Bicyclic heteroaryl derivatives

Patent metadata

Field	Value
Publication number	US-2019233427-A1
Application number	US-201716339345-A
Country	US
Kind code	A1
Filing date	Oct 2, 2017
Priority date	Oct 4, 2016
Publication date	Aug 1, 2019
Grant date	—

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; and R 1 may be different if n is 2 or 3; R 2 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, CN, lower alkoxy or lower alkoxy substituted by halogen; X is CH or N; m is 1, 2 or 3; -( ) m is —(CH 2 ) m —; n is 1, 2 or 3; Ar is a five membered heteroaryl group, selected from formula (A), (B), (C), (D), (E) or (F), wherein R 3 is hydrogen, methyl or chloro; R 4 is hydrogen or methyl; R 5 is F, Cl, CHF 2 or CF 3 ; 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-infarct dementia, dementia pugilistica or Down syndrome.

First claim

1 . 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;
 and R 1 may be different if n is 2 or 3;
R 2 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, CN, lower alkoxy or lower alkoxy substituted by halogen;
X is CH or N;
m is 1, 2 or 3;
-( ) m is —(CH 2 ) m —;
n is 1, 2 or 3;
Ar is a five membered heteroaryl group, selected from

 wherein
 R 3 is hydrogen, methyl or chloro;
 R 4 is hydrogen or methyl;
 R 5 is F, Cl, CHF 2 or CF 3 ;

or a pharmaceutically active acid addition salt thereof.

2 . A compound of formula I-1 according to claim 1 ,

wherein
R 1 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, lower alkoxy or lower alkoxy substituted by halogen;
 and R 1 may be different if n is 2 or 3;
R 2 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, CN, lower alkoxy or lower alkoxy substituted by halogen;
X is CH or N;
m is 1, 2 or 3;
n is 1, 2 or 3;
R 3 is hydrogen, methyl or chloro;
R 4 is hydrogen or methyl;
-( ) m is —(CH 2 ) m —;

or a pharmaceutically active acid addition salt thereof.

3 . A compound of formula I-1 according to claim 2 , which compounds are
N-[3-(difluoromethoxy)-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 4-(3,4-difluorophenyl)-N-[3-methoxy-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 4-(3,4-difluorophenyl)-N-[3-methoxy-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine 4-(3,4-difluorophenyl)-N-[3-fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[4-(3-chloro-1,2,4-triazol-1-yl)-3-methoxy-phenyl]4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 4-(3,4-difluorophenyl)-N-[3-fluoro-4-(5-methyl-1,2,4-triazol-1-yl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 4-(3,4-difluorophenyl)-N-[3-fluoro-4-(1,2,4-triazol-1-yl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[3-methoxy-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[4-(3-chloro-1,2,4-triazol-1-yl)-3-fluoro-phenyl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 4-(3,4-difluorophenyl)-N-[4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 5-[[4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]amino]-2-(3-methyl-1,2,4-triazol-1-yl)benzonitrile 4-(3-fluorophenyl)-N-[3-methoxy-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 4-(4-fluorophenyl)-N-[3-methoxy-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[3-(difluoromethoxy)-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 4-(3,5-difluorophenyl)-N-[3-methoxy-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine or N-[3-methoxy-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-4-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine.

4 . A compound of formula I-2 according to claim 1 ,

wherein
R 1 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, lower alkoxy or lower alkoxy substituted by halogen;
 and R 1 may be different if n is 2 or 3;
R 2 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, CN, lower alkoxy or lower alkoxy substituted by halogen;
X is CH or N;
m is 1, 2 or 3;
n is 1, 2 or 3;
R 5 is F, Cl, CHF 2 or CF 3 ;
-( ) m is —(CH 2 ) m —;

or a pharmaceutically active acid addition salt thereof.

5 . A compound of formula I-2 according to claim 4 , which compounds are
4-(3,4-difluorophenyl)-N-[3-methoxy-4-[4-(trifluoromethyl)imidazol-1-yl]phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[6-(4-chloroimidazol-1-yl)-5-methoxy-3-pyridyl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[4-(4-chloroimidazol-1-yl)-3-methoxy-phenyl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[4-(4-chloroimidazol-1-yl)-3-methoxy-phenyl]-4-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine 4-(3,4-difluorophenyl)-N-[3-methoxy-4-[4-(trifluoromethyl)imidazol-1-yl]phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a][1,3]diazepin-2-amine N-[4-(4-chloroimidazol-1-yl)-3-methoxy-phenyl]-4-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[4-(4-chloroimidazol-1-yl)-3-fluoro-phenyl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[4-(4-chloroimidazol-1-yl)phenyl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo [1,5-a]pyrimidin-2-amine 2-(4-chloroimidazol-1-yl)-5-[[4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]amino]benzonitrile 2-[4-(difluoromethyl)imidazol-1-yl]-5-[[4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]amino]benzonitrile N-[3-chloro-4-(4-chloroimidazol-1-yl)phenyl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[4-(4-chloroimidazol-1-yl)-3-methoxy-phenyl]-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[4-(4-chloroimidazol-1-yl)-3-methoxy-phenyl]-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 2-(4-chloroimidazol-1-yl)-5-[[4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]amino]benzonitrile N-[4-(4-chloroimidazol-1-yl)-3-fluoro-phenyl]-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[6-(4-chloroimidazol-1-yl)-5-methoxy-3-pyridyl]-4-(4-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine 4-(3,4-difluorophenyl)-N-[4-(4-fluoroimidazol-1-yl)-3-methoxy-phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[4-(4-chloroimidazol-1-yl)-3-methoxy-phenyl]-4-(3,5-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine N-[4-(4-chloroimidazol-1-yl)-3-methoxy-phenyl]-4-[4-(trifluoromethyl)phenyl]-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine N-[4-(4-chloroimidazol-1-yl)-3-methoxy-phenyl]-4-(2,3,4-trifluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine or N-[4-(4-chloroimidazol-1-yl)-3-methoxy-phenyl]-4-(3,4-difluorophenyl)-5,6-dihydroimidazo[1,2-b][1,2,4]triazol-2-amine.

6 . A compound of formula I-3 according to claim 1 ,

wherein
R 1 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, lower alkoxy or lower alkoxy substituted by halogen;
 and R 1 may be different if n is 2 or 3;
R 2 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, CN, lower alkoxy or lower alkoxy substituted by halogen;
X is CH or N;
m is 1, 2 or 3;
n is 1, 2 or 3;
-( ) m is —(CH 2 ) m —;

or a pharmaceutically active acid addition salt thereof.

7 . A compound of formula I-3 according

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title