IP Library › Granted Patent US 10,421,718

Granted Patent B2

US 10,421,718 · App. 15/814,600 · Granted Sep 24, 2019

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

C07D207/327 A61K31/192 A61K31/404 A61K31/44 A61K31/4439 A61K31/496 C07C53/18 C07C63/66 C07C65/19 C07C65/28 C07C211/27 C07C217/84 C07C229/56 C07C229/64 C07C233/11 C07C233/64 C07C233/65 C07C235/58 C07C255/54 C07C255/55 C07C311/08 C07C311/16 C07C311/17 C07C317/14 C07C317/44 C07D207/08 C07D207/12 C07D207/14 C07D207/16 C07D209/08 C07D211/70 C07D213/55 C07D213/64 C07D213/74 C07D215/14 C07D231/12 C07D235/06 C07D239/26 C07D249/06 C07D277/30 C07D295/155 C07D307/79 C07D333/54 C07D401/04 C07D401/10 C07D403/10 C07D409/10 C07D417/10 C07D471/04 C07D487/04 C07C2601/02

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Quick Facts

Patent No.: US 10,421,718
App. No.: 15/814,600
Granted: Sep 24, 2019
Kind: B2

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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 (437)

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 at least one compound of formula (IX):

or a hydrate, solvate, polymorph, pharmaceutically acceptable salt, or prodrug thereof, wherein:

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 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 at least one 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 at least one compound selected from the group consisting of:

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

2-(1-methyl-1H-indol-6-yl)-3-(2-phenylethynyl)benzoic acid;

2-[3-(methoxycarbonyl)-1H-indol-6-yl]-3-(2-phenylethynyl)benzoic acid;

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

3-(4-amino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid;

3-(4-carboxy-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid;

2-(1H-indol-6-yl)-3-(4-methoxy-phenylethynyl)-benzoic acid;

3-(4-carbamoyl-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid;

2-(1H-indol-6-yl)-3-[4-(piperazine-1-carbonyl)-phenylethynyl]-benzoic acid;

3-(4-acetylamino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid;

2-(1H-indol-6-yl)-3-{4-[(pyridine-3-carbonyl)-amino]-phenylethynyl}-benzoic acid;

2-(1H-indol-6-yl)-3-(4-methanesulfonylamino-phenylethynyl)-benzoic acid;

2-(1H-indol-6-yl)-3-[4-(thiophene-2-sulfonylamino)-phenylethynyl]-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;

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

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

2-(1H-indol-6-yl)-3-((4-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)benzoic acid;

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

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

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

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

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

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

3-((3-(3-chloro-4-fluorophenylsulfonamido)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;

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

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

2-(1H-indol-6-yl)-3-((3-(thiophene-2-sulfonamido)phenyl)ethynyl)benzoic acid;

3-((3-acetamido-5-fluorophenyl)ethynyl)-2-(1H-indol-6-yl)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;

3-(4-hydroxybut-1-ynyl)-2-(1H-indol-6-yl) benzoic acid;

3-(3-amino-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid;

3-(3-hydroxy-3-phenylprop-1-ynyl)-2-(1H-indol-6-yl)benzoic acid;

3-(3-hydroxy-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid;

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

2-(2-(ethoxycarbonyl)-1H-indol-6-yl)-3-(phenylethynyl)benzoic acid;

3-((3-carbamoyl-5-methoxyphenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;

3-((4-fluoro-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;

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

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

or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

4. The method of claim 3 , wherein the at least one compound is administered to the subject as part of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

5. A method of treating or ameliorating a cancer caused by EBNA1 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula (IX):

or a hydrate, solvate, polymorph, pharmaceutically acceptable salt, or prodrug thereof, wherein:

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.

6. The method of claim 5 , wherein the cancer is at least one selected from the group consisting of nasopharyngeal carcinoma, gastric carcinomas, non-Hodgkin's lymphoma, anaplastic large-cell lymphoma, angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, B-cell lymphoma, Burkitt's lymphoma, reticuloendotheliosis, reticulosis, microglioma, diffuse large B-cell lymphoma, extranodal T/NK lymphoma/angiocentric lymphoma, follicular lymphoma, immunoblastic lymphoma, mucosa-associated lymphatic tissue lymphoma, B-cell chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal large B cell lymphoma, lymphoplasmactic lymphoma, nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lyphomatoid granulomatosis, angioimmunoblastic lymphadenopathy, leiomyosarcomas, X-linked lymphoproliferative disease, post-transplant lymphoproliferative disorders, Hodgkin's lymphoma, and breast cancer.

7. 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 at least one compound of Formula (IX):

or a hydrate, solvate, polymorph, pharmaceutically acceptable salt, or prodrug thereof, wherein:

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.

8. The method of claim 7 , wherein the compound is administered to the subject as part of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

9. 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 at least one compound selected from the group consisting of: