Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing.

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.

Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine.

A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.

Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin.

A highly efficient asymmetric synthesis of the key tetrahydropyranol intermediate of DPP-4 inhibitor omarigliptin (1) is described. The successful development of a protecting-group- and precious-metal-free synthesis was achieved via the discovery of a practical asymmetric Henry reaction and the application of a one-pot nitro-Michael-lactolization-dehydration through-process. Other features of the synthesis include a highly efficient MsCl-mediated dehydration and a crystallization-induced dynamic resolution for exceptional ee and dr upgrade. The synthesis of this complex intermediate utilizes simple starting materials and proceeds in four linear steps.

Enantioselective decarboxylative amination: synthesis of axially chiral allenyl amines.

Getting axed: synthesis of the title amines, bearing functionality (R(1) and R(2)), involves the enantioselective palladium-catalyzed decarboxylation of allenyl N-tosylcarbamates. The reaction proceeds smoothly using both the chiral ligands (S)- and (R)-DTBM-Segphos (1) to afford the allenyl amines in good yields and with high enantioseletivities.

Catalytic asymmetric synthesis of optically active allenes from terminal alkynes.

CuBr and ZnI(2) have been developed as catalysts or subcatalysts for the efficient asymmetric synthesis of axially chiral allenols with up to 97% ee from readily available propargylic alcohols, aliphatic or aromatic aldehyde, pyrrolidine, and commerically available ligands. The alcohol unit in the terminal alkynes plays a very important role for ensuring high enantioselectivity via coordination.

Palladium-catalyzed decarboxylation of allenyl 3-oxoalkanoates: an efficient synthesis of 3,4-allenyl ketones.

An efficient synthesis of 3,4-allenyl ketones via the Pd-catalyzed decarboxylative coupling of the readily available 3-oxoalkanoates is reported. The C-C bond forming reaction occurs under mild conditions producing CO(2) as the only byproduct.