Aldosterone synthase inhibitors
The present invention relates to compounds of formula I: and pharmaceutically acceptable salts thereof, wherein Cy, R 1 and R 2 are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
1. A compound of the formula I
wherein:
Cy is a monocyclic or bicyclic ring system selected from C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl,
wherein each of the said C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally and independently substituted with one, two, or three substituent groups selected from halogen, —C 1-3 -alkyl, —OC 1-3 -alkyl, —CF 3 , cyano, oxo, —N(C 1-3 -alkyl) 2 , —NH(C 1-3 -alkyl), —NHCOC 1-3 -alkyl, —C(O)C 1-3 -alkyl, —C(O)OC 1-3 alkyl, hydroxyC 1-3 alkyl, or heteroaryl; and
R 1 and R 2 are independently selected from H, C 1-3 alkyl, hydroxyC 1-3 alkyl, —CH 2 NHC(O)OC 1-4 alkyl, —CH 2 OC(O)C 1-4 alkyl, —C(O)OC 1-4 -alkyl, —C(O)H, —COOH, —C(O)NHC 1-4 -alkyl and C(O)N(C 1-4 -alkyl) 2 ; or
R 1 and R 2 taken together form a C 3-6 cycloalkyl or C 3-6 -heterocyclyl;
or a salt thereof.
2. The compound of formula I according to claim 1 , wherein:
Cy is a phenyl, cyclohexyl, indanyl, 2,3-dihydrobenzofuranyl or tetrahydroquinolinyl group, each optionally substituted with one, two, or three substituent groups independently selected from —Cl, —F, C 1-3 alkyl, oxo and CN; and
R 1 and R 2 are independently selected from H, C 1-3 alkyl, hydroxyC 1-3 alkyl, —CH 2 NHC(O)OC 1-4 alkyl, —C(O)N(C 1-4 -alkyl) 2 and —CH 2 OC(O)C 1-4 alkyl.
3. The compound of formula I according to claim 1 , wherein:
Cy is phenyl optionally substituted with one, two, or three substituent groups independently selected from —Cl, —F, C 1-3 alkyl and CN.
4. The compound of formula I according to claim 1 , wherein:
Cy is phenyl substituted with CN and optionally substituted with one or two additional groups independently selected from —Cl, —F and C 1-3 alkyl;
R 1 is —CH 3 ; and
R 2 is —CH 3 or —CH 2 OH.
5. The compound according to claim 4 , wherein:
R 2 is —CH 2 OH.
6. The compound according to claim 4 , wherein:
R 2 is —CH 3 .
7. The compound according to claim 1 selected from the group consisting of
and the pharmaceutically acceptable salts thereof.
8. The compound according to claim 7 selected from the group consisting of compound numbers 1-11, 13, 15, 18, 19, 22, 23, 26, 28, 29A, 29B, 30-33, 35, 39, 41, 42, 45 and 46.
9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient or carrier.
10. A method of treating a disease or disorder that can be alleviated by inhibition of aldosterone synthase selected from diabetic nephropathy, glomerulosclerosis, glomerulonephritis, IGA nephropathy, nephritic syndrome, focal segmental glomerulosclerosis (FSGS), hypertension, pulmonary arterial hypertension, Conn's syndrome, systolic heart failure, diastolic heart failure, left ventricular dysfunction, left ventricular stiffness and fibrosis, left ventricular filing abnormalities, arterial stiffness, atherosclerosis and cardiovascular morbidity associated with primary or secondary hyperaldosteronism, adrenal hyperplasia and primary and secondary hyperaldosteronism comprising administering a therapeutically effective amount of a compound according to claim 1 to patient in need thereof.
11. The method according to claim 10 , wherein the disease or disorder is selected from diabetic nephropathy, glomerulosclerosis, glomerulonephritis, IGA nephropathy, nephritic syndrome and focal segmental glomerulosclerosis (FSGS).
12. The method according to claim 10 , wherein the disease is diabetic nephropathy.
13. The compound according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
18. The compound according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
20. The compound according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
22. The compound according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising the compound according to claim 13 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
24. A pharmaceutical composition comprising the compound according to claim 14 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
25. A pharmaceutical composition comprising the compound according to claim 15 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
26. A pharmaceutical composition comprising the compound according to claim 16 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
27. A pharmaceutical composition comprising the compound according to claim 17 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising the compound according to claim 18 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
29. A pharmaceutical composition comprising the compound according to claim 19 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
30. A pharmaceutical composition comprising the compound according to claim 20 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
31. A pharmaceutical composition comprising the compound according to claim 21 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
32. A pharmaceutical composition comprising the compound according to claim 22 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
33. The method according to claim 10 , wherein the compound of formula (I) is
or pharmaceutically acceptable salt thereof.
34. The method according to claim 10 , wherein the compound of formula (I) is
or pharmaceutically acceptable salt thereof.
35. The method according to claim 10 , wherein the compound of formula (I) is
or pharmaceutically acceptable salt thereof.
36. The method according to claim 10 , wherein the compound of formula (I) is
or pharmaceutically acceptable salt thereof.
37. The method according to claim 10 , wherein the compound of formula (I) is
or pharmaceutically acceptable salt thereof.
38. The method according to claim 10 , wherein the compound of formula (I) is
or pharmaceutically acceptable salt thereof.
39. The method according to claim 10 , wherein the compound of formula (I) is
or pharmaceutically acceptable salt thereof.
40. The method according to claim 10 , wherein the compound of formula (I) is
or pharmaceutically acceptable salt thereof.
41. The method according to claim 10 , wherein the compound of formula (I) is
or pharmaceutically acceptable salt thereof.
42. The method according to claim 10 , wherein the compound of formula (I) is
or pharmaceutically acceptable salt thereof.