Novel Compounds as STING Modulators for Treating Hepatitis B Virus Infections

Important Compound Classes

Title

Chemical Compounds

Patent Publication Number

WO 2020/202091 A1

Publication Date

October 8, 2020

Priority Application

US 62/830,111, US 62/938,846, and US 62/938,946

Priority Date

April 5, 2019, November 21, 2019, and November 21, 2019

Inventors

King, B. W.; Peat, A. J.; Pero, J. E.; Spletstoser, J. T.; Li, P.

Assignee Company

GlaxoSmithKline Intellectual Property Development Limited, Great Britain

Disease Area

Hepatitis B virus infections

Biological Target

STING (Stimulator of Interferon Genes) proteins

Summary

Hepatitis B is a viral disease transmitted parenterally by contaminated material such as blood and blood products and contaminated needles and sexually and vertically from infected or carrier mothers to their offspring. Hepatitis B virus (HBV) is the second most significant carcinogen behind tobacco, causing from 60% to 80% of all primary liver cancer. HBV is 100 times more contagious than HIV. Hepatitis B viral infections are a continuing medical problem.

Interferon was first described as a substance which could protect cells from viral infections. The adaptor protein STING (Stimulator of Interferon Genes) has been identified as a central signaling molecule in the innate immune response to cytosolic nucleic acids. STING is critical for responses to cytosolic DNA of pathogen or host origin and of unusual nucleic acids called Cyclic Dinucleotides (CDNs). Targeting STING with small molecules may be a promising new approach for treating hepatitis B virus infections.

The present application describes a series of novel STING modulators and is useful for treatment of Hepatitis B virus infections. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

A is C₂–C₆alkyl or C₂–C₆alkenyl, wherein C₂–C₆alkyl or C₂–C₆alkenyl is independently optionally substituted by 1–2 substituents selected from -R_c, OH, and -OR_c;

R₁ and R₂ are independently absent or C₂–C₆alkenyl;

W₁, X₁, Y₁, and Z₁ are each independently -CR₃, -CR_3′, -CR_3′′, -CR_3′′′, or N, with the proviso that no more than two of W₁, X₁, Y₁, and Z₁ may be N;

W₂, X₂, Y₂, and Z₂ are each independently -CR₄, -CR_4′, -CR_4′′, -CR_4′′′, or N, with the proviso that no more than two of W₁, X₁, Y₁, and Z₁ may be N;

R₃, R_3′, R_3′′, R_3′′′, R₄, R_4′, R_4′′, R_4′′′, R₉, R₁₀, R₁₁, and R₁₂ are each independently selected from H, C₁–C₄alkoxyl, C₁–C₄alkyl, -COO-C₁–C₄alkyl, C_4–7heterocycloalkyl, -C₁–C₄alkylC_4–7heterocycloalkyl, and -OC₁–C₄alkylC_4–7heterocycloalkyl, wherein the C_4–7heterocycloalkyl of the C₁–C₄alkylC_4–7heterocycloalkyl, or the OC_4–7heterocycloalkyl of the C₁–C₄alkylC_4–7heterocycloalkyl comprises one or more heteroatoms selected from O and N, wherein the C_4–7heterocycloalkyl, the C_4–7heterocycloalkyl of the C₁–C₄alkylC_4–7heterocycloalkyl, the C_4–7heterocycloalkyl of the -OC₁–C₄alkylC_4–7heterocycloalkyl is substituted by 1–4 substituents R_′, R_′′, R_′′′, and R_′′′′, wherein R_′, R_′′, R_′′′, and R_′′′′ are each independently selected from -R_c, OH, and -OR_c;

R₅ and R₆ are independently C₁–C₄alkyl;

R₇ and R₈ are independently H or C₁–C₄alkyl;

R_c is independently C₁–C₄alkyl optionally substituted by a substituent selected from -OH or C₁–C₄alkoxyl.

Key Structures

Biological Assay

PBMC agonist assay and STING FRET assay were performed. The compounds described in this application were tested for their ability to modulate PBMC and STING. PBMC agonist EC₅₀ (nM) and STING FRET IC₅₀ (μM) values are shown in the following table.

Biological Data

The table below shows representative compounds were tested for PBMC and STING modulation. The biological data obtained from testing representative examples are listed in the following table.

For PBMC agonist assay: EC₅₀: “+++++” means <1 nM; “++++” means 1 nM to <10 nM; “+++” means 10 nM to <100 nM; “++” means 100 nM to <500 nM and “+” means ≥500 nM.

For STING FRET assay: IC₅₀: “+++++” means <1 nM; “++++” means 1 nM to <10 nM; “+++” means 10 nM to <100 nM; “++” means 100 nM to <500 nM and “+” means ≥500 nM.

Claims

Total claims: 22

Compound claims: 15

Method of inhibition claims: 1

Method of treatment claims: 1

Method of reduction claims: 2

Method of promotion claims: 1

Use of compound claims: 2

Recent Review Articles

• 1.Zhang H.; You Q.; Xu X.. J. Med. Chem. 2020, 63, 3785.
• 2.Feng X.; Liu D.; Li Z.; Bian J.. Drug Discovery Today 2020, 25, 230.
• 3.Liu K.; Lan Y.; Li X.; Li M.; Cui L.; Luo H.; Luo L.. Biomed. Pharmacother. 2020, 132, 110945.
• 4.Sun Y.; Cheng Y.. Trends Parasitol. 2020, 36, 773.
• 5.Cui X.; Zhang R.; Cen S.; Zhou J.. Eur. J. Med. Chem. 2019, 182, 111591.

The author declares no competing financial interest.