IP Library › Granted Patent US 12,258,314
Granted Patent B2
US 12,258,314 · App. 17/558,877 · Granted Mar 25, 2025

EBNA1 inhibitors and their method of use

Inventors: Troy E. Messick (Upper Darby, PA); Garry R. Smith (Royersford, PA); Allen B. Reitz (Lansdale, PA); Paul M. Lieberman (Wynnewood, PA); Mark E. McDONNELL (Lansdale, PA); Yan Zhang (Fort Washington, PA); Venkata Velvadapu (Ankeny, IA)
Assignee: THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY
C07D207/327A61K31/192A61K31/404A61K31/44A61K31/4439A61K31/496C07C53/18C07C63/66C07C65/19C07C65/28C07C211/27C07C217/84C07C229/56C07C229/64C07C233/11C07C233/64C07C233/65C07C235/58C07C255/54C07C255/55C07C311/08C07C311/16C07C311/17C07C317/14C07C317/44C07D207/08C07D207/12C07D207/14C07D207/16C07D209/08C07D211/70C07D213/55C07D213/64C07D213/74C07D215/14C07D231/12C07D235/06C07D239/26C07D249/06C07D277/30C07D295/155C07D307/79C07D333/54C07D401/04C07D401/10C07D403/10C07D409/10C07D417/10C07D471/04C07D487/04C07C2601/02
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,258,314
App. No.
17/558,877
Granted
Mar 25, 2025
Kind
B2
Abstract

Pharmaceutical compositions of the invention comprise EBNA1 inhibitors useful for the treatment of diseases caused by EBNA1 activity such as cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis. Pharmaceutical compositions of the invention also comprise EBNA1 inhibitors useful for the treatment of diseases caused by latent Epstein-Barr Virus (EBV) infection. Pharmaceutical compositions of the invention also comprise EBNA1 inhibitors useful for the treatment of diseases caused by lytic Epstein-Barr Virus (EBV) infection.

Claims (42)

1. A method of treating or ameliorating a disease caused by EBNA1 activity in a subject, wherein the disease caused by EBNA1 activity is at least one selected from the group consisting of infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis,

the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IX):

or a solvate or salt thereof, wherein:

R 1 is selected from the group consisting of optionally substituted thiazolyl, optionally substituted pyridyl, optionally substituted benzyl,

R 2 is

R 3 is 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 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;

L 2 is (CH 2 ) m ; and

m is 0, 1, 2, or 3.

2. The method of claim 1 , wherein the compound is administered to the subject as part of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

3. A method of treating or ameliorating a disease caused by EBNA1 activity in a subject, wherein the disease caused by EBNA1 activity is at least one selected from the group consisting of infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis,

the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of:

2-(1-methyl-1H-indol-5-yl)-3-[2-(1,3-thiazol-4-yl) ethynyl] benzoic acid;

2-(3-(Methoxycarbonyl)-1H-indol-6-yl)-3-(thiazol-4-ylethynyl) benzoic acid;

2-(1H-indol-6-yl)-3-(thiazol-4-ylethynyl) benzoic acid;

3-((6-aminopyridin-2-yl) ethynyl)-2-(1H-indol-6-yl) benzoic acid;

3-((2-aminopyridin-4-yl) ethynyl)-2-(1H-indol-6-yl) benzoic acid;

2-(1H-indol-6-yl)-3-[2-(pyridin-4-yl) ethynyl] benzoic acid; and

or a salt or solvate thereof.

4. A method of treating or ameliorating Epstein-Barr Virus infection in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (IX):

or a solvate or salt thereof, wherein:

R 1 is selected from the group consisting of optionally substituted thiazolyl, optionally substituted pyridyl, optionally substituted benzyl,

R 2 is

R 3 is 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 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;

L 2 is (CH 2 ) m ; and

m is 0, 1, 2, or 3;

optionally wherein the compound is administered as part of a composition further comprising at least one excipient.

