EBNA1 inhibitors and their method of use

1. A compound of formula (IX):

or a hydrate, solvate, or pharmaceutically acceptable salt,

wherein:

R 1 is selected from the group consisting of optionally substituted phenyl,

R 2 is selected from the group consisting of optionally substituted phenyl,

R 3 is CO 2 R 4d ;

R 4d is selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 3-6 branched alkyl;

R 8a , R 8b , R 8c , and R 8d are each independently selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 3-6 branched alkyl;

R 9a , R 9b , R 9c , and R 9d are each independently selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 3-6 branched alkyl;

L 2 is (CH 2 ) m ; and

m is 0;

wherein each phenyl is independently optionally substituted with at least one substituent independently selected from the group consisting of halogen, —CN, —OR 10 , —NR 10 C(═O)R 10 , —S(═O) 2 R 10 , —S(═O) 2 OR 10 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 10 , —C(═O)OR 10 , —C(═O)N(R 10 ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-14 cycloalkyl, and phenyl,

wherein each occurrence of R 10 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and phenyl, or two R 10 units taken together with the atom(s) to which they are bound form a 3-7 membered ring.

2. The compound of claim 1 , wherein R 4d is selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 3-6 branched alkyl.

3. The compound of claim 1 , wherein R 4d is hydrogen.

4. A composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable excipient.

5. A method for treating or ameliorating a disease caused by EBNA1 activity, wherein the disease is infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis, the method comprising administering to a subject a therapeutically effective amount of at least one compound of claim 1 .

6. A method for treating and ameliorating a cancer caused by EBNA1 activity, the method comprising administering to a subject a therapeutically effective amount of at least one compound of claim 1 .

7. The method of claim 6 , wherein the cancer is 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, or breast cancer.

8. A method for treating or ameliorating Epstein-Barr Virus infection, the method comprising administering to a subject a therapeutically effective amount of at least one compound of claim 1 .

9. The method of claim 8 , wherein the Epstein-Barr Virus infection is lytic or latent.

10. A compound 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;

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]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;

3-[2-(5-hydroxypyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;

3-[2-(1H-1,3-benzodiazol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;

3-[2-(1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;

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

3-[2-(4-methylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;

3-[2-(3,5-difluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;

3-{2-[3-(difluoromethoxy)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;

2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(2-phenylethynyl)benzoic acid;

3-(2-{imidazo[1,2-a]pyrazin-6-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid;

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

3-[2-(4-methoxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;

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

3-[2-(pyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;

3-[2-(3-methoxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;

3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid;

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

3-[3-(1H-imidazol-1-yl)prop-1-yn-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid;

2-{4-[(dimethylamino)methyl]phenyl}-3-(2-phenylethynyl)benzoic acid;

2-(4-methanesulfonylphenyl)-3-(2-phenylethynyl)benzoic acid;

2-(4-methoxyphenyl)-3-(2-phenylethynyl)benzoic acid;

2-(3-methoxyphenyl)-3-(2-phenylethynyl)benzoic acid;

2-(2-methoxyphenyl)-3-(2-phenylethynyl)benzoic acid;

2-phenyl-3-(2-phenylethynyl)benzoic acid;

2-(4-methylphenyl)-3-(2-phenylethynyl)benzoic acid;

2-[3-(hydroxymethyl)phenyl]-3-(2-phenylethynyl)benzoic acid;

2-[4-(hydroxymethyl)phenyl]-3-(2-phenylethynyl)benzoic acid;

2-(3-methanesulfonamidophenyl)-3-(2-phenylethynyl)benzoic acid;

2-{2-[(2-hydroxyethyl)sulfamoyl]phenyl}-3-(2-phenylethynyl)benzoic acid;

2-[4-(cyclopropylcarbamoyl)phenyl]-3-(2-phenylethynyl)benzoic acid;

2-(dimethyl-1,2-oxazol-4-yl)-3-(2-phenylethynyl)benzoic acid;

3-(3-{[3-(1H-imidazol-1-yl)propyl]amino}prop-1-yn-1-yl)-2-phenylbenzoic acid;

3-{2-[3-(aminomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;

3-{2-[3-(3,5-difluorobenzenesulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;

3-{2-[3-(cyclopropanesulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid;

2-(3-methoxyphenyl)-3-(2-{1H-pyrrolo [2,3-b]pyridin-3-yl}ethynyl)benzoic acid;

2-(3-methoxyphenyl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid;

2-[4-(dimethylamino)phenyl]-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;

2-phenyl-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;

3′-hydroxy-4′-methoxy-6-pyridin-4-ylethynyl-biphenyl-2-carboxylic acid;

5′-hydroxy-3′-methoxy-6-pyridin-4-ylethynyl-biphenyl-2-carboxylic acid;

2-(3,5-dimethyl-isoxazol-4-yl)-3-pyridin-4-ylethynyl-benzoic acid;

2-(2,5-dimethyl-pyrrol-1-yl)-3-pyridin-4-ylethynyl-benzoic acid;

3-(3-carbamoyl-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid;

3-(3-carboxy-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid;

2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-hydroxymethyl-phenyl ethynyl)-benzoic acid;

2-(2,5-dimethyl-pyrrol-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-ylethynyl)-benzoic acid;

3-(3-acetylamino-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid;

2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-methoxy-phenylethynyl)-benzoic acid;

4′-dimethylaminomethyl-6-phenylethynyl-biphenyl-2-carboxylic acid;

4′-Amino-6-((3-hydroxyphenyl)ethynyl)-5′-methoxybiphenyl-2-carboxylic acid;

5′-acetamido-6-(phenylethynyl)biphenyl-2-carboxylic acid;

2-(4-methylphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;

3-[2-(3-hydroxyphenyl)ethynyl]-2-(4-methyl phenyl)benzoic acid;

3-[2-(3-hydroxyphenyl)ethynyl]-2-(3-methanesulfonamidophenyl) benzoic acid;

2-(3-carbamoylphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid;

2-(3-hydroxyphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid;

2-(3-chloro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl] benzoic acid;

2-(3-fluoro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;

2-(3,5-dimethoxyphenyl)-3-[2-(pyridin-4-yl)ethynyl] benzoic acid;

3-[2-(3-hydroxyphenyl)ethynyl]-2-(2-phenoxyphenyl) benzoic acid;

2-(3,5-dimethoxyphenyl)-3-[2-(3-hydroxyphenyl) ethynyl]benzoic acid;

or a pharmaceutically acceptable salt, carboxylic ester, or solvate thereof.

11. The compound of claim 10 , wherein the carboxylic ester is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.

12. A composition comprising at least one compound of claim 10 and at least one pharmaceutically acceptable excipient.

13. A method for treating and ameliorating a disease caused by EBNA1 activity, wherein the disease is infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis, the method comprising administering to a subject a therapeutically effective amount of at least one compound of claim 10 .

14. A method for treating or ameliorating a cancer caused by EBNA1 activity, the method comprising administering to a subject a therapeutically effective amount of at least one compound of claim 10 .

15. The method of claim 14 , wherein the cancer is 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, or breast cancer.

16. A method for treating or ameliorating Epstein-Barr Virus infection, the method comprising administering to a subject a therapeutically effective amount of at least one compound of claim 10 .

17. The method of claim 16 , wherein the Epstein-Barr Virus infection is lytic or latent.