New phenyl-dihydropyridine derivatives as aldosterone synthase inhibitors

Patent metadata

Field	Value
Publication number	US-2016229807-A1
Application number	US-201615098738-A
Country	US
Kind code	A1
Filing date	Apr 14, 2016
Priority date	Oct 17, 2013
Publication date	Aug 11, 2016
Grant date	—

Abstract

The invention provides novel compounds having the general formula (I)

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , A 1 and n are as described herein, compositions including the compounds and methods of using the compounds.

First claim

1 . A Compound of formula (I)

wherein
R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H, halogen, cyano, nitro, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy and cycloalkoxy;
R 6 is H, alkyl, haloalkyl, cycloalkyl, substituted aryl or substituted heteroaryl, wherein substituted aryl or substituted heteroaryl are substituted with R 18 , R 19 and R 20 ;
R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently selected from H, halogen, alkyl and haloalkyl;
A 1 is —(CR 14 R 15 ) p —C(O)NR 16 R 17 or —(CR 14 R 15 ) p —C(O)OR 17 ;
R 14 and R 15 are independently selected from H, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;
R 16 is H, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl or haloalkoxyalkyl;
R 17 is H, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkoxyalkyl, substituted aryl or substituted heteroaryl, wherein substituted aryl and substituted heteroaryl are substituted with R 21 , R 22 and R 23 ;
or R 16 and R 17 together with the nitrogen to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R 21 , R 22 and R 23 ;
R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are independently selected from H, halogen, alkyl, haloalkyl, cycloalkyl, alkoxy and haloalkoxy;
n is zero, 1 or 2;
p is zero, 1 or 2;
and pharmaceutically acceptable salts thereof.

2 . The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H, halogen and haloalkyl.

3 . The compound of claim 1 , wherein R 1 and R 2 are independently selected from H and halogen.

4 . The compound of claim 1 , wherein R 3 is haloalkyl.

5 . The compound of claim 1 , wherein R 4 and R 5 are H.

6 . The compound of claim 1 , wherein n is zero and R 6 , R 7 , R 8 and R 9 are H.

7 . The of claim 1 , wherein R 12 is H, alkyl or substituted aryl, wherein substituted aryl is substituted with R 18 , R 19 and R 20 .

8 . The compound of claim 1 , wherein R 18 , R 19 and R 20 are H.

9 . The compound of claim 1 , wherein A 1 is
—(CR 14 R 15 ) p —C(O)NR 16 R 17 .

10 . The compound of claim 1 , wherein R 16 is H.

11 . The compound of claim 1 , wherein R 17 is H, alkyl, alkoxyalkyl or substituted heteroaryl, wherein substituted heteroaryl is substituted with R 21 , R 22 and R 23 or R 16 and R 17 together with the nitrogen to which they are attached form a substituted heterocycloalkyl, wherein substituted heterocycloalkyl is substituted with R 21 , R 22 and R 23 .

12 . The compound of claim 1 , wherein R 17 is H, alkyl, alkoxyalkyl or substituted heteroaryl, wherein substituted heteroaryl is substituted with R 21 , R 22 and R 23 .

13 . The compound of claim 1 , wherein R 21 , R 22 and R 23 are independently selected from H and alkyl.

14 . The compound of claim 1 , wherein R 14 and R 15 are H.

15 . The compound of claim 1 , wherein p is zero or 1.

16 . The compound of claim 1 , selected from
Ethyl 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)acetate; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-methylacetamide; N-Ethyl-2-[4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-acetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyri din-7-yl)-N-propylacetamide; N-Cyclopropyl-2-[4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-acetamide; N-(cyclopropylmethyl)-2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)acetamide; 2-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5#H!-[2]pyrindin-7-yl]-#N!-(2-methoxy-ethyl)-acetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyri din-7-yl)-1-(piperidin-1-yl)ethanone; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyri din-7-yl)-1-morpholinoethanone; 2-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5#H!-[2]pyrindin-7-yl]-#N!-isoxazol-3-yl-acetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyri din-7-yl)-N-(1H-pyrazol-3-yl)acetamide; 2-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyri din-7-yl)-N,N-dimethylacetamide; N-ethyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-methylacetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyri din-7-yl)-N-isopropyl-N-methylacetamide; N-cyclopropyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-methylacetamide; N-cyclopropyl-N-ethyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)acetamide; 1-(azetidin-1-yl)-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)ethanone; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1-(3-methoxyazetidin-1-yl)ethanone; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1-(pyrrolidin-1-yl)ethanone; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1-((S)-2-methylpyrrolidin-1-yl)ethanone; Ethyl 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetate; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)ethanol; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-N-methylacetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-N,N-dimethylacetamide; (S)-2-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydroisoquinolin-8-yl]-N,N-dimethylacetamide; (R)-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-N,N-dimethylacetamide; N-ethyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide; N-cyclopropyl-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide; N-(cyclopropylmethyl)-2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide; 2-(4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)-N-(2-methoxyethyl)acetamide; and pharmaceutically acceptable salts thereof.

17 . A process to prepare a compound of claim 1 comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III);

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 , n and p are as defined herein, R 24 is alkyl and A 1 is —(CR 14 R 15 )—C(O)NR 16 R 17 .

18 . (canceled)

19 . A pharmaceutical composition comprising a compound according to claim 1 and a therapeutically inert carrier.

20 - 22 . (canceled)

23 . A method for the treatment or prophylaxis chronic kidney disease, congestive heart failure, hypertensi

Assignees

• Hoffmann La Roche

Inventors

• Aebi Johannes
• Amrein Kurt
• Britton Robert
• Hornsperger Benoit
• Kuhn Bernd
• Maerki Hans P
• Martin Rainer E
• Mayweg Alexander V
• Tan Xuefei

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P5/40

  Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids · CPC title