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The formation of C-N bond via cross-coupling reactions [1][2][3] represents an important addition to the synthetic methodologies for the preparation of nitrogen-containing compounds in pharmaceuticals, crop-protection chemicals and material sciences. In contrast to the powerful C-C bond cross-coupling reactions of Suzuki 4a and Stille, 4b a need remains for mild (weak base and room temperature) and general C-N bond cross-coupling reactions for a wide variety of N-H-containing substrates. In recent years, Buchwald 1a and Hartwig 1b have pioneered palladiumcatalyzed C-N cross-couplings of aryl halides with amines, anilines, mono-nitrogen azoles and carbamates, in general involving either strong base (t-BuONa) or elevated temperatures. Arylbismuths 1c-d and arylleads 1e have been demonstrated to undergo copper-promoted N-arylation also at elevated temperatures. More recently, the copper-promoted N-arylation with arylboronic acids for diverse N-H-containing substrates was discovered by Chan 2 and Lam. 3 This methodology was further extended to include, with limited success, arylstannanes. 3b In further pursuit of an optimum arylmetalloid for this versatile copper-promoted N-arylation reaction, we would like to report that hypervalent aryl siloxanes are an efficient alternative to arylboronic acids for C-N bond formation. This new discovery offers the advantage of performing a one-pot room-temperature N-arylation in the absence of strong base, starting with aryl iodide, via the in situ generation of aryl siloxanes. Organosilicon compounds have recently been shown [5][6][7] to be effective reagents for C-C bond cross-couplings.

Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).

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As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K(i) of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.

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