Dihydroquinoline pyrazolyl compounds

Patent metadata

Field	Value
Publication number	US-2017226079-A1
Application number	US-201715498957-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 15 , R 16 , R 17 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 are independently selected from H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;
R 2 , R 3 and R 4 are independently selected from H, halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;
R 9 is alkylsulfanylalkyl, alkylsulfonylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, hetroarylalkyl, substituted heteroarylalkyl or the group A, wherein substituted aryl, substituted arylalkyl, substituted heteroaryl and substituted heteroarylalkyl are substituted with one to three sub stituents selected from the group consisting of alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, cyano, alkoxy, haloalkoxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl and haloalkylsulfonyl;

R 10 is pyrazolyl, substituted pyrazolyl, pyridinyl or substituted pyridinyl, wherein substituted pyrazolyl and substituted pyridinyl are substituted with one to three substituents selected from the group consisting of alkyl, halogen, haloalkyl, cycloalkyl and halocycloalkyl;
R 15 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;
R 16 and R 17 are independently selected from H, alkyl and cycloalkyl;
n is zero or 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 and R 3 are H.

5 . The compound according to claim 1 wherein R 4 is H or halogen.

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

7 . The compound according to claim 1 wherein R 15 is H.

8 . The compound according to claim 1 , wherein R 16 and R 17 are H.

9 . The compound according to claim 1 wherein n is 0.

10 . The compound according to claim 1 wherein R 1 is alkyl, R 2 , R 3 , R 5 , R 6 , R 7 , R8, R 15 , R 16 and R 17 are H, R 4 is H or halogen and n is 0.

11 . The compound according to claim 10 , wherein R 9 is alkylsulfanylalkyl, alkylsulfonylalkyl, substituted aryl, substituted arylalkyl or the group A, wherein substituted aryl and substituted arylalkyl are substituted with one to three substituents selected from alkyl, halogen, cyano, alkoxy, alkylsulfanyl and alkyl sulfonyl.

12 . The compound according to claim 1 , wherein R 9 is alkylsulfanylalkyl, alkylsulfonylalkyl, substituted aryl, substituted arylalkyl or the group A, wherein substituted aryl and substituted arylalkyl are substituted with one to three substituents selected from alkyl, halogen, cyano, alkoxy, alkylsulfanyl and alkylsulfonyl.

13 . The compound according to claim 1 wherein R 10 is either pyrazolyl substituted by one alkyl or pyridinyl substituted by one halogen.

14 . The compound of claim 11 wherein R 9 is the group A and R 10 is either pyrazolyl substituted by one alkyl or pyridinyl substituted by one halogen.

15 . The compound according to claim 1 wherein R 9 is aryl substituted with one to three substituents selected from alkyl, halogen, cyano, alkoxy, alkylsulfanyl and alkyl sulfonyl.

16 . The compound according to claim 11 wherein R 9 is aryl substituted with one to three substituents selected from alkyl, halogen, cyano, alkoxy, alkylsulfanyl and alkylsulfonyl.

17 . The compound according to claim 1 , which compound is selected from the group consisting of:
4-[[5-(1-Methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile; 6-[4-(4-Chlorophenoxy)-1H-pyrazol-5-yl]-1-methyl-3,4-dihydroquinolin-2-one; 3-Methoxy-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile; 3-Chloro-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile; 2-Fluoro-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile; 2-Chloro-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile; 6-[4-(3-Chlorophenoxy)-1H-pyrazol-5-yl]-1-methyl-3,4-dihydroquinolin-2-one; 1-Methyl-6-[4-(4-methylsulfanylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one; 1-Methyl-6-[4-(3-methylsulfanylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one; 1-Methyl-6-[4-(3-methylsulfonylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one; 1-Methyl-6-[4-(4-methylsulfonylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one; 1-Methyl-6-[4-(2-methylsulfanylethoxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one; (rac)-1-Methyl-6-[4-(1-methylsulfanylpropan-2-yloxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one; 1-Methyl-6-[4-(2-methylsulfonylethoxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one; 6-[4-[(4-Methoxyphenyl)methoxy]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one; 6-[4-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]oxymethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one; and, 5-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]oxymethyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one; or, a pharmaceutically acceptable salt thereof.

18 . A process to prepare a compound according to to claim 1 comprising the reaction of a compound of formula (II) in the presence of hydrazine hydrate;

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

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

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• A61P9/04

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

• A61P9/12

  Antihypertensives · CPC title

• A61P5/38

  of the suprarenal hormones · CPC title

• A61P5/42

  for decreasing, blocking or antagonising the activity of mineralocorticosteroids · CPC title

• A61P13/12

  of the kidneys · CPC title