1092953-04-2

Upstream product

• 1092952-98-1 ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate 
• 141-97-9 ethyl acetoacetate 
• 59142-68-6 2-bromo-4-fluorobenzaldehyde 

Downstream Products

• 1092970-12-1 ethyl (R,S)-6-(2-bromo-4-fluorophenyl)-4-(morpholinomethyl)-2-(thiazol-2-yl)-1,6-dihydropyrimidine-5-carboxylate 
• 1571212-16-2 3-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-3-yl)propanoic acid 
• 1571214-87-3 2-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)acetic acid 
• 1571212-14-0 2-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-3-yl)acetic acid 
• 1571211-95-4 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-2-carboxylic acid 
• 1571219-25-4 ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-2-(hydroxymethyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate 
• 1571217-89-4 ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-(methylcarbamoyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate 
• 1571214-96-4 isopropyl 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-yl)methyl)morpholine-3-carboxylate 

Relevant academic research and scientific papers

Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors

GLS4, a potent antiviral drug candidate, has been widely studied and entered into phase II clinical trials. Nevertheless, the therapeutic application of GLS4 is limited due to poor water solubility, short half-life, and low bioavailability. In order to improve the hydrophilicity and pharmacokinetic (PK) properties of GLS4, herein, we retained the dominant fragments, and used a scaffold hopping strategy to replace the easily metabolized morpholine ring of GLS4 with diverse sizes of spiro rings consisting of hydrogen bond donor and acceptor substituents. Potent in vitro anti-HBV activity and low cytotoxicity were observed for compound 4r (EC50 = 0.20 ± 0.00 μM, CC50 > 87.03 μM), which was more potent than the positive control lamivudine (EC50 = 0.37 ± 0.04 μM, CC50 > 100.00 μM) in this assay and was about a quarter as effective as GLS4 (EC50 = 0.045 ± 0.01 μM, CC50 > 99.20 μM). Preliminary structure-activity relationship (SAR) analysis and molecular docking studies were carried out to explore potential interactions and binding mode between compounds and target protein. In terms of the physicochemical properties, 4r was predicted to be consistent with the rule-of-five, which means 4r may have favourable absorption and permeation. Finally, ADMET and PK characteristics of 4r and GLS4 were predicted to be comparable in most aspects, implying that the two compounds may have similar profiles in vivo.

Dihydropyrimidine-spiro derivative as well as preparation method and application thereof

The invention provides a dihydropyrimidine-spiro derivative as well as a preparation method and application thereof. The compound has a structure as shown in a formula I. The invention further relates to a preparation method of the compound with the structure shown in the formula I, a pharmaceutical composition and application of the compound in preparation of anti-HBV drugs.

Dihydropyrimidine-pomalidomide conjugate as well as preparation method and application thereof

The invention provides a dihydropyrimidine-pomalidomide conjugate as well as a preparation method and application thereof. The conjugate has a structure as shown in a formula I. The invention further relates to a preparation method of the compound with the structure as shown in the formula I, a pharmaceutical composition and application of the compound in preparation of anti-HBV drugs.

Design, synthesis, and evaluation of novel heteroaryldihydropyrimidine derivatives as non-nucleoside hepatitis B virus inhibitors by exploring the solvent-exposed region

In continuation of our efforts toward the discovery of potent non-nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have explored the solvent-exposed protein region of heteroaryldihydropyrimidine derivatives. Herein, the morpholine ring of GLS4 was replaced with substituted sulfonamides and triazoles to generate novel non-nucleoside HBV inhibitors with desirable potency. In in vitro biological evaluation, several derivatives showed good anti-HBV DNA replication activity compared to lamivudine. In particular, compound II-1 displayed the most potent activity against HBV DNA replication (IC50?=?0.35?±?0.04?μM). The preliminary structure–activity relationships of the new compounds were summarized, which may help in discovering more potent anti-HBV agents via rational drug design.

Dihydropyrimidine prodrug, preparation method and applications thereof

The invention discloses a dihydropyrimidine prodrug, a preparation method and applications thereof, wherein the compound has a structure defined in the specification. The invention further relates toa preparation method of the compound, a pharmaceutical composition, and applications of the compound in the preparation of anti-HBV drugs.

3-((R)-4-(((R)-6-(2-Bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic Acid (HEC72702), a Novel Hepatitis B Virus Capsid Inhibitor Based on Clinical Candidate GLS4

The inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. On the basis of the preclinical properties and clinical results of GLS4, we carried out further investigation to seek a better candidate compound with appropriate anti-HBV potency, reduced hERG activity, decreased CYP enzyme induction, and improved pharmacokinetic (PK) properties. To this end, we have successfully found that morpholine carboxyl analogues with comparable anti-HBV activities to that of GLS4 showed decreased hERG activities, but they displayed strong CYP3A4 induction in a concentration-dependent manner, except for morpholine propionic acid analogues. After several rounds of modification, compound 58 (HEC72702), which had an (R)-morpholine-2-propionic acid at the C6 position of its dihydropyrimidine core ring, was found to display no induction of the CYP1A2, CYP3A4, or CYP2B6 enzyme at the high concentration of 10 μM. In particular, it demonstrated a good systemic exposure and high oral bioavailability and achieved a viral-load reduction greater than 2 log in a hydrodynamic-injected (HDI) HBV mouse model and has now been selected for further development.

Dihydropyrimidine-sulfonamide derivative and preparation method and application thereof

The invention discloses a dihydropyrimidine-sulfonamide derivative and a preparation method and an application thereof. The compound has a structure shown in a formula I. The invention further relatesto the preparation method of the compound containing the structure of the formula I and a pharmaceutical composition, and provides the application of the compound in preparation of an anti-HBV drug.

Dihydropyrimidine-phosphoramide derivative, and preparation method and application thereof

The invention discloses a dihydropyrimidine-phosphoramide derivative, and a preparation method and an application thereof. The above compound has a structure represented by formula I. The invention also relates to the preparation method of the compound represented by formula I, a medicinal composition containing the compound, and the application of the compound in the preparation of anti-HBV drugs.

DIHYDROPYRIMIDO LOOP DERIVATIVE AS HBV INHIBITOR

Disclosed is a dihydropyrimido fused ring derivative as a HBV inhibitor, and in particular relates to a compound shown as formula (I) or a pharmaceutically acceptable salt thereof.

Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4)

Inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. Herein we described our lead optimization studies including the synthesis, molecular docking studies and structure-activity relationship (SAR) studies of a series of novel heteroaryldihydropyrimidine (HAP) inhibitors of HBV capsid assembly inhibitors, and the discovery of a potent inhibitor of HBV capsid assembly of GLS4 (ethyl 4-[2-bromo-4-fluorophenyl]-6-[morpholino-methyl]-2-[2-thiazolyl]-1,4-dihydro-pyrimidine-5-carboxylate) which is now in clinical phase 2. GLS4 demonstrated potent inhibitory activities in HBV HepG2.2.15 cell assay with an EC50value of 1 nM, and it also exhibited high potency against various drug-resistant HBV viral strains with EC50values in the range of 10–20 nM, more potent than the typical HBV polymerase inhibitors such as lamivudine, telbivudine, and entecavir. Pharmacokinetic profiles of GLS4 were favorable and safety evaluation including acute toxicity and repeated toxicity study indicated that GLS4 was safe enough to support clinical experiments in human.