5-aryl-1-imino-1-oxo-[1,2,4]thiadiazines

Patent metadata

Field	Value
Publication number	US-9605006-B2
Application number	US-201415105725-A
Country	US
Kind code	B2
Filing date	Dec 17, 2014
Priority date	Dec 20, 2013
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

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) C 1-6 -alkyl, and
ii) halogen-C 1-6 -alkyl;

R 2 is selected from the group consisting of
i) hydrogen,
ii) halogen;
iii) —NH—C(═O)—R 4 ,
iv) aryl,
v) aryl, substituted by 1-3 substituents individually selected from cyano, C 1-6 -alkyl, halogen-C 1-6 -alkyl and halogen
vi) heteroaryl,
vii) heteroaryl, substituted by 1-3 substituents individually selected from R 6 , and
viii) —C≡C—R 5 ;

R 3 is halogen;
R 4 is selected from the group consisting of
i) heteroaryl, and
ii) heteroaryl, optionally substituted by 1-3 substituents individually selected from R 6 ,

R 5 is selected from the group consisting of
i) aryl,
ii) aryl, optionally substituted by 1-3 substituents individually selected from cyano, C 1-6 -alkyl, halogen-C 1-6 -alkyl and halogen
iii) heteroaryl, and
iv) heteroaryl, optionally substituted by 1-3 substituents individually selected from cyano, C 1-6 -alkyl, halogen-C 1-6 -alkyl and halogen;

R 6 is selected from the group consisting of
i) cyano,
ii) halogen;
iii) C 1-6 -alkyl,
iv) halogen-C 1-6 -alkyl,
v) C 2-6 -alkynyl-O—,
vi) heteroaryl, and
vii) heteroaryl, optionally substituted by 1-3 substituents individually selected from cyano, C 1-6 -alkyl, C 1-6 -alkoxy, halogen-C 1-6 -alkyl, halogen-C 1-6 -alkoxy and halogen;

R 7 is selected from the group consisting of
i) halogen, and
ii) halogen-C 1-6 -alkyl;

m is 1 or 2;
n is 0 or 1; and
p is 0, 1 or 2;
or pharmaceutically acceptable salts thereof.

2. The compound of formula I′ according to claim 1 , wherein p is 0.

3. The compound of formula I′ according to claim 1 , that is of formula I,

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

R 2 is selected from the group consisting of
i) hydrogen,
ii) halogen;
iii) —NH—C(═O )—R 4 ,
iv) aryl,
v) aryl, substituted by 1-3 substituents individually selected from cyano, C 1-6 -alkyl, halogen-C 1-6 -alkyl and halogen
vi) heteroaryl,
vii) heteroaryl, substituted by 1-3 substituents individually selected from cyano, C 1-6 -alkyl, halogen-C 1-6 -alkyl and halogen, and
viii) —C≡C—R 5 ;

R 3 is halogen;
R 4 is selected from the group consisting of
i) heteroaryl, and
ii) heteroaryl, optionally substituted by 1-3 substituents individually selected from cyano, C 1-6 -alkyl, halogen-C 1-6 -alkyl and halogen;

R 5 is selected from the group consisting of
i) heteroaryl, and

ii) heteroaryl, optionally substituted by 1-3 substituents individually selected from cyano, C 1-6 -alkyl, halogen-C 1-6 -alkyl and halogen;
m is 1 or 2; and
n is 0 or 1;
or pharmaceutically acceptable salts thereof.

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

5. The compound of formula I′ according to claim 1 , wherein m is 2.

6. The compound of formula I′ according to claim 1 , wherein R 1 is methyl.

7. The compound of formula I′ according to claim 1 , wherein R 2 is —NH—C(═O)—R 4 .

8. The compound of formula I′ according to claim 1 , wherein R 4 is heteroaryl, optionally substituted by cyano.

9. The compound of formula I′ according to claim 1 , wherein R 2 is heteroaryl, optionally substituted by cyano.

10. The compound of formula I′ according to claim 1 , wherein R 2 is —C≡C—R 5 .

11. The compound of formula I′ according to claim 1 , wherein R 5 is heteroaryl, optionally substituted by halogen and halogen-C 1-6 -alkyl.

