Imidazo[1,2-b]pyridazines as IL-17A Inhibitors for Treating Psoriasis, Rheumatoid Arthritis, and Multiple Sclerosis

Important Compound Classes

Title

Imidazo[1,2-b]pyridazine IL-17A Inhibitors

Patent Publication Number

WO 2020/146194 A1

Publication Date

July 16, 2020

Priority Application

US 62/789,247 and US 62/842,770

Priority Date

January 7, 2019, and May 3, 2019

Inventors

Coates, D. A.; Frimpong, K.; Holloway, W. G.; Jones, S. B.; Levinson, A. M.; Lugar, C. W., III; Richett, M. E.; Watson, B. M.; Woodman, M. E.

Assignee Company

Eli Lilly and Company, USA

Disease Area

Psoriasis, rheumatoid arthritis, and multiple sclerosis

Biological Target

IL-17A

Summary

The interleukin (IL)-17 family consists of six cytokines (IL-17A through IL-17F). IL-17 receptor (IL-17R) refers to the heterodimer formed by the IL-17RA and IL-17RC subunits. IL-17A is a major pathological cytokine secreted from Th17 cells, which may act as a homodimer or a heterodimer to signal through IL-17R. IL-17A is well-established as a pro-inflammatory cytokine which plays a key part in chronic inflammation and is a major driver of tissue damage. IL-17A induces normal immune and inflammatory responses to pathogens, but can also contribute to chronic autoimmune diseases including psoriasis, spondylarthritis, rheumatoid arthritis, and multiple sclerosis.

The critical importance of the IL-23/IL-17 axis to the pathogenesis of psoriatic disease has resulted in many new biological treatments targeting these cytokines. These biologics dramatically improve skin and joint symptoms in patients with moderate-to-severe psoriasis and psoriatic arthritis. There are currently no highly efficacious orally administered treatments for moderate to severe psoriasis. A small molecule IL-17A inhibitor may provide efficacy comparable to anti-IL-17A antibodies for psoriasis. In addition, anti-drug antibodies against anti-IL-17A antibodies may arise in some patients and may reduce the efficacy of antibodies directed to IL-17A over time. This inactivation pathway would not be operative for small molecule IL-17A inhibitors.

The present application describes a series of novel imidazo[1,2-b]pyridazine as IL-17A inhibitors for the treatment of psoriasis, rheumatoid arthritis, and multiple sclerosis. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = CH or N;

R₁ = −CH₃, −CH₂F, −CHF₂, −CF₃, −CH₂CH₃, −CH₂CF₃, −CH(CH₃)₂, −CH₂CHF₂, −CH₂CH₂F, −CF(CH₃)₂, −CF₂CH₃, −OCH₃, , , , , ; and

R₂ = −H or −CH₂OCH₃.

Key Structures

Biological Assay

The IL-17A to IL-17RA AlphaLISA binding assay and cell-based human IL-17A neutralization assay in HT-29 in cells were performed. The compounds described in this application were tested for their ability to inhibit IL-17A. The IL-17A alphalisa and HT-29 IC₅₀ (nM) are shown in the following Table.

Biological Data

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

Claims

Total claims: 18

Compound claims: 14

Pharmaceutical composition claims: 1

Method of treating claims: 2

Use of compound claims: 1

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.