Pyrimidine scaffold

The first example of adenosine receptor antagonist, containing the pyrazolo-triazolo-pyrimidine scaffold (Baraldi et al. 2002a) was reported by Gatta and co-workers (Gatta et al. 1993). 

Several solid-phase approaches to afford purines were performed. Some may involve selective substitution of the purine directly others begin by construction of a pyrimidine scaffold followed by closure of the imidazole ring. 

Fig. 4.8. Uncommon pyrimidine scaffolds derived from Biginelli-type condensations.

The pyrimidine scaffold is found in the antivirals zidovudine, stavudine (anti-HI 0, and sorivudine (antiherpes). 

Pyrazolo[l,5-estrogenic properties of the pyrazolo[l,5-a]pyrimidine scaffold [82]. The 6-OH-pyrazolo[l,5-a]pyrim-idine derivatives synthesized (e.g. 54) showed low affinity for either ERa or ERp,... 

Sharma S, Rodriguez AL, Conn PJ et al (2008) Synthesis and SAR of a mGluR5 allosteric partial antagonist lead unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold. Bioorg Med Chem Lett 18 4098 4101... 

In the next two MCRs, two heterocyclic rings are constructed in the same reaction step. The first example is a rather complicated synthesis of pyrido[2,3-d] pyrimidine scaffolds 49 via a one-pot MW-assisted condensation of a a,j8-unsaturated ester, malononitrile or cyanoacetate, and an amidine (Scheme 17.36) [90]. 

Yoneda et al. have prepared a series of atropisomeric 5-deazaflavins, 464 and 465, with axial chirality at the pyrimidine scaffold (92TL3169,... 

Another example of annelation was demonstrated by Hoffmann-La Roche at the thiazolo[4,5-d]pyrimidine scaffold synthesis and decoration. Under thionation with P2S5, the acylated 6-aminopyrimidine 195 gives the corresponding thioamide, which cyclised spontaneously into thiazolo[4,5-d]pyrimidine thione 196. Thione 196 was used further transformation for synthesis of key building block 197 applied for the preparation of the library 198 (Scheme 42) [185]. 

The synthesis of pyrido[2,3-d]pyrimidines has attracted considerable interest in heterocyclic chemistry. This ring system constitutes a deaza-analogue of the pyrazino[2,3-d]pyrimidine heterocychc core of fohc acid, analogues which can exhibit a wide range of biological properties as folate antagonists. Thus, the synthesis of this motif by MCR imder microwave-assisted conditions has the potential to rapidly introduce diversity into a biologically relevant scaffold. 

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]. 

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). 

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

All three systems are amenable to sequential substitutions, giving opportunities for use as scaffolds and also, particularly for pyrimidines, rapid muticomponent, often one pot , ring constructions are possible. Both these features give great potential for combinatorial chemistry and library construction. 

Recent literature examples involve the use of the Suzuki protocol for the highspeed decoration of various heterocyclic scaffolds of pharmacological or biological interest, including pyrimidines [45], pyridazines [46], pyrazines [47], chromanes [48], and pyrazoles [49] (Scheme 6.19). 

Pyrazolo[l,5-a]pyrimidine, the central scaffold in zaleplon, is present in 5, 6 and 7. Compound 5 inhibits the binding of tritiated benzodiazepine in synaptosomal fractions from rat cortex [20] and 6 and 7 inhibit the al GABAa subunit with K, — 53 nM and 17nM, respectively, and showed sedative-hypnotic action following i.p. administration to mice (<90% inhibition of motor activity)... 

Grafting a scaffold to a polymeric support sometimes involves heterocycles having more than one atom susceptible to SNAr reactions. Characteristic examples for syntheses involving SNAr resin capture reactions are derivatizations of pyrazines,11 pyrimidines,12 and triazines.13,14... 

The capture of 4,6-dichloro-2-(methylthio)pyrimidine (8) was performed in DMF with diisopropylethylamine (DIPEA, Huenig s base) as a base and tetrabutylammonium bromide as a catalyst at 90°. The substitution of the remaining chlorine atom on the polymer-bound scaffold requires harsher conditions. Thus the immobilized 6-chlorothiomethylpyrimidine (9) could be substituted with aliphatic amines in neat amine at 140°. The coupling with anilines could be afforded consistently only by using KO Bu as base and [18]crown-6. Also, the use of Pd catalysts gave positive results, but failures were observed occasionally. Finally, the substitution of the thiomethyl group in resin-bound 2-(methylthio)pyrimidine-4,6-diamines... 

In a separate report, the regioselectivity and reactivity problems in the substitution of pyrimidines were avoided using 4,6-dichloro-5-nitropyrimi-dine as starting material,17 a very electron-poor heterocycle, which is highly reactive in nucleophilic aromatic substitutions. It reacts readily with the free amino group of the (trialkoxybenzhydrylamine) Rink linker on solid phase. This heterocycle could serve as a scaffold by itself and could also be used as a building block (precursor) to make other heterocycles such as purines. 

While the early examples of this cyclocondensation process typically involved a / -ketoester, aromatic aldehyde and urea, the scope of this heterocycle synthesis has now been extended considerably by variation of all three building blocks, allowing access to a large number of multifunctionalized pyrimidine derivatives. For this particular heterocyclic scaffold the acronym DHPM has been adopted in the literature and is also used throughout this chapter. Owing to the importance of multi-component reactions in combinatorial chemistry there has been renewed interest in the Biginelli reaction, and the number of publications and patents describing... 

Scheme 17 illustrates another fluorous sulfonate-based synthesis of library scaffolds. The tagged substrates were taken through aldol condensation and cycloaddition reactions to form the pyrimidine ring 18. The intermediates were then reacted with boronic acids for Suzuki reactions to form biaryl compounds 19 [31], reacted with HCO2H to give traceless detagged products 20 [34], or reacted with amine to form products 21 [33]. 

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