Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-2020199153-A1
Application number	US-201716466202-A
Country	US
Kind code	A1
Filing date	Dec 13, 2017
Priority date	Dec 15, 2016
Publication date	Jun 25, 2020
Grant date	—

Abstract

The present disclosure provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula (I): (Formula (I)) wherein variables X, Y, R 2 , R 3 , R 4 , R 5 , R 6 , and n 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

1 . A compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
X is S or O;
Y is O or NR 1 ;
R 1 is —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, or 6-membered nitrogen-containing heteroaryl,
wherein the C 1-6 alkyl of —C(O)C 1-6 alkyl and —C(O)OC 1-6 alkyl is optionally substituted with 1 to 3 fluoro substituents, and
wherein the heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen, C 1-6 alkyl, or C 1-6 alkoxy;
R 2 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1 to 3 fluoro substituents;
R 3 is halogen;
R 4 is H or F;
one of R 5 and R 6 is F or H and the other of R 5 and R 6 is a 6-membered nitrogen-containing heteroaryl, which heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, C 1-6 alkyl, C 1-6 alkoxy, 2-propynyloxy, 2-butynyloxy, 3-butyn-2-yloxy, or (3-methyl-1,2,4-oxadiazol-5-yl)methoxy,
wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with 1 to 4 substituents independently selected from F or methoxy; and
n is 0 or 1.

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 III

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 III′

5 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein n is 0.

6 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein n is 1.

7 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein X is O.

8 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein X is S.

9 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein Y is O.

10 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein Y is NR 1 .

11 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 1 is

12 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 1 is a 6-membered nitrogen-containing heteroaryl, wherein the heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen, C 1-6 alkyl, or C 1-6 alkoxy.

13 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 1 is pyrimidinyl optionally substituted with 1 to 3 substituents independently selected from halogen, C 1-6 alkyl, or C 1-6 alkoxy.

14 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 1 is

15 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 2 is H, methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

16 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 2 is trifluoromethyl.

17 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 3 is F.

18 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 5 and R 6 is F or H and the other of R 5 and R 6 is pyridyl or pyrazinyl, which pyridyl or pyrazinyl is optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, C 1-6 alkyl, C 1-6 alkoxy, 2-propynyloxy, 2-butynyloxy, 3-butyn-2-yloxy, or (3-methyl-1,2,4-oxadiazol-5-yl)methoxy,
wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with 1 to 4 substituents independently selected from F or methoxy.

19 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 5 and R 6 is F or H and the other of R 5 and R 6 is pyridyl or pyrazinyl, which pyridyl or pyrazinyl is optionally substituted with 1 to 3 substituents independently selected from —CN, C 1-6 alkyl, C 1-6 alkoxy, 2-propynyloxy, 2-butynyloxy, 3-butyn-2-yloxy, or (3-methyl-1,2,4-oxadiazol-5-yl)methoxy,
wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with 1 to 4 substituents independently selected from F or methoxy.

20 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein one of R 6 and R 5 is

21 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein one of R 6 and R 5 is

22 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 4 is H and R 5 is H; R 4 is H and R 6 is H; R 4 is F and R 5 is H R 4 is F and R 6 is H; or R 4 is H and R 6 is F.

23 .- 25 . (canceled)

26 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein
R 4 is H; and R 5 is F.

27 . (canceled)

28 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, selected from
(4aS,7aR)-7a-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-amine; (4aR,7aS)-7a-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,6,7,7

Assignees

• Amgen Inc

Inventors

• Allen Jennifer R
• Bourbeau Matthew P
• Chen Ning
• Liu Qingyian
• Pettus Liping H
• Siegmund Aaron C

Classifications

• C07D498/04

  Ortho-condensed systems · 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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title