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WO2003051896A1 - Bibliotheques a cytidine et composes de ces bibliotheques dont la synthese repose sur des strategies combinatoires en phase solide - Google Patents

Bibliotheques a cytidine et composes de ces bibliotheques dont la synthese repose sur des strategies combinatoires en phase solide Download PDF

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WO2003051896A1
WO2003051896A1 PCT/US2002/035558 US0235558W WO03051896A1 WO 2003051896 A1 WO2003051896 A1 WO 2003051896A1 US 0235558 W US0235558 W US 0235558W WO 03051896 A1 WO03051896 A1 WO 03051896A1
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substituted
alkyl
alkynyl
alkenyl
aryl
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Haoyun An
Jean-Luc Girardet
Yili Ding
Dinesh Barawkar
Zhi Hong
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Valeant Research and Development
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Ribapharm Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • 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
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the field of the invention is combinatorial nucleoside libraries and related compounds.
  • nucleosides and related compounds interact with many biological targets, and some nucleoside analogues have been used as antimetabolites for treatment of cancers and viral infections. After entry into the cell, many nucleoside analogues can be phosphorylated to monophosphates by nucleoside kinases, and then further phosphorylated by nucleoside monophosphate kinases and nucleoside diphosphate kinases to give nucleoside triphosphates. Once a nucleoside analogue is converted to its triphosphate inside the cell, it can be incorporated into DNA or RNA.
  • nucleoside analogue triphosphates are very potent, competitive inhibitors of DNA or RNA polymerases, which can significantly reduce the rate at which the natural nucleoside can be incorporated.
  • Many anti-HIV nucleoside analogues fall into this category, including 3'-C-azido-3'- deoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and 2',3'-didehydro-2',3'- dideoxythymidine.
  • nucleoside analogues can also act in other ways, for example, causing apoptosis of cancer cells and/or modulating immune systems.
  • nucleoside antimetabolites a number of nucleoside analogues that show very potent anticancer and antiviral activities act through still other mechanisms.
  • Some well-known nucleoside anticancer drugs are thymidylate synthase inhibitors such as 5-fluorouridine, and adenosine deaminase inhibitors such as 2-chloroadenosine.
  • a well-studied anticancer compound, neplanocin A is an inhibitor of S-adenosylhomocysteine hydrolase, which shows potent anticancer and antiviral activities.
  • cytosine nucleoside analogs have shown significant antiviral and antineoplastic activity (see e.g., Carbone et al., Biochem Pharmacol. 2001 Jul 1;62(1):101-10; or Miura et al., Jpn J Cancer Res. 2001 May;92(5):562- 7; or Christensen et al., Antiviral Res. 2000 Nov;48(2):131-42). Many of those cytosine analogs, however, have relatively significant side effects. Moreover, numerous of the cytosine analogs have modifications in the sugar moiety while retaining the pyrimidine portion unchanged.
  • nucleoside analogues that inhibit tumor growth or viral infections are also toxic to normal mammalian cells, primarily because these nucleoside analogues lack adequate selectivity between the normal cells and the virus-infected host cells or cancer cells. For this reason many otherwise promising nucleoside analogues fail to become therapeutics in the treatment of various diseases.
  • nucleosides, nucleotides, and their analogs could be made through a combinatorial chemistry approach, a large number of such compounds could be synthesized within months instead of decades, and large libraries could be developed.
  • nucleoside analogues were usually designed as potential inhibitors of DNA or RNA polymerases and several other enzymes and receptors, including inosine monophosphate dehydrogenase, protein kinases, and adenosine receptors. If a vast number of diversified nucleoside analogues could be created, their use may be far beyond these previously recognized biological targets, which would open a new era for the use of nucleoside analogues as human therapeutics.
  • nucleoside analogues contain a sugar moiety and a nucleoside base, which are linked together through a glycosidic bond.
  • the formation of the glycosidic bond can be achieved through a few types of condensation reactions.
  • most of the reactions do not give a good yield of desired products, which may not be suitable to generations of nucleoside libraries.
  • the glycosidic bonds in many nucleosides are in labile to acidic condition, and many useful reactions in combinatorial chemistry approaches cannot be used in the generation of nucleoside analogue libraries.
  • an amino acid substituted cytidine library will comprise library compounds according to Formula 1 A or IB
  • A, X, Y, Z, Ri, and R 2 are defined as in the respective portions of the detailed description below.
  • a 2'-O-alkylcytidine library will comprise library compounds according to Formula 2C and 2D
  • 2'-O-alkyl substituted libraries include libraries and compounds according to Formulae 2E and 2F (2'O-methyl-N4-substituted cytidines)
  • an N-substituted cytidine library will comprise library compounds according to Formulae 3 A and 3B
  • contemplated nucleoside libraries and compounds include compounds according to Formula 21, 2K, 2M, or 20
  • contemplated nucleoside libraries and compounds include compounds according to Formula 2U, 2V, or 2W
  • contemplated nucleoside libraries and compounds include compounds according to Formula 2Z
  • R is defined as in the respective portions of the detailed description below.
  • nucleoside library refers to a plurality of chemically distinct nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs wherein at least some of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs include, or have been synthesized from a common precursor.
  • nucleoside library a plurality of nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs that were prepared using l'-azido or l'-amino ribofuranose as a building block/precursor is considered a nucleoside library under the scope of this definition. Therefore, the term "common precursor" may encompass a starting material in a first step in a synthesis as well as a synthesis intermediate (i.e., a compound derived from a starting material).
  • At least one step in the synthesis of one of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs is concurrent with at least one step in the synthesis of another one of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs, and synthesis is preferably at least partially automated.
  • nucleoside library a collection of individually synthesized nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs, and especially a collection of compounds not obtained from a nucleoside library, is not considered a nucleoside library because such nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs will not have a common precursor, and because such nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs are not concurrently produced.
  • the complexity of contemplated libraries is at least 20 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs, more typically at least 100 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs, and most typically at least 1000 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs. Consequently, a typical format of a nucleoside library will include multi-well plates, or a plurality of small volume (i.e., less than 1ml) vessels coupled to each other.
  • library compound refers to a nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog within a nucleoside library.
  • heterocycle and “heterocyclic base” are used interchangeably herein and refer to any compound in which a plurality of atoms form a ring via a plurality of covalent bonds, wherein the ring includes at least one atom other than a carbon atom.
  • heterocyclic bases include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine).
  • heterocylces may be fused (i.e., covalently bound) to another ring or heterocycle, and are thus termed "fused heterocycle” or "fused heterocyclic base” as used herein.
  • fused heterocycles include a 5-membered ring fused to a 6-membered ring (e.g., purine, pyrrolo[2,3-d]pyrimidine), and a 6-membered ring fused to another 6-membered or higher ring (e.g., pyrido[4,5-d]pyrimidine, benzodiazepine). Examples of these and further preferred heterocyclic bases are given below.
  • Still further contemplated heterocyclic bases may be aromatic, or may include one or more double or triple bonds.
  • contemplated heterocyclic bases and fused heterocycles may further be substituted in one or more positions (see below).
  • sugar refers to all carbohydrates and derivatives thereof, wherein particularly contemplated derivatives include deletion, substitution or addition of a chemical group or atom in the sugar.
  • particularly contemplated deletions include 2'-deoxy and/or 3'-deoxy sugars.
  • Especially contemplated substitutions include replacement of the ring-oxygen with sulfur or methylene, or replacement of a hydroxyl group with a halogen, an amino-, sulfhydryl-, or methyl group, and especially contemplated additions include methylene phosphonate groups.
  • Further contemplated sugars also include sugar analogs (i.e., not naturally occurring sugars), and particularly carbocyclic ring systems.
  • carbocyclic ring system refers to any molecule in which a plurality of carbon atoms form a ring, and in especially contemplated carbocyclic ring systems the ring is formed from 3, 4, 5, or 6 carbon atoms. Examples of these and further preferred sugars are given below.
  • nucleoside refers to all compounds in which a heterocyclic base is covalently coupled to a sugar, and an especially preferred coupling of the nucleoside to the sugar includes a Cl'-(glycosidic) bond of a carbon atom in a sugar to a carbon- or heteroatom (typically nitrogen) in the heterocyclic base.
  • nucleoside analog refers to all nucleosides in which the sugar is not a ribofuranose and/or in which the heterocyclic base is not a naturally occurring base (e.g., A, G, C, T, I, etc.).
  • nucleotide refers to a nucleoside to which a phosphate group is coupled to the sugar.
  • nucleotide analog refers to a nucleoside analog to which a phosphate group is coupled to the sugar.
  • nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog also includes all prodrug forms of a nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog, wherein the prodrug form may be activated/converted to the active drug/nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog in one or more than one step, and wherein the activation/conversion of the prodrug into the active drug/nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog may occur intracellularly or extracellularly (in a single step or multiple steps).
  • Especially contemplated prodrug forms include those that confer a particular specificity towards a diseased or infected cell or organ, and exemplary contemplated prodrug forms are described in "Prodrugs” by Kenneth B. Sloan (Marcel Dekker; ISBN: 0824786297), "Design of Prodrugs” by Hans Bundgaard (ASIN: 044480675X), or in copending US application number 09/594410, filed 06/16/2000, all of which are incorporated by reference herein.
  • Particularly suitable prodrug forms of the above compounds may include a moiety that is covalently coupled to at least one of the C2'-OH, C3'-OH, and C5'-OH, wherein the moiety is preferentially cleaved from the compound in a target cell (e.g., Hepatocyte) or a target organ (e.g., liver).
  • a target cell e.g., Hepatocyte
  • a target organ e.g., liver
  • cleavage of the prodrug into the active form of the drug is mediated (at least in part) by a cellular enzyme, and particularly receptor, transporter and cytochrome-associated enzyme systems (e.g., CYP- system).
  • Especially contemplated prodrugs comprise a cyclic phosphate, cyclic phosphonate and or a cyclic phosphoamidates, which are preferentially cleaved in a hepatocyte to produce contemplated compounds.
  • a cyclic phosphate, cyclic phosphonate and or a cyclic phosphoamidates which are preferentially cleaved in a hepatocyte to produce contemplated compounds.
  • prodrug forms are disclosed in WO 01/47935 (Novel Bisamidate Phosphonate Prodrugs), WO 01/18013 (Prodrugs For Liver Specific Drug Delivery), WO 00/52015 (Novel Phosphorus-Containing Prodrugs), and WO 99/45016 (Novel Prodrugs For Phosphorus-Containing Compounds), all of which are incorporated by reference herein. Consequently, especially suitable prodrug forms include those targeting a hepatocyte or the liver.
