Diazepinone Compounds as Sppl2a Inhibitors for Treating Autoimmune Diseases and Lymphomas

Important Compound Classes

Title

Compounds and Compositions as Sppl2a Inhibitors

Patent Publication Number

WO 2022/058902 A1

URL:https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022058902

Publication Date

March 24, 2022

Priority Application

US 63/079,604

Priority Date

September 17, 2020

Inventors

Brandl, T.; Ehrhardt, C.; Epple, R.; Markert, C.; Rigollier, P.; Velcicky, J.

Assignee Company

Novartis AG, Switzerland

Disease Area

Autoimmune diseases and lymphomas

Biological Target

Sppl2a

Summary

The protein signal peptide peptidase-like protease 2a (Sppl2a) appears to play a role in innate and adaptive immunity by cleaving different transmembrane-anchored proteins and thereby affecting the function of a variety of immune cells. Sppl2a was initially described as the protease cleaving the membrane-spanning portion of TNF-α and thereby controlling the release of IL-12 from dendritic cells. Inhibition of this protease may be relevant for the repression of detrimental, uncontrolled immune responses, e.g., pathological conditions where autoantibodies might be critical to autoimmune diseases. Sppl2a inhibition might influence the proliferation of B-cell lymphomas.

The present application describes a series of novel diazepinone compounds as Sppl2a inhibitors for the treatment of autoimmune diseases and lymphomas. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

Y = CH₂ or C=O;

R₁ = H, C₁–C₆ alkyl or halogen; R₂ = H or halogen;

R₃ = H, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₃–C₆ cycloalkyl, C₁–C₆ alkyl-phenyl, or C₁–C₆ alkyl substituted with C₁–C₆ alkoxy;

R₄ = H, C₁–C₆ alkyl, or C₁–C₆alkyl-phenyl;

R₁₀ = -NHC(=O)R₅, -C(=O)NHR₅, or 9- or 10-membered bicyclic heteroaryl having 1–4 heteroatoms as ring members selected from N, O, and S, wherein the bicyclic heteroaryl is unsubstituted or the bicyclic heteroaryl is substituted with one or more R₆; and

R₁₁ = H, C₁–C₆ alkyl, or halogen.

Key Structures

Biological Assay

The Sppl2a TL assay was performed. The compounds described in this application were tested for their ability to inhibit Sppl2a. The Sppl2a IC₅₀ (μM) are shown in the table below.

Biological Data

The table below shows representative compounds tested for Sppl2a inhibition and the biological data obtained from testing representative examples.

Claims

Total claims: 19

Compound claims: 13

Pharmaceutical composition claims: 1

Method of treatment claims: 4

Combination claims: 1

The author declares no competing financial interest.