Synthetic pGpG analogs, methods of preparation and methods of use

Patent metadata

Field	Value
Publication number	US-9688715-B2
Application number	US-201314405511-A
Country	US
Kind code	B2
Filing date	Jun 17, 2013
Priority date	Jun 22, 2012
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

The present invention relates to compounds according to Formula I: and salts thereof, wherein R 1 , R 2 , R 3 , R 4 , and L are as defined herein. Methods for preparing compounds of Formula I are also provided. The present invention further includes methods of treating and preventing bacterial infections, and methods of identifying pGpG-binding domains in bacteria, using the compounds of Formula I.

First claim

What is claimed is:

1. A compound of Formula I or a salt thereof:

wherein:
L is selected from the group consisting of:

R 1 is selected from the group consisting of hydrogen, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyloxy and —OPO 3 H 2 ;
R 2 is selected from the group consisting of:
hydrogen,
—PO 3 H 2 ,

R 3 is selected from the group consisting of:
hydrogen,
—PO 3 H 2 ,

R 4 is selected from the group consisting of hydrogen, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyloxy and —OPO 3 H 2 .

2. A compound according to claim 1 , or a salt thereof, wherein at least one of R 1 , R 2 , R 3 , and R 4 is hydrogen.

3. A compound according to claim 2 or a salt thereof, wherein at least one of R 1 and R 4 is hydrogen.

4. A compound according to claim 2 , wherein L is:

5. A compound according to claim 1 , or a salt thereof, selected from the group consisting of:
2-amino-9-((2R,3R,4S,5S)-4-(4-(((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazol-1-yl)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5S)-4-(4-((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)-1H-1,2,3-triazol-1-yl)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5R)-4-((1-((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5S)-4-(2-(2-((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)ethyl)hydrazinyl)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5R)-4-(((2-((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)ethyl)amino)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5S)-4-(2-(((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)hydrazinyl)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5R)-4-(((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)amino)oxy)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
3-((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)amino)-4-(((2S,3S,4R,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-ylamino)cyclobut-3-ene-1,2-dione;
2-amino-9-((2R,3R,4S,5S)-4-((2-((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)amino)propan-2-yl)amino)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5S)-4-((2-((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)amino)-1,1,1,3,3,3-hexafluoropropan-2-yl)amino)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5S)-4-((((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)amino)dimethylsilyl)amino)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
1-(((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)-3-((2S,3S,4R,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)urea;
2-amino-9-((2R,3R,4S,5R)-5-((1-((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5R)-5-(1-((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5S)-5-(4-((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5R)-5-(2-(2-((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)hydrazinyl)ethyl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5R)-5-(2-((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)amino)ethyl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5R)-5-((2-((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)hydrazinyl)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5R)-5-(((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)amino)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
3-(((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)amino)-4-((((2R,3S,4R,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)cyclobut-3-ene-1,2-dione;
2-amino-9-((2R,3R,4S,5R)-5-(((2-(((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)amino)propan-2-yl)amino)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5R)-5-(((2-(((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)amino)-1,1,1,3,3,3-hexafluoropropan-2-yl)amino)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,3R,4S,5R)-5-((((((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)amino)dimethylsilyl)amino)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
1-((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)-3-(((2R,3S,4R,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)urea;
2-amino-9-((2R,4S,5R)-5-((1-((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)methyl)-4-hydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,4S,5R)-5-(1-((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)-4-hydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,4S,5R)-5-((4-((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-hydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,4S,5R)-5-(2-(2-((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)hydrazinyl)ethyl)-4-hydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,4S,5R)-5-(2-((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)amino)ethyl)-4-hydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
3-(((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)amino)-4-((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-hydroxytetrahydrofuran-2-ylmethyl)amino)cyclobut-3-ene-1,2-dione;
2-amino-9-((2R,4S,5R)-5-(((((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)amino)methyl)-4-hydroxytetrahydrofuran-2-yl)-1H-purin-6(9H)-one;
2-amino-9-((2R,4S,5R)-5-(((2-(((2S,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl

Assignees

• Temple University—Of the Commonwealth System of Higher Education

Inventors

• Wuest William Martin

Classifications

• C07H19/20

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• G01N33/56911

  Bacteria · CPC title

• C07H19/16

  Purine radicals · CPC title

• C07H23/00 Primary

  Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12 (esters with inorganic acids C07H11/00) · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title