WO2003051881A1

WO2003051881A1 - Substituted purine nucleoside libraries and compounds by solid-phase combinatorial strategies

Info

Publication number: WO2003051881A1
Application number: PCT/US2002/040414
Authority: WO
Inventors: Haoyun An; Esmir Gunic; Yung-Hyo Koh; Huanming Chen; Dinesh Barawkar; Weijian Zhang; Jean-Luc Girardet; Frank Rong; Zhi Hong
Original assignee: Ribapharm Inc.
Priority date: 2001-12-17
Filing date: 2002-12-17
Publication date: 2003-06-26
Also published as: AU2002359732A1; WO2003051881B1

Abstract

Nucleoside analog libraries are prepared in a combinatorial library approach. In some preferred aspects, library diversity is generated using solid phase-coupled nucleosides in a series of at least two modification reactions, and contemplated libraries and compounds include various 2-C-substituted purines, 3-deoxy/aza-6-substituted purines, substituted 2-thioadenosines, 2-amino-6,8-disubstituted purines, 2,8-disubstituted guanosines, 6-substituted purines, 2,6-disubstituted adenosines, and 6,8-disubstituted adenosines. Particularly preferred compounds include nucleoside analogs generated using contemplated libraries, which may be useful in treatment of various conditions, particularly viral infections and neoplastic diseases.

Description

SUBSTITUTED PURINE NUCLEOSIDE LIBRARIES AND COMPOUNDS BY SOLID-PHASE COMBINATORIAL STRATEGIES

Priority Claim

This application claims priority to US 60/342,441 filed December 17, 2001.

Field of The Invention

The field ofthe invention is combinatorial nucleoside libraries and related compounds.

Background of The Invention

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. Incorporation of certain unnatural nucleoside analogues into nucleic acid replicates or transcripts can interrupt gene expression by early chain termination, or by interfering with function ofthe modified nucleic acids. In addition, certain nucleoside analogue triphosphates are very potent, competitive inhibitors of DNA or RNA polymerases, which can significantly reduce the rate at which the natural nucleosides 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.

Various nucleoside analogues can also act in other ways, for example, causing apoptosis of cancer cells and/or modulating immune systems. In addition to 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-fiuo ouridine, 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. Many of these nucleoside analogues that can 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.

Selective inhibition of cancer cells or host cells infected by viruses has been an important subject for some time, and tremendous efforts have been made to search for more selective nucleoside analogues. In general, however, a large pool of nucleoside analogues is thought to be necessary in order to identify highly selective nucleoside analogues. Unfortunately, the classical method of synthesizing nucleosides and nucleotides having desired physiochemical properties, and then screening them individually, takes a significant • amount of time to identify a lead molecule. Although thousands of nucleoside analogues were synthesized over the past decades, if both sugar and base modifications are considered, many additional analogues are still waiting to be synthesized.

During the last few years, combinatorial chemistry has been used to generate huge numbers of organic compounds, resulting in large compound libraries. If nucleosides could be made through a combinatorial chemistry approach, a large number of nucleoside analogues could be synthesized within months instead of decades, and large nucleoside libraries could be developed.

A combinatorial chemistry approach to nucleosides may also encourage a focus beyond previously addressed biological targets. For example, in the past 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.

The generation of combinatorial libraries of chemical compounds by employing solid phase synthesis is well known in the art. For example, Geysen, et al. (Proc. Natl. Acac. Sci. USA, 3998 (1984)) describes the construction of a multi-amino acid peptide library; Houghton, et al. (Nature, 354, 84 (1991)) describes the generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery; Lam, et al. (Nature, 354, 82 (1991)) describes a method of synthesis of linear peptides on a solid support such as polystyrene or polyacrylamide resin.

Although a combinatorial chemistry approach has been proven to work well with many types of compounds, there are certain hurdles to the generation of nucleoside libraries. Among numerous other difficulties, most nucleoside analogues contain a sugar moiety and a nucleoside base, which are linked together through a glycosidic bond. The formation ofthe glycosidic bond can be achieved through a few types of condensation reactions. However, most ofthe reactions do not give a very good yield of desired products, which may not be suitable to generation of nucleoside libraries. Moreover, 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. As a result, many researchers focused their attention to areas in pharmaceutical chemistry that appear to present easier access to potential therapeutic molecules, and there seems to be a lack of methods for generating libraries of nucleosides and nucleotides using solid phase synthesis. Therefore, there is still a need to provide methods for generation of nucleoside and nucleotide libraries.

Summary of the Invention

The present invention is directed to nucleoside analog libraries and compounds represented in and derived from these libraries. Contemplated nucleoside analog libraries and their compounds especially include various 2-C-substituted purines, 3-deoxy/aza-6- substituted purines, substituted 2-thioadenosines, 2-amino-6,8-disubstituted purines, 2,8- disubstituted guanosines, 6-substituted purines, 2,6-disubstituted adenosines, and 6,8- disubstituted adenosines.

In one aspect ofthe inventive subject matter, 2'-C-substituted nucleoside libraries and compounds include nucleosides in which a sugar is covalently bound to a purine having a substituent in a 2-position, wherein the substituent ofthe purine has a carbon atom that forms a covalent bond with the 2-position ofthe purine (with the proviso that the 2-C-substituent is not -C≡C-R, with R being alkyl or substituted alkyl). It is especially contemplated that in such libraries and compounds the carbon atom in the substituent is a chiral center, and it is further contemplated that the 2-C-substituted purine is formed by reacting an amino acid, an alkyl carboxylic acid, an arylcarboxylic acid, an alkenylcarboxylic acid, an alkynylcarboxylic acid, or a heterocyclic carboxylic acid with 5- amino-4-imidazolylcarboxamide that is covalently bound to the sugar. Exemplary libraries and compounds will include compounds according to Formulae 1 A and IB wherein the substituents are described as in the respective portion ofthe detailed description below.

Formula IA Formula IB

In a further aspect ofthe inventive subject matter, contemplated libraries and compounds include nucleosides according to Formulae 2A and 2B, wherein the substituents are described as in the respective portion ofthe detailed description below.

O PG OH

In a still further aspect ofthe inventive subject matter, contemplated libraries and compounds include nucleosides according to Formulae 2C and 2D, wherein the substituents are described as in the respective portion ofthe detailed description below.

o PG OH

In yet another aspect ofthe inventive subject matter, contemplated libraries and compounds include nucleosides according to Formula 3, wherein the substituents are described as in the respective portion ofthe detailed description below.

Formula 3

In a further aspect ofthe inventive subject matter, contemplated libraries and compounds include nucleosides according to Formulae 4 and 4A, wherein the substituents are described as in the respective portion ofthe detailed description below.

, Formula 4A

In a still further aspect ofthe inventive subject matter, contemplated libraries and compounds include nucleosides according to Formula 5, wherein the substituents are described as in the respective portion ofthe detailed description below. Formula 5

In still another aspect ofthe inventive subject matter, contemplated libraries and compounds include nucleosides according to Formula 6, wherein the substituents are described as in the respective portion ofthe detailed description below.

In yet another aspect ofthe inventive subject matter, contemplated libraries and compounds include nucleosides according to Formulae 7 or 8, wherein the substituents are described as in the respective portion ofthe detailed description below.

Various objects, features, aspects and advantages ofthe present invention will become more apparent from the following detailed description of preferred embodiments ofthe invention.

Detailed Description

The term "nucleoside library" as used herein refers to a plurality of chemically distinct nucleosides, wherein at least some ofthe nucleosides have been synthesized from a common synthesis intermediate. The term "synthesis intermediate" explicitly excludes starting materials ofthe synthesis. It is generally contemplated that the complexity of contemplated libraries is at least 20 distinct nucleosides, more typically at least 100 distinct nucleosides, and most typically at least 1,000 distinct nucleosides. The term "library compound" as used herein refers to a nucleoside within the nucleoside library.

As also used herein, the terms "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. Particularly contemplated heterocyclic bases include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine). Further contemplated 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). 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.

As further used herein, the term "sugar" refers to all carbohydrates and derivatives thereof, wherein particularly contemplated derivatives include deletion, substitution or addition of a chemical group in the sugar. For example, especially contemplated deletions include 2'-deoxy and/or 3 '-deoxy sugars. Especially contemplated substitutions include replacement ofthe 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. The term " carbocyclic ring system" as used herein 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.

The term "nucleoside" refers to all compounds in which a heterocyclic base is covalently coupled to a sugar, and an especially preferred coupling ofthe 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. The term "nucleoside analog" as used herein 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.), however, also includes nucleosides. It should further be particularly appreciated that the term nucleoside also includes all prodrug forms of a nucleoside, wherein the prodrug form may be activated/converted to the active drug/nucleoside in one or more than one step, and wherein the activation/conversion ofthe prodrug into the active drug/nucleoside 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.

As still further used herein, the term "multiple component condensation" refers to a reaction between at least two distinct molecules and a sugar or sugar portion of a molecule, in which at least one ofthe two molecules forms a covalent bond with the sugar portion, wherein the reaction may be carried out simultaneously or sequentially (which may further involve an optional purification step).

The terms "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. The term "substituted alkyl" as used herein refers to any alkyl that further comprises a functional group, and particularly contemplated functional groups include nucleophilic (e.g., -NH₂, -OH, -SH, -NC, etc.) and 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., -NH₃ ⁺), halogens (e.g., -F, -Cl), and all chemically reasonable combinations thereof. The terms "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. The term "substituted alkenyl" as used herein refers to any alkenyl that further comprises a functional group, and particularly contemplated functional groups include those discussed above.

Furthermore, the terms "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. The term "substituted alkynyl" as used herein refers to any alkynyl that further comprises a functional group, and particularly contemplated functional groups include those discussed above. The terms "aryl" and "unsubstituted aryl" are used interchangeably herein and refer to any aromatic cyclic alkenyl or alkynyl. The term "substituted aryl" as used herein refers to any aryl that further comprises a functional group, and particularly contemplated functional groups include those discussed above. The term "alkaryl" is employed where the aryl is further covalently bound to an alkyl, alkenyl, or alkynyl.

Thus, the term "substituted" as used herein also refers to a replacement of a chemical group or substituent (typically H or OH) with a functional group, and particularly contemplated functional groups include nucleophilic (e.g., -NH₂, -OH, -SH, -NC, etc.) and 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., -NHs ), halogens (e.g., -F, -Cl), and all chemically reasonable combinations thereof. Thus, the term "substituent" includes nucleophilic (e.g., -NH₂, -OH, -SH, -NC, etc.) and 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., -NH₃ ⁺), halogens (e.g., -F, -Cl), and all chemically reasonable combinations thereof.

Contemplated Sugars

It is contemplated that suitable sugars will have a general formula of C_nH_2nO_n, wherein n is between 2 and 8, and wherein (where applicable) the sugar is in the D- or L- configuration. Moreover, it should be appreciated that there are numerous equivalent modifications of such sugars known in the art (sugar analogs), and all of such modifications are specifically included herein. For example, some contemplated alternative sugars will include sugars in which the heteroatom in the cyclic portion ofthe 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 C₅' esters), alkyl groups, alkoxygroups, halogens, amino groups and amines, sulfur-containing substituents, etc. It is still further contemplated that all contemplated substituents (hydroxyl substituents and non-hydroxyl substituents) may be directed in the alpha or beta position. Numerous ofthe 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 EP199,451. An exemplary collection of further contemplated sugars and sugar analogs is depicted below, wherein all ofthe exemplary sugars may be in D- or L-configuration, and wherein at least one ofthe substituents may further be in either alpha or beta orientation.

0~ ^"CH3/R/CF3 HO* )H Het⁵ > H

^H

X_;Y,Z = 0,S,Se,NH,NR,CH_2l CHR, P(θ), P(0)OR

R = H, OH, NHR, halo, CH₂OH, COOH, N₃, alkyl, aryl, alkynyl, heterocycles, OR, S , P(0)(OR)₂

OCOR, NHCOR, NHS0₂R, NH₂NH₂, amidine, substituted amidine, quanidine, substituted gyanidine

An especially contemplated class of sugars comprises alkylated sugars, wherein one or more alkyl groups (or other substituents, including alkenyl, alkynyl, aryl, halogen, CF₃, CHF₂,

CCI3, CHC1₂, N₃, NH₂, etc.) are covalently bound to sugar at the C'ι, C'₂,C'₃,C₄, or C₅ atom. In such allcylated sugars, it is especially preferred that the sugar portion comprises a furanose (most preferably a D- or L-ribofuranose), and that at least one ofthe alkyl groups is a methyl group. Of course, it should be recognized that the alkyl group may or may not be substituted with one or more substituents. One exemplary class of preferred sugars is depicted below:

in which B is hydrogen, hydroxyl, or a heterocyclic base, 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. However, 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). Further contemplated 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). An exemplary collection of appropriate heterocyclic bases is depicted below, wherein all ofthe 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 ofthe contemplated heterocyclic bases may be coupled to contemplated sugars via a carbon atom or a non-carbon atom in the heterocyclic base.

Contemplated Solid Phases

It is generally contemplated that all known types of solid phases are suitable for use herein, so long as contemplated nucleosides (or sugar, or heterocyclic base) can be coupled to such solid phases, and so long as the coupled nucleoside (or sugar, or heterocyclic base) will remain coupled to the solid phase during at least one chemical reaction on the nucleoside (or sugar, or heterocyclic base). Especially contemplated solid phases (i.e., solid supports) 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 NH₂ resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany). Alternatively, 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).

Consequently, it should be recognized that there are numerous methods of coupling nucleosides, sugars, or heterocyclic bases to solid phases that may be appropriate, and a particular method will generally depend on the particular type of solid phase and/or type of sugar. Thus, all of such known methods are contemplated suitable for use herein, and exemplary suitable solid phase coupling reactions 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.

Contemplated Combinatorial Reactions

It is generally contemplated that all known types of 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 (with may include the wall ofthe 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. There are numerous methods and protocols for combinatorial chemistry known in the art, and exemplary suitable protocols and methods are described in "Solid-Phase Synthesis and Combinatorial Technologies" by Pierfausto Seneci (John Wiley & Sons; ISBN: 0471331953) or in "Combinatorial Chemistry and Molecular Diversity in Drug Discovery" by Eric M. Gordon and James F. Kerwin (Wiley-Liss; ISBN: 0471155187). Although synthesis using combinatorial strategies are generally preferred, it should be recognized that contemplated compounds (and libraries) may also be synthesized in a 'conventional' synthetic approach using a strategy other than solid-phase combinatorial chemistry. Thus, contemplated compounds may be synthesized by well known solution-phase/general synthetic/medicinal chemistry approaches.

Contemplated Libraries and Nucleosides

The inventors discovered that nucleoside analog libraries can be prepared in various combinatorial library approaches, including libraries in which diverse heterocyclic bases and/or diverse nucleoside substituents are prepared from precursor nucleosides (or modified sugars) that are derivatized in subsequent/parallel modification reactions.

2-C-substituted Purine Libraries

The inventors have discovered that 2-C-substituted purine nucleoside libraries and library compounds may be synthesized, wherein the nucleoside comprises a sugar that is covalently bound to a purine (or purine analog) having a substituent in the 2-position, wherein the substituent ofthe purine has a carbon atom that forms a covalent bond with the 2-position ofthe purine. With respect to the library compounds, it is contemplated that when the 2-C- substituent is -C≡C-R, that R is not alkyl or substituted alkyl.

In an especially preferred aspect ofthe inventive subject matter, the carbon atom (that forms the covalent bond to the purine in 2-position) in the substituent forms a chiral center, and in still further preferred aspects, the 2-C-substituted purine is formed by reacting a^' carboxylic acid (e.g., an amino acid, an alkyl carboxylic acid, an arylcarboxylic acid, an alkenylcarboxylic acid, an alkynylcarboxylic acid, or a heterocyclic carboxylic acid) with a substituted or unsubstituted 5-amino-4-imidazolylcarboxamide that is covalently bound to the sugar.

Scheme 1 depicts an exemplary synthetic approach for a 2-C-substituted ribofuranosylpurine library, in which l-ribofuranosyl-5-amino-4-imidazolylcarboxamide is reacted with a protected amino acid to form the corresponding protected 2-C-substituted ribofuranosylpurine, which is either deprotected to form a 2-C-substituted ribofuranosylpurine, or which may further be reacted (after coupling the sugar to a solid phase and protecting the OH groups ofthe sugar) in a combinatorial approach with a nucleophile (preferably a primary or secondary amine) that replaces a previously introduced leaving group. Deprotection and cleavage ofthe (library) nucleoside will then yield me (collection oij desired nucleoside(s).

Scheme 1

With respect to the sugar, it should be appreciated that the particular nature ofthe sugar is not limiting to the inventive subject matter. Consequently, numerous alternative sugars are also appropriate, and particularly contemplated 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 suitable sugars include those described in the section entitled "Contemplated Sugars", and it is especially contemplated that where the sugar has a C₂' and/or C₃' substituent other than a hydroxyl group, such alternative sugars may include hydrogen, a halogen, or an azide group in at least one of these positions (in either alpha or beta orientation). Moreover, the coupling ofthe heterocyclic base to the sugar may be in a position other than the Ci'-position, and it is especially contemplated that where the sugar is a pentose or hexose, alternative positions include the C₂' and C₃'-position.

Consequently, the nature of protecting groups for the sugar may 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. 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, however, 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 NH₂ resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany). Moreover, while it is generally preferred that a solid phase is employed in the combinatorial approach, it should also be recognized that the solid phase may also be omitted where appropriate.

With respect to contemplated heterocyclic bases, it should be appreciated that while 5- amino-4-imidazolylcarboxamide is a preferred commercially available heterocyclic base, numerous alternative heterocyclic bases are also appropriate so long as such heterocyclic bases provide at least 2 amino groups that are positioned such that the at least two amino groups can react with a carboxylic acid to form a ring. For example, suitable heterocyclic bases may include aromatic or (at least partially saturated) ring systems that comprise at least one ring of at least 3 atoms (triazine, diazole, etc.). While it is generally contemplated that alternative heterocyclic bases include nitrogen as the heteroatom, alternative heteroatoms (e.g., O, S, P, Se, etc.) are also contemplated. Further exemplary suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above (so long as such heterocyclic bases include at least 2 amino groups that are positioned such that the at least two amino groups can react with a carboxylic acid to form a ring). It is further contemplated that many ofthe preferred and/or alternative heterocyclic bases are commercially available. However, it should be recognized that where a particular heterocyclic base is not commercially available, suitable bases can be prepared without undue experimentation from commercially available precursors using protocols well known in the art (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).

Particularly contemplated protected amino acids for reaction with the heterocyclic base include all naturally occurring proteinogenic amino acids in L-configuration, however, it should be recognized that the particular chemical nature and/or the stereochemical configuration is not limiting to the inventive subject matter. Consequently, suitable amino acids may also include D-amino acids, non-natural amino acids, and various non-amino acids, so long as such acids will react with the amino groups ofthe heterocyclic base to form a ring. Examples for suitable acids include alkyl carboxylic acids, arylcarboxylic acids, alkenylcarboxylic acids, alkynylcarboxylic acids, and heterocyclic carboxylic acids, all of which may further include one or more substituents (e.g., OH, SH, NH₂, COOH, CONH, CNHNH₂, etc.). It is generally contemplated that many ofthe contemplated carboxylic acids are commercially available, however, it should be recognized that where a particular carboxylic acid is not commercially available, such carboxylic acids can be prepared without undue experimentation from commercially available precursors using protocols well known in the art (supra). Cyclization ofthe two amino groups with contemplated carboxylic acids may be performed using various procedures well known in the art, and all ofthe known protocols are deemed suitable for use herein.

In a further aspect ofthe inventive subject matter, 2-C-substituted purine nucleosides formed using contemplated reactions may further be modified by reaction of such compounds with a nucleophilic reagent that replaces a previously introduced leaving group. There are numerous leaving groups known in the art, all of which are deemed suitable for use herein. However, preferred leaving groups include TIP SCI, which may be introduced in the 6- position ofthe previously formed purine base and subsequently replaced with a nucleophilic reagent.

