Pyridyl-triazabicycles

Patent metadata

Field	Value
Publication number	US-10047102-B2
Application number	US-201515314718-A
Country	US
Kind code	B2
Filing date	Jul 21, 2015
Priority date	Jul 25, 2014
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

The present invention provides a compound of formula (I) having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease.

First claim

The invention claimed is:

1. A compound of formula I,

wherein
R 1 is selected from the group consisting of
i) aryl,
ii) aryl, substituted by 1-3 substituents individually selected from cyano, C 1-6 -alkyl, halogen-C 1-6 -alkyl and halogen
iii) heteroaryl,
iv) heteroaryl, substituted by 1-3 substituents individually selected from cyano, C 1-6 -alkyl, halogen-C 1-6 -alkyl and halogen, and

R 2 together with R 4 is selected from the group consisting of
i) —(CH 2 ) x —, wherein x=3 or 4; substituted by 1 or 2 halogen-C 1-6 -alkyl, and
ii) —(CH 2 )—(CY 2 ) z —(CH 2 )—, wherein each individual Y=H or F and z=1 or 2;

R 3 is selected from the group consisting of
i) C 1-6 -alkyl, and
ii) halogen-C 1-6 -alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , which is of formula Ia, wherein R 1 , R 2 , R 3 and R 4 are as described in claim 1

3. The compound according to claim 1 , wherein R 1 is heteroaryl, substituted by 1-2 substituents individually selected from cyano and C 1-6 -alkyl.

4. The compound according to claim 1 , wherein R 1 is pyridyl, substituted by 1-2 substituents individually selected from cyano and C 1-6 -alkyl.

5. The compound according to claim 1 , wherein R 1 is 5-cyano-3-methyl-pyridin-2yl or 5-cyano-pyridin-2yl.

6. The compound according to claim 1 , wherein R 2 and R 4 together are —(CH 2 )—(CY 2 ) z —(CH 2 )—, Y is H and z is 2.

7. The compound according to claim 1 , wherein R 3 is C 1-6 -alkyl.

8. The compound according claim 1 , wherein R 3 is methyl.

9. The compound according to claim 1 , wherein R 3 is halogen-C 1-6 -alkyl.

10. The compound according to claim 1 , wherein R 3 is —CH 2 F.

11. The compound according to claim 1 , wherein R 3 is —CHF 2 .

12. The compound according to claim 1 , selected from the group consisting of:
5-Cyano-pyridine-2-carboxylic acid [6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,
N-[6-[(1S,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ 6 -thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide,
5-Cyano-3-methyl-pyridine-2-carboxylic acid [6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,
5-Cyano-pyridine-2-carboxylic acid [6-((3R,4aR)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amid,
N-[6-[(1R,10S)-8-Amino-10-(difluoromethyl)-1-oxo-1λ 6 -thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide,
N-[6-[(1R,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ 6 -thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide, and
N-[6-[(1S,10S)-8-Amino-10-(difluoromethyl)-1-oxo-1λ 6 -thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide.

13. The compound according to claim 1 , selected from the group consisting of:
5-Cyano-pyridine-2-carboxylic acid [6-((3R,4aR)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amid,
5-Cyano-pyridine-2-carboxylic acid [6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,
5-Cyano-3-methyl-pyridine-2-carboxylic acid [6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,
N-[6-[(1S,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ 6 -thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide, and
N-[6-[(1R,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ 6 -thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide.

14. A process, comprising the step of reacting a compound of formula XI′ with a compound of formula XII′ to a compound of formula I,

wherein R 1 , R 2 , R 3 and R 4 are as defined in claim 1 .

15. A pharmaceutical composition, comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.

16. A method of treating Alzheimer's disease, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a human being or animal in need thereof.

Assignees

• Hoffmann La Roche

Inventors

• Bartels Bjoern
• Dolente Cosimo
• Guba Wolfgang
• Haap Wolfgang
• Kuglstatter Andreas
• Sander Ulrike Obst
• Peters Jens-Uwe
• Rogers-Evans Mark
• Woltering Thomas
• Schnider Christian
• Wermuth Roger

Classifications

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/549

  having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · 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