WO2003052053A2

WO2003052053A2 - Nucleoside libraries and compounds by mcc combinatorial strategies on solid support

Info

Publication number: WO2003052053A2
Application number: PCT/US2002/034025
Authority: WO
Inventors: Zhi Hong; Frank Rong; Haoyun An; Weijian Zhang
Original assignee: Ribapharm Inc.
Priority date: 2001-12-17
Filing date: 2002-10-23
Publication date: 2003-06-26
Also published as: AU2002349905A1; WO2003052053A3; AU2002349905A8

Abstract

Nucleoside analog libraries and compounds contained herein are prepared in a solid phase combinatorial library approach. In some preferred aspects, diverse heterocyclic bases and/or diverse nucleoside substituents are prepared in a multiple component condensation (MCC), while in other preferred aspects library diversity is generated using solid phase-coupled nucleosides in a series of at least two modification reactions. 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

NUCLEOSIDE LIBRARIES AND COMPOUNDS BY MCC COMBINATORIAL

STRATEGIES ON SOLID SUPPORT

Field of The Invention The field of the 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 of the modified nucleic acids. In addition, certain nucleoside analogue triphosphates are a very potent, competitive inhibitor of DNA or RNA polymerases, which can significantly reduce the rate at which the natural nucleoside can be incorporated. Many anti-HIV nucleoside analogues fall into this category, including 3'-C-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and 2',3'- didehydro-2',3'-dideoxythymidine.

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-fluorouridine, and adenosine deaminase inhibitors such as 2-chloroadenosine. A well-studied anticancer compound, neplanocin A, is an inhibitor of S-adenosylhomocysteine hydrolase, which shows potent anticancer and antiviral activities.

Unfortunately, many 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 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 other than nucleosides, nucleotides, and their analogs resulting in large compound libraries. If nucleosides, nucleotides, and their analogs could be made through a combinatorial chemistry approach, a large number of such compounds could be synthesized within months instead of decades, and large libraries could be developed.

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 other than nucleosides, nucleotides, and their analogs 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 numerous problems 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 of the glycosidic bond can be achieved through a few types of condensation reactions. However, most of the reactions do not give a good yield of desired products, which may not be suitable to a 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 an 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.

Consequently, although there are various nucleoside analogs known in the art, all or almost all of them suffer from various disadvantages. Moreover, while numerous single nucleoside molecules may be prepared following known procedures, combinatorial approaches to nucleoside libraries have not been successful. Therefore, there is still a need to provide new nucleosides and nucleoside analogs and methods for generation of libraries for same.

Summary of the Invention

The present invention is directed to libraries comprising nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs, and compounds within such libraries.

Preferably, the libraries are prepared using solid phase combinatorial strategies, in which each of the library compounds comprises a heterocyclic base covalently bound to a sugar, and wherein the heterocyclic base is formed by a multiple component condensation. Further especially contemplated libraries (and compounds within the libraries) are prepared using solid phase combinatorial strategies, in which a library has at least two library compounds with each of the library compounds having a substituent covalently bound to a sugar, wherein the substituent is formed by a multiple component condensation. However, it should be recognized that individual, or a group of selected nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs may also be synthesized in a classical solution based synthesis (i. e. , without library generation).

hi one aspect of the inventive subject matter, preferred heterocyclic bases comprise an imidazole, an imidazoline, a thiazolidine, a benzodiazepine, or a dihydropyrimidine, which may be l'-N-glycosidically, l'-C-glycosidically, 3'-N-glycosidically, or 3'-C- glycosidically bound to the sugar portion, and in further preferred aspects of contemplated sugars especially include a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar is in D-configuration or L-configuration.

hi another aspect of the inventive subject matter, contemplated libraries will comprise ribofuranosylimidazole nucleosides according to Formula 1 or Formula 1 A

Formula 1A

wherein A, Ri, R₂, and R₃ are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula 1 or 1 A wherein A Ri, R₂, and R₃ are also defined as in the respective portions of the detailed description below. The bond in the N-A covalent bond in particularly preferred compounds couples the nitrogen atom of the N-A bond to a Ci', a C₂', or a C₃' atom of the sugar, or a to carbon atom of R

In a further aspect of the inventive subject matter, contemplated libraries will comprise ribofuranosyl benzodiazepine nucleosides according to Formula 2: Formula 2

wherein A, Ri, R₂, and R are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula 2 wherein A, Ri, R₂, and R₃ are also defined as in the respective portions of the detailed description below. It is particularly preferred that in such compounds the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to an atom selected from the group consisting of a Ci' atom of the sugar, a C₂' atom of the sugar, a C₃' atom of the sugar, and a carbon atom of R

In a still further aspect of the inventive subject matter, contemplated libraries will comprise 3',2',5',r-imidazole substituted nucleosides according to Formula 3

Formula 3

wherein B^PG, Ar, R_ls R₂, and R₃ are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula 3 A

Formula 3A

wherein B, Ar, Ri, R₂, and R₃ are also defined as in the respective portions of the detailed description below.

In a yet further aspect of the inventive subject matter, contemplated libraries will comprise dihydropyrimidine nucleosides according to Formula 4 or Formula 4A

wherein A, E, X, Ri, R₂, and R₃ are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula A, wherein A, E, X, Ri, R₂, and R₃ are also defined as in the respective portions of the detailed description below. It is still further preferred that in such compounds the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to an atom selected from the group consisting of a Ci' atom of the sugar, a C₂' atom of the sugar, a C₃' atom of the sugar, a C₅' atom of the sugar, and a carbon atom of R₄.

In another aspect of the inventive subject matter, contemplated libraries will comprise 3',2',5',1 '-heterocyclic nucleoside according to Formula 5 or 6

wherein B^PG, R_1} R₂, R , and R4 are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formulae 5A or 6A, wherein B, Ri, R₂, R₃, and are defined as in the respective portions of the detailed description below

Formula 5A Formula 6A

In still another aspect of the inventive subject matter, contemplated libraries will comprise thiadiazolinone nucleosides according for Formula 7

Formula 7

wherein B^PG, Ri, R₂, and R are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula 7A

Formula 7A

wherein B, Ri, R₂, and R₃, are also defined as in the respective portions of the detailed description below. In yet another aspect of the inventive subject matter, contemplated libraries will comprise 3',2',5'-substituted amino nucleosides according to Formulae 8 and 9

wherein B^PG, Ri, R₂, and R₃ are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula 8A and 9A

wherein B, R_1} R₂, and R₃ are also defined as in the respective portions of the detailed description below.

hi still further aspects of the inventive subject matter, contemplated libraries will comprise N-substituted benzodiazepine nucleosides according to Formula 10

Formula 10

wherein A, Ri, R₂, and R₃ are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived frbm such libraries will have a corresponding structure according to Formula 10. In still further aspects of the inventive subject matter, contemplated libraries will comprise substituted C-pyrrole nucleosides according to Formula 11

Formula 11

wherein A, Ri, R₂, Ei_. and E₂ are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula 11.

In yet another aspect of the inventive subject matter, contemplated libraries will comprise substituted C-dihydropyrimidine nucleosides according to Formula 12

Formula 12

wherein A, Ri, and R₂ are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula 12.

hi still another aspect of the inventive subject matter, contemplated libraries will comprise substituted tetrazole nucleosides according to Formula 13

Formula 13

wherein A, Ri, R₂, R₃, and ₄ are defined as in the respective portions of the detailed description below. Consequently, contemplated nucleosides derived from such libraries will have a corresponding structure according to Formula 13.

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

Detailed Description

The term "nucleoside library" as used herein refers to a plurality of chemically distinct nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs wherein at least some of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs include, or have been synthesized from a common precursor.