Especially contemplated nucleophilic reagents include various nitrogen-containing reagents (e.g., various primary and secondary amines, RNH₂, RRNH), thiols (RSH), alcohols (ROH), and Grignard reagents (RMgX). There are numerous substituted and unsubstituted amines, thiols, alcohols, or Grignard-type alkyls (nucleophilic reagents) commercially available, and where such substrates are not commercially available, it is contemplated that they may be prepared from commercially available precursors using protocols well lαiown in the art (supra). Exemplary nucleophilic reagents are listed below in the experimental section.

It is still further contemplated that the so formed purine may further be reacted on the 8-position with various substituents in a substitution reaction in which hydrogen is replaced with an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, CN, N₃, CF₃, COOH, NHR, or NHNHR, wherein R is 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. Alternatively, these substituents in the 8-position may also be incorporated by use of appropriately substituted contemplated heterocyclic bases prior to the cyclization reaction.

Particularly contemplated alternative heterocyclic bases include those in which the 8- position is covalently bound to a hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, CN, N_3s CF₃, COOH, NHR, or NHNHR with R selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl.

Thus, it should be recognized that nucleoside libraries will have at least two library compounds according to Formula 1, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Y, R_ls R₂, R₃, and R₄ wherein a second compound ofthe plurality of compounds has a second set of substituents A, X, Y, R_ls R₂, R₃, and R₄

Formula 1

wherein A is a protected or unprotected sugar covalently bound to a solid phase, X is O , S, NH, NHNH, NHO, or CH₂, Y is CH₂ or NH, and R_h R₂, R₃, and R₄ 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, a substituted aryl, CN, N , CF₃, COOH, NHR, or NHNHR with R selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, and wherein not all ofthe substituents A, X, Y, R_ls R₂, R₃, and R₄ in the first set are the same as the substituents A, X, Y, R_ls R₂, R , and Rt in the second set. Particularly preferred sugars include ribofuranose, substituted ribofuranose, carbocyclic ring systems, and arabinose, wherein the sugar is in a D-configuration or in an L-configuration.

Consequently, contemplated compounds may have a structure according to Formula 1

wherein A is a sugar (preferably ribofuranose, substituted ribofuranose, carbocyclic ring systems, and arabinose, all of which may be in D-configuration or L-configuration), X is O, S, NH, NHO, NHNH, or CH₂, Y is CH₂ or NH, and R_h R₂, R₃, and j 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, a substituted aryl, CN, N₃, CF₃, COOH, NHR, or NHNHR with R selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl.

Alternatively, and especially where alternative heterocyclic bases having a structure according to Formula 1 A are employed, contemplated compounds may also have a structure according to Formula IB

wherein A is a sugar (preferably ribofuranose, substituted ribofuranose, carbocyclic ring systems, and arabinose, all of which may be in D-configuration or L-configuration), D=E is C=C, C=N, N=C, or N=N, X is O, S, NH, alkyl, aryl, alkenyl, alkynyl, or alkaryl, R R₂, R₃, and R₄ 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, a substituted aryl, CN, N₃, CF₃, COOH, NHR, or NHNHR with R 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.

Thus further contemplated libraries may include a first library compound with a structure according to Formula IB (supra) with a first set of substituents A, D, E, X, R_l5 R₂, R₃, and R₄, and a second library compound with a structure according to Formula IB (supra) with a second set of substituents A, D, E, X, R_ls R₂, R₃, and P^, wherein A is a protected or unprotected sugar covalently bound to a solid phase; X is O, S, NH, alkyl, aryl, alkenyl, alkynyl, or alkaryl; D=E is C=C, C=N, N=C, or N=N; R_1; R₂, R₃, and R4 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, a substituted aryl, CN, N₃, CF₃, COOH, NHR, and NHNHR; wherein R is selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl; and wherein not all ofthe substituents A, D, E, X, R_l3 R₂, R₃, and P in the first set are the same as the substituents A, D, E, X, Ri, R₂, R₃, and R4 in the second set. 3'-Deoxy/aza-6-substituted Purine Libraries

In another aspect ofthe inventive subject matter, the inventors have discovered that 3- deoxy-6-substituted purine libraries may be produced following a synthetic scheme as depicted in Scheme 2. Here, the amino group in the heterocyclic base is protected and the 2'- and 3'- hydroxyl groups are converted into the corresponding 2',3'-epoxy group to form a protected 2',3'-epoxyguanosine, which is subsequently reduced to the corresponding 3'- deoxynucleoside. The so generated 3'-deoxynucleoside is then coupled to a solid phase (preferably via the C₅'-atom) and the keto-oxygen ofthe heterocyclic base is replaced with a leaving group (preferably TPSC1), which is replaced with a set of nucleophilic reagents (preferably primary amines) to generate molecular diversity. In further steps, the nucleosides are cleaved from the solid support and deprotected to the corresponding (library) nucleoside.

Scheme 2

With respect to the sugar, it should be appreciated that the particular nature ofthe sugar is not limiting to the inventive subject matter so long as alternative sugars include a vicinal diol, which is preferably a C₂' and C₃' hydroxyl group. Consequently, numerous alternative sugars are also appropriate, and particularly contemplated 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. Consequently, the nature of protecting groups for the sugar may vary considerably, and while it is particularly contemplated that suitable protection groups include trityl-, benzyl-, acetyl-, and TBDMS groups, numerous alternative protection groups are also considered suitable. For example, suitable alternative protection groups and their reactions are 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. Therefore, it is contemplated that all lαiown 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, however, 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 NH₂ resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany). Furthermore, it is generally preferred that contemplated sugars are coupled to the solid phase via the C₅'-atom, however, in alternative aspects coupling to an atom other than the C₅'-atom is also considered suitable.

Similarly, while guanosine is generally preferred as a heterocyclic base, it should be recognized that various alternative heterocyclic bases are also appropriate, and especially contemplated heterocyclic bases include those with at least one keto-oxygen and at least one amino group (e.g., substituted guanines, pyrrolopyrimidines, etc.). Further suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above. It should further be appreciated that many ofthe contemplated heterocyclic bases (and especially guanine) are commercially available, and where a particular alternative heterocyclic base is not commercially available, it is contemplated that such heterocyclic bases may be synthesized from a commercially available precursor without undue experimentation following procedures well known in the art (see e.g., "Modern Methods in Carbohydrate Synthesis" by Shaheer H. Khan (Gordon & Breach Science Pub; ISBN:

3718659212)). Furthermore, it should be recognized that suitable heterocyclic bases may also be coupled to a sugar moiety to form a nucleoside, and that all known nucleosides are suitable for use in conjunction with the teachings presented herein. However, especially preferred nucleosides include those in which the heterocyclic base has at least one keto-oxygen and at least one amino group (supra).

Epoxidation ofthe 2'- and 3'-hydroxyls to a 2',3'-epoxy group is preferably performed as described below (see experimental section), however, it should be recognized that numerous alternative reactions are also suitable, and all ofthe known epoxidation reactions for sugars are considered suitable for use herein. Similarly, reduction ofthe epoxy group to the corresponding alcohol and hydrogen at the C₂' and C₃'-atom, respectively, is preferably performed as described below. However, alternative methods to convert the epoxy group to the corresponding alcohol and hydrogen at the C₂' and C₃'-atom, respectively, are also considered appropriate and may include catalytic reduction and/or electrochemical reduction.

With respect to the nucleophilic reagents, it is contemplated that suitable reagents include all reagents that can replace a leaving group (and preferably OTPS) from the heterocyclic base. Therefore, particularly contemplated nucleophilic reagents include various nucleophiles (e.g., primary and secondary amines, thiols, alcohols, Grignard reagents, etc.). Exemplary nucleophilic reagents include RNH , RR'NH, RSH, ROH, etc, 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 and a substituted aryl. There are numerous nucleophilic reagents commercially available, and it is contemplated that where a particular reagent is not commercially available, such contemplated reagents may be synthesized from commercially available precursors following protocols well known in the art. Further contemplated reagents are listed below in the experimental section.

Alternatively, as depicted in Scheme 3, a 3 '-deoxy sugar is coupled to heterocyclic base in a condensation reaction to form the corresponding 3'-deoxynucleoside₅ which is then subjected to one or more derivatization reactions. In a preferred aspect, the 3'- deoxynucleoside is a 3'-deoxyguanosine that is converted to the corresponding 3'-deoxy-6- chloroguanosine and coupled to a solid phase (preferably via the C₅'-atom). In a further reaction, the chlorine atom in the heterocyclic base is replaced with a set of nucleophilic reagents (preferably primary and/or secondary amines) to generate molecular diversity. In further steps, the nucleosides are cleaved from the solid support and deprotected to the corresponding (library) nucleoside.

Scheme 3

With respect to the heterocyclic base, the sugar, the protecting groups, and the solid phase, the same considerations as described for Scheme 2 above apply. Coupling ofthe appropriate sugar to a particular heterocyclic base will generally follow protocols well known in the art. While it is generally preferred that in a synthetic route as depicted in Scheme 3 the leaving group is a halogen, and most preferably chloride, alternative leaving groups are also considered suitable. For example, where appropriate, suitable leaving groups may include Tosyl groups, Mesyl groups, etc.

Furthermore, suitable nucleophilic reagents include all reagents that can replace a leaving group (and preferably Cl) from the heterocyclic base. Therefore, particularly contemplated nucleophilic reagents include various nucleophiles (e.g., primary and secondary amines, thiols, alcohols, Grignard reagents, etc.). Exemplary nucleophilic reagents include RNH₂, RR'NH, RSH, ROH, etc, 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 and a substituted aryl. There are numerous nucleophilic reagents commercially available, and it is contemplated that where a particular reagent is not commercially available, such contemplated reagents may be synthesized from commercially available precursors following protocols well known in the art. Further contemplated reagents are listed below in the experimental section.

In yet another alternative route, as depicted in Scheme 5, a 3'-deoxy-6-substituted purine library (and the corresponding library compounds) may be prepared starting from 3'- deoxyguanosine (synthesis see above), wherein the keto-oxygen ofthe heterocyclic base is converted into a leaving group that is subsequently replaced in an aromatic substitution reaction to yield the corresponding 3'-deoxy-6-C-substituted purine. Further reaction ofthe 3'- deoxy-6-C-substituted purine with a set of electrophilic reagents (in which the nucleoside may or may not be coupled to a solid phase) results in the corresponding library of corresponding 3'-deoxy-6-C-substituted purines.

Scheme 5

With respect to the heterocyclic base, the sugar, the protecting groups, and the solid phase, the same considerations as described for Scheme 2 above apply. While it is generally preferred that a vinyl group is introduced into the heterocyclic base via a C-C bond fonnation reaction (e.g., Heck, Stille, Suzuki reaction), other reactions may also be employed and include, among other reactions, nucleophilic substitution using a Grignard reagent. With respect to the substituent that is introduced into the heterocyclic base at the 6-position, it is contemplated that a particular substituent is to some extent determined by the particular reaction that is employed. However, it is generally preferred that suitable substituents include at least one reactive group that can be modified in a subsequent or later reaction. Consequently, especially contemplated substituents include substituted alkyls, substituted and unsubstituted alkenyls, substituted and unsubstituted alkynyl, and/or substituted and unsubstituted aryls.

Depending on the reactive group in the substituent, it is contemplated that the substituent may further be modified in various manners. For example, where the reactive group comprises a diene, a further reactant to modify the substituent includes dienophiles. Similarly, where the reactive group comprises a double bond or other electrophilic group, a reactant to modify the substituent particularly includes nucleophiles (e.g., RXH with X being NH, NR, S, O, or C), and where the reactive group comprises an electrophilic group, a reactant to modify the substituent particularly includes nucleophiles. Thus, particularly preferred 6-substituents may have the general structure R-Y-R', wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, R' is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, and wherein Y is NH, NR, S, O, or CH₂.

Consequently, a nucleoside library may comprise a plurality of library compounds according to Formula 2 A, wherein a first compound ofthe plurality of compounds has a first set of substituents X and R, and wherein a second compound ofthe plurality of compounds has a second set of substituents X and R

b^PG

wherein X is NR, S, O, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl; R is 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; or where XR together are R-Y-R', wherein

R and R' are independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, R' is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, and wherein Y is NH, NR, S, O, or CH₂; NH^PG is a protected amino group, O^PG is a protected hydroxyl group, • is a solid phase, and wherein not all ofthe substituents X and R in the first set are the same as the substituents X and R in the second set. Thus, contemplated compounds may have a structure according to Formula 2B

OH

wherein X is NR, S, O, or CH₂, R is 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; or where XR together are R-Y-R', wherein R and R' are independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, R' is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, and wherein Y is NH, NR, S, O, or CH₂.

In still further alternative aspects ofthe inventive subject matter, and especially where 3'-azidosugar nucleoside libraries are desired, 3'-azido-6-substituted purine nucleoside libraries and their corresponding library compounds may be synthesized as shown in Scheme 4. Here, a suitably protected 2',3'-epoxyguanosine is reacted with aN₃ ^" donor to the corresponding 3'-azidoguanosine, which is subsequently coupled to a solid phase (preferably via the C₅'-atom), and in a further reaction, the amino group ofthe heterocyclic base is protected with a protecting group. In a still further reaction, the keto-oxygen ofthe heterocyclic base is converted into a leaving group that is subsequently replaced by a set of nucleophiles to generate molecular diversity. Deprotection and cleavage ofthe nucleosides from the solid support will then yield the 3'-azido-6-substituted purine nucleoside library compounds.

Scheme 4

With respect to the heterocyclic base, the sugar, the protecting groups, the solid phase, the introduction and nature ofthe substituent in the 6-position ofthe heterocyclic base the same considerations as described for Scheme 2 above apply. Furthermore, it is contemplated that while NaN₃ is the preferred N₃ ^" donor, numerous alternative methods of introduction of the azide group in the sugar are also contemplated and include KN₃ as the N₃ ^" donor.

Still further, it is contemplated that the amino-protecting group at the heterocyclic base need not be removed. Consequently, contemplated libraries and library compounds also include compounds in which the 2-amino position is derivatized with a suitable reactive reagent. Among various other groups, preferred reactive reagents include electrophilic reagents, most preferably activated acids. For example, suitable reactive reagents have the general formula RCOC1, RCSC1, RC(=NH)C1, and RC(=NR')C1 wherein R and R' are independently hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl. Consequently, a nucleoside library may comprise a plurality of library compounds according to Formula 2C, wherein a first compound ofthe plurality of compounds has a first set of substituents X, Y, and R, and wherein a second compound ofthe plurality of compounds has a second set of substituents X, Y, and R

^PG

wherein X is NR, S, O, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl; Y is hydrogen, C(O)R', C(NH)R', or C(S)R'; R and R' 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; O^PG is a protected OH, • is a solid phase, and wherein not all ofthe substituents X, Y, and Rin the first set are the same as the substituents X, Y, and R in the second set.

Thus, contemplated compounds may have a structure according to Formula 2D

wherein X is NR, S, O, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl; Y is hydrogen, C(O)R', C(NH)R', or C(S)R'; R and R' 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.

Substituted 2-Thioadenosine Libraries

The inventors have discovered that substituted 2-thioadenosine libraries can be prepared by reacting a protected and solid phase-bound 2-amino-6-chloropurine riboside with a disulfide compound to generate the corresponding substituted 2-thio-6-chloropurine riboside. In a further set of reactions, the chloro group serves as a leaving group in a substitution reaction through which a second set of substituents can be introduced as depicted in Scheme 6.

Scheme 6

With respect to the sugar, it should be appreciated that the particular nature ofthe sugar is not limiting to the inventive subject matter. Consequently, numerous alternative sugars are also appropriate, and particularly contemplated alternative sugars include various substituted ribofuranoses, carbocyclic ring systems with 5 or 6 carbon atoms, and arabinose, wherein the sugar may be in D-or L-configuration. Where substituents in the 3'-position other than OH (e.g., halogen, N₃, or NH₂) are contemplated, it should be appreciated that such substituents can be introduced following various procedures well known in the art (see e.g., WO88/00050, US 3817982, or US 4880782). Consequently, the nature of protecting groups for the sugar may 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. For example, suitable alternative protection groups and their reactions are 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. 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, however, 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 NH₂ resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany). Still further, it should be appreciated that while coupling ofthe nucleoside to the solid phase is preferably via the C₅'-atom ofthe sugar, alternative coupling are also contemplated and especially include coupling to the C₂'- or C₃'-atom ofthe sugar.

Similarly, while 2-amino-6-chloropurine is generally preferred (among other advantages: commercially available), it should be recognized that various alternative heterocyclic bases are also appropriate, and especially contemplated heterocyclic bases include those with at least one halogen (preferably Cl) and at least one amino group (e.g., substituted guanines, pyrrolopyrimidines, etc.). Further suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above.

It is also contemplated that many of contemplated nucleosides (e.g., 2-amino-6- chloropurine riboside) are commercially available, and where a particular alternative nucleoside is not commercially available, it is contemplated that such nucleosides may be synthesized from a commercially available precursor without undue experimentation following procedures well lαiown in the art (see e.g., "Modern Methods in Carbohydrate Synthesis" by Shaheer H. Khan (Gordon & Breach Science Pub; ISBN: 3718659212)).

With respect to the disulfide compound, it should be appreciated that all disulfide reagents are suitable for use in conjunction with the teachings presented herein. However, especially contemplated disulfide reagents include R1-S-S-R1', in which Ri and Ri' may or may not be identical (and wherein R₁ and Ri' are independently hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5-membered heterocycle, a 6-membered heterocycle, or a fused heterocycle). It should further be appreciated that all, or almost all ofthe contemplated disulfide reagents may be produced from oxidation ofthe corresponding thiols, and all methods of forming a disulfide from thiols are contemplated suitable herein. A vast number of thiols are commercially available. However, where a particular thiol is not commercially available, it should be recognized that such thiols may be produced from commercially available precursors without undue experimentation following protocols well lαiown in the art.

Likewise, it is contemplated that the second set of substituents may be introduced into the heterocyclic ring at the 6-position using a wide variety of reagents. However, particularly contemplated reagents include nucleophilic reagents, and especially suitable nucleophilic reagents include all reagents that can replace a leaving group (and preferably Cl) from the heterocyclic base. Therefore, particularly contemplated nucleophilic reagents include various nucleophiles (e.g., primary and secondary amines, thiols, alcohols, Grignard reagents, etc.). Exemplary nucleophilic reagents include RNH₂, RR*NH, RSH, ROH, R-CH₂CH₂NH₂, RNH-NH₂, etc, 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 and a substituted aryl. There are numerous nucleophilic reagents commercially available, and it is contemplated that where a particular reagent is not commercially available, such contemplated reagents may be synthesized from commercially available precursors following protocols well known in the art. Further contemplated suitable nucleophilic reagents are listed below in the experimental section. Consequently, it is contemplated that a nucleoside library will include a plurality of compounds according to Formula 3, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Ri and R₂ and wherein a second compound ofthe plurality of compounds has a second set of substituents A, X, Ri and R₂

Formula 3

wherein A is a protected or unprotected sugar covalently bound to a solid phase, Ri is selected from the group consisting of hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle; X is NH, S, O, CH, CH₂CH₂NH, or NHNH, and R₂ is 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 ofthe substituents A, X, Ri and R₂ in the first set are the same as the substituents A, X, Ri and R₂ in the second set.

Thus, contemplated compounds will include a compound according to Formula 3

Formula 3

wherein A is a sugar, X is NH, S, O, CH, CH₂CH₂NH, or NHNH; R_x is selected from the group consisting of hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5-membered heterocycle, a 6-membered heterocycle, and a fused heterocycle; and R₂ is 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. 2-Amino-6,8-disubstituted Purine Libraries

In a further aspect ofthe inventive subject matter, the inventors have discovered that 2-amino-6,8-disubstituted purine libraries can be prepared by partially protecting an 8-bromo- purine nucleoside, and then reacting the heterocyclic base with a tributyl-tin reagent in a C-C bond forming reaction (e.g., Heck, Stille, Suzuki reaction) to form the corresponding 8- substituted partially protected nucleoside. In a further reaction, the so formed 8-substituted partially protected nucleoside is then coupled to a solid phase, and the keto-oxygen in the heterocyclic base is converted to a leaving group (preferably to OTPS using TPSCl), which is in a further step replaced by a nucleophilic reagent (preferably a primary or secondary amine). Cleavage ofthe nucleoside from the solid phase and deprotection will then yield the corresponding library nucleosides. An exemplary scheme for the generation of 2-amino-6,8- disubstituted purine libraries is given below in Scheme 7.

