (I) according to claim 1 , wherein R 2 , R 3 and R 4 are each hydrogen; and R 5 is F or hydrogen.
16. A compound of formula (I) according to claim 1 , wherein R 1 is C 4-6 alkyl; R 2 is CH 3 , and R 3 , R 4 and R 5 are each hydrogen.
17. A compound of formula (I) according to claim 1 , wherein R 1 is C 4-6 alkyl; R 2 , R 4 and R 5 are each hydrogen; and R 3 is CH 3 .
18. A compound of formula (I) according to claim 1 , wherein R 1 is C 4-6 alkyl; R 2 , R 3 and R 5 are each hydrogen; and R 4 is CF 3 or CH 3 .
19. A compound of formula (I) according to claim 1 , wherein R 1 is C 4-6 alkyl; R 2 , R 3 and R 4 are each hydrogen; and R 5 is F or hydrogen.
20. A compound of formula (I) according to claim 1 , wherein R 1 is selected from the group consisting of n-butyl, n-pentyl and n-hexyl.
21. A compound of formula (I) according to claim 1 , wherein R 1 is n-butyl, and R 2 is CH 3 , and R 3 , R 4 and R 5 are each hydrogen.
22. A compound of formula (I) according to claim 1 , wherein R 1 is n-butyl; R 2 , R 4 and R 5 are each hydrogen; and R 3 is CH 3 .
23. A compound of formula (I) according to claim 1 , wherein R 1 is n-butyl; R 2 , R 3 and R 5 are each hydrogen; and R 4 is CF 3 or CH 3 .
24. A compound of formula (I) according to claim 1 , wherein R 1 is n-butyl; R 2 , R 3 and R 4 are each hydrogen; and R 5 is F or hydrogen.
25. A compound according to claim 1 , wherein said compound is selected from the group consisting of
26. A method of activating TLR 7 and/or TLR 8 in a cell, comprising contacting said cell with a therapeutically effective amount of at least one compound as claimed in claim 25 .
27. A method of inducing interferon production in a cell, comprising contacting said cell with a therapeutically effective amount of at least one compound as claimed in claim 25 .
28. The method of claim 4 , wherein the cell is in a human subject.
29. The method of claim 5 , wherein the cell is in a human subject.
30. The method of claim 26 , wherein the cell is in a human subject.
31. The method of claim 27 , wherein the cell is in a human subject.
32. A method of preparing a compound of formula (I), said method comprising reacting a compound of formula A
with a compound of formula A-1
R 1 —NH 2 A-1
to form the compound of formula B
reducing the compound of formula B to form a compound of formula D
and
reacting the compound of formula D with a compound of formula D-1
to form a compound of formula I
wherein R 1 is C 1-6 alkyl, optionally substituted by one or more substituents independently selected from the group consisting of aryl, halogen, OH, NH 2 , CO 2 H, CO 2 C 1-3 alkyl, C(O)NHC 1-3 alkyl, C(O)NHSO 2 C 1-3 alkyl, C 1-3 alkyl, C 3-6 cycloalkyl, SO 2 C 1-3 alkyl, S(O)C 1-3 alkyl, SO 2 NHC 1-3 alkyl, heterocyclyl and CN;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, aryl, —CF 3 and heterocyclyl; or
R 2 and R 3 form a 5-7 membered saturated or partially saturated monocyclic moiety optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,
R 3 and R 4 form a 5-7 membered saturated or partially saturated monocyclic moiety optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or
R 4 and R 5 form a 5-7 membered saturated or partially saturated monocyclic moiety optionally comprising one or more heteroatoms selected from nitrogen, oxygen or sulfur.
33. The method of claim 32 , wherein the compound of formula B is reduced to form a compound of formula C
and
the compound of formula C is reduced to form a compound of formula D