  • Still further particularly preferred prodrugs include those described by Renze et al. in Nucleosides Nucleotides Nucleic Acids 2001 Apr-Jul;20(4-7):931-4, by Balzarini et al. in Mol Pharmacol 2000 Nov;58(5):928-35, or in U.S. Pat. No. 6,312,662 to Erion et al., U.S. Pat. No. 6,271,212 to Chu et al., U.S. Pat. No. 6,207,648 to Chen et al., U.S. Pat. No. 6,166,089 and U.S. Pat. No. 6,077,837 to Kozak, U.S. Pat. No.
  • prodrugs include those comprising a phosphate and/or phosphonate non-cyclic ester, and an exemplary collection of suitable prodrugs is described in U.S. Pat. No. 6,339,154 to Shepard et al., U.S. Pat. No. 6,352,991 to Zemlicka et al, and U.S. Pat. No. 6,348,587 to Schinazi et al. Still further particularly contemplated prodrug forms are described in FASEB J. 2000 Sep;14(12):1784- 92, Pharm. Res. 1999, Aug 16:8 1179-1185, and Antimicrob Agents Chemother 2000, Mar 44:3 477-483, all of which are incorporated by reference herein.
  • alkyl and “unsubstituted alkyl” are used interchangeably herein and refer to any linear, branched, or cyclic hydrocarbon in which all carbon-carbon bonds are single bonds.
  • alkenyl and “unsubstituted alkenyl” are used interchangeably herein and refer to any linear, branched, or cyclic alkyl with at least one carbon-carbon double bond.
  • alkynyl and “unsubstituted alkynyl” are used interchangeably herein and refer to any linear, branched, or cyclic alkyl or alkenyl with at least one carbon-carbon triple bond.
  • aryl and “unsubstituted aryl” are used interchangeably herein and refer to any aromatic cyclic alkenyl or alkynyl.
  • alkaryl is employed where an aryl is covalently bound to an alkyl, alkenyl, or alkynyl.
  • substituted refers to a replacement of an atom or chemical group (e.g. , H, NH 2 , or OH) with a functional group
  • functional groups include nucleophilic groups (e.g., -NH 2 , -OH, -SH, -NC, etc.), electrophilic groups (e.g., C(O)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -N *), and halogens (e.g., -F, -Cl), and all chemically reasonable combinations thereof.
  • nucleophilic groups e.g., -NH 2 , -OH, -SH, -NC, etc.
  • electrophilic groups e.g., C(O)OR, C(X)OH, etc.
  • polar groups e
  • the term "functional group” as used herein refers to a nucleophilic group (e.g., -NH 2 , -OH, -SH, -NC, -CN etc.), an electrophilic group (e.g., C(O)OR, C(X)OH, C(Halogen)OR, etc.), a polar group (e.g., -OH), a non-polar group ⁇ e.g., aryl, alkyl, alkenyl, alkynyl, etc.), an ionic group (e.g., -NH 3 -1 ;, and a halogen.
  • a nucleophilic group e.g., -NH 2 , -OH, -SH, -NC, -CN etc.
  • an electrophilic group e.g., C(O)OR, C(X)OH, C(Halogen)OR, etc.
  • a polar group e.g., -OH
  • suitable sugars will have a general formula of C n H 2n O n , wherein n is between 2 and 8, and wherein (where applicable) the sugar is in the D- or L-configuration.
  • sugar analogs there are numerous equivalent modifications of such sugars known in the art (sugar analogs), and all of such modifications are specifically included herein.
  • some contemplated alternative sugars will include sugars in which the heteroatom in the cyclic portion of the sugar is an atom other than oxygen (e.g., sulfur, carbon, or nitrogen) analogs, while other alternative sugars may not be cyclic but in a linear (open-chain) form. Suitable sugars may also include one or more double bonds.
  • Still further specifically contemplated alternative sugars include those with one or more non-hydroxyl substituents, and particularly contemplated substituents include mono-, di-, and triphosphates (preferably as C 5 ' esters), alkyl groups, alkoxy groups, halogens, amino groups and amines, sulfur-containing substituents, etc.
  • Particularly contemplated modifications include substituted ribofuranoses, wherein the substituent on the substituted ribofuranose is a -CR substituent on at least at one of the 2' and 3' carbon atom, with R being Ci-io alkyl, alkenyl, alkynyl, aryl, heterocycle, CF 3 , CF 2 H, CC1 3 , CC1 2 H, CH 2 OH, CN, COOR', and CONHR, and with R being C MO alkyl, alkenyl, alkynyl, aryl. It is still further contemplated that all contemplated substituents (hydroxyl substituents and non-hydroxyl substituents) may be directed in the alpha or beta position.
  • contemplated sugars and sugar analogs are commercially available. However, where contemplated sugars are not commercially available, it should be recognized that there are various methods known in the art to synthesize such sugars. For example, suitable protocols can be found in "Modern Methods in Carbohydrate Synthesis” by Shaheer H. Khan (Gordon & Breach Science Pub; ISBN: 3718659212), in U.S. Pat Nos. 4,880,782 and 3,817,982, in WO88/00050, or in EP 199,451.
  • An exemplary collection of further contemplated sugars and sugar analogs is depicted below, wherein all of the exemplary sugars may be in D- or L-configuration, and wherein at least one of the substituents may further be in either alpha or beta orientation.
  • X, Y,Z ⁇ ,S, Se, NH, NR, CH 2 , CHR.P(O), P(0)OR
  • R H,OH,NHR,halo,CH 2 OH,COOH,N 3 , alkyl, aryl, alkynyl, heterocycles, OR, SR, P( ⁇ )( ⁇ R) 2
  • An especially contemplated class of sugars comprises alkylated sugars, wherein one or more alkyl groups (or other substituents, including alkenyl, alkynyl, aryl, halogen, CF 3 , CHF 2 , CC1 3 , CHCI 2 , N 3 , NH 2 , etc.) are covalently bound to sugar at the C',, C ⁇ C ⁇ d, or C 5 atom.
  • the sugar portion comprises a furanose (most preferably a D- or L-ribofuranose), and that at least one of the alkyl groups is a methyl group.
  • the alkyl group may or may not be substituted with one or more substituents.
  • One exemplary class of preferred sugars is depicted below:
  • R is independently hydrogen, hydroxyl, substituted or unsubstituted alkyl (branched, linear, or cyclic), with R including between one and twenty carbon atoms.
  • Contemplated Heterocyclic Bases It is generally contemplated that all compounds in which a plurality of atoms (wherein at least one atom is an atom other than a carbon atom) form a ring via a plurality of covalent bonds are considered a suitable heterocyclic base.
  • particularly contemplated heterocyclic bases have between one and three rings, wherein especially preferred rings include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine).
  • heterocylces may be fused (i.e., covalently bound) to another ring or heterocycle, and are thus termed "fused heterocycle" as used herein.
  • Especially contemplated fused heterocycles include a 5- membered ring fused to a 6-membered ring (e.g., purine, pyrrolo[2,3-d]pyrimidine), and a 6-membered ring fused to another 6-membered or higher ring (e.g., pyrido[4,5-d]pyrimidine, benzodiazepine).
  • cytidine heterocyclic bases are especially contemplated, an exemplary collection of alternative heterocyclic bases is depicted below, wherein all of the depicted heterocyclic bases may further include one or more substituents, double and triple bonds, and any chemically reasonable combination thereof. It should further be appreciated that all of the contemplated heterocyclic bases may be coupled to contemplated sugars via a carbon atom or a non-carbon atom in the heterocyclic base.
  • nucleosides or sugar, or heterocyclic base
  • coupled nucleoside or sugar, or heterocyclic base
  • contemplated solid phases include Merrifield resins, ArgoGel (available from Argonaut, San Francisco, CA), Sasrin resin (a polystyrene resin available from Bachem Bioscience, Switzerland), TentaGel S AC, TentaGel PHB, or TentaGel S NH 2 resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany).
  • contemplated solid supports may also include glass, as described in U. S. Pat. No. 5,143,854.
  • Another preferred solid support comprises a "soluble" polymer support, which may be fabricated by copolymerization of polyethylene glycol, polyvinylalcohol, or polyvinylalcohol with polyvinyl pyrrolidine or derivatives thereof (e.g., see Janda and Hyunsoo (1996) Methods Enzymol. 267:234-247; Gravert and Janda (1997) Chemical Reviews 97:489-509; and Janda and Hyunsoo, PCT publication No. WO 96/03418).
  • combinatorial reactions and/or reaction sequences may be used in conjunction with the teaching presented herein so long as such combinatorial reactions between a substrate and at least two distinct reagents will result in at least two distinct products. Contemplated combinatorial reactions and/or reaction sequences may therefore be performed sequentially, in parallel, or in any chemically reasonable combination thereof. It is still further contemplated that suitable combinatorial reactions and/or reaction sequences may be performed in a single compartment or multiple compartments.
  • Preferred combinatorial reactions and/or reaction sequences include at least one step in which a substrate or reaction intermediate is coupled to a solid phase (which may include the wall of the reaction compartment or a solid or soluble polymers), and that the solid phase is physically separated from another substrate on another solid phase. While not limiting to the inventive subject matter, it is generally preferred that contemplated solid phase synthesis is at least partially automated.
  • a substrate or reaction intermediate is coupled to a solid phase (which may include the wall of the reaction compartment or a solid or soluble polymers), and that the solid phase is physically separated from another substrate on another solid phase.
  • nucleoside analog libraries and especially cytidine nucleoside libraries, library compounds and their analogs can be prepared in various combinatorial library approaches.
  • Particularly preferred approaches include those in which diverse heterocyclic bases and/or diverse nucleoside substituents are prepared from precursor nucleosides that are modified in a series of at least two subsequent and/or parallel modification reactions.
  • amino acid substituted cytidine libraries may be produced following a general synthetic procedure as described in Scheme 1 below.
  • 5-bromouridine is converted to the corresponding 5-amino uridine, which is then used as a nucleophilic substrate in a reaction with a first set of reagents (e.g. , activated and/or protected amino acids) to form a first set of amino acid derivatives of the nucleoside.
  • a first set of reagents e.g. , activated and/or protected amino acids
  • a leaving group e.g., nitrotriazole
  • the amino group in the amino acid may be employed as a nucleophile to displace the leaving group and consequently to form a ring structure in an intramolecular reaction.