5. The method of claim 4 , wherein the Epstein-Barr Virus infection is lytic or latent.

6. A method of treating or ameliorating Epstein-Barr Virus (EBV) infection in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of:

2-(1-methyl-1H-indol-5-yl)-3-[2-(1,3-thiazol-4-yl) ethynyl] benzoic acid;

2-(3-(Methoxycarbonyl)-1H-indol-6-yl)-3-(thiazol-4-ylethynyl) benzoic acid;

2-(1H-indol-6-yl)-3-(thiazol-4-ylethynyl) benzoic acid;

3-((6-aminopyridin-2-yl) ethynyl)-2-(1H-indol-6-yl) benzoic acid;

3-((2-aminopyridin-4-yl) ethynyl)-2-(1H-indol-6-yl) benzoic acid;

2-(1H-indol-6-yl)-3-[2-(pyridin-4-yl) ethynyl] benzoic acid; and

or a salt or solvate thereof.

7. The method of claim 6 , wherein the Epstein-Barr Virus infection is lytic or latent.

Continuity (5)
Continuation 16519590 · Jul 23, 2019
Continuation 15814600 · Nov 16, 2017
Continuation 15036211
Provisional Application 61904555 · Nov 15, 2013
Related Publication 20220396551A1 · Dec 15, 2022
References Cited (67)
US 4638002A · Szekely et al. · 1987 [cited by applicant]
US 5155248A · Ullrich et al. · 1992 [cited by applicant]
US 5185454A · Bader et al. · 1993 [cited by applicant]
US 5356919A · Djuric et al. · 1994 [cited by applicant]
US 6166028A · Bloom et al. · 2000 [cited by applicant]
US 11242317B2 · Messick · 2022 [cited by examiner]
US 20030032623A1 · Ban et al. · 2003 [cited by applicant]
US 20030199511A1 · Li et al. · 2003 [cited by applicant]
US 20040044041A1 · Kuduk et al. · 2004 [cited by applicant]
US 20060030613A1 · Conte-Mayweg et al. · 2006 [cited by applicant]
US 20060258645A1 · Failli et al. · 2006 [cited by applicant]
US 20080153802A1 · Lessene et al. · 2008 [cited by applicant]
US 20090171091A1 · Thombare et al. · 2009 [cited by applicant]
US 20110009447A1 · Huth et al. · 2011 [cited by applicant]
US 20130040949A1 · Gray et al. · 2013 [cited by applicant]
US 20140113897A1 · Lieberman et al. · 2014 [cited by applicant]
CN 1634810A · 2005 [cited by applicant]
DE 3936297A1 · 1991 [cited by applicant]
DE 10021246A1 · 2001 [cited by applicant]
JP 2004510697A · 2004 [cited by applicant]
JP 2004512259A · 2004 [cited by applicant]
JP 2008506702A · 2008 [cited by applicant]
JP 2008520662A · 2008 [cited by applicant]
WO 0153274A1 · 2001 [cited by applicant]
WO 0190101A1 · 2001 [cited by applicant]
WO 2006002474A1 · 2006 [cited by applicant]
WO 2006019831A1 · 2006 [cited by applicant]
WO 2006055070A2 · 2006 [cited by applicant]
WO 2007002433A1 · 2007 [cited by applicant]
WO 2007002587A2 · 2007 [cited by applicant]
WO 2007023242A1 · 2007 [cited by applicant]
WO 2010048332A2 · 2010 [cited by applicant]
WO 2010092043A1 · 2010 [cited by applicant]
WO 2010100475A1 · 2010 [cited by applicant]
WO 2010118009A1 · 2010 [cited by applicant]
WO 2010124047A1 · 2010 [cited by applicant]
WO 2010127440A1 · 2010 [cited by applicant]
WO 2011082098A1 · 2011 [cited by applicant]
WO 2011090911A1 · 2011 [cited by applicant]
WO 2012098416A1 · 2012 [cited by applicant]
WO 2012162291A1 · 2012 [cited by applicant]
WO 2014145022A1 · 2014 [cited by applicant]
WO 2015073864A1 · 2015 [cited by applicant]
Mundo et al (Modern Pathology 33:2407-2421, 2020) (Year: 2020). [cited by examiner]
European Patent Application No. 14861658—Supplemental Partial European Search Report dated Apr. 25, 2017. [cited by applicant]
International Search Report and Written Opinion, PCT/US2014/065765, dated Apr. 15, 2015. [cited by applicant]
PubChem. Compound Summary for: CID 1962039. Create Date: Dec. 5, 2007 [retrieved on Mar. 31, 2015]. Retrieved from the Internet: <URL: https//pubchem.ncbi.nlm.nih.gov/compound/19612039>. entire document. [cited by applicant]
STN registration file RN 1244017-13-7, 2010. [cited by applicant]
STN registration file RN 873330-62.2, 2006. [cited by applicant]
STN Registry 178742-95-5, 1996. [cited by applicant]
STN Registry RN 10601-99-7, 1984. [cited by applicant]
STN Registry RN 1244017-13-7, 2010. [cited by applicant]
STN Registry RN 1259291-73-0, Jan. 13, 2011 [retrieved online Aug. 10, 2021]. [cited by applicant]
STN Registry RN 87330-62, 2006. [cited by applicant]
“2-[2-Carboxy-6-(2-phenylethynyl)phenyl]-3-(2-phenylethynyl)benzoic acid”, PubChem CID 22140186 (2007), 10 pages. [cited by applicant]
“Methyl 3-(3-ethoxy-3-oxoprop-1-ynyl)-2-(2-iodo-6-methoxycarbonylphenyl)benzoate”, PubChem CID 299282 (2005), 16 pages. [cited by applicant]
Bochkarev , et al., “Crystal Structure of the DNA-Binding Domain of the Epstein-Barr Virus Origin-Binding Protein, EBNA1, Bound to DNA”, 1996, Cell 84:791-800. [cited by applicant]
Crawford , et al., “The Preparation of Some Alkyl-substituted Benxoic Acids”, Jan. 1, 1952—Retrieved from the Internet: URL:http://pubs.rsc.org/en/content/articlepdf/1952/jr/jr9520004443 [retrieved on Apr. 7, 2017]. [cited by applicant]
Faigl , et al., “Organometallic Approach to the Functionalization of Alkyl Groups Containing 1-Phenylpyrroles.”, 2006, Synthetic Communications 36:2841-2849 Abstract. [cited by applicant]
Gao , et al., “Discovery and Optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)benzamides as Novel Selective and Orally Bioavailable Discoidin Domain Receptor 1 (DDR1) Inhibitors”, J. Med. Chem., 2013, 56 (8)… [cited by applicant]
Ghosh , et al., “Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents.”, 2012, Blood 119(4):1008-1017. [cited by applicant]
Kim , et al., “Palladium-Catalyzed Domino Cyclization (5-exo/3-exo), Ring-Expansion by Palladium Rearrangement, and Aromatization: An Expedient Synthesis of 4-Arylnicotinates from Morita-Baylis-Hillman Adducts.”, 2013, … [cited by applicant]
Li , et al., “Discover of selective inhibitors agains EBNA1 via high throughput in silico virtual screening.”, PLoS One, Apr. 12, 2010, vol. 5, No. 4, pp. e10126. [cited by applicant]
Liu , et al., “Studies of Phenylethynyl-pyrrolo[1,2-a]pyrazine as mGluR5 Antagonists Using 3D-QSAR Method”, Asian Journal of Chemistry; vol. 24, No. 1 (2012), 238-248. [cited by applicant]
Newman , et al., “The Synthesis of 6,6′-Diethynyldiphenic Anhydride.”, 1971, J Org Chem 36(10:1398-1401. [cited by applicant]
Shimakage , et al., “Significant role of macrophages in human cancers associate with Epstein-Barr virus (Review).”, Oncology Reports 32:1763-1771, 2014. [cited by applicant]
Thompson , et al., “Development of a High-Throughput Screen for Inhibitors of Epstein-Barr Virus EBNA1”, Journal of Biomolecular Screening 15(9); 2010 pp. 1107-1115. [cited by applicant]