12. The compound of formula I′ according to claim 1 , that is selected from the group consisting of:
(3RS,4aRS)-3-(2-fluoro-phenyl)-3-methyl-4a-oxo-3 ,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-1-ylamine,
(3RS,4aSR)-3-(2-fluoro-phenyl)-3-methyl-4a-oxo-3 ,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-1-ylamine,
(3R,4aR)-3-(2-fluoro-phenyl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-1-ylamine,
(3R,4aS)-3-(2-fluoro-phenyl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-1-ylamine,
(3R,4aR)-3-(2-Fluoro-5-iodo-phenyl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-1-ylamine,
(3R,4aS)-3-(2-Fluoro-5-iodo-phenyl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-1-ylamine,
5-cyano-pyridine-2-carboxylic acid[3-((3RS,4aRS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-3-yl)-4-fluoro-phenyl]-amide,
5-cyano-pyridine-2-carboxylic acid[3-((3RS,4aSR)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-3-yl)-4-fluoro-phenyl]-amide,
5-cyano-pyridine-2-carboxylic acid[3-((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)-4-fluoro-phenyl]-amide,
5-cyano-pyridine-2-carboxylic acid[3-((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)-4-fluoro-phenyl]-amide,
5-[3-((3R,4aR)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ 6 -thia2,5,9a-triaza-benzocyclohepten-3-yl)-4-fluoro-phenyl]-nicotinonitrile,
(3R,4aR)-3-(2-Fluoro-5-pyrimidin-5-yl-phenyl)-3-methyl-4a-oxo-3,4,6,7,8,9hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-1-ylamine,
5-Chloro-pyridine-2-carboxylic acid[3-((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)-4-fluoro-phenyl]-amide,
5-[3-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ6-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-4-fluoro-phenyl]-nicotinonitrile,
(3R,4aS)-3-(2-Fluoro-5-pyrimidin-5-yl-phenyl)-3-methyl-4a-oxo-3,4,6,7,8,9hexahydro-4aλ 6 -thia-2,5,9a-triaza-benzocyclohepten-1-ylamine,
5-Cyano-3-methyl-pyridine-2-carboxylic acid [3-((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)-4-fluoro-phenyl]-amide,
5-Chloro-pyridine-2-carboxylic acid [3-((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)-4-fluoro-phenyl]-amide,
5-Cyano-3-methyl-pyridine-2-carboxylic acid [3-((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)-4-fluoro-phenyl]-amide,
(9R,11R)-7-amino-9-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-9-methyl-2,3,4,5,9,10-hexahydro-[1,2,4]thiadiazino[1,2-a][1,2,7]thiadiazepine 11-oxide 2,2,2-trifluoroacetate,
(9R,11S)-7-amino-9-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-9-methyl-2,3,4,5,9,10-hexahydro-[1,2,4]thiadiazino[1,2-a][1,2,7]thiadiazepine 11-oxide 2,2,2-trifluoroacetate,
6-(4-(3-((9R, 11 S)-7-amino-9-methyl-11-oxido-2,3,4,5,9,10-hexahydro-[1,2,4]thiadiazino[1,2-a][1,2,7]thiadiazepin-9-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile 2,2,2-trifluoroacetate,
4-((3-((9R,11R)-7-amino-9-methyl-11-oxido-2,3,4,5,9,10-hexahydro-[1,2,4]thiadiazino[1,2-a][1,2,7]thiadiazepin-9-yl)-4-fluorophenyl)ethynyl)benzonitrile 2,2,2-trifluoroacetate,
(9R,11R)-7-amino-9-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)pheny

Assignees

• Hoffmann La Roche

Inventors

• Guba Wolfgang
• Haap Wolfgang
• Kuglstatter Andreas
• Peters Jens-Uwe
• Sander Ulrike Obst
• Schnider Christian
• Wermuth Roger
• Woltering Thomas

Classifications

• A61P43/00

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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · 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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title