  • nucleoside With respect to the nucleoside, it should be recognized that 5-bromouridine is a preferred starting material and commercially available from various sources. However, it should also be appreciated that numerous alternative reagents are also suitable. For example, there are various 5-bromouracil analogs (e.g., substituted and unsubstituted deoxy- and dideoxy analogs) commercially available. Moreover, it should be recognized that suitable nucleoside analogs may also be prepared with sugar moieties other than a ribofuranose fiom a coupling reaction between (commercially available) 5-bromouracil and a suitable sugar following standard coupling procedures well known in the art.
  • 5-bromouracil e.g., substituted and unsubstituted deoxy- and dideoxy analogs
  • suitable nucleoside analogs may also be prepared with sugar moieties other than a ribofuranose fiom a coupling reaction between (commercially available) 5-bromouracil and a suitable sugar following standard coup
  • sugars include various substituted ribofuranoses, carbocyclic ring systems with 5 or 6 carbon atoms, and arabinose, wherein the sugar is in a D-configuration or in an L-configuration.
  • Further contemplated sugars include those previously described in the section entitled "Contemplated Sugars", and it is especially contemplated that where the sugar has a C 2 ' and/or C 3 ' substituent other than a hydroxyl group, alternative sugars may include hydrogen, a methyl group, a halogen, or an azide group in at least one of these positions (in either alpha or beta orientation).
  • protecting groups for the sugar will vary considerably, and while it is particularly contemplated that suitable protection groups include benzyl-, acetyl-, and TBDMS groups, numerous alternative protection groups are also considered suitable. Among other groups, a collection of appropriate alternative protection groups and their reactions is described in Protective Groups in Organic Synthesis by Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons; ISBN: 0471160199.
  • solid phase and methods of coupling the solid phase to the nucleoside will at least in part depend on the particular sugar and position of coupling. Therefore, it is contemplated that all known solid phases are suitable for use in conjunction with the teachings presented herein, and exemplary suitable solid phases are described, for example, in Organic Synthesis on Solid Phase - Supports, Linkers, Reactions; by Florencio Zaragoza Dorwald et al. John Wiley & Sons; ISBN: 3527299505, or in Solid-Phase Synthesis and Combinatorial Technologies by Pierfausto Seneci, John Wiley & Sons; ISBN: 0471331953.
  • Preferred solid phases include Merrifield resins, ArgoGel (available from Argonaut, San Francisco, CA), Sasrin resin (a polystyrene resin available from Bachem Bioscience, Switzerland), TentaGel S AC, TentaGel PHB, or TentaGel S NH 2 resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany).
  • alternative heterocyclic bases are also appropriate and particularly contemplated alternative heterocyclic bases include pyrimidine heterocyclic bases with at least one halogen substituent and at least one keto group. While not limiting to the inventive subject matter, alternative heterocyclic bases may further include substituents other than halogens and keto groups, and especially contemplated substituents include hydroxyls, amino groups, and azido groups. Suitable alternative heterocyclic bases include those listed above in the section entitled "Contemplated Heterocyclic Bases". With respect to the first set of reagents, it is generally preferred that such reagents are amino acids, which may be in D-or L-configuration.
  • a chiral center may be introduced into the nucleoside.
  • suitable amino acids are naturally occurring amino acids, non-natural amino acids (e.g. , beta-amino acids, or amino acids including a halogen or heteroatom other than N, O, or S) are also contemplated.
  • suitable amino acids may have the general formula R-C(H)(NH 2 )COOH, wherein R is hydrogen, a functional group, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl.
  • suitable reagents may have the formula N(H)(R)COOH, N(H)(R)CSOH, or may be RSO H, wherein R is defined as above.
  • reagents other than amino acids are also suitable substrates for the first reaction with the amino group, so long as such reagents can react (with or without prior activation or catalyst) with the amino group of the heterocyclic base to form a covalent bond with the base.
  • an alternative first set of reagents especially include an electrophilic group (e.g., carboxylic acids which may or may not be branched, substituted, or include an aromatic moiety, and may have a general formula of R-COOH, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl).
  • an electrophilic group e.g., carboxylic acids which may or may not be branched, substituted, or include an aromatic moiety, and may have a general formula of R-COOH, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl).
  • a suitable second set of reagents will include all nucleophiles capable of reacting with the carbon atom in the heterocyclic base to which the nitrotriazole leaving group is attached to expel the leaving group from the base.
  • nucleophiles include R-NH 2 , RR'NH, R-SH, or R-OH, wherein R can be hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl.
  • suitable nucleophiles may also include Grignard reagents, or similarly reactive compounds.
  • nucleoside libraries with at least two library compounds can be synthesized, wherein one of the at least two library compounds has a structure according to Formula 1A with a first set of substituents A, X, Y, Ri, and R 2 , wherein another one of the at least two library compounds has a structure according to Formula 1A with a second set of substituents A, X, Y, Ri, and R 2 Formula 1A
  • A is a protected or unprotected sugar bound to a solid phase
  • X is NH, NR', S, or O
  • R, R, and R 2 are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl, and wherein not all of the substituents A, X, Y, Ri, and R 2 in the first set are the same as the substituents A, X, Y, Ri, and R 2 in the second set.
  • the sugar is selected from the group consisting of a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar is in a D-configuration or in an L-configuration, and wherein the substituent on the substituted ribofuranose is a -CR substituent on at least at one of the 2' and 3' carbon atoms, with R being C MO alkyl, alkenyl, alkynyl, aryl, heterocycle, CF 3 , CF 2 H, CC1 3 , CC1 2 H, CH 2 OH, CN, COOR', and CONHR*, and with R being C 0 alkyl, alkenyl, alkynyl, aryl.
  • 2'-O-alkylcytidine libraries can be generated using a procedure as outlined in Scheme 2A below, in which a substituted dihydropyrimidine nucleoside (here: 5-iodouridine) is first converted to the corresponding 2'-O-substituted pyrimidine and bound to a solid phase.
  • the 2'-O-substituted pyrimidine is further reacted with a first set of reagents in a Heck reaction to form a first set of products using a first set of reagents.
  • At least one of the keto groups in the pyrimidine moiety of a first set of products is then reacted with TIPS to generate a leaving group, which is subsequently exchanged with a nucleophilic reagent (second set of reagents), thereby generating a second set of products that may further be derivatized if the reactive group is present (e.g., -NH 2 group).
  • a nucleophilic reagent second set of reagents
  • nucleoside With respect to the nucleoside, it should be recognized that 5-iodouracil is a preferred starting material and commercially available from various sources. However, it should also be appreciated that numerous alternative reagents are also suitable. For example, there are various 5-iodouracil analogs (e.g., substituted and unsubstituted deoxy- and dideoxy analogs) commercially available. Moreover, it should be recognized that suitable nucleoside analogs may also be prepared with sugar moieties other than a ribofuranose from a coupling reaction between (commercially available) 5-iodouracil and a suitable sugar following standard coupling procedures well known in the art.
  • alternative sugars include various substituted ribofuranoses, carbocyclic ring systems with 5 or 6 carbon atoms, and arabinose, wherein the sugar is in a D-configuration or in an L-configuration.
  • Further contemplated sugars include those previously described in the section entitled "Contemplated Sugars", and it is especially contemplated that where the sugar has a C 2 ' and/or C 3 ' substituent other than a hydroxyl group, alternative sugars may include hydrogen, a halogen, or an azide group in at least one of these positions (in either alpha or beta orientation).
  • protecting groups for the sugar will vary considerably, and while it is particularly contemplated that suitable protection groups include benzyl-, acetyl-, and TBDMS groups, numerous alternative protection groups are also considered suitable. Among other groups, a collection of appropriate alternative protection groups and their reactions is described in Protective Groups in Organic Synthesis by Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons; ISBN: 0471160199. Furthermore, the solid phase and methods of coupling the solid phase to the nucleoside will at least in part depend on the particular sugar and position of coupling.
  • Preferred solid phases include Merrifield resins, ArgoGel (available from Argonaut, San Francisco, CA), Sasrin resin (a polystyrene resin available from Bachem Bioscience, Switzerland), TentaGel S AC, TentaGel PHB, or TentaGel S NH 2 resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany).
  • alternative heterocyclic bases are also appropriate and particularly contemplated alternative heterocyclic bases include pyrimidine heterocyclic bases with at least one halogen substituent and at least one keto group. While not limiting to the inventive subject matter, alternative heterocyclic bases may also include substituents other than halogens and keto groups, and especially contemplated substituents include hydroxyls, amino groups, and azido groups. Suitable alternative heterocyclic bases include those listed above in the section entitled "Contemplated Heterocyclic Bases".
  • Preferred first sets of reagents include all reagents that can react in a Heck reaction with the heterocyclic base at the 5 -position to form a covalent bond with the heterocyclic base. Therefore, generally preferred first sets of reagents include those with a double or a triple bond, and particularly preferred first reagents will have a general structure of R-C ⁇ CH, wherein R is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • first sets of reagents may also include reagents that can react in a Stille reaction (coupling of a halogenide with an tin-organic compound with Pd as catalyst).
  • suitable first reagents also include reagents of the general formula RSnR' 3 , wherein R is defined as above, and R' is typically butyl.
  • R is defined as above
  • R' is typically butyl.
  • Many of contemplated first sets of reagents are commercially available, and all of these are considered suitable for use herein.
  • first sets of reagents are not commercially available, all or almost all of them can be produced following procedures well known in the art without expenditure of undue experimentation (see e.g., Advanced Organic Chemistry: Structure and Mechanisms (Part A) by Francis A.
  • such reagents generally include all reagents that can displace the leaving group attached to the heterocyclic base and particularly include NH 3 , NH 2 OH, RNH 2 , RNHR, RNHNH 2 , RONH 2 , RNHOH, RSO 2 NH 2 , CN, N 3 , and guanidine, wherein R is hydrogen, a functional group, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • the amino group can further be reacted with an activated ester or other electrophilic compound, including RCoA, RCOC1, RCSC1, RSO2C1, and various isothiocyanates and isocyanates (wherein R is defined as above).
  • an activated ester or other electrophilic compound including RCoA, RCOC1, RCSC1, RSO2C1, and various isothiocyanates and isocyanates (wherein R is defined as above).
  • R is defined as above.
  • first sets of reagents are not commercially available, all or almost all of them can be produced following procedures well known in the art without expenditure of undue experimentation (see e.g., Advanced Organic Chemistry: Structure and Mechanisms (Part A) by Francis A. Carey, Richard J. Sundberg; Plenum Pub Corp; ISBN: 0306462435; or Advanced Organic Chemistry : Reactions and Synthesis (Part B) by Francis Carey, Richard J. Sundberg; Plenum Pub Corp; ISBN: 0306434571, or Compendium of Organic Synthetic Methods, Volume 9, by Michael B. Smith, John Wiley & Sons; ISBN: 0471145793).
