Novel Triazatricycle Compounds for Treating Autoimmune Diseases

Important Compound Classes

Title

Triazatricycle Compounds for the Treatment of Autoimmune Disease

Patent Publication Number

WO 2021/099285 A1

Publication Date

May 27, 2021

Priority Application

CN PCT/CN2019/119511

Priority Date

November 19, 2019

Inventors

Dey, F.; Shen, H.; Xu, H.; Zhu, W.; Zhou, G.

Assignee Company

F. Hoffmann-La Roche AG, Switzerland and Hoffmann-La Roche Inc., USA

Disease Area

Autoimmune diseases

Biological Target

TLR7, TLR8, and TLR9

Summary

Autoimmune connective tissue disease (CTD) include prototypical autoimmune syndromes such as Systemic Lupus Erythematosus (SLE), primary Sjogren’s syndrome (pSjS), mixed connective tissue disease, dermatomyositis/polymyositis (DM/PM), rheumatoid arthritis (RA), and systemic sclerosis (SSc). With the exception of RA, effective and safe therapies are not available to the patients.

Toll Like Receptors (TLRs) are an important family of pattern recognition receptors (PRR), which can initiate broad immune responses in a wide variety of immune cells. As natural host defense sensors, endosomal TLR7, -8, and -9 recognize nucleic acids derived from viruses and bacteria; specifically, TLR7/8 and TLR9 recognize single-stranded RNA (ssRNA) and single-stranded CpG-DNA, respectively. However, the aberrant nucleic acid-sensing of TLR7, -8, and -9 is considered vital in the broad spectrum of autoimmune and autoinflammatory diseases. Consistently, in lupus mouse models, TLR7 is required for anti-RNA antibodies, and TLR9 is required for antinucleosome antibody. Taken together, TLR7, -8, and -9 pathways represent new therapeutic targets for the treatment of autoimmune disease, for which no effective steroid-free and noncytotoxic oral drugs exist.

The present application describes a series of novel triazatricycle compounds as TLR7, -8, and -9 inhibitors that are useful for treatment of autoimmune diseases, which include systemic lupus erythematosus or lupus nephritis. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₄ = C_1–6alkyl, C_1–6alkoxy, haloC_1–6alkyl, halogen, nitro or cyano;

R_4a = C_1–6alkyl, C_3–7cycloalkyl;

R₅, R_5a and R_5b = H and deuterium;

R₆ = H or halogen;

R₂ = H or C_1–6alkyl;

R₃ = 5–7 membered monocyclic aryl or heteroaryl, heteroaryloxy or 7–12 membered bicyclic heterocyclyl; and

X = CH and Y = N; or X = N and Y = CH.

Key Structures

Biological Assay

HEK293-Blue-hTLR-7 cell assay, HEK293-Blue-hTLR-8 cell assay, and HEK293-Blue-hTLR-9 cell assay were performed. The compounds described in this application were tested for their ability to inhibit TLR7, -8, and -9. The HEK/hTLR7 IC₅₀ (nM), HEK/hTLR8 IC₅₀ (nM), and HEK/hTLR9 IC₅₀ (nM) are shown in the following Table.

Biological Data

The Table below shows representative compounds were tested for TLR7, -8, and -9 inhibition. The biological data obtained from testing representative examples are listed in the following Table.

Claims

Total claims: 22

Compound claims: 15

Pharmaceutical composition claims: 1

Method of treatment claims: 1

Method of preparation claims: 1

Use of compound claims: 4

Recent Review Articles

• 1.Wang X.; Liu Y.; Han X.; Zou G.; Zhu W.; Shen H.; Liu H.. Bioorg. Med. Chem. Lett. 2021, 44, 128101.
• 2.Asami J.; Shimizu T.. Protein Sci. 2021, 30, 761.
• 3.Federico S.; Pozzetti L.; Papa A.; Carullo G.; Gemma S.; Butini S.; Campiani G.; Relitti N.. J. Med. Chem. 2020, 63, 13466.
• 4.Patinote C.; Karroum N. B.; Moarbess G.; Cirnat N.; Kassab I.; Bonnet P.; Deleuze-Masquefa C.. Eur. J. Med. Chem. 2020, 193, 112238.
• 5.Patra M. C.; Shah M.; Choi S.. Semin. Cancer Biol. 2020, 64, 61.
• 6.Dvornikova K. A.; Bystrova E. Y.; Platonova O. N.; Churilov L. P.. Autoimmun. Rev. 2020, 19, 102496.

The author declares no competing financial interest.