Aminopyrimidine derivatives as LRRK2 modulators

• US 8,796,296 B2
• Filed: 11/28/2012
• Issued: 08/05/2014
• Est. Priority Date: 11/29/2011
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Baker-Glenn, Charles, Chambers, Mark, Chan, Bryan K., Estrada, Anthony, Sweeney, Zachary Kevin
• Primary Examiner(s): Rao, Deepak
• Assistant Examiner(s): Pagano, Alexander R
• Application Number:
  US13/687,429
• Publication Number:
  US 20130158006A1
• Time in Patent Office: 615 Days
• Field of Search: 544/320, 544/321, 544/324, 544/323, 514/272, 514/275
• US Class Current: 514/272
• 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: 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/08 for leprosy
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• 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 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 498/08 Bridged systems

Abstract

Compounds of the formula I:

or pharmaceutically acceptable salts thereof,
wherein A, X, R¹, R², R³ and R⁴ are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson'"'"'s disease.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein X is —

NH—

or —

O—

.

3. The compound of claim 1, wherein R¹ is C_1-6alkyl.

4. The compound of claim 1, wherein R² is:

halo;

halo-C_1-6alkyl;

or cyano.

5. The compound of claim 1, wherein R² is chloro, trifluoromethyl or cyano.

6. The compound of claim 1, wherein R² is trifluoromethyl.

7. The compound of claim 1, wherein R³ is halo or C_1-6alkoxy.

8. The compound of claim 1, wherein R³ is halo or methoxy.

9. The compound of claim 1, wherein R⁴ is halo or C_1-6alkoxy.

10. The compound of claim 1, wherein R⁴ is halo or methoxy.

11. The compound of claim 1, wherein R⁵ is:

oxo;

C_1-6alkyl;

or —

C(O)—

NR^bR^c.

12. The compound of claim 1, wherein each R⁶ is independently:

C_1-6alkyl, hydroxy-C_1-6alkyl, C_1-6alkoxy-C_1-6alkyl, heterocyclyl, oxo, or —

C(O)—

NR^bR^c.

13. The compound of claim 1, wherein said compound is of formula IIa or IIb:

14. The compound of claim 13, wherein m is 0 or 1.

15. The compound of claim 13, wherein Z is —

C(R⁷)₂—

.

16. The compound of claim 13, wherein Z is —

NR⁸—

.

17. The compound of claim 13, wherein Z is —

O—

.

18. The compound of claim 13, wherein Z is absent.

19. A composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1.

20. 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.

21. The compound of claim 1, wherein said compound is selected from:

7-chloro-4-methyl-8-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one;

7-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-6-methoxy-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one;

5-methoxy-N,N-dimethyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzofuran-2-carboxamide

5-chloro-1,3-dimethyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-benzo[d]imidazol-2(3H)-one;

5-chloro-3-methyl-6-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo[d]oxazol-2(3H)-one;

N²-(6-chloro-2-methylbenzo[d]oxazol-5-yl)-N⁴-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

5-methoxy-2-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one;

6-chloro-5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-2-methylisoindolin-1-one;

6-chloro-2-methyl-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one;

2-cyclopropyl-4-methoxy-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one;

4-methoxy-2-methyl-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one;

6-methoxy-2,2,4-trimethyl-7-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2H-benzo[b][1,4]oxazin-3(4H)-one;

5-chloro-6-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)benzo[d]oxazol-2(3H)-one;

5-chloro-6-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methylbenzo[d]oxazol-2(3H)-one;

7-methoxy-2-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroisoquinolin-1(2H)-one;

2-(7-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-4-(methylamino)pyrimidine-5-carbonitrile;

7-methoxy-2-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phthalazin-1(2H)-one;

2-ethyl-4-methoxy-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one

2-(2-hydroxypropan-2-yl)-4-methoxy-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one;

4-methoxy-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-(oxetan-3-yl)isoindolin-1-one;

6-methoxy-2-methyl-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one;

(5-chloro-1-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-indol-3-yl)(morpholino)methanone;

2-(2-hydroxy-2-methylpropyl)-6-methoxy-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one;

5-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-(2-hydroxy-2-methylpropyl)-6-methoxyisoindolin-1-one;

6-methoxy-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-(oxetan-3-yl)isoindolin-1-one;

5-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-6-methoxy-2-(oxetan-3-yl)isoindolin-1-one;

5-chloro-N,N,1-trimethyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-indole-3-carboxamide;

(5-chloro-1-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-indol-3-yl)(piperazin-1-yl)methanone;

(5-chloro-6-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)(morpholino)methanone;

(5-methoxy-1-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-indol-3-yl)(morpholino)methanone;

(5-chloro-1-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-indol-3-yl)(4-methylpiperazin-1-yl)methanone;

(5-chloro-1-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-indol-3-yl)(4-ethylpiperazin-1-yl)methanone;

(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl(5-chloro-1-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;

4-methoxy-2-methyl-5-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one;

(5-methoxy-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzofuran-3-yl)(morpholino)methanone; and

5-methoxy-N,N-dimethyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzofuran-3-carboxamide.