Ac^O 56 Pyridine

59 60

Scheme 7 Alternatively, and especially where it is desired to form an ether bond with a substituent ofthe heterocyclic base in the 6-position, a synthetic strategy as depicted in Scheme 8 may be employed. Here, a partially protected 8-bromo-purine nucleoside is reacted at the heterocyclic base with a tributyl-tin reagent in a C-C bond forming reaction (e.g., Heck, Stille, Suzuki reaction) to form the corresponding 8-substituted partially protected nucleoside. In a further reaction, the so formed 8-substituted partially protected nucleoside is then coupled to a solid phase, and the keto-oxygen in the heterocyclic base is replaced by an alcohol under conditions as described below in the experimental section to form the corresponding ether-bound substituent. Cleavage ofthe nucleoside from the solid phase and deprotection will then yield the corresponding library nucleosides.

64

Scheme 8

With respect to the sugar, it should be appreciated that the particular nature ofthe sugar is not limiting to the inventive subject matter. Consequently, numerous alternative sugars are also appropriate, and particularly contemplated alternative sugars include various substituted ribofuranoses, carbocyclic ring systems with 5 or 6 carbon atoms, and arabinose, wherein the sugar may be in D-or L-configuration. Where substituents in the 3 '-position other than OH (e.g., halogen, N₃, or NH₂) are contemplated, it should be appreciated that such substituents can be introduced following various procedures well known in the art (see e.g., WO88/00050, US 3817982, or US 4880782).

Consequently, the nature of protecting groups for the sugar may 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. For example, suitable alternative protection groups and their reactions are 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. 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, however, 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 NH₂ resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany). Still further, it should be appreciated that while coupling ofthe nucleoside to the solid phase is preferably via the 2-amino group in the heterocyclic base, coupling may also be performed via the sugar (e.g., via the C₂'-, C '-, or C₅'-atom ofthe sugar).

Similarly, while 8-bromoguanine is generally preferred (among other advantages: commercially available), it should be recognized that various alternative heterocyclic bases are also appropriate, and especially contemplated heterocyclic bases include those with at least one halogen (preferably Br) in the 8-position, a keto group in the 6-position, and at least one amino group, preferably in the 2-position (e.g., substituted guanines, pyrrolopyrimidines, etc.). Further suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above. With respect to the tributyl-tin reagent it should be recognized that suitable reagents are not limited to a particular tributyl-tin reagent, and in further contemplated aspects, various reagents suitable for a C-C bind formation are also contemplated, including reagents for a Heck, Stille, and/or Suzuki reaction. Further suitable reagents include Grignard reagents. Consequently, suitable 8-substituents will include an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and/or a substituted aryl. Numerous such reagents are commercially available. However, where a particular reagent is not commercially available, it is contemplated that such reagents may be produced from a precursor without undue experimentation following procedures well known in the art.

Likewise, with respect to the nucleophilic reagents it is contemplated that suitable reagents include all reagents that can replace a leaving group (and preferably OTPS) from the heterocyclic base. Therefore, particularly contemplated nucleophilic reagents include various nucleophiles (e.g., primary and secondary amines, thiols, alcohols, Grignard reagents, etc.). Exemplary nucleophilic reagents include RNH₂, RR'NH, RSH, ROH, etc, 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 and a substituted aryl. There are numerous nucleophilic reagents commercially available, and it is contemplated that where a particular reagent is not commercially available, such contemplated reagents may be synthesized from commercially available precursors following protocols well known in the art. Further contemplated reagents are listed below in the experimental section.

Preferred alcohols include all primary alcohols with the general formula ROH, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a ^• substituted alkynyl, an aryl and a substituted aryl. However, it should be recognized that also secondary (RR'CHOH) and even tertiary (RR'R"COH) alcohols may be suitable for use herein.

Consequently, it is contemplated that a nucleoside library will include a plurality of compounds according to Formula 4, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Ri and R and wherein a second compound ofthe plurality of compounds has a second set of substituents A, X, Ri and R₂ Formula 4

wherein A is a protected or unprotected sugar; X is NH, S, O, CH, CH₂CH₂NH, or NHNH; R_t is selected from the group consisting of hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle; R₂ is 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 ofthe substituents A, X, Ri and R₂ in the first set are the same as the substituents A, X, Ri and R₂ in the second set.

Thus, contemplated compounds will include a compound according to Formula 4A

Formula 4A

wherein A is a sugar, X is NH, S, O, CH, CH₂CH₂NH, or NHNH; Ri is selected from the group consisting of hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5-membered heterocycle, a 6-membered heterocycle, and a fused heterocycle; and R₂ is 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.

2,8-disubstituted Guanosine Libraries

In a further aspect ofthe inventive subject matter, the inventors have discovered that 2,8-disubstituted guanosine libraries can be prepared from a commercially available purine nucleoside analog (here: 8-bromoguanosine), which is reacted to the corresponding 8- substituted nucleoside as described above in Schemes 7, and/or 8. The so formed 8-substituted nucleoside is then reacted with a suitable keto-oxygen protecting group at the heterocyclic base, and in a further step, the 2-amino group ofthe heterocyclic base is replaced with a fluorine atom via fiuorination with HF. The so modified and protected 8-substituted-2- fluoronucleoside is then coupled to a solid phase (preferably via the C₅'-atom ofthe sugar), and in a still further reaction, the fiuoro-group is replaced with a nucleophilic reagent (preferably a primary or secondary amine). An exemplary synthetic pathway is shown in Scheme 9 below.

68

Scheme 9

While it is generally preferred that the sugar portion of such nucleosides is a ribofuranose, numerous alternative sugar portions are also contemplated, and all known sugars and sugar analogs are contemplated suitable for use herein. However, particularly contemplated sugars and sugar analogs include substituted and unsubstituted ribofuranose, and arabinose. Further suitable sugars include those described in the section entitled "Contemplated Sugars", and it is especially contemplated that where the sugar has a C₂' and/or C₃' substituent other than a hydroxyl group, such alternative sugars may include hydrogen, O-alkyl, a halogen, or an azide group in at least one of these positions (in either alpha or beta orientation). Moreover, the coupling ofthe purine heterocyclic base to the sugar may be in a position other than the exposition, and it is especially contemplated that where the sugar is a pentose or hexose, alternative positions include the C₂' and C₃'-position.

Consequently, the nature of protecting groups for the sugar may 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. Suitable protecting groups for the amino group in the heterocyclic base are also well known in the art and all of such known groups are contemplated suitable herein. Among other groups, a collection of appropriate 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, it is contemplated that one or more ofthe above-described reactions may be performed while the nucleoside is, covalently coupled to a solid phase. It is generally contemplated that the nucleosides may be coupled to the solid phase at any position (i.e., in the heterocyclic base as well as in the sugar), however, it is especially preferred that the coupling ofthe solid phase to the nucleoside is via the C₅' position in the sugar. Appropriate solid phases 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, however, 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 NH₂ resin (polystyrene-polyethylene glycol copolymer resins available from Rappe Polymere, Tubingen, Germany).

While 8-bromoguanine is generally preferred (among other advantages: commercially available) as a heterocyclic base, it should be recognized that various alternative heterocyclic bases are also appropriate, and especially contemplated heterocyclic bases include those with at least one halogen (preferably Br) in 8-position, a keto group in 6-position, and at least one amino group, preferably in 2-position (e.g., substituted guanines, pyrrolopyrimidines, etc.). Further suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above.

Consequently, with respect to the introduction ofthe substituent in the 8-position of the heterocyclic base, the same considerations as described above in Schemes 7 and 8 apply. Thus, among other reagents, particularly contemplated reagents include all reagents that can form a covalent bond with carbon atom in a Heck reaction (e.g., R-C≡CH). However, alternative reagents also include reagents suitable for a Suzuki (e.g., arylB(OH)₂) or Stille (e.g., arylSnBu₃) reaction. Reaction conditions for all of such reactions are well lαiown in the art (see e.g., Can. J. Chem. (2000), Vol. 78 (7): 957-962, or Tetrahedron (2001) Vol., 57(14): 2787-2789). Especially preferred reagents include R-C≡CH, wherein R is alkyl, alkenyl, alkynyl, aryl, and alkaryl, all of which may further be substituted, and ArSnBu , wherein R is aryl and aralkyl, both of which may further be substituted. It is generally contemplated that almost all such reagents are commercially available. However, where a particular reagent is not commercially available, it should be recognized that such reagents can be prepared from commercially available precursors 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).

Similarly, it is contemplated that appropriate nucleophilic reagents may vary considerably, and it should be recognized that all nucleophilic reagents are suitable so long as such reagents can replace the fluorine atom in the heterocyclic base. However, especially preferred nucleophilic reagents include primary and secondary amines with the general formula RNH₂ or RR"NH, 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. Further contemplated nucleophilic reagents include various thiols (e.g., RSH), alcohols (e.g., R-OH), and Grignard compounds, wherein R is defined as above for the amines. Consequently, it is contemplated that a nucleoside library may comprise a plurality of compounds according to Formula 5, wherein a first compound ofthe plurality of compounds has a first set of substituents A, Ri, R₂, and R'₂ and wherein a second compound ofthe plurality of compounds has a second set of substituents A, R_ls R₂, and R'₂

Formula 5

wherein A is a protected or unprotected sugar covalently bound to a solid phase; Ri , R₂, and R'₂ are independently selected from the group consisting of hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5-membered heterocycle, a 6-membered heterocycle, and a fused heterocycle; and wherein not all ofthe substituents A, R_1; R₂, and R'₂ in the first set are the same as the substituents A, Ri, R₂, and R'₂ in the second set.

Thus, contemplated compounds include compounds according to Formula 5

wherein A is sugar; and wherein Ri , R₂, and R'₂ are independently selected from the group consisting of hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5-membered heterocycle, a 6-membered heterocycle, and a fused heterocycle. Particularly preferred sugars include ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar may be in D-configuration or in L-configuration. 6-substituted Purine Libraries

In a still further aspect ofthe inventive subject matter, the inventors discovered that a 6-substituted purine library can be synthesized from commercially available 6-chloropurine riboside by protecting the OH groups in the sugar and subsequent derivatization ofthe protected 6-chloropurine riboside to the corresponding protected 6-substituted purine using a nucleophilic reagent to replace the halogen (here: Cl) with a desired substituent as depicted in exemplary Scheme 10.

72

Scheme 10

With respect to the sugar, the protecting groups, and the solid phase, the same considerations as described for Scheme 1 above apply. Furthermore, it should be appreciated that while 6-chloropurine is a preferred heterocyclic base, numerous alternative heterocyclic bases are also contemplated, and especially contemplated alternative heterocyclic bases include those described in the section above with the title "Contemplated heterocyclic Bases", so long as such heterocyclic bases (additionally) include at least one halogen, and more preferably at least one chlorine atom. With respect to the nucleophilic reagent, it is contemplated that all reagents are suitable that will replace the leaving group (here: chlorine) in the heterocyclic base. However, particularly contemplated reagents include primary and secondary amines (RNH , RR"NH), alcohols (ROH), or thiols (RSH), wherein R or R" is independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid. Still further contemplated nucleophilic reagents include CN^", N₃ ^", Grignard reagents and reagents with similar reactivity.

Consequently, it is contemplated that a 6-substituted purine library will comprise a plurality of compounds according to Formula 6, wherein a first compound ofthe plurality of compounds has a first set of substituents Rand X wherein a second compound ofthe plurality of compounds has a second set of substituents R and X

Formula 6

wherein A is a protected or unprotected sugar bound to a solid phase; R is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid, X is NHNH, NHOH, S, O, NH, C(O), or a covalent bond; and wherein not all ofthe substituents Rand X in the first set are the same as the substituents Ri and R₂ in the second set.

Thus, a compound may have a structure according to Formula 6 (supra), wherein A is a sugar, R is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid, and X is NHNH, NHOH, S, O, NH, C(O), or a covalent bond.

2,6-Disubstituted Adenine Nucleoside Libraries

In a still further aspect ofthe inventive subject matter, the inventors discovered that various 2,6-disubstituted and 2,6,8-trisubstituted ribofuranosylpurine libraries can be prepared following various synthetic routes. For example, Scheme 11 depicts one exemplary route in which 6-chloroguanosine is iodinized to form the corresponding 6-chloro-2-iodopurihe riboside, which is then coupled (preferably via C₅'-atom ofthe sugar) to a solid phase. In a first derivatization reaction, a first nucleophilic reagent replaces the chlorine atom on the heterocyclic base to form a first product, which is then converted into a second product via a reaction with a second nucleophilic reagent. Cleavage ofthe second product from the solid phase yields the corresponding library nucleosides.

Scheme 11

Alternatively, as depicted in Scheme 12 below, the first product ^lfrom Scheme 11 may be reacted in a C-C bond formation reaction (e.g., Heck, Stille, or Suzuki reaction) to form a second product, which may then be cleaved from the solid phase to yield the corresponding library nucleosides.

Pd(PPh₃)₂CI₂ Pd(PPh₃)₂CI₂ Pd(PPh₃)₂CI₂ TEA 80 °C, 16 h K₂C0₃

80 °C, 16 h. 95 °C, 48 h

Scheme 12

In a still further alternative approach as shown in Scheme 13 below, a protected guanosine is reacted with an electrophile at the amino group ofthe heterocyclic base prior to coupling the protected nucleoside (preferably via C₅'-atom ofthe sugar) to a solid phase. In a further reaction, the keto-oxygen ofthe heterocyclic base is converted into a leaving group (preferably OTIPS). The so prepared compound is then derivatized in a first reaction with an alcohol to form the corresponding N-derivatized nucleoside, which is in a second reaction with a nucleophilic reagent (that replaces the leaving group) further converted to the desired solid phase-bound library nucleoside. Cleavage ofthe so formed nucleoside from the solid phase yields the corresponding library nucleosides.

84 85

86 87

90

Scheme 13

With respect to the sugar, it should be appreciated that the particular nature ofthe sugar is not limiting to the inventive subject matter. Consequently, numerous alternative sugars are also appropriate, and particularly contemplated 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 suitable sugars include those described in the section entitled "Contemplated Sugars", and it is especially contemplated that where the sugar has a C₂' and/or C ' substituent other than a hydroxyl group, such alternative sugars may include hydrogen, a halogen, or an azide group in at least one of these positions (in either alpha or beta orientation). Moreover, the coupling ofthe heterocyclic base to the sugar may be in a position other than the Cι'-position, and it is especially contemplated that where the sugar is a pentose or hexose, alternative positions include the C₂' and C₃'-position.

Consequently, the nature of protecting groups for the sugar may vary considerably, and while it is particularly contemplated that suitable protection groups include acetyl-, benzyl-, 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.

With respect to contemplated heterocyclic bases, it should be appreciated that numerous alternative heterocyclic bases are also appropriate and suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above. It is further contemplated that many ofthe preferred and/or alternative heterocyclic bases are commercially available. However, it should be recognized that where a particular heterocyclic base is not commercially available, suitable bases can be prepared without undue experimentation from commercially available precursors using protocols well known in the art (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).

Especially contemplated alternative heterocyclic bases include those that include a substituent in the 8-position. Suitable substituents for the 8-position may vary considerably and may include halogens, various saturated and unsaturated hydrocarbons (which may or may not be substituted, and may include an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid), CN, esters, ethers, etc. There are numerous 8-substituted purine nucleosides commercially available, and all of these are considered suitable for use herein. Moreover, where a particular 8-substituted purine nucleoside is not commercially available, it is contemplated that such nucleosides may be prepared following protocols well known in the art (e.g., bromination with NBS and subsequent substitution ofthe bromine with desired substituent, or other strategies as described above).

With respect to the nucleophilic reagents of Schemes 11 and 13, it is generally contemplated that all nucleophilic reagents with sufficient reactivity to replace a leaving group in the heterocyclic base are suitable for use herein. However, particularly contemplated reagents include primary and secondary amines (RNH₂, RR"NH), alcohols (ROH), or thiols (RSH), wherein R or R" is independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid. Still further contemplated nucleophilic reagents include CN^", N ^", Grignard reagents and reagents with similar reactivity. Similarly, it should be appreciated that all C-C bond forming reagents are generally considered appropriate as reagents for a synthesis according to Scheme 12. However, especially preferred reagents include reagents suitable for a Heck reaction (e.g., R- CH≡CH), a Stille reaction (e.g., R-Sn), and a Suzuki reaction (e.g., R-B(OH)₂).

In still further aspects, contemplated alcohols of Scheme 13 particularly include primary alcohols with a formula ROH. However, secondary and even tertiary alcohols are also contemplated and have the formulae RR'CHOH and RR'R"COH, respectively, wherein R, R', and R" are independently alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl, or a heterocycle. Consequently, it is contemplated that a 2,6-disubstituted adenine library will comprise a plurality of compounds according to Formula 7, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Y and Z, and wherein a second compound of the plurality of compounds has a second set of substituents A, X, Y and Z

wherein A is a protected or unprotected sugar bound to a solid phase, X is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid, Y is NRR', SR, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, or OR; Z is NRR', SR, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, or OR; wherein R and R' are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, and a heterocycle; and wherein not all ofthe substituents A, X, Y and Z in the first set are the same as the substituents A, X, Y and Z in the second set.

Thus, a compound may have a structure according to Formula 7 (supra), wherein A is a sugar; X is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid; Y is NRR', SR, OR, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, or an unsubstituted alkaryl; Z is NRR', SR, OR, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, or an unsubstituted alkaryl; wherein R and R' are independently selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, and a heterocycle. 6,8-disubstitttted Adenosine Libraries

In a still further aspect, the inventors discovered that 6,8-disubstituted adenosine libraries (and library compounds) can be synthesized, and exemplary synthetic schemes are depicted in Schemes 14-17 below. The introduction ofthe substituent in the 8-position is preferably performed via the corresponding 8-bromoadenosine as shown in Scheme 14. Here, the sugar portion of commercially available 8-bromoadenosine is first protected with suitable protecting groups, and the so protected 8-bromoadenosine is then subjected to a Suzuki reaction to yield the corresponding protected 8-substituted adenosine. Alternatively, 8- bromoadenosine may be subjected to a Stille-type reaction to yield the corresponding 8- substituted adenosine.

Scheme 14

The so prepared 8-substituted adenosine may then be coupled to a solid phase, preferably via the C5'-atom ofthe sugar, as depicted in Scheme 15 below. Further derivatization may then be achieved by reacting the 6-amino group ofthe heterocyclic base with an alcohol to form the corresponding 6,8-disubstituted adenosine, which may then be cleaved from the solid support thereby yielding the desired library nucleoside.

0MMTCI

Pyridine

Scheme 15

Alternatively, the 8-substituent may be introduced as shown in Scheme 16 below. Here, 8-bromoadenosine is reacted with an aromatic thiol (preferably toluene thiol) to form the corresponding 8-S-toluene nucleoside. The so prepared 8-S-toluene nucleoside is then protected on the sugar moiety and the toluene group is replaced with a cyano group that is transformed in several steps to the corresponding 8-methylcarboxylic acid ester. The 8- methylcarboxylic acid ester nucleoside is then coupled to a solid phase and derivatized at the 6-amino group with an alcohol. In a further reaction, the derivatized nucleoside is then reacted with amines to form the desired 6,8-substituted adenosine library nucleosides.

105 106

Scheme 16

Where it is particularly desirable that the 8-substituent in the heterocyclic base is not bound to the heterocyclic base via a carbon atom, an exemplary synthetic route as depicted in Scheme 17 below may be employed. Here, the bromine atom of 8-bromoadenosine is replaced by reacting the nucleoside with a nucleophilic reagent (preferably an alcohol or a thiol) to form the corresponding 8-substituted adenosine, which is then suitably protected at the sugar moiety and the 6-amino group before coupling the protected nucleoside to a solid phase. After coupling to the solid phase, the nucleoside is then further derivatized by reacting the 6-amino group with an alcohol to the corresponding 6,8-disubstituted library nucleoside. Deprotection and cleavage from the solid phase will then yield the desired library nucleoside.

