Amidation scaffolds

Publications describing Btk inhibitors are scarce [39], but a recent upturn in patent activity points to intensifying medicinal chemistry efforts. The field is dominated by two classes irreversible inhibitors and reversible inhibitors which are based on an imidazopyrazine-amide scaffold (Figure 2). 

Some of the other scaffolds used to synthetize Kvl.5 channel inhibitors are prototypes of vicinally substituted heterocycles, such as the tetrazole 2f shown in Table 1. This series was developed to circumvent a metabolic liability of thiazolidinone derivatives previously identified as potent Kvl.5 blockers [54]. Some chemistry efforts have been directed toward novel structures that provide practical advantages in addition to Kvl.5 potency. This is the case of Kvl.5 inhibitors based on a diisopropyl amide scaffold [50]. 

Two artificial neutral phosphate receptors with multi amide scaffolds have well-defined structures, on the basis of fluorescence titration. X-ray analysis and NMR studies, which promote efficient and selective complexation with phosphate in l.T binding stoichiometry e.g. (101). ... 

L.J. del Valle, M. Roa, A. Diaz, M.T. Casas, J. Puiggalf, A. Ro-drfguez-Galan, Electrospun nanofibers of a degradable poly(ester amide). Scaffolds loaded with antimicrobial agents, J. Polym. Res. 19 (2012) 9792-9804. 

From a medicinal chemist s point of view, oxadiazoles are among the most important heterocycles as they are one of the most commonly used bioisosters for amide and ester groups [67]. As such it is hardly surprising that the two regioisomeric oxadiazole scaffolds received the most interest in the field of microwave-assisted synthesis using polymer-supported reagents. 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

To perform Diels-Alder reactions on solid phase, the 2(lH)-pyrazinone scaffold is linked to a suitable support via its amide nitrogen atom. While N-l-substituted pyrazinones are readily accessible by the choice of an appropriate amine, it is not possible to prepare N-l-unsubstituted pyrazinones using the general strategy as previously outlined in the introduction. How-... 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

The C-6 carboxamide analogues of zanamivir, represented by the general structure 24, provided an avenue to introduce more hydrophobic side-chains onto the dihydropyran scaffold to interact with the hydrophobic regions of subsites S4 and S5 (reviewed in Islam and von Itzstein 2007). The most active tertiary amides (24 = alkyl) showed comparable inhibitory activity to their glycerol side-... 

Phosphinous amides 47-49 (Scheme 39), closely related to those in the scheme above but with a new scaffold supporting the sulfur and phosphorus functionalities, have been recently reported to catalyze the same reaction [ 166]. 

Contrary to an alkoxy benzene scaffold, secondary amides were generated via novel aldehyde linker 43 based upon an indole scaffold (Scheme 15) [52]. The indole resin was prepared from indole-3-carboxy-aldehyde in two steps and reacted with amines under reductive conditions to generate resin-bound secondary amines. Treatment of the resin with... 

Linear multinuclear metal complexes are attracting attention in the context of molecular electronics due to their projected use as molecular wires. 01igo(pyridyl)amido ligands are efficient scaffolds for lining up several Ni11 ions like a string. The first structurally characterized trinickel complex of this type, [Ni3(dpa)4Cl2] (dpa = bis(2-pyridyl)amide), showed a nearly linear Ni3 unit with Ni—Ni distances of around 244 pm.209 Penta-, hepta-, and nonanuclear systems have... 

We have now adjusted our molecular systems to provide a model in which both forces can operate simultaneously. The U-shaped relationship that exists between the imide function and amides of aryl amines creates a hydrogen bonding edge and a planar stacking surface that converge from perpendicular directions as in 44 to provide a microenvironment complementary to nucleic acid components. A large number of aromatic rings can be functionalized with this simple scaffold, and spacers (R) can also be incorporated. The imide function is a mimic of the thymine residues. 

For the synthesis of 2-519, the amines 2-516 were first treated with AlMe3 in benzene at r.t. and after addition of the enol acetates 2-515, easily accessible from 2-513 and 2-514, heated under reflux. Mechanistic investigations using on-line NMR spectroscopy, reveal that a metalated amide 2-517 is formed first. This then leads to a N-acyliminium ion 2-518 which undergoes an electrophilic substitution. Overall, three new bonds are formed selectively in the domino process, and the alkaloid scaffolds 2-519 are provided in very good yields of 79-89%. Interestingly, use of the keto esters 2-513 instead of 2-515 did not lead to the desired products 2-519. 

Recent patent disclosures reveal efforts to optimize within this template. The amide moiety has been cyclized to give dihydroisoquinolone inhibitors such as 9 and 10 [57]. Using various mono- and bicyclic core structure scaffolds, the amide has also been constrained in isoquinolone,... 

The second methodology involves direct introduction of glycosylated moieties onto a suitably functionalized meso-arylporphyrin scaffold, accessible from a natural source (protoporphyrin-IX) or by total synthesis. Several O-,133,145,146 S-,147 and N-glycoporphyrins148 (125-129) have thus been prepared (Fig. 12). Moreover, in order to explore the influence of the clustered peripheral saccharides around the porphyrin scaffolds, and to evaluate their photophysical properties, the synthesis of dodecavalent porphyrins bearing four trivalent glycodendrons via amide ligation (129) has been achieved.149... 

Scheme 9. (A) Different dendrimers as macromolecular scaffolds for MRI contrast agents ethylenediamine cored polyamido amine, generation 4 (PAMAM G4), top hyperbranched, ethylenediamine cored polyethylene imine (HB-PEI), bottom left hyperbranched, amino functionalized polyglycerol (HB-PG), bottom right. (B) Different moieties attached to the respective dendrimers via amide or thiourea bonds.

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