EBNA1 inhibitors and methods using same

Patent metadata

Field	Value
Publication number	US-10981867-B2
Application number	US-201916571896-A
Country	US
Kind code	B2
Filing date	Sep 16, 2019
Priority date	May 14, 2015
Publication date	Apr 20, 2021
Grant date	Apr 20, 2021

Abstract

The present invention provides EBNA1 inhibitors, and/or pharmaceutical compositions comprising the same, that are useful for the treatment of diseases caused by EBNA1 activity, such as, but not limited to, cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus and/or rheumatoid arthritis. The present invention further provides EBNA1 inhibitors, and/or pharmaceutical compositions comprising the same, that are useful for the treatment of diseases caused by latent Epstein-Barr Virus (EBV) infection and/or lytic EBV infection.

First claim

What is claimed is:

1. 3-Ethynyl-2-(1H-indol-6-yl)-benzoic acid methyl ester:

2. A method of preparing the compound 3-Ethynyl-2-(1H-indol-6-yl)-benzoic acid methyl ester, the method comprising desilylating 2-(1H-indo-6-yl)-3-triethylsilanylethynyl-benzoic acid methyl ester:

3. The method of claim 2 , wherein the desilylation comprises reacting the 2-(1H-indo-6-yl)-3-triethylsilanylethynyl-benzoic acid methyl ester and a fluoride source.

4. The method of claim 3 , wherein the fluoride source is tetrabutylammonium fluoride.

5. The method of claim 2 , wherein the 2-(1H-indol-6-yl)-3-triethylsilanylethynyl-benzoic acid methyl ester is prepared by reacting:
2-bromo-3-triethylsilanylethynyl-benzoic acid methyl ester:

and
6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-1H-indole, in the presence of a palladium catalyst.

6. The method of claim 5 , wherein the palladium catalyst comprises [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

7. The method of claim 5 , wherein the 2-bromo-3-triethylsilanylethynyl-benzoic acid methyl ester and the 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-1H-indole are reacted in the presence of a base.

8. The method of claim 7 , wherein the base comprises triethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, or potassium carbonate.

9. A method of preparing 2-(1H-indol-6-yl)-3-[4-(tetrahydropyran-4-yloxymethyl)phenylethynyl]-benzoic acid:

the method comprising hydrolyzing compound (14) with a base:

wherein:
R 1 =

R 2 -L 2 =

X 1 ═X 2 =X 3 ═CH; and
R 4d ═CH 3 .

10. The method of claim 9 , wherein compound (14) is prepared by contacting compound (16):

a palladium catalyst, a base, and compound R 1 —X (11), wherein X is chloride, bromide, iodide, methanesulfonate, trifluoromethanesulfonate, or tosylate.

11. The method of claim 10 , wherein the palladium catalyst comprises palladium (II) acetate, tetrakis(triphenylphosphine) palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, or bis(acetonitrile) dichloropalladium(II).

12. The method of claim 10 , wherein the base comprises triethylamine, diisopropylethylamine, pyridine, or 2,6-dimethylpyridine.

13. The method of claim 10 , wherein the contacting is performed in an organic solvent comprising N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, methylene chloride, or 1,2-dichloroethane.

Assignees

• Wistar Inst

Inventors

• Messick Troy E
• Smith Garry R
• Reitz Allen B
• Lieberman Paul M
• Mcdonnell Mark E
• Zhang Yan
• Carlsen Marianne
• Chen Shuai

Classifications

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D471/08

  Bridged systems · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/10

  linked by a carbon chain containing aromatic rings · CPC title