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US-20260124226-A1 - 4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO

US20260124226A1US 20260124226 A1US20260124226 A1US 20260124226A1US-20260124226-A1

Abstract

Disclosed are halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections. Such viral infections can include enterovirus, tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections.

Inventors

  • George R. Painter
  • Shuli Mao
  • Michael G. Natchus
  • Damien KUIPER
  • David Perryman

Assignees

  • EMORY UNIVERSITY

Dates

Publication Date
20260507
Application Date
20251105

Claims (20)

  1. 1 . A compound having the Formula XXX: or a pharmaceutically acceptable salt thereof, R 1 is a structure represented by a formula selected from: Q 2 is C(═O), O(C═O), S(C═O), NR 40 (C═O), C(═S), O(C═S), S(C═S), or NR 40 (C═S); Q 4 is C 5 -C 8 cycloalkyl, C-C 12 aryl, C 3 -C 12 heterocyclyl, or C 3 -C 12 heteroaryl; wherein Q 4 can be optionally independently substituted with one or more, the same or different, R 10 ; R 40 is in each case independently selected from hydrogen and C 1 -C 6 alkyl, optionally substituted one more times by R 10 ; R 10 is in each case independently deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) 2 amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl; and wherein R 10 is optionally substituted with one or more, the same or different, R 11 ; R 11 is in each case independently deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) 2 amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl; and lipid is independently a C 11 -C 22 alkyl, C 11 -C 22 alkoxy, or aryl substituted with an C 6 -C 18 alkyl group.
  2. 2 . The compound of claim 1 , wherein Q 2 is C(═O).
  3. 3 . The compound of claim 1 , wherein Q 2 is C(═O), O(C═O), C(═S), or O(C═S).
  4. 4 . The compound of claim 1 , wherein Q 4 is C 6 -C 12 aryl or C 3 -C 12 heteroaryl.
  5. 5 . The compound of claim 1 , wherein R 1 is: wherein Z 5 is selected from N and C—R 20e ; Z 6 is selected from N and C—R 20f ; Z 7 is selected from N and C—R 20g ; Z 8 is selected from N and C—R 20h ; Z 9 is selected from N and C—R 20i ; provided that no more than three of Z 5 , Z 6 , Z 7 , Z 8 , and Z 9 are N; R 20e , R 20f , R 20g , R 20h , R 20i , R 20o , and R 20p are each independently selected from hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl, OC 1 -C 6 alkyl, (C═O)C 1 -C 6 alkyl, (C═O)NR 40 C 1 -C 6 alkyl, (C═O)N(C 1 -C 6 alkyl) 2 , (C═O)OC 1 -C 6 alkyl or lipid; wherein said alkyl groups are optionally independently substituted with one or more, the same or different, R 10 ; wherein two of R 20e , R 20f , R 20g , R 20h , and R 20i may together form a ring, for example an optionally substituted 5- to 7-membered cycloalkyl or heterocyclyl ring; Z 10 is selected from N and C—R 20j ; Z 11 is selected from N—R 20k and C—R 20l R 20m ; R 20j , R 20l , and R 20m are each independently selected from hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl, OC 1 -C 6 alkyl, (C═O)C 1 -C 6 alkyl, (C═O)NR 40 C 1 -C 6 alkyl, (C═O)N(C 1 -C 6 alkyl) 2 , (C═O)OC 1 -C 6 alkyl, and lipid; wherein said alkyl groups are optionally independently substituted with one or more, the same or different, R 10 ; wherein any two of more of R 20j , R 20k , R 20l , R 20m , R 20o , and R 20p may together form a ring; R 20k is hydrogen or C 1 -C 6 alkyl optionally independently substituted with one or more, the same or different, R 10 ; and R 40 is in each case independently selected from hydrogen and C 1 -C 6 alkyl, optionally substituted one or more times by R 10 .
  6. 6 . The compound of claim 5 , wherein R 1 is:
  7. 7 . The compound of claim 5 , having the formula:
  8. 8 . The compound of claim 7 , wherein R 20e , R 20f , R 20g , R 20h , and R 20i are independently selected from hydrogen, deuterium, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, hydroxyl, amino, cyano, F, Cl, Br, and I, wherein at least one of R 20e , R 20f , R 20g , R 20h , and R 20i is not hydrogen.
  9. 9 . The compound of claim 5 , wherein R 20e , R 20f , R 20g , R 20h , and R 20i are independently selected hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, and halogen, wherein at least one of R 20e , R 20f , R 20g , R 20h , and R 20i is not hydrogen.
  10. 10 . The compound of claim 7 , wherein R 20e , R 20f , R 20g , R 20h , and R 20i are independently selected from hydrogen, CH 3 , OCH 3 , CF 3 , OCF 3 , and halogen.
  11. 11 . The compound of claim 10 , wherein at least one of R 20e , R 20f , R 20g , R 20h , and R 20i is not hydrogen.
  12. 12 . The compound of claim 11 , wherein at least one of R 20e , R 20f , R 20g , R 20h , and R 20i is halogen.
  13. 13 . The compound of claim 7 , wherein one or two of R 20e , R 20f , R 20g , R 20h , and R 20i is halogen and the others are hydrogen.
  14. 14 . The compound of claim 1 , wherein Q 4 is: wherein R h1 is CH 3 , OCH 3 , CF 3 , OCF 3 , I, Cl or F, and R h2 is H, CH 3 , OCH 3 , CF 3 , OCF 3 , I, Cl, or F.
