Novel Thienopyridines as RIPK2 Inhibitors for Treating Inflammatory Bowel Disease

Important Compound Classes

Title

Thienopyridine Inhibitors of RIPK2

Patent Publication Number

WO 2020/132384 A1

Publication Date

June 25, 2020

Priority Application

US 62/783,742

Priority Date

December 21, 2018

Inventors

Armbrust, K.; Romanov Michailidis, F.; Worm, K. I.; Ellis, J. M.

Assignee Company

Celgene Corporation, USA

Disease Area

Inflammatory bowel disease

Biological Target

Receptor interacting protein kinase 2 (RIPK2)

Summary

Receptor interacting protein kinase 2 (RIPK2) is associated with promoting infiltration of immune cells into the central nervous system. In particular, RIPK2 mediates pro-inflammatory signaling from nucleotide-binding oligomerization domain containing proteins 1 and 2 (NOD1 and NOD2) and is implicated in numerous autoinflammatory disorders. Autoinflammatory disorders, such as inflammatory bowel disease (IBD), can be debilitating and sometimes lead to life-threatening complications. In 2011, studies showed that approximately 1.6 million Americans suffered from IBD. Inhibition of RIPK2 is useful for treating certain diseases and disorders associated with autoinflammatory disorders such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), sarcoidosis, inflammatory arthritis, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.

The present application describes a series of novel thienopyridines as RIPK2 inhibitors for the treatment and/or prevention of inflammatory disorders, particularly such as inflammatory bowel disease. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from N, O, S; 9- to 10-membered bicyclic heterocyclic ring having 1 to 3 heteroatoms selected from N, O, S; 7- to 11-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms selected from N, O, S; and wherein R₁ is substituted with (R₂)_p;

R₂ = halogen, optionally substituted with C_1–6 aliphatic, -OR, -N(R)₂, -C(O)R, -C(O)OR, -SO₂R or an optionally substituted with 3- to 7-membered saturated heterocyclic ring having 1 to 2 heteroatoms selected from N, O, S;

R = H, optionally substituted with C_1–6 aliphatic, or an optionally substituted with 4- to 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms selected from N, O, S; or two R groups on a nitrogen atom, together with the atoms to which they are attached, form a 4- to 6-membered heterocyclic ring having 1 or two additional heteroatoms selected from N, O, S;

R₃ = halogen, CN, -N(R)₂, -OR, or optionally substituted with C_1–6 aliphatic;

X = H or halogen;

p = 0–4; and

q = 0–4.

Key Structures

Biological Assay

The standard TR-FRET screening RIPK2 inhibition assay was performed. The compounds described in this application were tested for their ability to inhibit RIPK2. The RIPK2 IC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for RIPK2 inhibition. The biological data obtained from testing representative examples are listed in the following table. For IC₅₀: “++++” means ≤10.0 nM; “+++” means 10.01–20.00 nM; “++” means 20.1–50.00 nM and “+” means ≥50.01 nM.

Claims

Total claims: 20

Compound claims: 15

Composition claims: 1

Use of compound claims: 4

Recent Review Articles

• 1.Cuny G. D.; Degterev A.. Semin. Cell Dev. Biol. 2020, in press.
• 2.Martens S.; Hofmans S.; Declercq W.; Augustyns K.; Vandenabeele P.. Trends Pharmacol. Sci. 2020, 41, 209.
• 3.Delanghe T.; Dondelinger Y.; Bertrand M. J. M.. Trends Cell Biol. 2020, 30, 189.
• 4.Roskoski R.Pharmacol. Res. 2019, 144, 19.
• 5.Jones L. H.Cell Chem. Biol. 2018, 25, 30.

The author declares no competing financial interest.