PYRAZOLE AMINOPYRIMIDINE DERIVATIVES AS LRRK2 MODULATORS

• US 20120157427A1
• Filed: 11/09/2011
• Published: 06/21/2012
• Est. Priority Date: 11/10/2010
• Status: Active Grant

• Current Assignee: F Hoffmann-La Roche AG (Roche Holding AG)
• Original Assignee: F Hoffmann-La Roche AG (Roche Holding AG)
• Inventors: Burdick, Daniel Jon, Chambers, Mark, Chen, Huifen, Estrada, Anthony, Sweeney, Zachary Kevin, Baker-Glenn, Charles, Chan, Bryan K.
• Granted Patent: US 8,815,882 B2
• Time in Patent Office: Days
• US Class Current: 514/210.2
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• 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 413/14 containing three or more hetero rings

Abstract

Compounds of the formula I:

• or pharmaceutically acceptable salts thereof,
• wherein 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 the 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;

halo-C_1-6alkyl;

C_1-6alkoxy-C_1-6alkyl;

amino-C_1-6alkyl;

C_1-6alkylsulfonyl-C_1-6alkyl;

C_3-6cycloalkyl;

or C_3-6cycloalkyl-C_1-6alkyl.

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

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

halo;

C_1-6alkoxy;

halo-C_1-6alkyl;

halo-C_1-6alkoxy;

C_3-6cycloalkyl wherein the C_3-6cycloalkyl portion is optionally substituted with C_1-6alkyl;

C_3-6cycloalkyl-C_1-6alkyl wherein the C_3-6cycloalkyl portion is optionally substituted with C_1-6alkyl;

tetrahydrofuranyl;

tetrahydrofuranyl-C_1-6alkyl;

oxetanyl;

or oxetan-C_1-6alkyl.

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:

fluoro;

bromo;

chloro;

iodo;

trifluoromethyl;

or cyano.

8. The compound of claim 1, wherein R³ is:

C_1-6alkyl;

halo-C_1-6alkyl;

hydroxy-C_1-6alkyl;

C_1-6alkoxy-C_1-6alkyl;

C_3-6cycloalkyl optionally one or more times with R⁶;

C_3-6cycloalkyl-C_1-6alkyl wherein the C_3-6cycloalkyl portion is optionally substituted one or more times with R⁶;

heterocyclyl optionally substituted one or more times with R⁷;

heterocyclyl-C_1-6alkyl wherein the heterocyclyl portion is optionally substituted one or more times with R⁷;

or —

C(O)—

R^d.

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

C_1-6alkyl;

hydroxy-C_1-6alkyl;

C_1-6alkoxy-C_1-6alkyl;

heterocyclyl optionally substituted one or more times with R⁷;

or heterocyclyl-C_1-6alkyl wherein the heterocyclyl portion is optionally substituted one or more times with R⁷.

10. The compound of claim 1, wherein R³ is:

methyl;

ethyl;

propyl;

isopropyl;

butyl;

cyclopropyl;

cyclopropylmethyl;

cyclobutyl;

methanesulfonyl;

ethylsulfonyl;

cyclopropylsulfonyl;

sec-butylsulfonyl;

morpholin-4-yl-ethyl;

oxetan-3-yl;

2-methoxyethyl;

2-hydroxy-2-methyl-propyl;

3-hydroxy-2-methyl-propan-2-yl;

2-methoxy-propyl;

tetrahydro-2H-pyran-4-yl;

tetrahydrofuran-3-yl;

2,6-dimethyltetrahydro-2H-pyran-4-yl;

tetrahydro-2H-pyran-3-yl);

phenyl;

4-(methylsulfonyl)phenyl);

4-cyano-phenyl;

4-fluoro-phenyl;

4-chloro-phenyl;

3,5-difluorophenyl;

4-(dimethylamino-carbonyl)-phenyl);

4-(cyclopropylsulfonyl)phenyl;

2,2,2-trifluoroethyl;

2-fluoroethyl;

difluoromethyl;

2-dimethyl-1,3-dioxan-5-yl;

1-methyl-cyclopropyl-carbonyl;

3-methylpyridin-4-yl;

2-methylpyridin-4-yl;

pyridin-2-yl;

pyrimidin-2-yl;

pyrimidin-5-yl;

pyridin-2-ylmethyl;

1-(pyridin-2-yl)ethyl;

cyclopropylsulfonyl;

1-cyano-1-methyl-ethyl;

2-cyano-ethyl;

1-cyano-ethyl;

2-cyano-2-methyl-propyl;

1-(2,2,2-trifluoroethyl)piperidin-4-yl;

1-(methylsulfonyl)azetidin-3-yl;

(3-methyloxetan-3-yl)methyl;

(1S,5S)-8-oxabicyclo[3.2.1]octan-3-yl;

1-(oxetan-3-yl)piperidin-4-yl;

1-acetyl-piperidin-4-yl;

