Mineralocorticoid receptor antagonists
View Patent ↗The present invention is directed to compounds of the Formula I: as well as pharmaceutically acceptable salts thereof, that may be useful for treating aldosterone-mediated diseases. The invention furthermore relates to specific diastereomers and enantiomers of the compounds, to processes for preparing compounds of the Formula I, to their potential use for the therapy and prophylaxis of the above-mentioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical compositions which comprise compounds of the Formula I.
1. A compound selected from
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 selected from
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 selected from
Compound No.
Structure
Name
1
N-(1-(3-(4-bromophenyl)-2- hydroxypentan-3-yl)-1H-indazol- 4-yl)methanesulfonamide (diastereomer C),
2
N-(1-(3-(4-bromophenyl)-2- hydroxypentan-3-yl)-1H-indazol- 4-yl)methanesulfonamide (diastereomer D),
3
N-(1-(3-(4-bromophenyl)-2- hydroxypentan-3-yl)-1H-indazol- 4-yl)methanesulfonamide (diastereomer A),
4
N-(1-(3-(4-bromophenyl)-2- hydroxypentan-3-yl)-1H-indazol- 4-yl)methanesulfonamide (diastereomer B),
5
N-(1-(3-(4-bromophenyl)-4- hydroxyhexan-3-yl)-1H-indazol- 4-yl(methanesulfonamide (diastereomer C),
6
N-(1-(3-(4-bromophenyl)-4- hydroxyhexan-3-yl)-1H-indazol- 4-yl)methanesulfonamide (diastereomer D),
7
N-(1-(3-(4-bromophenyl)-4- hydroxyhexan-3-yl)-1H-indazol-4- yl)methanesulfonamide (diastereomer A),
8
N-(1-(3-(4-bromophenyl)-4- hydroxyhexan-3-yl)-1H-indazol-4- yl)methanesulfonamide (diastereomer B),
9
N-(1-(4-hydroxy-3-(4- (trifluoromethyl)phenyl)hexan-3- yl)-1H-indazol-4- yl)methanesulfonamide (diastereomer A),
10
N-(1-(4-hydroxy-3-(4- (trifluoromethyl)phenyl)hexan-3- yl)-1H-indazol-4- yl)methanesulfonamide (diastereomer B),
11
N-(1-(1-hydroxy-2-(4- (trifluoromethyl)phenyl)butan-2- yl)-1H-indazol-4- yl)methanesulfonamide (enantiomer A),
12
2-(4-(methylsulfonamido)-1H- imdazol-1-yl)-2-(4- (trifluoromethyl)phenyl) butanamide (enantiomer A),
13
N-(1-(3-(4-cyanophenyl)-2- hydroxypentan-3-yl)-1H-indazol- 4-yl)methanesulfonamide (diastereomer A), or
14
N-(1-(3-(4-cyano)-4- hydroxyhexan-3-yl)-1H-indol-4- yl)methanesulfonamide (diastereomer C),
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 , selected from
Compound No.
Structure
Name
17
N-(6-fluoro-1-(4-hydroxy-3-(4- (trifluoromethyl)phenyl)hexan-3-yl)- 1H-indazol-4- yl)methanesulfonamide (Diastereomer A),
18
N-(6-fluoro-1-(4-hydroxy-3-(4- (trifluoromethyl)phenyl)hexan-3-yl)- 1H-indazol-4- yl)methanesulfonamide (Diastereomer B),
19
N-(1-(3-(4-cyanophenyl)-2- hydroxypentan-3-yl)-6-fluoro-1H- indazol-4-yl)methanesulfonamide (Diastereomer A),
20
N-(1-(3-(4-cyanophenyl)-4- hydroxyhexan-3-yl)-6-fluoro-1H- indazol-4-yl)methanesulfonamide (Diastereomer B),