  • contemplated 2'-O-substituted libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 2A with a first set of substituents X, Ri , R 2 , and R 3 , and wherein another one of the at least two library compounds has a structure according to Formula 2 A with a second set of substituents X, Ri, R 2 , and R 3
  • X is NH, NHO, NHNH, or ONH
  • Ri is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl
  • R 2 is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an aryl, a substituted aryl, and a heterocyclic base
  • R is selected from the group consisting of hydrogen, methyl, OH, OCH 3 , SH, SCH 3 , O-alkyl, O-alkenyl, O-alkynyl; wherein • comprises a solid phase, wherein not all of the substituents X, Ri, R 2 , and R 3 in the first set are the same as the substituents X, Rj, R 2 , and R in the second set; and with the proviso that that R
  • contemplated 2'-O-substituted libraries may also have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 2B with a first set of substituents X, Y, Ri, R 2 , and R 3 , and wherein another one of the at least two library compounds has a structure according to Formula 2B with a second set of substituents X, Y, Ri, R2, and R 3
  • Ri is selected from the group consisting of hydrogen an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl;
  • R 2 is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an aryl, a substituted aryl, and a heterocyclic base;
  • R 3 is selected from the group consisting of hydrogen, methyl, OH, OCH 3 , SH, SCH 3 , O-alkyl, O-alkenyl, O-alkynyl; wherein • comprises a solid phase, wherein not all of the substituents X, Ri, R 2 , and R 3 in the first set are the same as the substituents X, Ri , R
  • contemplated compounds will have a structure according to Formula 2C or 2D
  • R is selected from the group consisting of hydrogen an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl;
  • R 2 is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an aryl, a substituted aryl, and a heterocyclic base;
  • R 3 is selected from the group consisting of hydrogen, methyl, OH, OCH 3 , SH, SCH 3 , O-alkyl, O-alkenyl, O-alkynyl; with the proviso that that Ri is not H or CH 3 , when X-R 2 is NH 2 .
  • the sugar C2'- and C3'-substituents in Formulae 2A-2D are oriented in alpha orientation, one or more of the substituents may also be in beta orientation.
  • the sugar is selected from the group consisting of a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, and/or wherein the sugar is in a D-configuration or in an L-configuration
  • the substituent on the substituted ribofuranose is a -CR substituent on at least at one of the 2' and 3' carbon atoms, with R being C MO alkyl, alkenyl, alkynyl, aryl, heterocycle, CF 3 , CF 2 H, CC1 3 , CC1 2 H, CH 2 OH, CN, COOR', and
  • 2'-O-methyl-N4-substituted cytidine libraries may be generated in a library approach in which 2'-O-methyluridine is coupled via the C5'-position to a solid support.
  • the remaining hydroxyl (here: 3'-hydroxyl) groups are protected, and at least one of the keto groups of the heterocyclic base is reacted with a (preferably bulky) leaving group (here: TPS-C1).
  • TPS-C1 preferably bulky leaving group
  • the so prepared nucleoside may then be reacted with a set of amine reagents that will replace the leaving group, and thereby form the N4-substituted cytidine. After replacement, the nucleoside may then be deprotected and split from the solid support.
  • An exemplary synthetic route is depicted in Scheme 2B below:
  • suitable reagents to replace the leaving group include all nucleophilic reagents, and particularly include various primary and secondary amines. Numerous primary and secondary amines are known in the art, and many of those are commercially available. However, particularly preferred reagents have the formula R-NH2 or RR"NH, wherein R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl, or a substituted aryl.
  • contemplated 2'O-methyl-N4-substituted cytidine libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 2E with a first substituent R, and wherein another one of the at least two library compounds has a structure according to Formula 2E with a second substituent R
  • contemplated libraries include compounds according to Formula 2F Formula 2F
  • R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl.
  • sugar C2'- and C3'-substituents in Formulae 2E and 2F are oriented in alpha orientation, one or more of the substituents may also be in beta orientation.
  • suitable sugars need not be restricted to the sugar shown in Scheme 2C (ribofuranose), and numerous alternative sugars are also contemplated, including substituted ribofuranose, substituted or unsubstituted arabinose, xylose, and glucose. Further contemplated sugars are included in the section with the title "Contemplated Sugars”.
  • heterocyclic base it should be recognized that various alternative bases are also suitable, and exemplary alternative heterocyclic bases are described in the section entitled "Contemplated Heterocyclic Bases" above. However, it is generally preferred that suitable heterocyclic bases include pyrimidine bases.
  • the (non-2'-hydroxyl) groups in the sugar may be derivatized with various acyls, and especially contemplated acyls have the general structure R-C(O)-, wherein R may be a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or alkaryl.
  • Especially preferred first sets of reagents include various alkynyls and alkynyl derivatives, however, it should be appreciated that many compounds other than the below listed alkynyls (see examples) are also considered suitable for use herein and generally include all compounds that can replace iodine (preferably in a nucleophilic aromatic substitution). Consequently, particularly contemplated reagents include reagents that may replace iodine in a Stille-type reaction.
  • contemplated 2'O-methyl-5-substituted uridine libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 2G with a first substituent R, and wherein another one of the at least two library compounds has a structure according to Formula 2G with a second substituent R
  • contemplated library compounds will have a structure according to Formula G wherein R is an alkynyl or a substituted alkynyl.
  • the 5-substituted 2'-O-methyluridine library compounds may be employed as substrates in a further sequence of reactions in which at least one keto group (preferably the 4-oxo group) is replaced with a second set of substrates as depicted in Scheme 2D below.
  • the 5-substituted 2'-O-methyluridine library compounds are covalently coupled to a solid phase (preferably at the C5'-OH, however, alternative positions are also contemplated and include the C3'-OH), and remaining sugar hydroxyls are protected (e.g., via acetylation). Then, the 4-oxo group is reacted to form a leaving group (e.g., OTPS), which is subsequently replaced with a suitable second reagent from a second set of reagents.
  • OTPS a leaving group
  • the protecting groups, and the coupling of the sugar to the solid phase the same considerations as described above for 2'-O-alkyl-5- substituted cytidine libraries apply.
  • Particularly preferred second reagents include primary and secondary amines (i.e., R-NH 2 and RR'NH, wherein R and R' are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, and aralkyl, all of which may or may not be substituted), however, it should be appreciated that all nucleophilic reagents that will replace the leaving group are also considered suitable herein.
  • alternative second reagents include R-OH, R-SH, (R as defined above) and various Grignard compounds.
  • contemplated 2'-O-methyl-4,5-disubstituted cytidine libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 2H with a first set of substituents and R 2 , and wherein another one of the at least two library compounds has a structure according to Formula 2H with a second set of substituents Ri and R 2
  • Ri is an alkynyl or a substituted alkynyl
  • R 2 is NRR' with R and R independently being hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl.
  • N4-substituted cytidine libraries may be produced from a 5 -(substituted alkynyl) substituted protected uridine as depicted below in Scheme 2E.
  • a 2'-O-methyl- 3',5'-acetylated uridine with a 5-alkynyl-l-ol substituent is bound to a solid phase via the alcohol group in the substituent of the uridine ring.
  • Uridine/Cytidine nucleoside libraries can be prepared such that a commercially available nucleoside is employed as a starting material as depicted in Scheme 2F below.
  • 5-iodouridine is first protected with suitable sugar hydroxyl protection groups to form a protected 5-iodouridine, which is subsequently reacted with a first reagent from a first set of reagents (preferably electrophilic reagents) to form a 6-substituted protected uridine.
  • a first reagent from a first set of reagents (preferably electrophilic reagents) to form a 6-substituted protected uridine.
  • the 6-substituted protected uridine is then deprotected, the C5'-hydroxyl group of the sugar coupled to a solid support, and the remaining hydroxyl groups of the sugar (here: C2' and C3') again protected (here: acetylated).
  • the iodine group on the heterocyclic base is then exchanged in a Stille-type reaction with a second reagent from a second set of substrates (typically organo-tin compounds) to yield a library of 5,6-disubstituted uridine nucleosides, which may further be reacted with nitrotriazole in the 4-position (and/or 2-position) of the heterocyclic base to form a leaving group that can be replaced with a nucleophilic reagent.
  • a further reaction with a third reagent from a third set of reagents then yields a 4,5,6- trisubstituted uridine/cytidine nucleoside library.
  • R, RS, RC(O), ROC(O)
  • R 2 alkyl, alkenyl, alkynyl, 35 aryl
  • nucleoside With respect to the nucleoside, it should be recognized that 5-iodouridine is a preferred starting material and commercially available from various sources. However, it should also be appreciated that numerous alternative reagents are also suitable. For example, there are various 5-iodouridine analogs (e.g., substituted and unsubstituted deoxy- and dideoxy analogs) commercially available. Moreover, it should be recognized that suitable nucleoside analogs may also be prepared with sugar moieties other than a ribofuranose from a coupling reaction between (commercially available) 5-iodouracil and a suitable sugar following standard coupling procedures well known in the art.
  • sugars in alternative nucleosides include various substituted ribofuranoses, carbocyclic ring systems with 5 or 6 carbon atoms, and arabinose, wherein the sugar is in a D-configuration or in an L-configuration.
  • Further contemplated sugars include those previously described in the section entitled "Contemplated Sugars", and it is especially preferred that where the sugar has a C 2 ' and/or C ' substituent other than a hydroxyl group, alternative C2 * and/or C 3 ' substituents include hydrogen, a halogen, or an azide group in either alpha or beta orientation.
  • protecting groups for the sugar will vary considerably, and while it is particularly contemplated that suitable protection groups include benzyl-, acetyl-, and TBS groups, numerous alternative protection groups are also considered suitable. Among other groups, a collection of appropriate alternative protection groups and their reactions is described in Protective Groups in Organic Synthesis by Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons; ISBN: 0471160199.
  • solid phase and methods of coupling the solid phase to the nucleoside will at least in part depend on the particular sugar and position of coupling. Therefore, it is contemplated that all known solid phases are suitable for use in conjunction with the teachings presented herein, and exemplary suitable solid phases are described, for example, in Organic Synthesis on Solid Phase - Supports, Linkers, Reactions; by Florencio Zaragoza Dorwald et al. John Wiley & Sons; ISBN: 3527299505, or in Solid-Phase Synthesis and Combinatorial Technologies by Pierfausto Seneci, John Wiley & Sons; ISBN: 0471331953.