For example, a plurality of nucleosides, nucleotides,' nucleoside analogs, and/or nucleotide analogs that were prepared using l'-azido or l'-amino ribofuranose as a building block/precursor is considered a nucleoside library under the scope of this definition. Therefore, the term "common precursor" may encompass a starting material in a first step in a synthesis as well as a synthesis intermediate (i.e., a compound derived from a starting material). In another example, at least one step in the synthesis of one of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs is concurrent with at least one step in the synthesis of another one of the nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs, and synthesis is preferably at least partially automated. In contrast, a collection of individually synthesized nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs, and especially a collection of compounds not obtained from a nucleoside library, is not considered a nucleoside library because such nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs will not have a common precursor, and because such nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs are not concurrently produced.

It is further generally contemplated that the complexity of contemplated libraries is at least 20 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs, more typically at least 100 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs, and most typically at least 1000 distinct nucleosides, nucleotide, nucleoside analogs, and/or nucleotide analogs. Consequently, a typical format of a nucleoside library will include multi-well plates, or a plurality of small volume (i.e. , less than 1ml) vessels coupled to each other. The term "library compound" as used herein refers to a nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog within a 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" or "fused heterocyclic base" 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- djpyrimidine, 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. Moreover, contemplated heterocyclic bases and fused heterocycles may further be substituted in one or more positions (see below).

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 or atom in the sugar. For example, especially contemplated deletions include 2'-deoxy and/or 3'-deoxy sugars. Especially contemplated substitutions include replacement of the ring-oxygen with sulfur or methylene, or replacement of a hydroxyl group with a halogen, an amino-, sulfliydryl-, 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, A, 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 of the nucleoside to the sugar includes a CI '-(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.). Similarly, the term "nucleotide" refers to a nucleoside to which a phosphate group is coupled to the sugar. Likewise, the term "nucleotide analog" refers to a nucleoside analog to which a phosphate group is coupled to the sugar.

It should further be particularly appreciated that the terms nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog also includes all prodrug forms of a nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog, wherein the prodrug form may be activated/converted to the active drug/nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog in one or more than one step, and wherein the activation/conversion of the prodrug into the active drug/nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog may occur intracellularly or extracellularly (in a single step or multiple steps). Especially contemplated prodrug forms include those that confer a particular specificity towards a diseased or infected cell or organ, and exemplary contemplated prodrug forms are described in "Prodrugs" by Kenneth B. Sloan (Marcel Dekker; ISBN: 0824786297), "Design of Prodrugs" by Hans Bundgaard (ASIN: 044480675X), or in copending US application number 09/594410, filed 06/16/2000, all of which are incorporated by reference herein. Particularly suitable prodrug forms of the above compounds may include a moiety that is covalently coupled to at least one of the C2'-OH, C3'-OH, and C5'-OH, wherein the moiety is preferentially cleaved from the compound in a target cell (e.g., Hepatocyte) or a target organ (e.g., liver). While not limiting to the inventive subject matter it is preferred that cleavage of the prodrug into the active form of the drug is mediated (at least in part) by a cellular enzyme, particularly receptor, transporter and cytochrome-associated enzyme systems (e.g., CYP-system).

Especially contemplated prodrugs comprise a cyclic phosphate, cyclic phosphonate and/or cyclic phosphoamidates, which are preferentially cleaved in a hepatocyte to produce the compound according to Formula 1 or 2. There are numerous such prodrugs known in the art, and all of those are considered suitable for use herein. However, especially contemplated prodrug forms are disclosed in WO 01/47935 (Novel Bisamidate Phosphonate Prodrugs), WO 01/18013 (Prodrugs For Liver Specific Drug Delivery), WO 00/52015 (Novel Phosphorus-Containing Prodrugs ), and WO 99/45016 (Novel Prodrugs For Phosphorus-Containing Compounds), all of which are incorporated by reference herein. Consequently, especially suitable prodrug forms include those targeting a hepatocyte or the liver.

Still further particularly preferred prodrugs include those described by Renze et al. in Nucleosides Nucleotides Nucleic Acids 2001 Apr-Jul;20(4-7):931-4, by Balzarini et al. in Mol Pharmacol 2000 Nov;58(5):928-35, or in U.S. Pat. No. 6,312,662 to Erion et al., U.S. Pat. No. 6,271,212 to Chu et al., U.S. Pat. No. 6,207,648 to Chen et al, U.S. Pat. No. 6,166,089 and U.S. Pat. No. 6,077,837 to Kozak, U.S. Pat. No. 5,728,684 to Chen, and published U.S. Application with the number 20020052345 to Erion, all of which are incorporated by reference herein. Alternative contemplated prodrugs include those comprising a phosphate and/or phosphonate non-cyclic ester, and an exemplary collection of suitable prodrugs is described in U.S. Pat. No. 6,339,154 to Shepard et al., U.S. Pat. No. 6,352,991 to Zemlicka et al., and U.S. Pat. No. 6,348,587 to Schinazi et al. Still further particularly contemplated prodrug forms are described in FASEB J. 2000 Sep;14(12):1784- 92, Pharm. Res. 1999, Aug 16:8 1179-1185, and Antimicrob Agents Chemother 2000, Mar 44:3 477-483, all of which are incorporated by reference herein.

As still further used herein, the term "multiple component condensation" refers to reactions between at least two distinct molecules and a sugar or sugar portion of a molecule, in which at least one of the two molecules forms a covalent bond with the sugar portion, wherein the reactions 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 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. 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 terms "aryl" and "unsubstituted aryl" are used interchangeably herein and refer to any aromatic cyclic alkenyl or alkynyl. The term "alkaryl" is employed where an aryl is covalently bound to an alkyl, alkenyl, or alkynyl.

The term "substituted" as used herein refers to a replacement of an atom or chemical group (e.g., H, NH₂, or OH) with a functional group, and particularly contemplated functional groups include nucleophilic groups (e.g., -NH₂, -OH, -SH, -NC, etc.), electrophilic groups (e.g., C(O)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH^, and halogens (e.g., -F, -CI), and all chemically reasonable combinations thereof. Thus, the term "functional group" as used herein refers to nucleophilic groups (e.g., -NH₂, -OH, -SH, -NC, -CN etc.), electrophilic groups (e.g., C(O)OR, C(X)OH, C(Halogen)OR, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NHs ^"), and halogens.

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 of contemplated alternative sugars will include sugars in which the heteroatom in the cyclic portion of the sugar is an atom other than oxygen (e.g., sulfur, carbon, or nitrogen) analogs, while other alternative sugars may not be cyclic but in a linear (open-chain) form. Suitable sugars may also include one or more double bonds.

Still further specifically contemplated alternative sugars include those with one or more non-hydroxyl substituents, and particularly contemplated substituents include mono-, di-, and triphosphates (preferably as 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 of the 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 "Mode 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 of the exemplary sugars may be in D- or L-configuration, and wherein at least one of the substituents (typically H or OH) on the Cι'-C ' atom of the sugar may be in either alpha or beta orientation.

X , Y,, Z = O , S , S e, NH, NR, CH ₂₎ C HR, P(θ), P(0 )O

R = H, O H , NHR, halo, CH -OH, C O OH, N₃, alkyl, aryl, alkynyl, heterocycles, OR, SR,-P (0)(O R)₂

O COR, NHCOR, N HS0₂R, NH₂NH₂, am idine, substituted amidine, quanidine, substituted gyanidine An especially contemplated class of sugars comprises alkylated sugars, wherein one or more alkyl groups (or other groups, including alkenyl, alkynyl, aryl, halogen, CF₃, CHF , CC1₃, CHC1₂, N₃, NH₂, etc.) are covalently bound to sugar at the C'ι, C'₂,C'₃,C₄, and/or C₅ atom, such alkylated sugars, it is especially preferred that the sugar portion comprises a furanose (most preferably a D- or L-ribofuranose), and that at least one of the alkyl groups is a methyl group. 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 (see below), R is independently hydrogen, hydroxyl, substituted or unsubstituted alkyl (branched, linear, or cyclic), with R including between one and twenty carbon atoms.