1-(cyclopropyl-carbonyl)-piperidin-4-yl;

1-methyl-piperidin-4-yl;

1-methyl-2-oxo-piperidin-5-yl;

2-oxo-piperidin-5-yl;

1-(isopropyl-carbonyl)-piperidin-4-yl;

1-(oxetan-3-yl)azetidin-3-yl;

1-(cyclopropyl-carbonyl)-piperidin-4-yl;

2-methoxycyclopentyl;

3-methoxycyclopentyl;

1-methoxy-2-methylpropan-2-yl;

tetrahydro-2H-1,1-dioxo-thiopyran-4-yl;

3-fluoro-1-(oxetan-3-yl)piperidin-4-yl;

1-methoxypropan-2-yl;

1-(2,2,2-trifluoroethyl)azetidin-3-yl);

1-(oxetan-3-yl)pyrrolidin-3-yl;

1-isopropylazetidin-3-yl;

3-fluoro-1-methylpiperidin-4-yl;

1-ethyl-3-fluoropiperidin-4-yl;

1-methylpyrrolidin-3-yl;

2-methoxyethyl)piperidin-4-yl);

1-methyl-1-(methylamino-carbonyl)-ethyl;

2-methyl-2-morpholino-propyl;

4,4-difluorocyclohexyl;

morpholin-4-yl-carbonyl;

dimethylamino-carbonyl-methyl;

methylamino-carbonyl-methyl;

1-methyl-1-(dimethylamino-carbonyl)-ethyl;

pyrrolidin-′

-yl-carbonyl;

1-cyamo-cyclopropyl;

1-(pyrrolidin-′

-yl-carbonyl)-ethyl;

1-(dimethylamino-carbonyl)-ethyl;

1-(methoxy-carbonyl)-ethyl;

1-(tert-butylamino-carbonyl)-1-methyl-ethyl;

1-(2,2,2-trifluoroethyllamino-carbonyl)-1-methyl-ethyl;

1-(ethylamino-carbonyl)-1-methyl-ethyl;

1-(cyclopropylmethylamino-carbonyl)-1-methyl-ethyl;

1-(ethylamino-carbonyl)-cyclobutyl;

1-(isopropylamino-carbonyl)-1-methyl-ethyl;

1-cyano-cyclobutyl;

2-methoxy-1-methyl-ethyl;

1-methyl-1-(methoxy-carbonyl)-ethyl;

2-methoxy-2-methyl-propan-1-yl;

1-(oxetan-3-yl)-pyrrolidin-3-yl;

isopropylsulfonyl;

butane-2-sulfonyl;

1-(2-fluoroethyl)-piperidin-4-yl;

3-fluoro-1-methyl-piperidin-4-yl;

1-ethyl-3-fluoro-piperidin-4-yl;

pyridin-3-ylmethyl;

6-methyl-pyridin-2-ylmethyl;

2-(morpholin-1-yl)-1,1,dimethyl-ethyl;

pyrimdin-2-yl-methyl;

3-fluoro-1-(oxetan-3-yl)-piperidin-4-yl;

1-(oxetan-3-yl)-piperidin-3-yl;

1-([1,3]Dioxolan-2-ylmethyl)-piperidin-4-yl;

pyridazin-3-ylmethyl;

piperidin-3-yl;

pyrazin-2-ylmethyl;

2-hydroxy-3-methyl-butan-1-yl;

1-([1,3]Dioxolan-2-ylmethyl)-pyrrolidin-3-yl;

pyrimidin-4-ylmethyl;

1-methyl-1H-pyrazol-3-ylmethyl;

1-methyl-1-(4H-[1,2,4]triazol-3-yl)-ethyl;

1-methyl-1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethyl;

3-fluoro-piperidin-4-yl;

2-hydroxy-cyclopentyl;

dimethyl-[1,3]dioxan-5-yl;

2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl;

2-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl;

2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl;

2-(1-methyl-1H-pyrazol-4-yl)propan-2-yl;

2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl;

2-(1-methyl-1H-pyrazol-5-yl;

2-(4H-1,2,4-triazol-3-yl)propan-2-yl;

or 1-methyl-1H-pyrazole-4-yl.

11. The compound of claim 1, wherein R⁴ is hydrogen;

C_1-6alkyl;

halo;

or C_3-6cycloalkyl optionally substituted with C_1-6alkyl.

12. The compound of claim 1, wherein R⁴ is hydrogen or C_1-6alkyl.

13. The compound of claim 1, wherein R⁴ is chloro or methyl.

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

15. The compound of claim 1, wherein R⁵ is hydrogen or methyl.

16. The compound of claim 1, wherein said compounds are of formula II

17. The compound of claim 1, wherein said compound is of formula III

18. The compound of claim 1, wherein said compound is of formula IV

19. The compound of claim 1, wherein said compound is of formula V

20. A composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1.

21. 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.