1329170-34-4

Upstream product

• 76513-69-4 (2-trimethylethylsilylethoxy)methyl chloride 
• 1329167-30-7 tert-butyl N-[(1S)-1-(4-{2-amino-4-[(methoxycarbonyl)-amino]phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)but-3-en-1-yl]carbamate 
• 54594-06-8 D-allylglycine 
• 1329167-29-4 tert-butyl N-[(1S)-1-(4-{2-bromo-4-[(methoxycarbonyl)-amino]phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)but-3-en-1-yl]carbamate 
• 1329167-28-3 {3-bromo-4-[2-((S)-1-tert-butoxycarbonylaminobut-3-enyl)-3H-imidazol-4-yl]phenyl}carbamic acid methyl ester 

Downstream Products

• 1329170-99-1 (R)-methyl 2-(N-(2-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5-((methoxycarbonyl)amino)phenyl)-2,2,2-trifluoroacetamido)pent-4-enoate 
• 1422510-86-8 methyl (9R,14S)-14-{[(3R)-3-(3-chlorophenyl)-3-hydroxypropyl]amino}-17-cyano-5-[(methoxycarbonyl)amino]-8-(trifluoroacetyl)-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.0^2,7]octadeca-1⁽¹⁷⁾,2,4,6,15⁽¹⁸⁾-pentaene-9-carboxylate 
• 1422510-87-9 methyl (9R,14S)-14-[(6R)-6-(3-chlorophenyl)-2-oxo-1,3-oxazinan-3-yl]-17-cyano-5-[(methoxycarbonyl)amino]-8-(trifluoroacetyl)-16-{[2-(trimethylsilyl)ethoxy]methyl}-8,16,18-triazatricyclo[13.2.1.0^2,7]octadeca-1⁽¹⁷⁾,2,4,6,15⁽¹⁸⁾-pentaene-9-carboxylate 
• 1329170-35-5 (R)-methyl 2-(2-(2-((S)-1-(tert-butoxycarbonylamino)but-3-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5-(methoxycarbonylamino)phenylamino)pent-4-enoate 

Relevant academic research and scientific papers

Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa

The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.

CYCLIC P1 LINKERS AS FACTOR XIA INHIBITORS

The present invention provides compounds of Formula (Ia): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

NOVEL MACROCYCLES AS FACTOR XIA INHIBITORS

The present invention provides compounds of Formula (Ia): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.