5,6-DIHYDRO-2H-[1,4]OXAZIN-3-YL-AMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)

• US 20160152581A1
• Filed: 02/05/2016
• Published: 06/02/2016
• Est. Priority Date: 06/09/2010
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Trabanco-Su?rez, Andr?s Avelino, Rombouts, Frederik Jan Rita, Tresadern, Gary John, Van Gool, Michiel Luc Maria, MacDonald, Gregor James, Martinez Lamenca, Carolina, Gijsen, Henricus Jacobus Maria
• Granted Patent: US 9,828,350 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 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 Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 265/30 not condensed with other rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings

Abstract

The present invention relates to novel 5,6-dihydro-2H-[1,4]oxazin-3-ylamine derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer'"'"'s disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down'"'"'s syndrome, dementia associated with stroke, dementia associated with Parkinson'"'"'s disease and dementia associated with beta-amyloid.

Claims

1. A compound of Formula (I)

2. The compound according to claim 1 wherein R¹, R² and R³ are hydrogen, and L is —

N(R⁷)CO—

wherein R⁷ is hydrogen.

3. The compound according to claim 2 wherein R¹, R² and R³ are hydrogen, L is —

N(R⁷)CO—

wherein R⁷ is hydrogen, and R⁵ is methyl, ethyl or cyclopropyl.

4. The compound according to claim 2 wherein R¹, R² and R³ are hydrogen, L is —

N(R⁷)CO—

wherein R⁷ is hydrogen, R⁵ is methyl, ethyl or cyclopropyl, X², X³ and X⁴ are CH, and X¹ is CH, CF or N.

5. The compound according to claim 2 wherein R¹, R² and R³ are hydrogen, L is —

N(R⁷)CO—

wherein R⁷ is hydrogen, R⁵ is methyl, ethyl or cyclopropyl, and Ar is pyridyl, or pyrazyl, each optionally substituted with one or two substituents selected from halo, cyano, methoxy, trifluoroethoxy and difluoromethyl.

6. The compound according to claim 1 wherein R¹ and R² are hydrogen, R³ is fluoro, and L is —

N(R⁷)CO—

wherein R⁷ is hydrogen.

7. A compound according to claim 1 wherein the compound is selected from the group consisting of:

(5R,6S)—

N-[3-[5-amino-2-fluoro-3,6-dihydro-3-methyl-2-(trifluoromethyl)-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-cyano-2-pyridinecarboxamide;

(5R,6R)—

N-[3-[5-amino-3,6-dihydro-3-methyl-2-(trifluoromethyl)-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-3,5-dichloro-2-pyridinecarboxamide;

(5R,6R)—

N-[3-[5-amino-3,6-dihydro-3-methyl-2-(trifluoromethyl)-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-methoxy-2-pyrazinecarboxamide; and

(5R,6R)—

N-[3-[5-amino-3,6-dihydro-3-methyl-2-(trifluoromethyl)-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-cyano-2-pyridinecarboxamide.

8. A compound according to claim 7 wherein the compound is (5R,6R)—

N-[3-[5-amino-3,6-dihydro-3-methyl-2-(trifluoromethyl)-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-methoxy-2-pyrazinecarboxamide.

9. A compound according to claim 7 wherein the compound is (5R,6R)—

N-[3-[5-amino-3,6-dihydro-3-methyl-2-(trifluoromethyl)-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-cyano-2-pyridinecarboxamide.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

11. A process for preparing a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of claim 1.

12. A method of treating a disorder selected from the group consisting of Alzheimer'"'"'s disease, mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down'"'"'s syndrome, dementia associated with stroke, dementia associated with Parkinson'"'"'s disease and dementia associated with beta-amyloid, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of claim 1.

13. A method of claim 12 wherein said disorder is Alzheimer'"'"'s disease.