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EP-3448392-B1 - ALKYNE CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO

EP3448392B1EP 3448392 B1EP3448392 B1EP 3448392B1EP-3448392-B1

Inventors

  • BLUEMLING, Gregory
  • DE LA ROSA, ABEL
  • PAINTER, GEORGE
  • KUIPER, Damien
  • KOLYKHALOV, ALEXANDER

Dates

Publication Date
20260513
Application Date
20170428

Claims (13)

  1. A compound of the following formula: or pharmaceutically acceptable salts thereof wherein, X is OCH 2 , OCHMe, OCMe 2 , OCHF, OCF 2 , or OCD 2 ; W is N or CR 7 Z is N or CR 8 ; R 1 is selected from H or from one of the following formulae: Y is O or S; Y 1 is OH, OAryl, OAlkyl, or BH 3 - M + ; Y 2 is OH or BH 3 - M + ; Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl; R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl; R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid; R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl; R 6 is methyl, ethyl, tert-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy; R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, or cyano; R 8 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano; or a compound of the following formula: or pharmaceutically acceptable salts thereof wherein, X is OCH 2 , OCHMe, OCMe 2 , OCHF, OCF 2 , or OCD 2 ; W is N or CR 7 ; R 1 is selected from H or from one of the following formulae: Y is O or S; Y 1 is OH, OAryl, OAlkyl, or BH 3 - M + ; Y 2 is OH or BH 3 - M + ; Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl; R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl; R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid; R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl; R 6 is methyl, ethyl, tert-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy; R 7 is D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, or cyano; or a compound of the following formula: or pharmaceutically acceptable salts thereof wherein, X is OCMe 2 , OCHF, OCF 2 , or OCD 2 ; R 1 is selected from H or from one of the following formulae: Y is O or S; Y 1 is OH, OAryl, OAlkyl, or BH 3 - M + ; Y 2 is OH or BH 3 - M + ; Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl; R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl; R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid; R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl; R 6 is methyl, ethyl, tert-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy.
  2. A compound as claimed in claim 1 selected from the following:
  3. A compound as claimed in claim 1 selected from the following:
  4. A compound as claimed in claim 1 selected from the following:
  5. A compound of the following formula: or pharmaceutically acceptable salts thereof wherein, X is OCH 2 , OCHMe, OCMe 2 , OCHF, OCF 2 , or OCD 2 ; R 1 is selected from H or from one of the following formulae: Y is O or S; Y 1 is OH, OAryl, OAlkyl, or BH 3 - M + ; Y 2 is OH or BH 3 - M + ; Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl; R 2 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, cyclopropyl, fluoro, chloro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl; R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid; R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl; R 6 is methyl, ethyl, tert-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy; R 7 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, or cyano; R 8 is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, methoxy, ethoxy, alkoxy, substituted amino, or cyano; or a compound of the following formula: or pharmaceutically acceptable salts thereof wherein, X is OCH 2 , OCHMe, OCMe 2 , OCHF, OCF 2 , or OCD 2 ; R 1 is selected from H or from one of the following formulae: Y is O or S; Y 1 is OH, OAryl, OAlkyl, or BH 3 - M + ; Y 2 is OH or BH 3 - M + ; Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl; R 2 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, fluoro, hydroxymethyl, aminomethyl, vinyl, or cyclobutyl; R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid; R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl; R 6 is methyl, ethyl, tert-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy; R 8 is H, D, alkyl, or halo; or a compound of the following formula: or pharmaceutically acceptable salts thereof wherein, X is OCHMe, OCMe 2 , OCHF, OCF 2 , or OCD 2 ; R 1 is selected from H or from one of the following formulae: Y is O or S; Y 1 is OH, OAryl, OAlkyl, or BH 3 - M + ; Y 2 is OH or BH 3 - M + ; Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl; R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid; R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl; R 6 is methyl, ethyl, tert-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy; R 8 is H, D, alkyl, or halo; or a compound of the following formula: or pharmaceutically acceptable salts thereof wherein, R 1 is selected from H or from one of the following formulae: Y is O or S; Y 1 is OH, OAryl, OAlkyl, or BH 3 - M + ; Y 2 is OH or BH 3 - M + ; Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl; R 4 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid; R 5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22 alkoxy, C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, or substituted heteroaryl; R 6 is methyl, ethyl, tert-butyl, C 1-22 alkoxy, C 1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy; R 8 is H, D, alkyl, or halo.
  6. A compound as claimed in claim 5 selected from the following:
  7. A compound as claimed in claim 5 selected from the following:
  8. A compound as claimed in claim 5 selected from the following:
  9. A pharmaceutical composition for use in the treatment or prevention of a viral infection comprising a compound of any of claims 1-8, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, wherein the viral infection is caused by an infectious agent comprising a RNA virus.
  10. The pharmaceutical composition for use according to claim 9 wherein the RNA virus comprises hepaciviruses, flaviviruses or Zika virus.
  11. A liposomal composition comprising a compound of any of claims 1-8, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
  12. A compound as claimed in any of claims 1-8 for use in treating or preventing infections caused by RNA viruses.
  13. The compound for use according to claim 12 wherein the RNA virus comprises hepaciviruses, flaviviruses, or Zika virus.

Description

FIELD This disclosure relates to alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to nucleosides optionally conjugated to a phosphorus oxide or salts thereof. In certain embodiments, the disclosure relates to conjugate compounds or salts thereof comprising an amino acid ester, a lipid or a sphingolipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside. In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising these compounds for uses in treating infectious diseases, viral infections, and cancer. BACKGROUND Nucleoside and nucleotide phosphates and phosphonates are clinically useful as antiviral agents. Two examples are tenofovir disoproxil fumarate for the treatment of human immunodeficiency virus and adefovir dipivoxil for the treatment of hepatitis B virus infections. Administration of three or more antiretroviral agents in combination, e.g., Highly Active Antiretroviral Therapy (HAART), has significantly reduced the morbidity and mortality associated with HIV infection. However, there is a growing need for new antiviral agents to address the critical issues of resistance and penetration into viral sanctuaries (commonly referred to as privileged compartments). Permeability into privileged compartments may be partially responsible for the current inability of chemotherapy to totally clear a patient of HIV infection and the emergence of resistance. Anti-viral agents that are unphosphorylated nucleotides and nucleotide derivatives need to be phosphorylated to actively inhibit viral replication. Nucleoside analogues enter a cell via two types of broad-specificity transporters, concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs). Once inside, they utilize the host's nucleoside salvage pathway for sequential phosphorylation by deoxynucleoside kinases (dNKs), deoxynucleoside monophosphate kinases (dNMPKs) and nucleoside diphosphate kinase (NDPK). However, intracellular activation of these compounds is often compromised by the high substrate specificity of the host's endogenous kinases. In vitro and in vivo studies have demonstrated that the first and/or second phosphorylation, catalyzed by dNKs and dNMPKs, often represent the rate-limiting steps in nucleoside analogue activation. Thus, there is a need to identifying improved antiviral nucleoside analogues with structural features that are sufficiently activated by cellular kinases. McGuigan et al., J Med Chem, 2005, 48(10), 3504-3515, report phenylmethoxyalaninyl phosphoramidate of abacavir as a prodrug leads to enhancement of antiviral potency. Painter et al., Antimicrob Agents Chemother, 2007, 51(10), 3505-3509, report promoting the oral availability of tenofovir with a hexadecyloxypropyl prodrug ester, designated CMX157. Sphingolipids play roles in cell-cell and cell-substratum interactions, and help regulate growth and differentiation by a variety of mechanisms, such as inhibition of growth factor receptor kinases and effects on numerous cellular signal transduction systems. U.S. patent 6,610,835 discloses sphingosine analogues. It also discloses methods of treating infections and cancer. Pruett et al., J. Lipid Res. 2008, 49(8), 1621-1639, report on sphingosine and derivatives.Bushnev et al., ARKIVOC, 2010, (viii):263-277, report an asymmetric synthetic method for preparing sphingolipid derivatives. Dougherty et al., Org. Lett. 2006, 8(4), 649-652, report the synthesis of 1-deoxysphingosine derivatives. Wiseman et al., Org. Lett. 2005, 7(15), 3155-3157, report 1-deoxy-5-hydroxysphingolipids in anticancer and stereoselective syntheses of 2-amino-3,5-diols. WO 2013/044030 relates to nucleoside derivatives with 2'-chloroacetylenyl substitution and methods for their preparation and use. Further related nucleosides may also be found in WO2015/200219 A1, WO2008/095993, WO 2014/100505 A1, WO 2014/100498, WO 2013/096680 A1, WO 2014/033617 A1, WO 2014/078463 A1, WO 2010/015637 A1. References cited herein are not an admission of prior art. SUMMARY The present invention provides a compound or pharmaceutically acceptable salt thereof according to claim 1. The present invention further provides a compound or pharmaceutically acceptable salt thereof according to claim 5. The invention further provides a phameceutical composition for use according to claim 9. The invention further provides a liposomal composition according to claim 11. The invention further provides a compound for use acording to claim 12. DETAILED DESCRIPTION This disclosure relates to alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to nucleosides optionally conjugated to a phosphorus oxide or salts thereof. In certain embodiments, the disclosure relates to conjugate compounds or salts thereof comprising an amino acid ester,