Kinase inhibitors and methods of use thereof

• US 9,096,594 B2
• Filed: 10/11/2013
• Issued: 08/04/2015
• Est. Priority Date: 10/12/2012
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: Dana-Farber Cancer Institute, The General Hospital Corporation (Mass General Brigham, Inc.), The Broad Institute, Inc.
• Inventors: Wagner, Florence Fevrier, Pan, Jennifer Q., Dandapani, Sivaraman, Germain, Andrew, Holson, Edward, Munoz, Benito, Nag, Partha P., Weiwer, Michel, Lewis, Michael C., Haggarty, Stephen J., Bishop, Joshua A., Stegmaier, Kimberly, Banerji, Versha
• Primary Examiner(s): DESAI, RITA J
• Application Number:
  US14/052,661
• Publication Number:
  US 20140107141A1
• Time in Patent Office: 662 Days
• Field of Search: 546/82, 546/15, 514/278, 514/293
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/4747 spiro-condensed
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/10 Spiro-condensed systems

Abstract

The present invention provides compounds of formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting kinase (e.g., GSK3 (e.g., GSK3α or GSK3β) or CK1) activity. The present invention further provides methods of using the compounds described herein for treating kinase-mediated disorders, such as neurological diseases, psychiatric disorders, metabolic disorders, and cancer.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein the compound is of formula II:

3. The compound of claim 1, wherein the compound is of formula III:

4. The compound of claim 1, wherein R³ is hydrogen.

5. The compound of claim 1, wherein R³ is optionally substituted aliphatic.

6. The compound of claim 1, wherein R³ is trifluoromethyl.

7. The compound of claim 1, wherein R² is optionally substituted aliphatic.

8. The compound of claim 1, wherein R^5a and R^5b are methyl.

9. The compound of claim 2, wherein n is 0, 1, or 2.

10. The compound of claim 1, wherein the compound is one of the following:

11. A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. A method of inhibiting GSK3 comprising contacting GSK3 with an effective amount of a compound of claim 1.

13. The compound of claim 1, wherein R¹ is optionally substituted pyridyl.

14. The compound of claim 1, wherein R¹ is unsubstituted 3-pyridyl.

15. The compound of claim 1, wherein R² is methyl.

16. The compound of claim 1, wherein R³ is methyl.

17. The compound of claim 1, wherein R³ is optionally substituted alkynyl or —

CN.

18. The compound of claim 1, wherein R³ is optionally substituted alkyl.

19. The compound of claim 1, wherein R³ is substituted or unsubstituted cycloalkyl.

20. The compound of claim 1, wherein R³ is cyclopropyl.

21. The compound of claim 1, wherein R² is optionally substituted alkyl.

22. The compound of claim 1, wherein R² is ethyl.