Bridged piperidine derivatives

Patent metadata

Field	Value
Publication number	US-10899766-B2
Application number	US-201716337348-A
Country	US
Kind code	B2
Filing date	Sep 28, 2017
Priority date	Sep 29, 2016
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

The present invention relates to a compound of formula (I), wherein R 1 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, lower alkoxy or lower alkoxy substituted by halogen; R may be the same or different, if n=2 or 3; n is 1, 2 or 3; m is 1, 2 or 3; Ar is a five or six membered heteroaryl group, selected from (II), (III), (IV) or (V) wherein R 2 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen or lower alkoxy; R 3 is hydrogen or halogen; -( ) m-is —(CH 2 ) m — or to pharmaceutically active acid addition salts thereof. The compounds may be used for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-in-farct dementia, dementia pugilistica or Down syndrome.

First claim

The invention claimed is:

1. A compound of formula I,

wherein:
each R 1 is independently hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, or lower alkoxy substituted by halogen;
n is 1, 2 or 3;
m is 1, 2 or 3;
Ar is a five or six membered heteroaryl group, selected from:

wherein:
R 2 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, or lower alkoxy;
R 3 is hydrogen or halogen; and

—( ) m — is —(CH 2 ) m —;
or a pharmaceutically active acid addition salt thereof.

2. A compound of formula I-1

wherein:
each R 1 is independently hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy or lower alkoxy substituted by halogen;
n is 1, 2 or 3;
m is 1, 2 or 3;
R 2 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, or lower alkoxy; and
—( ) m — is —(CH 2 ) m —;
or a pharmaceutically active acid addition salt thereof.

3. A compound of formula I-1 according to claim 2 , selected from:
4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[ 2 -(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(1R,5 S,8S)-3-(2-chloro-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine;
4-[4-(trifluoromethyl)phenyl]-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-[4-(trifluoromethyl)phenyl]-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine;
4-(3-fluoro-4-methyl-phenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine;
N-[1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-[2(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-[2(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(4-fluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3,5-difluorophenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3-fluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3,5-difluorophenyl)-N-[(1R,5S,8S)-3-(2-methoxy-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine; and 4-(4-methoxyphenyl)-N-[(1R,5S,8S)-3-[2-(trifluoromethyl)-4-pyridyl]-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine, or a pharmaceutically active acid addition salt thereof.

4. A compound of formula I-2,

wherein:
each R 1 is independently hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy or lower alkoxy substituted by halogen;
n is 1, 2 or 3;
m is 1, 2 or 3;
R 2 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, or lower alkoxy;
R 3 is hydrogen or halogen; and
—( ) m — is —(CH 2 ) m —;
or a pharmaceutically active acid addition salt thereof.

5. A compound of formula I-2 according to claim 4 , selected from the group consisting of:
4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3,4-difluorophenyl)-N-[(1R,5S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine;
N-[(1R,5 S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(1R,5 S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine;
4-(3-fluoro-4-methyl-phenyl)-N-[(1R,5 S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[1R, 5 S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine;
N-[(1R,5 S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluoro-4-methyl-phenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3,4-difluorophenyl)-N-[(1R,5 S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(1R,5 S,8S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3,4-difluorophenyl)-N-[(1R,5 S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3,4-difluorophenyl)-N-[(1R,5 S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine;
4-(3,4-difluorophenyl)-N-[(1R,5 S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine;
N-[(1R,5 S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(1R,5 S,8S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3-fluorophenyl)-N-[(1R,5 S, 8 S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(4-fluorophenyl)-N-[(1R,5 S, 8 S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(4-fluorophenyl)-N-[(1R,5 S, 8 S)-3-(6-methoxypyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3,5-difluorophenyl)-N-[(1R,5 S,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(1R,5S,8S)-3-(5-fluoro-6-methyl-pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-(3-fluorophenyl)-N

Assignees

• Hoffmann La Roche

Inventors

• Bartels Bjoern
• Jakob-Roetne Roland
• Limberg Anja
• Neidhart Werner
• Ratni Hasane
• Reutlinger Michael
• Sarie Jérôme Charles
• Vastakaite Greta

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title