6,7-dihydro-pyrazolo[1,5-a]pyrazin-4-ylamine derivatives useful as inhibitors of beta-secretase (BACE)

• US 9,346,811 B2
• Filed: 02/29/2012
• Issued: 05/24/2016
• Est. Priority Date: 03/01/2011
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Trabanco-Surez, Andrs Avelino, Gijsen, Henricus Jacobus Maria, Van Gool, Michiel Luc Maria, Vega Ramiro, Juan Antonio, Delgado-Jimnez, Francisca
• Primary Examiner(s): Carter, Kendra D
• Application Number:
  US14/002,169
• Publication Number:
  US 20140005200A1
• Time in Patent Office: 1,546 Days
• US Class Current: 1/1
• 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 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 6,7-dihydro-pyrazolo[1,5-a]pyrazin-4-yl-amine 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 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 hydrogen and C_1-3alkyl;

X¹, X², X³, X⁴ are independently C(R⁴) wherein each R⁴ is selected from hydrogen and halo;

L is a bond or —

N(R⁵)CO—

, wherein R⁵ is hydrogen;

Ar is homoaryl or heteroaryl;

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

heteroaryl is selected from the group consisting of pyridyl, pyrimidyl, and pyrazyl, each optionally substituted with one or two substituents selected from the group consisting of halo, cyano, C_1-3alkyl, C_1-3alkyloxy, and polyhalo-C_1-3alkyloxy;

or

an addition salt or a solvate thereof.

3. The compound of claim 1 wherein,

R¹ and R² are hydrogen;

X¹, X², X³, X⁴ are CH;

L is a bond or —

N(R⁵)CO—

, wherein R⁵ is hydrogen;

Ar is homoaryl or heteroaryl;

wherein homoaryl is phenyl substituted with chloro;

heteroaryl is selected from the group consisting of pyridyl and pyrimidyl, each optionally substituted with one or two substituents selected from the group consisting of chloro, fluoro, cyano, methyl, and methoxy;

or

an addition salt or a solvate 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 of claim 1 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 of claim 1.

7. 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 wherein X¹, X², X³, X⁴ independently C(R⁴) or N, provided that no more than one thereof represent N.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 3 and a pharmaceutically acceptable carrier.

9. A process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 3 and a pharmaceutically acceptable carrier, characterized in that the pharmaceutically acceptable carrier is intimately mixed with the therapeutically effective amount of said compound.

10. 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 3.

11. 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 pharmaceutical composition as defined in claim 5 wherein in said compound of claim 1, X¹, X², X³, X⁴ are independently C(R⁴) or N, provided that no more than one thereof represent N.

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 pharmaceutical composition as defined in claim 8.