Novel Difluorocyclohexyl Derivatives as IL-17 Modulators for Treating Inflammatory and Autoimmune Diseases

Important Compound Classes

Title

Difluorocyclohexyl Derivatives as IL-17 Modulators

Patent Publication Number

WO 2021/204801 A1

URL: https://patents.google.com/patent/WO2021204801A1/en

Publication Date

October 14, 2021

Priority Application

GB 2005153.8 and GB 2009617.8

Priority Date

April 7, 2020, and June 24, 2020

Inventors

Chovatia, P. T.; Foley, A. M.; Haslett, G. W.; Hutchings, M. C.; Johnson, J. A.; Lecomte, F. C.; Monck, N. J. T.; Quincey, J. R.; Rampalakos, K.; Reuberson, J. T.; Smalley, A. P.; Trani, G.; Vaidya, D. G.

Assignee Company

UCB Biopharma SRL, Belgium

Disease Area

Inflammatory and autoimmune diseases

Biological Target

IL-17

Summary

The interleukin (IL)-17 or IL-17A is a proinflammatory cytokine and the founder member of the IL-17 family. Subsequently, five additional members of the family (IL-17B to IL-17F) have been identified, including the most closely related, IL-17F (ML-1), which shares approximately 55% amino acid sequence homology with IL-17A. IL-17A and IL-17F are expressed by the recently defined autoimmune related subset of T helper cells, TH17, that also express IL-21 and IL-22 signature cytokines. IL-17A and IL-17F are expressed as homodimers but may also be expressed as the IL-17A/F heterodimer. IL-17A and IL-17F signal through the receptors IL-17R, IL-17RC, or an IL-17RA/RC receptor complex. Both IL-17A an IL-17F have been associated with a number of autoimmune diseases.

The present application describes a series of novel difluorocyclohexyl derivatives as IL-17 modulators for the treatment of inflammatory and autoimmune diseases. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

A = C-R₁ or N; E = C-R₂ or N; R₃ = −NR_3aR_3b;

R_4a = H, F, OH; or R_4a = C_1–4 alkyl, optionally substituted by one or more substituents;

R_4b = H, F, or C_1–4 alkyl; and

R₆ = −OR_6a or −NR_6bR_6c or R₆ = C_1–6 alkyl, C_3–9 cycloalkyl, C_3–9 cycloalkyl(C_1–6)alkyl, aryl, aryl(C_1–6) alkyl, C_3–7 heterocycloalkyl, C_3–7 heterocycloalkyl(C_1–6)alkyl, heteroaryl or heteroaryl(C_1–6) alkyl), any of which group may be optionally substituted by one or more substituents.

Key Structures

Biological Assay

The inhibition of IL-17A-induced IL-6 release from the human dermal fibroblast (HDF) cell line assay was performed. The compounds described in this application were tested for their ability to inhibit IL-17. The IL-17 pIC₅₀ are shown in the following table.

Biological Data

The table below shows representative compounds were tested for IL-17 inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 21

Compound claims: 15

Pharmaceutical composition claims: 2

Method of treatment claims: 2

Use of compound claims: 2

Recent Review Articles

• 1.Ghoreschi K.; Balato A.; Enerback C.; Sabat R.. Lancet 2021, 397, 754.
• 2.Loft N.; Halling A.; Egeberg A.; Skov L.. J. Am. Acad. Dermatol. 2021, 84, 130.
• 3.Marson J. W.; Snyder M. L.; Lebwohl M. G.. Med. Clin. North Am. 2021, 105, 627.
• 4.Griffiths C. E. M.; Armstrong A. W.; Gudjonsson J. E.; Barker J. N. W. N.. Lancet 2021, 397, 1301.
• 5.Stober C.Best Pract. Res. Clin. Rheumatol. 2021, 35, 101694.
• 6.Higgins E.Medicine 2021, 49, 361.

The author declares no competing financial interest.