  • Preferred solid phases include Merrifield resins, ArgoGel (available from Argonaut, San Francisco, CA), Sasrin resin (a polystyrene resin available from Bachem Bioscience, Switzerland), TentaGel S AC, TentaGel PHB, or TentaGel S NH 2 resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany).
  • alternative heterocyclic bases are also appropriate and particularly contemplated alternative heterocyclic bases include pyrimidine heterocyclic bases with at least one acidic proton, at least one halogen substituent, and at least one keto group. While not limiting to the inventive subject matter, alternative heterocyclic bases may also include substituents other than halogens and keto groups, and especially contemplated substituents include hydroxyls, amino groups, and azido groups.
  • the first set of reagents are electrophilic reagents, and it is especially preferred that the first set of reagents have a structure RSX, RC(O)X, and/or ROC(O)X, wherein R is alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl, and wherein X is a halogen.
  • R is alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl, and wherein X is a halogen.
  • a suitable second set of reagents will include all reagents capable of replacing a halogen (most typically an iodine) on the heterocyclic base in a Stille-type reaction (J. Org. Chem. (1983), 48: 4634 or Can. J. Chem (2000), 78: 957-962).
  • second reagents include tin organic and/or tributyltin organic compounds in which the organic moiety may be an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl.
  • third reagent it is contemplated that all reagents capable of a nucleophilic substitution of a leaving group coupled to the heterocyclic base are considered suitable for use herein.
  • contemplated 4,5,6-trisubstituted uridine libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 21 with a first set of substituents A, Ri, R 2 , and R 3 , and wherein another one of the at least two library compounds has a structure according to Formula 21 with a second set of substituents A, Ri, R 2 , and R 3
  • A is a protected or unprotected sugar bound to a solid phase
  • Rj is RS-, RC(O)-, or ROC(O)-
  • R 2 is R
  • R 3 is RNH, RR'N, RNHNH, or RS, wherein R and R are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl.
  • contemplated 4,5,6-trisubstituted uridine/cytidine nucleosides may have a structure according to Formula 2J
  • A is a protected or unprotected sugar
  • R ⁇ is RS-, RC(O)-, or ROC(O)-
  • R 2 is R
  • R 3 is RNH, RR'N, RNHNH, or RS-, wherein R and R' are independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl.
  • the sugar is selected from the group consisting of a ribofuranose, a substituted ribofuranose, an arabinose, and a xylofuranose, wherein the substituent on the substituted ribofuranose is a -CR substituent on at least at one of the 2' and 3' carbon atom, with R being C MO alkyl, alkenyl, alkynyl, aryl, heterocycle, CF 3 , CF 2 H, CC1 3 , CC1 2 H, CH 2 OH, CN, COOR, and CONHR', and with R' being Ci-io alkyl, alkenyl, alkynyl, aryl.
  • 5,6-disubstituted uridine nucleoside libraries and compounds may be produced such that reaction of the library nucleosides with the third substrate is omitted, and in which the 5,6-disubstituted uridine nucleosides are deprotected and cleaved of the resin as shown in Scheme 2G below.
  • the acetyl protection groups are removed via reaction with methanolamine, and the solid phase is cleaved from the nucleoside (library) with TFA.
  • alternative deprotection and cleaving methods are also suitable and well known to a person of ordinary skill in the art.
  • the sugar, the heterocyclic base, the solid phase, the coupling of the sugar to the solid phase, and the protection group the same considerations as described above for the 4,5,6-trisubstituted uridine/cytidine libraries apply.
  • 5,6-disubstituted uridine libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 2K with a first set of substituents A, Ri, and R 2 , and wherein another one of the at least two library compounds has a structure according to Formula 2K with a second set of substituents
  • R ⁇ is RS, RC(O), or ROC(O)
  • R 2 is R, wherein R may be hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl, and wherein not all of the first set of substituents A, Ri, and R 2 , are the same as the second set of substituents A, Ri, and R 2 .
  • contemplated 5,6-disubstituted uridine nucleosides may have a structure according to Formula 2L
  • A is a protected or unprotected sugar
  • Ri is RS, RC(O), or ROC(O)
  • R 2 is R, wherein R may be hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl.
  • Particularly preferred sugars include substituted and unsubstituted ribofuranose, substituted and unsubstituted arabinose, and substituted and unsubstituted xylofuranose.
  • 4,6-disubstituted Uridine/Cytidine Nucleoside Libraries The inventors still further discovered that 4,6-disubstituted uridine/cytidine libraries and compounds may be synthesized in a protocol in which commercially available uridine is employed as a starting material.
  • the sugar hydroxyl groups in the uridine are first protected with suitable protection groups to form a protected uridine, which is then reacted with a first reagent from a first set of reagents (preferably electrophilic compounds) to generate a first set of 6-substituted uridine nucleosides.
  • the protecting groups are cleaved from the sugar portion and the nucleoside is coupled to a solid phase (preferably via the C5' OH group) while the remaining sugar hydroxyl groups are again reacted with a protection group (here: acetyl).
  • a protection group here: acetyl.
  • at least one oxo group in the heterocyclic base preferably the oxo group in 4-position
  • a leaving group preferably nitrotriazole
  • the protecting groups may be removed from the sugar and the nucleoside may be cleaved from the solid support.
  • Preferred first sets of reagents include electrophilic reagents, and it is especially preferred that the first set of reagents have a structure RSX, RC(O)X, and/or ROC(O)X, wherein R is alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl, and wherein X is a halogen.
  • second set of reagents it is contemplated that all reagents capable of a nucleophilic substitution of a leaving group coupled to the heterocyclic base are considered suitable for use herein.
  • second reagents include various primary and secondary amines (R-NH 2 and RR"NH with R and R' as described above), various sulfides (R-SH with R as defined above), and various hydrazines (R-NHNH 2 with R as defined above).
  • contemplated 4,6-disubstituted uridine/cytidine libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 2M with a first set of substituents A, Ri, and R 2 , and wherein another one of the at least two library compounds has a structure according to Formula 2M with a second set of substituents A, Ri, and R 2
  • A is a protected or unprotected sugar bound to a solid phase
  • Ri is RS, RC(O), or ROC(O)
  • R 2 is RNH, RR'N, RNHNH, or RS, wherein R and R are independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl, and wherein the first set of substituents A, Ri, and R 2 is not the same as the second set of substituents A, Ri, and R 2 .
  • contemplated 4,6-disubstituted uridine/cytidine nucleosides may have a structure according to Formula 2N
  • A is a protected or unprotected sugar
  • R) is RS, RC(O), or ROC(O)
  • R 2 is RNH, RR'N, RNHNH, or RS
  • R and R' are independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl.
  • Particularly preferred sugars include substituted and unsubstituted ribofuranose, substituted and unsubstituted arabinose, and substituted and unsubstituted xylofuranose.
  • 4,5-disubstituted uridine/cytidine libraries and compounds may be synthesized in a protocol in which commercially available 5- iodouridine is employed as a starting material.
  • the sugar hydroxyl groups in the 5-iodouridine are first protected with suitable protection groups to form a protected uridine, which is further coupled (preferably via the C5' OH group) to a solid phase.
  • the 5-iodouridine is then reacted in a Stille-type reaction with a first reagent from a first set of reagents (preferably organo-tin compounds) to generate a first set of 5-substituted uridine nucleosides.
  • At least one oxo group in the heterocyclic base (preferably the oxo group in 4-position) is reacted with a leaving group (preferably nitrotriazole), which is subsequently replaced by a second reagent from a second set of reagents (preferably nucleophiles) to further increase diversity of the nucleoside library.
  • the protecting groups may be removed from the sugar and the nucleoside may be cleaved from the solid support to yield the corresponding 4,5-disubstituted nucleosides.
  • R 2 alkyl, alkenyl, alkynyl, ar V' 50
  • Preferred first sets of reagents include all reagents capable of replacing a halogen (most typically an iodine) on the heterocyclic base in a Stille-type reaction (J. Org. Chem. (1983), 48: 4634 or Can. J. Chem (2000), 78: 957-962).
  • second reagents include tin organic and/or tributyl-tin organic compounds in which the organic moiety may be an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl.
  • second set of reagents it is contemplated that all reagents capable of a nucleophilic substitution of a leaving group coupled to the heterocyclic base are considered suitable for use herein.
  • second reagents include various primary and secondary amines (R-NH 2 and RR"NH with R and R as described above), various sulfides (R-SH with R as defined above), and various hydrazines (R-NHNH 2 with R as defined above).
  • contemplated 4,5-disubstituted uridine/cytidine libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 2O with a first set of substituents A, R ⁇ , and R 2 , and wherein another one of the at least two library compounds has a structure according to Formula 2O with a second set of substituents A, Ri, and R2
  • A is a protected or unprotected sugar bound to a solid phase
  • Ri is R
  • R 2 is RNH, RR'N, RNHNH, or RS
  • R and R' are independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl, and wherein the first set of substituents A, Ri, and R 2 is not the same as the second set of substituents A, Ri, and R 2 .
  • contemplated 4,5-disubstituted uridine/cytidine nucleosides may have a structure according to Formula 2P
  • A is a protected or unprotected sugar
  • Ri is R
  • R 2 is RNH, RR'N, RNHNH, or RS
  • R and R' are independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, an alkaryl, or a substituted alkaryl.
  • Particularly preferred sugars include substituted and unsubstituted ribofuranose, substituted and unsubstituted arabinose, and substituted and unsubstituted xylofuranose.
  • 4,5-disubstituted cytosine nucleoside libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula IB with a first set of substituents Z, X, Ri, and R 2 , wherein another one of the at least two library compounds has a structure according to Formula IB with a second set of substituents Z, X, Ri, and R 2
  • X is NH, S, or O
  • Z is hydrogen, N 3 , NH 2 , OH, SH, or NHR wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl
  • Ri and R 2 are independently selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl; wherein • comprises a solid phase, and wherein not all of the substituents Z, X, Ri, and R 2 in the first set are the same as the substituents Z, X, Ri, and R 2 in the second set.
  • contemplated compounds may have a structure according to formula IB'
  • X is NH, S, or O
  • Z is hydrogen, N 3 , NH , OH, SH, or NHR wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl
  • Ri and R 2 are independently selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl.
  • anhydrotriazine nucleoside libraries may be synthesized following an exemplary synthetic scheme as depicted in Scheme 2J below.
  • synthesis may start from 4'-thio-3'-azido-5-aza-arabinocytidine, which may be synthesized by glycosylation of per-acetyl-4'-thioazidoarabinose with 5-azacytosine and subsequent deprotection with ammonia as described by Hanna et al. in Nucleosides Nucleotides (1997), 16, 129-144.
