Nucleosides with antiviral and anticancer activity

A composition of matter comprising compound of formula V:

• wherein
• R11 is adenine, guanine, cytosine, thymine, or uracil, optionally substituted by 1, 2, or 3 U;
• wherein each U is independently halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, hydroxy(C1-C6)alkyl, —(CH2)1-4P(═O)(ORw)2, aryl, aryl(C1-C6)alkyl, or NRxRy;
• one of R12 and R13 is azido and the other is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, —N(Rz)C(═O)N(Raa)(Rab), —N(Rz)C(═O)ORac, or NRadRae;
• R14 is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, aryl(C1-C6)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted by 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
• R15 is an amino acid or a peptide;
• W is oxy, thio, or methylene;
• each Rw is independently hydrogen or (C1-C6)alkyl;
• Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rx and Ry together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• Rz is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• Raa and Rab are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• or Raa and Rab together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• and
• Rac is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• and
• Rad and Rae are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rad and Rae together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• or a pharmaceutically acceptable salt thereof;
• linked to a reagent that is capable of targeting the compound to a tumor or cancer cell;
• wherein the reagent is a peptide, polyclonal antibody, or monoclonal antibody.

A compound of formula I:

• wherein
• R1 is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, or NRaRb;
• R2 and R3 are each independently hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, or NRcRd;
• R4 is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, aryl(C1-C6)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted with 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
• R5 is an amino acid or a peptide;
• X is oxy, thio, or methylene;
• Ra and Rb are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Ra and Rb together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• Rc and Rd are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, (C1-C6)alkanoyl, —C(═O)N(Re)(Rf), or —C(═O)ORg;
• or Rc and Rd together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• Re and Rf are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• or Re and Rf together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• and Rg is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• or a pharmaceutically acceptable salt thereof.

The compound of formula II:

• wherein
• R6 is adenine, guanine, cytosine, thymine, 3-deazaadenine, or uracil, optionally substituted by 1, 2, or 3 Y;
• wherein each Y is independently halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, hydroxy(C1-C6)alkyl, —(CH2)1-4P(═O)(ORk)2, aryl, aryl(C1-C6)alkyl, or NRmRn, and wherein any aryl ring may optionally be substituted with 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino
• one of R7 and R8 is —N(Rb)C(═O)N(Rp)(Rq), or N(Ro)C(═O)ORr, and the other is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, or NRaRc
• R9 is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, aryl(C1-C6)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted by 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
• R10 is an amino acid or a peptide;
• X is oxy, thio, or methylene;
• each Rk is independently hydrogen or (C1-C6)alkyl;
• Rm and Rn are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rm and Rn together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• Ro is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• Rp and Rq are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• or Rp and Rq together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• and
• Rr is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• and
• Rs and Rt are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rs and Rt together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• or a pharmaceutically acceptable salt thereof.

The compound 3-deaza adenosine-5′-N-(1-carbomethoxy-2-phenylethyl)phosphoramidate;

• 3-deaza adenosine-5′-N-(1-carbomethoxy-2-indolylethyl)phosphoramidate;
• 3-deaza aristeromycin-5′-N-(1-carbomethoxy-2-phenylethyl)phosphoramidate;
• 3-deaza adenosine-5′-N-(1-methylaminocarbonyl-2-phenylethyl)phosphoramidate;
• or 3-deaza adenosine-5′-N-[1-methylamino-carbonyl-2-(3-indolyl)ethyl]phosphoramidate;
• or a pharmaceutically acceptable salt thereof.

A therapeutic method comprising treating breast cancer by administering to a mammal in need of such therapy, an effective amount of a compound of formula VII:

• wherein
• R16 is adenine, guanine, cytosine, thymine, 3-deazaadenine, or uracil, optionally substituted by 1, 2, or 3 U;
• wherein each U is independently halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, hydroxy(C1-C6)alkyl, —(CH2)1-4P(═O)(ORk)2, aryl, aryl(C1-C6)alkyl, or NRxRy;
• one of R17 and R18 is hydroxy and the other is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, —N(Rz)C(═O)N(Raa)(Rab), —N(Rz)C(═O)ORac, or NRadRae;
• R19 is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, aryl(C1-C6)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted by 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
• R20 is an amino acid or a peptide;
• W is oxy, thio, or methylene;
• each Rw is independently hydrogen or (C1-C6)alkyl;
• Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rx and Ry together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• Rz is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• Raa and Rab are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• or Raa and Rab together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• and
• Rag is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• and
• Rad and Rae are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rad and Rae together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• or a pharmaceutically acceptable salt thereof.

A process for preparing a compound of formula V:

• wherein
• R11 is adenine, guanine, cytosine, thymine, 3-deazaadenine, or uracil, optionally substituted by 1, 2, or 3 U;
• wherein each U is independently halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, hydroxy(C1-C6)alkyl, —(CH2)1-4P(═O)(ORv)2, aryl, aryl(C1-C6)alkyl, or NRxRy;
• one of R12 and R13 is azido and the other is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, —N(Rz)C(═O)N(Raa)(Rab), —N(Rz)C(═O)ORac, or NRadRae;
• R14 is hydrogen;
• R15 is an amino acid or a peptide;
• W is oxy, thio, or methylene;
• each Rw is independently hydrogen or (C1-C6)alkyl;
• Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rx and Ry together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• Rz is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• Raa and Rab are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• or Raa and Rab together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• and
• Rac is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• and
• Rad and Rae are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rad and Rae together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• or a pharmaceutically acceptable salt thereof;
• the process comprising deprotecting a corresponding compound of formula 46
• wherein Pg is a suitable removable protecting group.

A process for preparing a compound of formula VII:

• wherein
• R16 is adenine, guanine, cytosine, thymine, 3-deazaadenine, or uracil, optionally substituted by 1, 2, or 3 U;
• wherein each U is independently halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, hydroxy(C1-C6)alkyl, —(CH2)1-4P(═O)(ORw)2, aryl, aryl(C1-C6)alkyl, or NRxRy;
• one of R17 and R18 is hydroxy and the other is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, —N(Rz)C(═O)N(Raa)(Rab), —N(Rz)C(═O)ORac, or NRadRae;
• R19 is hydrogen;
• R20 is an amino acid or a peptide;
• W is oxy, thio, or methylene;
• each Rw is independently hydrogen or (C1-C6)alkyl;
• Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rx and Ry together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• Rx is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• Raa and Rab are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• or Raa and Rab together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• and
• Rac is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• and
• Rad and Rae are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rad and Rae together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• or a pharmaceutically acceptable salt thereof;
• the process comprising deprotecting a corresponding compound of formula 47:
• wherein Pg is a suitable removable protecting group.

The compound 3′-Azido-3′-deoxythymidine-5′-methylaminoglycinylphosphoramidate;

• 3′-Azido-3′-deoxythymidine-5′-methylamino-L-alaninylphosphoramidate;
• 3′-Azido-3′-deoxythymidine-5′-methylamino-L-valinylphosphoramidate;
• 3′-Azido-3′-deoxythymidine-5′-methylamino-L-leucinyl-phosphoramidate;
• 3′-Azido-3′-deoxythymidine-5′-methylamino-L-phenylalaninyl-phosphoramidate;
• 3′-Azido-3′-deoxythymidine-5′-methylamino-D-phenylalaninyl-phosphoramidate;
• 3′-Azido-3′-deoxythymidine-5′-methylamino-L-tyrosinylphosphoramidate;
• 3′-Azido-3′-deoxythymidine-5′-methylamino-L-tryptophanyl-phosphoramidate;
• 3′-Azido-3′-deoxythymidine-5′-methylamino-D-tryptophanyl-phosphoramidate;
• 3′-Azido-3′-deoxythymidine-5′-ethylamino-L-tryptophanyl-phosphoramidate;
• 3′-Azido-3′-deoxythymidine-5′-isopropylamino-L-tryptophanyl-phosphoramidate;
• 3′-Azido-3′-deoxythymidine-5′-cyclopropylamino-L-tryptophanyl-phosphoramidate;
• or 3′-Azido-3′-deoxythymidine-5′-cyclohexylamino-L-tryptophanyl-phosphoramidate;
• or a pharmaceutically acceptable salt thereof.

A composition of matter comprising a compound of formula V:

• wherein
• R11 is adenine, guanine, cytosine, thymine, or uracil, optionally substituted by 1, 2, or 3 U;
• wherein each U is independently halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, hydroxy(C1-C6)alkyl, —(CH2)1-4P(═O)(ORw)2, aryl, aryl(C1-C6)alkyl, or NRxRy;
• one of R12 and R13 is azido and the other is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, —N(Rz)C(═O)N(Raa)(Rab), —N(Rz)C(═O)ORac, or NRadRae;
• R14 is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, aryl(C1-C6)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted by 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
• R15 is an amino acid or a peptide;
• W is oxy, thio, or methylene;
• each Rw is independently hydrogen or (C1-C6)alkyl;
• Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rx and Ry together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• Rz is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• Raa and Rab are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• or Raa and Rab together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• and
• Rac is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
• and
• Rad and Rae are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl;
• or Rad and Rae together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
• or a pharmaceutically acceptable salt thereof;
• linked to a reagent that is capable of targeting the compound to a tumor or cancer cell;
• wherein the tumor or cancer cell is non phagocytic.