Bicyclic pyrazole LRRK2 small molecule inhibitors

• US 9,212,186 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, Chan, Bryan K., Dotson, Jennafer, Estrada, Anthony, Heffron, Timothy, Lyssikatos, Joseph, Sweeney, Zachary
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US14/531,349
• Publication Number:
  US 20150051201A1
• 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 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/20 Spiro-condensed systems

Abstract

Compounds of formula I:

• • or pharmaceutically acceptable salts thereof,
  • wherein X, R¹, R², R³ and A 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—

.

3. The compound of claim 1, wherein R³ is hydrogen or C_1-6alkyl.

4. The compound of claim 1, wherein R⁴ is C_1-6alkyl;

halo-C_1-6alkyl;

or halo.

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

halo-C_1-6alkyl;

or halo.

6. The compound of claim 1, wherein ring A is a five-membered ring.

7. The compound of claim 1, wherein ring A is a six-membered ring.

8. The compound of claim 1, wherein ring A is saturated.

9. The compound of claim 1, wherein ring A is carbocyclic.

10. The compound of claim 1, wherein ring A contains a heteroatom selected from O, N and S.

11. The compound of claim 1, wherein ring A is substituted at least once with a group R⁶.

12. The compound of claim 1, wherein R⁶ is C_1-6alkyl.

13. The compound of claim 1, wherein said compound is of formula IIA or formula IIB:

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

15. The compound of claim 1, wherein at least one of R⁷ is C_1-6alkyl.

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

N4-methyl-N2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

(S)—

N2-(4,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

(R)—

N2-(4,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

(S)—

N2-(4,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

(R)—

N2-(4,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

(S)—

N4-cyclopropyl-N2-(4,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

(R)—

N4-cyclopropyl-N2-(4,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-5-(trifluoromethyl)-N2-(4,7,7-trimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyrimidine-2,4-diamine;

N4-ethyl-N2-(4-methyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-N2-(4-methyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(4,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-N2-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-methyl-N4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N2-(6′

,7′

-dihydrospiro[oxetane-3,4′

-pyrazolo[5,1-c][1,4]oxazine]-3′

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

N2-(4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine;

N4-methyl-N2-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; and

N2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine.

17. A composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1.

18. 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.