Substituted Benzoazepines As Toll-Like Receptor Modulators

• US 20140066432A1
• Filed: 01/12/2012
• Published: 03/06/2014
• Est. Priority Date: 01/12/2011
• Status: Active Grant

• Current Assignee: VentiRx Pharmaceuticals, Inc. (Bristol-Myers Squibb Company), Array Biopharma Incorporated (Pfizer Inc.)
• Original Assignee: Array Biopharma Incorporated (Pfizer Inc.)
• Inventors: Howbert, James Jeffry, Hershberg, Robert, Burgess, Laurence E., Yang, Hong Woon
• Granted Patent: US 9,718,796 B2
• Time in Patent Office: Days
• US Class Current: 514/212.02
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 223/16 Benzazepines; Hydrogenated benzazepines
• CPC Class Codes: C07D 295/192 from aromatic carboxylic acids
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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:

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

3. The compound of claim 1, wherein R₄ is H, halogen, unsubstituted C₁-C₆ alkyl, —

C(O)OR₁₀, or —

C(O)NR_cR_d, where both R_c and R_d are alkyl.

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

C(O)OR₁₀, where R₁₀ is alkyl.

7. The compound of claim 3 wherein R₄ is —

C(O)NR_cR_d in which both R_c and R_d are propyl or at least one of R_c or R_d is alkyl substituted with one —

OH.

9. The compound of claim 7, wherein one of R_c and R_d is

10. The compound of claim 1, R₄ is Br, methyl or ethyl.

12. The compound of claim 1, wherein R₇ is

13. The compound of claim 12, wherein R₇ is not 3-methylphenyl nor 3,4-dichlorophenyl, or R₇ is not

15. The compound of claim 1, R₇ is

16. 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 is hydrogen, or one or more of R_a and R_b is alkyl substituted with R_e, or both R_a and R_b are alkyl.

20. 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.

21. 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.

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

25. The compound of claim 24, wherein R_2′

and R_3′

are each H or both R_2′

and R_3′

are each methyl.

26. The compound of claim 24, wherein R_2′

or R_3′

is unsubstituted or substituted C₁-C₆ alkyl.

29. The compound of claim 24, wherein R_2′

and R_3′

, together with the carbon atom to which they are attached, form a saturated carbocycle having from 3 to 7 members.

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

33. 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.

34. A method of treating an autoimmune disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.

5-6. -6. (canceled)

8. (canceled)

11. (canceled)

14. (canceled)

17-19. -19. (canceled)

22-23. -23. (canceled)

27-28. -28. (canceled)

30. (canceled)

32. A compound selected from one of those in Table 1 or Table 1A.