91 113

1) RC1 (BrΛ)

Excess ROH, RSH DIEA DMF, NaOCH₃ 2) Ac₂0, py

114 115

116 X = S or O R = aliphatic or aromatic

X = S or O 119

X= S or O

R = aliphatic or aromatic R, RI = aliphatic or aromatic

Scheme 17 With respect to the sugar, the solid phase, and the protecting groups, the same considerations as described above apply. Similarly, while 8-bromoadenine is generally preferred (among other advantages: commercially available), it should be recognized that various alternative heterocyclic bases are also appropriate, and especially contemplated heterocyclic bases include those with at least one halogen (preferably Br) in the 8-position, and at least one amino group, preferably in the 6-position (e.g., substituted adenines, pyrrolopyrimidines, etc.). Further suitable heterocyclic bases are depicted in the section entitled "Contemplated Heterocyclic Bases" above.

Furthermore, it is contemplated that all reagents lαiown for Heck, Stille, or Suzuki reactions are suitable for the introduction ofthe 8-substituent as described in Scheme 14. Therefore, contemplated reagents include R-C≡C-R', R-C≡CH, R-SnBu₃, and R-B(OH)₂, wherein R and R' are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl or a substituted aryl.

Similarly, it should be appreciated that preferred alcohols for derivatization ofthe 6- amino group as depicted in Schemes 15, 16, and 17 include all primary alcohols with the general formula ROH, wherein R is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl. However, it should be recognized that also secondary (RR'CHOH) and even tertiary (RR'R"COH) alcohols may be suitable for use herein.

Still further, it is contemplated that appropriate nucleophilic reagents for derivatization ofthe 8 -methyl carboxylic acid ester substituent (Scheme 16) may vary considerably, and it should be recognized that all nucleophilic reagents are suitable so long as such reagents can form a covalent bond with the 8-methyl carboxylic acid ester substituent. However, especially preferred nucleophilic reagents include primary and secondary amines with the general formula RNH₂ or RR"NH, 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. Further contemplated nucleophilic reagents include various thiols (e.g., RSH), alcohols (e.g., R-OH), and Grignard compounds, wherein R is defined as above for the amines. Moreover, where the 8-substituent is introduced as depicted in Scheme 17, suitable reagents include all nucleophilic reagents as indicated directly above. Consequently, it is contemplated that a 6,8-disubstituted adenosine library will comprise a plurality of compounds according to Formula 8, wherein a first compound ofthe plurality of compounds has a first set of substituents A, R_ls R₂, and R₃, wherein a second compound ofthe plurality of compounds has a second set of substituents A, Ri, R₂, and R₃

Formula 8

wherein A is a protected or unprotected sugar covalently bound to a solid phase; R_t is R, OR, SR, or C(O)NR₂R₃; R₂ and R₃ 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; wherein R is 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; and wherein not all ofthe substituents R_l5 R₂, and R₃ in the first set are the same as the substituents R_1; R₂, and R₃ in the second set.

Thus, contemplated compounds may include compounds having a structure according to Formula 8 (supra) wherein A is a sugar; Ri is R, OR, SR, or C(O)NR R₃; R₂ and R₃ 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; and wherein R is 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. Preferred libraries and library compounds include those in which 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.

Uses of contemplated libraries and compounds

It is generally contemplated that all libraries will comprise one or more nucleosides that have numerous biological activities, and especially contemplated biological activities include in vitro and in vivo inhibition of DNA and/or RNA polymerases, reverse transcriptases, and ligases. Therefore, contemplated nucleosides will exhibit particular usefulness as in vitro and/or in vivo antiviral agents, antineoplastic agents, or immunomodulatory agents. Still further, it is contemplated that 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. Where modulation of Type 1 and Type 2 cytokines occurs, it is contemplated that the modulation 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.

Where contemplated nucleosides are administered in a pharmacological composition, it is contemplated that suitable nucleosides can be formulated in admixture with a pharmaceutically acceptable carrier. For example, 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). Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose. Of course, one of ordinary skill in the art may modify the formulations within the teachings ofthe specification to provide numerous formulations for a particular route of administration. In particular, 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 ofthe art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics ofthe present compounds for maximum beneficial effect in a patient. In certain pharmaceutical dosage forms, prodrug forms of contemplated nucleosides may be formed for various puposes, including reduction of toxicity, increasing the organ- or target cell specificity, etc. Among various prodrug forms, acylated (acetylated or other) derivatives, pyridine esters and various salt forms ofthe present compounds are preferred. 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. One of ordinary skill in the art will also take advantage of favorable pharmacokinetic parameters ofthe 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 ofthe compound.

In addition, 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 ofthe 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.

Examples

With respect to the exemplary synthetic schemes below, it should be recognized that while these schemes provide a particular sequence of reactions, numerous alternative reaction steps and conditions may be performed. Among other parameters, reaction times, temperatures, and solvent conditions may vary considerably. For example, where a particular reagent or set of reagents is less reactive than the reagent or set of reagents indicated in the schemes, the temperature or concentration may be increased.

Similarly, the sequence of derivatization or derivatizations may be altered where appropriate. Moreover, additional reagents not indicated in the exemplary schemes may be included to obtain a particular nucleoside or nucleoside library. Still further, one or more reactions may be performed on solid support where no solid support is indicated in the schemes described below (or vice versa). Thus, although synthesis of contemplated compounds and libraries preferably employs solid phase combinatorial strategies, it should be appreciated that numerous alternative synthetic strategies, including solution phase and general/medicinal chemistry strategies are also suitable for synthesis of contemplated compounds and libraries.

AICAR (5-Aminoimidazole-4-carboxamide-l-β-4-riboside) Scaffold (Scheme 1)

Compound 2: Compound 1 (2.58 g, 10 mmol) was taken into anhydrous methanol (100 ml) and to this was added sodium methoxide (32 ml). This reaction mixture was heated at 60 °C till it gave a clear solution and then BOC protected amino acid ester (amino acid can have side chain protecting groups cleavable by acid) or any other ester was added and kept stirring for 24 hrs at 60 °C. The reaction was brought to neutral pH by adding Amberlite CG50 resin, filtered and then concentrated to dryness. This was further purified by silica gel column chromatography.

Compound 3. To a solution of compound 2 in dichloromethane was added 50% volume of trifluoroacetic acid. The reaction mixture was stirred for 2 hours and worked up with water. The organic phase was concentrated and the residue was purified by flash chromatography on a silica gel column to provide product 3.

Resin 4. To a solution of compound 2 (1.25 mmol) in anhydrous pyridine (10 ml) was added MMTr-Cl solid support (1 mmol). The resulting mixture was shaken at room temperature for 48 hrs. The resin was filtered and successively washed with DMF, MeOH and CH₂C1₂.

Resin 5. A mixture of resin 4 (0.1 mmol), anhydrous DMF (2 ml), t-butyldimthylsilyl chloride (5 mmol) and imidazole (10 mmol) was shaken at room temperature for 60 hrs. The resin was filtered and successively washed with DMF, MeOH and CH₂C1₂.

Resin 6. To a mixture of resin 5 (0.1 mmol) and anhydrous CH₂C1₂ (2 ml) were added Triisopropylbenzenesulfonyl chloride (0.3 g 1 mmol), DMAP (0.012 gm, 0.1 mmol) and TEA (0.55 ml, 4 mmol). The reaction mixture was shaken at room temperature for 24 hrs. The resin was filtered and washed with DMF, methanol and CH₂C1₂ successively.

Compound 7. A mixture of resin 6 (0.1 mmol) anhydrous NMP containing 1.0 M solution of primary or secondary amine was shaken at 70 °C for 24 hrs. The resin was filtered and then washed successively with DMF, methanol and CH₂C1₂. The resulted resin was further treated by 0.1 M tetrabutylammonium fluoride in THF for 16 hrs to remove the silyl protecting group, and then treated by trimethylsilyl iodide in acetonitrile for 2 hrs to remove the t-Boc protecting group. The final product was cleaved from solid support with 2% TFA in ethylenedichloride.

N²-(Dimethylamino)methyleneguanosine (9) (Scheme 2).

100 g of guanosine (8) was suspended in 1000 ml of anhydrous methanol, and 168 ml of N,N-dimethylformamide dimethyl acetal was added under argon. The suspension was stirred for 4 days at room temperature. The resulting white precipitates were filtered and washed with cold methanol, and dried under reduced pressure to afford pure product 9.

2',3'-Anhydro-N²-(dimethylamino)methyleneguanosine (10): To a suspension of 2-N- (dimethylamino)methyleneguanosine (9) (22 g) in 800 ml of acetonitrile containing 1.2 ml of water was added 36.6 ml of α-acetoxyisobutyryl bromide. The reaction mixture was stirred at room temperature for 2-3 hours resulting in a clear solution. The solvent was removed in vacuo. The white solid was dried over phosphorus pentaoxide in vacuo for 1-2 hours, then dissolved in 250 ml of anhydrous methanol. 80 ml of 25% sodium methoxide in methanol was added to the above solution under argon. The resulting mixture was stirred at room temperature for 40 min and was neutralized with 5% acetic acid to pH 5-6. After cooling, the resulting solid was filtered, washed with cold methanol and dried under reduced pressure to give pure product 10.

2',3'-Anhydro-5'-O-trityl-N²-(dimethylamino)methyleneguanosine (11): To a solution of 2',3^,-anhydro-N2-(dimethylamino)methyleneguanosine (10) (6.4 g) and trityl chloride (8.36 g) in 100 ml of anhydrous DMF was added 21 ml of 2,6-lutidine at room temperature. The resulting solution was stirred at room temperature for 2-3 days. The reaction mixture was poured into 3000 ml of ice water with vigorous stirring. The white solid was filtered and washed with water. The crude product was dissolved in chloroform and the layers were separated. The water phase was extracted with chloroform. The combined chloroform solution was dried over anhydrous sodium sulfate, filtered, and concentrated to a small volume. The concentrated solution was added dropwise to 2000 ml of hexanes with vigorous stirring. The solid was filtered, washed with hexanes and dried in vacuo to provide pure product 11.

3'-Deoxy-5'-O-tritylguanosine (12): A solution of 2',3'-anhydro-5'-O-trityl-N2- (dimethylamino)methyleneguanosine (11) (5.6 g) in 100 ml of dry THF was degassed under argon for 30 min and 100 ml of super-hydride (IM in THF) was added dropwise at 0 °C. The reaction mixture was stirred overnight at room temperature under argon atmosphere. 5% Acetic acid aqueous solution (200 ml) was added dropwise (at the beginning of addition, it must be very slow, drop by drop). The argon or air was passed through the reaction mixture for 1-2 hours. The mixture was concentrated in vacuo to half volume and cooled at 0 °C. The white precipitate was filtered, washed with water and dried over phosphorus pentaoxide in vacuo at 70-80 °C to give product 12.

2'-O-Acetyl-3'-deoxy-5'-O-tritylguanosine (13): To a suspension of compound 12 (5.1 g) and 92 mg of DMAP in a mixture of anhydrous acetonitrile (125 ml) and triethylamine (1.8 ml) was added 1.1 ml of acetic anhydride at room temperature. The reaction mixture was stirred at room temperature for 4-6 hours. The resulting precipitate was filtered and washed with acetonitrile to give pure compounds after drying in vacuo. The filtrate was concentrated in vacuo to small volume, then poured into ice-water with vigorous stirring. The precipitate was filtered and washed with water. The solid was dried in vacuo and recrystallized from methanol to give pure compound 13.

2',N²-Diacetyl-3'-deoxy-5'-O-tritylguanosine (14): To a suspension of 2'-O-acetyl-3'- deoxy-5'-O-tritylguanosine (13) (10 g) in 200 ml of anhydrous pyridine was added 50 ml of acetic anhydride at room temperature. The resulting mixture was stirred at 80 °C for 5 hours and then cooled brown reaction mixture was poured into 2 L of ice-water with vigorous stirring. The resulting precipitate was filtered, washed with cold water, and dried at 80 °C in vacuo to give 10 g of product.

2\N²-Diacetyl-3'-deoxyguanosine (15): 2',N²~O-Diacetyl-3'-deoxy-5'-O- tritylguanosine (14) (10 g) was dissolved in 150 ml of hexafluoroisopropanol in a high- pressure reaction vessel. The reaction mixture was stirred at 80 °C for 3 days and concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using chloroform-methanol (15:1) as an eluent to give pure product 15 as a foam. 2',N²-Diacetyl-3'τdeoxy-5'-O-(4-methoxytritylresin)guanosine (16): To a solution of 2',N²-O-diacetyl-3'-deoxyguanosine (15) (7.0 g, 0.02 mol) in 58 ml of anhydrous pyridine under argon was added 4-methoxytrityl chloride resin (5.78 g, 10 mmol). The resulting mixture was shaken at room temperature for 3 days. The resin was filtered, washed with anhydrous pyridine and dry ether respectively, and then dried over P₂O₅ in vacuo.

2',N²-Diacetyl-3'-deoxy-5'-O-(4-methoxytritylresin)-O⁶-(2,4,6-triisopropyl- benzenesulfonyl)guanosine (17): To a suspension of 2',N²-diacetyl-3'-deoxy-5'-O-(4- methoxytritylresin)guanosine (16) (5.0 g), DMAP (300 mg) and 5 ml of triethylamine in 50 ml of anhydrous dichloromethane was added 2,4,6-triisopropylbenzenesulfonyl chloride (6.0 g) at 0 °C. The resulting mixture was shaken at room temperature for 24 hours. The resin was filtered, washed with dichloromethane and acetone, and dried over P₂O₅ in vacuo.

2-Acetylamino-6-substituted-9-(3-deoxy-β-D-ribofuranosyl)purine (18): 6-Substituted Amines: Benzylamine, morpholine, piperidine, propylamine, octylamine, 2,3- dimethylphenylamine. A mixture of 2 ',N -diacetyl-3'-deoxy-5'-O-(4-methoxytritylresin)-O - (2,4,6-triisopropylbenzenesulfonyl)guanosine (17) (50 mg), 0.75 ml of IM amine in 1-methy- 2-pyrrolidinone, and 0.75 ml of IM diisopropylethylamine (DIPEA) in l-methy-2- pyrrolidinone was shaken at 70 °C for 2 days. The resin was filtered and washed three times with methanol and dichloromethane. The resin was then treated withl .5% TFA in dichloromethane to give the corresponding compound.

6-Substituted Alcohols and phenols: Benzyl alcohol, 4-Chlorophenol: A mixture of 2' ,N²-diacetyl-3 ' -deoxy-5 ' -O-(4-methoxytritylresin)-O⁶-(2,4,6- triisopropylbenzenesulfonyl)guanosine (17) (50 mg), 0.75 ml of IM alcohol or phenol in dichloroethane, and 0.4 ml of IM DABCO in dichloroethane was shaken overnight at room temperature. After 0.3 ml of IM DBU in dichloroethane was added, the resulting mixture was shaken at 70 °C for 2 days. The resin was filtered and washed three times with methanol and dichloromethane. Then, the resin was treated with 1.5% TFA in dichloromethane to give the corresponding compound.

6-Substituted tbio-alcohols and thio-phenols: Cyclohexyl mercaptan, 4- chlorothiophenol: A mixture of 2',N²-diacetyl-3'-dDeoxy-5'-O-(4-methoxytritylresin)-O⁶- (2,4,6-triisopropylbenzenesulfonyl)guanosine (17), (50 mg) 0.75 ml of IM thio-alcohols and thio-phenols in dichloroethane, and 0.75 ml of IM N-methyl-2-pyrrolidine in dichloroethane was shaken at 70 °C for 2 days. The resin was filtered and washed tliree times with methanol and dichloromethane. Then, the resin was treated with 1.5% TFA in dichloromethane to give the corresponding compounds.

2-Amino-6-substituted-amino-9-(3-deoxy-β-D-ribofuranosyl)purine (19): A mixture of 2',N²-Diacetyl-3'-Deoxy-5'-O-(4-methoxytritylresin)-O⁶-(2,4,6- triisopropylbenzenesulfonyl)guanosine (18) (50 mg), 0.75 ml of IM amine in l-methy-2- pyrrolidinone, and 0.75 ml of IM diisopropylethylamine (DIPEA) in l-methy-2-pyrrolidinone was shaken at 70 °C for 2 days. The resin was filtered, washed three times with methanol and dichloromethane. After 1.5 ml of 2M dimethylamine in methanol was added, the mixture was shaken at 70 °C for 24 hours. The resin was filtered and washed three times with methanol and dichloromethane. The resin was treated with 1.5% TFA in dichloromethane to give the corresponding compound.

5-0-Benzoyl-l,2-0-isopropylidene-a-D-xylofuranose (21) (Scheme 3)

To a solution of 1,2-O-isopropylidene-α-D-xylofuranose (20) (90 g, 0.47 mole) in 450 ml of anhydrous pyridine was dropwise added 57.6 ml of benzoyl chloride (0.5 mole) at -10 ~ -20 °C with stirring. The mixture was stirred for an additional 1 hour at -5 ~ -10 °C and then poured into 3.7 L of crushed ice water with vigorously stirring. The resulting precipitate was collected by filtration and washed with cold water. After drying at room temperature by air and then over P₂O₅ in vacuo, 136 g of white solid product 21 was obtained.

3-Deoxy-5-O-bBenzoyl-l,2-O-isopropylidene-α-D-xylofuranose (23): A solution of 5-O-benzoyl-l,2-O-isopropylidene-α-D-xylofuranose (21) (14.7 g, 0.05 mole) and 1,1'- thiocarbonyldiimidazole (13.4 g, 0.075 mole) in 150 ml of anhydrous dichloromethane was refluxed under stirring for 4 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water and the aqueous phase was back- extracted with ethyl acetate. The combined organic phase was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was dried under reduced pressure. A solution ofthe solid thiocarbamate product 22 in 350 ml of anhydrous toluene was degassed with argon for 45 minutes. A solution of AlBN (5.6 g) and tributyltin (17.7 ml) in 200 ml of anhydrous toluene was also degassed with argon in a separate flask for 30 minutes. The tin hydride solution was added dropwise to the refluxing solution of 22 under argon over 30 minutes. The reaction mixture was refluxed under stirring for 4 hours. The solvent was evaporated in vacuo and the residue was partitioned between acetonitrile and hexanes. The acetonitrile portion was washed several times with hexanes. Evaporation ofthe acetonitrile portion gave an oily residue, which was purified by vacuum distillation to give pure product 23 as a colorless oil.

l,2-Di-O-acetyl-5-O-benzoyl-3-deoxy-D-erythropentose (24): To a well stirred solution of 3-deoxy-5-O-benzoyl-l,2-O-isopropylidene-α-D-xylofuranose (23) (18.4 g, 0.066 mole) in 320 ml of glacial acetic acid and 36.4 ml of acetic anhydride was added dropwise 14.9 ml of concentrated sulfuric acid while the temperature ofthe reaction mixture was still kept at 15 - 20 °C. The resulting solution was kept at room temperature overnight, and then poured into 2500 ml of vigorously stirred 10% sodium acetate aqueous solution at 0 °C. After 30 minutes, the mixture was extracted with tliree 300 ml portions of chloroform. The combined organic phase was washed successively with saturated sodium bicarbonate solution (2x900 ml), followed by water (900 ml), and dried over anhydrous sodium sulfate. Evaporation ofthe solvent under reduced pressure at 60 °C gave product 24 as a colorless syrup.

9,N²-Diacetylguanine (26): To a suspension of guanine (25) (15.1 g, 0.1 mole) in 150 ml of anhydrous DMF was added acetic anhydride (30.6 g, 0.3 mole) at room temperature. The mixture was heated at 160 °C for 2 hours to yield a clear solution. The reaction mixture was cooled to 0 °C, and the resulting crystalline was filtered and washed with ethanol to give 20.8 g of product 26 as a white solid.