21
N-(1-{2-hydroxy-3-[4-(pentafluoro- λ 6 -sulfanyl)phenyl]pentan-3-yl}-1H- indazol-4-yl)methanesulfonamide (Diasteromer A),
22
N-(1-{2-hydroxy-3-[4-(pentafluoro- λ 6 -sulfanyl)phenyl]pentan-3-yl}-1H- indazol-4-yl)methanesulfonamide (Diasteromer B),
23
N-(1-{2-hydroxy-3-[4-(pentafluoro- λ 6 -sulfanyl)phenyl]pentan-3-yl}-1H- indazol-4-yl)methanesulfonamide (Diasteromer C),
24
N-(1-{2-hydroxy-3-[4-(pentafluoro- λ 6 -sulfanyl)phenyl]pentan-3-yl}-1H- indazol-4-yl)methanesulfonamide (Diasteromer D),
25
N-(1-{4-hydroxy-3-[4-(pentafluoro- λ 6 -sulfanyl)phenyl]hexan-3-yl}-1H- indazol-4-yl)methanesulfonamide (Diastereomers A and B),
26
N-(1-{4-hydroxy-3-[4-(pentafluoro- λ 6 -sulfanyl)phenyl]hexan-3-yl}-1H- indazol-4-yl)methanesulfonamide (Diastereomers A and B), or
27
2-{4-[(methylsulfonyl)amino]-1H- indazol-1-yl}-2-[4-(pentafluoro-λ 6 - sulfanyl)phenyl]butanamide (racemic),
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 selected from
31
N-(6-fluoro-1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-3-
yl)-1H-indazol-4-yl)methanesulfonamide (diastereomer A),
32
N-(6-fluoro-1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-3-
yl)-1H-indazol-4-yl)methanesulfonamide (diastereomer B),
33
N-(6-fluoro-1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-3-
yl)-1H-indazol-4-yl)methanesulfonamide (diastereomer C), or
34
N-(6-fluoro-1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-3-
yl)-1H-indazol-4-yl)methanesulfonamide (diastereomer D),
or a pharmaceutically acceptable salt thereof.
6. A compound of claim 1 selected from
Com-
pound
No.
Structure
Name
35
N-(1-(1,1-difluoro-4- hydroxy-3-(4- (trifluoromethyl) phenyl)pentan-3-yl)- 1H-indazol-4- yl)methanesulfonamide (Diastereomer C),
36
N-(1-(1,1-difluoro-4- hydroxy-3-(4- (trifluoromethyl) phenyl)pentan-3-yl)- 1H-indazol-4- yl)methanesulfonamide (Diastereomer D),
37
N-(1-(1,1-difluoro-4- hydroxy-3-(4- (trifluoromethyl) phenyl)pentan-3-yl)- 1H-indazol-4- yl)methanesulfonamide (Diastereomer A),
38
N-(1-(1,1-difluoro-4- hydroxy-3-(4- (trifluoromethyl) phenyl)pentan-3-yl)- 1H-indazol-4- yl)methanesulfonamide (Diastereomer B),
39
N-(1-(1,1-difluoro-4- hydroxy-3-(4- (trifluoromethyl) phenyl)hexan-3-yl)-1H- indazol-4- yl)methanesulfonamide (Diastereomer C),
40
N-(1-(1,1-difluoro-4- hydroxy-3-(4- (trifluoromethyl) phenyl)hexan-3-yl)-1H- indazol-4- yl)methanesulfonamide (Diastereomer D),
41
N-(1-(1,1-difluoro-4- hydroxy-3-(4- (trifluoromethyl) phenyl)hexan-3-yl)-1H- indazol-4- yl)methanesulfonamide (Diastereomer A), or
42
N-(1-(1,1-difluoro-4- hydroxy-3-(4- (trifluoromethyl) phenyl)hexan-3-yl)-1H- indazol-4- yl)methanesulfonamide (Diastereomer B),
or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1 , selected from
Compound No.
