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Recent visible-light photoredox catalyzed C(sp3)–C(sp2) cross-coupling provides a novel transformation to potentially enable the synthesis of medicinal chemistry targets. Here, we report a profiling study of photocatalytic C(sp3)–C(sp2) cross-coupling, both decarboxylative coupling and cross-electrophile coupling, with 18 pharmaceutically relevant aryl halides by using either Kessil lamp or our newly developed integrated photoreactor. Integrated photoreactor accelerates reaction rate and improves reaction success rate. Cross-electrophile coupling gives higher success rate with broad substrate scope on alkyl halides than that of the decarboxylative coupling. In addition, a successful application example on a discovery program demonstrates the efficient synthesis of medicinal chemistry targets via photocatalytic C(sp3)–C(sp2) cross-coupling by using our integrated photoreactor.

SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.

In a lead optimization effort towards NS5B NNI inhibitors, two multi-step parallel libraries were designed and successfully synthesized. Through this effort we discovered compound 9B, which achieved rigorous and delicate balance of inhibition across the common genotypes and mutants with10 nM potency. In addition, the bicyclic compounds 9B exhibited improved FASSIF solubility over the tetracyclic compound MK-8876. This strategic approach demonstrated that, even within limited reaction scope, multi-step parallel libraries could provide access to more complex chemical space. This expedient access facilitates diverse, purpose-driven optimization of SAR and physicochemical properties.

Tryptophan hydroxylase (TPH) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. Here we describe the discovery of substituted triazines as a novel class of tryptophan hydroxylase inhibitors. This class of TPH inhibitors can selectively reduce serotonin levels in murine intestine after oral administration without affecting levels in the brain. These TPH inhibitors may provide novel treatments for gastrointestinal disorders associated with dysregulation of the serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome.

A synthesis of cage-shaped compounds-(1 S ,4 S ,5 R )-4-hydroxy-2,6-diazabicyclo[3.3.0]octane and (1 S ,4 R ,5 R )-4-hydroxy-2-oxa-6-azabicyclo[3.3.0]octane described. The test for enantioselective catalysis also reported.

A facile synthesis of D-ribo-C18-Phytosphingosine from divinylcarbinol via Sharpless asymmetric epoxidation and Sharpless asymmetric dihydroxylation was described.

Facile syntheses of (−)-anisomycin and 3097-B1 from divinylcarbinol 3 in an overall yield of 12.2% and 13.2%, respectively are described.

A synthesis of cage-shaped pyrrolidylpyrrolidine compound --- (1S,4S,5R)-N-tosyl-4-hydroxy-2,6-diazabicyclo[3,3,0]-octane (1) is described.

A facile synthesis of (2 S , 3 R , 4 S )-4-amino-5-cyclohexyl-1-morpholino-2, pentanediol (ACMP), the C-terminal compounds of renin inhibitor BW-175 is described.

The one-pot synthesis of α,β-dihydroxy sulfides via titanium-promoted oxirane ring opening of (2R,3S) 1,2-epoxy-4-penten-3-ol by various thiols is described.

Facile syntheses of (−)-anisomycin and 3097-B1 from divinylcarbinol 3 in an overall yield of 12.2% and 13.2%, respectively are described.