N²-Acety-6-O-(diphenylcarbamoyl)lguanine (27); Diphenylcarbamoyl chloride (6.37 g, 0.028 mole) was added portionwise to a suspension of 9,N2-diacetylguanine (26) (5.88 g,

0.025 mole) in 8.7 ml of diisopropylethylamine (0.05 mole) and 120 ml of anhydrous pyridine under stirring. The stirring was continued at room temperature for 1 hour and 10 ml of water was added and stirring was continued for 10 minutes. The volatile was evaporated and the residue was co-evaporated with toluene (3 x 20 ml) at 110 °C. The crude product was treated with 1 : 1 mixture of ethanol and water (300 ml) for 1.5 hours. Upon cooling, the product was filtered and washed with 98% ethanol until the washings were colorless. Further drying in vacuo provided 9.1 g of product 27. 9-(2-O-Ace1yl-5-O-berιzoyl-3-deoxy-β-D-ribofuranosyl)-N^z-acety-6-O- (diphenylcarbamoyl)lguanine (28): Bis(trimethylsilyl)acetamide (2.1 ml, 8.4 mmol) was added to a suspension of N²-acety-6-O-(diphenylcarbamoyl)lguanine (27) (1.6 g, 4.2 mmol) in 40 ml of anhydrous dichloroethane, and the resulting reaction mixture in a stopped flask was stirred at 80 °C for 15 min. The clear solution was concentrated, and the residue was dissolved in 20 ml of anhydrous toluene. Trimethylsilyl trifluoromethanesulfonate (1 ml, 5.46 mmol) and a solution of l,2-di-O-acetyl-5-O-benzoyl-3-deoxy-D-erythropentose (24) (1.61 g, 5 mmol) in 20 ml of anhydrous toluene were added. The resulting reaction mixture was stirred at 80 °C for 1 hour. The cooled solution was diluted with 200 ml of ethyl acetate. The solution was washed with saturated sodium bicarbonate solution (2 x 200 ml) and brine (200 ml). The organic phase was dried over sodium sulfate and concentrated. The residue was purified by chromatography on a silica gel column using chloroform as an eluent to give pure product 28 as a foam.

3 '-Deoxyguanosine (29): 9-(2-O-Acetyl-5-O-berιzoyl-3-deoxy-β-D-ribofuranosy )-N²- acety-6-O-(diphenylcarbamoyl)lguanine (28) (1.0 g) was dissolved in 20 ml of saturated ammonia methanol solution at -20 °C with well sealed high-pressure reaction equipment. This resulting reaction mixture was stirred at 80°C for 24 hours, and then cooled to -20 °C. The solvent was removed in vacuo, and the residue was recrystallized from water to give pure product 29 as a white solid.

2',5'-O-Diacetyl-3'-deoxyguanosine (30): To a suspension of 3 '-deoxyguanosine (29) (0.53 g, 2 mmol), DMAP (18.3 mg, 0.15 mmol) and triethylamine (0.74 ml, 5.3 mmol) in 25 ml of anhydrous acetonitrile was added acetic anhydride (0.45 ml, 4.8 mmol) at room temperature. After stirring for 3 hours, 0.25 ml of methanol was added to the mixture and the stirring was continued for an additional 5 min. The reaction mixture was evaporated to dryness, and the residue was recrystallized from methanol to give pure product 30 as a white solid.

2 '-O-Acetyl-3 '-deoxy-5 '-0-trityl-0⁶-(4-methylbenzenesulfonyl) guanosine (42)

(Scheme 5)

Toluene-4-sulfonyl chloride (3.8 g, 20 mmol) was added to a suspension of 2'-O- acetyl-3' -deoxy-5 '-O-tritylguanosine (13) (5.5 g, 10 mmol), triethylamine (2.87 ml, 20 mmol), and DMAP (244 mg, 2 mmol) in 150 ml of anhydrous dichloromethane at 0 °C under argon. The reaction mixture was stirred at room temperature overnight. A clear brown solution was obtained. The reaction mixture was diluted with dichloromethane and washed successively with water and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated to a small volume, and then added to 1000 ml of hexanes with vigorous stirring at room temperature. The resulting precipitate was filtered and washed with hexanes to give product 42 as a white solid.

2-Amino-6-vinyl-9-(2-O-acetyl-3-deoxy-5-O-tri1yl-β-D-ribofuranosyl)purine (43): A solution of 2 ' -O-acetyl-3 ' -deoxy-5 ' -O-trityl-O⁶-(4-methylbenzenesulfonyl)-guanosine (42) (0.71 g, 1 mmol), lithium chloride (85 mg, 2 mmol), and of Pd(PPh₃)₄ (231 mg, 0.2 mmol) in 15 ml of anhydrous dioxane was stirred under argon at room temperature for 10 min. Tributyl(vinyl)tin (1.46 ml, 5 mmol) was added and the mixture was heated under reflux for 4 hours. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on a silica gel column using chloroform-methanol (50:1) as an eluent to give pure product 43 as a yellow foam.

2-Amino-6-substituted-ethyl-9-(2-O-acetyl-5-O-trityl-3-deoxy-β-D- ribofuranosyl)purine (49) (solution phase approach): 6-(2-(amino acid ester)ethyl): L-Cystein ethyl ester, DL-Homocystein, H-Ser-Ome: To a solution of 2-amino-6-vinyl-9-(2-O-acetyl-3- deoxy-5-O-trityl-β-D-ribofuranosyl)purine (43) (1 equiv) in chloroform-methanol (50:1) or ethanol was added amino acid ester (1 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo, and the residue was purified by flash chromatography on a silica gel column using chloroform-methanol (50: 1) as an eluent to give the corresponding pure product.

6-(2-(Substituted-amino)ethyl): aniline, 2,3-methylaniline, 3,4,5-trimethoxyaniline: A solution of 2-amino-6-vinyl-9-(2-O-ace1 l-3-deoxy-5-O-fri1 l-β-D-ribofuranosyl)purine (43) (1 equiv), camphorsulfonic acid (0.5 equiv), and anilines (1.05 eq.) in dichloromethane was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column using chloroform-methanol (50:1) as an eluent to give the corresponding pure product. 6-(2-(Substituted-mercapto)ethyl): thiophenol, isoamyl mercaptan: To a solution of 2- amino-6-yinyl-9-(2-O-acetyl-3-deoxy-5-O-trityl-β-D-ribofuranosyl)purine (43) (1 equiv) in ethanol was added mercaptans (2 equiv) at room temperature. The mixture was stirred at 60 °C for 2 hour. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column using chloroform-methanol (50:1) as an eluent to give the corresponding pure product.

2-Amino-6-vinyl-9-(2-O-ace1 l-3-deoxy-β-D-ribofuranosyl)purine (44): A solution of 2-amino-6-vinyl-9-(2-O-ace1yl-3-deoxy-5-O-tri1yl-β-D-ribofuranosyl)purine (43) in a 1 :1 mixture of formic acid and diethyl ether was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo at room temperature and the residue was chromatographed on a silica gel column using chloroform-methanol (30:l)as an eluent to give the corresponding pure product 44.

Guanosine Libraries

2 ',3 ',5 '-Tri-O-acetyl-8-phenylguanosine (56) (Scheme 7)

A mixture of 2',3',5'-tri-O-acetyl-8-biOmoguanosine (55) (5.7g, 12 mmol), Cul (0.66 g, 3.5 mmol), and triphenylphosphme (0.9 lg, 3.5 mmol) in anhydrous DMF (180 mL) was purged with argon for 30 min. To the reaction mixture were added Pd(OAc)₂ (0.26g, 1.2 mmol) and tributylphenyltin (7.6 mL, 23 mmol). The reaction mixture was heated at 90 °C with stirring under argon for 3 days. The mixture was cooled to room temperature and filtered tlirough a Celite pad. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography on a silic gel column using CH₂Cl₂:MeOH (90:10) as an eluent to yield 4.4 g (79%) of product 56 as a pale yellow foam.

General Procedure for 2-Amino-6,8-disubstituted Purine Riboside Libraries

(Scheme 7)

2',3',5'-Tri-O-acetyl-2-N-PSMMTr -6-oxo-8-ρhenylpurine riboside (57). To a reaction vessel containing MMTrCl resin (0.48 g, 1.73 mmol/g, 0.82 mmol) was added a solution of 56 (0.44 g, 0.91 mmol), triethylamine (0.56 mL, 4.1 mmol), 4- dimethylaminopyridine (56 mg, 0.45 mmol) in anhydrous CH₂C1₂ (4 mL). The reaction mixture was shaken at room temperature for 2 days. The mixture was quenched by the addition of methanol (1 mL), followed by shaking for 30 min. The resin was then filtered, and washed with DMF (3 x 15 mL), MeOH (3 x 15 mL), and CH₂C1₂ (3 x 15 mL). The washed resin was dried in vacuo at 45°C overnight to yield 0.17 g (63%) of product 57.

2-Amino-6-(N-alkyl)-8-phenylpurine riboside (60): To each reaction vessel containing resin nucleoside 57 (70 mg) was added a solution of triethylamine (0.10 mL) and 4-dimethylaminopyridine (9 mg) in anhydrous CH₂C1₂ (1.0 mL). To the mixture was added a solution of triisopropylbenzenesulfonyl chloride (0.10 g) in anhydrous CH₂C1₂ (0.5 mL). After being shaken at room temperature for 24 h, the mixture was filtered. The resin was washed with DMF (3 x 1 mL), MeOH (3 x 1 mL), and CH₂C1₂ (3 x 1 mL) to yield resin nucleoside 58. To each reaction vessel containing the resin 58 was added a 0.5 M solution of appropriate amines in anliydrous l-methyl-2-pyrrolidinone (1.5 mL). The vessels were shalcen at 50 °C for 2 days and cooled down to room temperature. The resin was filtered and washed with DMF (3 x 1 mL), MeOH (3 x 1 mL), and CH₂C1₂ (3 1 mL) to yield resin nucleoside 59. To the resin 59 was added a 2 M solution of methamine in methanol (1.5 mL). After being shaken at room temperature for 30 h, the resin was filtered and washed with DMF (3 x 1 mL), MeOH (3 x 1 mL), and CH₂C1₂ (3 x 1 mL). For cleavage of nucleosides from the resin, a 30% solution of l,l,l,3,3,3-hexafluoro-2-propanol in anliydrous dichloroethane (1.5 mL) was added to each reaction vessel. The vessels were shaken at 50°C for 24 h and the solutions were pushed down into the receiving vessels while keeping the temperature at 50 °C. The reaction vessels were washed with a 1 :1 mixture of MeOH:CH₂Cl₂ (1.5 mL). The combined solution (3 mL) was concentrated to yield product 60.

General Procedure for 2-Amino-6,8-Disubstituted Purine Riboside Libraries

(Scheme 8)

2-Amino-6-alkoxy-8-phenylpurine riboside (64). To each reaction vessel containing nucleoside resin 62 (70 mg) was added a 1.5 M solution of appropriate alcohols in anhydrous THF (0.4 mL). The reaction vessel was cooled to 0 °C. After keeping at 0 °C for 15 min, a solution of triphenylphosphme and diethyl azodicarboxylate (1.5 mL, freshly prepared from 75 mL of 1.0 M Ph₃P in anhydrous THF and 30 mL of 2.0 M DEAD in anhydrous THF) was added. The mixture was shaken at room temperature for 36 h. The resin was filtered and washed with DMF (3 x 1 mL), MeOH (3 x 1 mL), and CH₂C1₂ (3 x 1 mL) to yield resin nucleoside 63. To the resin 63 was added a 2 M solution of methylamine in methanol (1.5 mL). After being shaken at room temperature for 30 h, the resin was filtered and washed with DMF (3 x 1 mL), MeOH (3 x 1 mL), and CH₂C1₂ (3 x 1 mL). For cleavage of nucleosides from the resin, a 30% solution of l,l,l,3,3,3-hexafluoro-2-propanol in anhydrous dichloroethane (1.5 mL) was added to each reaction vessel. The vessels were shaken at 50 °C for 24 h and the solutions were pushed down into the receiving vessels while keeping the temperature at 50 °C. The reaction vessels were washed with a 1 :1 mixture of MeOH:CH₂Cl₂ (1.5 mL). The combined solution (3 mL) was concentrated to yield 64.

General Procedure for 2,8-Disubstituted Guanosine Libraries (Scheme 9)

2-Amino-6-[2-(4-nitrophenyl)ethoxy]-8-phenylpurine riboside (65). To a stirred solution of 61 (4.4 g, 9.1 mmol), 4-nitrophenethyl alcohol (1.7 g, 10 mmol) and triphenylphosphine (2.9 g, 11 mmol) in anliydrous dioxane (150 mL) under argon was added a solution of diethyl azodicarboxylate (1.7 mL, 11 mmol) in anhydrous dioxane (10 mL) dropwise for 1 h. After stirring at room temperature for 22 h, the mixture was concentrated to dryness. The residue was purified by flash chromatography on a silica gel column using CH₂Cl₂:EtOAc (75:25) as an eluent to give 2',3',5'-tri-O-acetyl-2-amino-6-[2-(4- nitrophenyl)ethoxy]-8-phenylpurine riboside as a yellow solid. The product was dissolved in methanolic ammonia (50 mL, saturated) at 0 °C and the solution was stirred at room temperature in a sealed bomb for 15 h. The bomb was cooled to 0°C before opening to the air and the mixture was concentrated. The residue was purified by flash chromatography on a silica gel column using CH₂Cl₂:MeOH (90:10) as an eluent providing 3.1 g (66% for 2 steps) of 65 as a pale foam.

2-Fluoro-6-[2-(4-nitrophenyl)ethoxy]-8-phenylpurine riboside (66): Compound 65 (1.6 g, 3.2 mmol) was dissolved in 60% HF solution in pyridine (130mL) at -50 °C under argon in a polypropylene flask. To the solution was added tert-butyl nitrite (0.56 mL, 4.7 mmol) via syringe over 10 min, while the temperature was maintained at —50 °C. After stirring at -40 °C for an additional 30 min, the mixture was diluted with CHC1₃ (100 mL) and poured into K₂CO₃ (30 g). To the mixture was added H₂O (100 mL) carefully. The aqueous layer was extracted with CHC1₃ (2 x 200 mL) and the combined organic solution was washed with brine (1 x 100 mL), dried with Na₂SO₄, and concentrated to dryness. The residue was purified by flash chromatography on a silica gel column using CH₂Cl₂:MeOH (95:5) as an eluent to yield 1.28 g (79%) of product 66 as a yellow solid. 5'-O-PSMMTr-2-fluoro-6-[2-(4-nitrophenyl)ethoxy]-8-phenylpurine riboside (67): A solution of 66 (7.0 g, 14 mmol) in anhydrous pyridine (45 mL) was added to a reaction vessel containing MMTrCl resin (5.6 g, 1.73 mmol/g, 9.7 mmol). The reaction mixture was shaken at room temperature for 3 days. The mixture was quenched by the addition of methanol (6 mL), followed by shaking for 30 min. The resin was filtered, and washed with DMF (3 x 15 mL), MeOH (3 x 15 mL), and CH₂C1₂ (3 x 15 mL). The washed resin was dried in vacuo at 45 °C overnight to yield 9.8 g (91%) of product 67.

2-(N-Alkyl)-8-phenylguanosine library (68): To each reaction vessel containing 70 mg of resin nucleoside 67 was added a 0.5 M solution of appropriate amines in anhydrous 1- methyl-2-pyrrolidinone (1.6 mL). The vessels were shaken at 60 °C for 4 hrs and then shaken at 80 °C for 20 h to make animation complete. The vessels were cooled down, filtered and washed with DMF (3 x 1 mL), MeOH (3 x 1 mL), and CH₂C1₂ (3 x 1 mL). To each reaction vessel was added a 0.2 M solution of l,8-diazabicyclo[5,4,0]undec-7-ene in anhydrous pyridine (1.5 mL). The vessels were shaken at room temperature for 16 h, filtered and washed with DMF (3 x 1 mL), 10% AcOH in DMF (3 x 1 mL), MeOH (3 x 1 mL), and CH₂C1₂ (3 x 1 mL). For cleavage of nucleosides from the resin, a 30% solution of l,l,l,3,3,3-hexafluoro-2- propanol in anhydrous dichloroethane (1.5 mL) was added to each reaction vessel. The vessels were shaken at 50 °C for 24 h and the solution was pushed down into the receiving vessels while keeping the temperature at 50 °C. The reaction vessels were washed with a 1 : 1 mixture of MeOH:CH₂Cl₂ (1.5 mL). The combined solution (3 mL) was concentrated to yield product 68.

2, 6-Disubstituted Purine Nucleoside Libraires (Scheme 11)

6-Chloro-2-iodoadenosine (75): To a suspension of 74 (20 g, 66.2 mmol), Cul (13.4 g, 87 mmol), CH₂I₂ (53.4 mL, 66.4 mmol) and Iodine (17 g, 66.6 mmol) in THF (500 mL) was added isoamylnitrite (30 mL, 216 mmol) at room temperature. The reaction mixture was heated to reflux for 3 h, cooled to room temperature and filtered. The solvent was evaporated and the residue was purified by flash chromatography on a silica gel column to yield 14.0 g (39%) of product 75.

5'-Resin 76. A solution of 75 (20.0 g, 48.5 mmol) and 2,6-lutidine (7.5 mL) in anhydrous THF (145 mL) was added to a reaction vessel containing MMTCl-resin (17.95 g, 32.3 mmol). The reaction mixture was shaken at room temperature for 64 h. The reaction mixture was quenched by the addition of methanol (10 mL), followed by shaking for 30 min. The suspension was then filtered, and washed with DMF (3x30 mL), MeOH (3x30 mL), and CH₂C1₂ (3x30 mL). The washed resin was dried in vacuo at 45 °C overnight to yield 27.7 g (80%) of product 76.

6-Chloro substitution. (General procedure from more reactive amines for 77a). To a suspension of 76 (70 mg, 65 μmol) in toluene (500 μL) and NMP (500 μL) was added benzylamine (55 μL, 0.5 mmol). The reaction mixture was shaken at 40 °C for 12 hours and filtered. The resin was washed with CH₂C1₂ (3x3 mL), MeOH (3x3 mL), DMF (3x3 mL) and CH₂C1₂ (1x3 mL). The washed resin was dried overnight in vacuo at 45°C to yield 77a.

6-Chloro substitution. (General procedure from less reactive amines for 77b). To a suspension of 76 (70 mg, 65 μmol) in toluene (500 μL) and NMP (500 μL) was added aniline (77 μL, 0.84 mmol). The reaction mixture was shaken at 60 °C for 12 hours and filtered. The resin was washed and dried as 77a to yield 77b.

2-Iodo substitution. (General procedure from more reactive amines for 78a). To a suspension of 77a (65 μmol) in toluene (500 μL) and NMP (500 μL) was added allylamine (150 μL, 2.0 mmol). The reaction mixture was shaken at 80 °C for 3 days and filtered. The resin was washed and dried as 77a to yield 78a.

2-Iodo substitution. (General procedure from less reactive amines for 78b). To a suspension of 77b (0.065 mmol) in toluene (500 μL) and NMP (500 μL) was added amino acetaldehyde dimethyl acetal (218 μL, 2.0 mmol). The reaction mixture was shaken at 95 °C for 3 days and filtered. The resin was washed and dried as 77a to yield 78b.

3-Benzylamino-l-allylamino-7-(β-D-ribofuranosyl)purine (79). (General procedure). A mixture of 78a and hexafluoroisopropanol (HFIP) (400 μL, 30% in DCE) was shaken at 45 °C for 24 h. The suspension was filtered, and the filtrate was evaporated to yield 23 mg (93% for 3 steps) of 79. 2-C,6-Disubstituted Purine Nucleoside Libraries (Scheme 12)

Acetylation for 80. To an anhydrous suspension of 77 (440 mg, 0.40 mmol) in DCM (1800 μL) and pyridine (165 μL, 2 mmol) was added acetic anhydride (190 μL, 2 mmol). The reaction mixture was shalcen at room temperature for 18 h. MeOH (0.5 mL) was added to quench the reaction. The resin solution was filtered, and then washed with CH₂C1₂ (3x3 mL), MeOH (3x3 mL), DMF (3x3 mL) and CH₂C1₂ (1x3 mL). The washed resin was dried in vacuo at 45 °C overnight to yield 80.

General Procedure (Heck) for 81a. To a suspension of 80 (50 mg, 50 μmol) in degassed DMF (1 mL) were added dichlorobis(triphenylphosphine) palladium (II) (Pd(PPh₃)₂Cl₂) (1.75 mg, 2.5 μmol), triethylamine (21 μL, 0.15 mmol), and phenyl acetylene (16.5 μL, 0.15 mmol). The reaction mixture was shaken at 80 °C for 16 h. The suspension was filtered, washed and dried in a similar manner to 80 to yield 81a.