Structure
Name
43
N-(1-(4,4-difluoro-1-hydroxy- 2-(4-(trifluoromethyl)phenyl) butan-2-yl)-1H-indazol-4- yl)methanesulfonamide (Enantiomer A),
44
N-(1-(4,4-difluoro-1-hydroxy-2- (4-(trifluoromethyl)phenyl) butan-2-yl)-1H-indazol-4- yl)methanesulfonamide (Enantiomer B),
45
4,4-difluoro-2-(4-(methyl- sulfonamido)-1H-indazol-1- yl)-2-(4-(trifluoromethyl)phenyl) butanamide (Enanliomer A), or
46
4,4-ditluoro-2-(4-(methyl- sulfonamido)-1H-indazol-1- yl)-2-(4-(trifluoromethyl)phenyl) butanamide (Enantiomer B),
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 , selected from
Compound
Number
Structure
Name
47
N-(1-(1,1-difluoro-2-hydroxy-3-(4- (trifluoromethyl)phenyl)pentan-3- yl)-1H-indazol-4- yl)methanesulfonamide (Diastereomer A),
48
N-(1-(1,1-difluoro-2-hydroxy-3-(4- (trifluoromethyl)phenyl)pentan-3- yl)-1H-indazol-4- yl)methanesulfonamide (Diastereomer B),
49
N-(1-(1,1-difluoro-2-hydroxy-3-(4- (trifluoromethyl)phenyl)pentan-3- yl)-1H-indazol-4- yl)ethanesulfonamide (Diastereomer A),
50
N-(1-(1,1-difluoro-2-hydroxy-3-(4- (trifluoromethyl)phenyl)pentan-3- yl)-1H-indazol-4- yl)ethanesulfonamide (Diastereomer B),
51
N-(1-(1,1-difluoro-2-hydroxy-3-(4- (trifluoromethyl)phenyl)pentan-3- yl)-6-fluoro-1H-indazol-4- yl)methanesulfonamide (diastereomer A),
52
N-(1-(1,1-difluoro-2-hydroxy-3-(4- (trifluoromethyl)phenyl)pentan-3- yl)-6-fluoro-1H-indazol-4- 1)methanesulfonamide (diastereomer B),
53
N-(1-(1,1-difluoro-2-hydroxy-3-(4- (trifluoromethyl)phenyl)pentan-3- yl)-6-fluoro-1H-indazol-4- yl)ethanesulfonamide (diastereomer A), or
54
N-(1-(1,1-difluoro-2-hydroxy-3-(4- (trifluoromethyl)phenyl)pentan-3- yl)-6-fluoro-1H-indazol-4- yl)ethanesulfonamide (diastereomer B),
or a pharmaceutically acceptable salt thereof.
9. A compound of claim 1 selected from
Compound
Number
Structure
Name
55
N-(1-(1,1-difluoro-4-hydroxy- 3-(4- (trifluoromethyl)phenyl)hexan- 3-yl)-1H-indazol-4- yl)ethanesulfonamide (Diastereomer C),
56
N-(1-(1,1-difluoro-4-hydroxy- 3-(4- (trifluoromethyl)phenyl)hexan- 3-yl)-1H-indazol-4- yl)ethanesulfonamide (Diastereomer D),
57
N-(1-(1,1-difluoro-4-hydroxy- 3-(4- (trifluoromethyl)phenyl)pentan- 3-yl)-1H-indazol-4- yl)ethanesulfonamide (Diastereomer C), or
58
N-(1-(1,1-difluoro-4-hydroxy- 3-(4- (trifluoromethyl)phenyl)pentan- 3-yl)-1H-indazol-4- yl)ethanesulfonamide (Diastereomer D),
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 selected from
N-(1-(3-(4-bromophenyl)-2-hydroxypentan-3-yl)-1H-indazol-4-yl) methanesulfonamide (diastereomer D);
N-(1-(4-hydroxy-3-(4-(trifluoromethyl)phenyl)hexan-3-yl)-1H-indazol-4-yl)methanesulfonamide (diastereomer A);
N-(6-fluoro-1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-1H-indazol-4-yl)methanesulfonamide (diastereomer A);
N-(1-(1,1-difluoro-2-hydroxy-3-(4-(trifluoromethyl)phenyl) pentan-3-yl)-1H-indazol-4-yl)methanesulfonamide (Diastereomer A)
N-(1-(1,1-difluoro-4-hydroxy-3-(4-(trifluoromethyl)phenyl) pentan-3-yl)-1H-indazol-4-yl)methanesulfonamide (Diastereomer C); or
4,4-difluoro-2-(4-(methylsulfonamido)-1H-indazol-1-yl)-2-(4-(trifluoromethyl)phenyl) butanamide (Enantiomer A);
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprised of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 11 further comprises a second pharmaceutically active agent.
13. A method of treating heart failure, hypertension, or atherosclerosis in a human patient in need of, comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
14. A method of treating a physiological or pathologic disease, selected from Conn's Syndrome, heart failure, primary and secondary hyperaldosteronism, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter's Syndrome, atherosclerosis, retinopathy, choriretinopathy, obstructive sleep apnea, psychoses, memory disturbances, depression, and bipolar disorder, comprising administering to a patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.