5,6-dihydro-imidazo[1,2-a]pyrazin-8-ylamine derivatives useful as inhibitors of beta-secretase (BACE)

• US 9,840,507 B2
• Filed: 12/21/2011
• Issued: 12/12/2017
• Est. Priority Date: 12/22/2010
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Trabanco-Surez, Andrs Avelino, Delgado-Jimnez, Francisca, Vega Ramiro, Juan Antonio, Tresadern, Gary John, Gijsen, Henricus Jacobus Maria, Oehlrich, Daniel
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US13/995,523
• Publication Number:
  US 20130274266A1
• Time in Patent Office: 2,183 Days
• Field of Search: 514249, 544350
• 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 487/04 Ortho-condensed systems

Abstract

The present invention relates to novel 5,6-dihydro-imidazo[1,2-a]pyrazin-8-ylamine inhibitors of beta-secretase, having the structure shown in Formula (I)

wherein R¹, R², R³, R⁴, X¹, X², X³, X⁴, L and Ar are defined in the specification. 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, cerebrovascular amyloid angiopathy, multi-infarct dementia, Down'"'"'s syndrome, dementia associated with stroke, dementia associated with Parkinson'"'"'s disease or dementia associated with beta-amyloid.

Claims

1. A compound of Formula (I)

2. The compound of claim 1 wherein,

R¹ and R² are independently selected from the group consisting of hydrogen, CH₂F, CHF₂, CF₃, chloro, bromo and cyano;

R³ is C_1-3alkyl, CH₂F, CHF₂, or CF₃;

X¹ and X³ are independently CH or CF;

X² and X⁴ are CH;

L is —

N(R⁵)CO—

, wherein R⁵ is hydrogen;

Ar is homoaryl or heteroaryl;

wherein homoaryl is phenyl substituted with one or two substituents selected from the group consisting of halo, cyano, C_1-3alkyl, and C_1-3alkyloxy;

heteroaryl is selected from the group consisting of pyridyl, pyrimidyl, pyridazyl, pyrazolyl, oxazolyl and isothiazolyl, each optionally substituted with one or two substituents selected from the group consisting of halo, cyano, C_1-3alkyl, C_1-3alkyloxy, CH₂F, CHF₂, and CF₃;

or

an addition salt thereof.

3. The compound of claim 1 wherein,

R¹ is hydrogen, CH₂F, CHF₂, CF₃, chloro, bromo or cyano;

R² is hydrogen, chloro, cyano, CH₂F, CHF₂, or CF₃;

R³ is methyl, CH₂F, CHF₂, or CF₃;

X¹ is CF;

X², X³, and X⁴ are CH;

L is —

N(R⁵)CO—

, wherein R⁵ is hydrogen;

Ar is heteroaryl;

wherein heteroaryl is selected from the group consisting of pyridyl, pyrazyl and pyrazolyl, each substituted with one or two substituents selected from the group consisting of chloro, fluoro, cyano, methyl, methoxy, ethoxy, CH₂F, CHF₂, and CF₃;

or

an addition salt thereof.

4. The compound of claim 1 wherein the carbon atom substituted with R³ has the R-configuration.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

6. A process for preparing a pharmaceutical composition as defined in claim 5, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as defined in any one of claims 1 to 4.

7. A method of inhibiting beta-site APP-cleaving enzyme 1 activity in a subject, comprising administering to said subject in need thereof, a therapeutically effective amount of a compound as defined in any one of claims 1 to 4 or a pharmaceutical composition as defined in claim 5.