COMPOUNDS, COMPOSITIONS, AND METHODS

• US 20170362206A1
• Filed: 06/15/2017
• Published: 12/21/2017
• Est. Priority Date: 06/16/2016
• Status: Abandoned Application

• 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
• Application Number:
  US15/624,566
• Publication Number:
  US 20170362206A1
• Time in Patent Office: 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 I:

2. A compound of claim 1 of formula Ia:

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

4. The compound of claim 2, wherein at least one of R⁸ and R⁹ is hydrogen.

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

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

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

8. The compound of claim 7, wherein R¹ is cyclopropyl, cyclobutyl, hydroxycylobut-3-yl, cyanocylobut-3-yl, triazol-2yl-cyclobut-3-yl, triazol-1-yl-cyclobut-3-yl, or fluorocyclobut-3-yl.

9. The compound of claim 1, wherein R¹ is CD₃, ethyl, or prop-2-yl.

10. The compound of claim 1, wherein R² is halo, cyano, C_1-6 alkyl optionally substituted with halo.

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

12. The compound of claim 10, wherein R² is —

CF₃.

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

N(R¹¹)(R¹²).

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

NH(CH₃), or —

NH(CH₂CH₃).

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

16. The compound of claim 1, wherein R⁵ is cyano, optionally substituted C_1-6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted C_1-6 alkylsulfonyl, —

C(O)R¹⁰, or —

C(O)N(R¹¹)(R¹²).

17. The compound of claim 16, wherein R⁵ is cyano, —

C(O)R¹⁰, —

C(O)N(R¹¹)(R¹²), C_1-6 alkylsulfonyl, acyl, heteroaryl optionally substituted with C_1-6 alkyl, cycloalkyl optionally substituted with one to three oxo or C_1-6 alkyl, heterocyclyl optionally substituted with one to three halo, C_1-6 alkyl, C_1-6 alkyl substituted with cyano, hydroxyl, alkylsulfonyl, heterocyclyl, hydroxy, alkoxy, or heteroaryl, or C_1-6 cycloalkyl substituted with cyano, aminocarbonyl, or alkoxycarbonyl.

18. The compound of claim 16, wherein R⁵ is 2-(triazol-2-yl)propan-2-yl, 2-pyrimidin-2-ylpropan-2-yl, N,N-dimethylamido, 2-methylpropan-2-yl, methyl sulfonyl, cyano, 2-hydroxypropan-2-yl, methylcarbonyl, 5-methylpyrrolidin-2-one-5-yl, 1-(triazol-2-yl)ethyl, 2-methyl sulfonylpropan-2-yl, 5-methyl-1,3-oxazol-4-yl)pyrazol-3-yl, 3-methyloxetan-3-yl, 1-cyano-cycloprop-2-yl,pyrrolidin-2-one-5-yl, 1, 1-dioxo-1,2-thiazolidin-2-yl, 7-methyl-5,6-dihydropyrrolo[1,2-a]imidazol-7-yl, 1-ethoxycarbonyl-cycloprop-2-yl, 1-aminocarbonyl-cycloprop-2-yl, 7-methyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl, 2-methoxypropan-2-yl, 2-cyanopropan-2-yl, 3-methyloxolan-2-one-3-yl, oxabicyclo[3.1.0]hexan-2-one-3-yl, 1-methyl-pyrrolidin-2-one-yl, cyclopropyl, 1-ethyl-4,4-difluoropiperid-3-yl, 4,4-difluoropiperid-3-yl, or 2-methyl-1-oxo-cyclopent-2-yl.

19. 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 fluoroalkyl;

R³ is —

N(R¹¹)(R¹²) or C_1-6 alkoxy; and

R⁴ is H.

20. A compound of Table 1A, Table 1B, Table 2A or Table 2B, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

21. A pharmaceutical composition comprising a compound of Table 1A, Table 1B, Table 2A or Table 2B, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

22. A method for treating a disease or condition mediated, at least in part, by LRRK2, the method comprising administering an effective amount of the pharmaceutical composition of claim 21 to a subject in need thereof.

23. The method of claim 22, wherein the disease or condition is a neurodegenerative disease.

24. The method of claim 23, wherein the neurodegenerative disease is Parkinson'"'"'s disease or dementia.

25. The method of claim 22, wherein the disease or condition is a central nervous system (CNS) disorder.

26. The method of claim 25, wherein the CNS disorder is Alzheimer'"'"'s disease or L-Dopa induced dyskinesia.

27. The method of claim 22, wherein the disease or condition is a cancer.

28. The method of claim 27, wherein the cancer is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, or multiple myeloma.

29. The method of claim 22, wherein the disease or condition is an inflammatory disease.

30. The method of claim 29, wherein the inflammatory disease is leprosy, Crohn'"'"'s disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.

31. A method for enhancing cognitive memory, the method comprising administering an effective amount of the pharmaceutical composition of claim 21 to a subject in need thereof.

32-36. -36. (canceled)