Important Compound Classes
Title
Substituted 3,4-Dihydroquinazoline for the Treatment and Prophylaxis of Hepatitis B Virus Infection
Patent Publication Number
WO 2021/063856 A1
Publication Date
April 8, 2021
Priority Application
CN PCT/CN2019/109510
Priority Date
September 30, 2019
Inventors
Chen, D.; Chen, W.; Feng, S.; Li, C.; Qiu, Z.; Tan, X.; Wu, G.
Assignee Company
F. Hoffmann-La Roche AG, Switzerland and Hoffmann-La Roche Inc., USA
Disease Area
Hepatitis B virus infection
Biological Target
cccDNA (covalently closed circular DNA)
Summary
Hepatitis B virus (HBV) infection is one of the most prevalent viral infections and is a leading cause of chronic hepatitis. It is estimated that worldwide, around 2 billion people have evidence of past or present infection with HBV. Over 250 million individuals are currently chronically infected with HBV and are therefore at high risk to develop liver fibrosis, cirrhosis, and hepatocellular carcinoma. Many countries in the world administer the hepatitis B vaccine at birth or in early childhood. However, the vaccine has no impact on people who were infected before the wide use of vaccine.
HBV chronic infection is caused by the persistence of covalently closed circular DNA (cccDNA), which exists as an episomal form in hepatocyte nuclei. cccDNA serves as the template for viral RNA transcription and subsequent viral DNA generation. Only a few copies of cccDNA per liver cell can establish or reinitiate viral replication. Therefore, a complete cure for chronic hepatitis B will require the elimination of cccDNA or the permanent silencing of cccDNA. However, cccDNA is intrinsically very stable, and the currently available therapeutics cannot eliminate cccDNA or permanently silence cccDNA.
The present application describes a series of novel substituted 3,4-dihydroquinazoline derivatives as inhibitors of cccDNA (covalently closed circular DNA) that are useful for the treatment of Hepatitis B virus infection. Furthermore, the application discloses the compounds and their preparation, use, pharmaceutical composition, and treatment.
Definitions
R1 = H, halogen, C1–6alkyl, or haloC1–6alkyl;
R2 = H, halogen, C1–6alkyl, or haloC1–6alkyl;
R3 = H, carboxy, C1–6alkyl, haloC1–6alkyl, hydroxyC1–6alkyl, C1–6alkoxycarbonyl, C3–7cycloalkyl, aminocarbonyl, hydroxyC1–6alkylaminocarbonyl, or heterocyclylcarbonyl;
R4 = H or C1–6alkyl;
R5 = H, C1–6alkyl, or hydroxyC1–6alkyl; and
R6 = phenyl or heterocyclyl; wherein phenyl or heterocyclyl is unsubstituted or substituted by one, two, or three substituents independently selected from halogen, C1–6alkyl, C1–6alkoxy, hydroxyC1–6alkoxy, C1–6alkoxycarbonylphenyl, carboxyC1–6alkoxyC1–6alkoxy, carboxyC3–7cycloalkylC1–6alkoxy, and heterocyclyl.
Key Structures
Biological Assay
The Engineered HepDES19 primary screen assay was performed. The assay was employed to screen for novel cccDNA inhibitors. HepDES19 is a cccDNA-producing cell line. The compounds described in this application were tested for their ability to inhibit HepDES19 (cccDNA). The HepDES19 IC50 (μM) values are shown in the following Table.
Biological Data
The Table below shows representative compounds that were tested for HepDES19 inhibition. The biological data obtained from testing the representative examples are listed in the following Table.
Claims
Total claims: 25
Compound claims: 16
Pharmaceutical composition claims: 1
Method of treatment claims: 1
Method of preparation claims: 1
Use of compound claims: 6
Recent Review Articles
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Tsukuda S.; Watashi K.. Antiviral Res. 2020, 182, 104925.
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Martinez M. G.; Villeret F.; Testoni B.; Zoulim F.. Liver Int. 2020, 40 (Suppl. 1), 27..
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Liao Z.; Jiang W.; Ye L.; Li T.; Yu X.; Liu L.. Biochim. Biophys. Acta, Rev. Cancer 2020, 1874, 188392.
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Xia Y.; Guo H.. Antiviral Res. 2020, 180, 104824.
The author declares no competing financial interest.