Cyclopropyl fused thiazine derivatives as beta-secretase inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-10889581-B2
Application number	US-201716466199-A
Country	US
Kind code	B2
Filing date	Dec 13, 2017
Priority date	Dec 15, 2016
Publication date	Jan 12, 2021
Grant date	Jan 12, 2021

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:

wherein variables A, R 1 , R 2 , R 2′ , R 3 , R 4 , and R 5 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
A is N, CH, or CR 4 ;
R 1 is H, —CN, C 1-6 alkyl, C 2-6 alkenyl, —C 1-4 alkyl-C(O)NR 1′ R 1′ , —C 1-4 alkyl-C(O)-heterocycloalkyl, —(HC═CH)—C(O)NR 1′ R 1′ , —(HC═CH)—C(O)-heterocycloalkyl, —C(O)NR 1′ R 1′ , or —C(O)-heterocycloalkyl, wherein the C 1-6 alkyl and the C 2-6 alkenyl are (i) optionally substituted with one to three fluoro substituents or (ii) optionally substituted with CN, OH, methoxy, or a 5-membered nitrogen-containing heteroaryl, wherein the 5-membered nitrogen-containing heteroaryl is optionally substituted with C 1-4 alkyl;
R 1′ is, independently, H or C 1-4 alkyl;
R 2 and R 2′ are independently H or halogen;
R 3 is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with one to three fluoro substituents;
R 4 is halogen;
R 5 is H, C 3-6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with one to three substituents independently selected from halogen, —CN, C 1-4 alkyl, 2-propynyloxy, 2-butynyloxy, or oxazolylmethoxy.

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
R 1 is —CN,

6. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 2 and R 2′ are H.

7. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 2 and R 2′ are F.

8. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 3 is methyl, —CH 2 F, or CHF 2 .

9. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 3 is methyl or —CH 2 F.

10. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 4 is F.

11. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein R 5 is H, cyclopropyl, phenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyrazinyl is optionally substituted with one or two substituents independently selected from F, Cl, —CN, methyl, 2-propynyloxy, 2-butynyloxy, or 2-oxazolylmethoxy.

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

13. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, selected from
6-((3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(hydroxymethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)nicotinonitrile;
6-((3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)nicotinonitrile;
(1S,5S,6S)-5-(5-((5-chloropyridin-2-yl)ethynyl)-2-fluorophenyl)-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine;
5-((3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)pyrazine-2-carbonitrile;
6-((3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)-5-methylnicotinonitrile;
(1S,5S,6S)-5-(5-((5-(but-2-yn-1-yloxy)pyridin-2-yl)ethynyl)-2-fluorophenyl)-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine;
6-((3-((1R,5S,6S)-3-amino-1-(cyanomethyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)nicotinonitrile;
6-((3-((1R,5S,6S)-3-amino-1-((E)-2-cyanovinyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)nicotinonitrile;
(1S,5S,6S)-5-(2-fluoro-5-((5-(oxazol-2-ylmethoxy)pyridin-2-yl)ethynyl)phenyl)-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine;
2-((3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)thiazole-5-carbonitrile;
6-((3-((1 S,5 S,6R)-3-amino-7,7-difluoro-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)nicotinonitrile;
6-((3-((1R,5 S, 6 S)-3-amino-5-(fluoromethyl)-1-((E)-3-morpholino-3-oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)nicotinonitrile;
(E)-3-((1R,5 S, 6 S)-3-amino-5-(5-((5-cyanopyridin-2-yl)ethynyl)-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)-N,N-dimethylacrylamide;
2-((1R,5 S,6S)-3-amino-5-(5-((5-cyanopyridin-2-yl)ethynyl)-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acetamide;
6-((5-((1 S,5 S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-6-fluoropyridin-3-yl)ethynyl)nicotinonitrile;
6-((3-((1 S,5 S,6S)-3-amino-5-(fluoromethyl)-1-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)nicotinonitrile;
6-((3-((1R,5 S, 6 S)-3-amino-5-(fluoromethyl)-1-((E)-3-morpholino-3-oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)-5-methylnicotinonitrile;
(E)-3-((1R,5 S,6S)-3-amino-5-(5-((5-chloropyrimidin-2-yl)ethynyl)-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)-1-morpholinoprop-2-en-1-one;
(E)-3-((1R,5 S,6S)-3-amino-5-(2-fluoro-5-((3-methylisothiazol-5-yl)ethynyl)phenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)-1-morpholinoprop-2-en-1-one;
6-((3-((1 S,5 S,6S)-3-amino-5-(fluoromethyl)-1-(3-morpholino-3-oxopropyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)nicotinonitrile;
6-((3-((1 S,5 S,6S)-3-amino-5-(fluoromethyl)-1-(3-morpholino-3-oxopropyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)-5-methylnicotinonitrile;
2-((3-((1R,5 S, 6 S)-3-amino-5-(fluoromethyl)-1-((E)-3-morpholino-3-oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)pyrimidine-5-carbonitrile;
4-((3-((1R,5 S, 6 S)-3-amino-5-(fluoromethyl)-1-((E)-3-morpholino-3-oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)ethynyl)benzonitri

Assignees

• Amgen Inc

Inventors

• Allen Jennifer R
• Amegadzie Albert
• Bourbeau Matthew P
• Chen Jian J
• Frohn Michael J
• Harrington Paul E
• Low Jonathan D
• Ma Vu V
• Nguyen Thomas T
• Pickrell Alexander
• Reeves Corey

Classifications

• 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

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D279/08

  condensed with carbocyclic rings or ring systems · CPC title