3-oxa-8-azabicyclo[3.2.1]octane derivatives and their use in the treatment of cancer and hemoglobinopathies

• US 10,519,167 B2
• Filed: 03/09/2017
• Issued: 12/31/2019
• Est. Priority Date: 03/09/2016
• Status: Active Grant

• Current Assignee: CTxT Pty., Ltd.
• Original Assignee: CTxT Pty., Ltd.
• Inventors: Stupple, Paul Anthony
• Primary Examiner(s): Rahmani, Niloofar
• Application Number:
  US16/082,256
• Publication Number:
  US 20190092786A1
• Time in Patent Office: 1,027 Days
• Field of Search: 5142305
• CPC Class Codes: A61K 31/5386 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 217/16 substituted by oxygen atoms
• CPC Class Codes: C07D 498/08 Bridged systems

Abstract

A compound of formula Ia, Ib, Ic or Id: wherein: n is 1 or 2; R^N is H or Me; R¹ is optionally one or more halo or methyl groups; R^2a and R^2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH₂OH; R^2c and R^2d (if present) are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH₂OH; R^3a and R^3b are independently selected from H and Me; R^4a is selected from OH, —NH₂, —C(═O)NH₂, and —CH₂OH; R^4b is either H or Me; R⁵ is either H or Me; m is 1 or 2; q is 0 or 1; R^11a, R^11b, R^11c and R^11d are independently selected from H, halo, C_1-4 alkyl, C_1-4 fluoroalkyl, C_3-4 cycloalkyl, C_1-4 alkyloxy, NH—C_1-4 alkyl and cyano; R^12a and R^12b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH₂OH; R^12c and R^12d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH₂OH; R^12e is H or Me; R^13a and R^13b are independently selected from H and Me; R¹⁴ is either H or Me; R^16a and R^16b are independently selected from H and Me; R⁶ is selected from H, OMe, and OEt.

Claims

1. A compound of formula Ia, Ib, Ic or Id:

2. A compound according to claim 1, wherein n is 1.

3. A compound according to claim 1, wherein R^N is H.

4. A compound according to claim 1, wherein there are no R¹ substituents.

5. A compound according to claim 1, wherein R^2a, R^2b, R^2c and R^2d (if present) are all H.

6. A compound according to claim 1, wherein R^3a and R^3b are both H.

7. A compound according to claim 1, wherein R^4a is OH.

8. A compound according to claim 1, wherein R^4b is H.

9. A compound according to claim 1, wherein R⁵ is H.

10. A compound according to claim 1 which is of formula Ia1, Ib1 or Ic1:

11. A compound according to claim 1, wherein the compound is the (S)-enantiomer at the carbon atom to which R^4b and R^4a are attached.

12. A compound according to claim 1, wherein m is 1.

13. A compound according to claim 12, wherein q is 0.

14. A compound according to claim 11, wherein R^11a, R^11b, R^11c and R^11d are all H.

15. A compound according to claim 11, wherein R^12a, R_12b, R^12c and R^12d are all H.

16. A compound according to claim 11, wherein R^13a and R^13b are both H.

17. A compound according to claim 11, wherein R¹⁴ is H.

18. A compound according to claim 11, wherein ^16a and R^16b are both H.

19. A compound according to claim 11, wherein R⁵ is H.

20. A compound according to claim 1 which is of formula Id1:

21. A compound according to claim 11, which has the following stereochemistry:

22. A compound according to claim 1, wherein R⁶ is OEt.

23. A compound according to claim 1 which is selected from:

2-Ethoxy-N—

((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-4-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)benzamide hydrochloride (1); and

N—

((S)-3-((2,3-Dihydro-1H-inden-2-yl)amino)-2-hydroxypropyl)-2-ethoxy-4-(-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carbonyl)benzamide (2).

24. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.