Pyrazole aminopyrimidine derivatives as LRRK2 modulators

• US 9,212,173 B2
• Filed: 11/03/2014
• Issued: 12/15/2015
• Est. Priority Date: 05/03/2012
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Baker-Glenn, Charles, Burdick, Daniel Jon, Chan, Bryan K., Chambers, Mark, Chen, Huifen, Estrada, Anthony, Sweeney, Zachary Kevin
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US14/531,271
• Publication Number:
  US 20150051238A1
• Time in Patent Office: 407 Days
• Field of Search: 544/295, 514/275
• US Class Current: 1/1
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

Pyrazole compounds that are modulators of LRRK2, methods of making the compounds, and methods for using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson'"'"'s disease.

Claims

1. A compound selected from:

N²-(1′

,5-dimethyl-1′

H-1,4′

-bipyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N²-(1′

,3-dimethyl-1′

H-1,4′

-bipyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

4-(cyclopropylamino)-2-((5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile;

4-(cyclopropylamino)-2-((3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carbonitrile;

2-((1-(1-cyanopropyl)-5-methyl-1H-pyrazol-4-yl)amino)-4-(cyclopropylamino)pyrimidine-5-carbonitrile;

N2-(1-(1-fluoro-2-methylpropan-2-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

2-((5-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)-4-(ethylamino)pyrimidine-5-carbonitrile;

5-bromo-N²-(1,5-dimethyl-1H-pyrazol-4-yl)-N⁴-methylpyrimidine-2,4-diamine;

2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propan-1-ol;

1-((5-chloro-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)methyl)cyclopropanol;

N2-(3-chloro-1-(2-(4-ethyl-4H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(3-chloro-1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(3-chloro-1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(3-chloro-1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-N2-(3-methyl-1-(3-methyloxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(1-(2-(1,4-dimethyl-1H-imidazol-2-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(1-(2-(1,4-dimethyl-1H-imidazol-2-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-N2-(3-methyl-1-(2-(5-methyloxazol-2-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-ethyl-N2-(3-methyl-1-(3-methyloxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-ethyl-N2-(1-((2-methoxyethyl)sulfonyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(1-((2-methoxyethyl)sulfonyl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(1-((2-methoxyethyl)sulfonyl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(5-chloro-1-(2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-N2-(5-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-N2-(5-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-N2-(3-methyl-1-(2-(pyrimidin-2-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(3-chloro-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N⁴-ethyl-N²-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-ethyl-N2-(1-(2-(5-ethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-ethyl-N2-(1-(2-(1-isopropyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(3-chloro-1-(2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-N2-(5-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-ethyl-N2-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-ethyl-N2-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-N2-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(1-(3-fluorotetrahydro-2H-pyran-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(1-(3-fluorotetrahydro-2H-pyran-4-yl)-3-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(1-(3-fluorotetrahydro-2H-pyran-4-yl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(1-((3R)-3-fluorotetrahydro-2H-pyran-4-yl)-5-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

3-methyl-3-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)butanenitrile;

2-((3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)methyl)butanenitrile;

3-methyl-3-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)butanenitrile;

2-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile;

2-methyl-2-(1-methyl-5-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-3-yl)propanenitrile;

2-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-(cyclopropylamino)pyrimidine-5-carbonitrile;

2-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-(cyclopropylamino)pyrimidine-5-carbonitrile;

2-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-(ethylamino)pyrimidine-5-carbonitrile;

2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)butanenitrile; and

5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1-methyl-1H-pyrazole-3-carbonitrile,

or a pharmaceutical salt thereof.

2. A composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1.

3. A method for treating Parkinson'"'"'s disease, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.