Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug

This paper describes the efficient scale-up synthesis of the potent negative allosteric glutamate N2B (GluN2B) inhibitor <b>1</b> (BMS-986169), which relies upon a stereospecific S_N2 alkylation strategy and a robust process for the preparation of its phosphate prodrug <b>28</b> (BMS-986163) from parent <b>1</b> using POCl₃. A deoxyfluorination reaction employing bis­(2-methoxyethyl)­aminosulfur trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce a fluorine substituent. The optimized routes have been demonstrated to provide APIs suitable for toxicological studies in vivo

Discovery of Potent Heterodimeric Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Sustained Antitumor Activity

The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds <b>15</b> and <b>17</b> further demonstrate curative efficacy in human melanoma and lung cancer xenograft models and are promising candidates for advanced studies

Discovery of Potent Heterodimeric Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Sustained Antitumor Activity

The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds <b>15</b> and <b>17</b> further demonstrate curative efficacy in human melanoma and lung cancer xenograft models and are promising candidates for advanced studies

Discovery of a Potent and Orally Bioavailable Dual Antagonist of CC Chemokine Receptors 2 and 5

We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a γ-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of <b>13d</b>, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation

Discovery of 6‑Fluoro-5‑(<i>R</i>)‑(3‑(<i>S</i>)‑(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4<i>H</i>)‑yl)-2-methylphenyl)-2‑(<i>S</i>)‑(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro‑1<i>H</i>‑carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure–activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, <b>14f</b> (BMS-986142) was advanced into clinical studies