  15. 15 . The compound of claim 1 , wherein the compound is selected from:
  16. 16 . The compound of claim 1 , having the formula:
  17. 17 . The compound of claim 1 , having the formula:
  18. 18 . The compound of claim 1 , having the formula:
  19. 19 . A method of treating or preventing a viral infection in a subject in need thereof comprising administering in effective amount of the compound of claim 1 to the subject.
  20. 20 . The method of claim 19 , wherein the viral infection comprises an infection with arterivirus, arenavirus, bunyavirus, calcivirus, coronavirus, filovirus, orbovirus, orthomyxovirus, paramyxovirus, picornavirus, or togovirus.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of International Patent Application No. PCT/US2024/027749, filed May 3, 2024, which claims priority to U.S. Provisional Application No. 63/500,416, filed May 5, 2023; U.S. Provisional Application No. 63/534,748, filed Aug. 25, 2023; U.S. Provisional Application No. 63/588,255, filed Oct. 5, 2023; and U.S. Provisional Application No. 63/571,795, filed Mar. 29, 2024; the disclosures of which are incorporated herein by reference. STATEMENT ACKNOWLEDGING GOVERNMENT SUPPORT This invention was made with government support under Grant No. W15QKN-16-9-1002 awarded by the Department of Defense and Grant No. AI171403 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD This disclosure relates to halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections, for example, respiratory viruses, enteroviruses, tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections, and conditions caused by these viruses. BACKGROUND New antiviral agents to treat or prevent a variety of viral infections are urgently needed. For example, the causative agents for Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively) and Chikungunya fever (CHIK) are vector-borne viruses (family Togaviridae, genus Alphavirus) that can be transmitted to humans through mosquito bites. The equine encephalitis viruses are CDC Category B pathogens, and the CHIK virus is Category C. There is considerable concern about the use of virulent strains of VEE virus, delivered via aerosol, as a bioweapon against warfighters. Animal studies have demonstrated that infection with VEE virus by aerosol exposure rapidly leads to a massive infection of the brain, with high mortality and morbidity. See Roy et al., Pathogenesis of aerosolized Eastern equine encephalitis virus infection in guinea pigs. Virol J, 2009, 6:170. What are needed are new compounds and treatments for viral infections. The compounds and methods disclosed herein addressed these needs. References cited herein are not an admission of prior art. SUMMARY This disclosure relates to halogen, e.g., 4′-halogen, containing nucleotide and nucleoside therapeutic compositions and uses related thereto. Included are nucleosides optionally conjugated to a phosphorus oxide or salts thereof, prodrugs or conjugate compounds or salts thereof comprising an amino acid ester, lipid or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside. In certain embodiments, the disclosure relates to a compound having a structure represented by a formula: or a subset of the foregoing, or a pharmaceutically acceptable salt, derivative, or prodrug thereof, as defined herein. In the foregoing formulas, the various substituent groups are understood to have the meaning as further disclosed herein below. In certain embodiments, the disclosure contemplates derivatives of compounds disclosed herein, such as those containing one or more, the same or different, substituents. In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein. In certain embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, or aqueous buffer, such as a saline or phosphate buffer. In certain embodiments, the disclosed pharmaceutical compositions can comprise a compound disclosed herein and a propellant. In certain embodiments, the propellant is an aerosolizing propellant such as compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HFAs), 1,1,1,2,-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or combinations thereof. In certain embodiments, the disclosure contemplates a pressurized or unpressurized container comprising a compound or pharmaceutical composition as described herein. In certain embodiments, the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer. In certain embodiments, the disclosure relates to methods of increasing bioavailability for treating or preventing a viral infection comprising administering an effective amount of a compound of Formulas XXIX-XXXIVb, or a pharmaceutical composition comprising a compound of Formulas XXIX-XXXIVb and a pharmaceutically acceptable excipient, disclosed herein to a subject in need thereof. In certain embodiments, the disclosure relates to methods of treating or preventing a viral infection comprising administering an effective amount of a co