ARYLNAPHTHALENE COMPOUNDS AS VACUOLAR-ATPASE INHIBITORS AND THE USE THEREOF

20210230149

17/223106

April 06, 2021

Ebola virus and Marburg virus are filoviruses and are responsible for outbreaks that cause up to 90% fatality, including the recent outbreak in West Africa that has resulted in over 11,000 deaths. The present disclosure generally relates to series novel arylnaphthalene compounds, having a formula (I) or a pharmaceutically acceptable salt thereof, as a vacuolar-ATPase inhibitor that are useful for the treatment for a broad spectrum of viral infections, including those infections caused by filoviruses. Pharmaceutical composition matters and methods of use are within the scope of this invention. [chemical expression included]

Purdue Research Foundation (West Lafayette, IN, US)

1. A compound having a formula [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein A is C═O, CR2, CH2, CHR, O, S, NH, NR, wherein R is an alkyl; B is hydrogen (H), deuterium (D), or fluorine (F); X is C═O, CR2, CH2, CHR, O, S, NH, NR, wherein R is an alkyl; Y is O, CF2, CH2, CHR, S, NH, NR, wherein R is an alkyl; R1 is hydrogen, an alkyl, alkylamide, alkenyl, alkenylamide, alkenylamino, alkynyl, alkynylamide, alkynylamino, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl; and R2, R3, and R4 are each independently selected from the group consisting of hydrogen, deuterium, —CN, —CF3, and a halo.

2. The compound according to claim 1, wherein R1 is [chemical expression included] —CH2CH2O(CH2)nR7, —CH2CH2CH2O(CH2)nR7, —CH2CH2CH2CH2O(CH2)nR7, —CH2(CH2)nR7, or, wherein n=1˜4 and R7 is [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] wherein Z is a halogen, C1˜C3 alkyl, —CF3, —CN, or —CONR2, wherein R is hydrogen or a C1˜C3 alkyl, and * represents site of attachment.

3. The compound according to claim 1, wherein the compound has the following formula: [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein B is hydrogen (H), deuterium (D), or fluorine (F); X is CR2, CH2, CHR, O, S, NH, NR, wherein R is an alkyl; R2, R3, and R4 are each independently selected from the group consisting of hydrogen, deuterium, —CN, —CF3, and a halo; and R1 is [chemical expression included] —CH2CH2O(CH2)nR7, —CH2CH2CH2O(CH2)nR7, —CH2CH2CH2CH2O(CH2)nR7, —CH2(CH2)nR7, or, wherein n=1˜4 and R7 is [chemical expression included] [chemical expression included] wherein Z is a halogen, C1˜C3 alkyl, —CF3, —CN, or —CONR2, wherein R is hydrogen or a C1˜C3 alkyl, and * represents site of attachment.

4. The compound according to claim 3, wherein the compound has the formula (III), [chemical expression included] wherein R1 is selected from the group consisting of [chemical expression included] —CH2CH2O(CH2)nR7, —CH2CH2CH2O(CH2)nR7, —CH2CH2CH2CH2O(CH2)nR7, —CH2(CH2)nR7, or, wherein n=1˜4 and R7 is [chemical expression included] [chemical expression included] [chemical expression included] wherein Z is a halogen, C1˜C3 alkyl, —CF3, —CN, or —CONR2, wherein R is hydrogen or a C1˜C3 alkyl, and * represents site of attachment.

5. The compound according to claim 3, wherein B is deuterium and R2, R3, and R4 are hydrogen.

6. The compound according to claim 3, wherein B is fluorine (F); and R2, R3, and R4 are hydrogen.

7. The compound according to claim 3, wherein B, R2, R3, and R4 are hydrogen.

8. The compound according to claim 3, wherein said compound has the following structure: [chemical expression included] [chemical expression included]

9. A pharmaceutical composition comprising one or more compounds of claim 1, or a pharmaceutically acceptable salt thereof, together with one or more diluents, excipients or carriers.

