Substituted Benzoazepines As Toll-Like Receptor Modulators

• US 20140088085A1
• Filed: 01/12/2012
• Published: 03/27/2014
• Est. Priority Date: 01/12/2011
• Status: Abandoned Application

• Current Assignee: VentiRx Pharmaceuticals, Inc. (Bristol-Myers Squibb Company), Array Biopharma Incorporated (Pfizer Inc.)
• Original Assignee: VentiRx Pharmaceuticals, Inc. (Bristol-Myers Squibb Company), Array Biopharma Incorporated (Pfizer Inc.)
• Inventors: Burgess, Laurence E., Doherty, George A., Eary, C. Todd, Groneberg, Robert D., Jones, Zachary, Howbert, James Jeffry, Hershberg, Robert, Lyssikatos, Joseph P., Yang, Hong Woon
• Application Number:
  US13/979,634
• Publication Number:
  US 20140088085A1
• Time in Patent Office: Days
• US Class Current: 514/214.02
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 223/16 Benzazepines; Hydrogenated benzazepines
• CPC Class Codes: C07D 243/14 1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Provided are compositions and methods useful for modulation of signaling through the Toll-like receptors TLR7 and/or TLR8. The compositions and methods have use in treating or preventing disease, including cancer, autoimmune disease, fibrotic disease, cardiovascular disease, infectious disease, inflammatory disorder, graft rejection, or graft-versus-host disease.

Claims

1. A compound having the formula I or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, wherein R₇ is

3. The compound of claim 1, wherein at least one of R_a and R_b is not hydrogen, or one of R_a and R_b is alkyl and the other of R_a and R_b is hydrogen, or one of R_a and R_b is alkyl substituted with R_e, or both R_a and R_b are alkyl.

7. The compound of claim 1, wherein one of R_a and R_b is R_e, and the other of R_a and R_b is hydrogen.

8. The compound of claim 1, wherein R₈ is not hydrogen.

9. The compound of claim 1, wherein N₁ and one of R_a or R_b are connected to form a saturated, partially unsaturated, or unsaturated heterocycle having 5-7 ring members and the other of R_a or R_b is hydrogen, or absent as necessary to accommodate ring unsaturation.

11. The compound of claim 9, wherein N₁ and one of R_a or R_b are connected to form or

12. The compound of claim 1, wherein at least one of R₂ and R₃ is not hydrogen, or R₂ and R₃ are connected to form a saturated carbocycle.

15. The compound of claim 1, Z is N.

19. The compound of claim 1, wherein R₄ is —

OR₁₀ and R₁₀ is alkyl or R₄ is —

NR_cR_d in which R_c and R_d are both alkyl.

20. The compound of claim 19, wherein R₄ is —

O-ethyl or —

N(propyl)₂.

27. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

28. A method of treating a TLR7- and/or TLR8-mediated condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

29. A method of treating an autoimmune condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

4-6. -6. (canceled)

10. (canceled)

13-14. -14. (canceled)

16. A compound having the formula II or a pharmaceutically acceptable salt thereof:

17. The compound of claim 16, wherein R_f and R_g together with the nitrogen atom to which they are attached form a saturated heterocyclic ring.

18. The compound of claim 17, wherein R_f and R_g together with the nitrogen atom to which they are attached form pyrrolidine.

23. The compound of claim 16, wherein at least one of R_c or R_d is alkyl substituted with one —

OH.

24. The compound of claim 23, wherein at least one of R_c and R_d is

21-22. -22. (canceled)

25. A compound selected from

26. (canceled)