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The synthesis of a series of ( R )-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5 is described. SAR around C-5 of the uracil led to the discovery that a 2-thienyl or (2-phenyl)thiazol-4-yl group is required for optimal receptor binding. The best compound from the series had a binding affinity of 2 nM ( K i ) for the human GnRH receptor. A novel and convenient preparation of N -1-(2,6-difluorobenzyl)-6-methyluracil is also described.

Uracils possessing N-3 side chains derived from various amino alcohols were designed and synthesized as potent human gonadotropin releasing hormone receptor antagonists. The compounds herein presented displayed superior metabolic stability than their predecessor molecules. Selected compounds from this series featured good oral bioavailability in mice and cynomolgus monkeys.

A new class of small molecule GnRH antagonists, the 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils, was designed and a novel stereoselective synthesis for these compounds was developed. The stereochemical integrities of key intermediates (S)-6 and (R)-6 were confirmed by a combination of X-ray crystallography and chiral HPLC determinations. SAR studies were performed, which allowed the identification of derivatives (R)-9f, (R)-9h and (R)-12 as potent hGnRH antagonists (Ki=20 nM).

Based on SAR from bicyclic GnRH antagonists such as 6-aminomethyl-7-arylpyrrolo[1,2-a]pyrimid-4-ones (1) and 2-aryl-3-aminomethylimidazolo[1,2-a]pyrimid-5-ones (2a,b), a series of novel uracil compounds (4) were derived as the GnRH antagonists. Their syntheses and initial SAR are discussed herein. This is the first time that monocycle-based GnRH receptor antagonists are reported.

SAR studies of 2-arylimidazolo[1,2- a ]pyrimid-5-ones 10a – m , which were derived from initial lead 3a , resulted in the discovery of a series of potent nonpeptide human GnRH receptor antagonists. Compounds with good potency (e.g., 10e , K i =7.5 nM) were prepared by introduction of a 2-(2-pyridyl)ethyl at the basic nitrogen and a 3-pentyl ester at the 6-position of the bicyclic core.

In the process of developing GnRH receptor antagonists, a novel base-catalyzed cyclization of compounds 5a–b was discovered, which led to the formation of the 2-aryl pyrrolo[1,2-a]pyrimid-7-one core stuctures 6a–b. These intermediates were further modified at positions 1, 2, 4 and 6 to afford a series of potent GnRH antagonists with low nanomolar Ki values.

Initial SAR studies on 1-aminomethyl-2-aryl-3-cyano-pyrrolo[1,2- a ]pyrimid-7-one-6-carboxylates as human GnRH receptor antagonists were discussed. 2-(2-Methylaminoethyl)pyridine was discovered to be a key feature for generating active compounds. The best compound from the series had 25 nM ( K i ) binding affinity to human GnRH receptor.

SAR studies of 2-arylimidazolo[1,2- a ]pyrimid-5-ones 10a – m , which were derived from initial lead 3a , resulted in the discovery of a series of potent nonpeptide human GnRH receptor antagonists. Compounds with good potency (e.g., 10e , K i =7.5 nM) were prepared by introduction of a 2-(2-pyridyl)ethyl at the basic nitrogen and a 3-pentyl ester at the 6-position of the bicyclic core.

SAR studies of lead GnRH receptor antagonists 2a and 2b reported earlier resulted in the discovery of compound 10b which showed much higher potency ( K i =4.6 nM, compared with 2b , K i =230 nM) in which the 7-position of the imidazolo[1,2- a ]pyrimidone core was substituted with a methyl group, and the ester at the 6-position was replaced by the 3-methoxyphenyl group.

A novel and powerful approach for the synthesis of heterometallic complexes containing RuII and OsII is described. Palladium-catalyzed cross-coupling reactions between [(bpy)2M1(L1)]2+ and [(bpy)2M2(L2)]2+ (where L1 and L2 are bromo- and ethynyl-functionalized 1,10-phenanthroline ligands) provide heteronuclear complexes in a single synthetic step.

Based on the SAR from bicyclic gonadotropin-releasing hormone (GnRH) antagonists such as 6-aminomethyl-7-aryl-pyrrolo[1,2-a]pyrimid-4-ones (5) and 2-aryl-3-aminomethyl-imidazolo[1,2-a]pyrimid-5-ones (6a,b), a series of novel uracil compounds (8) were derived as GnRH antagonists. The synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed herein. Introduction of a small methyl substituent at the beta-position of the N3 side-chain improved the GnRH binding potency by 5-10-fold. Introduction of a methyl group of (R)-configuration at the alpha-carbon of the N-3 side-chain gave a modest improvement in binding affinity over the unsubstituted ethylene analogues. This modification enabled us to make uracil compounds without the labile 2-pyridylethyl motif on the basic nitrogen while still maintained excellent potency against the hGnRH receptor.

4-Benzylquinolines 5 , based on a series of isoquinolines 1 , were prepared and tested as inhibitors of the IGF/IGFBP-3 complex based on their ability to displace IGF-I from its binding to IGF-binding protein-3. SAR studies on the 6,7-dihydroxy moiety of the quinoline 5a showed that the catecol moiety could be replaced with other functional groups. Computational modeling of the 5a /mini-IGFBP-5 complex revealed the possible binding site of 5a on IGFBP-5.

A series of 1-benzoyl isoquinolines, based on compound 1, was synthesized and evaluated for their ability to displace IGF-I from its complex with IGF_binding protein-3. Successful modifications of 1 included the replacement of the 3,4-dihydroxybenzoyl group with a substituted benzyl group. These alternations culminated in the discovery of compounds such as 7o which had excellent in vitro potency (Ki=9.4 nM) but with one less of the labile catechol functionality of 1.

A new class of small molecule GnRH antagonists, the 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones, was designed and a novel synthesis for these compounds was developed. The synthesis utilizes a base-catalyzed intramolecular cyclization of fluoromethyl pyrimidone 5 to generate the bicyclic core. Amongst the compounds synthesized, we discovered some highly potent GnRH receptor antagonists (e.g., 12, K(i)=9 nM), which showed enhanced stability towards acidic physiological conditions compared to the des-fluoro analogues.

SAR studies of lead GnRH receptor antagonists 2a and 2b reported earlier resulted in the discovery of compound 10b which showed much higher potency ( K i =4.6 nM, compared with 2b , K i =230 nM) in which the 7-position of the imidazolo[1,2- a ]pyrimidone core was substituted with a methyl group, and the ester at the 6-position was replaced by the 3-methoxyphenyl group.

Initial SAR studies on 1-aminomethyl-2-aryl-3-cyano-pyrrolo[1,2- a ]pyrimid-7-one-6-carboxylates as human GnRH receptor antagonists were discussed. 2-(2-Methylaminoethyl)pyridine was discovered to be a key feature for generating active compounds. The best compound from the series had 25 nM ( K i ) binding affinity to human GnRH receptor.