10. The compound according to claim 1, wherein the compound is an antiviral agent.

11. The compound according to claim 1, wherein the compound is an antiviral agent for the treatment of a viral infection by flaviviridae viruses, including Dengue virus, West Nile virus, Yellow fever virus, Japanese encephalitis virus, Powassan virus, Zika virus, and Usutu virus; respiratory viruses, including MERS coronavirus, Influenza A H1N1 virus, Respiratory syncytial virus; Arenaviridae virus, including Tacaribe virus, Pichinde virus, Junin virus, Lassa fever virus, Lymphocytic Choriomeningitis virus; Filoviridae virus, including Ebolavirus, Marburgvirus; Togaviridae virus, including Venezuelan equine encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, and Chikungunya virus; Mayarovirus; and Hantavirus.

12. A method for treating a patient with a viral infection, comprising the step of administering a therapeutically effective amount of one or more compounds of claim 1, and one or more carriers, diluents, or excipients, to a patient in need of relief from said infection.

13. A method for treating a patient with a viral infection, comprising the step of administering a therapeutically effective amount of a compound of claim 1 in combination with one or more other compounds of the same or different mode of action, and one or more carriers, diluents, or excipients, to a patient in need of relief from said viral infection.

14. A drug conjugate comprising one or more compounds of claim 1, wherein the conjugate confers cell-type or tissue type targeting or the conjugate targets another pathway that synergizes the action of compounds of claim 1.

15. A pharmaceutical composition comprising nanoparticles of one or more compounds of claim 1, together with one or more diluents, excipients or carriers.

16. A method for treating a patient with an infection, comprising the step of administering a therapeutically effective amount of one or more compounds, together with one or more carriers, diluents, or excipients, to a patient in need of relief from said infection, the compound having formula (I): [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein A is C═O, CR2, CH2, CHR, O, S, NH, NR, wherein R is an alkyl; B is hydrogen (H), deuterium (D), or fluorine (F); X is C═O, CR2, CH2, CHR, O, S, NH, NR, wherein R is an alkyl; Y is O, CF2, CH2, CHR, S, NH, NR, wherein R is an alkyl; R1 is hydrogen, an alkyl, alkylamide, alkenyl, alkenylamide, alkenylamino, alkynyl, alkynylamide, alkynylamino, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycll, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl; and R2, R3, and R4 are each independently selected from the group consisting of hydrogen, deuterium, —CN, —CF3, and a halo.

17. The method according to claim 16, wherein said compound has a formula [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein B is hydrogen (H), deuterium (D), or fluorine (F); X is CR2, CH2, CHR, O, S, NH, NR, wherein R is an alkyl; R2, R3, and R4 are each independently selected from the group consisting of hydrogen, deuterium, —CN, —CF3, and a halo; and R1 is [chemical expression included] —CH2CH2O(CH2)nR7, —CH2CH2CH2O(CH2)nR7, —CH2CH2CH2CH2O(CH2)nR7, —CH2(CH2)nR7, or, wherein n=1˜4 and R7 is [chemical expression included] [chemical expression included] [chemical expression included] wherein Z is a halogen, C1˜C3 alkyl, —CF3, —CN, or —CONR2, wherein R is hydrogen or a C1˜C3 alkyl, and * represents site of attachment.

18. The method according to claim 16, wherein said compound has the formula (III), [chemical expression included] wherein R1 is selected from the group consisting of [chemical expression included] —CH2CH2O(CH2)nR7, —CH2CH2CH2O(CH2)nR7, —CH2CH2CH2CH2O(CH2)nR7, —CH2(CH2)nR7, or, wherein n=1˜4 and R7 is [chemical expression included] [chemical expression included] [chemical expression included] wherein Z is a halogen, C1˜C3 alkyl, —CF3, —CN, or —CONR2, wherein R is hydrogen or a C1˜C3 alkyl, and * represents site of attachment.

19. The method according to claim 16, wherein said infection is a viral infection.

20. The method according to claim 19, wherein said viral infection is an infection by flaviviridae viruses, including Dengue virus, West Nile virus, Yellow fever virus, Japanese encephalitis virus, Powassan virus, Zika virus, and Usutu virus; respiratory viruses, including MERS coronavirus, Influenza A H1N1 virus, Respiratory syncytial virus; Arenaviridae virus, including Tacaribe virus, Pichinde virus, Junin virus, Lassa fever virus, Lymphocytic Choriomeningitis virus; Filoviridae virus, including Ebolavirus, Marburgvirus; Togaviridae virus, including Venezuelan equine encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, and Chikungunya virus; Mayarovirus; and Hantavirus.

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