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INHIBITORS OF HEPATITIS C VIRUS POLYMERASE

The present invention provides, among other things, compounds represented by the general Formula (I) and pharmaceutically acceptable salts thereof, wherein X, Y, R1A, R1B, R2, and R3 are as defined in classes and sub-classes herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.

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Reference:
Thiazole | C3H9266NS – PubChem,
Thiazole | chemical compound | Britannica

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A mixed-spin spin-crossover thiozolylimine [Fe4L6]8+ cage

The self-assembly of a mixed-spin [Fe4L6]8+ tetrahedral cage is reported. The cage undergoes temperature induced spin-crossover with a 29 K hystereisis. Variable temperature X-ray photoelectron spectroscopy (VT-XPS), combined with SQUID data, allowed differentiation between the surface and bulk magnetic properties.

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Reference:
Thiazole | C3H9256NS – PubChem,
Thiazole | chemical compound | Britannica

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Disclosed are pyridinone compounds, method for preparing these compounds, and methods for treating fibrotic disorders.

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Thiazole | C3H9326NS – PubChem,
Thiazole | chemical compound | Britannica

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The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.

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Thiazole | C3H9257NS – PubChem,
Thiazole | chemical compound | Britannica

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The invention relates to synthesis of alpha-hydroxy carboxylic ester with 2-hydroxy propylene cyanide and corresponding aldehyde or ketone. The existing common alpha-hydroxy carboxylic ester generally needs superior cyan such as trimethylsilyl cyanide, and then hydrolysis is carried out on the cyan, so that the reaction operation is relatively complicated, and post treatment is a trouble. According to the method, 2-hydroxy propylene cyanide and corresponding aldehyde or ketone are mixed directly, 4-dimethylamino-pyridne of the catalysis amount is added, alcohol compound is taken as the solvent, and the product can be obtained by stirring for 10-120 minutes. The method for synthesizing the alpha-hydroxy carboxylic ester is safe and has high efficiency.

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Thiazole | C3H9281NS – PubChem,
Thiazole | chemical compound | Britannica

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New compounds containing [1,2,4]triazolo [1,5-a]pyridine (I), pyrazolo [1,5-a]pyridine (II), 1H-1,3-benzodiazole (III) and imidazo [1,2-a]pyrimidine (IV) backbones were designed and synthesized for PDE10A interaction. Among these compounds, 1H-1,3-benzodiazoles and imidazo [1,2-a]pyrimidines showed the highest affinity for PDE10A enzyme as well as good metabolic stability. Both classes of compounds were identified as selective and potent PDE10A enzyme inhibitors.

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Thiazole | C3H9313NS – PubChem,
Thiazole | chemical compound | Britannica

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A new type of chiral sulfonium salts that are characterized by a bicyclic system has been designed and synthesized from alpha-amino acids. Their corresponding ylides, which were prepared by basic treatment of the sulfonium salts, reacted smoothly with a broad array of simple and chiral aldehydes to provide trans-epoxy amides in reasonable to very good yields and excellent stereoselectivities (>98 %). The obtained epoxy amides were found to be useful as synthetic building blocks. Thus, they were reduced into their corresponding epoxy alcohols and subjected to oxirane-ring-opening reactions with different types of nucleophiles.

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Thiazole | C3H9356NS – PubChem,
Thiazole | chemical compound | Britannica

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Formyl-selective deuteration of aldehydes is of high interest for labeling purposes and for optimizing properties of drug candidates. Herein, we report a mild general method for formyl-selective deuterium labeling of aldehydes with D2O, an inexpensive deuterium source, via a synergistic combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and thiol catalysis. This highly efficient, scalable reaction showed excellent deuterium incorporation, a broad substrate scope, and excellent functional group tolerance and selectivity and is therefore a practical method for late-stage modification of synthetic intermediates in medicinal chemistry and for generating libraries of deuterated compounds.

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Thiazole | C3H9324NS – PubChem,
Thiazole | chemical compound | Britannica

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Due largely to the emergence of multi-drug-resistant HIV strains, the development of new HIV protease inhibitors remains a high priority for the pharmaceutical industry. Toward this end, we previously identified a 4-hydroxy-5,6-dihydropyrone lead compound (CI-1029, 1) which possesses excellent activity against the protease enzyme, good antiviral efficacy in cellular assays, and promising bioavailability in several animal species. The search for a suitable back-up candidate centered on the replacement of the aniline moiety at C-6 with an appropriately substituted heterocyle. In general, this series of heterocyclic inhibitors displayed good activity (in both enzymatic and cellular tests) and low cellular toxicity; furthermore, several analogues exhibited improved pharmacokinetic parameters in animal models. The compound with the best combination of high potency, low toxicity, and favorable bioavailabilty was (S)-3-(2-tertbutyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6- isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (13-(S)). This thiophene derivative also exhibited excellent antiviral efficacy against mutant HIV protease and resistant HIV strains. For these reasons, compound 13-(S) was chosen for further preclinical evaluation.

Due largely to the emergence of multi-drug-resistant HIV strains, the development of new HIV protease inhibitors remains a high priority for the pharmaceutical industry. Toward this end, we previously identified a 4-hydroxy-5,6-dihydropyrone lead compound (CI-1029, 1) which possesses excellent activity against the protease enzyme, good antiviral efficacy in cellular assays, and promising bioavailability in several animal species. The search for a suitable back-up candidate centered on the replacement of the aniline moiety at C-6 with an appropriately substituted heterocyle. In general, this series of heterocyclic inhibitors displayed good activity (in both enzymatic and cellular tests) and low cellular toxicity; furthermore, several analogues exhibited improved pharmacokinetic parameters in animal models. The compound with the best combination of high potency, low toxicity, and favorable bioavailabilty was (S)-3-(2-tertbutyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6- isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (13-(S)). This thiophene derivative also exhibited excellent antiviral efficacy against mutant HIV protease and resistant HIV strains. For these reasons, compound 13-(S) was chosen for further preclinical evaluation.

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Reference£º
Thiazole | C3H9325NS – PubChem,
Thiazole | chemical compound | Britannica

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A novel class of tetrahydro-pyrazinopyrimidine-2-carboxamides have been identified as HIV-1 integrase inhibitors. Optimization of the initial lead culminated in the discovery of a series of compounds with high potency on the enzyme and an antiviral cell-based activity equivalent to that showed by Raltegravir, the first in class HIV-1 integrase inhibitor.

A novel class of tetrahydro-pyrazinopyrimidine-2-carboxamides have been identified as HIV-1 integrase inhibitors. Optimization of the initial lead culminated in the discovery of a series of compounds with high potency on the enzyme and an antiviral cell-based activity equivalent to that showed by Raltegravir, the first in class HIV-1 integrase inhibitor.

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Reference£º
Thiazole | C3H9354NS – PubChem,
Thiazole | chemical compound | Britannica