Thiazine derivatives as beta-secretase inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-2020062743-A1
Application number	US-201716466209-A
Country	US
Kind code	A1
Filing date	Dec 13, 2017
Priority date	Dec 15, 2016
Publication date	Feb 27, 2020
Grant date	—

Abstract

The present disclosure provides a class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: (see Formula I structure) wherein variables R 1 , R 1′ , R 2 , R 2′ , R 3 , R 4 , R 5 , R 6 , R 7 , and b of Formula I are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, and uses of the compounds and compositions for treatment of disorders and/or conditions related to Aβ plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, and other central nervous system conditions.

First claim

What is claimed is:

1 . A compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 1 and R 1′ , independently, are H, C 1-6 alkyl, —C(O)OC 1-6 alkyl, —C(O)NHC 1-6 alkyl, or —C(O)-heterocycloalkyl, wherein the C 1-6 alkyl and the C 1-6 alkyl portions of —C(O)OC 1-6 alkyl and —C(O)NHC 1-6 alkyl are optionally substituted with one to three fluoro substituents;
R 2 and R 2′ are H;
b is a single bond, if R 1 , R 1′ , R 2 and R 2′ are present;
b is a double bond, if one of R 1 and R 1′ and one of R 2 and R 2′ is not present;
R 3 is C 1-4 alkyl;
R 4 is halogen;
R 5 is H or F; and
one of R 6 and R 7 is F or H and the other of R 6 and R 7 is a 6-membered nitrogen-containing heteroaryl, which heteroaryl is optionally substituted with halogen, —CN, or 2-propynyloxy, wherein at least one of R 5 , R 6 , or R 7 is F.

2 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein the compound of Formula I is a compound of Formula II

3 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein the compound of Formula I is a compound of Formula IIIA

4 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein the compound of Formula I is a compound of Formula IIIB

5 . The compound according to any one of claims 1 , 2 , and 4 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 1 is H,

and
R 1′ is H or methyl.

6 . The compound according to any one of claims 1 , 2 , 4 , and 5 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 1′ is methyl.

7 . The compound according to any one of claims 1 - 6 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 3 is methyl.

8 . The compound according to any one of claims 1 - 7 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 4 is F.

9 . The compound according to any one of claims 1 - 8 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 6 and R 7 is F or H and the other of R 6 and R 7 is pyridyl or pyrazinyl, which pyridyl or pyrazinyl is optionally substituted with Cl, —CN, or 2-propynyloxy.

10 . The compound according to any one of claims 1 - 8 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 6 and R 7 is F or H and the other of R 6 and R 7 is pyridyl or pyrazinyl, which pyridyl or pyrazinyl is optionally substituted with —CN or 2-propynyloxy.

11 . The compound according to any one of claims 1 - 9 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein one of R 6 and R 7 is

12 . The compound according to any one of claims 1 - 10 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein one of R 6 and R 7 is

13 . The compound according to any one of claims 1 - 12 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 5 is F; and R 6 is H.

14 . The compound according to any one of claims 1 - 12 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 5 is F; and R 7 is H.

15 . The compound according to any one of claims 1 - 12 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 5 is H; and R 6 is F.

16 . The compound according to any one of claims 1 - 12 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 5 is H; and R 7 is F.

17 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, selected from
(S,Z)-4-(5-(2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-amine; (S,Z)-6-(2-(3-(2-amino-4-methyl-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile; (S,Z)-4-(5-(2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine; (S,Z)-6-(2-(3-(2-amino-4-methyl-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile; (4S,6R)-methyl 2-amino-4-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazine-6-carboxylate; (4S,6S)-methyl 2-amino-4-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazine-6-carboxylate; (4S,6S)-methyl 2-amino-4-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazine-6-carboxylate; (4S,6R)-methyl 2-amino-4-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazine-6-carboxylate; (4S,6R)-methyl 2-amino-4-(5-((Z)-2-(5-cyanopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazine-6-carboxylate; (4S,6S)-methyl 2-amino-4-(5-((Z)-2-(5-cyanopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazine-6-carboxylate; 6-((Z)-2-(3-((4S,6S)-2-amino-4,6-dimethyl-6-(morpholine-4-carbonyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile; 6-((Z)-2-(3-((4S,6R)-2-amino-4,6-dimethyl-6-(morpholine-4-carbonyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile; (4S,6R)-2-amino-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(2-propyn-1-yloxy)-2-pyrazinyl)ethenyl)phenyl)-N,4,6-trimethyl-5,6-dihydro-4H-1,3-thiazine-6-carboxamide; (4S,6S)-2-amino-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(2-propyn-1-yloxy)-2-pyrazinyl)ethenyl)phenyl)-N,4,6-trimethyl-5,6-dihydro-4H-1,3-thiazine-6-carboxamide; ((4S,6S)-2-amino-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-6-yl)(morpholino)methanone; (4S,6S)-2-amino-N-(2,2-difluoroethyl)-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazine-6-carboxamide; or (4S,6S)-2-amino-4-(5-((Z)-2-(5-cyanopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-N,4,6-trimethyl-5,6-dihydro-4H-1,3-thiazine-6-carboxamide.

18 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, selected from
(S,Z)-6-(2-(3-(2-amino-4-methyl-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile; (S,Z)-6-(2-(3-(2-amino

Assignees

• Amgen Inc

Inventors

• Bourbeau Matthew P
• Harrington Paul E
• Liu Qingyian

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D417/10 Primary

  linked by a carbon chain containing aromatic rings · 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