754193-45-8

Upstream product

• 17417-09-3 2-fluoro-5-nitrobenzonitrile 
• 218301-47-4 1-(3-cyano-4-fluoro-phenyl)-3-trifluoromethyl-5-(furan-2-yl)-pyrazole 
• 53312-81-5 3-cyano-4-fluoroaniline 
• 209960-58-7 1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic Acid 

Downstream Products

• 855869-83-9 2-(3-cyano-4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [2-methoxy-4-(2-methyl-imidazol-1-yl)-phenyl]-amide 
• 754193-49-2 1-(3'-cyano-4'-fluorophenyl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-methyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide 
• 754193-50-5 1-(3'-cyano-4'-fluorophenyl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-ethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide 
• 855869-81-7 2-(3-cyano-4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [2-cyano-4-(2-methyl-imidazol-1-yl)-phenyl]-amide 
• 754193-51-6 1-(3'-cyano-4'-fluorophenyl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-isopropyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide 
• 855869-60-2 2-(3-cyano-4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (2-fluoro-4-morpholin-4-yl-phenyl)-amide 
• 754193-52-7 1-(3'-cyano-4'-fluorophenyl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-pyrrolidin-1-ylmethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide 
• 540510-49-4 N-[4-[(2-tert-butyldimethylsilyloxymethyl)-1H-imidazol-1-yl]-2-fluorophenyl]-1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide 
• 540510-45-0 benzyl {1-[4-({[1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)-3-fluorophenyl]-1H-imidazol-2-yl}methyl(methyl)carbamate 
• 218301-83-8 methyl 1-(4'-fluoro-3'-cyanophenyl)-3-trifluoromethyl-5-pyrazolecarboxylic acid ester 
• 335275-99-5 2-(3-cyano-4-fluorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (2-fluoro-4-iodophenyl)amide 
• 855869-58-8 2-(3-cyano-4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide 
• 405940-74-1 1-(3'-cyano-4'-fluorophenyl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide 
• 882037-00-5 2-(3-cyano-4-fluoro-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (3-fluoro-2'-trimethylsilanyloxymethyl-biphenyl-4-yl)-amide 

Relevant academic research and scientific papers

NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS

The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula (I) or pharmaceutically acceptable salt or prodrug forms thereof, wherein J is N or NH and D may be C(=NH)NH2, which are useful as inhibitors of factor Xa.

Aminobenzisoxazoles with biaryl P4 moieties as potent, selective, and orally bioavailable factor Xa inhibitors

We have previously reported on a series of aminobenzisoxazoles as potent, selective, and orally bioavailable factor Xa inhibitors, which culminated in the discovery of razaxaban. Herein, we describe another approach to improve factor Xa inhibitory potency

Discovery of 1-(3′-aminobenzisoxazol-5′-yl)-3-trifluoromethyl- N-[2-fluoro-4-[(2′-dimethylaminomethyl)imidazol-1-yl]phenyl] -1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor

Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P1 ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P4 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).

NOVEL GUANIDINE MIMICS AS FACTOR Xa INHIBITORS

The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula (I) or pharmaceutically acceptable salt forms thereof, wherein rings D-E represent guanidine mimics, which are useful as inhibitors of factor Xa.

Guanidine mimics as factor Xa inhibitors

The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula I: or pharmaceutically acceptable salt forms thereof, wherein rings D—E represent guanidine mimics, which are useful as inhibitors of factor Xa.