General Procedure (Stille) for 81b. To a suspension of 80 (50 mg, 50 μmol) in degassed DMF (1 mL) was added Pd(PPh₃)₂Cl₂ (1.75 mg, 2.5 μmol) and 2-(tributylstannyl)- furan (47 μL, 0.15 mmol). The reaction mixture was shalcen at 80 °C h for 16 h. The resin solution was filtered, washed and dried in a similar manner to 80 to yield 81b.

General Procedure (Suzuki) for 81c. To a suspension of 80 (50 mg, 50 μmol) in degassed DMF (1 mL) was added 4-phenyl-boronic acid (13 mg, 0.1 mmol), K₂CO₃ (14 mg, 0.1 mmol), and Pd(PPh )₂Cl₂ (3.5 mg, 5 μmol). The reaction mixture was shalcen at 95 °C for 48 h. The resin solution was filtered, washed and dried in a similar manner to 80 to yield 81c.

General Procedure for deprotection (for 82a). A mixture of 81a (50 μmol) and methanolic ammonia (1 mL, saturated at 0 °C) was shaken at room temperature for 16 h. The resin solution was filtered, washed and dried in a similar manner to 80 to yield 82a.

82b and 82c were prepared in the same fashion as described for 82a from 81b and 81c, respectively.

6-(2,2-Dimethoxyethylamino)-2-( henylethynyl)-9-(β-D-ribofuranosyl)purine (83a) (General Procedure for cleavage). A mixture of 82a and hexafluoroisopropanol (HFIP) (1 mL, 30% in DCD was shalcen at 45 °C for 24 h. The solution was then filtered, and the filtrate was evaporated to yield 6.3 mg of 83a.

6-(2,2-Dimethoxyethylamino)-2-(fiιraιι-2-yl)-9-(β-D-ribofuranosyl)purine (83b). This compound was prepared in the same fashion described for 83 a, except 82b was used instead of 82a to yield 7.0 mg of 83b.

6-(2,2-Dimethoxyethylamino)-2-(phenylj-9-(β-Dribofuranosyl)purine (83c). This compound was prepared in the same fashion described for 83a, except 82c was used instead of 82a to yield 17.1 mg of 83c.

2, 6-Disubstituted Purine Nucleoside Libraries (Scheme 13)

, 3', 5'-O-Tri-TBDMS-guanosine (84): Guanosine (8) (25 g, 88.33 mmol, dried at 110 °C, 24 h, high vacuum, with P₂O₅) was suspended in DMF (500 ml) and treated with imidazole (48.2 g, 706.5 mmol) and TBDMSCl (53.2 g, 353.35 mmol). The resulting reaction mixture was stirred at room temperature for 24 h. MeOH was added and the mixture was stirred at room temperature for 20 min. The mixture was concentrated and the resulting syrup was partitioned between EtOAc and aqueous sodium carbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with water, dried, and concentrated to give a syrup, which crystallized (quantitative) upon overnight drying in vacuo.

2-N-Dichloroacetyl-2',3'-O-di-TBDMS-guanosine (85): To a solution of 2',3',5'-O- tri-TBDMS-guanosine (84) (5.0 g, 7.95 mmol) in 1,4-dioxane (30 ml) was added dichloroacetic anhydride (5 ml), and the resulting mixture was stirred at 150 °C for 15 min. The yellow solution was cooled down to room temperature and poured into cold water. The aqueous solution was extracted with DCM (3x50 ml). The organic phase was washed with water (5x20 ml), dried (MgSO₄) and concentrated to give a syrup which was dissolved in THF (30 ml) and treated with 90% TFA aqueous solution (10 ml). The mixture was stirred at room temperature for 2 h, diluted with water and extracted with DCM (3x50 ml). The DCM solution was washed with water, dried (MgSO₄) and concentrated. The residue was purified by flash chromatography on a silica gel column using hexanes:EtOAc (1 : 1 to 0: 1) as eluents to give 3.7 g (75%) for 2 steps) as a yellow foam.

Attachment 85 on solid support: To a mixture of 2-N-dichloroacetyl-2', 3'-O-di- TBDMS-guanosine (85) (900 mg, 1.45 mmol) and DMAP (9 mg) in pyridine (4.3 ml) was added mono-methoxytrityl chloride styrene resin (Nova, 0.537 g, 1.80 mmol/g, 0.967 mmol). The mixture was shaken at room temperature for 48 h. The resin was filtered, washed with pyridine (4x5 ml) and ethyl ether (4x5 ml), and dried in Vacuo in the presence of KOH at room temperature for 4 h to give a brown-yellow resin 86 (1.0 g, 82%).

6-O-Triisopropyl-2-N-dichloroacetyl-2', 3'-O-di-TBDMS-guanosine (87): A mixture of resin 86 (1.0 g, -0.79 mmol) in DCM ( 5 ml) was treated with Et₃N (1.89 ml ), triisopropylbenzenesulfonyl chloride (1.76 g, 5.8 mmol) and DMAP (8 mg). The mixture was shalcen at room temperature for 3 h. The resin was filtered, washed with DMF (4x10 ml), DCM (4x10 ml), dried in vacuo at room temperature for 16 h.

Solid-phase synthesis of 2, 6-disubstituted purine nucleoside library 90. Ninety-six individual reactions were performed in a single 96-well microtiter plate to produce one product per well. For the reaction, 0.05 mmol ofthe MMT-styrene resin 87 bound nucleoside per well served as the scaffold. Twelve amines (10 equiv) in column 1-12 and eight alcohols (10 equiv) in rows A-H were used for the construction ofthe library as follows. The MMT- styrene resin bound nucleoside (3.2 g, 1.5 mmol/g) was partitioned equally into a 96-well polyethylene microtiter plate. DEAD (120 mmol) was added to Ph₃P (240 mmol) in THF/DCM (1 : 1) to malce a solution (DEAD IM, Ph₃P 2M). This solution was left at 0 °C for 1 h and added to each well (1.25 ml each). The alcohols (1 M in DCM, 0.5 ml, 10 equiv) were each added to the appropriate wells. The plate was shalcen at room temperature for 16 h and the wells were drained and washed with DMF (10 ml) and DCM (10 ml). Twelve amines (1 M in DCM, 0.5 ml, 10 equiv) were each added to all the wells containing resin 88. The plate was shalcen at 50 °C for 16 h. The resin was washed with DMF (10 ml), DCM (10 ml), MeOH (10 ml), DCM (10 ml). A solution of methylamine and TBAF in THF (both 1 M) was added to all the wells (10 equiv each). The plate was shalcen at 50 °C for 4 h. The resin was washed liberally with DMF, DCM, MeOH and DCM. The products were cleaved from the resin by 1% TFA in DCM (2 x 600 μl) and washed into a second 96-well plate. The resins were rinsed with DCM (200 μl) and MeOH (200 μl). The combined solution was concentrated under reduced pressure to provide library 90.

6, 8-Disubstituted Adenosine Libraries (Schemes 14 and 15)

8-(Hex-l-ynyl)adenosine (92a): General Procedure (Heck). A solution of 8-bromo adenosine (91) (8.00 g, 23.1 mmol), triphenylphosphme (303 mg, 1.16 mmol), Cul (220 mg, 1.16 mmol) in dry DMF (200 mL) was purged with argon for 30 min. To the reaction mixture were added tris(dibenzylidenacetone)-dipalladium (0) (Pd₂(dba)₃) (635 mg, 0.69 mmol), triethylamine (14 mL, 100 mmol), and 1-hexyne (8.00 mL, 69.3 mmol). The reaction mixture was heated at 60 °C with stirring for 16 h. The reaction mixture was cooled and filtered through a Celite pad. The filtrate was concentrated and co-concentrated with EtOH (25 mL). The residue was suspended in CHC1₃ (15 mL), stirred for 5 min, and filtered to yield 7.3 g (92%) of product 92a.

8-(4-t-Butyl-phenylethynyl)adenosine (92b): This compound was prepared in the same fashion as described for 92a, except that 4-tert-butyl phenyl acetylene was used instead of 1-hexyne.

8-Phenylethynyladenosine (92c): This compound was prepared in the same fashion as described for 92a, except that phenyl acetylene was used instead of 1-hexyne.

8-(Hex-5-ynenitrile)-6-yladenosine (92d): This compound was prepared in the same fashion as described for 92a, except that hex-5-ynenitrile was used instead of 1-hexyne.

8-(3-Methyl-but-l-yne)-l-yladenosine (92e): This compound was prepared in the same fashion as described for 92a, except 3-methyl-but-l-yne was used instead of 1-hexyne.

8-(3-Cyclohexyl-l-propyn)-l-yladenosine (92f): This compound was prepared in the same fashion as described for 92a, except 3-cyclohexyl-l-propyne was used instead of 1- hexyne.

8-(4-Phenyl-butyn)-l-yladenosine (92 ): This compound was prepared in the same fashion as described for 92a, except that phenyl but-3-yne was used instead of 1-hexyne. 8-(Furan-2-yι)-adenosme (92n): General Procedure (Stille). A solution of 91 (8.77 g, 25.3 mmol), triphenylphosphine (681 mg, 2.53 mmol), Cul (481 mg, 2.53 mmol) in dry DMF (200 mL) was purged with argon for 30 min. To this solution was added tris(dibenzylidenacetone)-dipalladium (0) (Pd₂(dba)₃) (1.16 g, 1.27 mmol) and 2- (tributylstannyl)furan (23.9 mL, 76 mmol). The reaction mixture was heated at 105 °C with stirring for 3 days. The cooled reaction mixture was filtered tlirough a Celite pad and the filtrate was concentrated. The residue was purified by flash chromatography on a silica gel column using MeOH:CH₂Cl₂ (20:80) as an eluent to give 5.67 g (67%) of product 92n.

8-Thiophen-2-yladenosine (92o). Tins compound was prepared in the same fashion as described for 92n, except that 2-(tributylstannyl)thiophene was used instead of 2- (tributylstannyl)furan.

8-Methyladenosine (92p): This compound was prepared in the same fashion as described for 92n, except that tetramethyltin was used instead of 2-(tributylstannyl)furan.

8-Phenyladenosine (92q): This compound was prepared in the same fashion as described for 92n, except that tributyl-phenylstannane was used instead of 2- (tributylstannyl)furan.

5'-O-(t-Butyldimethylsilanyl)-8-(hexyn-l-yl)adenosine (93a): General Procedure. To a solution of 92a (3.7 g, 8.01 mmol, 1 equiv) in dry pyridine (3.6 mL/mmol) was added t- butylchlorodimethylsilane (1.1 equiv). The reaction mixture was stirred at room temperature for 16 h and quenched by the addition of EtOH (1 equiv). The mixture was stirred for 30 min and concentrated. The residue was diluted with EtOAc (10 mL/mmol) and the solution was washed withNaHCO₃ (1x10 mL/mmol) and brine (1x10 mL/mmol). The organic phase was dried over anhydrous Na₂SO₄ and concentrated to dryness. The residue was purified by flash chromatography on a silica gel column using EtOH:CHCl₃ (3:97 - 6:94) as eluents to yield 4.5 g (92%) of product 93a.

Compounds 93b-g, 93n-q, 93u were all prepared in a manner similar to 93a, except that 92b-g, 92n-q, 92u was used instead of 92a

2',3'-Di-O-acetyl-5'-O-(t-butyldimethylsilanyl)-8-bromoadenosine (95): To a solution of 91 (20.2 g, 58 mmol) in dry pyridine (250 mL) was added t-butylchlorodimethylsilane (10.6 g, 70 mmol) in small portions for 2 h. After stirring at room temperature for an additional 4 h, the mixture was cooled to 0 °C. Ac₂O (13.1 mL, 139 mmol) was added and the reaction mixture was kept at 4 °C for 12 h. The solution was quenched with EtOH (20 mL) and then concentrated. The residue was diluted in EtOAc (500 mL), washed with aqueous NaHCO (3x30 mL) and brine (1x30 mL). The organic phase was dried over anhydous Na₂SO₄ and concentrated. The residue was purified by flash chromatograhpy on a silic gel column using ethyl acetate as an eluent to yield 22.2 g (70% for 2 steps) of 95.

2',3 '-Di-O-acetyl-5 '-O-(t-butyldimethylsilanyl)-8-(4-fluorophenyl)adenosine (96r) : General Procedure (Suzuki). A solution of 95 (9.92 g, 18.2 mmol), 4-fluorophenyl boronic acid (5.10 g, 36.4 mmol) and Cul (481 mg, 2.53 mmol) in anhydrous DMF (200 mL) was purged with argon for 30 min. To this solution were added [l,l'-bis(diphenylphosphino)- ferrocenjdichloropalladium (II) (PdCl₂(dppf)) (1.99 g, 2.43 mmol) and K₂CO₃ (5.03 g, 36.4 mmol). The reaction mixture was heated at 95 °C with stirring for 2 days. The cooled reaction mixture was filtered through a Celite pad. The filtrate was concentrated. The residue was dissolved in EtOAc (500 mL), which was then washed with water (1x300 mL) and brine (1x300 mL). The organic phase was dried over anhydrous Na₂SO₄ and concentrated to dryness. The residue was purified by flash chromatography on a silica gel column using CH₂Cl₂:EtOAc (50:50 and 0:100) as eluents to yield 5.85 g (57%) of 96r.

2',3'-Di-O-acetyl-5'-O-(t-butyldimethylsilanyl)-8-(p-tolyl)adenosine (96s): This compound was prepared in the same fashion as described for 96r, except that p-tolylboronic acid was used instead of 4-fluorophenyl boronic acid.

2',3'-Di-O-acetyl-5'-O-(t-butyldimethylsilanyl)-8-( biphenyl-4-yl)adenosine (96t): This compound was prepared in the same fashion as described for 96r, except that 4-biphenyl boronic acid was used instead of 4-fluorophenyl boronic acid.

2',3'-Di-O-acetyl-N⁶-acetyl-8-(hexyn-l-yl)adenosine (97a): (General procedure for acetylation). To a suspension of 93a (4.5 g, 9.75 mmol, 1 eq) in dry pyridine (1 mL/mmol) and CH₂C1₂ (8 mL/mmol) was added Ac₂O (15 eq). The reaction mixture was stirred at room temperature for 5 days. To the reaction mixture were added pyridine (0.6 mL/mmol) and EtOH (0.6 mL/mmol), followed by stirring for 30 min. The solution was washed with aqueous NaHCO₃ (4x6 mL/mmol) and brine (1x6 mL/mmol). The organic phase was dried over anhydrous Na₂SO and concentrated to yield 94a. To a solution of 94a in dry THF (5 mL/mmol) was added tetrabutylammonium fluoride (1.2 equiv, IM in THF), which was pre- neutralized (to pH 7) with acetic acid. The reaction mixture was stirred at room temperature for 15 h and then concentrated to dryness. The residue was purified by flash chromatography oh a silica gel column using CH₂Cl₂:EtOAc (50:50, 35:65) as eluents to yield 3.66 g (79% for 2 steps) of 97a.

Compounds 97b-g, 97n-q, 97u all prepared in a manner similar to 97a, except that the 93b-g, 93n-q, 93u was used instead of 93a.

2',3'-Di-O-acetyl-5'-O-(t-butyldimethylsilanyl)-N⁶-acetyl-8-(4-fluorophenyl)- adenosine (94r): To a solution of 96r (5.85 g, 10.4 mmol) in a mixture of anhydrous pyridine (10 mL) and CH₂C1₂ (100 mL) was added Ac₂O (10 mL, 104 mmol). After stirring at room temperature for 5 days, the reaction mixture was quenched with pyridine (10 mL) and EtOH (10 mL). The solution was washed with aqueous NaHCO₃ solution (1x50 mL) and brine (1x50 mL). The organic phase was dried over anliydrous Na₂SO₄ and concentrated. The residue was purified by flash chromatography on a silica gel column using EtOAc-CH₂Cl₂ (50:50) as an eluent to yield 5.22 g (83%) of 94r.

Compounds 94s, 94t were prepared in a manner similar to 94r, except that the 96s, 96t was used instead of 96r.

2',3'-Di-O-acetyl-N⁶-acetyl-8-(4-fluorophenyl)adenosine (97r): To a solution of 94r (5.22 g, 8.67 mmol) in anhydrous THF (5 mL/mmol) was added tetrabutylammonium fluoride (1.2 eq, IM in THF), which was pre-neutralized (to pH 7) with acetic acid. The reaction mixture was stirred at room temperature for 15 h and then concentrated to dryness. The residue was purified by flash chromatography on a silica gel column using CH₂C1₂- EtOAc (50:50, 35:65) as eluents to yield 4.02 g (95%) of 97r.

Compounds 97s, 97t were prepared in a manner similar to 97r, except that the 94s, 94t was used instead of 94r.

2',3'-Di-O-acetyl-N⁶-acetyl-8-(hex-l-yl)adenosine (98h): General Procedure (Hydrogenation). A suspension of 97a (2.68g, 5.66 mmol, 1 eq) and Pd/C (100 mg/mmol, 5%) in MeOH (10 mL/mmol) was shalcen under H₂ atmosphere (30 psi) for 24 h. The mixture was filtered and the filtrate was concentrated to dryness to yield 2.7 g (100%o) of 98h.

2',3'-Di-O-acetyl-N⁶-acetyl-8-[2-(4-t-butylρhenyl)-ethyl]adenosine (98i). This compound was prepared in the same fashion as described for 98h, except 97b was used instead of 97a.

2',3'-Di-O-acetyl-N⁶-acetyl-8-phenethyladenosine (98j). This compound was prepared in the same fashion as described for 98h, except 97c was used instead of 97a.

2',3'-Di-O-acetyl-N⁶-acetyl-8-(5-cyanopentyl)adenosine (98k). This compound was prepared in the same fashion as described for 98h, except 97d was used instead of 97a.

2',3'-Di-O-acetyl-N⁶-acetyl-8-(3-methylbutyl)adenosine (981). This compound was prepared in the same fashion as described for 98h, except 97e was used instead of 97a.

2',3'-Di-O-acetyl-N⁶-acetyl-8-(3-cyclohexylpropyl)adenosine (98m). This compound was prepared in the same fashion as described for 98h, except 97f was used instead of 97a.

2',3'-Di-O-acetyl-5'-O-(4-methoxytrityl resin)-N⁶-acetyl-8-(hexyn-l-yl)adenosine (99a). General Procedure (Resin Loading). A solution of 97a (3.65 g, 1.5 equiv) in anhydrous pyridine (2.6 mL/mmol) was added to a reaction vessel containing MMTCl-resin (2.97 g, 1.73 g/mmol, 1.0 equiv). The reaction mixture was shalcen at room temperature for 2 days and quenched by the addition of MeOH (3 mL). After shaking for 30 min, the mixture was then filtered, and the resin was washed with DMF (3x15 mL), MeOH (3x15 mL), and CH₂C1₂ (3x15 mL). The washed resin was dried in vacuo at 45 °C overnight to yield 5.21 g (100% loading) of 99a.

Compounds 99b-u were all prepared in a manner similar to 99a, except that the 97b-u was used instead of 97a.

2',3'-Di-O-acetyl-5'-O-(4-methoxytrityl resin)-N⁶-acetyl-N⁶-R₁-8-(hexyn-l-yl)- adenosine (100a). General Procedure (Mitsunobu). To a reaction vessel containing 99a (lmmol, -100 mg) were added THF (0.5 mL), PPh₃ (0.80 mL, 1.5 M in THF), R OH (0.75 mL, 1.5 M in THF). The reaction mixture was cooled to -10°C and DEAD (0.5 mL, 2.0 M in THF)) was added. The reaction mixture was stirred at room temperature for 24 h and filtered. The resin was washed with DMF (4x3.0 mL), CH₂C1₂ (3x3.0 mL), MeOH (3x3.0 mL) and CH₂C1₂ (1x3.0 mL). The resin was then dried yielding 100a.

Compounds lOOb-u were all prepared in a manner similar to 100a, except that 99b-u was used instead of 99a.

