EBNA1 inhibitors and their method of use
Inventors
MESSICK, TROY E. • Smith, Garry R. • Reitz, Allen B. • Lieberman, Paul M. • McDonnell, Mark E. • Zhang, Yan • VELVADAPU, VENKATA
Assignees
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Publication Number
US-12258314-B2
Publication Date
2025-03-25
Expiration Date
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.
Core Innovation
The disclosure provides Epstein-Barr nuclear antigen 1 inhibitors and compounds of Formula (IX) for treating or ameliorating diseases caused by EBNA1 activity and Epstein-Barr Virus infection in a subject. The compounds include defined structural substituent selections, including R1, R3, R4d, R8a-R8e, R9a-R9e, L2 being (CH2)m, and m being 0, 1, 2, or 3, together with pharmaceutically acceptable salts, solvates, hydrates, polymorphs, prodrugs, complexes, and compositions including an excipient.
The disclosure further includes specific indole-ethynyl-benzoic acid compounds and related substituted ethynyl-linked indole, indazole, pyridine, imidazole, triazole, pyrazole, benzimidazole, and phenoxy derivatives. Exemplified compounds are characterized with 1H NMR and MS (ESI) data, and the examples include trifluoroacetate salt forms and structural variants bearing thiazolyl, pyridinyl, aminopyridinyl, and other heteroaryl substituents.
The background/problem being solved is presented as diseases caused by EBNA1 activity, including infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis, as well as Epstein-Barr Virus infection, including lytic or latent infection. The document frames EBNA1 as associated with EBV latency and links the compounds to treatment or amelioration of the stated disease states.
Claims Coverage
The independent claims cover methods of treating or ameliorating diseases caused by EBNA1 activity and methods of treating or ameliorating Epstein-Barr Virus infection. The claim coverage centers on administering therapeutically effective or effective amounts of Formula (IX) compounds or specified indole-ethynyl-benzoic acid compounds, with optional salt or solvate forms and, in one claim, optional excipient-containing compositions. Three inventive feature sets are consistently present.
Treating EBNA1-activity caused disease with Formula (IX) compounds
A method of treating or ameliorating a disease caused by EBNA1 activity in a subject, wherein the disease is at least one selected from infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis, comprising administering a therapeutically effective amount of a compound of Formula (IX) or a solvate or salt thereof, with R1 selected from optionally substituted thiazolyl, optionally substituted pyridyl, or optionally substituted benzyl; R3 is CO2R4d; R4d is selected from hydrogen, optionally substituted C1-6 linear alkyl, or optionally substituted C3-6 branched alkyl; R8a-R8e and R9a-R9e are each independently selected from hydrogen, optionally substituted C1-6 linear alkyl, or optionally substituted C3-6 branched alkyl; and L2 is (CH2)m where m is 0, 1, 2, or 3.
Treating EBNA1-activity caused disease with specified indole-ethynyl-benzoic acids
A method of treating or ameliorating a disease caused by EBNA1 activity in a subject, wherein the disease is at least one selected from infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis, comprising administering a therapeutically effective amount of a compound selected from 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; and 2-(1H-indol-6-yl)-3-[2-(pyridin-4-yl) ethynyl] benzoic acid, or a salt or solvate thereof.
Treating EBV infection with Formula (IX) compounds
A method of treating or ameliorating Epstein-Barr Virus infection in a subject comprising administering an effective amount of a compound of Formula (IX) or a solvate or salt thereof, with the same defined substituent selections for R1, R3, R4d, R8a-R8e, R9a-R9e, L2, and m, optionally wherein the compound is administered as part of a composition further comprising at least one excipient.
The claim coverage is directed to treating or ameliorating EBNA1 activity-associated diseases and EBV infection by administering defined Formula (IX) compounds or selected indole-ethynyl-benzoic acid compounds. The covered compound scope includes defined substituent selections and optional salt or solvate forms, with one claim also including optional excipient-containing compositions.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating or ameliorating infectious mononucleosis caused by EBNA1 activity in a subject.
Treating or ameliorating chronic fatigue syndrome caused by EBNA1 activity in a subject.
Treating or ameliorating multiple sclerosis caused by EBNA1 activity in a subject.
Treating or ameliorating systemic lupus erythematosus caused by EBNA1 activity in a subject.
Treating or ameliorating rheumatoid arthritis caused by EBNA1 activity in a subject.
Treating or ameliorating Epstein-Barr Virus infection in a subject.
Treating or ameliorating Epstein-Barr Virus infection in a subject, including lytic or latent infection.
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