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(1aR,12bS)-8-cyclohexyl-11-fluoro-N-((1-methylcyclopropyl)sulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,2b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide for use in treating HCV

The invention relates to an administration unit comprising a compound of formula and/or pharmaceutically acceptable salts thereof, and to a packaging comprising the administration unit according to the invention.

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INHIBITORS OF HEPATITIS C VIRUS

The present application includes novel inhibitors of HCV, compositions containing such compounds, therapeutic methods that include the administration of such compounds.

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Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an alpha-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere

Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an alpha-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.

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COMPOUNDS

The present invention features compounds of Formula (I) and (Ia), pharmaceutical compositions and use in the treatment of viral disease:

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NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS

The present invention discloses compounds according to Formula I: Wherein R 1a, R 1b, R 2, R 4, R5, R 6, R 7, R 8, W, X, Y, Z, Cy, and the subscript a are as defined herein. The present invention relates to compounds inhibiting autotaxin (NPP2 or ENPP2), methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of diseases involving fibrotic diseases,proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases by administering the compound of the invention.

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PYRIMIDOPYRIMIDINONES USEFUL AS WEE-1 KINASE INHIBITORS

The present invention relates to compounds that are useful as inhibitors of the activity of Wee-1 kinase. The present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds in the treatment of cancer and methods of treating cancer.

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HETEROCYCLIC COMPOUND

Provided is a compound or a salt thereof, which has an excellent JAK inhibitory action, and is useful as a prophylactic or therapeutic agent for autoimmune diseases (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren’s syndrome, Behcet’s syndrome, multiple sclerosis, systemic lupus erythematosus, etc.), cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis, etc.) and the like. The present invention relates to a compound represented by the formula (I) wherein each symbol is as defined in the present specification, or a salt thereof.

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Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode

With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations.

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Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.

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PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA

Provided are compounds of formula (I) or a pharmaceutically acceptable salts or stereoisomer thereof, which are PI3K-delta inhibitors, and are useful for the treatment of PI3K-delts-mediated diseases such as inflammation, asthma, COPD and cancer.

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