Bicyclic compounds and their uses
The present invention provides a compound, or a pharmaceutically acceptable salt thereof, of formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 26 , R 27 , y, R, M, W, L, V, T, Y, J, K and A are as described herein, therapeutic uses of said compounds, uses of said compounds as research chemicals, a pharmaceutical composition and combinations comprising said compounds, and methods for manufacturing the compounds of the invention.
1. A compound, or a pharmaceutically acceptable salt thereof, selected from:
or a pharmaceutically acceptable salt thereof.
2. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is in non-zwitterionic form.
3. The compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is in zwitterionic form.
4. The compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is a sodium salt.
5. The compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is in amorphous form.
6. The compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , in crystalline form.
7. A combination comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , and one or more additional therapeutically active agents.
8. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , and one or more pharmaceutically acceptable carriers.
9. A method of modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, according to claim 1 .
10. A method of inhibiting WRN in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, according to claim 1 .
11. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, according to claim 1 .
12. The method according to claim 11 , wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
13. A compound which is
or a pharmaceutically acceptable salt thereof.
14. The compound, or a pharmaceutically acceptable salt thereof, according to claim 13 , wherein the compound is in non-zwitterionic form.
15. The compound, or a pharmaceutically acceptable salt thereof, according to claim 13 , wherein the compound is in zwitterionic form.
16. The compound, or a pharmaceutically acceptable salt thereof, according to claim 13 , wherein the compound is a sodium salt.
17. The compound, or a pharmaceutically acceptable salt thereof, according to claim 13 , wherein the compound is in amorphous form.
18. The compound, or a pharmaceutically acceptable salt thereof, according to claim 13 , which is in crystalline form.
19. A combination comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 13 , and one or more additional therapeutically active agents.
20. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 13 , and one or more pharmaceutically acceptable carriers.
21. A compound which is
or a pharmaceutically acceptable salt thereof.
22. The compound, or a pharmaceutically acceptable salt thereof, according to claim 21 , wherein the compound is in non-zwitterionic form.
23. The compound, or a pharmaceutically acceptable salt thereof, according to claim 21 , wherein the compound is in zwitterionic form.
24. The compound, or a pharmaceutically acceptable salt thereof, according to claim 21 , wherein the compound is a sodium salt.
25. The compound, or a pharmaceutically acceptable salt thereof, according to claim 21 , wherein the compound is in amorphous form.
26. The compound, or a pharmaceutically acceptable salt thereof, according to claim 21 , which is in crystalline form.
27. A combination comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 21 , and one or more additional therapeutically active agents.
28. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 21 , and one or more pharmaceutically acceptable carriers.
29. A compound selected from the group consisting of:
(R)—N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-oxo[1,2,4]triazolo [1,5-a]pyrimidin-4(7H)-yl)acetamide; and
N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo[1,2,4]triazolo [1,5-a]pyrimidin-4 (7H)-yl)acetamide,
or a pharmaceutically acceptable salt thereof.
30. A method of modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, according to claim 21 .
31. A method of inhibiting WRN in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, according to claim 21 .
32. A method of treating a disorder or disease which can be treated by WRN inhibition in a subject, comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, according to claim 21 .
33. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, according to claim 21 .
34. The method of claim 33 , wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
35. The method of claim 34 , wherein the cancer is selected from colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, and ovarian cancer.
36. The method of claim 34 , wherein the cancer is colorectal cancer.
37. A compound which is