Pyridine scaffold

Moody and coworkers have also applied this methodology to the preparation of a library of functionalized pyridine scaffold 49 with two points of diversity by coupling ynone 47 with enamine 48. 

Petitjean A, Lehn JM (2007) Conformational switching of the pyridine-pyrimidine-pyridine scaffold for ion-controlled FRET. Inorganica Chim Acta 360 849-856... 

Yadav and co-workers [70] described two very efficient and unprecedented one-pot high-yielding synthetic approaches to imidazo[l,2-a]pyridine scaffolds... 

In order to assemble the imidazo[l,2-a]pyridine scaffold, 2-amino-3-chloropyridine was reacted with 2-bromo-p-fluoroacetophenone <03OL1369>. The product was transformed in five steps to a desired antiviral template. 

Two unprecedented one-pot synthetic protocols for the synthesis of imi-dazo[l,2-a]pyridine scaffolds (v) from carbohydrates have also been described by... 

Ishizaki and Hoshino prepared optically active secondary alkynyl alcohols (up to 95% e.e.) by the catalytic asymmetric addition of alkyl zinc reagents to both aromatic and aliphatic aldehydes. The chiral ligands studied were based on the pyridine scaffold. Of the three aryl substitutions studied, the a-napthyl derivative was found to be superior (Scheme 21.10). Mechanistically, it was proposed that (S)-l would react with dialkynyl zinc alkoxide A and ethyl zinc alkoxide B. Coordination of additional di-alkynyl zinc and alkynylethyl zinc with these alkoxides (A, B) would give C and D, respectively (Scheme 21.11). More bulky alkoxide (C) would have severe steric interactions with the alkynyl group and pyridine moiety, which might cause undesired conformational changes of the l-zinc complexes. Consequently, the enatioselectivity would be decreased. 

Bohlmann-Rahtz method has also been applied in the solution-phase synthesis of a library of functionalized pyridine scaffold as well as the preparation of a 2,3 6 3"-terpyridine scaffold as an a-helix mimetic. ... 

The privileged pyridine scaffold is present in a large number of marketed drugs including esomeprazole (Nexium), loratadine (Claritin), and the recently approved cancer therapeutic crizotinib (Xalkori). Sabitha and coworkers have developed the first general method for the synthesis of... 

While the importance and the production of pyridines has been well studied, a number of new pyridine-containing natural products and materials with promising biochemical, physical, and chemical properties have been reported in 2013. This chapter will provide an overview and summary of some of the advances in the field of pyridine chemistry. Some attention will be paid to key areas of utility for materials with a pyridine scaffold this review will focus primarily on the preparations and reactions of pyridines and their benzo derivatives. 

The chemical space of CatA inhibitors was recently expanded to 5-amino derivatives of compound 9a [46]. In general, compounds of this novel series are highly active. Also, an extension of the 5-membered pyrazole heterocycle to a pyridine scaffold was possible [47]. Some typical examples from both patent applications are presented in Figure 23.19, a more detailed discussion of the SAR in these novel series will be published elsewhere. 

From a medicinal chemistry campaign, novel substituted benzene sulfonamides were identified as selective cannabinoid CB2 receptor ligands. In order to improve the metabolic stability and bioavailability of these compounds, the benzene core was replaced by a pyridine scaffold. Herein we present a series of novel 2-amino pyridine CB2 selective agonists. The synthesis, SAR and in vivo efficacy of these compounds will be presented. 

Another example of imidazole ring formation in aqueous medium is reported by Proenca and Costa [65]. A one-pot condensation/cyclization reaction involving l-(cyanomethyl)pyridinimn chloride 94 and salicylaldehyde 95 in aqueous sodimn carbonate solution leads to the formation of chromeno-imidazo[l,2-a]pyridine scaffold 96 with 47-71% yield. The reaction is general to electron-donating groups (EDG) and electron-withdrawing groups (EWG). A representative example is shown in Scheme 31. 

SCHEME 31 Condensation/cyclization reaction involving l-(cyanomethyl)pyridinium cWoride and sallcylaldehyde in aqueous sodium carbonate solution forming chromeno-imidazo[l,2-a]pyridine scaffold. 

The [4+2] cycloaddition reactions of some triazole substituted 3,5-dichloro-2(lH)-pyrazinones have been studied by Kaval et al. (2006). They developed the required intermediates from the corresponding 3,5-dichloropyrazinones, following either a nucleophilic substitution or a Sonogashira reaction to install the alkyne handle on the scaffold. The various triazole derivatives linked to the pyrazinones were synthesized through a microwave-assisted CuAAC reaction. Then [4+2] cycloaddition reactions were carried out under microwave irradiations with dimethyl acetylenedicaiboxylate (DMAD) at 180-200 °C for 10-20 min, and the corresponding highly decorated pyridine and pyridine scaffolds were isolated in good yields. 

In addition to the formation of the pyridine framework by de novo approaches (see section 8.1) or by the cycloaddition/cycloreversion sequence (see section 8.2), one can employ reactions that proceed through a rearrangement pathway. The Boekelheide reaction (see section 8.3.1) involves the rearrangement of an existing pyridine skeleton to a more functionalized scaffold, while the Ciamician-Dennstedt reaction (section 8.3.2) generates the pyridine nucleus by rearrangement of an alternative heterocycle. 

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

As the Diels-Alder reactions of 2( lff)-pyrazinones with richly substituted acetylenes can be used to generate diversely substituted pyridines and pyridi-nones, these cyclo additions were investigated under microwave irradiation conditions on the 1,2,3-triazole decorated pyrazinone scaffold. As a proof of concept, the pyrazinones bearing a 1,4-disubstituted-1,2,3-triazole unit, linked via a C-0 bond, were reacted with the symmetrical dienophile dimethyl acetylenedicarboxylate (DMAD), in view of minimizing regioselect-ivity problems (Scheme 28). 

Six-membered heterocycles have also been extensively used to mimic the central pyrazole scaffold of limonabant (382). Merck and Co. has utilised pyiidines (510) [314], and pyrimidines (511) [315] in this capacity. Sanofi-Aventis has also claimed a series of pyridine-based analogues [316], as exemplified by (512) and additionally the non-heteroatom containing terphenyl (513) [317]. 

Merck has recently utilised a furo[2,3-b]pyridine core (554) as a bioisosteric replacement for the pyrazole scaffold of rimonabant (382) [328]. The same basic pharmacophore, that of two halo-substituted aryl groups and a third hydrophobic motif proximal to a hydrogen-bond acceptor, can be witnessed in the benzodioxole-based compounds, such as (555), disclosed by Roche [329]. 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

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