5'-O-(4-Methoxytrityl resin)-N⁶-Rι-8-(hexyn-l-yl)adenosine (101a). To the resin 100a was added methylamine (3.5 mL, 2M in MeOH). The reaction mixture was stirred at room temperature for 6 h. The solution was filtered, and the resin was washed with DMF (4x3.0 mL), CH₂C1₂ (3x3.0 mL), MeOH (3x3.0 mL) and CH₂C1₂ (1x3.0 mL). The resin was then dried yielding 101a.

Compounds lOlb-u were all prepared in a manner similar to 101a, except that lOOb-u was used instead of 100a.

N⁶-Rr8-(Hexyn-l-yl)adenosine (102a). To the resin 101a was added TFA (3.5 mL, 1.5% in DCE). The reaction mixture was shalcen at room temperature for 5 min and filtered. The resin was rinsed with CH₂Cl₂:MeOH (1:1, 0.5 mL). The filtrate was concentrated, dissolved in methanolic ammonia:CH₂Cl₂:MeOH (1 :6:6, 5 mL) and concentrated again to dryness to yield 102a.

Compounds 102b-u were all prepared in a manner similar to 102a, except that lOlb-u was used instead of 101a.

8-Amidio-6-Alkymanio Aadenosine Libraries (Scheme 16)

8-(4-Methylphenyl)thioadenosine (103). To a solution of 8-Bromoadenosine (91) (70 g, 202 mmol) in methanol (500 ml) were added p-thiocresol (9.3 g, 240 mmol) and triethylamine (60 ml, 400 mmol). The reaction mixture was refluxed overnight. After cooling the resulted yellow crystalline material was filtered, washed thoroughly with methanol and dried to provide 73 g (93%) of product 103.

2', 3', 5'-Tri-O-acetyl-8-(4methylphenyl)thioadenosine (104). To a solution of 8- (4methylphenyl)thioadenosine (103) (72 g, 185 mmol) in anhydrous pyridine (150 ml) was added acetic anhydride (140 ml). The reaction mixture was stirred at room temperature for. 4 h and poured into the ice- water with vigorous stirring. The yellowish precipitate was collected and thoroughly washed with water. The crude product was re-dissolved in CHC1₃ and dried over anliydrous MgSO to remove water. Evaporation ofthe solvent generated 90 g (94%) of product 104.

2', 3', 5'-Tri-O-acetyl-8-(4methylphenyl)sulphonyladenosine (105). Tri-O-acetyl-8-- (4methylphenyl)thioadenosine (104) (80 g, 155 mmol) was dissolved in 80 % acetic acid (600 ml). A solution of KMnO₄ (73.2 g, 462 mmol) in water was added. The reaction mixture was stirred in at room temperature for 5-6 h and decolorized by adding 30 % H₂O₂ solution. The mixture was extracted with chloroform and the chloroform layer was further treated with ice- cooled saturated NaHCO₃ solution and stirred for 3-5 h. The combined organic phase was dried over anhydrous MgSO and evaporated to give 74 g (88 %) of product 105.

8-Carbonylimidomethoxyadenosine (106). 8-(4-Methylphenyl) sulphonyl -2',3',5'-tri- O-acetyladenosine (105) (73 g, 133 mmol) and sodium cyanide (10 g, 200 mmol) were dissolved in DMF and stirred at room temperature for 4.5 h. The reaction mixture was neutralized with IN HCl and extracted with ethyl acetate. The organic phase was dried over anhydrous MgSO₄ and concentrated. The residue (31.5 g crude) was dissolved in anhydrous methanol (200 ml) and 2.5 g of sodium methoxide was added. After stirring at room temperature overnight, the precipitate was filtered and washed thoroughly with methanol to give 31.5 g of product 106.

8-Carbonylmethoxyadenosine (107). A stirred mixture of 8- carbonylimidomethoxyadenosine (106) (30g, 92mmol) in methanol (400ml) and water (IL) was cooled to 0 °C. 1 N HCl was added into the reaction mixture. After stirring at 0 °C for 2 hours, the reaction mixture was neutralized with sodium bicarbonate solution. The precipitate thus obtained was filtered and washed thoroughly with ice cold water and dried to give 21 g (70%) of product 107.

2',3'-O-Acetyl-6-N-acetyl-8-carbonylmethoxyadenosine (108). 8- Carbonylmethoxyadenosine (107) (20 g, 61.53 mmol) was dissolved in dry pyridine and tert- butyldimethylsilylchloride (10 g, 67 mmol) was added. After stirring at room temperature for 6 h, the reaction mixture was poured into the saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous MgSO₄ and concentrated. The residue was purified by flash chromatography on a silica gel column providing 26 g (97%) product. Above product (26 g, 60 mmol) was dissolved in pyridine (70 ml) and dichloromethane (700 ml). Acetic anhydride (70 ml) was added and the reaction mixture was stirred at room temperature for 48 hours. 20 ml more acetic anhydride was added and stirring was continued for 72 hours. The mixture was poured into a saturated sodium bicarbonate solution, extracted with chloroform. The organic phase was dried over anhydrous MgSO and concentrated. The residue was purified by flash chromatography on a silica gel column (24.8 g, 73 %). The above product (24 g, 43 mmol) was dissolved in THF (250 ml) and aceticacid (10 ml). Tetrabutylammoniumflouride (IM solution, 100 ml) was added slowly into the reaction mixture. After stirring at room temperature for 2 hours, the solvent was evaporated and the residue was purified by flash chromatography on a silica gel column to 18.5 g (95%) of pure product 108.

Resin 109. A mixture of 2',3'-O-acetyl-6-N-acetyl-8-carbonylmethoxyadenosine (108) (24 g, 53.2 mmol), anhydrous pyridine (120 ml) and MMTrCl resin (23.5 g, 41.63 mmol) was shaken at room temperature for 36 hours. The mixture was treated with 30 ml of methanol and left for 30 minutes. The resin was filtered off and washed thoroughly with 3X100ml MeOH, 3X100 ml CH₂C1₂, 3X100 ml DMF, 3XmeOH to provide 35.5 g of resin 109 after being dried for two days at 50 °C in the oven.

Resin 110. (Mitsunobu reaction). To each sealed reaction vessel containing ~50 mg (~0.045-0.05 mmol) ofthe loaded resin 109 was added 0.4 mL of 1.5 M alcohols in anhydrous THF. The reaction vessel were cooled to 0 °C (for ACT synthesizer, -10 °C was recommended since heat transfer between the reaction block and the cooling block is not very efficient). After keeping at -10 °C for 15 min, 1.5 mL of Ph₃P/DEAD solution (freshly prepared from 75 mL of 1.0 M Ph₃P in anhydrous THF and 30 mL of 2.0 M DEAD in anhydrous THF) was added. The reaction vessels were shalcen at room temperature for 30-36 h and washed with DMF (3x), with MeOH (3X), and with DCM (3x).

Resin 111. 1.7 mL of 2.0 M amines in DMF was added to each reaction vessel and the reaction vessels were shalcen at room temperature for 16 h for small or reactive primary amines, or at 65 °C for 24 h for large primary or reactive secondary amines. The resins were washed as described above. Adenosine Library 112. To each reaction vessel was added 1.7 mL of 2.0 M methyl amine in methanol. The vessels were shalcen at room temperature overnight (12-16 h). The resins were washed with DMF (3x), with MeOH (3x), with DCM (3x). To each reaction vessel was added 1.0 mL of 1% TFA in DCE. The vessels were shalcen at room temperature for 5 min and 0.5 mL of MeOH was added. The vessels were shaken for 5 min again. 150 mg basic resin (Amberlite IRA-93, supplied by ICN, washed with MeOH) was added to each vessel, which was then shaken for 5 min. The solutions were pushed into the receiving vials. The reaction vessels were washed with 0.5 mL of MeOH/DCM (1:1). Evaporation ofthe solvent provided library 112.

General Procedure for the Solid Phase Synthesis of 8-Thioalkyl/ 8-alkyloxy-6N-alkyl adenosine Libraries (Scheme 17)

5'-O-TBDMS-8-Mercaptoadenosine (113). To a solution of 8-bromoadenosine (91) (10 g, 28.89 mmol) in anhydrous DMF (180 ml) and anhydrous pyridine (20 ml) was added tert-butyldimethylsilylchloride (94.57, 30.33 mmol). The reaction mixture was stirred at room temperature for 3 days, poured into the cold water and left at 0 °C for 2 h. A white solid thus obtained was filtered and re-dissolved in methanol/ethaήol. The solvent was evaporated and the white solid was further dried under vacuum overnight. Crude material (11 g , 24 mmol) was taken in 100 ml DMF. NaSH solution (8.6 M/water; 72 mmol in 8.37 ml) was added. After stirring at room temperature for 24 h, DMF was evaporated under vacuum. To the residue was added water (300 ml) and the resulting mixture was neutralized with 10 % aceticacid /water to pH 4. The precipitate thus obtained was filtered and washed thoroughly with water and dried. Recrystallization from methanol/chloroform gave 10.2 g (85%) of product 113.

General Procedure for the Synthesis of 8-S-Alkyl (aliphatic)adenosine Derivatives 115 ( Procedure A). To a mixture of 5'-O-TBDMS-8-mercatoadenosine (113) (2.9 g, 7 mmol) and N,N-diisopropylethylamine (3.7 ml, 21 mmol) in anhydrous THF (30 ml) was added alkylhalide (eg; allylbromide; 2.78 ml, 21mmol). After refluxing overnight, the mixture was concentrated and the residue was purified by flash chromatography to give desired product 115. 8-(l-Propenyl)thio-5'-O-TBDMS-adenosine was synthesized using the above mentioned procedure. Yield :2.3 g (73 %). 8-(Cyclohexylmethyl)thio-5'-O-TBDMS- adenosine was synthesized using the above mentioned procedure. Yield: 2.7 g (70 %).

General Procedure for the Synthesis of 8-S-Alkyl (aromatic)adenosine Derivatives (Procedure B). A solution of aromatic thiol (20 mmol) and sodium methoxide in methanol (15 mmol) in anhydrous methanol (10 ml) was refluxed for 30 minutes. A solution of 8- bromoadenosine (91) (7.0 g, 20 mmol) in anhydrous DMF (50 ml) was added. The reaction mixture was further stirred for 24 h and concentrated. The residue was re-dissolved in methanol and adsorbed on a silica gel column for purification.

8-(Pyrimidin-2)thio-adenosine was synthesized using the above mentioned procedure. Yield: 79 %

8-(2-Methylthiadiazole-5-thio)-adenosine was synthesized using the procedure described above. Yield: 67%

8-Cyclohexylthio-adenosine was synthesized using the procedure described above. Yield: 56 %

Compound 115. 5'-O-TBDMS-8-S-aryladenosine (10 mmol) in anhydrous pyridine was added tert-butyldimethylsilylchloride (12 mmol). After stirring at room temperature for 8 h, the reaction mixture was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous MgSO and concentrated. The pure compound was obtained by the silica gel column purification. Yield (88-92%).

General Procedure for the Synthesis of 8-O-Alkyl Adenosine Derivatives 114. To a mixture of sodium alkoxide (25 mmol) in anhydrous DMF (30 ml) was added 8- bromoadenosine (91) (20 mmol). The mixture was heated at 90°C for 24 hours and concentrated. The residue was re-dissolved in methanol and adsorbed on a silica gel for column purification.

8-O-Ethyl-adenosine has been synthesized using the procedure described above. Yield. 87% Compound 115. To a solution of 5'-O-TBDMS-8-O-allcyl-adenosine (10 mmol) in anhydrous pyridine was added tert-butyldimethylsilylchloride (12 mmol). After stirring at room temperature for 8 h, the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous ' MgSO₄ and concentrated. The residue was purified by silica gel chromatography to give the desired product 115.

General Procedure for the Synthesis of 8-S/O-alkyl/aryl-2',3'-O-diacetyl-6-N-acetyl Adenosine Derivatives 116. 8-S/O-Alkyl/aryl-5'-O-TBDMS- adenosine (115) (10 mmol) was dissolved in pyridine (7 ml) and dichloromethane (70 ml). Acetic anhydride (10 ml) was added and stirred at room temperature for 48 hours. 2 ml more of acetic anhydride was added and stirring was continued for 72 h. The reaction mixture was poured into a saturated sodium bicarbonate solution and extracted with chloroform. The organic phase was dried over MgSO₄ and concentrated. The residue was purified by silica gel chromatography to yield (68- 75 %).

Compound 117. 5'-O-TBDMS-2',3'-O-diacetyl-6-N-acetyl-8-S/O-allcyl/aryl- adenosine (116) (8 mmol) was dissolved in THF (25 ml) and acetic acid (1 ml). Tetrabutylammoniumflouride (IM solution , 10ml) was added slowly into the reaction mixture. After stirring at room temperature for 2 hours, the solvent was evaporated and the residue was purified by silica gel chromatography to give desired product 117.

The following compounds were synthesized using the procedure described above: 2',3'-O-Diacetyl-6-N-acetyl-8-(l-propenyl)thioadenosine: Yield: 86%. 2',3'-O-Diacetyl-6-N- acetyl-8-S-cyclohexyl-adenosine: Yield: 78%. 2',3'-O-Acetyl-6-N-acetyl-8-O-ethyl- adenosine: Yield: 83%)

Resin 118. 2',3'-O-Diacetyl-6-N-acetyl-8-S/O-allcyl/aryl-adenosine (117) (6 mmol) was dissolved in dry pyridine (20 ml) and MMTrCl resin (5mmol) was added. The mixture was shalcen well at room temperature for 36 hours. The mixture was treated with 10 ml methanol and left for 30 minutes. Resin was filtered off and washed thoroughly with 3X100ml MeOH, 3X100ml CH₂C1₂, 3X100ml DMF, 3XMeOH. The resin 118 was dried for two days at 50 °C in the oven. General Procedure for the Synthesis of Library 119. (Mitsunobu reaction). To each sealed reaction vessel containing ~50 mg (-0.045-0.05 mmol) ofthe loaded resin 118 was added 0.4 mL of 1.5 M alcohols in anhydrous THF. The reaction vessel was cooled to 0 °C. After keeping at -10 °C for 15 min, 1.5, mL of Ph P/DEAD solution (freshly prepared from 75 mL of 1.0 M Ph₃P in anliydrous THF and 30 mL of 2.0 M DEAD in anhydrous THF) was added. The reaction vessels are shalcen at room temperature for 30-36 h and washed with DMF (3x), with MeOH (3X), and with DCM (3x). To each reaction vessel was added 1.7 mL of 2.0 M methyl amine in methanol. The vessels were shaken at room temperature overnight (12-16 h) and washed with DMF (3x), with MeOH (3x), with DCM (3x). To each reaction vessel was added 1.0 mL of 1% TFA in DCE. The vessels were shalcen at rt for 5 min and 0.5 mL of MeOH was added. The vessels were shalcen for 5 min again. 150 mg of basic resin (Amberlite IRA-93, supplied by ICN, washed with MeOH) is added to each vessel, which was then shalcen for 5 min. The solutions were pushed into the receiving vials. The reaction vessels were washed with 0.5 mL of MeOH/DCM (1:1). Evaporation ofthe solvent provided library 119.

Exemplary Amino Acid and Acid Ester Building Blocks for Scheme 1

Boc-Alanine-OH, N-_α-Boc-N_α-methyl-alanine-OH, Boc-NH-(CH₂)„-COOH, Boc- arginine(MMTr)-OH , Boc-aspargine(MMTr)-OH, Boc-cyclohexylalanine-OH, Boc- cysteine(MMTr)-OH, Boc-glutamine(MMTr)-OH, Boc-glycine-OH, Boc-histidine(MMTr)- OH, Boc-leucine-OH, Boc-lycine(Boc)-OH, Boc-methionine-OH, Boc-norleucine-OH, Boc- norvaline-OH, Boc-phenylalanine-OH , Boc-phenylglycine-OH, Boc-proine-OH, Boc- sarcosine-OH, Boc-serine(OtBu)-OH, Boc-threonine(tBu)-OH, Boc-tryptophan(Boc)-OH, Boc-tyrosine(tBu)-OH, Boc-valine-OH, as well as other natural and non-natural amino acids.

Methyl cyclopropane carboxylate, ethyl cyclobutane carboxylate, methyl cyclohexane carboxylate, methyl cyclohexanepropionate, methyl acrylate, methyl methacrylate, methyl crotonate, methyl 3,3-dimethylacrylate, methyl trans-3-pentenoate, ethyl 2-methyl-4- pentenoate, methyl 1-cyclopentene-l -carboxylate, methyl 1-cyclohexylmethyl 1- methoxybicyclo[2,2,2]-oct-5-ene-2-carboxylate, ethyl 1-piperadineacetate, ethyl 1- piperadinepropionate, ethyl 1-methylnipecotate, ethyl 1 -methyl- 1,2,3, 6-tetrahydro-4- pyridinecarboxylate, methyl 4-marpholinepropionate, methyl pyruvate, methyl acetoacetate, methyl 2-oxocyclopentanecarboxylate, ethyl 2-cyclohexanonecarboxylate, ethyl 3-(l- adamantyl-3-oxopropionate, methyl 2-oxo-l-cycloheptanecarboxylate, methyl 2-oxo-l- ^' cyclooctanecarboxylate, methyl phenylacetate, methyl diphenylacetate, methyl 2,3,4,5,6- pentafluorophenylacetate, methyl 4-methoxyphenylacetate, methyl 1-naphtaleneacetate, methyl 2-nitrobenzoate, methyl 3-nitrobenzoate, methyl 4-nitrobenzoate as well as other aliphatic/aromatic /hetercyclic carboxylic acids.

