Compounds, compositions, and methods

• US 9,932,325 B2
• Filed: 10/25/2017
• Issued: 04/03/2018
• Est. Priority Date: 06/16/2016
• Status: Active Grant

• Current Assignee: Denali Therapeutics Inc.
• Original Assignee: Denali Therapeutics Inc.
• Inventors: Estrada, Anthony A., Feng, Jianwen A., Lyssikatos, Joseph P., Sweeney, Zachary K., de Vicente Fidalgo, Javier
• Primary Examiner(s): Shameem, Golam M
• Application Number:
  US15/793,882
• Publication Number:
  US 20180051009A1
• Time in Patent Office: 160 Days
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 59/002 Heterocyclic compounds
• 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 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/20 : Spiro-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems

Abstract

The present disclosure relates generally to LRRK2 inhibitors, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and methods of making and using thereof.

Claims

1. A compound of formula Ia:

2. The compound of claim 1, wherein R⁶ and R⁷ are methyl.

3. The compound of claim 1, wherein at least one of R⁸ and R⁹ is hydrogen.

4. The compound of claim 3, wherein both R⁸ and R⁹ are hydrogen.

5. The compound of claim 1, wherein R¹ is optionally substituted cyclopropyl or optionally substituted cyclobutyl.

6. The compound of claim 5, wherein R¹ is cyclopropyl independently substituted with one or more halo, hydroxy, cyano, or heteroaryl.

7. The compound of claim 6, wherein R¹ is cyclopropyl, cyclobutyl, hydroxycyclobut-3-yl, cyanocyclobut-3-yl, triazol-2yl-cyclobut-3-yl, triazol-1-yl-cyclobut-3-yl, or fluorocyclobut-3-yl.

8. The compound of claim 1, wherein R¹ is CD₃, ethyl, prop-2-yl, or methyl optionally substituted with halo.

9. The compound of claim 1, wherein R² is halo, cyano, or C_1-6 alkyl optionally substituted with one or more halo.

10. The compound of claim 9, wherein R² is bromo.

11. The compound of claim 9, wherein R² is —

CF₃.

12. The compound of claim 1, wherein R³ is optionally substituted cycloalkyl, optionally substituted C_1-6alkoxy, or —

N(R¹¹)(R¹²).

13. The compound of claim 1, wherein R³ is cyclopropyl, methoxy, 1,1-difluoroethy-2-ylamino, cyclopropylamino, —

NH(CH₃), or —

NH(CH₂CH₃).

14. The compound of claim 1, wherein R⁴ is hydrogen.

15. The compound of claim 1, wherein R¹ is cycloalkyl independently substituted with one or more hydroxy, cyano, or heteroaryl;

R² is halo or C_1-6 haloalkyl;

R³ is —

N(R¹¹)(R¹²) or C_1-6 alkoxy; and

R⁴ is H.

16. The compound of claim 15, wherein R¹² is optionally substituted C_1-6 alkyl.

17. The compound of claim 15, wherein R¹¹ is H and R¹² is ethyl.

20. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

18. A compound, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein the compound is selected from:

19. A compound, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein the compound is selected from:

21. A compound having the structure:

22. A pharmaceutical composition comprising the compound of claim 21 and a pharmaceutically acceptable excipient.

23. A compound having the structure:

24. A pharmaceutical composition comprising the compound of claim 23 and a pharmaceutically acceptable excipient.

25. A compound having the structure:

26. A pharmaceutical composition comprising the compound of claim 25 and a pharmaceutically acceptable excipient.

27. A compound having the structure:

28. A pharmaceutical composition comprising the compound of claim 27 and a pharmaceutically acceptable excipient.

29. A compound having the structure:

30. A pharmaceutical composition comprising the compound of claim 29 and a pharmaceutically acceptable excipient.