Novel Amide-Substituted Heterocyclic Compounds for Treating Inflammatory and Autoimmune Diseases

Important Compound Classes

Title

Amide-Disubstituted Pyridine or Pyridazine Compounds

Patent Publication Number

WO 2020/159904 A1

Publication Date

August 6, 2020

Priority Application

US 62/798,566

Priority Date

January 30, 2019

Inventors

Sherwood, T. C.; Yang, M. G.; Gilmore, J. L.; Zhang, Y.; Xiao, Z.; Liu, Q.

Assignee Company

Bristol-Myers Squibb Company, USA

Disease Area

Inflammatory and autoimmune diseases

Biological Target

Cytokines interleukin (IL) and/or interferons (IFNs)

Summary

The heterodimeric cytokines interleukin (IL)-12 and IL-23, which share a common p40 subunit, are produced by activated antigen-presenting cells and are critical in the differentiation and proliferation of Th1 and Th17 cells, two effector T cell lineages, which play key roles in autoimmunity. IL-23 is composed of the p40 subunit along with q unique p19 subunits. IL-23, acting through a heterodimeric receptor composed of IL-23R and IL-12β1, is essential for the survival and expansion of Th17 cells, which produce proinflammatory cytokines such as IL-17A, IL-17F, IL-6, and TNF-α. These cytokines are critical in mediating the pathobiology of several autoimmune diseases. IL-12, in addition to the p40 subunit in common with IL-23, contains a p35 subunit and acts through a heterodimeric receptor composed of IL-12Rβ1 and IL-12Rβ2. IL-12 is essential for Th1 cell development and secretion of IFNγ, a cytokine which plays a critical role in immunity by stimulating MHC expression, class switching of B cells to IgG subclasses, and the activation of macrophages.

In human disease, high expression of p40 and p19 has been measured in psoriatic lesions, and Th17 cells have been identified in active lesions in the brain from MS patients and in the gut mucosa of patients with active Crohn’s disease. Moreover, genome-wide association studies have identified several loci associated with chronic inflammatory and autoimmune diseases that encode factors that function in the IL-23 and IL-12 pathways. Indeed, anti-p40 treatments, which inhibit both IL-12 and IL-23 as well as IL-23-specific anti-p19 therapies, are shown to be efficacious in the treatment of autoimmunity in diseases including psoriasis, Crohn’s disease, and psoriatic arthritis.

The Type I group of interferons (IFNs) include IFNα, IFNβ, IFNε, IFNκ, and IFNω. Type I IFNs have multiple effects in both the innate and adaptive immune system. Patients with systemic lupus erythematosus (SLE) have demonstrated increased serum levels of IFNα, and serum IFNα levels correlate with disease activity and severity. In addition to lupus, Type I interferons are important in the pathobiology of Sjogren’s syndrome and scleroderma. Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of nonreceptor tyrosine kinases and is critical in regulating IL-12, IL-23, and Type I interferons in both mice and humans. The present application describes a series of novel amide-disubstituted heterocyclic compounds for modulating cytokines interleukin (IL) and/or interferons, such as IL-12, IL-23, and/or IFNα for the treatment of inflammatory and autoimmune diseases. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = N or CH;

R₁ = H, CD₃, C_1–3 alkyl, or C_3–6 cycloalkyl;

R₂ = C_1–6 alkyl, C_1–6 alkoxy, -(CH₂)₁-3–14 membered carbocyclic substituted with 0–1 R_2a, -NR_aC_1–6 alkyl substituted with 0–2 R_2a, -NR_a-aryl substituted with 0–2 R_2a, -NR_a-heterocycle substituted with 0–2 R_2a, -NR_aCO-C_1–6 alkyl, -NR_a-C_3–6 cycloalkyl substituted with 0–2 R_2a or a 5–8 membered heterocycle substituted with 0–3 R_2a;

R_2a = H, CN, halogen, C_1–6 alkyl, C_3–6 cycloalkyl, C_3–6 aryl or a 5–8 membered heterocycle;

R₃ = C_1–3 alkyl, C_1–3 alkoxy, -NHS(O)_pR_a or -S(O)_pR_a,R₄ is absent or a 5–7 membered heterocycle substituted with 0–3 R₅;

R₅ = H, halogen, C_1–3 alkyl, C_1–3 alkoxy, -(CH₂)_r 5–8 membered heterocycle substituted with 0–2 R_5a or -CO- 3–8 membered heterocycle;

R_5a = SO₂-, C_1–6 alkyl or COO-C_1–6 alkyl;

R_a = C_1–3 alkyl or C_3–6 cycloalkyl;

p = 1 or 2;

r = 0, 1, 2, 3, 4 or 5.

Key Structures

Biological Assay

The human whole blood (WB) IFNα assay was performed. The compounds described in this application were tested for their ability to inhibit IFNα. The human WB IFNα-induced STAT phosphorylation IC₅₀ (μM) values are shown in the following table.

Biological Data

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

Claims

Total claims: 12

Compound claims: 9

Pharmaceutical composition claims: 1

Method of treatment claims: 2

Recent Review Articles

• 1.Chyuan I.; Lai J.. Biochem. Pharmacol. 2020, 175, 113928.
• 2.Leppkes M.; Neurath M. F.. Pharmacol. Res. 2020, 158, 104835.
• 3.Tanaka Y.Int. J. Rheum. Dis. 2020, 23, 465.
• 4.Hazel K.; O’Connor A.. Ther. Adv. Chronic Dis. 2020, 11, 1.
• 5.Aringer M.; Leuchten N.; Dorner T. Z.. Z. Rheumatol. 2020, 79, 232.
• 6.Charras A.; Arvaniti P.; Le Dantec C.; Arleevskaya M. I.; Zachou K.; Dalekos G. N.; Bordon A.; Renaudineau Y.. Clin. Rev. Allergy Immunol. 2020, 58, 182.

The author declares no competing financial interest.