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 2021/204800 A1

Publication Date

October 14, 2021

Priority Application

GB 2005151.2 and GB 2009912.3

Priority Date

April 7, 2020 and June 29, 2020

Inventors

Chovatia, P. T.; Haslett, G. W.; Lecomte, F. C.; Madden, J.; Monck, N. J. T.; Norman, T. J.; Rampalakos, K.; Smalley, A. P.; Straker, R.; Suganthan, S.; Xuan, M.; Yousuf, Z.

Assignee Company

UCB Biopharma SRL, Belgium

Disease Area

Inflammatory and autoimmune diseases

Biological Target

IL-17

Summary

Interleukin (IL)-17, or IL-17A, is a proinflammatory cytokine and the founding 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 expresses IL-21 and IL-22 signature cytokines. IL-17A and IL-17F are expressed as homodimers but may also be expressed as an IL-17A/F heterodimer. IL-17A and IL-17F signal through receptors IL-17R and IL-17RC or through an IL-17RA/RC receptor complex. Both IL-17A and 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. Furthermore, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

A = C-R₁ or N;

E = C–R₂ or N;

Y = −O–, −N(R₃)–, −C(R_4a)(R_4b)–, −S–, −S(O)–, −S(O)₂–, or −S(O)(N-R₅)–;

Z = heteroaryl, which may be optionally substituted with one or more substituents; 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 by 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 IC₅₀ (nM) are shown in the following table.

Biological Data

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

Claims

Total claims: 19

Compound claims: 13

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.