Gilead Sciences, Inc.

Gilead Pharmasset LLC

Amgen Inc.

Leland Stanford Junior University

Lars V Heumann

Scott Alan Wolckenhauer

Ganapati Reddy Pamulapati

Keshab Sarma

Ernest A Carra

Andrew S Thompson

Julio Cesar Medina

Jonathan B Houze

Ning Chen

Frank Kayser

Xiaohui Du

Xiaoqi Chen

Gregory Notte

Jeffrey Thomas Mihalic

Zhihua Ma

David John Kopecky

Zice Fu

Paul John Dransfield

Vatee Pattaropong

Xianghong Wang

Alan C Cheng

Xiaodong Wang

Wen-Chen Yeh

Julie Anne Heath

Steven H Olson

Richard V Connors

Jeffrey Deignan

Su-Jen Lai

Gayathri Swaminath

Brandon Heath Brown

Yinhong Chen

Aarif Yusuf Khakoo

James S Harvey

Katie Ann Keaton

Dustin S Siegel

Jennifer R Zhang

Matthew Irvine Brown

Bing Shi

Nobuko Nishimura

Winston C Tse

Kevin Chao Yang

Paul A Wender

Matthew R Kaller

Gediminas J Brizgys

Benjamin James Roberts

Martin Gerald Teresk

Katrien Brak

Silvio A Campagna

Shinji Fujimori

Kevin McCormack Allan

Xiang Wang

Nate Larson

Christopher M Levins

Anna Chiu

Troy Evan Reynolds

Malgorzata Wanska

Stephen Paul Lathrop

Andrew C Stevens

Tiago Vieira

Robert Ronald Milburn

Sean Timothy Neville

Pavel Robertovich Badalov

Katie Ann Brown

Detian Gao

Grace May

Adam James Schrier

Edward Doerffler

Daniel B Horne

Robert William Scott

Bruce Ross

Chiajen Lai

Willard Lew

Andrew W Waltman

Stacy Bremner

Zilin Huang

Elizabeth J Mieuli

Nolan Griggs

Dietrich P Steinhuebel

Anna Michelle Wagner

Shahrokh Kazerani

Grace May Huynh

Andrei Chtchemelinine

Vinh Xuan Ngo

Trevor James Rainey

Todd A Wenderski

Brenda J Burke Chan

Andrew S Thomson

Sachin Dhar

Morin Mae Frick

Sankar Mohan

Mark Charles Whitcomb

Kevin M Allan

Amanda Lynn Vandehey

Brian Michael O'Keefe

Silvio Campagna

Erik Rueden

Chrisopher M Levins

Clarissa Tadeus

Rainer Kramer

Carolyn Gauntlett

The present invention relates to novel salts and crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate for use in treating viral infections. In some embodiments, the viral infection is caused by a virus selected from the group consisting of Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, and Paramyxoviridae.

Crystalline forms of (s)-2-ethylbutyl 2-(((s)-(((2r,3s,4r,5r)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate

The present disclosure relates to methods and intermediates useful for preparing a compound of formula I. or a co-crystal, solvate, salt or combination thereof.

Methods and intermediates for preparing therapeutic compounds

The present disclosure generally describes methods of preparing 1'-cyano nucleosides, such as a compound of Formula (I). For example, the compound of Formula (I) can be prepared from a compound of Formula (II-a) in a flow reactor.

Methods of preparing 1'-cyano nucleosides

Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate

Provided are methods of preparing compounds and pharmaceutical compositions comprising a compound Formula VIII for treating Filoviridae virus infections. In one aspect, the compound of Formula VIII is formed from a reaction mixture comprising the compound of Formula IX, the compound of Formula X, a coupling agent such as magnesium chloride and a non-nucleophilic base such as diisopropylethylamine. The compound of Formula IX can be formed from a compound of Formula V and a cyanating agent. The compound of Formula V can be synthesized from a reaction mixture comprising a deprotonating agent such as phenylmagnesium chloride; a silylating agent such as chlorotrimethylsilane; a coupling agent such as isopropylmagnesium chloride, an additive such as LaCl-2LiCl, LaCl, CeCl, NdCl, or YCl; a compound of Formula VI; and 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine. The compounds, compositions, and methods provided are particularly useful for the treatment of Marburg virus, Ebola virus and Cueva virus infections.

Methods for the preparation of ribosides

The present disclosure provides processes for the preparation of a compound of formula: which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates.

Processes for preparing antiviral compounds

Compounds of Formula (I) and Formula (II), pharmaceutically acceptable salt thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and may have use in treating cardiovascular and other conditions. Compounds of Formula I and Formula II have the following structures: where the definitions of the variables are provided herein.

Heteroaryl-substituted triazoles as APJ receptor agonists

The present invention relates to novel salts and crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate having the structure:  for use in treating viral infections. One crystalline form of the compound can be characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 22.3&#xb0;, 16.9&#xb0;, and 16.2&#xb0; 2-&#x3b8;&#xb1;0.2&#xb0; 2-&#x3b8;. In some embodiments, the viral infection is caused by a virus selected from the group consisting of Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, and Paramyxoviridae.

Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate

Compounds of Formula (I) and Formula (II), pharmaceutically acceptable salt thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and have use in treating cardiovascular and other conditions. Compounds of Formula (I) and Formula (II) have the following structures: (I); (II). Intermediates (V) are also claimed. 

Triazole furan compounds as agonists of the APJ receptor

Embodiments of the present disclosure provide for prostratin analogs, bryostatin analogs, prodrugs of prostratin and prostratin analogs, methods of making prostratin analogs, and methods of making prodrugs of prostratin and prostratin analogs, methods of use of prostratin analogs, bryostatin analogs, and prodrugs thereof, and the like.

Prostratin analogs, bryostatin analogs, prodrugs, synthetic methods, and methods of use

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Redwood City, CA, United States of America

Lars V Heumann