Practical Synthesis of A Macrocyclic HCV Protease Inhibitor: A High-Yielding Macrolactam Formation

A practical synthesis of a macrocyclic HCV protease inhibitor, MK-1220, is described. The key features are a new synthesis of the trisubstituted isoquinoline, Sonogashira fragment coupling, and a high-yielding, 18-membered macrolactam formation

Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an <i>anti</i>-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales

Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an <i>anti</i>-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales

Discovery of 5‑Amino‑<i>N</i>‑(1<i>H</i>‑pyrazol-4-yl)pyrazolo[1,5‑<i>a</i>]pyrimidine-3-carboxamide Inhibitors of IRAK4

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-<i>N</i>-(1<i>H</i>-pyrazol-4-yl)­pyrazolo­[1,5-<i>a</i>]­pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing

1,3,8-Triazaspiro[4.5]decane-2,4-diones as Efficacious Pan-Inhibitors of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia

The discovery of 1,3,8-triazaspiro[4.5]­decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]­decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C–N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1–3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia