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Discovery and in Vivo Evaluation of the Potent and Selective PI3Kdelta Inhibitors 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430)

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kdelta inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.

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Development of dual casein kinase 1delta/1epsilon (CK1delta/epsilon) inhibitors for treatment of breast cancer

Casein kinase 1delta/epsilon have been identified as promising therapeutic target for oncology application, including breast and brain cancer. Here, we described our continued efforts in optimization of a lead series of purine scaffold inhibitors that led to identification of two new CK1delta/epsilon inhibitors 17 and 28 displaying low nanomolar values in antiproliferative assays against the human MDA-MB-231 triple negative breast cancer cell line and have physical, in vitro and in vivo pharmacokinetic properties suitable for use in proof of principle animal xenograft studies against human cancers.

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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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NOVEL INHIBITOR COMPOUNDS OF PHOSPHODIESTERASE TYPE 10A

The present invention relates to novel compounds of the formula I which are inhibitors of phosphodiesterase type 10A and to their use for the manufacture of a medicament and which thus are suitable for treating or controlling of medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders

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PYRIDIN-3-YL ACETIC ACID DERIVATIVES AS INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION

Disclosed are compounds of Formula I, including pharmaceutically acceptable salts, pharmaceutical compositions comprising the compounds, methods for making the compounds and their use in inhibiting HIV integrase and treating those infected with HIV or AIDS. (I)

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HETEROCYCLIC COMPOUNDS AS PI3K-y INHIBITORS

This application relates to compounds of Formula (I): or pharmaceutically acceptable salts or stereoisomers thereof, which are inhibitors of PI3K-gamma which are useful for the treatment of disorders such as autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.

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DIPEPTIDE ANALOGS AS COAGULATION FACTOR INHIBITORS

Disclosed are novel dipeptide analogs compounds of Formula (I), (II) or (III) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof, which are inhibitors of factor XIa and/or plasma kallikrein, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of thrombotic diseases.

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FLUOROPHENYL BICYCLIC HETEROARYL COMPOUNDS

The present invention provides a compound of formula (I); a method for manufacturing the compounds of the invention, and its use as a IGF-1R inhibitor. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition

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HETEROCYCLIC COMPOUND

The present invention provides an agent for the prophylaxis or treatment of autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren’s syndrome, Behcet’s disease, multiple sclerosis, systemic lupus erythematosus etc.) and the like, which has a superior Tyk2 inhibitory action. The present invention relates to a compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof.

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Brief introduction of (R)-4-(tert-Butoxycarbonyl)thiomorpholine-3-carboxylic acid

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Chemistry is the experimental and theoretical study of materials on their properties at both the macroscopic and microscopic levels. 114525-81-4. In a patent£¬Which mentioned a new discovery about 114525-81-4, molcular formula is C10H17NO4S, introducing its new discovery.

MODULATORS OF THE G PROTEIN-COUPLED MAS RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO

The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof that are useful in methods of treatment and alleviation of diseases and disorders of the heart, brain, kidney, immune, and reproductive system resulting from ischemia, or reperfusion subsequent to ischemia, and any downstream complication(s) related thereto. The present invention further relates to methods of treatment and alleviation of diseases and disorders of the vasculature resulting from vasoconstriction or hypertension and any downstream complications resulting from elevated blood pressure and/or reduced tissue perfusion

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Thiomorpholine – Wikipedia,
Thiomorpholine | C4H9NS – PubChem