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US-12622896-B2 - Antiviral compounds, compositions and methods of use

US12622896B2US 12622896 B2US12622896 B2US 12622896B2US-12622896-B2

Abstract

Provided herein are antiviral compounds having the structure of Formula (I) and compositions thereof for use in the treatment of viral infection. In particular, the compounds of Formula (I) are capable of interfering with the export of viral mRNA processing as reflected in the altered accumulation of viral RNA isoforms as well as transport from the nucleus to the cytoplasm. Such compounds show a reduction of HIV, adenovirus and coronavirus infection of cells. The invention provides compounds that may be suitable for the treatment of HIV/AIDS.

Inventors

  • David Scott Grierson
  • Maryam Zamiri
  • Peter K. Cheung
  • Benoit Chabot
  • Alan Walter Cochrane

Assignees

  • THE UNIVERSITY OF BRITISH COLUMBIA
  • THE GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO
  • SOCIETE DE COMMERCIALISATION DES PRODUITS DE LA RECHERCHE APPLIQUEE SOCPRA SCIENCES SANTE ET HUMAINES S.E.C.

Dates

Publication Date
20260512
Application Date
20201215

Claims (12)

  1. 1 . A compound, the compound having the structure of Formula I: wherein, X 1 is selected from S and O; X 2 is selected from S and O; Z 1 is selected from CH and N; Z 2 is selected from CH, N and CR 4 ; Z 3 is selected from CH, N and CR 3 ; T 1 is selected from H, CH 2 OH, CH 2 OJ 4 , and CH 2 CH 2 OJ 4 ; T 2 is selected from NO 2 , CF 3 , OCF 3 , CN, and CH 2 OH CO 2 J 5 ; M is H; R 1 is selected from H, CH 3 , CH 2 OH, CH 2 CH 2 OJ 7 , CO 2 J 7 , CON(J 7 ) 2 , NO 2 , CN, F, Cl, Br, I, CF 3 , OCF 3 , SO 2 J 7 , NJ 7 J 7 and N 3 ; R 2 is selected from H, CH 3 , CH 2 OH, CH 2 CH 2 OJ 7 , CO 2 J 7 , CON(J 7 ) 2 , NO 2 , CN, F, Cl, Br, I, CF 3 , OCF 3 , SO 2 J 7 , NJ 7 J 7 and N 3 ; R 3 is selected from H, NO 2 , CN, F, Cl, Br, I, CF 3 , N J 7 J 7 and N 3 ; R 4 is selected from H, NO 2 , CN, F, Cl, Br, I, CF 3 , N J 7 J 7 and N 3 ; J 4 is selected from H, and a 1-6 carbon linear, branched or cyclic alkyl; J 5 is 1-6 carbon linear, branched or cyclic alkyl; and J 7 is selected from H, and a 1-6 carbon linear, branched or cyclic alkyl.
  2. 2 . The compound of claim 1 , wherein the compound has the structure of Formula II: wherein, X 1 is selected from S and O; X 2 is selected from S and O; Z 1 is selected from CH and N; T 1 is selected from H, CH 2 OH, CH 2 OJ 4 , and CH 2 CH 2 OJ 4 ; T 2 is selected from NO 2 , CF 3 , OCF 3 , CN, and CH 2 OH CO 2 J 5 ; M is H; R 1 is selected from H, CH 2 OH, CH 2 CH 2 OJ 7 , CO 2 J 7 , CON(J 7 ) 2 , NO 2 , CN, F, Cl, Br, I, CF 3 , OCF 3 , SO 2 J 7 , N J 7 J 7 and N 3 ; R 2 is selected from H, CH 2 OH, CH 2 CH 2 OJ 7 , CO 2 J 7 , CON(J 7 ) 2 , NO 2 , CN, F, Cl, Br, I, CF 3 , OCF 3 , SO 2 J 7 , N J 7 J 7 and N 3 ; R 3 is selected from H, NO 2 , CN, F, Cl, Br, I, CF 3 , N J 7 J 7 and N 3 ; R 4 is selected from H, NO 2 , CN, F, Cl, Br, I, CF 3 , N J 7 J 7 and N 3 ; J 4 is selected from H, and a 1-6 carbon linear, branched or cyclic alkyl; J 5 is 1-6 carbon linear, branched or cyclic alkyl; and J 7 is selected from H, and a 1-6 carbon linear, branched or cyclic alkyl.
  3. 3 . The compound of claim 1 , wherein X 1 is S; X 2 is S; and Z 1 is N.
  4. 4 . The compound of claim 1 , wherein T 1 is selected from H and CH 2 OJ 4 ; and T 2 is selected from NO 2 , CF 3 and CN.
  5. 5 . The compound of claim 1 , wherein R 1 is selected from H, CO 2 J 7 , NO 2 , CN, F, Cl, Br, CF 3 , OCF 3 , SO 2 J 7 and N 3 ; R 2 is selected from H, CH 2 OH, NO 2 , CN, F, Cl, Br, CF 3 , and N 3 ; R 3 is selected from H, NO 2 , CN, F, Cl, Br, CF 3 , and N 3 ; and R 4 is selected from H, NO 2 , CN, F, Cl, Br, CF 3 , and N 3 .
  6. 6 . The compound of claim 1 , wherein the compound is selected from one or more of:
  7. 7 . The compound claim 1 , wherein the compound is selected from one or more of:
  8. 8 . The compound of claim 2 , wherein X 1 is S; X 2 is S; and Z 1 is N.
  9. 9 . The compound of claim 2 , wherein T 1 is selected from H and CH 2 OJ 4 ; and T 2 is selected from NO 2 , CF 3 , and CN.
  10. 10 . The compound of claim 2 , wherein R 1 is selected from H, CO 2 J 7 , NO 2 , F, Cl, Br, CF 3 , OCF 3 , SO 2 J 7 and N 3 ; R 2 is selected from H, NO 2 , CN, F, Cl, and Br; R 3 is selected from H, F, Cl, and Br; and R 4 is selected from H.
  11. 11 . The compound of claim 2 , wherein the compound is selected from one or more of:
  12. 12 . The compound of claim 2 , wherein the compound is selected from one or more of:

