Ebna1 inhibitors and their method of use

Patent metadata

Field	Value
Publication number	US-2016289185-A1
Application number	US-201415036211-A
Country	US
Kind code	A1
Filing date	Nov 14, 2014
Priority date	Nov 15, 2013
Publication date	Oct 6, 2016
Grant date	—

Abstract

The invention provides EBNA1 inhibitors, and 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 compounds and compositions of the invention are further useful for the treatment of diseases caused by latent Epstein-Barr Virus (EBV) infection. The compounds and compositions of the invention are further useful for the treatment of diseases caused by lytic EBV infection.

First claim

1 . A compound having formula (I):

or at least one selected from the group consisting of hydrates, solvates, polymorphs, pharmaceutically acceptable salts, prodrugs, and complexes thereof, wherein:
X 1 is selected from the group consisting of CR 4a and N;
X 2 is selected from the group consisting of CR 4b and N;
X 3 is selected from the group consisting of CR 4c and N;
R 1 is selected from the group consisting of optionally substituted C 1-6 linear alkyl, optionally substituted C 3-6 branched alkyl, optionally substituted C 3-6 cyclic alkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted benzyl, optionally substituted heteroaryl methyl,

R 2 is selected from the group consisting of hydrogen, NR 10a R 10b , fluorine, optionally substituted phenyl, optionally substituted heteroaryl,

R 3 is selected from the group consisting of CO 2 R 4d ,

R 4d is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, and optionally substituted C 3-6 branched alkyl;
R 4a , R 4b and R 4c are each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, and hydrogen;
R 5 is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, and optionally substituted C 3-6 branched alkyl;
R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, and optionally substituted C 3-6 branched alkyl;
R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, and optionally substituted C 3-6 branched alkyl;
R 8a , R 8b , R 8c , R 8d , and R 8e are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, and optionally substituted C 3-6 branched alkyl;
R 9a , R 9b , R 9c , R 9d , and R 9e are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, and optionally substituted C 3-6 branched alkyl;
R 10a and R 10b are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, and optionally substituted C 3-6 branched alkyl;
L 1 is selected from the group consisting of

and (CH 2 ) n ;
L 2 is selected from a group consisting of NH, (CH 2 ) m ,

wherein “**” indicates the point of attachment for R 2 ;
n is 0, 1, 2, or 3; and
m is 0, 1, 2, or 3.

2 . The compound of claim 1 , wherein the compound is at least one selected from the group consisting of:

or at least one selected from the group consisting of hydrates, solvates, polymorphs, pharmaceutically acceptable salts, prodrugs, and complexes thereof.

3 - 5 . (canceled)

6 . The compound of claim 1 , wherein the compound is at least one selected from the group consisting of:

or at least one selected from the group consisting of hydrates, solvates, polymorphs, pharmaceutically acceptable salts, prodrugs, and complexes thereof.

7 - 9 . (canceled)

10 . The compound of claim 1 , wherein the compound is at least one selected from the group consisting of

or at least one selected from the group consisting of hydrates, solvates, polymorphs, pharmaceutically acceptable salts, prodrugs, and complexes thereof.

11 - 13 . (canceled)

14 . The compound of claim 1 , wherein the compound is at least one selected from the group consisting of:

or at least one selected from the group consisting of hydrates, solvates, polymorphs, pharmaceutically acceptable salts, prodrugs, and complexes thereof.

15 - 17 . (canceled)

18 . The compound of claim 1 , wherein the compound is at least one selected from the group consisting of:
3-{2-[3-(methylsulfamoyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(1H-indol-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(3-methanesulfonamidophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 2-(1H-pyrrol-1-yl)-3-[2-(3-sulfamoylphenyl)ethynyl]benzoic acid; 3-[2-(3-carbamoylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-(2-{imidazo[1,2-a]pyridin-6-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(2-hydroxypyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(1H-indazol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-{2-[3-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid; 3-(2-{3-[(2-carboxy-2,2-dimethylethyl)amino]phenyl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid; 3-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid; 3-(2-{imidazo[1,2-a]pyridin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid; 3-(2-{imidazo[1,2-a]pyridin-5-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid; 2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethynyl)benzoic acid; 3-[2-(1-methyl-1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(1-methyl-1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(1-benzothiophen-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(1H-indol-7-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-{2-[2-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid; 3-{2-[4-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid; 2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[2-(4-methylphenyl)ethynyl]benzoic acid; 2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid; 3-[2-(2,3-dihydro-1H-indol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(1-methyl-1H-pyrazol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(1,2-dimethyl-1H-imidazol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(1-methyl-1H-imidazol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(1-methyl-1H-imidazol-2-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 2-(1H-pyrrol-1-yl)-3-[2-(1,3-thiazol-5-yl)ethynyl]benzoic acid; 2-(1H-pyrrol-1-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid; 2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-6-yl}ethynyl)benzoic acid; 3-{2-[3-(2-hydroxypropan-2-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid; 3-(3-hydroxy-4-methylpent-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid; 3-(3-hydroxy-3-phenylprop-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid; 2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid; 3-[2-(1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 2-(1H-pyrrol-1-yl)-3-(2-{[1,2,4]triazolo[1,5-a]pyridin-7-yl}ethynyl)benzoic acid; 3-{2-[3-(dimethylsulfamoyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid; 3-[2-(3-fluoro-5-hydroxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; 3-{2-[3-(hydroxymethyl)phenyl]ethyny

Assignees

• Wistar Inst

Inventors

• Messick Troy E
• Smith Garry R
• Reitz Allen B
• Lieberman Paul M
• Mcdonnell Mark E
• Zhang Yan
• Velvadapu Venkata

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/22

  for herpes viruses · CPC title