Contemplated Heterocyclic Bases

It is generally contemplated that all compounds in wliich 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 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, and/or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine).

Further contemplated heterocycles 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 of the depicted heterocyclic bases may further include one or more substituents, double and triple bonds, and any chemically reasonable combination thereof. It should also be appreciated that all of the contemplated heterocyclic bases may be coupled to contemplated sugars via a carbon atom or a non-carbon atom in the heterocyclic base.

Contemplated Solid Phases

It is generally contemplated that all known types of solid phases are suitable for use herein, so long as contemplated nucleosides, nucleotides, nucleoside analogs, and/or nucleotide analogs (or sugar, or heterocyclic base) can be coupled to such solid phases, and so long as the coupled nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog (or sugar, or heterocyclic base) will remain coupled to the solid phase during at least one chemical reaction on the nucleoside, nucleotide, nucleoside analog, and/or nucleotide analog (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 Bache 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. 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.

Further 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 of the reaction compartment or a solid or soluble polymer), 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).

Contemplated Libraries and Nucleosides

The inventors discovered that nucleoside analog libraries can be prepared in various combinatorial library approaches, particularly approaches in which diverse heterocyclic bases and/or diverse nucleoside substituents are prepared in a multiple component condensation (MCC) reaction.

More particularly, the inventors contemplate that a nucleoside library may have at least two library compounds, wherein each of the library compounds comprises a heterocyclic base covalently bound to a sugar, and wherein the heterocyclic base is formed by a multiple component condensation. Especially contemplated heterocyclic bases comprise various imidazoles, imidazolines, thiazolidines, benzodiazepines, and dihydropyrimidines, wherein all of the contemplated heterocyclic bases maybe l'-N- glycosidically, l'-C-glycosidically, 2'-N-glycosidically, 3'-N-glycosidically, or 3'-C- glycosidically bound to the sugar portion. Furthermore, contemplated nucleoside libraries may have at least two library compounds, wherein each of the library compounds comprises a moiety covalently bound to a sugar, and wherein the moiety is formed by a multiple component condensation

For example, contemplated libraries include those in which a heterocyclic base coupled to the C 1 '-atom of a sugar (e.g. , ribofuranosylimidazole libraries, ribofuranosyl benzodiazepine libraries, imidazole substituted libraries, and dihydropyrimidine libraries) is built via an MCC, and further contemplated libraries include those in which a heterocyclic base is added as a sugar substituent to a nucleoside (e.g., 3',2',5',l'-heterocyclic libraries), and those in which a linear sugar substituent is added to the sugar of a nucleoside via an MCC reaction (e.g., 3',2',5'-substituted amino acid nucleoside libraries). Some of these exemplary libraries are described in more detail below.

Ribofuranosylimidazole Libraries

Scheme 1 depicts a general synthetic approach for a ribofuranosylimidazole library, in which a protected sugar (here: protected ribofuranose) is converted to the corresponding CI'- ribofuranose azide and further coupled to a solid phase via the C5'-atom. The azide is then reduced to the amine, which serves as a nucleophilic group that is used to react with at least one of three substrates in an MCC reaction to form a substituted imidazole. For example, a first set of various first substrates reacts with the amine group in a first set of separate reactions, then the products from the first set of reactions will react with a second set of various second substrates in a second set of reactions, and third set of separate reactions with various third substrates will use the products from the second set of reactions. The product of the third set of reactions is then converted to the imidazole ring. In another example, a series of protected and solid phase-bound amino sugars may also be reacted with a series of three distinct substrates, respectively, wherein each sugar and three substrates are in a separate reaction vessel. Thus, it should be appreciated that all combinations of Rι-R₃ in the substrates will potentially be represented in the so generated library. After formation of the substituted imidazole ring, the protecting groups may be removed and the sugar is cleaved from the solid phase.

Alternatively, as depicted in Scheme 1 A below, the heterocyclic base can be constructed in an alternative fashion using a carboxylic acid group on the sugar portion. Consequently, contemplated nucleosides will include a heterocyclic base that is coupled via a C-C bond to the sugar portion.

13

Again, a first set of various first substrates may react with the COOH group in a first set of separate reactions, then the products from the first set of reactions will react with a second set of various second substrates in a second set of reactions, and a third set of separate reactions with Various third substrates will use the products from the second set of reactions. The product of the third set of reactions is then converted to the imidazole ring. Alternatively, a series of protected and solid phase-bound carboxylic acid sugars may also be reacted with a series of three distinct substrates, respectively, wherein each sugar and three substrates are in a separate reaction vessel. Thus, it should be appreciated that all combinations of Rι-R₃ in the substrates will potentially be represented in the so generated library. After formation of the substituted imidazole ring, the protecting groups maybe removed and the sugar cleaved from the solid phase.

With respect to the sugar, it should be appreciated that numerous alternative sugars are also appropriate, and especially contemplated alternative sugars include sugar derivatives of sugars with four, five, or six carbon atoms. Exemplary contemplated sugars are described and depicted above. Furthermore, it should be appreciated that the azide group may be introduced into the sugar in a position other than the Cl'-position. Consequently, it should be recognized that the imidazole moiety may also be formed in the C2'-, C3'-, or C5'- position. There are numerous methods known in the art to introduce an N₃ group into the C2'-, C3'-, or C5'-position of a sugar, and all such methods are contemplated herein (see e.g., Nucleic Acids Res. 1979, 6, 625; or in Bioorg. Med. Chem. Lett. 1996, 6, 2993-2998). Similarly, selective oxidation of a hydroxyl group in a sugar to form a COOH group is well known in the art, and all of those methods are considered suitable for use herein (see e.g., "Modern Methods in Carbohydrate Synthesis" by Shaheer H. Khan (Gordon & Breach Science Pub; ISBN: 3718659212)).

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.

i further alternative aspects, it is also contemplated that Ri, R₂, and R₃ in the three substrates may vary considerably, and it is especially contemplated that Ri, R₂, and R₃ are independently selected from the group consisting of hydrogen, a functional group, 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. Furthermore, it should be recognized that at least one of Ri, R₂, and R₃ may comprise a sugar.

Preparation of various first substrates with RiCOCHO are well known in the art and all known protocols to generate 2-oxoaldehydes are considered suitable for use herein (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 Classics in Total Synthesis: Targets, Strategies, Methods, by K. C. Nicolaou, E. J. Sorensen; John Wiley & Son Ltd; ISBN: 3527292314). Moreover, numerous 2-oxoaldehydes are commercially available and may be used for synthesis of contemplated libraries.

Likewise, numerous second substrates R COOH are commercially available, and where such substrates are not commercially available, it is contemplated that they may be prepared from commercially available precursors (e.g., via oxidation of corresponding alcohols or aldehydes, hydrolysis of corresponding esters, etc.) using protocols well known in the art (supra). Similarly, numerous third substrates R NC are commercially available, and where such substrates are not commercially available, it is contemplated that they may also be prepared from commercially available precursors using protocols well known in the art (supra).

With respect to the solid phase 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). Thus, it should be appreciated that nucleoside libraries with at least two library compounds can be synthesized, wherein one of the at least two library compounds has a structure according to Formula 1 with a first set of substituents A, Ri, R₂, and R₃, wherein another one of the at least two library compounds has a structure according to Formula 1 with a second set of substituents A, Ri, R₂, and R₃:

Formula 1

wherein A is selected from the group consisting of ₄, a protected sugar that is covalently bound to a solid phase, and an unprotected sugar that is covalently bound to a solid phase; Ri, R₂, R₃, and R₄ are independently hydrogen, a functional group, 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, with the proviso that when A is R , then one of Ri, R₂, and R₃ is a protected sugar that is covalently bound to a solid phase or an unprotected sugar that is covalently bound to a solid phase. In contemplated libraries, not all of the substituents A, Ri, R₂, and R₃ in the first set are the same as the substituents A, R_l5 R₂, and R₃ in the second set.

