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Structure-based design of orally bioavailable 1 h -Pyrrolo[3,2- C ]pyridine inhibitors of mitotic kinase monopolar spindle 1 (MPS1)

The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.

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METHODS FOR THE TREATMENT OF CARDIOVASCULAR DISORDERS

The present invention discloses compounds according to Formula (I): or a pharmaceutically acceptable salt thereof, or a solvate or the salt of a solvate thereof, pharmaceutical compositions comprising the same, and methods of treatment using the same, for use in the prophylaxis and/or treatment of cardiovascular disorders and/or dyslipidemia, by administering the compound according to Formula (I).

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Parallel synthesis and structure-activity relationships of a series of highly potent, selective, and neutral factor Xa inhibitors

Parallel synthesis and iterative optimization led to the discovery of a series of potent and specific factor Xa inhibitors demonstrating excellent in vitro activity with promising pharmacokinetics.

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CYCLOHEXYLPYRAZOLE-LACTAM DERIVATIVES AS INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE 1

The present invention discloses novel compounds of Formula (I): having 11beta-HSD type 1 antagonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compound

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Optimization of Isothiazolo[4,3- b]pyridine-Based Inhibitors of Cyclin G Associated Kinase (GAK) with Broad-Spectrum Antiviral Activity

There is an urgent need for strategies to combat dengue and other emerging viral infections. We reported that cyclin G-associated kinase (GAK), a cellular regulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, regulates intracellular trafficking of multiple unrelated RNA viruses during early and late stages of the viral lifecycle. We also reported the discovery of potent, selective GAK inhibitors based on an isothiazolo[4,3-b]pyridine scaffold, albeit with moderate antiviral activity. Here, we describe our efforts leading to the discovery of novel isothiazolo[4,3-b]pyridines that maintain high GAK affinity and selectivity. These compounds demonstrate improved in vitro activity against dengue virus, including in human primary dendritic cells, and efficacy against the unrelated Ebola and chikungunya viruses. Moreover, inhibition of GAK activity was validated as an important mechanism of antiviral action of these compounds. These findings demonstrate the potential utility of a GAK-targeted broad-spectrum approach for combating currently untreatable emerging viral infections.

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Indazole derivatives for use in the treatment of influenza virus infection

The present invention is directed to compounds for use in the treatment or prevention of influenza virus infection.

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Evaluation and optimization of synthetic routes from dihydroartemisinin to the alkylamino-artemisinins artemiside and artemisone: A test of N-glycosylation methodologies on a lipophilic peroxide

10-Alkylamino-artemisinins including artemiside and artemisone display enhanced activities against malaria. Earlier, dihydroartemisinin (DHA) TMS ether was converted by trimethylsilyl bromide into the 10-beta-bromide that with amine nucleophiles provided the amino-artemisinins. In an attempt to develop more economic approaches, direct N-glycosylation of DHA was examined but 2-deoxyartemisinin was invariably obtained. However, hydroxyl group activation by conversion into the 10beta-halide in non-polar solvents with anhydrous HCl and Group I and II metal halides, oxalyl chloride or thionyl chloride with catalytic DMSO, and oxalyl bromide did succeed. The beta-halides were converted in situ by thiomorpholine into artemiside, and by thiomorpholine-1,1-dioxide into artemisone respectively in scalable reactions. Hydrogen peroxide-acetonitrile or the urea-hydrogen peroxide complex efficiently oxidized the sulfide artemiside to the sulfone artemisone. Overall, a generalized approach to 10-alkylamino-artemisinins is now available.

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NEW TETRACYCLIC COMPOUNDS

This disclosure relates to new tetracyclic compounds that may be used to modulate a histamine receptor in an individual. The compounds in one embodiment are tetracyclic [4,3- b]indoles. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

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THIAZOLE AND OXAZOLE KINASE INHIBITORS

The present invention provides thiazole and oxazole compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents

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1,2,3-Triazole-containing hybrids as potential anticancer agents: Current developments, action mechanisms and structure-activity relationships

Anticancer agents are critical for the cancer treatment, but side effects and the drug resistance associated with the currently used anticancer agents create an urgent need to explore novel drugs with low side effects and high efficacy. 1,2,3-Triazole is privileged building block in the discovery of new anticancer agents, and some of its derivatives have already been applied in clinics or under clinical trials for fighting against cancers. Hybrid molecules occupy an important position in cancer control, and hybridization of 1,2,3-triazole framework with other anticancer pharmacophores may provide valuable therapeutic intervention for the treatment of cancer, especially drug-resistant cancer. This review emphasizes the recent advances in 1,2,3-triazole-containing hybrids with anticancer potential, covering articles published between 2015 and 2019, and the structure-activity relationships, together with mechanisms of action are also discussed.

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