Oxazine derivatives and their use in the treatment of disease

Patent metadata

Field	Value
Publication number	US-9284284-B2
Application number	US-201214350938-A
Country	US
Kind code	B2
Filing date	Oct 11, 2012
Priority date	Oct 13, 2011
Publication date	Mar 15, 2016
Grant date	Mar 15, 2016

Abstract

The invention relates to novel oxazine derivatives of formula (I), and pharmaceutically acceptable salts thereof, in which all of the variables are as defined in the specification, pharmaceutical compositions thereof, combinations thereof, and their use as medicaments, particularly for the treatment of Alzheimer's Disease or diabetes via inhibition of BACE-1 or BACE-2.

First claim

The invention claimed is:

1. A compound of the formula (I), or a pharmaceutically acceptable salt thereof:

wherein
n represents 0 or 1;
X represents CH or N;
R 1 represents:
phenyl, optionally substituted by 1, 2 or 3 substituents independently selected from R 10 ;
a group G 1 selected from furan-2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl and pyrazin-2-yl, wherein G 1 is optionally substituted by 1, 2 or 3 substituents independently selected from R 10 ; or
a group G 2 selected from isothiazolo[4,5-b]pyridin-3-yl, isothiazolo[4,5-b]pyrazin-3-yl, benzo[d]isothiazol-3-yl, indazol-3-yl, benzo[d]isoxazol-3-yl, pyrido[3,2-d]pyrimidin-4-yl, [1,7]naphthyridin-8-yl and imidazol[1,2-a]pyrazin-8-yl, wherein G 2 is optionally substituted by 1, 2 or 3 substituents independently selected from R 11 ;

R 2 , R 3 and R 4 independently represent hydrogen, halogen or C 1-3 alkyl;
R 5 represents C 1-3 alkyl, halogen-C 1-3 alkyl or C 1-3 alkoxy-C 1-3 alkyl;
R 6 and R 7 independently represent hydrogen or C 1-3 alkyl;
R 8 and R 9 independently represent hydrogen, C 1-3 alkyl, halogen-C 1-3 alkyl or C 1-3 alkoxy; or R 8 and R 9 taken together are cyclopropyl;
R 10 represents halogen, cyano, hydroxy, halogen-C 1-3 alkoxy, C 1-3 alkoxy, C 1-3 alkoxy-C 1-3 alkoxy, nitro or amino; and
R 11 represents halogen, cyano, hydroxy, halogen-C 1-3 alkyl, halogen-C 1-3 alkoxy, C 1-3 alkoxy, C 1-3 alkoxy-C 1-3 alkyl or C 1-3 alkoxy-C 1-3 alkoxy.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 represents halogen, cyano, hydroxy, halogen-C 1-3 alkoxy, C 1-3 alkoxy or C 1-3 alkoxy-C 1-3 alkoxy.

3. A compound according to claim 1 of formula (Ia), or a pharmaceutically acceptable salt thereof:

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n represents 0.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X represents CH.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 represents phenyl optionally substituted by 1 or 2 substituents independently selected from R 10 .

7. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 represents a group G 1 selected from furan-2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl and pyrazin-2-yl, wherein G 1 is optionally substituted by 1, 2 or 3 substituents independently selected from R 10 .

8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 represents a group G 2 selected from benzo[d]isothiazol-3-yl, indazol-3-yl, benzo[d]isoxazol-3-yl, pyrido[3,2-d]pyrimidin-4-yl, [1,7]naphthyridin-8-yl and imidazol[1,2-a]pyrazin-8-yl, wherein G 2 is optionally substituted by 1, 2 or 3 substituents independently selected from R 11 .

9. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 represents hydrogen.

10. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 represents hydrogen or fluoro.

11. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 represents hydrogen or fluoro.

12. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 represents methyl, fluoromethyl or difluoromethyl.

13. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 both represent hydrogen.

14. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 independently represent hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl.

15. A compound according to claim 1 which is selected from:
[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-(6-bromo-benzo[d]isothiazol-3-yl)-amine;
[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-(6-bromo-1-methyl-1H-indazol-3-yl)-amine;
[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-benzo[d]isoxazol-3-yl-amine;
5-{2-Fluoro-5-[(furan-2-ylmethyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
5-[5-(4-Bromo-2-chloro-benzylamino)-2-fluoro-phenyl]-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
5-{5-[(4-Bromo-furan-2-ylmethyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-(7-chloropyrido[3,2-d]pyrimidin-4-yl)-amine;
[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-(3-bromo-[1,7]naphthyridin-8-yl)-amine;
8-[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenylamino]-[1,7]naphthyridine-3-carbonitrile;
[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-[3-(2-methoxy-ethoxy)-[1,7]naphthyridin-8-yl]-amine;
[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-[3-(2-chloro-ethoxy)-[1,7]naphthyridin-8-yl]-amine;
[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-(2-methyl-imidazo[1,2-a]pyrazin-8-yl)-amine;
[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-imidazo[1,2-a]pyrazin-8-yl-amine;
[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-(3-bromo-imidazo[1,2-a]pyrazin-8-yl)-amine;
(R)-5-Difluoromethyl-5-[2-fluoro-5-(3-methoxy-pyridin-2-ylamino)-phenyl]-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
(R)-5-Difluoromethyl-5-[2-fluoro-5-(pyrimidin-2-ylamino)-phenyl]-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
(R)-5-Difluoromethyl-5-[2-fluoro-5-(4-methoxy-pyrimidin-2-ylamino)-phenyl]-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
(R)-5-Difluoromethyl-5-[2-fluoro-5-(3-methoxy-pyrazin-2-ylamino)-phenyl]-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
(R)-5-Difluoromethyl-5-[5-(3-ethoxy-pyridin-2-ylamino)-2-fluoro-phenyl]-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
(R)-5-{5-[3-(2,2-Difluoro-ethoxy)-pyridin-2-ylamino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
(R)-5-Difluoromethyl-5-[2-fluoro-5-(5-methoxy-pyrimidin-4-ylamino)-phenyl]-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
(R)-5-[5-(3-Difluoromethoxy-pyridin-2-ylamino)-2-fluoro-phenyl]-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
[3-((3R,6R)-5-Amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-(7-chloro-pyrido[3,2-d]pyrimidin-4-yl)-amine;
[3-((3R,6R)-5-Amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-(7-trifluoromethyl-pyrido[3,2-d]pyrimidin-4-yl)-amine;
(2R,5R)-5-[2-Fluoro-5-(3-methoxy-pyridin-2-ylamino)-phenyl]-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
(R)-5-Difluoromethyl-5-[2-fluoro-5-(3-methoxy-5-nitro-pyridin-2-ylamino)-phenyl]-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
N*2*-[3-((R)-5-Amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-3-methoxy-pyridine-2,5-diamine;
[6-((3R,6R)-5-Amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]-(7-trifluoromethyl-pyrido[3,2-d]pyrimidin-4-yl)-amine;
(2R,5R)-5-[3-Fluoro-6-(2-methoxy-phenylamino)-pyridin-2-yl]-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine;
2-[6-((3R,6R)-5-Amino-3,6-dimethyl-6-trifluor

Assignees

• Hurth Konstanze
• Jacquier Sebastien
• Machauer Rainer
• Rueeger Heinrich
• Tintelnot-Blomley Marina
• Veenstra Siem Jacob
• Voegtle Markus
• Novartis Ag

Inventors

• Hurth Konstanze
• Jacquier Sebastien
• Machauer Rainer
• Rueeger Heinrich
• Tintelnot-Blomley Marina
• Veenstra Siem Jacob
• Voegtle Markus

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · 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