Bicyclic heteroaryl derivatives

Patent metadata

Field	Value
Publication number	US-10647721-B2
Application number	US-201716339345-A
Country	US
Kind code	B2
Filing date	Oct 2, 2017
Priority date	Oct 4, 2016
Publication date	May 12, 2020
Grant date	May 12, 2020

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

The invention claimed is:

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; and
Ar is a five membered heteroaryl group, selected from

wherein
R 3 is hydrogen, methyl or chloro;
R 4 is hydrogen or methyl; and
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; 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 , which compound is:
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, CI, CHF 2 or CF 3 ; 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 , which compound is:
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

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