  • the 4'-thio-3'-azido-5-aza-arabinocytidine is coupled to a solid phase and the 2'-hydroxyl group is protected.
  • the amino group in the heterocyclic base may then be reacted with a first set of reagents (e.g., an activated electrophilic reagent or electrophilic reagent in the presence of a catalyst).
  • a first set of reagents e.g., an activated electrophilic reagent or electrophilic reagent in the presence of a catalyst.
  • the azido group is then reduced to the corresponding amino group with subsequent (or in some cases concurrent) formation of the corresponding anhydronucleoside and cleavage from the solid phase.
  • nucleosides other that 4'-thio-3'-azido-5-aza-arabinocytidine are also suitable, and alternative starting materials particularly include nucleosides with modified sugar moiety and/or modified heterocyclic base (relative to 4'-thio-3'-azido-5-aza-arabinocytidine).
  • suitable modified sugar moieties include all natural and non-natural sugars so long as alternative sugars include a nucleophilic C' 2 -substituent in alpha orientation that has sufficient reactivity to form a covalent bond in a reaction with the heterocyclic base.
  • Exemplary suitable sugar moieties are depicted in structures 2Q and 2R below
  • X is H, OH, SH, N 3 , CN, NH 2 , NHR', NHCOR', NHSO 2 R', COOH, COOR', CH 2 NO 2 , Cl, F, Br, alkyl, alkenyl, or alkynyl; and R is alkyl, aryl, R'CO, R'SO 2 , R'NHCO, R ⁇ HCS, R ⁇ H, SH, OH, N 3 , R'O, or H; wherein R' is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or aralkyl; and wherein R, is H, N 3 , NH 2 , RCO, or RCONH, and R 2 is H, CH 3 , CF 3
  • modified heterocyclic bases other than 5- azacytosine may also be used in the synthesis of contemplated compounds, and especially preferred alternative heterocyclic bases include 5-substituted cytosine as depicted in structures 2S and 2T below:
  • Particularly preferred first sets of reagents include substituted and unsubstituted acid chlorides, which may or may not have at least one double bond (which may further be conjugated or not conjugated with another double bond), and which may have the general formula RCOC1, wherein R is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or alkaryl.
  • suitable first set of reagents may also include numerous compounds other than substituted and unsubstituted acid chlorides, and it is generally preferred that such compounds will include an electrophilic center with sufficient reactivity to form a covalent bond with the amino group in the heterocyclic base.
  • contemplated anhydronucleosides may have a structure according to Formula 2U
  • R is H, N 3 , NH 2 , R'CO, or R'CONH
  • R 3 is H, R', COR', SO R, or OCOR with R being hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, and aralkyl
  • contemplated compounds include the following compounds having a structure according to Formulae 2V and 2W, where the heterocyclic base is a triazine or purine base:
  • X is H, OH, SH, N 3 , CN, NH 2 , NHR, NHCOR, NHSO 2 R', COOH, COOR, CH 2 NO 2 , Cl, F, Br, alkyl, alkenyl, or alkynyl;
  • Y is O, S, NH, CH 2 , CHR;
  • Z is N or CH; and
  • R is independently alkyl, aryl, R'CO, R'SO 2 , R'NHCO, R'NHCS, R'NH, SH, OH, N 3 , R'O, H; and wherein R' is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or aralkyl.
  • triazine C-Nucleoside Libraries may be synthesized following an exemplary synthetic scheme as depicted in Scheme 2K below.
  • a 2',3 '-protected Cl'-aldehyde sugar is coupled to a solid phase, and the aldehyde is reacted with methanol to form the corresponding methoxy derivative, which is subsequently reacted with substituted diamine compound (or set of distinct substituted diamine compounds) to form the substituted triazine heterocyclic base.
  • the substituted triazine heterocyclic base is derivatized with a first set of reagents (various primary amines) to further increase the complexity of the so generated library. Deprotection of the sugar alcohol groups and cleavage of the library compounds from the solid phase will then yield triazine C-nucleoside libraries and their compounds.
  • sugars other than a beta C' ⁇ -aldehyde ribofuranose are also suitable, and particularly contemplated alternative sugars include substituted and unsubstituted alpha Ci-aldehyde ribofuranose, and various substituted and unsubstituted furanose and pyranose sugars with a C' ⁇ -aldehyde group (which may be in alpha or beta orientation).
  • exemplary suitable sugars include those that are described in the section "Contemplated Sugars", and among those particularly sugars with a Ci-aldehyde group.
  • suitable sugars may be in the D- and/or L-configuration. With respect to the protection groups and the solid phase, the same considerations as described in the sections above apply.
  • Especially preferred substituted diamine compounds will have a general structure according to Structure 2X below
  • R is R', X is O, S, or NHR', Y is N or CH, and wherein R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or alkaryl. It is generally contemplated that many of the compounds according to Structure 2X are commercially available.
  • the first set of reagents may vary considerably. However, it is generally preferred that such reagents are primary amines with the general formula R-NH 2 , wherein R may be a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or alkaryl. Exemplary primary amines are listed in the experimental section below.
  • R may be hydrogen, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or alkaryl.
  • contemplated compounds may have a structure according to structure 2Y' and 2Z'.
  • R is independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or alkaryl, and X is N or CH.
  • 4,5, 6-substituted cytidine libraries can be generated using a procedure as outlined in Scheme 3 below, in which a 5,6-disubstituted uracil nucleoside (or population of distinct substituted uracil nucleosides) is first converted to the corresponding protected 6-substituted uracil and bound to a solid phase.
  • the protected and bound substituted uracil is further reacted with TPS-Cl to generate a leaving group, which is exchanged with a nucleophile, and more preferably an NH 2 -containing reagent as indicated in the scheme, thereby generating a first set of N-substituted-6-substituted cytidine products.
  • Contemplated 5-substituents therefore especially include an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.
  • 5,6-dialkyluracil is a preferred starting material and commercially available from various sources. It should also be appreciated that numerous alternative reagents are also suitable, including various 6- substituted analogs (e.g., 6-amino, 6-aza, 6-carboxy, or 6-propyl substituted uracil), most of which are commercially available. It is generally preferred, however, that the 6-substituent is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl or a substituted aryl.
  • 6-substituent is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl or a substituted aryl.
  • heterocyclic bases with particular 5- and 6-substituents are not commercially available, it should be appreciated that such heterocyclic bases may be produced from the corresponding pyrimidine base following protocols similar to those described in WO88/04662.
  • suitable nucleoside analogs may also be prepared with sugar moieties other than a ribofuranose from a coupling reaction between (commercially available) 6-substituted uracil and a suitable sugar following standard coupling procedures well known in the art.
  • Particularly contemplated sugars include various substituted ribofuranoses, carbocyclic ring systems with 5 or 6 carbon atoms, and arabinose, wherein the sugar is in a D-configuration or in an L-configuration.
  • sugars include those previously described herein (supra), and it is especially contemplated that where the sugar has a C 2 ' and/or C ' substituent other than a hydroxyl group, alternative sugars may include hydrogen, a halogen, or an azide group in at least one of these positions (in either alpha or beta orientation).
  • especially preferred alternative sugars include an amino group at the C3' position, wherein the amino group may be mono- or disubstituted (-NH 2 , -NHR, or -NRR').
  • protecting groups for the sugar will vary considerably, and while it is particularly contemplated that suitable protection groups include benzyl-, acetyl-, and TBDMS groups, numerous alternative protection groups are also considered suitable. Among other groups, a collection of appropriate alternative protection groups and their reactions is described in Protective Groups in Organic Synthesis by Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons; ISBN: 0471160199.
  • solid phase and methods of coupling the solid phase to the nucleoside will at least in part depend on the particular sugar and position of coupling. Therefore, it is contemplated that all known solid phases are suitable for use in conjunction with the teachings presented herein, and exemplary suitable solid phases are described, for example, in Organic Synthesis on Solid Phase - Supports, Linkers, Reactions; by Florencio Zaragoza Dorwald et al. John Wiley & Sons; ISBN: 3527299505, or in Solid-Phase Synthesis and Combinatorial Technologies by Pierfausto Seneci, John Wiley & Sons; ISBN: 0471331953.
  • Preferred solid phases include Merrifield resins, ArgoGel (available from Argonaut, San Francisco, CA), Sasrin resin (a polystyrene resin available from Bachem Bioscience, Switzerland), TentaGel S AC, TentaGel PHB, or TentaGel S NH 2 resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany).
  • Preferred nucleophiles that replace the leaving group on the heterocyclic base particularly include NH ⁇ -containing reagents.
  • NH ⁇ -containing reagents For example, hydroxylamine, NH 3 , primary amines (e.g. , R-NH 2 , R-NHNH 2 , RONH 2 , RSO 2 NH 2 ), and secondary amines (e.g. , R 1 R 2 NH), wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl or a substituted aryl are considered suitable for use herein.
  • numerous alternative amines are also contemplated so long as the exchange of the amine for the leaving group will transform the substituted uracil into an N-substituted cytidine.
  • contemplated N-substituted cytidine libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 3A with a first set of substituents X, R, Ri, R 2 , and R 3 , and wherein another one of the at least two library compounds has a structure according to Formula 3 A with a second set of substituents X, R, Ri, R 2 , and R
  • X is NH, NHO, NHNH, or ONH, NHSO 2 , R and R, are independently selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl; an aryl and a substituted aryl; R 2 is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an aryl, a substituted aryl, and a heterocyclic base; and R 3 is selected from the group consisting of hydrogen, OH, OCH 3 , SH, SCH 3 , O-alkyl, O-alkenyl, O-alkynyl, with the proviso that R and Ri is not H at the same time; wherein • comprises a solid phase, and wherein not all of the substituents X, R, Ri, R 2 , and R 3 in the first set are the same as the substituents X
  • contemplated library compounds may have a structure according to Formula 3A'
  • R and Ri are independently selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl;
  • R 2 is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an aryl, a substituted aryl, and a heterocyclic base;
  • R 3 is selected from the group consisting of hydrogen, OH, OCH 3 , SH, SCH 3 , O-alkyl, O-alkenyl, O-alkynyl, with the proviso that R and Ri is not H at the same time.
  • contemplated N-substituted cytidine libraries may have at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 3B with a first set of substituents X, Y, R, Ri, R 2 , R 3 , R t , R 5 , and R , and wherein another one of the at least two library compounds has a structure according to Formula 3B with a second set of substituents X, Y, R, Ri, R 2 , R 3 , Rt, R 5 , and R_
  • X is NH, NHO, NHNH, or ONH, NHSO 2 , Y is C(O), CONH, CSNH, or SO 2 , Ri, R 2 , R t , R 5 , and R ⁇ are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl; R 3 is selected from the group consisting of hydrogen, OH, OCH 3 , SH, SCH , O-alkyl, O-alkenyl, and O-alkynyl, and wherein not all of the substituents X, Y, Ri, R 2 , R 3 , R t , R 5 , and Re in the first set are the same as the substituents X, Y, Ri, R2, R 3 , R t , R 5 , and R_ in
  • X is NH, NHO, NHNH, or ONH, NHSO 2
  • Y is C(O), CONH, CSNH, or SO 2
  • Ri, R 2 , R t , R 5 , and R are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl
  • R 3 is selected from the group consisting of hydrogen, OH, OCH , SH, SCH 3 , O-alkyl, O-alkenyl, and O-alkynyl.
  • the libraries according to the inventive subject matter may be used to facilitate structure-activity analysis of nucleoside-type compounds.
  • contemplated libraries will provide a researcher with rapid information on the impact of a particular substituent in a particular position of the library compound.
  • libraries according to the inventive subject matter will exhibit a significant source of revenue for a seller since in most cases purchase of a library of nucleosides, nucleoside analogs, nucleotides, and/or nucleotide analogs will be less costly to a user than individual synthesis of these compounds.
  • the library compounds may serve as in vitro and/or in vivo substrates or inhibitors with particularly desirable physicochemical and/or biological properties.
  • the library compounds may act as inhibitors of DNA and/or RNA for various nucleoside-using enzymes, and especially polymerases, reverse transcriptases, and ligases. Therefore, contemplated nucleosides will exhibit particular usefulness as in vitro and/or in vivo antiviral agent, antineoplastic agent, or immunomodulatory agent.
  • nucleosides according to the inventive subject matter may be incorporated into oligo- or polynucleotides, which will then exhibit altered hybridization characteristics with single or double stranded DNA in vitro and in vivo.
  • Particularly contemplated antiviral activities include at least partial reduction of viral titers of respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex type 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, Hanta virus (hemorrhagic fever), human papilloma virus (HPV), and measles virus.
  • Especially contemplated immunomodulatory activity includes at least partial reduction of clinical symptoms and signs in arthritis, psoriasis, inflammatory bowel disease, juvenile diabetes, lupus, multiple sclerosis, gout and gouty arthritis, rheumatoid arthritis, rejection of transplantation, giant cell arteritis, allergy and asthma, but also modulation of some portion of a mammal's immune system, and especially modulation of cytokine profiles of Type 1 and Type 2.
  • modulation of Type 1 and Type 2 cytokines may include suppression of both Type 1 and Type 2, suppression of Type 1 and stimulation of Type 2, or suppression of Type 2 and stimulation of Type 1.
  • nucleosides are administered in a pharmacological composition
  • suitable nucleosides can be formulated in admixture with a pharmaceutically acceptable carrier.
  • contemplated nucleosides can be administered orally as pharmacologically acceptable salts, or intravenously in physiological saline solution (e.g. , buffered to a pH of about 7.2 to 7.5).
  • physiological saline solution e.g. , buffered to a pH of about 7.2 to 7.5.
  • physiological saline solution e.g. , buffered to a pH of about 7.2 to 7.5
  • Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose.
  • one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration.
  • contemplated nucleosides may be modified to render them more soluble in water or other vehicle, which for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.) that are well within the ordinary skill in the art. It is also well within the ordinary skill of the art 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 a patient.
  • prodrug forms of contemplated nucleosides may be formed for various purposes, including reduction of toxicity, increasing the organ- or target cell specificity, etc.
  • One of ordinary skill in the art will recognize how to readily modify the present compounds to pro-drug forms to facilitate delivery of active compounds to a target site within the host organism or patient (see above).
  • One of ordinary skill in the art will also take advantage of favorable pharmacokinetic parameters of the pro-drug forms, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect of the compound.
  • contemplated compounds may be administered alone or in combination with other agents for the treatment of various diseases or conditions.
  • Combination therapies according to the present invention comprise the administration of at least one compound of the present invention or a functional derivative thereof and at least one other pharmaceutically active ingredient.
  • the active ingredient(s) and pharmaceutically active agents may be administered separately or together and when administered separately this may occur simultaneously or separately in any order.
  • the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • contemplated agents for combination with contemplated compounds it is especially preferred that such agents include interferon, and particularly IFN-alpha or IFN-beta (or fragments thereof). Examples
  • 5-Amino Uridine (2) 5-Bromo Uridine (1) (3.23 gm, 10 mmol) was taken into a pre- cooled steel bomb and to this was added liquid ammonia (75 ml). This steel bomb was closed and kept for 24 hrs at 60°C. The bomb was opened after cooling in dry ice and left open overnight at room temperature for ammonia to evaporate. This solid 5-amino uridine was used for next step without further purification. 5-N-(Fmoc-NH-amino acid)-5-amino-uridine (3).
  • 5-iodouridine is converted to the corresponding 2-O-methyl- 5-iodouridine following procedures well known in the art.
  • the so formed 2-O-methyl-5- iodouridine is subsequently coupled to a solid phase as described for various nucleosides below, and a Heck reaction is employed to replace the iodine with the desired substituent under conditions similar to those described in R.F. Heck. Org. React. ⁇ .Y. 27, 345 (1982); J.E. Plevyak and R.F. Heck. J. Org. Chem. 43, 2454 (1978); M. Hiroshige, J.R. Hauske, P. Zhou. J. Am. Chem. Soc. 117, 11590 (1995); or D.A.
  • the resultant uridine-substituted resin was swelled in 20 ml of pyridine, 10 ml of dichloromethane and 3.0 ml of triethylamine.
  • T-Butyldimethylsilychloride (5.27 g, 5 eq.) and imidazole (2.38 g, 5 eq) were added to the mixture followed by 5 ml of DMF to improve the solubility.
  • the mixture was shaken at room temperature for 24 hours and filtered.
  • the resin was washed 4 times with pyridine-DMF (1 :1) and 3 times with dichloromethane, and dried under vacuum to provide dried resin 10 loaded with protected cytidine.
  • the resin was washed 5 times with pyridine-DMF (1 :1) and 3 times with dichloromethane, and dried under vacuum to provide 7.2 g of resin 11 which is confirmed by MAS NMR spectrometry and ready for the parallel array synthesis of nucleoside library 13.
  • the solutions of the 96 samples were dried to provide 96 nucleosides 13 in 20 - 30 mg.
  • the samples were analyzed by TLC and LC-MS spectrometry. LC-MS analysis of these samples confirmed the integrity and purity. Sample purity of the samples range from 70-100%.
  • Reaction a 25 (6 mmol), MMTCI resin (4 g), pyridine (50 mL), DAMP (100 mg), room temperature 48 hours.
  • Reaction b 26 (6 g), TIPC1 (4 equiv.), Et 3 N (6 equiv.), DMAP (100 mg), CH 2 C1 2 , room temperature.
  • Reaction c 27 (60 mg), R'R"NH (1 M in DMF, 0.75 mL), DIEA (IM in DMF, 0.75 ml), room temperature 12 hours, 60°C for 12 hours, 90°C for 24 hours; then (CH 3 ) 2 NH, methanol, 12 hours, 1% TFA in CH 2 C1 2 , 2 min.
  • Tetrabutylammonium fluoride (1 M in tetrahydrofuran, 4.3 mL) was added to a solution of 31 (1 g, 0.12 mmol) in tetrahydrofuran, and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated, and the residue was subjected to silica gel chromatography to give 32 (0.5 g).
  • Triphenylphosphine 250 mg, 0.95 mmol
  • cupric iodide 180 mg, 0.95 mmol
  • tris(dibenzylideneacetone)dipalladium(0) 390 mg, 0.43 mmol
  • resin 33 5.6 g, 5.3 mmol
  • dimethylformamide 40 mL
  • triethylamine 1.8 mL, 13 mmol
  • phenyl acetylene 2.0 mL, 19 mmol
  • the resin was washed with dimethylformamide (3 x 10 mL), methanol (3 x 10 mL) and methylene chloride (3 x 10 mL). The resin was dried under high vacuum at 40 °C. Mass: 5.3 g.
  • Triphenylphosphine (505 mg, 1.9 mmol), cupric iodide (370 mg, 1.9 mmol) and palladium(II) acetate (190 mg, 0.80 mmol) were added to a suspension of resin 3 (5.8 g, 5.5 mmol) in a mixture of dimethylformamide (20 mL) and 2-(tributylstannyl)furan (6.0 mL, 19 mmol) (Stille reaction). The reaction mixture was shaken at 70 °C for 16 h, then the resin was filtered from the hot solution.
  • the resin was washed with dimethylformamide (3 x 10 mL), methanol (3 x 10 mL) and methylene chloride (3 x 10 mL). The resin was dried under high vacuum at 40 °C. Mass: 5.3 g.
  • a methylamine solution (1.0 M in methanol, 1 mL) was added to resin 36 and the reaction mixture was shaken at room temperature for 16 h, then filtered. The resin was washed with methanol (3 x 1 mL), and methylene chloride (3 x 1 mL).
  • a methylamine solution (1.0 M in methanol, 1 mL) was added to resin 34 (50 mg, 0.04 mmol) (for preparation of 34, see Scheme 2F) and the reaction mixture was shaken at room temperature for 16 h, then filtered.
  • the resin 47 was washed with methanol (3 x 1 mL), and methylene chloride (3 x 1 mL).
  • a 1.5% solution of TFA in dichloroethane (1 mL) was added to the resin 47 and the reaction mixture was shaken for 2 min, then methanol (1 mL) was added and the resin was filtered.
  • the resin was washed with methanol (3 x 0.25 mL). The filtrate was evaporated under high vacuum at room temperature to give the desired nucleoside 48.
  • Tetrabutylammonium fluoride (1 M in tetrahydrofuran, 4.3 mL) was added to a solution of 40 (0.85 g, 1.2 mmol) in tetrahydrofuran, and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated, and the residue was subjected to silica gel chromatography to give 41 (0.4 g). Compound 41 (10.9 g, 31 mmol) was added to a suspension of 4-methoxytrityl resin (10.5 g, 18 mmol) in pyridine (80 mL). The reaction mixture was shaken for 48 h at room temperature, and then methanol (10 mL) was added.
  • the resin was filtered and washed with pyridine (3 x 10 mL), and methanol (3 x 10 mL) and methylene chloride (3 x 10 mL).
