Aminopyrimidine derivatives as LRRK2 modulators

• US 9,145,402 B2
• Filed: 11/28/2012
• Issued: 09/29/2015
• 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, Shore, Daniel, Sweeney, Zachary Kevin, Chen, Huifen
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Sackey, Ebenezer O
• Application Number:
  US13/687,411
• Publication Number:
  US 20130158032A1
• Time in Patent Office: 1,035 Days
• Field of Search: 514/235.8, 514/275, 544/323, 544/122
• US Class Current: 1/1
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds of the formula I:

or pharmaceutically acceptable salts thereof,
wherein m, n. X, R¹, R², R³, R⁴ and R⁵ 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 m is 0 or 1.

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

NH—

or —

O—

.

4. The compound of claim 1, wherein R¹ is ethyl.

5. The compound of claim 1, wherein R¹ is methyl.

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

halo;

halo-C_1-6alkyl;

or cyano.

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

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

9. The compound of claim 1, wherein R³ is methoxy.

10. The compound of claim 1, wherein R⁴ is fluoro, chloro, methyl or methoxy.

11. The compound of claim 1, wherein R⁵ is C_1-6alkyl-sulfonyl or cyano.

12. The compound of claim 1, wherein R⁵ is C_1-6alkyl-sulfonyl.

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

methanesulfonyl;

cyano;

morpholin-4-yl-methyl;

morpholin-4-yl;

morpholin-4-yl-sulfonyl;

or trifluoromethyl.

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

methanesulfonyl;

cyano;

or morpholin-4-yl-methyl.

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

methanesulfonyl;

or cyano.

16. The compound of claim 1, wherein R⁵ is cyano.

17. The compound of claim 1, wherein R⁵ is methanesulfonyl.

18. A composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1.

19. 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.

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

N2-(2-Methoxy-4-(methylsulfonyl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

5-Chloro-N2-(2-methoxy-4-(methylsulfonyl)phenyl)-N4-methylpyrimidine-2,4-diamine;

2-Fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile;

3-Methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile;

4-(5-Chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzonitrile;

(2-Chloro-4-methanesulfonyl-phenyl)-(5-chloro-4-methoxy-pyrimidin-2-yl)-amine;

N2-(2-Chloro-4-methanesulfonyl-phenyl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine;

5-Chloro-N2-(2-chloro-4-methanesulfonyl-phenyl)-N4-methyl-pyrimidine-2,4-diamine;

N2-(2-Methoxy-4-morpholin-4-ylmethyl-phenyl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine;

5-Chloro-2-methyl-4-(4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-benzonitrile;

2-(5-Fluoro-2-methoxy-4-morpholin-4-ylmethyl-phenylamino)-4-methylamino-pyrimidine-5-carbonitrile;

4-Ethylamino-2-(5-fluoro-2-methoxy-4-morpholin-4-ylmethyl-phenylamino)-pyrimidine-5-carbonitrile;

5 -Methoxy-2-methyl-4-(4-methylamino-5 -trifluoromethyl-pyrimidin-2-ylamino)-benzonitrile;

5-Chloro-N2[2-(2-fluoro-ethoxy)-4-morpholin-4-ylmethyl-phenyl]-N4-methyl-pyrimidine-2,4-diamine;

N2-(5-Fluoro-4-methanesulfonyl-2-methoxy-phenyl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine;

N2-(2-Isopropoxy-4-methanesulfonyl-phenyl)-N4-methyl-5 -trifluoromethyl-pyrimidine-2,4-diamine;

5-Chloro-N2-[2-(2-fluoro-ethoxy)-4-methanesulfonyl-phenyl]-N4-methyl-pyrimidine-2,4-diamine;

(5-Chloro-4-methoxy-pyrimidin-2-yl)-[2-(2-fluoro-ethoxy)-4-methanesulfonyl-phenyl]-amine;

N2[2-(2-Fluoro-ethoxy)-4-methanesulfonyl-phenyl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine;

N2-(5-Chloro-4-methanesulfonyl-2-methoxy-phenyl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine;

N2[5-Fluoro-2-(2-fluoro-ethoxy)-4-morpholin-4-ylmethyl-phenyl]-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine;

N4-Ethyl-N2-[5-fluoro-2-(2-fluoro-ethoxy)-4-morpholin-4-ylmethyl-phenyl]-5-trifluoromethyl-pyrimidine-2,4-diamine;

N2-(4-Methanesulfonyl-2-methoxy-5-methyl-phenyl)-N4-methyl-5-trifluoromethyl-pyrimidine-2,4-diamine;

5-chloro-N2-(2-methoxy-4-morpholinophenyl)-N4-methylpyrimidine-2,4-diamine;

4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid;

N2-(2-methoxy-4-(morpholinosulfonyl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(2-methoxy-4-(trifluoromethyl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

5-chloro-N2-(2-methoxy-4-(trifluoromethyl)phenyl)-N4-methylpyrimidine-2,4-diamine;

2-chloro-4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-5-methoxybenzoic acid;

1-(2-fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)pyrrolidin-2-one;

4-(2-fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)morpholin-3-one;

1-(2-fluoro-5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)piperidin-2-one;

N2-(5-fluoro-2-methoxy-4-(oxetan-3-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-ethyl-N2-(2-methoxy-5-methyl-4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(4-(ethylsulfonyl)-2-methoxy-5 -methylphenyl)-N4-methyl-5 -(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(2-methoxy-5-methyl-4-(methylsulfonyl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(5-fluoro-2-methoxy-4-(morpholinomethyl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine; and

N4-ethyl-N2-(8-(methylsulfonyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine.