A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log  D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.

Allyl cyanides are found to add across alkynes in the presence of a nickel catalyst prepared from Ni(cod)2 and P(4-CF3-C6H4)3 in situ to give variously functionalized di- or trisubstituted acrylonitriles in highly stereoselective manners possibly via a pi-allylnickel species as an intermediate. alpha-Siloxyallyl cyanides also react at the gamma-position of a cyano group with both internal and terminal alkynes having various functional groups to give silyl enol ethers, which give the corresponding aldehydes or ketones upon hydrolysis.

Nickel/Lewis acid dual catalysis was found to effect the carbocyanation reaction of alkynes using arylacetonitriles, giving a range of triply substituted acrylonitriles; the reaction of optically active alpha-phenylpropionitrile suggested a reaction mechanism that involves oxidative addition of a C-CN bond with retention of its absolute configuration.

Allyl cyanides are found to add across alkynes in the presence of a nickel/P(4-CF(3)-C(6)H(4))(3) catalyst to give polysubstituted 2,5-hexadienenitriles with defined stereo- and regiochemistry. Use of AlMe(2)Cl or AlMe(3) as a Lewis acid cocatalyst accelerates the reaction and expands the substrate scope significantly. The cyano group in the allylcyanation products can be transformed to a hydroxymethyl or aminomethyl group to afford highly substituted allylic alcohols or amines. Alpha-siloxyallyl cyanides also add across alkynes selectively at the less hindered gamma-carbon to allow introduction of 3-oxo-propyl functionality after hydrolysis of the resulting silyl enol ethers. This particular carbocyanation reaction has been applied to the stereoselective construction of the trisubstituted double bond of plaunotol, an antibacterial natural product active against Helicobacter pylori.

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