Consequently, contemplated compounds may have a structure according to Formula 1 (supra) wherein A is R₄, a protected sugar, or an unprotected sugar; Ri, R₂, R₃, and R₄ are independently hydrogen, a functional group, 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, with the proviso that when A is R , then one of Ri, R₂, and R₃ is a protected sugar or an unprotected sugar.

In particularly preferred compounds and libraries, the sugar is a ribofuranose, a substituted ribofuranose (e.g., 2'-beta methyl ribofuranose), a carbocyclic ring system, or an arabinose, wherein the sugar is in D-configuration or i L-configuration. It is still further preferred that in such compounds and libraries the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to the

atom, the C₂' atom, or the C₃' atom of the sugar, or to a carbon atom of R₄.

Ribofuranosylbenzodiazepine Libraries

Scheme 2 depicts a general synthetic approach for a ribofuranosylimidazole library, in which a Cl'-azidosugar (here: Cl'-azidoribofuranose) is protected and coupled via the C5'-atom to a solid phase. The protected and coupled sugar is then converted to the corresponding amino sugar. The amino group in the amine sugar serves as a nucleophilic group that is used to react with at least one of the three substrates in an MCC reaction to form a substituted benzodiazepine. For example, a first set of various first substrates reacts with the amine group in a first set of reactions, then the products from the first set of reactions will react with a second set of various second substrates in a second set of reactions, and a third set of reactions with various third substrates will use the products from the second set of reactions. The product of the third set of reactions is then converted to form the benzodiazepine ring. Thus, it should be particularly appreciated that all combinations of Rι-R₃ in the substrates will potentially be represented in the so generated library. After formation of the substituted benzodiazepine ring, the protecting groups are removed and the sugar is cleaved from the solid phase.

14

Deprotection and Cleavage

Scheme 2 16

With respect to the solid phase, the sugar, the introduction of the azido- and protection groups (and consequently the positioning of the benzodiazepine on contemplated sugars), the same considerations as described above for the Ribofuranosylimidazole libraries apply. It is further contemplated that Ri, R₂, and R in the substrates may vary considerably, and it is especially contemplated that Ri, R , and R₃ are independently hydrogen, a functional group, 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.

Preparation of various first substrates with RjCOCHO are well known in the art and all known protocols to generate 2-oxoaldehydes are considered suitable for use herein (supra). Moreover, numerous 2-oxoaldehydes are commercially available and may also be used for synthesis of contemplated libraries. Exemplary 2-oxoaldehydes are listed in the experimental section below. Likewise, numerous second substrates (substituted and unsubstituted aminobenzoic acids) are 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 known in the art (supra). Exemplary substituted and unsubstituted aminobenzoic acids are listed in the experimental section below. Likewise, numerous third substrates R₃NC are commercially available, and where such substrates are not commercially available, it is contemplated that they may also be prepared from commercially available precursors using protocols well known in the art (supra).

Thus, it should be appreciated that nucleoside libraries with at least two library compounds can be synthesized, wherein one of the at least two library compounds has a structure according to Formula 2 with a first set of substituents A, Ri, R₂, and R₃, and wherein another one of the at least two library compounds has a structure according to Formula 2 with a second set of substituents A, Ri, R₂, and R₃

Formula 2

wherein A is R₄, a protected sugar that is covalently bound to a solid phase, or an unprotected sugar that is covalently bound to a solid phase; and Ri, R₂, R₃, and are independently hydrogen, a functional group, 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, with the proviso that when A is R , then one of Ri, R₂, and R₃ is a protected sugar that is covalently bound to a solid phase or an unprotected sugar that is covalently bound to a solid phase; and wherein not all of the substituents Ri, R₂, and R₃ in the first set are the same as the substituents Rj, R₂, and R₃ in the second set.

Consequently, it is contemplated that contemplated compounds may have a structure according to formula 2 (supra) wherein A is R₄, a protected sugar, or an unprotected sugar, and Ri, R₂, R₃, and are independently hydrogen, a functional group, 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, with the proviso that when A is I , then one of R_ls R₂, and R₃ is a protected sugar or an unprotected sugar.

h particularly preferred libraries and compounds, the sugar comprises a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, or an arabinose, wherein the sugar is in the D- or L-configuration. In still further preferred aspects of such libraries and compounds, the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to the Ci' atom, the C ' atom, or the C₃' atom of the sugar, or to a carbon atom of .

3',2',5M',-Imidazole Substituted Libraries Scheme 3 depicts a general synthetic approach for an imidazole substituted nucleoside library, in which a protected nucleoside comprising an amino sugar (here: 3'-aminoribofuranose) is coupled via the C5'-atom to a solid phase. The amino group of the sugar in the nucleoside serves as a nucleophilic group that is used to react with at least one of the three substrates in an MCC reaction to form a substituted imidazole. For example, a first set of distinct first substrates reacts with the amino group in a first set of reactions, then the products from the first set of reactions will react with a second set of distinct second substrates in a second set of reactions, and a third set of reactions with distinct third substrates will use the products from the second set of reactions. The product of the third set of reactions is then converted to the substituted imidazole ring. Thus, it should be appreciated that all combinations of Ri in the sugar and R₂, R₃, and Ar in the substrates will potentially be represented in the so generated library. After formation of the substituted imidazole ring, the protecting groups are removed and the sugar is cleaved from the solid phase.

Same approach can be used to make novel 2'-, 1'- and 5'-heterocyclic and different sugar substituted nucleosides

Scheme 3

With respect to the sugar, the protecting groups, the solid phase and coupling conditions of the sugar to the solid phase the same considerations as described for the Ribofuranosylimidazole libraries apply. Furthermore, it should be appreciated that all known methods of producing the C3 '-amino nucleosides are considered suitable for use herein, and exemplary methods are described, for example, in Tetrahedron Lett. 1989, 30, 2329-2332; or in Nucleosides Nucleotides 1995, 14, 409-412; or in reel. Trav. Chim. Pays- Bas, 1986, 105, 85-91.

Moreover, it is generally contemplated that all known substituents for Ri in the amino sugar are considered suitable for use herein, however, particularly preferred substituents include hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, and S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl. The synthesis, of sugars with preferred substituents is well known in the art, and exemplary protocols can be found in "Modern Methods in Carbohydrate Synthesis" by Shaheer H. Khan (Gordon & Breach Science Pub; ISBN: 3718659212), in U.S. Pat. Nos. 4,880,782 and 3,817,982, in WO88/00050, or in EP 199,451. Still further, while the Scheme 3 depicts the C2' and C3' sugar substituents in alpha orientation, it should be recognized that the particular orientation of one or more sugar substituents (i.e., the CI', C2', C3', and/or C4') is not limiting to the inventive subject matter. Consequently, each of the substituents (including the heterocyclic base) may be in alpha or beta orientation. I

Still further, it should be appreciated that suitable heterocyclic bases may vary considerably, and it is generally contemplated that all known heterocyclic bases are appropriate for use herein. Exemplary heterocyclic bases are described in the section entitled "Contemplated Heterocyclic Bases" above. Depending on the particular nature of the heterocyclic base, it is contemplated that one or more substituents or reactive groups in the heterocyclic may be protected by a suitably selected protecting group.

It is further contemplated that Ar, R₂, and R₃ in the substrates may vary considerably, and it is especially contemplated that R₂, and R are independently hydrogen, a functional group, 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. Similarly, Ar may vary considerably and contemplated Ar include a substituted aryl, an unsubstituted aryl, a substituted heterocycle, and an unsubstituted heterocycle, and especially phenyl.

Preparation of various first substrates with ArCOCHO are well known in the art and all known protocols to generate aromatically substituted glyoxals and/or substituted and unsubstituted 2-oxoaldehydes are considered suitable for use herein (supra). Moreover, numerous aromatically substituted glyoxals and/or substituted and unsubstituted 2- oxoaldehydes are commercially available and may be used for synthesis of contemplated libraries. Likewise, numerous second substrates (substituted and unsubstituted carboxylic acids) R₂COOH are 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 known in the art (supra). Similarly, numerous third substrates R₃NC are commercially available, and where such substrates are not commercially available, it is contemplated that they may also be prepared from commercially available precursors using protocols well known in the art (supra).

Thus, it should be recognized that substituted imidazole nucleoside libraries with at least two library compounds can be prepared wherein one of the at least two library

Pf compounds has a structure according to Formula 3 with a first set of substituents B , Ar, Ri, R₂, and R₃, and wherein another one of the at least two library compounds has a structure according to Formula 3 with a second set of substituents B^PG, Ar, Ri, R₂, and R₃: Formula 3

wherein B^PG is a protected or unprotected heterocyclic base, Ar is a substituted aryl, an unsubstituted aryl, a substituted heterocycle, or an unsubstituted heterocycle; Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl, and R and R₃ are independently hydrogen, a functional group, 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, wherein not all of the substituents B^PG, Ar, Ri, R₂, and R₃ in the first set are the same as the substituents

B -PG , Ar, Ri, R₂, and R₃ in the second set, and wherein • comprises a solid phase.

Consequently, contemplated compounds may have a structure according to formula 3A wherein B is a heterocyclic base, Ar is a substituted aryl, an unsubstituted aryl, a substituted heterocycle, or an^'unsubstituted heterocycle; Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl, and R₂ and R₃ are independently hydrogen, a functional group, 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. Formula 3A

Dihydropyrimidine Libraries

Scheme 4 depicts a general synthetic approach for a substituted dihydropyrimidine library, in wliich a protected CI'- amino sugar (here: l'-aminoribofuranose) is coupled via the C5'-atom to a solid phase. The amino group of the sugar in the nucleoside serves as a nucleophilic group that is used to react in an MCC reaction to form a substituted dihydropyrimidine. For example, a first set of various first substrates reacts with the amino group in a first set of reactions, then the products from the first set of reactions will react with a second set of various second substrates in a second set of reactions, and a third set of reactions with various third substrates will use the products from the second set of reactions. The product of the third set of reactions is then converted to the substituted dihydropyrimidine ring. Thus, it should be appreciated that all combinations of Rι-R₃ in the substrates will potentially be represented in the so generated library. After formation of the substituted dihydropyrimidine ring, the protecting groups are removed and the sugar is cleaved from the solid phase.

x=o,s Same approach can be used to make novel _E = _COOR, COR, CN, NO₂, _etc

2'-, T- and 5'-heterocyclic and different sugar _Ri, _R2, _R3 = _{H; aIkyI aryl) heterocyc}i_es substituted nucleosides

Scheme 4

With respect to the solid phase, the amino sugar, the protecting groups, and the coupling conditions of the sugar to the solid phase the same considerations as described above apply. It is further contemplated that E, X, R_1} R₂, and R₃ in the substrates may vary considerably, and it is generally contemplated that E is any electron- withdrawing group (i.e., a group with a -I effect, including COOR, COR, CN, NO₂, Halogen, etc.), while X is preferably O or S. Still further, and depending on the particular reaction conditions, it should be recognized that the sugar may also be coupled to the dihydropyrimidine in a position of the substituents Ri and R₂.

It should further be appreciated that where instead of the Cl'-amino sugar a Cl'- carboxylic acid sugar is employed, the heterocyclic base will be coupled to the sugar via a C-C bond (in analogy to the alternative route depicted in Scheme 1 A above). Consequently, the sugar and the R₂ substituent of Scheme 4 in contemplated libraries and compounds will be exchanged.

Depending on the particular choice of first, second, and/or third substrates, R_1} R₂, and R₃ are independently hydrogen, a functional group, 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.

Preparation of various first substrates with RiNCX (with X being O or S) are well known in the art and all known protocols to generate various isothiocyanates and/or various isocyanates are considered suitable for use herein (supra). Moreover, numerous substituted isothiocyanates and/or substituted isocyanates are commercially available and may be used for synthesis of contemplated libraries. Likewise, numerous second substrates (various aldehydes) R₂CHO are 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 known in the art (supra). Likewise, numerous third substrates (substituted methylbutenes) are commercially available, and where such substrates are not commercially available, it is contemplated that they may also be prepared from commercially available precursors using protocols well known in the art (supra).

Thus, it should be recognized that dihydropyrimidine nucleoside libraries can be prepared with at least two library compounds wherein one of the at least two library compounds has a structure according to Formula 4 or 4A with a first set of substituents A, E, X, Ri, R₂, and R₃, wherein another one of the at least two library compounds has a structure according to Formula 4 or 4 A with a second set of substituents A, E, X, Ri, R₂, and R₃:

wherein A is a protected sugar covalently bound to a solid phase, or an unprotected sugar covalently bound to a solid phase; E is an electron withdrawing group, X is O or S, and R_ls R₂, and R₃ are independently hydrogen, a functional group, 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, and wherein not all of the substituents E, X, Ri, R₂, and R₃ in the first set are the same as the substituents E, X, Ri, R₂, and R₃ in the second set.

Consequently, it should be recognized that contemplated compounds may have a structure according to Formula 4 or 4A (supra) wherein A is a protected sugar or an unprotected sugar; E is an electron withdrawing group, X is O or S, and Ri, R₂, and R₃ are independently hydrogen, a functional group, 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.

Further contemplated compounds may have the dihydropyrimidine moiety bound to the C₂' atom, C₃' atom or C₅' atom of the sugar (when the protected amino sugar is a C₂' amino sugar, a C₃' amino sugar, or a C₅' amino sugar). Particularly preferred sugars include a ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar is in D- or L-configuration. It is still further preferred that in such compounds the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to an atom selected from the group consisting of a Ci' atom of the sugar, a C₂' atom of the sugar, a C₃' atom of the sugar, and a C₅' atom of the sugar.

3\2!,5M'-Heterocyclic Libraries (A)

Scheme 5 depicts a general synthetic approach for a 3',2',5',l'-heterocyclic library, in which a protected nucleoside (here: with any naturally occurring heterocyclic base) with an amino sugar (here: 3'-aminoribofuranose) is coupled via the C5'-atom to a solid phase. The amino group of the sugar in the nucleoside serves as a nucleophilic group that is used to react with at least one of three substrates in an MCC reaction to form a substituted heterocycle. It should be particularly appreciated that all combinations of Ri in the amino sugar and R₂-R₄ in the substrates of the MCC reaction will potentially be represented in the so generated library. After formation of the substituted heterocyclic ring, the protecting groups are removed and the sugar is cleaved from the solid phase.

a-A etc.

The same approach can be used to make novel V-, 5'- and l'-amino nucleoside libraries. RNH2, RCO, and RNC at 1', 2', 3' are used to make novel nucleoside libraries from different sugars.

Scheme 5

For example, a first set of various first substrates reacts with the amino group in a first set of reactions, then the products from the first set of reactions will react with a second set of various second substrates in a second set of reactions, and a third set of reactions with various third substrates will use the products from the second set of reactions.

With respect to the sugar, the solid phase, the protecting groups, the heterocyclic base, and coupling conditions of the sugar to the solid phase the same considerations as described above for the 3',2',5',l',-imidazole substituted libraries apply. It should further be appreciated that all known methods of producing the C3'-amino nucleosides are considered suitable for use herein, and exemplary methods are described, for example, in Tetrahedron Lett. 1989, 30, 2329-2332; or in Nucleosides Nucleotides 1995, 14, 409-412; or in Reel. Trav. Chim. Pays-Bas, 1986, 105, 85-91.

It is further contemplated that R , R₃, and R₄ in the substrates may vary considerably, and it is especially contemplated that R₂, R₃, and R₄ are independently hydrogen, a functional group, 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. Similarly, Ri may vary considerably and particularly contemplated Ri include hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl. With respect to the protected heterocyclic base it is contemplated that all known heterocyclic bases are appropriate (supra), and especially contemplated heterocyclic bases include guanine, adenenine, cytidine, thymine, uracil, inosine, and all known modifications thereof.

Preparation of various first substrates with R₂C(O)R₃ are well known in the art and all known protocols to generate various ketones (in which R₂ and R₃ may or may not be different) are considered suitable for use herein (supra; e.g., via addition, oxidation, reduction, or substitution). Moreover, numerous substituted ketones are commercially available and maybe used for synthesis of contemplated libraries. The second substrate SCN^" is commercially available as the corresponding salt (potassium thiocyanate), and numerous third substrates (isonitriles, R₃NC) are also commercially available. Where ' particular third substrates are not commercially available, it is contemplated that such substrates may also be prepared from commercially available precursors using protocols well known in the art (supra, ox A. W. Hofmann, Ann. 146, 107 (1868); Ber. 3, 767 (1870), or P. A. S. Smith, N. W. Kalenda, J. Org. Chem. 23, 1599 (1958); M. B. Frankel et al., Tetrahedron Letters 1959, 5; H. L. Jackson, B. C. McKusick, Org. Syn. coll. vol. IN, 438 (1963); W. P. Weber, G. W. Gokel, Tetrahedron Letters 1972, 1637).

It should still further be appreciated that the MCC generated heterocyclic base may also be coupled to atoms other than the C3'-atom of the nucleoside, and alternative positions include the CI'- and C2'-position (then, the amino group in the amino sugar of the nucleoside is in the corresponding CI'- and C2'-position).

Thus, it should be recognized that nucleoside libraries can be prepared in which at least one of the at least two library compounds has a structure according to Formula 5 with a first set of substituents B , Ri, R₂, R₃, and R-_t and wherein another one of the at least two library compounds has a structure according to Formula 5 with a second set of substituents B^PG, R_l5 R₂, R₃ and R₄: Formula 5

f wherein B is a protected or unprotected heterocyclic base, Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; R₂, R₃, and ₄ are independently hydrogen, a functional group, 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, and wherein not all of the substituents B^PG, Ri, R₂, R₃, and R₄ in the first set are the same as the substituents B^PG, Ri, R₂, R₃, and R in the second set, and wherein • comprises a solid phase.

Consequently, contemplated compounds may have a structure according to formula

5A

Formula 5A

wherein B is a heterocyclic base, Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; R₂, R₃, and R are independently hydrogen, a functional group, 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. Particularly preferred sugars in contemplated compounds and libraries include ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar is in D- or L-configuration.

3'.2'.5M '-Heterocyclic Libaries (B)

Scheme 6 depicts a general synthetic approach for another 3',2',5',l'-heterocyclic library, in which a protected nucleoside (here: with any naturally occurring heterocyclic base) with an amino sugar (here: 3'-aminoribofuranose) is coupled via the C5'-atom to a solid phase. The amino group of the sugar in the nucleoside serves as a nucleophilic group that is used to react with at least one of two substrates in an MCC reaction (first set of reactions with various first substrates, then a second set of reactions with various second substrates using products from the first set of reactions) to form a substituted heterocycle. It should be particularly appreciated that all combinations of Ri in the sugar and R₂-R₃ in the substrates will potentially be represented in the so generated library. After formation of the substituted heterocyclic ring, the protecting groups are removed and the sugar is cleaved from the solid phase.

7-deaza-A etc. cles

The similar approach can be used to make novel 2'-, 5'- and l'-amino nucleoside libraries. RCHO and RNH2 at 1', 2', and 3' positions of different sugars are used to make novel nucleoside libraries. .

Scheme 6 With respect to the sugar, the solid phase, the protecting groups, the heterocyclic base, and coupling conditions of the sugaΛo the solid phase the same considerations as described above for the 3',2',5',l'-Heterocyclic Libaries (A) apply. It should further be appreciated that all known methods of producing the C3'-amino nucleosides are considered suitable for use herein, and exemplary methods are described, for example, in Tetrahedron Lett. 1989, 30, 2329-2332; or in Nucleosides Nucleotides 1995, 14, 409-412; or in reel. Trav. Chim. Pays-Bas, 1986, 105, 85-91. It is further contemplated that R₂ and R₃ in the substrates may vary considerably, and it is especially contemplated that R₂ and R₃ are independently hydrogen, a functional group, 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.

Similarly, i may vary considerably and particularly contemplated Ri include hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl. With respect to the protected heterocyclic base it is contemplated that all known heterocyclic bases are appropriate (supra), and especially contemplated heterocyclic bases include guanine, adenenine, cytidine, thymine, uracil, inosine, and all known modifications thereof.

Numerous preparation methods for various first substrates with R₂CHO are well known in the art and all known protocols to generate various aldehydes are considered suitable for use herein (supra). Moreover, numerous aldehydes are commercially available and maybe used for synthesis of contemplated libraries. Similarly, many second substrates (various alpha- or beta-thio carboxylic acids) are commercially available and where particular second substrates are not commercially available, it is contemplated that such substrates may be prepared from commercially available precursors using protocols well known in the art (supra). It should still further be appreciated that the MCC generated heterocyclic base may also be coupled to atoms other than the C3'-atom of the nucleoside, and alternative positions include the CI'-, C2'-, and C5'-position (then, the amino group in the amino sugar of the nucleoside is in the corresponding CI'-, C2'-, and C5'-position).

Thus, it should be recognized that heterocyclic nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 6 with a first set of substituents B^PG, Ri, R₂ and R₃, wherein another one of the at least two library compounds has a structure according to Formula 6 with a second set of substituents B^PG, Ri, R and R₃:

Formula 6

wherein B^PG is a protected or unprotected heterocyclic base, Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; R₂ and R₃ are independently hydrogen, a functional group, 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, and wherein not all of the substituents B^PG, Ri, R₂, and R₃ in the first set are the same as the substituents B^PG, Ri, R₂, and R in the second set, and wherein • comprises a solid phase.

Consequently, it should be recognized that contemplated compounds may have a structure according to formula 6 A

Formula 6A

wherein B is a heterocyclic base, Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; and R₂ and R₃ are independently hydrogen, a functional group, 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. Particularly preferred sugars in contemplated compounds and libraries include ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar is in D- or L-configuration.

S^'ST-Thiadiazolinone Libraries

Scheme 7 depicts a general synthetic approach for a 3',2',5',l'-thiadiazolinone library, in which a protected nucleoside (here: with a naturally occurring heterocyclic base) with an azido sugar (here: 3'-azidoribofuranose) is coupled via the C5'-atom to a solid phase. The azido group is reduced to an amino group which then serves as a nucleophilic group that is used to react with at least one of two substrates in an MCC reaction (e.g., a first set of reactions with various first substrates, then a second set of reactions with various second substrates using products from the first set of reactions) to form a substituted thiadiazolinone. It should be particularly appreciated that all combinations of Ri in the sugar and R₂-R₃ in the substrates will potentially be represented in the so generated library. After formation of the substituted heterocyclic ring, the protecting groups are removed and the sugar is cleaved from the solid phase.

R' = OCH₃, OTBDMS, '

I OTBDMS

eaza-A etc.

Scheme

Note: 1, The similar aporoach is used to make 2'-, 1'- and 5'-heterocyclic substituted nucleoside libraries. 2, 17273757-NCS, NCO, or NC on the different sugars are also used for this and other MCC reactions. With respect to the sugar, the solid phase and coupling conditions of the sugar to the solid phase the same considerations as described above for the 3',2',5',1 '-Heterocyclic Libaries (B) apply. It should further be appreciated that all known methods of producing the C3 '-azido nucleosides are considered suitable for use herein, and exemplary methods are described, for example, in Nucleic Acids Res. 1979, 6, 625; or in Bioorg. Med. Chem. Lett. 1996, 6, 2993-2998.

It is further contemplated that R₂ and R₃ in the substrates may vary considerably, and it is especially contemplated that R₂ and R₃ are independently hydrogen, a functional group, 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.

Similarly, Ri may vary considerably and particularly contemplated Ri include hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl. With respect to the protected heterocyclic base it is contemplated that all known heterocyclic bases are appropriate (supra), and especially contemplated heterocyclic bases include guanine, adenenine, cytidine, thymine, uracil, inosine, and all known modifications thereof.

Numerous preparation methods for various first substrates R₂NCS are well known in the art and all known protocols to generate various isothiocyanates are considered suitable for use herein (supra). Moreover, numerous isothiocyanates are commercially available and maybe used for synthesis of contemplated libraries. Similarly, numerous second substrates R₂NCO are commercially available and where a particular isocyanate is not commercially available, it is contemplated that such substrates may be prepared from commercially available precursors using protocols well known in the art (supra).

It should still further be appreciated that the MCC generated heterocyclic base may also be coupled to atoms other than the C3'-atom of the nucleoside, and alternative positions include the CI'-, C2'-, and C5'-position (then, the amino group in the azido sugar of the nucleoside is in the corresponding CI'-, C2'-, and C5 '-position). Thus, it should be recognized that thiadiazolinone nucleoside libraries with at least two library compounds can be prepared in wliich one of the at least two library compounds has a structure according to Formula 7 with a first set of substituents B , Ri, R₂ and R₃, and wherein another one of the at least two library compounds has a structure according to Formula 7 with a second set of substituents B^PG, Ri, R and R₃:

Formula 7

wherein B^PG is a protected or unprotected heterocyclic base, Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; R₂ and R₃ are independently hydrogen, a functional group, 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, wherein not all of the substituents B Pf , Ri, R₂, and R₃ in the first set are the same as the substituents B^PG, Ri, R₂, and R₃ in the second set, and wherein • comprises a solid phase.

Consequently, it should be recognized that contemplated compounds may have a structure according to formula 7A

Formula 7A

wherein B is a heterocyclic base, Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; R₂ and R₃ are independently hydrogen, a functional group, 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. Particularly preferred alternative sugars in contemplated compounds and libraries include ribofuranose, a substituted ribofuranose, a carbocyclic ring system, and an arabinose, wherein the sugar is in D- or L-configuration.

3',2',5'- Amino Nucleoside Libraries (A)

Scheme 8 depicts a general synthetic approach for a 3',2',5'-substituted amino nucleoside library, in which a protected nucleoside (here: with a purine heterocyclic base) with an amino sugar (here: 3'-aminoribofuranose) is coupled via the C5'-atom to a solid phase. The amino group is used to react with a set of substrates to form a substituted amino nucleoside. After formation of the substituted amino nucleoside, the protecting groups are removed and the sugar is cleaved from the solid phase.

deprotection TFA

Similar libraries can be made from 2' and 5'-amiπo nucleosides

Scheme 8 With respect to the sugar, the heterocyclic base, the solid phase and coupling conditions of the sugar to the solid phase the same considerations as described above for the 3 ',2', 5 ',1 '-Heterocyclic Libaries (B) apply. It should further be appreciated that all known methods of producing the C3 '-amino nucleosides are considered suitable for use herein, and exemplary methods are described, for example, in Tetrahedron Lett. 1989, 30, 2329-2332; or in Nucleosides Nucleotides 1995, 14, 409-412; or in reel. Trav. Chim. Pays-Bas, 1986, 105, 85-91.

It is further contemplated that R₂ in the substrate may vary considerably, and it is especially contemplated that R₂ is hydrogen, a functional group, 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.

Similarly, Ri may vary considerably and particularly contemplated Ri include hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl. With respect to the protected heterocyclic base it is contemplated that suitable heterocyclic bases need not be restricted to a purine base and that all known heterocyclic bases are appropriate. Especially contemplated heterocyclic bases include guanine, adenenine, cytidine, thymine, uracil, inosine, and all known modifications thereof.

Numerous preparation methods for various substrates (RCOC1, RCSC1, RSO₂Cl, RNCO, RNCS, RBr, etc.) are well known in the art, and all known protocols to generate such substrates are considered suitable for use herein (supra). Moreover, numerous of such substrates are commercially available and maybe used for synthesis of contemplated libraries. It should still further be appreciated that the substituted amino group may also be coupled to atoms other than the C3'-atom of the nucleoside, and alternative positions include the C2'-, and C5'-position (then, the amino group in the amino sugar of the nucleoside is in the corresponding C2'-, and C5'-position). It should still further be appreciated that the hydrogen in the substituted amino group may further be replaced with a group R₃ (as defined below) using various reaction conditions well known in the art (e.g., by starting out with a substituted -3 '-amino group). Thus, it should be recognized that substituted amino nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 8 with a first set of substituents B , R_ls R₂ and R₃, wherein another one of the at least two library compounds has a structure according to Formula 8 with a second set of substituents B^PG, Ri, R₂ and R :

Formula !

R — R. R₂

wherein B^PG is a protected or unprotected heterocyclic base, Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl, and R₂ is COW, CSW, SO₂W, CONHW, CSNHW, or W; R₃ is hydrogen or W, wherein W is hydrogen, a functional group, 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, and wherein not all of the substituents B^PG, Ri, R₂, and R₃ in the first set are the same as the substituents B^PG, Ri, R₂, and R₃ in the second set, and wherein • comprises a solid phase.

Consequently, it should be recognized that contemplated compounds may have a structure according to formula 8A

Formula 8A

R₃— N ^" i R₂

wherein B is a heterocyclic base, Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl, and R₂ is COW, CSW, SO₂W, CONHW, CSNHW, and W; R₃ is hydrogen or W, wherein W is a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted aryl, an unsubstituted aryl, a substituted heterocycle, and an unsubstituted heterocycle.

3', 2', 5'-Amino Nucleoside Libraries ( )

The inventors further discovered that nucleoside analog libraries can be prepared in a reaction sequence comprising a multiple component condensation that forms an open-chain substituent on a nucleoside or nucleoside analog, and a particularly preferred aspect is described below.

Scheme 9 depicts a general synthetic approach for a 3', 2', 5'-amino nucleoside library, in which a protected nucleoside with an amino sugar (here: 3'-aminoribofuranose) is coupled via the C5'-atom to a solid phase. The amino group then serves as a nucleophilic group that is used to react with at least one of two substrates in an MCC reaction (a first set of reactions with various first substrates, then a second set of reactions with various second substrates using products from the first set of reactions) to form a substituted linear substituent. It should be particularly appreciated that all combinations of Ri in the sugar and R -R₃ in the substrates will potentially be represented in the so generated library. After formation of the substituted linear substituent, the protecting groups are removed and the sugar is cleaved from the solid phase.

OTBDMS,

-^OTBDMS

etc.

Similar libraries can be made from 2'and 5'-amino nucleosides

Scheme 9

With respect to the sugar, the protecting groups, the heterocyclic base, the solid phase and coupling conditions of the sugar to the solid phase the same considerations as described above for the 3', 2', 5'-Amino Nucleoside Libraries (A) apply. It should further be appreciated that all known methods of producing the C3'- amino nucleosides are considered suitable for use herein, and exemplary methods are described, for example, in Tetrahedron Lett. 1989, 30, 2329-2332; or in Nucleosides Nucleotides 1995, 14, 409-412; or in Reel. Trav. Chim. Pays-Bas, 1986, 105, 85-91.

