Dihydroquinoline pyrazolyl compounds

Patent metadata

Field	Value
Publication number	US-2017226085-A1
Application number	US-201715498960-A
Country	US
Kind code	A1
Filing date	Apr 27, 2017
Priority date	Oct 31, 2014
Publication date	Aug 10, 2017
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 , R 13 , R 14 , R 15 , R 16 , R 17 , m and n are as described herein, compositions including the compounds and methods of using the compounds.

First claim

We claim:

1 . A compound of formula (I)

wherein:
R 1 , R 5 , R 6 , R 7 and R 8 in each occurrence are independently selected from H, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;
R 2 , R 3 and R 4 in each occurrence are independently selected from H, halogen, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;
R 9 , R 12 , R 13 , R 16 and R 17 in each occurrence are (i) independently selected from H, alkyl and cycloalkyl, and, R 11 together with R 14 form —CH 2 CH 2 —, or, (ii) R 9 , R 16 and R 17 in each occurrence are independently selected from H, alkyl and cycloalkyl and R 12 together with R 11 and R 13 together with R 14 both form —CH 2 ;
R 10 is alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, wherein substituted aryl, substituted arylalkyl, substituted heteroaryl and substituted heteroarylalkyl are substituted with one to three substituents selected from alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, cyano, alkoxy, haloalkoxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl and haloalkylsulfonyl;
A is —C(O)— or —S(O) 2 —
n is zero or 1;
m is 1;
or, pharmaceutically acceptable salts thereof.

2 . The compound according to claim 1 , wherein R 1 is alkyl.

3 . The compound according to claim 1 wherein R 5 , R 6 , R 7 and R 8 are H.

4 . The compound according to claim 1 wherein R 2 is H.

5 . The compound according to claim 1 wherein one of R 3 and R 4 is H and the other one is halogen.

6 . The compound according to claim 1 wherein R 3 and R 4 are H.

7 . The compound according to claim 1 wherein R 16 is H or alkyl.

8 . The compound according to claim 1 wherein R 9 , R 12 , R 13 and R 17 are H.

9 . The compound according to claim 1 wherein R 9 , R 12 , R 13 , R 16 and R 17 are H.

10 . The compound according to claim 1 wherein n is 1.

11 . The compound according to claim 1 wherein A is —C(O)—.

12 . The compound according to claim 1 wherein R 9 , R 12 , R 13 , R 16 and R 17 in each occurrence are independently selected from H, alkyl and cycloalkyl, and, R 11 together with R 14 form —CH 2 CH 2 —,

13 . The compound according to claim 1 wherein R 9 , R 16 and R 17 in each occurrence are independently selected from H, alkyl and cycloalkyl and R 12 together with R 11 and R 13 together with R 14 both form —CH 2 ;

14 . The compound according to claim 1 wherein R 10 is alkyl or heteroaryl substituted with one to three substituents selected from alkyl, halogen, cyano, alkoxy, alkylsulfanyl and alkylsulfonyl.

15 . The compound according to claim 14 wherein R 10 is alkyl or substituted pyrazolyl, substituted imidazolyl or substituted pyridinyl.

16 . The compound according to claim 15 , wherein R 10 is alkyl or substituted pyrazolyl, substituted imidazolyl or substituted pyridinyl, wherein substituted pyrazolyl, substituted imidazolyl and substituted pyridinyl are substituted with one alkyl or one halogen.

17 . The compound according to claim 16 wherein R 10 is substituted pyrazolyl, substituted imidazolyl or substituted pyridinyl.

18 . The compound according to claim 1 which compound is selected from the group consisting of:
6-[4-[(1-Acetyl-4-piperidyl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
1-Methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
6-[4-[(1-Ethylsulfonyl-4-piperidyl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one;
5-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;
6-[4-[(1-Ethylsulfonylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;
5-Fluoro-1-methyl-6-[4-[[1-(2-methylpyrazole-3-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
5-Fluoro-1-methyl-6-[4-[[1-(1-methylimidazole-2-carbonyl)piperidin-4-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
6-[4-[(1-Acetylpiperidin-4-yl)methyl]-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one;
1-Methyl-6-[4-[[1-(2-methylpyrazole-3-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
5-Chloro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
5-Chloro-6-[4-[[1-(3-chloropyridine-2-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
5-Chloro-1-methyl-6-[4-[[1-(2-methylpyrazole-3-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
5-Chloro-6-[4-[[1-(3-chloropyridine-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
1-Methyl-6-[4-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
1-Methyl-6-[4-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
1-Methyl-6-[4-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
6-[4-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
(rac)-6-[4-[1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one;
(rac)-6-[4-[1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;
6-[4-[(1S or 1R)-1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;
6-[4-[(1R or 1S)-1-(1-Acetylpiperidin-4-yl)ethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;
5-Chloro-6-[4-[(2-ethylsulfonyl-2-azaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
6-[4-[(2-Acetyl-2-azaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one; and,
5-Chloro-1-methyl-6-[4-[[2-(1-methylpyrazole-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one; or,
a pharmaceutically acceptable salts thereof.

19 . A process to prepare a compound according to 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 13 , R 14 , R 15 , R 16 , R 17 , m and n are 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 13 , R 14 , R 15 , R 16 , R 17 , m and n are as defined in claim 1 and X and X is halogen or hydroxy.

20 . A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier, diluent or excipient.

21 . A method for the treatment of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome, which method comprises administering to a patient in need thereof, an therapeutically effective amount of a compound according claim 1 .

Assignees

• Hoffmann La Roche

Inventors

• Aebi Johannes
• Amrein Kurt
• Hornsperger Benoit
• Kuhn Bernd
• Liu Yongfu
• Maerki Hans P
• Martin Rainer E
• Mayweg Alexander V
• Tan Xuefei
• Wang Lisha
• Li Dongbo
• Wu Jun

Classifications

• A61P9/04

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

• A61P9/12

  Antihypertensives · CPC title

• A61P5/40

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

• A61P13/12

  of the kidneys · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title