Azaindole derivatives as CFTR modulators

• US 9,732,080 B2
• Filed: 08/05/2015
• Issued: 08/15/2017
• Est. Priority Date: 11/03/2006
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Bear, Brian, Hadida-Ruah, Sara, Miller, Mark, Zhou, Jinglan
• Primary Examiner(s): West, Theodore R
• Application Number:
  US14/818,698
• Publication Number:
  US 20150336956A1
• Time in Patent Office: 741 Days
• Field of Search: None
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

Claims

1. A method of increasing CFTR transporters in a membrane of a cell,

comprising the step of contacting said cell with a compound according to formula I:

2. A method of treating a condition, disease, or disorder in a patient, comprising the step of administering to said patient a compound according to formula I:

3. The method according to claim 2, wherein Ar¹ is an optionally substituted ring selected from:

4. The method according to claim 2, wherein w is 0-3.

5. The method according to claim 2, wherein W is a bond.

6. The method according to claim 2, wherein W is a (C1-C6) alkylidene chain wherein up to two non-adjacent methylene unit of W is optionally replaced by —

O—

.

7. The method according to claim 2, wherein R^w is a C1-C6 aliphatic.

8. The method according to claim 2, wherein R^w is C6-C10 aryl.

9. The method compound according to claim 2, wherein R^w is 3-10 membered monocyclic or bicyclic heterocyclic ring.

10. The method compound according to claim 2, wherein R^w is 5-10 membered monocyclic or bicyclic heteroaryl ring.

11. The method according to claim 2, wherein —

WR^w is selected from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tertbutyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

12. The method according to claim 2, wherein two R^xare two adjacent R¹ taken together to form

13. The method according to claim 2, wherein ring A is

14. The method according to claim 2, wherein Ar¹ is attached through atom G₂.

15. The method according to claim 2, wherein Ar¹ is attached through atom G₃.

16. The method according to claim 2, wherein said compound has formula IIIA or formula IIIB:

17. The method according to claim 16, wherein G₃ in formula IIIA is a C.

18. The method according to claim 16, wherein G₂ in formula IIIB is a C.

19. The method according to claim 2, wherein ring B is fused to a 5-6 membered heterocyclic ring having up to 3 heteroatoms selected from O.

20. The method according to claim 2, wherein ring B is fused to a 5-6 membered heteroaryl ring having up to 3-heteroatoms independently selected from O, N, and S.

21. The method according to claim 2, wherein said ring fused to ring B is selected from:

22. The method according to claim 2, wherein said compound has formula IVA, formula IVB, or formula IVC:

23. The method according to claim 22, Wherein R^w that is attached to carbon no. 2 is R² or R³.

24. The method according to claim 22, wherein R^w that is attached to carbon no. 2 is an optionally substituted C1-C6 alkyl.

25. The method according to claim 22, wherein R^w that is attached to carbon no. 2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobuyl, 1-methylcyclopropyl, and tert-butyl.

26. The method according to claim 22, wherein R^w that is attached to carbon no. 2 is tert-butyl.

27. The method according to claim 2, wherein said compound has formula VA, formula VB, or formula VC:

28. The method according to claim 27, wherein W is a C1-C6 alkylidene substituted with a hydroxy or alkoxy group.

29. The method according to claim 27, wherein W is a C1-C6 alkylidene substituted with a hydroxy group.

30. The method according to claim 27, wherein R^w is OH.

31. The method according to claim 27, wherein W is C1-C6 alkylidene and R^w is OR₆.

32. The method according to claim 27, -WR^w is —

C₂H₄OH or —

CH₂CH(OH)CH₂OH.

33. The method according to claim 2, wherein the compound is selected from: