Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals
  • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
  • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals
  • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

• the present invention is directed to nucleotide compounds and compositions and uses thereof to treat the Hepatitis C virus ("HCV").
• HCV Hepatitis C virus
• Hepatitis C is an RNA single stranded virus and member of the Hepacivirus genus. It is estimated that 75% of all cases of liver disease are caused by HCV. HCV infection can lead to cirrhosis and liver cancer, and if left to progress, liver failure which may require a liver transplant. Approximately 170-200 million people worldwide are infected, with an estimated 3-4 million infections in the United States.
• RNA polymerase is a key component in the targeting of RNA single stranded viruses.
• HCV non-structural protein NS5B RNA-dependent RNA polymerase is a key enzyme responsible for initiating and catalyzing viral RNA synthesis.
• HCV NS5B is an attractive target for the current drug discovery and development of anti-HCV agents.
• NS5B inhibitors There are two major subclasses of NS5B inhibitors: nucleoside analogs, which are anabolized to their active triphosphates - which act as alternative substrates for the polymerase - and non- nucleoside inhibitors (NNIs), which bind to allosteric regions on the protein.
• Nucleoside or nucleotide inhibitors mimic natural polymerase substrate and act as chain terminators. They inhibit the initiation of RNA transcription and elongation of a nascent RNA chain.
• RNA viral proteins may also be targeted in combination therapies.
• HCV proteins that are additional targets for therapeutic approaches are NS3/4A (a serine protease) and NS5A (a non- structural protein that is an essential component of HCV replicase and exerts a range of effects on cellular pathways).
• NS3/4A a serine protease
• NS5A a non- structural protein that is an essential component of HCV replicase and exerts a range of effects on cellular pathways.
• sofosbuvir Sovaldi , Gilead Sciences
• Sovaldi ® is a uridine phosphoramidate prodrug that is taken up by hepatocytes and undergoes intracellular activation to afford the active metabolite; 2'-deoxy- 2'-a-fluoro-P-C-methyluridine-5'-tri hosphate; see structures below:
• Sovaldi ® is the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the need for co-administration of interferon. Sovaldi ® is the third drug with breakthrough therapy designation to receive FDA approval.
• Harvoni ® ledispasvir, a NS5A inhibitor, and sofosbuvir
• Harvoni ® is the first combination pill approved to treat chronic HCV genotype 1 infection. It is also the first approved regimen that does not require administration with interferon or ribavirin.
• VIEKIRA PakTM a multipill pack containing dasabuvir (a non-nucleoside NS5B polymerase inhibitor), ombitasvir (a NS5A inhibitor), paritaprevir (a NS3/4A inhibitor), and ritonavir.
• the VIEKIRA Pak can be used with or without the ribavirin to treat genotype 1 HCV infected patients including patients with compensated cirrhosis.
• VIEKIRA PakTM does not require interferon co-therapy.
• interferon alpha-2b or pegylated interferon alpha-2b include interferon alpha-2b or pegylated interferon alpha-2b (Pegintron ® ), which can be administered with ribavirin (Rebetol ® ), NS3/4A telaprevir (Incivek ® , Vertex and Johnson & Johnson), boceprevir (VictrelisTM, Merck), simeprevir (OlysioTM, Johnson & Johnson), paritaprevir (Abb Vie), Ombitasvir (Abb Vie), (NNI) Dasabuvir (ABT-333) and Merck's ZepatierTM (a single-tablet combination of the two drugs grazoprevir and elbasvir).
• NS5B polymerase inhibitors are currently under development.
• Merck is developing the uridine nucleotide prodrug MK-3682 (formerly Idenix IDX21437). The drug is currently in Phase II combination trials.
• the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII and including P-D-2'-deoxy-2'-a-fluoro-2'-P- C-substituted-N 6 -(mono- or di-methyl) purine nucleotides are highly active against the HCV virus when administered in an effective amount to a host in need thereof.
• the host can be a human or any animal that carries the viral infection.
• Disclosed nucleotides include those with nanomolar activity against HCV in vitro and therapeutic indices that range to 25,000 or more.
• N 6 -(methyl) purine nucleosides of disclosed compounds had not been developed or specifically disclosed as drug candidates prior to this invention.
• 3'-azido-N 6 -dimethyl-2,6-diaminopurine is not substantially deaminated by adenosine deaminase over a long period (120 minutes), and for that reason it had been considered an inappropriate compound to derivatize as a drug (see for example, WO 2010/091386, page 86 and corresponding US Patent 8,609,627).
• compounds of the present invention are anabolized to a 5 -monophosphate of the N 6 -substituted-purine without substantial N 6 - deamination and then subsequently anabolized at the 6-position to generate active guanine triphosphate compounds, in a manner that provides exceptional activity and therapeutic index.
• compound 25 also has a therapeutic index of greater than 25,000.
• the metabolism of the P-D-2'-deoxy-2'-a-fluoro-2'-P-methyl-N 6 - methyl-2,6-diaminopurine nucleoside as a phosphoramidate involves the production of a 5'- monophosphate and the subsequent anabolism of the N 6 -methyl-2,6-diaminopurine base to generate the P-D-2'-deoxy-2'-a-fluoro-2'-P-methyl-guanine nucleoside as the 5'- monophosphate.
• the monophosphate is then further anabolized to the active species; the 5'- triphosphate.
• the invention is:
• Y is R3 ⁇ 4 2 ;
• R 1 is Ci-Csalkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CH 2 F, CHF 2 , CF 3 , CH2CF3, CF 2 CH 3 and CF 2 CF 3 ), C2-C6 alkenyl, C 2 -Ce alkynyl, -(Co-C 2 alkyl)(C 3 -C6cycloalkyl), -(Co- C 2 alkyl)(heterocycle), -(Co-C 2 alkyl)(aryl), -(Co-C 2 alkyl)(heteroaryl), -OR 25 , -C(0)R 3C (including -C(0)CH 3 , -C(0)CH 2 CH 3 -C(0)CH(CH 3 ) 2 , -C(0)
• R 2 is hydrogen, Ci-Csalkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CFIF2, CFIF2, CF 3 , CH 2 CF 3 and CF 2 CF 3 ), -(Co-C 2 alkyl)(C 3 -C6cycloalkyl), -C(0)R 3C (including -C(0)CH 3 , -C(0)CH 2 CH 3 - C(0)CH(CH 3 ) 2 , -C(0)OCH 3 , -C(0)OC 2 H 5 , -C(0)OC 3 H 7 , -C(0)OC 4 H 9 , and -C(0)OC 5 Hn), -(Co- C 2 alkyl)(aryl), -(Co-C 2 alkyl)(heterocycle), -(
• R 1 and R 2 is methyl, CH2F, CFIF2 or CF 3 ;
• R is hydrogen, , diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or -C(0)R 3C ;
• R 3A can be selected from O " , OH, an -O-optionally substituted aryl, an -O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl; R can be selected from O " , OH, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester;
• R 3C is alkyl, alkenyl, alkynyl, -(Co-C2)(cycloalkyl), -(Co-C2)(heterocyclo), -(Co-C2)(aryl), -(Co-C 2 )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(Co-C 2 )(cycloalkyl), -0-(Co- C 2 )(heterocyclo), -0-(Co-C 2 )(aryl), or -0-(Co-C 2 )(heteroaryl), each of which can be optionally substituted;
• R 4 is a monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, including but not limited to a phosphoramidate, a thiophosphoramidate, or any other moiety that is metabolized to a monophosphate, diphosphate or triphosphate in vivo in the host human or animal; or
• R 3 and R 4 together with the oxygens that they are bonded to can form a 3 ',5 '-cyclic prodrug, including but not limited to, a 3 ',5 '-cyclic phosphate prodrug;
• R 12 is CH 3 , CH 2 F, CHF 2 , CF 3 , or ethynyl.
• the invention is:
• Y is NR3 ⁇ 4 2 ;
• R 1 is Ci-Csalkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CF 2 CH 3 and CF 2 CF 3 ), C 2 -Ce alkenyl, C 2 -Ce alkynyl, -(Co-C 2 alkyl)(C 3 -C6cycloalkyl), -(Co- C 2 alkyl)(heterocycle), -(Co-C 2 alkyl)(aryl), -(Co-C 2 alkyl)(heteroaryl), -OR 25 , -C(0)R 3C (including -C(0)CH 3 , -C(0)CH 2 CH 3 -C(0)CH(CH 3 ) 2
• R 1 and R 2 are methyl, CH2F, CFIF2 or CF3;
• R is hydrogen, diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or
• R 3A can be selected from O " , OH, an -O-optionally substituted aryl, an -O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl;
• R 3B can be selected from O " , OH, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester;
• R 3C is alkyl, alkenyl, alkynyl, -(Co-C2)(cycloalkyl), -(Co-C2)(heterocyclo), -(Co-C2)(aryl), -(Co-C 2 )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(Co-C 2 )(cycloalkyl), -0-(Co- C 2 )(heterocyclo), -0-(Co-C 2 )(aryl), -0-(Co-C 2 )(heteroaryl), -S-alkyl, -S-alkenyl, -S-alkynyl, -S- (Co-C 2 )(cycloalkyl), -S-(Co-C 2 )(heterocyclo), -S-(Co-C 2 )(aryl), or -S-(Co-C 2
• R 3D is alkyl, alkenyl, alkynyl, -(Co-C 2 )(cycloalkyl), -(Co-C 2 )(heterocyclo), -(Co-C 2 )(aryl), -(Co-C 2 )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(Co-C 2 )(cycloalkyl), -0-(Co- C2)(heterocyclo), -0-(Co-C2)(aryl), or -0-(Co-C2)(heteroaryl), each of which can be optionally substituted;
• R 4 is a monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, including but not limited to a phosphoramidate, a thiophosphoramidate, or any other moiety that is metabolized to a monophosphate, diphosphate or triphosphate in vivo in the host human or animal; or R 3 and R 4 together with the oxygens that they are bonded to can form a 3 ',5 '-cyclic prodrug, including but not limited to, a 3 ',5 '-cyclic phosphate prodrug;
• R 5 is Ci-Csalkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CHF 2 , CHF 2 , CF 3 , CH2CF3 and CF 2 CF 3 ), C2-C6 alkenyl, C 2 -Ce alkynyl, -(Co-C 2 alkyl)(C 3 -C6cycloalkyl), -(Co-C 2 alkyl)(heterocycle), -(Co- C 2 alkyl)(aryl), -(Co-C 2 alkyl)(heteroaryl), -OR 25 , -C(0)R 3C (including -C(0)CH 3 , - C(0)CH 2 CH 3 -C(0)CH(CH 3 ) 2 , -C(0)OCH 3
• R 6 is hydrogen, optionally substituted Ci-Csalkyl (including methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CFIF2, CHF2, CF 3 , CH 2 CF 3 and CF 2 CF 3 ), optionally substituted -(Co-C 2 alkyl)(C 3 -C 6 cycloalkyl), optionally substituted -(Co-C 2 alkyl)(heterocycle), optionally substituted -(Co-C 2 alkyl)(aryl), optionally substituted -(Co-C 2 alkyl)(heteroaryl), -C(0)R 3C (including -C(0)CH 3 , - C(0)CH 2 CH 3 -C(0)CH(CH 3 ) 2 , -C(0)OCH 3 , -C(0)OC
• R 5 and R 6 together with the nitrogen that they are bonded to can form a heterocyclic ring
• R 12 is CH 3 , CH2F, CHF2, CF 3 , or ethynyl
• R 23 is Ci-Csalkyl, -(Co-C2alkyl)(C 3 -C6cycloalkyl), -(Co-C2alkyl)(heterocycle)-(Co- 2alkyl)(aryl) or -(Co-C2alkyl)(heteroaryl) each of which can be optionally substituted;
• R 24 is hydrogen, Ci-Ce alkyl, -(Ci-C 2 alkyl)(C 3 -C6cycloalkyl),
• R 25 is hydrogen, Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(Co-C 2 alkyl)(C 3 - C6cycloalkyl), -(Co-C2alkyl)(C 3 -C6heterocycle), -(Co-C2alkyl)(aryl) or -(Co-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted;
• R 26 is independently selected from hydrogen, Ci-C 6 alkyl, -(Co-C2alkyl)(C 3 - C6cycloalkyl), -(Co-C2alkyl)(heterocycle), -(Co-C2alkyl)(aryl), or -(Co-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted;
• R 27 hydrogen or optionally substituted Ci-C 6 alkyl
• R 28 is Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(Co-C2alkyl)(C 3 -C6cycloalkyl), -(Co-C2alkyl)(C 3 -C6heterocycle), -(Co-C2alkyl)(aryl) or -(Co-C2alkyl)(heteroaryl) each of which can be optionally substituted;
• R is hydrogen, Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -Ce alkynyl, -(Co-C 2 alkyl)(C3- C6cycloalkyl), -(Co-C 2 alkyl)(C3-C6heterocycle), -(Co-C 2 alkyl)(aryl) or -(Co-C 2 alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally
• R 27 and R 29 together with the nitrogen that they are bonded to can form a heterocyclic ring
• R 30 is hydrogen, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
• R 29 and R 30 can be bonded together to form a heterocyclic ring
• x is 1, 2 or 3.
• the metabolism of the P-D-2'-deoxy-2'-a-fluoro-2'-P-methyl-N 6 -dimethyl-2,6- diaminopurine nucleotide involves both the formation of the P-D-2'-deoxy-2'-a-fluoro-2'-P- methyl-N 6 -dimethyl-2,6-diaminopurine nucleoside triphosphate as well as the generation of the corresponding guanine nucleoside triphosphate. See Scheme 2 and 3.
• 2'-Deoxy-2'-a-fluoro-2'-P-C-substituted-N 6 -substituted-2,6-diaminopurine nucleotides can be further substituted at the N 2 -position by alkylation or acylated which can modify the lipophilicity, pharmacokinetics and/or targeting of the nucleotide to the liver.
• 2'-deoxy-2'-a-fluoro-2'-P-C-substituted-N 6 -substituted-2,6-diaminopurine nucleotides modified at the 2-position of the diaminopurine can be dealkylated or deacylated by hepatic enzymes to further increase the specificity of the nucleotide derivatives both in vitro and in vivo, unless the N 2 -amino group is completely replaced by a different moiety, as described herein, such as fluoro.
• nucleoside phosphoramidate 2'-deoxy-2'-a-fluoro-2'-P- methyl-N 2 -methyl-N 6 -methyl-2,6-diaminopurine nucleoside phosphoramidate is dealkylated to 2'-deoxy-2'-a-fluoro-2'-P-methyl-N 6 -methyl-2,6-diaminopurine nucleoside phosphoramidate when incubated with a human liver S9 fraction in vitro, up to 60 minutes, these conditions mimics in vivo conditions.
• N 2 modifications will increase cell permeability and hepatitic targeting.
• the compounds described herein are provided in the ⁇ -D- configuration.
• the amino acid portion can be in the L- or D-configuration.
• the compounds can be provided in a ⁇ -L-configuration.
• any substituent group that exhibits chirality can be provided in racemic, enantiomeric, diastereomeric form or any mixture thereof.
• a phosphoramidate, thiophosphoramidate or other stabilized phosphorus prodrug in which the phosphorus exhibits chirality is used as the R 4 stabilized phosphate prodrug, it can be provided as an R or S chiral phosphorus derivative or a mixture thereof, including a racemic mixture. All of the combinations of these stereoconfigurations are included in the invention described herein.
• the present invention includes a compound of Formula I- VII, or a pharmaceutically acceptable composition, salt, or prodrug thereof, as described herein:
• the parent nucleoside i.e., the nucleoside wherein R 4 is hydrogen and the 5'-position thus has a hydroxyl group
• the parent nucleoside is not substantially deaminated by adenosine deaminase under conditions that mimic the in vivo environment (e.g., ambient temperature and aqueous physiological pH), for a period of 7 minutes, 10 minutes, 30 minutes, 60 minutes or 120 minutes. Unless otherwise stated, the time period is 30 minutes.
• the term "not substantially deaminated” means that the parent compound is not converted to the corresponding guanine derivative, or 6-oxo derivative, in an amount sufficient to provide a therapeutic effect in vivo.
• Compounds, methods, and compositions are provided for the treatment of a host infected with a HCV virus via administration of an effective amount of the compound or its pharmaceutically acceptable salt.
• the compounds and compositions can also be used to treat related conditions such as anti-HCV antibody positive and antigen positive conditions, viral-based chronic liver inflammation, liver cancer resulting from advanced hepatitis C, cirrhosis, chronic or acute hepatitis C, fulminant hepatitis C, chronic persistent hepatitis C and anti-HCV-based fatigue.
• the compound or formulations that include the compounds can also be used prophylactically to prevent or restrict the progression of clinical illness in individuals who are anti-HCV antibody or antigen positive or who have been exposed to hepatitis C.
• Y, R 3 and R 4 are as defined above.
• R 3 is hydrogen
• Y, R 3 and R 4 are as defined above.
• R 3 is hydrogen
• Y, R 3 , R 4 and R 22 are as defined above.
• R 41 is halogen (in particular F or CI), OR 3 , N 3 , H 2 or CN; and
• the phosphorus in any of the Formulas above may be chiral and thus can be provided as an R or S enantiomer or mixture thereof, including a racemic mixture.
• Compound 5 was separated into the enantiomer compounds 5-1 and 5-2.
• Compound 5-2 was also prepared by chiral synthesis and assigned compound 24.
• compounds, methods, and compositions are provided for the treatment of a host infected with or exposed to hepatitis C described herein.
• the compounds of the invention can be administered in an effective amount alone or in combination with another anti-HCV drug, to treat the infected host.
• it is useful to administer a combination of drugs that modulates the same or a different pathway or inhibits a different target in the virus.
• P-D-2'-D-2'-a-fluoro-2'-P-C-substituted-2-modified-N 6 -substituted purine nucleotides are NS5B polymerase inhibitors
• it may be useful to administer the compound to a host in combination with a protease inhibitor such as an NS3/4A protease inhibitor (for example, telaprevir (Incivek®) boceprevir (VictrelisTM) simeprevir (OlysioTM), or paritaprevir, or an NS5A inhibitor (for example, Ombitasvir).
• a protease inhibitor such as an NS3/4A protease inhibitor (for example, telaprevir (Incivek®) boceprevir (VictrelisTM) simeprevir (OlysioTM), or paritaprevir, or an NS5A inhibitor (for example, Ombitasvir).
• the compounds of the invention can also be administered in combination with a structurally different NS5B polymerase inhibitor such as another compound described herein or below, including Gilead's Sovaldi ® .
• NS5B polymerase inhibitor such as another compound described herein or below, including Gilead's Sovaldi ® .
• the compounds of the invention can also be administered in combination with interferon alfa-2a, which may be pegylated or otherwise modified, and/or ribavirin.
• the p-D-2'-D-2'-a-fluoro-2'-p-C-substituted-2-modified-N 6 -substituted purine nucleotides of the invention are typically administered orally, for example in pill or tablet form, but may be administered via an other route which the attending physician considers appropriate, including via intravenous, transdermal, subcutaneous, topical, parenteral, or other suitable route.
• Figure 1 is a sample chromatogram of a semi-prep run illustrating the separation of the stereoisomers of Compound 5 using a Phenominex Luna column as disclosed in Example 9.
• the y axis is shown in mAU and the x axis is measured in minutes.
• Figure 2 is a graph of the HCV replication inhibition curves for Compound 5-2 (Table 7) and Sofosbuvir.
• the y- axis is the percent of virus control and the x-axis is the concentration of drug in ⁇ .
• Figure 3 is a graph of the HCV replication inhibition curves for Compound 25 (Table 7) and Sofosbuvir.
• the y-axis is the percent of virus control and the x-axis is the concentration of drug in ⁇ .
• Figure 4 is an intra-assay comparison of the anti-HCV activity for Compounds 5-2, 25, 27 (Table 7) and Sofosbuvir.
• the y-axis is the percent of virus control and the x-axis is the concentration of drug in ⁇ . See, Example 27.
• Figure 5 is a graph that shows the stability of compounds 5-2; the N 2 -acetate of compound 5-2, the N 2 -butyrate of compound 5-2; the N 2 -methyl derivative of compound 5-2; and the N 2 -n-pentylcarbamate of compound 5-2 in human blood.
• the x axis is incubation time measured in minutes and the y axis is the measurement of the percent of the parent compound remaining.
• Figure 6 is a graph showing the in vitro time course dealkylation of 2'-deoxy-2'-a-fluoro- 2'-P-methyl-N 2 -methyl-N 6 -methyl-2,6-diaminopurine nucleoside phosphoramidate to 2'-deoxy- 2'-a-fluoro-2'-P-methyl-N 6 -methyl-2,6-diaminopurine nucleoside phosphoramidate in the presence of a human liver S9 fraction.
• the x axis is measured in minutes and the y axis is the measurement of the concentration of the compound remaining in nM.
• Figure 7 is a graph showing the stability of compounds 5-2; the N 2 -acetate of compound 5-2, the N 2 -butyrate of compound 5-2; the N 2 -methyl derivative of compound 5-2; and the N 2 -n- pentylcarbamate of compound 5-2 in the presence of a human liver S9 fraction.
• the x axis is measured in minutes and the y axis is the measurement of percent compound remaining.
• Figure 8 shows the predominant Compound 25 metabolites generated in human hepatocytes.
• the x axis is incubation time in hours.
• the y axis is intracellular concentration in pmol/10 6 cells. See Example 33.
• Figure 9 shows the predominant Compound 27 metabolites generated in human hepatocytes.
• the x axis is incubation time in hours.
• the y axis is intracellular concentration in pmol/10 6 cells. See Example 33.
• Figure 10 shows the predominant Compound 5-2 metabolites generated in human hepatocytes.
• the x axis is incubation time in hours.
• the y axis is intracellular concentration in pmol/10 6 cells. See Example 33.
• Figure 11 is a graph showing the activation pathways for Compounds 25, 27 and 5-2.
• Compounds 25, 27 and 5-2 are converted to their corresponding monophosphate analogs which are subsequently metabolized to a common MP analog; P-D-2'-deoxy-2'-a- fluoro-2'-P-methyl-guanine monophosphate.
• the monophosphate is then stepwise phosphorylated to the active triphosphate: P-D-2'-deoxy-2'-a-fluoro-2'-P-methyl-guanine triphosphate. See Example 33.
• the invention disclosed herein is a compound, method, and composition for the treatment of infections in or exposure to humans and other host animals of the HCV virus that includes the administration of an effective amount of a compound of Formula I- VII as described herein or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier.
• the compounds of this invention either possess antiviral activity, or are metabolized to a compound that exhibits such activity.
• the compounds and compositions can also be used to treat conditions related to or occurring as a result of a HCV viral exposure.
• the active compound can be used to treat HCV antibody positive and HCV antigen positive conditions, viral-based chronic liver inflammation, liver cancer resulting from advanced hepatitis C, cirrhosis, acute hepatitis C, fulminant hepatitis C, chronic persistent hepatitis C, and anti-HCV-based fatigue.
• the compounds or formulations that include the compounds can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are HCV antibody or HCV antigen positive or who have been exposed to hepatitis C.
• the compounds described herein are provided in the ⁇ -D- configuration.
• the compounds can be provided in a ⁇ -L- configuration.
• any substituent group that exhibits chirality can be provided in racemic, enantiomeric, diastereomeric form or any mixture thereof.
• a phosphoramidate, thiophosphoramidate or other stabilized phosphorus prodrug in which the phosphorus exhibits chirality is used as the R 4 stabilized phosphate prodrug, it can be provided as an R or S chiral phosphorus derivative or a mixture thereof, including a racemic mixture.
• the amino acid of the phosphoramidate or thiophosphoramidate can be in the D- or L-configuration, or a mixture thereof, including a racemic mixture. All of the combinations of these stereo configurations are included in the invention described herein.
• the present invention includes the following features:
• active compounds of the invention are those depicted, for example, in Formula I, which can be provided in a pharmaceutically acceptable composition, salt or prodrug thereof:
• Y is R3 ⁇ 4 2 ;
• R 1 is Ci-Csalkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CH 2 F, CH 2 F, CF 3 , CH 2 CF 3 , CF 2 CH 3 and CF 2 CF 3 ), C 2 -Ce alkenyl, C 2 -Ce alkynyl, -(Co-C 2 alkyl)(C 3 -C6cycloalkyl), -(Co- C 2 alkyl)(heterocycle), -(Co-C 2 alkyl)(aryl), -(Co-C 2 alkyl)(heteroaryl), -OR 25 , -C(0)R 3C (including -C(0)CH 3 , -C(0)CH 2 CH 3 -C(0)CH(CH 3 ) 2 ,
• R 2 is hydrogen, optionally substituted Ci-Csalkyl (including methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CHF2, CH2F, CF 3 , CH 2 CF 3 and CF 2 CF 3 ), optionally substituted -(Co-C 2 alkyl)(C 3 -C 6 cycloalkyl), optionally substituted -(Co-C 2 alkyl)(heterocycle), optionally substituted -(Co-C 2 alkyl)(aryl), optionally substituted -(Co-C2alkyl)(heteroaryl), -C(0)R 3C (including -C(0)CH 3 , - C(0)CH 2 CH 3 -C(0)CH(CH 3 ) 2 , -C(0)OCH 3 , -C(0)OC
• R 1 and R 2 is methyl, CH 2 F, CHF 2 or CF 3 ;
• R 3 is hydrogen, , diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or -C(0)R 3C ;
• R 3A can be selected from O " , OH, an -O-optionally substituted aryl, an -O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl;
• R 3B can be selected from O " , OH, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester;
• R 3C is alkyl, alkenyl, alkynyl, -(Co-C 2 )(cycloalkyl), -(Co-C 2 )(heterocyclo), -(Co-C 2 )(aryl), -(Co-C 2 )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(Co-C 2 )(cycloalkyl), -0-(Co- C 2 )(heterocyclo), -0-(Co-C 2 )(aryl), or -0-(Co-C 2 )(heteroaryl), each of which can be optionally substituted;
• R 4 is a monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, including but not limited to a phosphoramidate, a thiophosphoramidate, or any other moiety that is metabolized to a monophosphate, diphosphate or triphosphate in vivo in the host human or animal; or
• R 3 and R 4 together with the oxygens that they are bonded to can form a 3 ',5 '-cyclic prodrug, including but not limited to, a 3 ',5 '-cyclic phosphate prodrug;
• R 12 is CH 3 , CH 2 F, CHF 2 , CF 3 , or ethynyl.
• a stabilized phosphate prodrug is any moiety that can deliver a mono, di, or triphosphate.
• compounds of Formula la are disclosed:
• Y, R 3 and R 4 are as defined above.
• Y, R 3 and R 4 are as defined above.
• the compound is according to Formula Ic:
• R 7 is hydrogen, Ci-6alkyl; C3-7cycloalkyl; heteroaryl, heterocyclic, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with Ci- 6 alkyl, C 2 - 6 alkenyl, C2-6 alkynyl, Ci- 6 alkoxy, F, CI, Br, I, nitro, cyano, Ci- ehaloalkyl, -N(R 7' ) 2 , Ci-eacylamino, HSChCi-ealkyl, -S0 2 N(R 7' ) 2 , COR 7" , and -S0 2 Ci-6alkyl; (R 7' is independently hydrogen or Ci- 6 alkyl; R 7" is -OR 11 or-N(R 7 ) 2 );
• R 8 is hydrogen, Ci- 6 alkyl, or R 9a or R 9b and R 8 together are (CH 2 )n so as to form a cyclic ring that includes the adjoining N and C atoms; where n is 2 to 4;
• R 9a and R 9b are (i) independently selected from hydrogen, Ci- 6 alkyl, cycloalkyl, -(CH 2 )c( R 9 ) 2 , Ci-ehydroxyalkyl, — CH2SH, -(CH 2 ) 2 S(0)(Me, (1H- indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH 2 ) c COR 9" , aryl and aryl(Ci-3alkyl)-, the aryl groups can be optionally substituted with a group selected from hydroxyl, Ci- 6 alkyl, Ci- 6 alkoxy, halogen, nitro and cyano; (ii) R 9a and R 9b both are Ci- 6 alkyl; (iii) R 9a and R 9b together are (CH 2 ) r so as to form a spiro ring; (iv) R 9a is hydrogen and R 9b and R 8 together are (
• R 10 is hydrogen, Ci- 6 alkyl optionally substituted with an alkoxy, di(lower alkyl)-amino, or halogen, Ci- 6 haloalkyl, C 3 -7cycloalkyl, heterocycloalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyndinyl, substituted aryl, or substituted heteroaryl;
• R 11 is an optionally substituted Ci- 6 alkyl, an optionally substituted cycloalkyl; an optionally substituted C2- 6 alkynyl, an optionally substituted C2- 6 alkenyl, or optionally substituted acyl, which includes but is not limited to C(0)(Ci-6 alkyl); and
• Y, R 3 and R 12 are as defined herein.
• Y is R3 ⁇ 4 2 ;
• R 1 is Ci-Csalkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CH2F, CHF2, CF 3 , CH 2 CF 3 , CF 2 CH 3 and CF 2 CF 3 ), C2-C6 alkenyl, C 2 -C 6 alkynyl, -(Co-C2alkyl)(C 3 -C6cycloalkyl), -(Co- C 2 alkyl)(heterocycle), -(Co-C2alkyl)(aryl), -(Co-C2alkyl)(heteroaryl), -OR 25 , -C(0)R 3C (including -C(0)CH 3 , -C(0)CH 2 CH 3 -C(0)CH(CH 3 ) 2 , -C
• R 2 is hydrogen, optionally substituted Ci-Csalkyl (including methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CHF2, CHF 2 , CF 3 , CH2CF3 and CF2CF3), optionally substituted -(Co-C 2 alkyl)(C3-C 6 cycloalkyl), optionally substituted -(Co-C 2 alkyl)(heterocycle), optionally substituted -(Co-C 2 alkyl)(aryl), optionally substituted -(Co-C 2 alkyl)(heteroaryl), -C(0)R 3C (including -C(0)CH 3 , - C(0)CH 2 CH3-C(0)CH(CH 3 )2, -C(0)OCH 3 , -C(0)OC 2 H 5 ,
• R 1 and R 2 are methyl, CH2F, CFIF2 or CF3;
• R 3 is hydrogen, , diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or
• R 3A can be selected from O " , OH, an -O-optionally substituted aryl, an -O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl;
• R 3B can be selected from O " , OH, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester;
• R 3C is alkyl, alkenyl, alkynyl, -(Co-C 2 )(cycloalkyl), -(Co-C 2 )(heterocyclo), -(Co-C 2 )(aryl), -(Co-C 2 )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(Co-C 2 )(cycloalkyl), -0-(Co- C 2 )(heterocyclo), -0-(Co-C 2 )(aryl), -0-(Co-C 2 )(heteroaryl), -S-alkyl, -S-alkenyl, -S-alkynyl, -S- (Co-C 2 )(cycloalkyl), -S-(Co-C 2 )(heterocyclo), -S-(Co-C 2 )(aryl), or -S
• R 3D is alkyl, alkenyl, alkynyl, -(Co-C 2 )(cycloalkyl), -(Co-C 2 )(heterocyclo), -(Co-C 2 )(aryl), -(Co-C 2 )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(Co-C 2 )(cycloalkyl), -0-(Co- C 2 )(heterocyclo), -0-(Co-C 2 )(aryl), or -0-(Co-C 2 )(heteroaryl), each of which can be optionally substituted;
• R 4 is a monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, including but not limited to a phosphoramidate, a thiophosphoramidate, or any other moiety that is metabolized to a monophosphate, diphosphate or triphosphate in vivo in the host human or animal; or
• R 3 and R 4 together with the oxygens that they are bonded to can form a 3 ',5 '-cyclic prodrug, including but not limited to, a 3 ',5 '-cyclic phosphate prodrug;
• R 5 is Ci-Csalkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CHF 2 , CHF 2 , CF 3 , CH2CF3 and CF 2 CF 3 ), C2-C6 alkenyl, C 2 -Ce alkynyl, -(Co-C 2 alkyl)(C 3 -C6cycloalkyl), -(Co-C 2 alkyl)(heterocycle), -(Co- C 2 alkyl)(aryl), -(Co-C 2 alky
• R 6 is hydrogen, optionally substituted Ci-Csalkyl (including methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), Ci-Cshaloalkyl (including CHF2, CH2F, CF 3 , CH 2 CF 3 and CF 2 CF 3 ), optionally substituted -(Co-C 2 alkyl)(C 3 -C 6 cycloalkyl), optionally substituted -(Co-C 2 alkyl)(heterocycle), optionally substituted -(Co-C 2 alkyl)(aryl), optionally substituted -(Co-C 2 alkyl)(heteroaryl), -C(0)R 3C (including -C(0)CH 3 , - C(0)CH 2 CH 3 -C(0)CH(CH 3 ) 2 , -C(0)OCH 3 , -C(0)OC
• R 5 and R 6 together with the nitrogen that they are bonded to can form a heterocyclic ring
• R 12 is CH 3 , CH2F, CHF2, CF 3 , or ethynyl
• R 23 is Ci-Csalkyl, -(Co-C2alkyl)(C 3 -C6cycloalkyl), -(Co-C2alkyl)(heterocycle)-(Co- 2alkyl)(aryl) or -(Co-C2alkyl)(heteroaryl) each of which can be optionally substituted;
• R 24 is hydrogen, Ci-Ce alkyl, -(Ci-C 2 alkyl)(C 3 -C6cycloalkyl),
• R 25 is hydrogen, Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(Co-C 2 alkyl)(C 3 - C6cycloalkyl), -(Co-C2alkyl)(C 3 -C6heterocycle), -(Co-C2alkyl)(aryl) or -(Co-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted;
• R 26 is independently selected from hydrogen, Ci-C 6 alkyl, -(Co-C2alkyl)(C 3 - C6cycloalkyl), -(Co-C2alkyl)(heterocycle), -(Co-C2alkyl)(aryl), or -(Co-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted;
• R 27 hydrogen or optionally substituted Ci-C 6 alkyl
• R 28 is Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(Co-C2alkyl)(C 3 -C6cycloalkyl), -(Co-C2alkyl)(C 3 -C6heterocycle), -(Co-C2alkyl)(aryl) or -(Co-C2alkyl)(heteroaryl) each of which can be optionally substituted;
• R 29 is hydrogen, Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(Co-C 2 alkyl)(C 3 - C6cycloalkyl), -(Co-C2alkyl)(C 3 -C6heterocycle), -(Co-C2alkyl)(aryl) or -(Co-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted; or R 27 and R 29 together with the nitrogen that they are bonded to can form a heterocyclic ring;
• R 30 is hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
• R 29 and R 30 can be bonded together to form a heterocyclic ring
• x is 1, 2 or 3.
• Y, R 3 , R 4 and R 22 are as defined above.
• the compound is a ⁇ -D isomer with reference to the corresponding nucleoside (i.e., in the naturally occurring configuration).
• the compound is provided as a ⁇ -L isomer.
• the compound is typically at least 90% free of the opposite enantiomer, and can be at least 98%>, 99% or even 100%> free of the opposite enantiomer. Unless described otherwise, the compound is at least 90% free of the opposite enantiomer.
• the compound is according to Formula III:
• R 7 is hydrogen, Ci-6alkyl; C3-7cycloalkyl; heteroaryl, heterocyclic, or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with Ci-6alkyl, C 2 - 6 alkenyl, C 2 -6 alkynyl, Ci- 6 alkoxy, F, CI, Br, I, nitro, cyano, Ci- ehaloalkyl, -N(R 7' ) 2 , Ci-eacylamino, NHSChCi-ealkyl, -S0 2 N(R 7' ) 2 , COR 7" , and -SChCi-ealkyl; (R 7' is independently hydrogen or Ci- 6 alkyl; R 7" is -OR 11 or-N(R 7 ) 2 );
• R 8 is hydrogen, Ci- 6 alkyl, or R 9a or R 9b and R 8 together are (CH 2 ) n so as to form a cyclic ring that includes the adjoining N and C atoms; where n is 2 to 4;
• R 10 is hydrogen, Ci- 6 alkyl optionally substituted with an alkoxy, di(lower alkyl)-amino, or halogen, Ci- 6 haloalkyl, C 3 -7cycloalkyl, heterocycloalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
• R 11 is an optionally substituted Ci- 6 alkyl, an optionally substituted cycloalkyl; an optionally substituted C2- 6 alkynyl, an optionally substituted C2- 6 alkenyl, or optionally substituted acyl, which includes but is not limited to C(0)(Ci-6 alkyl); and
• Y, R 3 R 12 and R 22 are as defined above.
• compounds, methods, and compositions are provided for the treatment of a host infected with or exposed to hepatitis C.
• R 41 is halogen (in particular F or CI), OR 3 (including OH), N 3 , H 2 or CN; and the variables Y, R 3 , R 4 , and R 12 are described herein.
• compounds of Formula VII are disclosed:
• the metabolism of the P-D-2'-deoxy-2'-a-fluoro-2'-P-methyl-N 6 -methyl-2,6- diaminopurine nucleoside phosphoramidate involves the production of a 5 '-monophosphate and the subsequent anabolism of the N 6 -methyl-2,6-diaminopurine base to generate the ⁇ - ⁇ -2'- deoxy-2'-a-fluoro-2'-P-methyl-guanine nucleoside as the 5 '-monophosphate.
• the monophosphate is then further anabolized to the active species; the 5 '-triphosphate.
• the metabolic pathway for the P-D-2'-deoxy-2'-a-fluoro-2'-P- methyl-N 6 -methyl-2,6-diaminopurine nucleoside phosphoramidate is illustrated in Scheme 1 below.
• Stabilized phosphate prodrugs are moieties that can deliver a mono, di, or triphosphate in vivo.
• McGuigan has disclosed phosphoramidates in US Patent Nos. : 8,933,053; 8,759,318; 8,658,616; 8,263,575; 8, 119,779; 7,951,787 and 7,115,590.
• Alios has disclosed thiophosphoramidates in US 8,895,723 and 8,871,737 incorporated by reference herein.
• Alios has also disclosed cyclic nucleotides in US Patent No. 8,772,474 incorporated by reference herein.
• Idenix has disclosed cyclic phosphoramidates and phosphoramidate/SATE derivatives in WO 2013/177219 incorporated by reference herein. Idenix has also disclosed substituted carbonyloxymethylphosphoramidate compounds in WO 2013/039920 incorporated by reference herein.
• Hostetler has disclosed lipid phosphate prodrugs, see, for example, US 7,517,858. Hostetler has also disclosed lipid conjugates of phosphonate prodrugs, see, for example, US 8,889,658; 8,846,643; 8,710,030; 8,309,565; 8,008,308; and 7,790,703.
• Emory University has disclosed nucleotide sphingoid and lipid derivatives in WO 2014/124430.
• RFS Pharma has disclosed purine nucleoside monophosphate prodrugs in WO 2010/091386.
• Cocrystal Pharma Inc. has also disclosed purine nucleoside monophosphate prodrugs in US Patent No.: 9,173,893 incorporated by reference herein.
• HepDirectTM technology is disclosed in the article "Design, Synthesis, and Characterization of a Series of Cytochrome P(450) 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver," (J. Am. Chem. Soc. 126, 5154-5163 (2004).
• Additional phosphate prodrugs include, but are not limited to phosphate esters, 3 ',5 '-cyclic phosphates including CycloSAL, SATE derivatives (S-acyl- 2thioesters) and DTE (dithiodiethyl) prodrugs.
• phosphate esters 3 ',5 '-cyclic phosphates including CycloSAL, SATE derivatives (S-acyl- 2thioesters) and DTE (dithiodiethyl) prodrugs.
• CycloSAL SATE derivatives
• S-acyl- 2thioesters S-acyl- 2thioesters
• DTE dithiodiethyl prodrugs
• the stabilized phosphate prodrugs include, but are not limited to those described in U.S. Patent No. 9,173,893 and U.S. Patent No. 8,609,627, incorporated by reference herein, including for processes of preparation.
• 5'- prodrugs of Formula I-V can be represented by the group:
• 3 ',5 '-prodrugs of Formula I-V can be represented by the group:
• Z is O or S; R is selected from OR , fatty alcohol derived (for example but not limited to:
• R 34 , R 35 , and R 36 are as defined below;
• R 31 and R 32 when administered in vivo, are capable of providing the nucleoside monophosphate or thiomonophosphate, which may or may not be partially or fully resistant to 6- H2 deamination in a biological system.
• Representative R 31 and R 32 are independently selected from: (a) OR 34 where R 34 is selected from H, Li, Na, K, phenyl and pyridinyl; phenyl and pyridinyl are substituted with one to three substituents independently selected from the group consisting of (CH2)o-6C0 2 R 37 and (CH 2 )o-6CON(R 37 ) 2 ;
• R 37 is independently H, Ci-20 alkyl, the carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, and etc) or Ci-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C3-10 cycloalkyl, or cycloalkyl;
• a fatty alcohol such as oleyl alcohol, o
• R 36 is restricted to those sidechains occurring in natural L-amino acids, and R is H, Ci-20 alkyl, the carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, and etc) or Ci-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C3-10 cycloalkyl, or cycloalkyl
• R 31 and R 32 can come together to form a ring
• R is H, Ci-20 alkyl, Ci-20 alkenyl, the carbon chain derived from a fatty alcohol (such as oleyl alcohol, octacosanol, triacontanol, linoleyl alcohol, etc) or Ci-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C3-10 cycloalkyl, or cycloalkyl;
• R 31 and R 32 can come together to form a ring selected from
• R is O or H and R is selected from H, Ci-20 alkyl, Ci-20 alkenyl, the carbon chain derived from a fatty acid (such as oleic acid, linoleic acid, and the like), and Ci-20 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, such as phenyl, heteroaryl, such as pyridinyl, substituted aryl, or substituted heteroaryl; wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)- amino, fluoro, C3-10 cycloalkyl, or cycloalkyl.
• the compounds can be prepared, for example, by preparing the 5'-OH analogs, then converting these to the monophosphate analogs.
• Y is NR3 ⁇ 4 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is a stabilized phosphate prodrug;
• Y is NR*R 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, and R 4 is a stabilized thiophosphate prodrug;
• Y is NR R 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, and R 4 is a phosphoramidate;
• Y is NR*R 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, and R 4 is a thiophosphoramidate:
• Y is NR R 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, and R 4 is a monophosphate;
• Y is NR R 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, and R 4 is a diphosphate;
• Y is NR R 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, and R 4 is a triphosphate;
• Y is NR3 ⁇ 4 2 , R 1 is methyl, R 2 is methyl, R 3 is hydrogen, R 4 is a stabilized phosphate prodrug;
• Y is NR R 2 , R 1 is methyl, R 2 is methyl, R 3 is hydrogen, and R 4 is a stabilized thiophosphate prodrug;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is methyl, R 3 is hydrogen, and R 4 is a monophosphate;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is methyl, R 3 is hydrogen, and R 4 is a diphosphate;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is methyl, R 3 is hydrogen, and R 4 is a triphosphate;
• Y is NR R 2 , R 1 is methyl, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is a stabilized phosphate prodrug;
• Y is R3 ⁇ 4 2 , R 1 is methyl, R 2 is cyclopropyl, R 3 is hydrogen, and R 4 is a stabilized thiophosphate prodrug;
• Y is R3 ⁇ 4 2 , R 1 is methyl, R 2 is cyclopropyl, R 3 is hydrogen, and R 4 is a phosphoramidate;
• Y is R3 ⁇ 4 2 , R 1 is methyl, R 2 is cyclopropyl, R 3 is hydrogen, and
• R 4 is a thiophosphoramidate
• Y is NR*R 2 , R 1 is methyl, R 2 is cyclopropyl, R 3 is methyl, and R 4 is a diphosphate;
• Y is R3 ⁇ 4 2 , R 1 is methyl, R 2 is cyclopropyl, R 3 is hydrogen, and R 4 is a triphosphate;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is propyl, R 3 is hydrogen, R 4 is a stabilized phosphate prodrug;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is propyl, R 3 is hydrogen, and R 4 is a stabilized thiophosphate prodrug;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is propyl, R 3 is hydrogen, and R 4 is a phosphoramidate;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is propyl, R 3 is hydrogen, and R 4 is a thiophosphoramidate: (xxvi) in Formula la, Y is R 1 !* 2 , R 1 is methyl, R 2 is propyl, R 3 is hydrogen, and R 4 is a monophosphate;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is propyl, R 3 is hydrogen, and R 4 is a diphosphate;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is ethyl, R 3 is hydrogen, R 4 is a stabilized phosphate prodrug;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is ethyl, R 3 is hydrogen, and R 4 is a stabilized thiophosphate prodrug;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is ethyl, R 3 is hydrogen, and R 4 is a phosphoramidate;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is ethyl, R 3 is hydrogen, and R 4 is a thi ophosphorami date :
• Y is R ⁇ 2 , R 1 is methyl, R 2 is ethyl, R 3 is hydrogen, and R 4 is a monophosphate;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is ethyl, R 3 is hydrogen, and R 4 is a diphosphate;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is ethyl, R 3 is hydrogen, and R 4 is a triphosphate;
• Y is R3 ⁇ 4 2 , R 1 is methyl, R 2 is methyl, R 3 is hydrogen, R 4 is a stabilized phosphate prodrug;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is methyl, R 3 is hydrogen, and R 4 is a stabilized thiophosphate prodrug;
• R 4 is a phosphoramidate
• Y is R ⁇ 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is a stabilized phosphate prodrug;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, and R 4 is a stabilized thiophosphate prodrug;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, and R 4 is a phosphoramidate;
• Y is R ⁇ 2 , R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, and R 4 is a thiophosphoramidate:
• Y is R ⁇ 2 , R 1 is methyl, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is a stabilized phosphate prodrug;
• R 4 is a stabilized thiophosphate prodrug
• R 4 is a phosphoramidate
• R 4 is a thiophosphoramidate
• R 4 is a monophosphate
• the compound has an R 22 substituent.
• the R 22 is F, amide or carbamate.
• R 22 is chloro, bromo, cyano, azido, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, tert-butyl and n-pentyl, 1,1-dimethylpropyl, 2,2-dimtheylpropyl, 3- methylbutyl, 1-methylbutyl, 1-ethylpropyl, vinyl, allyl, 1-butynyl, 2-butynyl, acetylenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)-cyclopropyl, -(CH2)-cyclobutyl, - (CH2)-cycl
• Formula I R 12 variable is CH2F.
• Formula I R 12 variable is CHF2.
• the Formula I R 12 variable is CF 3 .
• a compound of Formula la is provided.
• Non-limiting examples of compounds of Formula la include:
• a thiophosphoramidate of Formula la is provided.
• Non-limiting examples of thiophosphoramidates of Formula la include, but are not limited to:
• a stabilized phosphate prodrug of Formula la is provided.
• Non- limiting examples of stabilized phosphate prodrugs of Formula la are illustrated below:
• a compound of Formula la is provided.
• Non-limiting examples of compounds of Formula la include:
• a thiophosphoramidate of Formula la is provided.
• Non-limiting examples of thiophosphoramidates of Formula la include, but are not limited to:
• a stabilized phosphate prodrug of Formula la is provided.
• Non- limiting examples of stabilized phosphate prodrugs of Formula la are illustrated below:
• a compound of Formula I is provided.
• Non-limiting examples of compounds of Formula I include:
• a compound of Formula II is provided.
• Non-limiting examples of compounds of Formula II include:
• R 3 is H and R 4 is
• R 3 is H and R 4 is
• a compound of Formula II is provided.
• Non-limiting examples of compounds of Formula II include:
• R 3 is H and R 4 is
• R 3 is H and R 4 is
• R 3 is H and R 4 is
• R 1 is CH3, R 2 is In some embodiments, R 1 is CH3, R 2 is In some embodiments, R 1 is CH3, R 2 is H, R 3 is H and R 4 is
• R 1 is CH3, R 2 is CH3, R 3 is H and R 4 In some embodiments, R 1 is CH3, R 2 is CH3, R 3 is H and R 4
• R 1 is CH3, R 2 is CH3, R 3 is H and R 4 is
• R 1 is cyclopropyl
• R 2 is CH3
• R 3 is H
• R 4 is
• R 1 is cyclopropyl
• R 2 is CH3
• R 3 is H
• R 4 is
• R 1 is cyclopropyl
• R 2 is CH3
• R 3 is H
• R 4 is
• alkyl shall mean within its context, a linear, or branch-chained fully saturated hydrocarbon radical or alkyl group which can be optionally substituted (for example, with halogen, including F).
• an alkyl group can have 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., Ci -C 8 alkyl), 1, 2, 3, 4, 5 or 6 carbon atoms (i.e., Ci-C 6 alkyl) or 1 to 4 carbon atoms (i.e., C1-C4 alkyl).
• alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.
• alkenyl refers to a non-aromatic hydrocarbon group which contains at least one double bond between adjacent carbon atoms and a similar structure to an alkyl group as otherwise described herein.
• an alkenyl group can have 2 to 8 carbon atoms (i.e., C 2 -C 8 alkenyl), or 2 to 4 carbon atoms (i.e., C 2 -C 4 alkenyl).
• the alkenyl group can be optionally substituted as described herein.
• alkynyl refers to a non-aromatic hydrocarbon group containing at least one triple bond between adjacent carbon atoms and a similar structure to an alkyl group as otherwise described herein.
• an alkynyl group can have 2 to 8 carbon atoms (i.e., C 2 -Cs alkyne,), or 2 to 4 carbon atoms (i.e., C 2 -C 4 alkynyl).
• alkynyl groups include, but are not limited to, acetylenic or ethynyl and propargyl.
• the alkynyl group can be optionally substituted as described herein.
• acyl refers to the moiety -C(0)R in which the carbonyl moiety is bonded to R, for example,
• R can be selected from alkoxy, alkyl, cycloalkyl, lower alkyl (i.e., C1-C4); alkoxyalkyl, including methoxymethyl; aralkyl- including benzyl, aryloxyalkyl- such as phenoxymethyl; aryl including phenyl optionally substituted with halogen, Ci to C 4 alkyl or Ci to C 4 alkoxy.
• acyl refers to a mono, di or triphosphate.
• lower acyl refers to an acyl group in which the carbonyl moiety is lower alkyl
• alkoxy refers to the group -OR' where -OR' is -O-alkyl, -O-alkenyl, -O- alkynyl, -0-(Co-C 2 )(cycloalkyl), -0-(Co-C 2 )(heterocyclo), -0-(Co-C 2 )(aryl), or -0-(Co- C 2 )(heteroaryl), each of which can be optionally substituted.
• amino refers to the group - H 2 .
• amino acid refers to a D- or L- natural or non- naturally occurring amino acid.
• Representative amino acids include, but are not limited to, alanine, ⁇ -alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine, among others.
• azido refers to the group -N 3 .
• aryl or "aromatic”, in context, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., phenyl or benzyl) or condensed rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound to the compound according to the present invention at any available stable position on the ring(s) or as otherwise indicated in the chemical structure presented.
• the aryl group can be optionally substituted as described herein.
• Cycloalkyl refers to a saturated (i.e., cycloalkyl) or partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms as a monocycle.
• Monocyclic carbocycles have 3 to 7 ring atoms, still more typically 5 or 6 ring atoms.
• Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, a n d l-cyclo-hex-3-enyl.
• cyano refers to the group -CN.
• halogen refers to chloro, bromo, fluoro or iodo.
• a heteroaryl ring system is a saturated or unsaturated ring with one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic) including but not limited to imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, purine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, etc., among others, which may be optionally substituted as described above.
• Heteroaryl groups include nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, purine, indazole, quinoline, isoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, perimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-
• heterocycle or “heterocyclo” refers to a cyclic group which contains at least one heteroatom, i.e., O, N, or S, and may be aromatic (heteroaryl) or non-aromatic.
• non-aromatic heterocyclic groups for use in the present invention include, for example, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, pyridone, 2- pyrrolidone, ethyl eneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide, and succinimide, among others, all of which may be optionally substituted.
• hydroxyl refers to the group -OH.
• nitro refers to the group -NO2.
• pharmaceutically acceptable salt or prodrug
• any pharmaceutically acceptable form such as an ester, phosphoramidate, thiophosphoramidate, phosphate ester, salt of an ester, or a related group
• P-D-2'-D-2'-a-fluoro-2'-P-C-substituted-2-modified-N 6 -substituted purine nucleotide which, upon administration to a patient, provides the desired active compound.
• Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate.
• Suitable inorganic salts may also be formed, including sulfate, nitrate, bicarbonate, and carbonate salts.
• Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
• Alkali metal for example, sodium, potassium, or lithium
• alkaline earth metal for example calcium
• “Pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention.
• Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
• Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, thiophoshoramidated, dethiophoshoramidated, phoshoramidated or dephosphoramidated to produce the active compound.
• the compounds of this invention possess antiviral activity against HCV, or are metabolized to a compound that exhibits such activity.
• the P-D-2'-D-2'-a-fluoro-2'- P-C-substituted-2-modified-N 6 -substituted purine nucleoside can also be administered as a 5'- phosphoether lipid, a bisphosphoramidate, a 3',5'-cyclic phosphoramidate, a 3',5'-cyclic thiophosphoramidate, a DTE conjugate, a mixed phosphoramidate-SATE derivative or a "SATE" derivative.
• phosphonic acid refers to the group -P(0)(OH) 2 .
• the term purine or pyrimidine base includes, but is not limited to, adenine, N 6 -alkylpurines, N 6 -acylpurines (wherein acyl is -C(0)alkyl, -C(0)(aryl)Co-C4alkyl, or -C(0)(Co-C4alkyl)aryl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -alkyl-6- thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluor
• Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include benzyl, trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl; methanesulfonyl, and p-toluenesulfonyl. Alternatively, the purine or pyrimidine base can optionally be substituted such that it forms a viable prodrug, which can be cleaved in vivo. Examples of appropriate substituents include an acyl moiety.
• substituted or “optionally substituted” indicates that the moiety can have at least one additional substituent including, but not limited to, halogen (F, CI, Br, I), OH, phenyl, benzyl, N 3 , CN, acyl, alkyl, including methyl; alkenyl, alkynyl, alkoxy, haloalkyl; including CHF 2 , CH 2 F and CF 3 ; etc.
• the term "substituted” or “optionally substituted” indicates that the moiety can have at least one additional substituent including, but not limited to, azido, cyano, halogen (fluoro, chloro, bromo, or iodo), alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, haloalkyl, hydroxyl, alkoxy, amino, - H(Ci-C6 unsubstituted alkyl), - H(Ci-Ce substituted alkyl), - H-(Co-C 2 alkyl)(C 3 -C 8 cycloalkyl), - H-(Co-C 2 alkyl)(C 3 - C 8 heterocycle),-NH-(Co-C 2 alkyl)(aryl), -N(Ci-Ce unsubstituted alkyl) 2 , -N(Ci-Ce unsubstituted al
• R 14 S(0)20R 15 comprise R 14 wherein R 14 is alkyl, haloalkyl, aralkyl or aryl.
• R 15 is alkyl, aryl or aralkyl.
• sulfonic acid refers to the group -SO2OH.
• thiol refers to the group -SH.
• nitrogen-protecting group refers to a moiety that is covalently attached to nitrogen and which can be removed, and typically replaced with hydrogen, when appropriate.
• a nitrogen-protecting group may be a group that is removed in vivo after administration to a host, in vitro by a cell, or it may be removed during a manufacturing process.
• Suitable nitrogen-protecting groups useful in the present invention are described by Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc.
• oxygen-protecting group refers to a moiety that is covalently attached to oxygen and which can be removed, and typically replaced with hydrogen, when appropriate.
• an oxygen-protecting group may be a group that is removed in vivo after administration to a host, in vitro by a cell, or it may be removed during a manufacturing process.
• Suitable oxygen-protecting groups useful in the present invention are described by Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc.
• Phosphate refers to the group -OP(0)(OH) 2 .
• Phosphate ester refers to mono, di, and tri phosphates unless otherwise indicated.
• phosphoamidate is a moiety that has a phosphorus bound to three oxygen groups and an amine (which may optionally be substituted).
• Suitable phosphoramidates useful in the present invention are described by Madela, Karolina and McGuigan in 2012, "Progress in the development of anti-hepatitis C virus nucleoside and nucleotide prodrugs", Future Medicinal Chemistry 4(5), pages 625-650 10: 1021/jm300074y and Anthony, McGuigan and Balzarini in 2004, "Aryloxy Phosphoramidate Triesters as Pro-Tides", Mini Reviews in Medicinal Chemistry 4(4), pages 371- 381.
• Phosphoramidate groups for use in the present invention include those of the structures:
• phosphoramidates for use in the present invention include those of the structure:
• R P1 is an optionally substituted linear, branched, or cyclic alkyl group, or an optionally substituted aryl, heteroaryl or heterocyclic group or a linked combination thereof;
• R P2 is a - R N1 R N2 group or a B' group
• R N1 and R N2 are each independently H, Ci-salkyl, (C3-C7cycloalkyl)Co-C4alkyl-, (aiyl)Co- C 4 alkyl-, (C3-C6heterocyclo)Co-C4alkyl-, or (heteroaryl)Co-C4alky-; which may be optionally substituted; or
• R N1 and R N2 along with the nitrogen atom to which that are attached, join to form a 3 to 7 membered heterocyclic ring;
• R 16 is hydrogen, (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C3-C 8 cycloalkyl)Co- C 4 alkyl-, (aryl)Co-C 4 alkyl-, (C3-C6heterocyclo)Co-C 4 alkyl-, (heteroaryl)Co-C 4 alky-, or the sidechain of an amino acid, for example a sidechain of an amino acid (as otherwise described herein) often selected from the group consisting of alanine, ⁇ -alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or ty
• R 17 is hydrogen, (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C3-C 8 cycloalkyl)Co- C 4 alkyl-, (aryl)Co-C 4 alkyl-, (C3-C6heterocyclo)Co-C 4 alkyl-, (heteroaryl)Co-C 4 alky-, or the sidechain of an amino acid, for example a sidechain of an amino acid (as otherwise described herein) often selected from the group consisting of alanine, ⁇ -alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or ty
• R 18 is hydrogen or Ci-C3alkyl
• R 16 and R 17 can form a (C3-C7)cycloalkyl or (C3-C7)heterocyclic group; or
• R 18 and R 16 or R 17 can form (C3-C6)heterocyclic group
• R 19 is hydrogen, (Ci-C 6 )alkyl, (C3-C 6 )alkenyl, (C3-C 6 )alkynyl, (C3-C 8 cycloalkyl)Co- C 4 alkyl-, (aryl) -C4alkyl-, (C3-C6heterocyclo)Co-C4alkyl-, (heteroaryl)Co-C4alky-; or
• R 20 is hydrogen, (Ci-C 3 )alkyl, (C3-C 8 cycloalkyl)Co-C4alkyl-, (aryl)Co-C4alkyl-, (C 3 - C6heterocyclo)Co-C4alkyl-, or (heteroaryl)Co-C4alky-;
• R 21 is hydrogen, (Ci-C 3 )alkyl, (C3-C 8 cycloalkyl)Co-C4alkyl-, (aryl)Co-C4alkyl-, (C 3 - C6heterocyclo)Co-C4alkyl-, or (heteroaryl)Co-C4alky-; and
• R 18 and R 19 are as defined above.
• R P1 groups include optionally substituted phenyl, naphthyl, and monocyclic heteroaryl groups, especially those groups (particularly lipophilic groups) which enhance bioavailability of the compounds in the cells of the patient and which exhibit reduced toxicity, enhanced therapeutic index and enhanced pharmacokinetics (the compounds are metabolized and excreted more slowly).
• phosphoramidate is used throughout the specification to describe a group that is found at the 5' or 3 ' position of the furanose ring of the nucleoside compound and forms a prodrug form of the nucleoside compound.
• phosphoramidates can be found at both the 5' and 3' position of the furanose ring of the nucleoside compound and form a prodrug form of the nucleoside compound.
• the phosphoramidate found at the 5' position of the furanose ring of the nucleoside can form a cyclic phosphoramidate compound by forming a bond with the 3'-hydroxyl substituent at the 3' position of the furanose ring of the nucleoside compound and form a prodrug form of the nucleoside compound.
• thiophosphoamidate is a moiety that has a phosphorus bound to sulfur, two oxygen groups and an amine (which may optionally be substituted).
• Thiophosphoramidates useful in the present invention are described in US Patent No. 8,772,474 and WO 2012/040124.
• Thiophosphoramidate groups for use in the present invention include those of the
• thiophosphoramidates include those of the structure:
• R P1 is an optionally substituted linear, branched, or cyclic alkyl group, or an optionally substituted aryl, heteroaryl or heterocyclic group or a linked combination thereof;
• R P2 is a - R N1 R N2 group or a B' group
• R N1 and R N2 are each independently H, Ci-Cs alkyl, (C3-C7cycloalkyl)Co-C 4 alkyl-, (aryl)Co-C4alkyl-, (C3-C6heterocyclo)Co-C4alkyl-, or (heteroaryl)Co-C4alky-; or
• R N1 and R N2 along with the nitrogen atom to which that are attached, join to form a 3 to 7 membered heterocyclic ring;
• R 16 is hydrogen, (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C3-C 8 cycloalkyl)Co- C 4 alkyl-, (aryl)Co-C 4 alkyl-, (C3-C6heterocyclo)Co-C 4 alkyl-, (heteroaryl)Co-C 4 alky-, or the sidechain of an amino acid, for example a sidechain of an amino acid (as otherwise described herein) often selected from the group consisting of alanine, ⁇ -alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or ty
• R 17 is hydrogen, (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C3-C 8 cycloalkyl)Co- C 4 alkyl-, (aryl)Co-C 4 alkyl-, (C3-C6heterocyclo)Co-C 4 alkyl-, (heteroaryl)Co-C 4 alky-, or the sidechain of an amino acid, for example a sidechain of an amino acid (as otherwise described herein) often selected from the group consisting of alanine, ⁇ -alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or ty
• R 18 is hydrogen or Ci-C3alkyl
• R 16 and R 17 can form a (C3-C7)cycloalkyl or (C3-C7)heterocyclic group; or
• R 18 and R 16 or R 17 can form (C 3 -C 6 ) heterocyclic group
• R 19 is hydrogen, (Ci-C 6 )alkyl, (C3-C 6 )alkenyl, (C3-C 6 )alkynyl, (C3-C 8 cycloalkyl)Co- C 4 alkyl-, (aryl) lo)Co-C4alkyl-, (heteroaryl)Co-C4alky-; or
• B' is a group
• R 18 , R 19 , R 20 and R 21 are as defined above.
• R P1 groups include optionally substituted phenyl, naphthyl, and monocyclic heteroaryl groups, especially those groups (particularly lipophilic groups) which enhance bioavailability of the compounds into the cells of the patient and which exhibit reduced toxicity, enhanced therapeutic index and enhanced pharmacokinetics (the compounds are metabolized and excreted more slowly).
• the thiophosphoramidate can be at the 5' or 3' position of the furanose ring of the nucleoside compound to form a prodrug form of the nucleoside compound. In one embodiment, thiophosphoramidates can be found at both the 5' and 3' position of the furanose ring of the nucleoside compound and form a prodrug form of the nucleoside compound.
• the thiophosphoramidate found at the 5' position of the furanose ring of the nucleoside can form a cyclic thiophosphoramidate compound by forming a bond with the 3'- hydroxyl substituent at the 3' position of the furanose ring of the nucleoside compound and form a prodrug form of the nucleoside compound.
• D-configuration refers to the principle configuration which mimics the natural configuration of sugar moieties as opposed to the unnatural occurring nucleosides or "L” configuration.
• ⁇ or “ ⁇ anomer” is used with reference to nucleoside analogs in which the nucleoside base is configured (disposed) above the plane of the furanose moiety in the nucleoside analog.
• coadminister and “coadministration” or combination therapy are used to describe the administration of at least one of the 2'-deoxy-2'-a-fluoro-2'-P-C-nucleoside compounds according to the present invention in combination with at least one other active agent, for example where appropriate at least one additional anti-HCV agent, including other - deoxy-2'-a-fluoro-2'-P-C-nucleoside agents which are disclosed herein.
• the timing of the coadministration is best determined by the medical specialist treating the patient. It is sometimes preferred that the agents be administered at the same time. Alternatively, the drugs selected for combination therapy may be administered at different times to the patient. Of course, when more than one viral or other infection or other condition is present, the present compounds may be combined with other agents to treat that other infection or condition as required.
• the term "host”, as used herein, refers to a unicellular or multicellular organism in which a HCV virus can replicate, including cell lines and animals, and typically a human.
• the term host specifically refers to infected cells, cells transfected with all or part of a HCV genome, and animals, in particular, primates (including chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient.
• Veterinary applications in certain indications, however, are clearly anticipated by the present invention (such as chimpanzees).
• the host can be for example, bovine, equine, avian, canine, feline, etc.
• the present invention includes compounds and the use of compounds with desired isotopic substitutions of atoms, at amounts above the natural abundance of the isotope, i.e., enriched.
• Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
• isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures.
• isotopes of carbon e.g., 13 C and 14 C, may be used.
• a preferred isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug.
• the deuterium can be bound in a location of bond breakage during metabolism (an a-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a ⁇ -deuterium kinetic isotope effect).
• Achillion Pharmaceuticals, Inc. (WO/2014/169278 and WO/2014/169280) describes deuteration of nucleotides to improve their pharmacokinetics or pharmacodynamics, including at the 5-position of the molecule.
• substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
• Substitution of deuterium for hydrogen at a site of metabolic break down can reduce the rate of or eliminate the metabolism at that bond.
• the hydrogen atom can be any isotope of hydrogen, including protium (3 ⁇ 4), deuterium ( 2 H) and tritium ( 3 H).
• isotopically-labeled refers to an analog that is a "deuterated analog", a " 13 C-labeled analog,” or a “deuterated/ 13 C-labeled analog.”
• deuterated analog means a compound described herein, whereby a H-isotope, i.e., hydrogen/protium (3 ⁇ 4), is substituted by a H-isotope, i.e., deuterium ( 2 H).
• Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium.
• the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest.
• it is deuterium that is 90, 95 or 99% enriched at a desired location. Unless indicated to the contrary, the deuteration is at least 80% at the selected location. Deuteration of the nucleoside can occur at any replaceable hydrogen that provides the desired results.
• Treatment refers to the administration of an active compound to a host that is infected with a HCV virus.
• prophylactic or preventative when used, refers to the administration of an active compound to prevent or reduce the likelihood of an occurrence of the viral disorder.
• the present invention includes both treatment and prophylactic or preventative therapies.
• the active compound is administered to a host who has been exposed to and thus at risk of infection by a hepatitis C virus infection.
• the invention is directed to a method of treatment or prophylaxis of a hepatitis C virus, including drug resistant and multidrug resistant forms of HCV and related disease states, conditions, or complications of an HCV infection, including cirrhosis and related hepatotoxicities, as well as other conditions that are secondary to a HCV infection, such as weakness, loss of appetite, weight loss, breast enlargement (especially in men), rash (especially on the palms), difficulty with clotting of blood, spider-like blood vessels on the skin, confusion, coma (encephalopathy), buildup of fluid in the abdominal cavity (ascites), esophageal varices, portal hypertension, kidney failure, enlarged spleen, decrease in blood cells, anemia, thrombocytopenia, jaundice, and hepatocellular cancer, among others.
• the method comprises administering to a host in need thereof an effective amount of at least one P-D-2'-D-2'-a-fluoro-2'-P-C-substituted-2-modified- N 6 -substituted purine nucleotide as described herein, optionally in combination with at least one additional bioactive agent, for example, an additional anti-HCV agent, further in combination with a pharmaceutically acceptable carrier additive and/or excipient.
• additional bioactive agent for example, an additional anti-HCV agent
• the present invention is a method for prevention or prophylaxis of a an HCV infection or a disease state or related or follow-on disease state, condition or complication of an HCV infection, including cirrhosis and related hepatotoxicities, weakness, loss of appetite, weight loss, breast enlargement (especially in men), rash (especially on the palms), difficulty with clotting of blood, spider-like blood vessels on the skin, confusion, coma (encephalopathy), buildup of fluid in the abdominal cavity (ascites), esophageal varices, portal hypertension, kidney failure, enlarged spleen, decrease in blood cells, anemia, thrombocytopenia, jaundice, and hepatocellular (liver) cancer, among others, said method comprising administering to a patient at risk with an effective amount of at least one compound according to the present invention as described above in combination with a pharmaceutically acceptable carrier, additive, or excipient, optionally in combination with another anti-HCV agent.
• the present invention comprising administering
• the 5 '-stabilized p-D-2'-D-2'-a-fluoro-2'-p-C-substituted-2-modified-N 6 -substituted purine nucleotide can be administered if desired as any salt or prodrug that upon administration to the recipient is capable of providing directly or indirectly the parent compound, or that exhibits activity itself.
• Nonlimiting examples are the pharmaceutically acceptable salts and a compound, which has been modified at a function group, such as a hydroxyl or amine function, to modify the biological activity, pharmacokinetics, half-life, controlled delivery, lipophilicity, absorption kinetics, ease of phosphorylation to the active 5 '-triphosphate or efficiency of delivery using a desired route of administration- of the compound.
• Methods to modify the properties of an active compound to achieve target properties are known to those of skill in the art or can easily be assessed by standard methods, for example, acylation, phosphorylation, thiophosphoramidation, phosphoramidation, phosphonation, alkylation, or pegylation.
• compositions according to the present invention comprise an anti-HCV virus effective amount of at least one of the 5'-stabilized ⁇ -D- 2'-D-2'-a-fluoro-2'-P-C-substituted-2-modified-N 6 -substituted purine nucleotide compounds described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient, further optionally in combination or alternation with at least one other active compound.
• compositions according to the present invention comprise an anti-HCV effective amount of at least one of the active ⁇ - ⁇ -2'- ⁇ -2'- ⁇ - fluoro-2'-P-C-substituted-2-modified-N 6 -substituted purine nucleotide compounds described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient, further optionally in combination with at least one other antiviral, such as an anti-HCV agent.
• the invention includes pharmaceutical compositions that include an effective amount to treat a hepatitis C virus infection, of one of the P-D-2'-D-2'-a-fluoro-2'-P-C-substituted-2- modified-N 6 -substituted purine nucleotide compounds of the present invention or its salt or prodrug, in a pharmaceutically acceptable carrier or excipient.
• the invention includes pharmaceutical compositions that include an effective amount to prevent a hepatitis C virus infection, of one of the P-D-2'-D-2'-a-fluoro-2'-P-C-substituted-2-modified-N 6 - substituted purine nucleotide compounds of the present invention or its salt or prodrug, in a pharmaceutically acceptable carrier or excipient.
• a therapeutically effective amount will vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics of the agent used, as well as the patient or subject (animal or human) to be treated, and such therapeutic amount can be determined by the attending physician or specialist.
• the 5 '-stabilized p-D-2'-D-2'-a-fluoro-2'-p-C-substituted-2- modified -N 6 -substituted purine nucleotide compounds according to the present invention can be formulated in an admixture with a pharmaceutically acceptable carrier.
• compositions in orally-administrable form may be administered via a parenteral, intravenous, intramuscular, topical, transdermal, buccal, subcutaneous, suppository, or other route, including intranasal spray.
• Intravenous and intramuscular formulations are often administered in sterile saline.
• One of ordinary skill in the art may modify the formulations to render them more soluble in water or other vehicle, for example, this can be easily accomplished by minor modifications (salt formulation, esterification, etc.) which are well within the ordinary skill in the art. It is also well within the routineers' skill to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
• the prodrug form of the compounds especially including acylated (acetylated or other), and ether (alkyl and related) derivatives, phosphate esters, thiophosphoramidates, phosphoramidates, and various salt forms of the present compounds, are preferred.
• acylated (acetylated or other) and ether (alkyl and related) derivatives, phosphate esters, thiophosphoramidates, phosphoramidates, and various salt forms of the present compounds.
• ether alkyl and related derivatives
• phosphate esters thiophosphoramidates
• phosphoramidates phosphoramidates
• various salt forms of the present compounds are preferred.
• One of ordinary skill in the art will recognize how to readily modify the present compounds to prodrug forms to facilitate delivery of active compounds to a targeted site within the host organism or patient.
• the routineer also will take advantage of favorable pharmacokinetic parameters of the prodrug forms, where applicable, in delivering the present compounds
• the amount of compound included within therapeutically active formulations according to the present invention is an effective amount for treating the HCV infection, reducing the likelihood of a HCV infection or the inhibition, reduction, and/or abolition of HCV or its secondary effects, including disease states, conditions, and/or complications which occur secondary to HCV.
• a therapeutically effective amount of the present compound in pharmaceutical dosage form usually ranges from about 0.001 mg/kg to about 100 mg/kg per day or more, more often, slightly less than about 0.1 mg/kg to more than about 25 mg/kg per day of the patient or considerably more, depending upon the compound used, the condition or infection treated and the route of administration.
• the active nucleoside compound according to the present invention is often administered in amounts ranging from about 0.1 mg/kg to about 15 mg/kg per day of the patient, depending upon the pharmacokinetics of the agent in the patient.
• This dosage range generally produces effective blood level concentrations of active compound which may range from about 0.001 to about 100, about 0.05 to about 100 micrograms/cc of blood in the patient.
• compositions will be administered in oral dosage form in amounts ranging from about 250 micrograms up to about 500 mg or more at least once a day, for example, at least 25, 50, 100, 150, 250 or 500 milligrams, up to four times a day.
• present compounds are often administered orally, but may be administered parenterally, topically, or in suppository form, as well as intranasally, as a nasal spray or as otherwise described herein.
• the amount of the compound according to the present invention to be administered ranges from about 0.01 mg/kg of the patient to about 500 mg/kg. or more of the patient or considerably more, depending upon the second agent to be co-administered and its potency against the virus, the condition of the patient and severity of the disease or infection to be treated and the route of administration.
• the other anti-HCV agent may for example be administered in amounts ranging from about 0.01 mg/kg to about 500 mg/kg.
• these compounds may be often administered in an amount ranging from about 0.5 mg/kg to about 50 mg/kg or more (usually up to about 100 mg/kg), generally depending upon the pharmacokinetics of the two agents in the patient. These dosage ranges generally produce effective blood level concentrations of active compound in the patient.
• a prophylactically or preventive effective amount of the compositions according to the present invention falls within the same concentration range as set forth above for therapeutically effective amount and is usually the same as a therapeutically effective amount.
• Administration of the active compound may range from continuous (intravenous drip) to several oral or intranasal administrations per day (for example, Q.I.D.) or transdermal administration and may include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal, and suppository administration, among other routes of administration.
• Enteric coated oral tablets may also be used to enhance bioavailability of the compounds for an oral route of administration.
• the most effective dosage form will depend upon the bioavailability/pharmacokinetics of the particular agent chosen as well as the severity of disease in the patient. Oral dosage forms are particularly preferred, because of ease of administration and prospective favorable patient compliance.
• a therapeutically effective amount of one or more of the compounds according to the present invention is often intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose.
• a carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
• any of the usual pharmaceutical media may be used.
• suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used.
• suitable carriers and additives including starches, sugar carriers, such as dextrose, manifold, lactose, and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used.
• the tablets or capsules may be enteric-coated or sustained release by standard techniques. The use of these dosage forms may significantly enhance the bioavailability of the compounds in the patient.
• the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients, including those which aid dispersion, also may be included.
• sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized.
• injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be employed.
• Liposomal suspensions may also be prepared by conventional methods to produce pharmaceutically acceptable carriers. This may be appropriate for the delivery of free nucleosides, acyl/alkyl nucleosides or phosphate ester prodrug forms of the nucleoside compounds according to the present invention.
• the compounds and compositions are used to treat, prevent or delay a HCV infection or a secondary disease state, condition or complication of HCV.
• Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication.
• the efficacy of a drug against an HCV infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with another, and perhaps even two or three other, antiviral compounds that induce a different mutation or act through a different pathway, from that of the principle drug.
• the pharmacokinetics, bio distribution, half-life, or other parameter of the drug can be altered by such combination therapy (which may include alternation therapy if considered concerted).
• P-D-2'-D-2'-a-fluoro-2'-P-C-substituted-2- modified- N 6 -substituted purine nucleotides are NS5B polymerase inhibitors, it may be useful to administer the compound to a host in combination with, for example a:
• Protease inhibitor such as an NS3/4A protease inhibitor
• Interferon alfa-2a which may be pegylated or otherwise modified, and/or ribavirin;
• iRNA including microRNA and SiRNA
• Viral antigen or partial antigen that induces a host antibody response Viral antigen or partial antigen that induces a host antibody response.
• anti-HCV agents that can be administered in combination with the ⁇ - D-2'-D-2'-a-fluoro-2'-P-C-substituted-2- modified-N 6 -substituted purine nucleotides of the invention are:
• protease inhibitors such as telaprevir (Incivek ® ), boceprevir (VictrelisTM), simeprevir (OlysioTM), paritaprevir (ABT-450), ACH-2684; AZD-7295; BMS-791325; danoprevir; Filibuvir; GS-9256; GS-9451; MK-5172; Setrobuvir; Sovaprevir; Tegobuvir; VX-135; VX-222 and ALS-220;
• protease inhibitors such as telaprevir (Incivek ® ), boceprevir (VictrelisTM), simeprevir (OlysioTM), paritaprevir (ABT-450), ACH-2684; AZD-7295; BMS-791325; danoprevir; Filibuvir; GS-9256; GS-9451; MK-5172; Setrobuvir; Sovaprevir; Tegobuvir
• NS5A inhibitor such as ACH-2928, ACH-3102, IDX-719, daclatasvir, ledispasvir and Ombitasvir (ABT-267);
• NS5B inhibitors such as ACH-3422; AZD-7295; Clemizole; ITX-5061; PPI-461;
• NS5B inhibitors such as ABT-333, MBX-700.
• the compound can be administered in combination or alternation with another drug that is typically used to treat hepatocellular carcinoma (HCC), for example, as described by Andrew Zhu in "New Agents on the Horizon in Hepatocellular Carcinoma" Therapeutic Advances in Medical Oncology, V 5(1), January 2013, 41-50.
• HCC hepatocellular carcinoma
• Suitable compounds for combination therapy where the host has or is at risk of HCC include anti- angiogenic agents, sunitinib, brivanib, linifanib, ramucirumab, bevacizumab, cediranib, pazopanib, TSU-68, lenvatinib, antibodies against EGFR, mTor inhibitors, MEK inhibitors, and histone decetylace inhibitors.
• Drugs that are currently approved for influenza are Amantadine, Rimantadine and Oseltamivir. Any of these drugs can be used in combination or alternation with an active compound provided herein to treat a viral infection susceptible to such.
• Ribavirin is used to treat measles, Influenza A, influenza B, parainfluenza, severe RSV bronchiolitis and SARS as well as other viral infections, and therefore is particularly useful in combination with the present compound for treatment of the host infected with a single stranded RNA virus.
• Palivizumab is approved for use in infants with high risk for RSV infection.
• Physicians are recommended to provide intensive support therapy, which may involve hospitalization, intravenous fluids, use of a ventilator to assist breathing, medications to control seizures, brain swelling, nausea and vomiting, and the use of antibiotics to prevent bacterial infections for making the disease even worse. This highlights the importance of the present compounds for viral medical therapy.
• THF Tetrahydrofuran (THF), anhydrous
• Li(OtBu)3AlH Lithium tri-tert-butoxyaluminum hydride
• PE Petroleum ether
• t-BuMgCl /-Butyl magnesium chloride
• t-BuOK Sodium tert-butoxide
• 2-Amino-6-chloropurine (2.63 g, 15.5 mmol) was suspended in t-BuOH (54 mL) under a nitrogen atmosphere. The reaction mixture was heated to 30 °C then potassium tert-butoxide (1.69 g, 15.1 mmol) was added. After 45 min a solution of bromofuranoside 2 (2.24 g, 5.12 mmol) dissolved in anhydrous MeCN (6 mL) was added, the reaction mixture was heated to 65 °C for 16 h then cooled down to room temperature. A saturated aq. H 4 C1 solution (70 mL) was added and the resulting solution was extracted with EtOAc (3 x 60mL).
• Step 2 Preparation of isopropyl ((((R,5)-(2R,3R,4R,5R)-5-(2-amino-6-(dimethylamino)-9H- purin-9-yl)-4-fluoro-3 -hy droxy-4-methyltetrahy drofuran-2-yl)methoxy)-phenoxy-phosphory 1)-J- alaninate (7).
• the reaction mixture was stirred at 0 °C for 30 min and 18 h at room temperature.
• the reaction was quenched with a saturated aq. NH4CI solution (4 mL) and extracted with EtOAc (3 x 5 mL).
• the combined organics were dried, filtered (Na 2 S0 4 ) and concentrated.
• the residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 90: 10) and then by reverse phase column chromatography (gradient H 2 0/MeOH 100:0 to 0: 100) to afford the product 7 (mixture of diastereomers, 35 mg, 58 ⁇ , 24%) as a white solid.
• reaction mixture was stirred at 0 °C for 30 min and 18 h at room temperature.
• the reaction was quenched with a saturated aq. H4CI solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na 2 SC"4 and concentrated.
• the residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 90: 10) and then by reverse phase column chromatography (gradient H 2 0/MeOH 100:0 to 0: 100) to afford product 9 (mixture of 2 diastereoisomers, 160 mg, 0.26 mmol, 45%) as a white solid.
• Example 4 Preparation of isopropyi ((((R ⁇ V)-(2R,3R,4R,5R)-5-(2,6-6is-methylamino-9H- purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy- phosphoryl)-L-alaninate (12).
• reaction was quenched with a saturated aq. NH4CI solution and extracted with EtOAc (3 times). The combined organics were dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 50:50) to yield product 12 (mixture of diastereomers, 13 mg, 0.02 mmol, 13%) as a white solid.
• TIPDSCI2 imidazole, DMF
• isobuiyryi chloride pyridine
• iii) i BA THF
• Example 5 Preparation of isopropyi ((((R,S)-(2R,3R,4R,5R)-5-(2-isobutyramido-6- methylamino-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)- phenoxy-phosphoryl)-L-alaninate (16).
• Step 4 Preparation of isopropyl ((((R,,S)-(2R,3R,4R,5R)-5-(2-isobutyramido-6-methylamino-9H- purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy-phosphoryl)-J- alaninate (16).
• reaction mixture was stirred at 0 °C for 30 min followed by 18 h at room temperature then quenched with a saturated aq. NH4CI solution (2 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 95:5) then reverse phase column chromatography (gradient H 2 0/MeOH 100:0 to 0: 100) to afford product 16 (mixture of 2 diastereoisomers, 25 mg, 0.04 mmol, 54%) as a white solid.
• Example 6 Preparation of isopropyi ((((R ⁇ V)-(2R,3R,4R,5R)-5-(2-amino-6-(N-methyl- ethylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)- phenoxy-phosphoryl)-L-alaninate (18).
• Step 2 Preparation of isopropyl ((((R,5)-(2R,3R,4R,5R)-5-(2-amino-6-(N-methyl-ethylamino)- 9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy- phosphoryl)-J-alaninate (18).
• reaction mixture was stirred at 0 °C for 30 min and 18 h at room temperature.
• the reaction was quenched with a saturated aq. H4CI solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na 2 S04 and concentrated.
• the residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 90: 10) to afford the product 18 (mixture of 2 diastereoisomers, 22 mg, 0.04 mmol, 40%) as a white solid.
• Example 7 Preparation of isopropyl ((((R ⁇ )-(2R,3R,4R,5R)-5-(2-amino-6-(N-methyl- propylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)- phenoxy-phosphoryl)-L-alaninate (20).
• reaction mixture was stirred at 0 °C for 30 min and 18 h at room temperature.
• the reaction was quenched with a saturated aq. H4CI solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na 2 SC"4 and concentrated.
• the residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 90: 10) to afford product 20 (mixture of 2 diastereoisomers, 22 mg, 0.03 mmol, 33%) as a white solid.
• Example 8 Preparation of Isopropyl ((((R ⁇ )-(2R,3R,4R,5R)-5-(2-amino-6-(N-methyl- cyclobutylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)-phenoxy-phosphoryl)-L-alaninate (22).
• reaction mixture was stirred at 0 °C for 30 min and 18 h at room temperature.
• the reaction was quenched with a saturated aq. H4CI solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na 2 S0 4 and concentrated.
• the residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 90: 10) and then by reverse phase column chromatography (gradient H 2 0/MeOH 100:0 to 0: 100) to afford product 22 (mixture of 2 diastereoisomers, 24 mg, 0.04 mmol, 28%) as a white solid.
• the base is potassium tert-butoxide.
• the mixture of organic solvents comprises tert-butanol and acetonitrile.
• the compound, (2R,3R,4R,5R)-5-(2,6-dichloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4- methyltetrahydrofuran-3-yl benzoate is treated with an amine, a base and an organic solvent at ambient temperature to generate 2-chloro-N 6 -substituted purines.
• the amine is methylamine.
• the base is triethylamine.
• the organic solvent is ethanol.
• 2-Chloro-N 6 -substituted purines can then be treated with an amine, and an organic solvent in a sealed tube at an elevated temperature of about 100 °C to generate N 2 ,N 6 -di substituted purine nucleosides of the present invention.
• the amine is methylamine.
• the organic solvent is ethanol.
• N 2 ,N 6 -Di substituted purine nucleosides of the present invention can be treated with a base, isopropyl ((R,S)- (pentafluorophenoxy)-phenoxy-phosphoryl)-J-alaninate and an organic solvent at a reduced temperature to generate compounds of Formula I-V.
• the base is tert-butyl magnesium chloride.
• the organic solvent is tetrahydrofuran.
• any of the active compounds described herein have a chiral phosphorus moiety.
• Any of the active compounds described herein can be provided as an isolated phosphorus enantiomeric form, for example, at least 80, 90, 95 or 98% of the R or S enantiomer, using methods known to those of skill in the art.
• there are a number of publications that describe how to obtain such compounds including but not limited to column chromatography, for example as described in Example 17 below and U.S. Patent No. 8,859,756; 8,642,756 and 8,333,309 to Ross, et al.
• Mobile phase B HPLC grade acetonitrile.
• the final weights of the 1 st and 2 nd peak correspond well to their percentages in the original mixture. (62.2% and 37.8% respectively).
• Step 2 Preparation of ((((5)-(2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4- fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy-phosphoryl)-J-alaninate.
• Example 12 Preparation of isopropyl ((((S)-(2R,3R,4R,5R)-5-(2-amino-6-(dimethylamino)- 9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy- hosphoryl)-L-alaninate (25).
• Step 2 Preparation of isopropyl ((((,S)-(2R,3R,4R,5R)-5-(2-amino-6-(dimethylamino)-9H-purin- 9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy-phosphoryl)-J- alaninate (25).
• Example 13 Preparation of isopropyl ((((R)-(2R,3R,4R,5R)-5-(2-amino-6-(dimethylamino)- 9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy- phosphoryl)-L-alaninate (26).
• Step 1 Preparation of (2R,3R,4R,5R)-5-(2-amino-6-(methylcyclopropanamino)-9H-purin-9-yl)- 4-fluoro-3-hydroxy-4-methyltetrahydrofuran-3-ol (8).
• Step 2 Preparation of isopropyl ((((,S)-(2R,3R,4R,5R)-5-(2-amino-6-(methylcyclopropanamino)-
• Example 15 Preparation of isopropyl ((((R)-(2R,3R,4R,5R)-5-(2-amino-6- (methylcyclopropanamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)-phenoxy-phosphoryl)-L-alaninate.
• Example 19 Preparation of isopropyl ((((R,S)-(2R,3R,4R,5R)-5-(2- dimethylamino-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-ethynyltetrahydrofuran-2- yl)methoxy)-phenoxy-phosphoryl)-L-alaninate
• reaction mixture was stirred at 0 °C for 30 min and 18 h at room temperature.
• the reaction was quenched with a saturated aq. H4CI solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na 2 S04 and concentrated.
• the residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 90: 10) to afford the product (mixture of 2 diastereoisomers, 12 mg, 0.02 mmol, 24%) as a white solid.
• Example 20 Preparation of isopropyl ((((R ⁇ V)-(2R,3R,4R,5R)-5-(2-amino-6-methylamino- 9H-purin-9-yl)-4-fluoro-3-hydroxy-4-ethynyltetrahydrofuran-2-yl)methoxy)-phenoxy- hosphoryl)-L-alaninate.
• Step 1 Preparation of isopropyl ((((R,,S)-(2R,3R,4R,5R)-5-(2-amino-6-methylamino-9H-purin-9- yl)-4-fluoro-3-hydroxy-4-ethynyltetrahydrofuran-2-yl)methoxy)-phenoxy-phosphoryl)-J- alaninate.
• reaction mixture was stirred at 0 °C for 30 min and 18 h at room temperature.
• the reaction was quenched with a saturated aq. H4CI solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na 2 S04 and concentrated.
• the residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 90: 10) to afford the product (mixture of 2 diastereoisomers, 9 mg, 0.02 mmol, 18%) as a white solid.
• Example 21 Preparation of isopropyl ((((R ⁇ V)-(2R,3R,4R,5R)-5-(2-amino-6-(N- methylcyclopropylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-ethynyltetrahydrofuran-2- yl)methoxy)-phenoxy-phosphoryl)-L-alaninate
• Step 1 Preparation of isopropyl ((((R,5)-(2R,3R,4R,5R)-5-(2-amino-6-(N- methylcyclopropylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-ethynyltetrahydrofuran-2- yl)methoxy)-phenoxy-phosphoryl)-J-alaninate.
• reaction mixture was stirred at 0 °C for 30 min and 18 h at room temperature.
• the reaction was quenched with a saturated aq. H4CI solution (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na 2 S04 and concentrated.
• the residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 90: 10) to afford the product (mixture of 2 diastereoisomers, 18 mg, 0.03 mmol, 26%) as a white solid.
• Step 3 Preparation of compound 59.
• Triethylamine (10.119 g) and Et 3 N 3HF (8.6 g, 5 eq) were added to an ice-cooled solution of 58 (7.3 g, 1 eq) in THF (100 mL) and the mixture was stirred for 1 h at room temperature.
• Huh-7 luc/ ' neo ET cells bearing a discistronic HCV genotype lb iuciferase reporter replicon were plated at 7.5 x 10 3 cells/ml in duplicate 96-well plates for the parallel determination of antiviral efficacy (ECso) and cytotoxicity (TC50). The plates were cultured for 24 hours prior to the addition of compounds.
• Six serial one half log dilutions of the test articles high test concentration of 100.0 ⁇ . ⁇ or high test concentration of 1.0 ⁇ . ⁇
• human interferon- alpha2b high test 10.0 U/ml
• the y-axis is the percent of virus control and the x-axis is the concentration of drug in ⁇ .
• Figure 3 illustrates the HCV replication inhibition curves for Compound 25 and Sofosbuvir.
• the y-axis is the percent of virus control and the x-axis is the concentration of drug in ⁇ .
• Figure 4 illustrates an intra-assay comparison of the anti-HCV activity for Compounds 5-2, 25, 27 and Sofosbuvir.
• the y-axis is the percent of virus control and the x-axis is the concentration of drug in ⁇ .
• Replicon resistance test vectors containing the NS5B genomic regions were prepared using viral RNA isolated from plasma of HCV patients. Each NS5B region was amplified by reverse- transcription polymerase chain reaction and cloned into an HCV replicon RTV which was then transferred by electroporation into Huh-7 cells. After incubation in the absence and presence of serially diluted test compounds for 72-96 hr, viral replication was measured by luciferase activity and 50% inhibitory concentrations (ICso values) were determined.
• ICso values 50% inhibitory concentrations
• Table 2 reports the ICso and IC95 values for compound 25, 27, 5-2 and Sofosbuvir against various clinical isolates containing wild-type and resistance-associated variants.
• a transient transfection assay was performed to determine the sensitivity of the wild type S282T mutant of HCV to test compounds.
• Huh-7 cells were electroporated in the presence of RNA transcribed from wild type or S282T HCV replicon plasmids from the T7 promoter.
• the transfected cells were seeded in to 96-well plates at 7.5 x 10 3 cells per well in Dulbecco's Modified Eagle's medium. After 24 hr of incubation, medium was removed and replaced with fresh medium containing no or various concentrations of test compounds.
• the anti-HCV activity was measured by luciferase endpoint with BriteliteTM Plus luminescence reporter gene kit (Perkin Elmer, Shelton, CT). Duplicate plates were treated and incubated in parallel for assessment of cellular toxicity by staining with the tetrazolium dye XTT.
• Table 3 reports the ICso and IC95 values for compounds 25, 27, 5-2 and Sofosbuvir against HCV wild type and S282T replicons.
• Figure 5 illustrates the excellent stability of compound 5-2 and all 2-amino derivatives in human blood.
• Figure 6 illustrates the in vitro time course dealkylation of the 2'-deoxy-2'- a-fluoro-2'-P-methyl-N 2 -methyl-N 6 -methyl-2,6-diaminopurine nucleoside phosphoramidate to 2'-deoxy-2'-a-fluoro-2'-P-methyl-N 6 -methyl-2,6-diaminopurine nucleoside phosphoramidate with a human liver S9 fraction.
• Figure 7 illustrates the in vitro time course dealkylation of the 2'-deoxy-2'- a-fluoro-2'-P-methyl-N 2 -methyl-N 6 -methyl-2,6-diaminopurine nucleoside phosphoramidate to 2'-deoxy-2'-a-fluoro-2'-P-methyl-N 6 -methyl-2,6-diaminopurine nucleoside phosphoramidate with a human liver S9 fraction.
• HCV (gtlb) NS5B polymerase Inhibition of HCV (gtlb) NS5B polymerase was determined in triplicate by measuring de novo polymerization in reaction mixtures containing serial dilutions of TA, in vitro transcribed viral RNA complementary to the HCV (-) strand 3'UTR region, polymerase, radiolabeled ribonucleotide, 250 ⁇ non-competing rNTPs, and 1 ⁇ competing rNTP. TA concentrations that produced 50% inhibition (ICso) were determined from resulting inhibition curves.
• ICso Human Bone Marrow Progenitor Cell Assay
• Fresh human bone marrow progenitor cells (Invitrogen) suspended in either BFU-E or GM-CSF-specific culture medium were added, at 10 5 cells/well, to triplicate serial dilutions of TA in 6-well plates. After 14-day incubations, colony counts were used to determine CCso values. BFU-E colonies were confirmed using the benzidene technique.
• Compounds 25, 27 and 5-2 show no cytotoxicity against bone marrow stem cells in vitro.

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