New dihydroquinoline pyrazolyl compounds

Patent metadata

Field	Value
Publication number	US-2017226116-A1
Application number	US-201715498969-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 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and m 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 and halocycloalkyl;
R 2 , R 3 and R 4 are independently selected from H, halogen, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;
R 12 , R 13 , R 17 and R 16 are in each occurrence are (i) independently selected from H, alkyl and cycloalkyl, and R 11 and R 14 together form —CH 2 —CH 2 —, —CH 2 (CH 3 )—CH 2 — or —CH 2 —CH 2 (CH 3 )—, or (ii) R 17 and R 16 are independently selected from H, alkyl and cycloalkyl and R 11 together with R 12 and R 13 together with R 14 together both form —CH 2 —;
R 10 is alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, hetroarylalkyl 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 —
m is 0 or 1; or,
a pharmaceutically acceptable salt 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 12 , R 13 and R 17 are H.

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

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

11 . The compound according to claim 10 wherein R 1 is alkyl, one of R 3 and R 4 is H and the other of R 3 and R 4 is halogen, R 16 is hydrogen or alkyl, and R 2 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 and R 17 are H.

12 . 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.

13 . The compound according to claim 12 wherein R 10 is alkyl or heteroaryl selected from substituted pyrazolyl, substituted imidazolyl or substituted pyridinyl, wherein substituted pyrazolyl, substituted imidazolyl and substituted pyridinyl.

14 . A compound according to claim 13 wherein R 10 is alkyl or heteroaryl substituted with one alkyl or one halogen.

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

16 . A compound according to claim 15 where R 11 and R 14 together form —CH 2 —CH 2 —, —CH 2 (CH 3 )—CH 2 — or —CH 2 —CH 2 (CH 3 )— and m is 0.

17 . A compound according to claim 15 wherein R 11 together with R 12 and R 13 together with R 14 together both form —CH 2 —, and m is 1.

18 . A compound according to claim 1 selected from the group consisting of:
5-Fluoro-1-methyl-6-[4-[[4-(1-methylpyrazole-4-carbonyl)piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
5-Chloro-1-methyl-6-[4-[[4-(1-methylpyrazole-4-carbonyl)piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
8-Chloro-1-methyl-6-[4-[[4-(1-methylpyrazole-4-carbonyl)piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
6-[4-[[(3R)-4-Acetyl-3-methyl-piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;
5-Fluoro-1-methyl-6-[4-[[(3R)-3-methyl-4-(1-methylpyrazole-4-carbonyl)piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
6-[4-[[(3R)-4-Acetyl-3-methyl-piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one;
5-Chloro-1-methyl-6-[4-[[(3R)-3-methyl-4-(1-methylpyrazole-4-carbonyl)piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
6-[4-[[(3R)-4-Acetyl-3-methyl-piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
1-Methyl-6-[4-[[(3R)-3-methyl-4-(1-methylpyrazole-4-carbonyl)piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
5-Chloro-1-methyl-6-[4-[[(2R)-2-methyl-4-(1-methylpyrazole-4-carbonyl)piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
5-Fluoro-1-methyl-6-[4-[[(2R)-2-methyl-4-(1-methylpyrazole-4-carbonyl)piperazin-1-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
5-Chloro-1-methyl-6-[4-[[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
5-Chloro-6-[4-[(2-ethylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
5-Fluoro-1-methyl-6-[4-[[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
6-[4-[(2-Ethylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
6-[4-[(2-Isopropylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
1-Methyl-6-[4-[[2-(4-methylpyridine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
6-[4-[(2-Acetyl-2,6-diazaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-5-chloro-1-methyl-3,4-dihydroquinolin-2-one;
8-Chloro-1-methyl-6-[4-[[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;
6-[4-[(2-Acetyl-2,6-diazaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-8-chloro-1-methyl-3,4-dihydroquinolin-2-one;
8-Chloro-6-[4-[(2-ethylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)methyl]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;
1-Methyl-6-[4-[[2-(1-methylimidazole-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one; and,
6-[4-[[2-(3-Chloropyridine-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-1H-pyrazol-3-yl]-1-methyl-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 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and m are defined according to claim 1 and X is halogen or hydroxy.

20 . A pharmaceutical composition comprising a compound according 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 a therapeutically effective amount of a compound according to claim 1 .

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/38

  of the suprarenal hormones · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title