Description

CROSS REFERENCE TO RELATED APPLICATION This application is a National Stage of International Application No. PCT/CA2020/051724 filed Dec. 15, 2020, which claims the benefit of U.S. Provisional Patent Application Ser. No. 62/948,672 filed Dec. 16, 2019, the disclosure of each of which is expressly incorporated herein by reference in its entirety. TECHNICAL FIELD This invention relates to therapeutic compounds, their uses and methods for the treatment of viral infection. The viral infection may be a retroviral infection or ones whose replication is dependent upon host cell RNA processing factors (for example, adenovirus, herpes, influenza, SARS, coronavirus). The compounds are shown to interfere with the RNA processing of both HIV-1 and adenovirus, as evidenced by changes in accumulation of viral RNA spliced forms and the modification of cellular proteins involved in regulating RNA processing. The invention provides compounds that may be suitable for the treatment of HIV AIDS as well as other viral infections (adenovirus, influenza, hepatitis B, herpes, coronavirus) dependent upon the activity of the RNA processing factors modified. BACKGROUND Acquired Immunodeficiency Syndrome (AIDS) is a disease of the immune system resulting from infection with Human Immunodeficiency Virus (HIV). The HIV virus is a retrovirus, which is a type of RNA virus that inserts a copy of its genome into the DNA of an infected host cell to change the genome of the host cell. Once inside the host cell's cytoplasm, the virus reverse-transcribes DNA from its RNA genome using a reverse transcriptase enzyme. The viral DNA is then incorporated into the host cell genome by an integrase enzyme to form a provirus. Both the reverse transcriptase enzyme and the integrase enzyme form part of the HIV virion. When the host cell transcribes and translates its own genomic DNA, the viral genes of the provirus are made into viral proteins suitable for assembly into new viruses. HIV are found as two species of Lentivirus: HIV-1 and HIV-2. Each type may be transmitted through direct contact with HIV-infected body fluids. The HIV virus is effective at disrupting the human immune system. Particular targets for HIV are helper T cells (especially, CD4+ T cells), macrophages, and dendritic cells. Following host infection levels of CD4+ T cells usually drop below a critical level whereby cell-mediated immunity is lost and the body becomes progressively more susceptible to opportunistic infections and cancers. To be diagnosed with AIDS, a person with HIV must have an AIDS-defining condition or have a CD4 count less than 200 cells/mm3. Highly active antiretroviral therapy (HAART), which is also sometimes referred to as combined Antiretroviral Therapy (cART) or Antiretroviral Therapy (ART), targets multiple viral proteins or processes, including: viral entry; reverse transcription; integration; transcription; and virus assembly and production. HAART is capable of reducing the viral load to below 50 copies and replenished the number of CD4+ T cells. However, despite increased survival rates, AIDS is now a chronic condition resulting in complications from long-term HAART (i.e. disrupted lipid metabolism). Despite the obvious benefits of HAART the treatment has low specificity, is highly toxic and expensive. Furthermore, HAART is thought to promote selection of viral mutants that are less susceptible to HAART. Lastly, HARRT does not address the problem of HIV reservoir, where dormant virus may reside in resting T cells. Recently, it was determined that the stilbene-based compound, 2-(2-(5-nitro-2-thienyl)vinyl)quinolone (known as 5350150), blocked HIV replication, through a mode of action that involved interference with the export of HIV mRNAs from the nucleus to the cytoplasm (Wong, Balachandran et al. 2013). Although 5350150 manifested its activity at concentrations below its toxicity threshold, the known photolabile/toxic properties of related thiophene substituted stilbene compounds strongly suggested that any effort to exploit the anti-HIV properties of this system would have to begin with replacement of the central stilbene double bond. SUMMARY This invention is based in part on the discovery that compounds described herein modulate viral infection. Fortuitously, it was found that the compounds described herein are capable of interfering with the processing and export of viral mRNAs from the nucleus to the cytoplasm. Such compounds show an inhibition of HIV, adenovirus and coronavirus replication post-entry. The invention provides compounds that may be suitable for the treatment of HIV AIDS and other viral diseases. In a first aspect, there is provided, a compound having the structure of Formula I: wherein, X1 may be selected from S, O and N-J1; X2 may be selected from S, O and N-J2; Z1 may be selected from CH, N and CE; Z2 may be selected from CH, N and CR4; Z3 may be selected from CH, N and CR3; E may be selected from an optionally substituted 1-6 carbon li