  • the resin 42 was dried under high vacuum at 40 °C. Mass: 10.2 g (97% yield).
  • a methylamine solution (1.0 M in methanol, 1 mL) was added to resin 44 and the reaction mixture was shaken at room temperature for 16 h, then filtered. The resin was washed with methanol (3 x 1 mL), and methylene chloride (3 x 1 mL). A 1.5% solution of TFA in dichloroethane (1 mL) was added to the resin 45 and the reaction mixture was shaken for 2 min, then methanol (1 mL) was added and the resin was filtered. The resin was washed with methanol (3 x 0.25 mL). The filtrate was evaporated under high vacuum at room temperature to give the desired nucleoside.
  • 5-Iodouridine (29) (11.4 g, 31 mmol) was added to a suspension of 4-methoxytrityl resin (10.5 g, 18 mmol) in pyridine (80 mL). The reaction mixture was shaken for 48 h at room temperature, then methanol (10 mL) was added. The reaction mixture was shaken for an additional 30 min, then the resin was filtered and washed with pyridine (3 x 10 mL), methanol (3 x 10 mL) and methylene chloride (3 x 10 mL). The resin was dried under high vacuum at 40 °C. Mass: 15.7 g (88% loading).
  • Triphenylphosphine 250 mg, 0.95 mmol
  • cupric iodide 180 mg, 0.95 mmol
  • tris(dibenzylideneacetone)dipalladium(0) 390 mg, 0.43 mmol
  • resin 49 5.3 g, 5.3 mmol
  • dimethylformamide 40 mL
  • triethylamine 1.8 mL, 13 mmol
  • phenyl acetylene 2.0 mL, 19 mmol
  • the resin 50a was washed with dimethylformamide (3 x 10 mL), methanol (3 x 10 mL) and methylene chloride (3 x 10 mL). The resin 50a was dried under high vacuum at 40 °C. Mass: 5.0 g.
  • Triphenylphosphine 270 mg, 1.0 mmol
  • cupric iodide 195 mg, 1.0 mmol
  • tris(dibenzylideneacetone)dipalladium(0) 420 mg, 0.46 mmol
  • resin 49 5.2 g, 5.7 mmol
  • dimethylformamide 40 mL
  • triethylamine 2.0 mL, 14 mmol
  • 3-butyn-l-ol 1.5 mL, 20 mmol
  • the resin was washed with dimethylformamide (3 x 10 mL), methanol (3 x 10 mL) and methylene chloride (3 x 10 mL).
  • the resin 50b was dried under high vacuum at 40 °C. Mass: 4.5 g.
  • Triphenylphosphine (505 mg, 1.9 mmol), cupric iodide (370 mg, 1.9 mmol) and palladium(II) acetate (190 mg, 0.80 mmol) were added to a suspension of resin 49 (5.5 g, 5.5 mmol) in a mixture of dimethylformamide (20 mL) and 2-(tributylstannyl)furan (6.0 mL, 19 mmol).
  • the reaction mixture was shaken at 70 °C for 16 h, then the resin was filtered from the hot solution.
  • the resin 50c was washed with dimethylformamide (3 x 10 mL), methanol (3 x 10 mL) and methylene chloride (3 x 10 mL). The resin 50c was dried under high vacuum at 40 °C. Mass: 5.0 g.
  • a methylamine solution (1.0 M in methanol, 1 mL) was added to resin 52 (50 mg, 0.04 mmol) and the reaction mixture was shaken at room temperature for 16 h, then filtered.
  • the resin 53 was washed with methanol (3 x 1 mL), and methylene chloride (3 x 1 mL).
  • a 1.5% solution of TFA in dichloroethane (1 mL) was added to the resin 53 and the reaction mixture was shaken for 2 min, then methanol (1 mL) was added and the resin was filtered.
  • the resin was washed with methanol (3 x 0.25 mL). The filtrate was evaporated under high vacuum at room temperature to give the desired nucleoside 54.
  • 2-Ethynylpyridine 5-Phenyl- 1 -pentyne, 4-(tert-Butyl)phenylacetylene, Phenylacetylene, 3-Dibutylamino-l-propyne, Phenyl propargyl ether, 5-Chloro-l -pentyne, 3- Diethylamino-1-propyne, 4-Phenyl-l-butyne, 1-Heptyne, l-Dimethylamino-2-propyne, 1- Pentyne, 2-Methyl-l-hexene, (Triethylsilyl)acetylene, 3 -Phenyl- 1-propyne, Methyl propargyl ether, 3 -Cyclopentyl- 1-propyne, 1-Ethynylcyclohexene, 3-Butyn-l-ol, Styrene, Vinylcyclohexane, 2-
  • Phenyl disulfide benzoyl chloride, p-toluoyl chloride, 4-biphenylcarbonyl chloride, 4-entylbenzoyl chloride, 2-naphtoyl chloride, 3-(trifluoromethyl)benzoyl chloride, 4- hexyloxy)benzoyl chloride and other related carboxylic acid chlorides.

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Abstract

L'invention concerne des bibliothèques d'analogues de nucléosides à substitution de cytidine et des composés de ces bibliothèques dont l'élaboration repose sur une approche de bibliothèque combinatoire. En particulier, les bases hétérocycliques préférées qui interviennent dans ces composés et ces bibliothèques sont les nucléosides à substitution de cytidine d'aminoacide, les nucléosides à substitution de cytidine en 2'-O, et les nucléosides à substitution de cytidine en N. Toutes les bases considérées peuvent être utiles dans le traitement de différents états, en particulier les infections virales et les maladies néoplasiques.
PCT/US2002/035558 2001-12-17 2002-11-05 Bibliotheques a cytidine et composes de ces bibliotheques dont la synthese repose sur des strategies combinatoires en phase solide Ceased WO2003051896A1 (fr)

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AU2002340387A AU2002340387A1 (en) 2001-12-17 2002-11-05 Cytidine libraries and compounds synthesized by solid-phase combinatorial strategies

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US34233601P 2001-12-17 2001-12-17
US60/342,336 2001-12-17

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WO2003051896A1 true WO2003051896A1 (fr) 2003-06-26

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6777395B2 (en) 2001-01-22 2004-08-17 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase of hepatitis C virus
US7105499B2 (en) 2001-01-22 2006-09-12 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US7524831B2 (en) 2005-03-02 2009-04-28 Schering Corporation Treatments for Flaviviridae virus infection
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
US8481712B2 (en) 2001-01-22 2013-07-09 Merck Sharp & Dohme Corp. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
US9061041B2 (en) 2011-04-13 2015-06-23 Merck Sharp & Dohme Corp. 2′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9150603B2 (en) 2011-04-13 2015-10-06 Merck Sharp & Dohme Corp. 2′-cyano substituted nucleoside derivatives and methods of use thereof useful for the treatment of viral diseases
US9156872B2 (en) 2011-04-13 2015-10-13 Merck Sharp & Dohme Corp. 2′-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9408863B2 (en) 2011-07-13 2016-08-09 Merck Sharp & Dohme Corp. 5′-substituted nucleoside analogs and methods of use thereof for the treatment of viral diseases
US9416154B2 (en) 2011-07-13 2016-08-16 Merck Sharp & Dohme Corp. 5′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3853845A (en) * 1971-08-18 1974-12-10 Icn Pharmaceuticals 5-n-aminoacyl-5-aminouridines
US4879214A (en) * 1988-11-15 1989-11-07 E. I. Du Pont De Nemours And Company Differentiation of nucleic acid segments on the basis of nucleotide differences
US5891684A (en) * 1992-10-15 1999-04-06 Ribozyme Pharmaceuticals, Inc. Base-modified enzymatic nucleic acid

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3853845A (en) * 1971-08-18 1974-12-10 Icn Pharmaceuticals 5-n-aminoacyl-5-aminouridines
US4879214A (en) * 1988-11-15 1989-11-07 E. I. Du Pont De Nemours And Company Differentiation of nucleic acid segments on the basis of nucleotide differences
US5891684A (en) * 1992-10-15 1999-04-06 Ribozyme Pharmaceuticals, Inc. Base-modified enzymatic nucleic acid

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PFISTER ET AL.: "The 2-(4-nitrophenyl)ethylsulfonyl (neps) group: a new type of protection in nucleoside chemistry", HELVETICA CHIMICA ACTA, vol. 78, no. 7, 1995, pages 1705 - 1737, XP002148304 *
PRYSTAS ET AL.: "Nucleic acids components and their analogues, LXXXV. Synthesis of 5-cyanouracil, 5-nitrouracil and 5-minouracil 1-glycosyl derivatives", COLLECTION CZECHOSLOVAK CHEMICAL COMMUNICATIONS, vol. 31, no. 10, 1996, pages 3990 - 4001, XP002964002 *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6777395B2 (en) 2001-01-22 2004-08-17 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase of hepatitis C virus
US7105499B2 (en) 2001-01-22 2006-09-12 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US7125855B2 (en) 2001-01-22 2006-10-24 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US7202224B2 (en) 2001-01-22 2007-04-10 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US8481712B2 (en) 2001-01-22 2013-07-09 Merck Sharp & Dohme Corp. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
US7524831B2 (en) 2005-03-02 2009-04-28 Schering Corporation Treatments for Flaviviridae virus infection
US7816339B2 (en) 2005-03-02 2010-10-19 Schering Corporation Treatments for Flaviviridae virus infection
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US9278990B2 (en) 2010-09-22 2016-03-08 Alios Biopharma, Inc. Substituted nucleotide analogs
US9061041B2 (en) 2011-04-13 2015-06-23 Merck Sharp & Dohme Corp. 2′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9150603B2 (en) 2011-04-13 2015-10-06 Merck Sharp & Dohme Corp. 2′-cyano substituted nucleoside derivatives and methods of use thereof useful for the treatment of viral diseases
US9156872B2 (en) 2011-04-13 2015-10-13 Merck Sharp & Dohme Corp. 2′-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9408863B2 (en) 2011-07-13 2016-08-09 Merck Sharp & Dohme Corp. 5′-substituted nucleoside analogs and methods of use thereof for the treatment of viral diseases
US9416154B2 (en) 2011-07-13 2016-08-16 Merck Sharp & Dohme Corp. 5′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9605018B2 (en) 2011-12-22 2017-03-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US9394330B2 (en) 2012-03-21 2016-07-19 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9856284B2 (en) 2012-03-21 2018-01-02 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US11278559B2 (en) 2014-02-13 2022-03-22 Ligand Pharmaceuticals Incorporated Prodrug compounds and their uses
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10150788B2 (en) 2014-07-02 2018-12-11 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses thereof
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

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