Exemplary Amino Building blocks (R-Nfyor RNHR) used for Libraries

l-(Benzyl)benzylamine, 2-phenyl-n-propylamine, m-trifluorobenzylamine, 2,2- diphenylethylamine, cyclobutylamine, methylcyclohexylamine, 2-methylpropylamine, allylcyclopentanylamine, N-methyl-4-piperidinylmethylamine, 4-hydroxypiperidine, 3- hydroxypiperidine, 1-benzylpiperazine, p-methoxybenzylamine, N,N- bis(isopropyl)aminoethylamine, 2-ethylhexylamine, 5-methyl-2-furanosylmethylamine, N,N- dimethylaminopropylamine, 3 -(N,N-dimethylamino)-2,2-dimethylpropylamine, 2- methylbutylamine, o-ethoxybenzylamine, 3-(2-methyl-N-piperidinylpropylamine, l-(2- aminoethyl)pyrrolidine, 2-morpholinylethylamine, N4-hydroxyethylpiperazine, N- methylethylenediamine, 3-morpholinylpropylamine, pyridinyl-2-ethylamine, butylamine, hexylamine, methylamine, 2-hydroxyethylamine, N,N-dimethylethylenediamine, 3- methoxypropylamine, 2-methoxylethylamine, ethylamine, 2-isopropylamine, methylethylamine, 2-methylthioethylamine, di-n-butylamine, dimethylamine, allylamine, cyclopantylamine, 2-(N-methyl-pyrrolidin-2-yl)ethylamine, tetrahydrofuranosyl-2- methylamine, piperidine, N-benzyl-4-aminopiperidine, aminomethylcyclopropane, cyclopropylamine, 3-methylpiperizine, 4-piperidin-l-ylpiperidine, cyclohexylamine, piperazine, 4-pyridin-2-ylpiperazine, 1-methylpiperazine, N-(2-methoxyphenyl)piperazine, N- pyrimidin-2-ylpiperazine, cycloheptylamine, p-trifluorobenzylamine, benzylamine, 3- imidazol-1-ylpropylamine, exo-2-aminonorborane, N-phenylethylenediamine, 1- methylbenzylamine, 3,4-(l,3-dioxolanyl)benzylamine, pyridin-2-ylmethylamine, pyridin-3- ylmethylamine, pyridin-4-ylmethylamine, thiophen-2-ylmethylamine, 3,3- dimethylbutylamine, o-methoxybenzylamine, l-(3-aminopropyl)pyrrolidin-2-one, N- methylethylenediamine, m-methylbenzylamine, 3-methylbutylamine, 2-methylbutylamine, heptylamine, 3-butoxypropyamine, 3-isopropoxypropylamine, 2-morpholin-4-ylpropylamine,

N 1 ,N 1 -diethylethylenediamime, 2-ethylthioethylamine, 4-(2-aminoethyl)phenol, furfurylamine, 4-aminomethylpiperidine, 2-(2-aminoethyl)pyridine, 2-phenoxyethylamine, 2- aminoethylthiophene, p-methoxybenzylamine, 2-(N,N-dimethylamino)ethylamine, 1-amino- 2-propanol, 5-methylfurfurylamine, 3-(dimethylamino)propylamine, o-methoxybenzylamine, l-(3-aminopropyl)-2-pipecoline, hydrazine, 4-hydroxypiperidine, ethylenediamine, 1,4- diaminobutane, N-methylpropylamine, trans- 1,4-diaminocyclohexane, 2,2,2- trifluoroethylamine, 3-chloropropylamine, 3-ethoxypropylamine, aminoacetaldehyde dimethyl acetal, 3-amino-l,2-propanediol, l,3-diamino-2-hydroxypropane, 1- aminopyrrolidine, 2-(2-aminoethyl)-l-methylpyrrolidine, 3-methylpiperidine, 2-piperidine methanol, 3-piperidine methanol, 1-aminohomopiperidine, homopiperazine, 4- aminomorpholine, 3-bromobenzylamine, piperonylamine, 1,2,3,4-tetrahydroisoquinoline, L- pro line methyl ester, l-(2-pyridyl)piperazine, 4-(2-aminoethyl)morpholine, l-(2- aminoethyl)piperidine, 3-aminopropipnitrile, 3-(aminomethyl)pyridine, 2- (aminomethyl)pyridine, thiomorpholine, l,4-dioxa-8-azaspiro(4,5)-decane, 2- hydroxylethylamine, l-(2-aminoethyl)pyrrolidine, aminomethylcyclohexane, 2- hydroxymethylpyrrolidine, 3-amino-l,2-propanediol acetone ketal, N-(2- hydroxyethyl)piperazine, N-phenylethylenediamine, 4-amino-2,2,6,6-tetramethylpiperidine, N-(4-nitrophenyl)ethylenediamine, 1 ,2-diphenylethylamine, 1 -(N,N-dimethylamino)-2- propylamine, 2-phenylpropylamine, 2-methylcyclopropylamine, 2-methylaziridine, aminomethylcyclopropane, l-aminomethyl-2-methylcyclopropane, butten-3-ylamine, 3- methyl-buten-2-ylamine, 3-methyl-buten-3-ylamine, 4-aminomethyl-l-cyclohexene, 3- phenylallylamine, 2,2-dimethylethylenediamine, 3-ethylhexylamine, 3-(N,N-dimethylamino)- 2,2-dimethylpropylamine, 2-methyl-N-aminopropylpiperidine, as well as other related aliphatic and aromatic primary and secondary amines that are good nucleophiles to react with leaving groups on the scaffolds.

Exemplary Building Blocks for C-C Bond Formation on the Heterocycles of Contemplated Nucleoside Libraries

' For Heck Reaction: 2-ethynylpyridine, 5 -phenyl- 1-pentyne, 4-(tert- butyl)phenylacetylene, phenylacetylene, 3-dibutylamino-l-propyne, phenyl propargyl ether, 5- chloro- 1-pentyne, 3-diethylamino-l-propyne, 4-phenyl-l-butyne, 1-heptyne, 1- dimethylamino-2-propyne, 1-pentyne, 2-methyl-l-hexene, (triethylsilyl)acetylene, 3 -phenyl- 1- propyne, methyl propargyl ether, 3-cyclopentyl-l-propyne, 1-ethynylcyclohexene, 3-butyn-l- ol, styrene, vinylcyclohexane, 2-(tributylstannyl)furan, 2-(tributylstannyl)thiophene, tetraphenyltin, 3-cyclohexyl-l-propyne, 4-methoxyphenylacetylene, 4-

(trifluoromethyl)phenyleneacetylene, 4-fluoroρhenylacetylene, 4-pentayn-l-ol, 4- methylphenylacetylene, 1-ethynylcyclopentanol, 3 -methyl- 1-propyne, 5-cyano-l-pentyne, cyclohexylethyne, 1-ethynylcyclohexene, 5-cyano-l-pentyne, l-dimethylamiho-2-propyne, N- methyl-N-propargylbenzylamine, 2-methyl-l-buten-3-yne, cyclopentylethyne, 4- nitrophenylacetylene, phenyl propargylsulfide, 4-methyl- 1-pentyne, propargyl ethylsulfide, 2- prop-2-ynyloxybenzothiazole, 4-ethoxy-l-prop-2-ynyl-l,5-dihydro-2H-pyrrol-2-one, 6- methyl-5-(2-propynyl)-2-thioxo-2,3-dihydro-4(lH)-pyrimidinone and related end-alkenes and alkynes.

For Stille Reaction: tetraethyltin, 2-(tributylstannyl)pyridine, tributylstannyl-4-t- butylbenzene, ethynyltri-n-butyltin, vinyltri-n-butyltin, allyltri-n-butyltin, phenylethynyltri-n- butyltin, phenyltri-n-butyltin, (2-methoxy-2-cyclohexen-l-yl)tributyltin, 5,6-dihydro-2- (tributylstannyl)-4H-pyran, tri-n-butyl(2-furanyl)tin, tri-n-butyl(2-thienyl)tin, tributyl(phenylethenyl)tin, 4-fluoro-(tri-n-butylstannyl)benzene, 5-fluoro-2-methoxy(tri-n- butylstannyl)benzene, 1 -methyl-2-(tributylstannyl)-lH-pyrrole, 5-methyl-2- tributylstannylthiophene, 2-tributylstannylthiazole, 2-trybutylstannylpyrrazine, tributyl[3- (trifluoromethyl)phenyl]stannane and other related organic tin reagents.

For Suzuki Reaction: phenylboronic acid, 4-tolylboronic acid, 2-thiopheneboronic acid, thiophene-3 -boronic acid, furan-2-boronic acid, cyclopentylboronic acid, 4-methylfuran- 2-boronic acid, 3-hydroxyphenyl)boronic acid, 5 -methylfuran-2 -boronic acid, 3- cyanophenylboronic acid, 4-cyanophenylboronic acid, (5-fornyl-3-furanyl)boronic acid, furan-3 -boronic acid and other related organic boronic acids.

Exemplary Building Blocks ROH for Mitsunobu Reaction

1-Butanol, 4-nitrophenethyl alcohol, 4-chlorobenzyl alcohol, 1-propanol, 4- nitrobenzyl alcohol, 4-methylbenzyl alcohol, .2-butanol, benzyl alcohol, 2-methyl-l-propanol, crotyl alcohol, 2-norbornanemethanol, 2-methylcyclopropane-methanol, 3-buten-l-ol, neopentyl alcohol, cyclohexylmethanol, 4-trifluorobenzyl alcohol, 3-methyl-2-butem-l-ol, cyclopentanemethanol, 3-methyl-3-buten-l-ol, 4-methyl- 1-pentanol, 3-chlorobenzyl alcohol, 3 -cyclohexane-1 -methanol, 3,3-dimethylbutanol, 3-trifluorobenzyl alcohol, cinnamyl alcohol, tetrahydrofurfuryl alcohol, ethanol, cyclopropyl alcohol, l-methyl-3-piperidinemethanol, decahydro-2-naphthol, 9-decen-l-ol, 3 -cyclopentyl- 1-propanol, l-methyl-2- pyrrolidineethanol, 3-methylbenzyl alcohol, 3-fluorobenzyl alcohol, 3-phenoxybenzyl alcohol, 4-isopropylbenzyl alcohol, 4-methoxybenzyl alcohol, 3,4-dimethoxybenzyl alcohol, 3,5-dimethylbenzyl alcohol, 4-benzyloxybenzyl alcohol, 2-phenylethanol, 4-fluorobenzyl alcohol, phenoxyethanol, benzyloxyethanol, 1-pentanol and 3-pentanol as well as aliphatic/aromatic/heterocyclic primary and secondary alcohols. The above compounds having an -SH group instead of an OH group have been used as thiol-containing building blocks for library synthesis.

Thus, specific embodiments and applications of substituted purine nucleoside libraries and compounds have been disclosed. It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit ofthe appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms "comprises" and "comprising" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced.

Claims

CLAIMSWhat is claimed is:

1. A nucleoside library comprising: a first library compound and a second library compound, wherein each ofthe first and second compounds comprises a sugar that is covalently bound to a purine having a substituent in the 2-position; wherein the substituent ofthe purine has a carbon atom that forms a covalent bond with the 2-position ofthe purine; and wherein the first library compound and the second library compound are chemically distinct.

2. The nucleoside library of claim 1 wherein the carbon atom in the substituent forms a chiral center.

3. The nucleoside library of claim 2, wherein the 2-C-substituted purine is formed by reacting a compound selected from the group consisting of an amino acid, an alkyl carboxylic acid, an arylcarboxylic acid, an alkenylcarboxylic acid, an alkynylcarboxylic acid, and a heterocyclic carboxylic acid with a 5-amino-4- imidazolylcarboxamide that is covalently bound to the sugar.

4. The nucleoside library of claim 1 wherein the first library compound has a structure according to Formula IA with a first set of substituents A, X, Y, Ri, R₂, R₃, and R₄, wherein the second library compound has a structure according to Formula 1 A with a second set of substituents A, X, Y, R_ls R₂, R₃, and _t

Formula IA

wherein A is a protected or unprotected sugar covalently bound to a solid phase;

X is O, S, NH, NHNH, NHO, or CH₂;

Y is CH₂ orNH; Ri, R₂, R , and j 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, a substituted aryl, CN, N , CF , COOH, NHR, and NHNHR; wherein R is selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl; and wherein not all ofthe substituents A, X, Y, R_ls R₂, R₃, and R₄ in the first set are the same as the substituents A, X, Y, Ri, R₂, R , and R in the second set.

5. The nucleoside library of claim 4 wherein 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.

6. The nucleoside library of claim 1 wherein the first library compound has a structure according to Formula IB with a first set of substituents A, D, E, X, R_ls R₂, R₃, and R₄, wherein the second library compound has a structure according to Formula IB with a second set of substituents A, D, E, X, Rr, R₂, R₃, and j

X is O, S, NH, alkyl, aryl, alkenyl, alkynyl, or alkaryl;

D=E is C=C, C=N, N=C, or N=N;

Ri, R₂, R , and R₄ 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, a substituted aryl, CN, N₃, CF₃, COOH, NHR, and

NHNHR; wherein R is selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl; and wherein not all ofthe substituents A, D, E, X, R_l5 R₂, R₃, and R in the first set are the same as the substituents A, D, E, X, R_l5 R₂, R₃, and _t in the second set.

7. The nucleoside library of claim 6 wherein 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.

8. A compound comprising a sugar that is covalently bound to a purine having a substituent in a 2-position, wherein the substituent ofthe purine has a carbon atom that forms a covalent bond with the 2-position ofthe purine, with the proviso that the 2-C-substituent is not -C≡C-R, with R being alkyl or substituted alkyl.

9. The compound of claim 8 wherein the carbon atom in the substituent forms a chiral center.

10. The compound of claim 9 wherein the 2-C-substituted purine is formed by reacting a compound selected from the group consisting of an amino acid, an alkyl carboxylic acid, an arylcarboxylic acid, an alkenylcarboxylic acid, an alkynylcarboxylic acid, and a heterocyclic carboxylic acid with a 5-amino-4-imidazolylcarboxamide that is covalently bound to the sugar.

11. The compound of claim 8 having a structure according to Formula 1 A

wherein A is a sugar;

X is O, S, NH, NHO, NHNH, or CH₂;

Y is CH₂ or NH; and

Ri, R₂, R₃, and t 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, a substituted aryl, CN, N₃, CF₃, COOH, NHR, and NHNHR; and wherein R selected from the group consisting of an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, a substituted aryl.

12. The compound of claim 11 wherein 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.

13. The compound of claim 8 having a structure according to Formula IB

wherein A is a sugar;

D=E is C=C, C=N, N=C, or N=N;

X is O, S, NH, alkyl, aryl, alkenyl, alkynyl, or alkaryl; and

R_la R₂, R₃, and _t 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, a substituted aryl, CN, N₃, CF₃, COOH, NHR, or

NHNHR; and wherein R is 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.

14. The compound of claim 13 wherein 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.

15. A nucleoside library comprising a plurality of library compounds according to Formula 2 A, wherein a first compound ofthe plurality of compounds has a first set of substituents X and R and wherein a second compound ofthe plurality of compounds has a second set of substituents X and R a 2A

QPG wherein X is NR, S, O, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl;

R is 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; or XR together are R-Y-R', wherein R and R' are independently an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, R' is hydrogen, an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, and wherein Y is NH, NR, S, O, or CH₂;

NH^PG is a protected amino group, O^PG is a protected hydroxyl group, and • is a solid phase; and wherein not all ofthe substituents X and R in the first set are the same as the substituents X and R in the second set.

16. A compound according to Formula 2B

Formula 2B

OH wherein X is NR, S, O, or CH₂; and R is selected from the group consisting of hydrogen, an allcyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl; or XR together are R-Y-R', wherein R and R' are independently an allcyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, R' is hydrogen, an allcyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, or a substituted aryl, and wherein Y is NH, NR, S, O, or CH₂.

17. A nucleoside library comprising a plurality of library compounds according to

Formula 2C, wherein a first compound ofthe plurality of compounds has a first set of substituents X, Y, and R, and wherein a second compound ofthe plurality of compounds has a second set of substituents X, Y, and R

Formula 2C

QPG wherein X is NR, S, O, allcyl, substituted allcyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl; Y is hydrogen, C(O)R, C(NH)R, or C(S)R'; R and R' are independently selected from the group consisting of hydrogen, an alkyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl; O^PG is a protected OH, and • is a solid phase; and wherein not all ofthe substituents X, Y, and Rin the first set are the same as the substituents X, Y, and R in the second set.

18. A compound according to Formula 2D Formula 2D

OH wherein X is NR, S, O, allcyl, substituted allcyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl; Y is hydrogen, C(O)R', C(NH)R', or C(S)R'; and R and R' are independently selected from the group consisting of hydrogen, an alkyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl.

19. A nucleoside library comprising a plurality of library compounds according to,

Formula 3, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Ri and R₂ and wherein a second compound ofthe plurality of compounds has a second set of substituents A, X, Ri and R₂

Formula 3

X is NH, S, O, CH, CH₂CH₂NH, or NHNH;

Ri is selected from the group consisting of hydrogen, a substituted allcyl, an unsubstituted allcyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle;

R₂ is selected from the group consisting of hydrogen, an alkyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl; and wherein not all ofthe substituents A, X, Ri and R₂ in the first set are the same as the substituents A, X, Ri and R₂ in the second set.

20. The nucleoside library of claim 19 wherein 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.

21. The nucleoside library of claim 20 wherein X is NH or NHNH, and wherein Ri is a cyclic allcyl or aryl.

22. A compound according to Formula 3

Formula 3

wherein A is a sugar;

X is NH, S, O, CH, CH₂CH₂NH, or NHNH;

Ri is selected from the group consisting of hydrogen, a substituted allcyl, an unsubstituted allcyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle; and

R₂ is selected from the group consisting of hydrogen, an allcyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl.

23. The compound of claim 22 wherein 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.

24. The compound of claim 23 wherein X is NH or NHNH, and wherein Ri is a cyclic allcyl or aryl.

25. A nucleoside library comprising a plurality of library compounds according to

Formula 4, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Ri and R₂, and wherein a second compound ofthe plurality of compounds has a second set of substituents A, X, Ri and R₂

Formula 4

wherein A is a protected or unprotected sugar;

X is NH, S, O, CH, CH₂CH₂NH, or NHNH;

Ri is selected from the group consisting of hydrogen, a substituted allcyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle;

R₂ is 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 ofthe substituents A, X, R_\ and R₂ in the first set are the same as the substituents A, X, Ri and R₂ in the second set.

26. The nucleoside library of claim 25 wherein 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.

27. The nucleoside library of claim 26 wherein X is O.

28. A compound according to Formula 4 A

Formula 4A

wherein A is a sugar;

X is NH, S, O, CH, CH₂CH₂NH, or NHNH;

Ri is selected from the group consisting of hydrogen, a substituted alkyl, an unsubstituted allcyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle; and

R₂ is selected from the group consisting of hydrogen, an alkyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, an aryl, and a substituted aryl.

29. The compound of claim 28 wherein 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.

30. The compound of claim 29 wherein X is O.

31. A nucleoside library comprising a plurality of library compounds according to Formula 5, wherein a first compound ofthe plurality of compounds has a first set of substituents A, Ri, R₂, and R'₂ , wherein a second compound ofthe plurality of compounds has a second set of substituents A, Ri, R₂, and R'₂

Rj , R₂, and R'₂ are independently selected from the group consisting of hydrogen, a substituted allcyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle; and wherein not all ofthe substituents A, R_ls R₂, and R'₂ in the first set are the same as the substituents A, R_l5 R₂, and R' in the second set.

32. The nucleoside library of claim 31 wherein 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.

33. A compound according to Formula 5

Formula 5

wherein A is a sugar; and

R\ , R₂, and R'₂ are independently selected from the group consisting of hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle.

34. The compound of claim 33 wherein 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.

35. A nucleoside library comprising a plurality of library compounds according to Formula 6, wherein a first compound ofthe plurality of compounds has a first set of substituents X and R, and wherein a second compound ofthe plurality of compounds has a second set of substituents X and R

Formula 6

wherein A is a protected or unprotected sugar bound to a solid phase; X is NHNH, NHOH, S, O, NH, C(O), or a covalent bond; R is hydrogen, an allcyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid; and wherein not all ofthe substituents Rand X in the first set are the same as the' substituents Ri and R₂ in the second set.

36. A nucleoside library comprising a plurality of library compounds according to

Formula 7, wherein a first compound ofthe plurality of compounds has a first set of substituents A, X, Y and Z , and wherein a second compound ofthe plurality of compounds has a second set of substituents A, X, Y and Z

Formula 7

wherein A is a protected or unprotected sugar bound to a solid phase;

X is hydrogen, an allcyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid; Y is NRR', SR, OR, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, or an unsubstituted alkaryl; Z is NRR', SR, OR, a substituted alkyl, an unsubstituted allcyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, or an unsubstituted alkaryl; wherein R and R' are independently selected from the group consisting of hydrogen, an allcyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, and a heterocycle; and wherein not all ofthe substituents A, X, Y and Z in the first set are the same as the substituents A, X, Y and Z in the second set.

37. The nucleoside library of claim 36 wherein 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.

38. A compound according to Formula 7

Formula 7

wherein A is a sugar bound to a solid phase;

X is hydrogen, an allcyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, a heterocycle, or an amino acid; Y is NRR', SR, OR, a substituted allcyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, or an unsubstituted alkaryl; Z is NRR', SR, OR, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substituted aryl, an unsubstituted aryl, a substituted alkaryl, or an unsubstituted alkaryl; and wherein R and R' are independently selected from the group consisting of hydrogen, an allcyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, a substituted alkynyl, and a heterocycle.

39. The compound of claim 38 wherein 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.

40. A nucleoside library comprising a plurality of library compounds according to Formula 8, wherein a first compound ofthe plurality of compounds has a first set of substituents A, Ri, R₂, and R₃, and wherein a second compound ofthe plurality of compounds has a second set of substituents A, Ri, R₂, and R₃

Formula 8

Ri is R, OR, SR, or C(O)NR₂R₃;

R₂ and R are independently selected from the group consisting of hydrogen, an alkyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl; wherein R is selected from the group consisting of an allcyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl; and wherein not all ofthe substituents Ri, R₂, and R₃ in the first set are the same as the substituents Ri, R₂, and R₃ in the second set.

41. The nucleoside library of claim 40 wherein 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.

42. A compound according to Formula 8

Formula 8

wherein A is a sugar;

R_t is R, OR, SR, or C(O)NR₂R₃;

R₂ and R are independently selected from the group consisting of hydrogen, an allcyl, a substituted allcyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl; and , wherein R is selected from the group consisting of an allcyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkynyl, and a substituted alkynyl, an aryl and a substituted aryl.

43. The compound of claim 43 wherein 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.