Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists

• US 9,994,559 B2
• Filed: 12/16/2015
• Issued: 06/12/2018
• Est. Priority Date: 12/17/2014
• Status: Active Grant

• Current Assignee: King's College London
• Original Assignee: King's College London
• Inventors: Borthwick, Alan David, Mills, Mark Trevor, Brown, Jane Theresa, Corcoran, Jonathan Patrick Thomas, De Castro Vasconcelos Goncalves, Maria Beatriz, Kalindjian, Sarkis Barret
• Primary Examiner(s): Aguirre, Amanda L
• Application Number:
  US15/533,492
• Publication Number:
  US 20170327489A1
• Time in Patent Office: 909 Days
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain bicycloheteroaryl-heteroaryl-benzoic acid compounds of the following formula (for convenience, collectively referred to herein as “BHBA compounds”), which, inter alia, are (selective) retinoic acid receptor beta (RARβ) (e.g., RARβ2) agonists. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to (selectively) activate RARβ (e.g., RARβ2), to cause or promote neurite development, neurite outgrowth, and/or neurite regeneration, and in the treatment of diseases and conditions that are mediated by RARβ (e.g., RARβ2), that are ameliorated by the activation of RARβ (e.g., RARβ2), etc., including, e.g., neurological injuries such as spinal cord injuries.

Claims

1. A compound selected from compounds of the following formula, and pharmaceutically acceptable salts thereof:

2. A compound according to claim 1, wherein —

R^A is —

H.

3. A compound according to claim 2, wherein:

X¹ is O, X² is N, and X³ is N;

or

X¹ is S, X² is N, and X³ is N;

or

X¹ is N, X² is S, and X³ is N.

4. A compound according to claim 2, wherein:

X¹ is O;

X² is N; and

X³ is N.

5. A compound according to claim 3, wherein:

Y¹ is O and Y² is CH;

or

Y¹ is O and Y² is CR^Y;

or

Y¹ is O and Y² is N; and

—

R^Y is -Me.

6. A compound according to claim 4, wherein:

Y¹ is O and Y² is CH;

or

Y¹ is O and Y² is CR^Y;

or

Y¹ is O and Y² is N; and

—

R^Y is -Me.

7. A compound according to claim 3, wherein:

Y¹ is O; and

Y² is CH.

8. A compound according to claim 4, wherein:

Y¹ is O; and

Y² is CH.

9. A compound according to claim 5, wherein:

—

R^Q1 is independently —

R^Q1A or —

R^Q1B;

—

R^Q1A is -Me;

—

R^Q1B is —

F or —

Cl;

—

R^Q2 is independently —

R^Q2A or —

R^Q2B;

—

R^Q2A is -Me;

—

R^Q2B is —

F or —

Cl;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

10. A compound according to claim 6, wherein:

—

R^Q1 is independently —

R^Q1A or —

R^Q1B;

—

R^Q1A is -Me;

—

R^Q1B is —

F or —

Cl;

—

R^Q2 is independently —

R^Q2A or —

R^Q2B;

—

R^Q2A is -Me;

—

R^Q2B is —

F or —

Cl;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

11. A compound according to claim 7, wherein:

—

R^Q1 is independently —

R^Q1A or —

R^Q1B;

—

R^Q1A is -Me;

—

R^Q1B is —

F or —

Cl;

—

R^Q2 is independently —

R^Q2A or —

R^Q2B;

—

R^Q2A is -Me;

—

R^Q2B is —

F or —

Cl;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

12. A compound according to claim 8, wherein:

—

R^Q1 is independently —

R^Q1A or —

R^Q1B;

—

R^Q1A is -Me;

—

R^Q1B is —

F or —

Cl;

—

R^Q2 is independently —

R^Q2A or —

R^Q2B;

—

R^Q2A is -Me;

—

R^Q2B is —

F or —

Cl;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

13. A compound according to claim 5, wherein:

—

R^Q1 is —

R^Q1A;

—

R^Q1A is -Me;

—

R^Q2 is —

R^Q2A;

—

R^Q2A is -Me;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

14. A compound according to claim 6, wherein:

—

R^Q1 is —

R^Q1A;

—

R^Q1A is -Me;

—

R^Q2 is —

R^Q2A;

—

R^Q2A is -Me;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

15. A compound according to claim 7, wherein:

—

R^Q1 is —

R^Q1A;

—

R^Q1A is -Me;

—

R^Q2 is —

R^Q2A;

—

R^Q2A is -Me;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

16. A compound according to claim 8, wherein:

—

R^Q1 is —

R^Q1A;

—

R^Q1A is -Me;

—

R^Q2 is —

R^Q2A;

—

R^Q2A is -Me;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

17. A compound according to claim 9, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

18. A compound according to claim 10, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

19. A compound according to claim 11, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

20. A compound according to claim 12, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

21. A compound according to claim 13, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

22. A compound according to claim 14, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

23. A compound according to claim 15, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

24. A compound according to claim 16, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

25. A compound according to claim 1, which is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:

26. A compound according to claim 1, which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:

27. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier, diluent, or excipient.

28. A method of preparing a pharmaceutical composition comprising mixing a compound according to claim 1, and a pharmaceutically acceptable carrier, diluent, or excipient.

29. A method of activating retinoic acid receptor β

(RARβ

) in vitro or in vivo, comprising contacting RARβ

with an effective amount of a compound according to claim 1.

30. A method of causing or promoting neurite development, neurite outgrowth, and/or neurite regeneration, comprising contacting a neuron, in vitro or in vivo, with an effective amount of a compound according to claim 1.