6-amino-5,6,7,8-tetrahydronaphthalen-2-yl or 3-aminochroman-7-yl derivatives

Patent metadata

Field	Value
Publication number	US-9957261-B2
Application number	US-201715416472-A
Country	US
Kind code	B2
Filing date	Jan 26, 2017
Priority date	Jul 30, 2014
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

The present invention relates to compounds TAAR receptor antagonists of formula I wherein X, R, L, Ar and R 1 are as described herein, compositions containing compounds of formula I, methods of manufacture of compounds of formula I and methods of treating psychiatric disorders with compounds of formula I.

First claim

We claim:

1. A compound of formula (I) wherein:

L is —C(O)NH—, —NHC(O)—, —NH— or —NHC(O)NH—;
Ar is phenyl, benzyl, naphthyl or first heteroaryl, said first heteroaryl selected from the group consisting of pyridinyl, pyrazolyl, pyrimidinyl, isoxazolyl and pyrazinyl, wherein Ar may be optionally substituted by one, two or three R 1 ;
R 1 is, in each occurrence, independently selected from the group consisting of (a) hydrogen, (b) lower alkyl, (c) lower alkoxy, (d) halogen, (e) cyano, (f) cycloalkyl, (g) NHC(O)-lower alkyl, (h) lower alkoxy substituted by halogen, (i) lower alkyl substituted by halogen, (j) phenyl optionally substituted by one or two halogen atoms, CF 3 O or lower alkyl, and (k) a second heteroaryl selected from furanyl, thiazolyl or thiophenyl each optionally substituted by halogen or lower alkyl;
X is CH 2 ;
R is hydrogen or halogen;
or a pharmaceutically acceptable acid addition salt thereof, and a racemic mixture, enantiomer or mixture of enantiomers.

2. The compound according to claim 1 wherein L is —C(O)NH—.

3. The compound according to claim 2 , said compound selected from the group consisting of:
N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)isonicotinamide;
N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-4-bromo-5-cyclopropyl-1H-pyrazole-3-carboxamide;
N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-1-(2,2-difluoroethyl)-5-propyl-1H-pyrazole-3-carboxamide;
(R)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-1-(2,2-difluoroethyl)-5-propyl-1H-pyrazole-3-carboxamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-1-(2,2-difluoroethyl)-5-propyl-1H-pyrazole-3-carboxamide;
(R)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-6-methyl-2-(trifluoromethyl)-pyrimidine-4-carboxamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-6-methyl-2-(trifluoromethyl)-pyrimidine-4-carboxamide;
(R)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-4-chlorobenzamide;
(R)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-chlorobenzamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-methylisonicotinamide;
(S)-2-acetamido-N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)isonicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-ethoxyisonicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-6-(trifluoromethyl)nicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-6-methoxynicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-4-chloro-3-(5-chlorofuran-2-yl)-1H-pyrazole-5-carboxamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-4-chloro-5-methylisoxazole-3-carboxamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-1-p-tolyl-1H-pyrazole-4-carboxamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-1-(3,4-dichlorophenyl)-1H-pyrazole-4-carboxamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole-4-carboxamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-fluoronicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-6-chloronicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-5,6-dichloronicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3,4-difluorobenzamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-naphthamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)isonicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2,6-dichloroisonicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-5-chloronicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-2-chloro-6-methylisonicotinamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3-ethyl-4-methyl-1H-pyrazole-5-carboxamide;
(S)—N-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-4-bromo-5-(2,2-difluoroethoxy)-1-ethyl-1H-pyrazole-3-carboxamide;
(S)—N-(6-amino-1-chloro-5,6,7,8-tetrahydronaphthalen-2-yl)-6-chloronicotinamide;
or,
a pharmaceutically acceptable acid addition salt thereof, and a racemic mixture, enantiomer or mixture of enantiomers.

4. The compound according to claim 1 , wherein L is —NHC(O)—.

5. The compound according to claim 4 , which compound is selected from the group consisting of:
6-amino-N-(6-ethoxypyridin-3-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(2-cyclopropylpyrimidin-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(5-(trifluoromethyl)pyrazin-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(4-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-((6-chloropyridin-3-yl)methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(6-chloropyridin-3-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(3-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(3-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(4-ethylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(4-chlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(4-fluorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(3-chlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(4-cyclopropylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
6-amino-N-(4-cyanophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide;
(R)-6-amino-N-(3-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide; and,
(S)-6-amino-N-(3-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide; or,
a pharmaceutically acceptable acid addition salt thereof, and a racemic mixture, enantiomer or mixture of enantiomers.

6. The compound according to claim 1 , wherein L is NH—.

7. The compound according to claim 6 , which compound is selected from the group consisting of:
(S)—N6-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)—N6-(5-chloropyrimidin-2-yl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)—N6-(5-(trifluoromethyl)pyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)—N6-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)-4-(6-amino-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzonitrile;
(S)—N6-(4-chlorophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)—N6-(4-ethylphenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)—N6-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)—N6-(4-fluorophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)—N6-(3-chlorophenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)—N6-(4-cyclopropylphenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)—N6-(4-chlorobenzyl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine;
(S)—N6-(3-Methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-2,6-diamine; or,
a pharmaceutically acceptable acid addition salt thereof, and a racemic mixture, enantiomer or mixture of enantiomers.

8. The compound according to claim 1 , wherein L is —NHC(O)NH—.

9. The compound according to claim 8 , which compound is selected from the group consisting of:
(S)-1-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)urea;
(S)-1-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3-(4-(trifluoromethyl)phenyl)urea;
(S)-1-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3-((5-chloropyridin-2-yl)methyl)urea;
(S)-1-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3-(3-(trifluoromethoxy)benzyl)urea;
(S)-1-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3-(4-ethylphenyl)urea;
(S)-1-(6-amino-5,6,7,8-t

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Cecere Giuseppe
• Galley Guido
• Goergler Annick
• Norcross Roger
• Pflieger Philippe
• Tirla Alina
• Schmid Philipp

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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