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Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (HBV)

A C1-C4-, C1-C6-technology, applied in the field of new antiviral agents, can solve problems such as poor efficacy, difficult synthesis, and mutagenicity

Pending Publication Date: 2021-06-25
AICURIS GMBH & CO KG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] Problems that may be encountered with antiviral drugs that act directly on HBV are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, low solubility and difficulty in synthesis

Method used

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  • Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (HBV)
  • Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (HBV)
  • Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (HBV)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0454] 2-Amino-N-(3-chloro-4-fluorophenyl)-4H,5H,6H,7H-[1,3]thiazolo[5,4-c]pyridine-5-carboxamide

[0455]

[0456] Rt (Method A) 2.95mins, m / z 327 / 329[M+H]+

[0457] 1 H NMR (400MHz, DMSO-d6) δ8.79 (s, 1H), 7.75 (dd, J = 6.9, 2.6Hz, 1H), 7.42 (ddd, J = 9.1, 4.4, 2.7Hz, 1H), 7.29 ( t, J = 9.1 Hz, 1H), 6.82 (s, 2H), 4.47-4.40 (m, 2H), 3.75-3.67 (m, 2H), 2.56-2.51 (m, 2H).

Embodiment 2

[0459]N-(3-chloro-4-fluorophenyl)-2-{[(1r,3r)-3-hydroxycyclobutyl]amino}-4H,5H,6H,7H-[1,3]thiazolo[ 5,4-c]pyridine-5-carboxamide

[0460]

[0461] Step 1: To tert-butyl 2-(((1r,3r)-3-hydroxycyclobutyl)amino)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (1.77 g, 5.44 mmol) was added 4M HCl in dioxane (15 mL, 60 mmol). The mixture was stirred at room temperature for 4 hours, then concentrated in vacuo. The residue was washed with toluene (twice) and CH 2 Cl 2 Stripping gave 1.54 g of a white solid which was used without further purification.

[0462] Step 2: To (1r,3r)-3-((4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)amino)cyclobutan-1-ol hydrochloride (50 mg, 0.191 mmol) and DIPEA (0.167 mL, 0.955 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added 2-chloro-1-fluoro-4-isocyanatobenzene ( 0.024 mL, 0.191 mmol). The mixture was stirred at r.t. for 30 minutes, then water was added. The product was extracted with EtOAc (2x4mL), and the combined organic ext...

Embodiment 3

[0466] N-(3-chloro-4-fluorophenyl)-2-{[1-(hydroxymethyl)cyclobutyl]amino}-4H,5H,6H,7H-[1,3]thiazolo[5, 4-c]pyridine-5-carboxamide

[0467]

[0468] Rt (Method A) 3.15mins, m / z 411 / 413[M+H]+

[0469] 1 H NMR (400MHz, DMSO-d6) δ8.81(s, 1H), 7.75(dd, J=6.9, 2.6Hz, 1H), 7.57(s, 1H), 7.45-7.39(m, 1H), 7.29( t,J=9.1Hz,1H),4.96(t,J=5.6Hz,1H),4.46-4.41(m,2H),3.75-3.67(m,2H),3.62(d,J=5.6Hz,2H ), 2.55-2.51(m,2H), 2.14-2.04(m,4H), 1.89-1.75(m,1H), 1.75-1.65(m,1H).

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PUM

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Abstract

The present invention relates generally to novel antiviral agents. Specifically, the present invention relates to compounds which can inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV replication cycle, compositions comprising such compounds, methods for inhibiting HBV viral replication, methods for treating or preventing HBV infection, and processes and intermediates for making the compounds.

Description

technical field [0001] The present invention generally relates to novel antiviral agents. Specifically, the present invention relates to compounds that can inhibit proteins encoded by hepatitis B virus (HBV) or interfere with the function of the HBV replication cycle, compositions comprising such compounds, methods for inhibiting HBV viral replication, and treatment or prevention of HBV infection and methods of making said compounds. Background technique [0002] Chronic HBV infection is a serious global health problem, affecting more than 5% of the world's population (more than 350 million people worldwide, 1.25 million people in the United States). Despite the availability of a prophylactic HBV vaccine, the burden of chronic HBV infection remains a major unresolved worldwide medical problem due to suboptimal standard treatment options and persistent rates of new infections in most parts of the developing world . Current treatments offer no cure and are limited to only t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04A61K31/437A61P31/20
CPCC07D513/04A61P31/20A61K31/437
Inventor 阿拉斯泰尔·唐纳德安德烈亚斯·乌尔班苏珊娜·邦斯曼
Owner AICURIS GMBH & CO KG