It is further contemplated that R₂ and R₃ in the substrates may vary considerably, and it is especially contemplated that R₂ and R₃ are independently hydrogen, a functional group, 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. Similarly, Ri may vary considerably and particularly contemplated Ri include hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl. With respect to the protected heterocyclic base it is contemplated that all known heterocyclic bases are appropriate (supra), and especially contemplated heterocyclic bases include guanine, adenenine, cytidine, thymine, uracil, inosine, and all known modifications thereof.

Numerous preparation methods for various first substrates R₂NC are well known in the art and all known protocols to generate such isocyano compounds are considered suitable for use herein (supra). Moreover, numerous isocyano compounds are commercially available and maybe used for synthesis of contemplated libraries. Similarly, numerous second substrates R₂CHO (aldehydes) are commercially available and where particular second substrates are not commercially available, it is contemplated that such aldehydes may be prepared from commercially available precursors using protocols well known in the art (supra).

It should still further be appreciated that the MCC generated linear substituent may also be coupled to atoms other than the C3'-atom of the nucleoside, and alternative positions particularly include the C2'-, and C5'-position (then, the amino group in the amino sugar of the nucleoside is in the corresponding C2'-, and C5'-position).

Thus, it should be recognized that such contemplated nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 9 with a first set of substituents B^PG, Ri, R₂ and R₃, wherein another one of the at least two library compounds has a structure according to Fonnula 9 with a second set of substituents B , Ri, R₂ and R₃:

wherein B^PG is a protected or unprotected heterocyclic base, Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl, and R₂ and R₃ are independently hydrogen, a functional group, 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, and wherein not all of the substituents B^PG, Ri, R₂, and R₃ in the first set are the same as the substituents B^PG, Ri, R₂, and R₃ in the second set, and wherein • comprises a solid phase.

Consequently, it should be recognized that contemplated compounds may have a structure according to formula 9A

Formula 9A

wherein B is a heterocyclic base, Ri is hydrogen, alkyl, alkenyl, alkynyl, O-alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, or S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; R₂ and R₃ are independently hydrogen, a functional group, 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.

N-substituted Benzodiazepine Nucleoside Libraries

The inventors still further discovered that nucleoside analog libraries can be prepared in a reaction sequence comprising a multiple component condensation that forms an N-substituted benzodiazepine heterocyclic base, and one particularly preferred aspect is described below.

Scheme 10 depicts a general synthetic approach for a N-substituted benzodiazepine nucleoside library, in which a protected sugar aldehyde (here: protected 1'- formylribofuranose) is coupled via the C5'-atom to a solid phase. The Ci aldehyde group then serves as an electrophilic group that is used to react with cyclohexylene isocyanate and at least one of two substrates in an MCC reaction (a first set of reactions with various first substrates, then a second set of reactions with various second substrates using products from the first set of reactions) to form a derivatized sugar. Each of the preferred sets of substrates for the MCC reaction includes at least one set of substituents i, R₂, and R₃. In a subsequent reaction, the derivatized sugar is cyclized to the corresponding N-substituted benzodiazepine. It should be particularly appreciated that all combinations of Ri and R₂ in the first set of substrates and R₃ in second set of substrates will potentially be represented in the so generated library. After cyclization, the protecting groups are removed and the sugar is cleaved from the solid phase.

Scheme 10

With respect to the protecting groups, the solid phase and coupling conditions of the l'-aldehyde sugar to the solid phase the same considerations as described above apply.

It should further be appreciated that suitable sugars need not be limited to the Ci-formylribofuranose, and numerous alternative sugars are also contemplated. Particularly preferred alternative sugars include various substituted Ci-formylribofuranoses and substituted and unsubstituted Ci-formylarabinoses, and further contemplated suitable sugars include those listed under the section "Contemplated Sugars". Moreover, it should be appreciated that while it is preferred that the aldehyde group is located on the Ci-carbon atom of the appropriate sugar, various alternative position for the aldehyde group also deemed suitable and include all non-glycosidic carbon atoms (especially C₂, C₃, and C₅). With respect to the first set of reagents, it is contemplated that all known primary amines are suitable for use herein and will have the general structure R-NH₂, wherein R may be 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 be appreciated that all or almost all of such primary amines are commercially available, and where a particular primary amine is not commercially available, it should be recognized that such amines may readily be synthesized from commercially available precursors following procedures 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 Classics in Total Synthesis: Targets, Strategies, Methods, by K. C. Nicolaou, E. J. Sorensen; John Wiley & Son Ltd; ISBN: 3527292314).

With respect to the second set of reagents, it is contemplated that numerous

N-substituted aminobenzoic acids are suitable for use herein, and that such reagents will preferable have one substituent Ri and one protecting/leaving group on the amino group, while the benzene moiety may further comprise a substituent R₃ as indicated in Scheme 10 above. Prefened substituents Ri and R₃ include independently hydrogen, a functional group, 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 is further contemplated that all known protecting groups may be suitable for coupling to the nitrogen atom, however, especially preferred protecting/leaving groups include Boc, and Fmoc. It is generally contemplated that numerous of such second reagents are commercially available. However, where a particular primary amine is not commercially available, it should be recognized that such amines may readily be synthesized from commercially available precursors following procedures well known in the art (supra). Moreover, with respect to the cyclohexylene isocyanate it is contemplated that numerous reagents other than cyclohexylene isocyanate are also appropriate, so long as such reagents include a isocyanate group that is bound to a moiety which can serve as (part of) a leaving group when the heterocyclic base is formed.

Thus, it should be recognized that such contemplated nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 10 with a first set of substituents A, R_ls R₂ and R₃, wherein another one of the at least two library compounds has a structure according to Formula 10 with a second set of substituents A, Ri, R₂ and R₃:

Formula 10

wherein A is a protected or unprotected sugar that is covalently bound to a solid phase, Ri, R₂, and R₃ are independently hydrogen, a functional group, 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, and wherein not all of the substituents A, R_ls R , and R₃ in the first set are the same as the substituents A, Ri, R₂, and R₃ in the second set.

Consequently, it should be recognized that contemplated compounds may have a structure according to formula 10 (supra), wherein A is a protected or unprotected sugar, and Ri, R₂, and R₃ are independently hydrogen, a functional group, 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.

Substituted C-Pyrrole Nucleoside Libraries

The inventors still further discovered that nucleoside analog libraries can be prepared in a reaction sequence comprising a multiple component condensation that forms a substituted C-pyrrole heterocyclic base, and one particularly preferred aspect is described below.

Scheme 11 depicts a general synthetic approach for a substituted C-pyrrole nucleoside library, in which a protected sugar aldehyde (here: protected 1'- formyhibofuranose) is coupled via the C5'-atom to a solid phase. The Ci aldehyde group then serves as an electrophilic group that is used to react with cyclohexylene isocyanate and at least one of two substrates in an MCC reaction (a first set of reactions with various first substrates, and a second set of reactions with various second substrates using products from the first set of reactions) to form a derivatized sugar, and in a subsequent reaction, the heterocyclic base is reacted with an alkynyl having two substituents Ei and E₂ to form a substituted C-pyrrole nucleoside. The protecting groups are removed and the sugar is cleaved from the solid phase. Thus, preferred sets of substrates for the MCC reaction include substituents Ei, E₂, Ri and R₂, respectively, and it should be particularly appreciated that all combinations of Ri and R₂ in the first and second set of substrates and Ei and E₂ in the substituted alkynyl will potentially be represented in the so generated library.

Scheme 11

With respect to the protecting groups, the solid phase and coupling conditions of the 1 '-aldehyde sugar to the solid phase the same considerations as described above for the ribofuranosylimidazole libraries apply. It should further be appreciated that suitable sugars need not be limited to the Ci-formylribofuranose, and numerous alternative sugars are also contemplated. Particularly preferred alternative sugars include various substituted - formylribofuranoses and substituted and unsubstituted Ci-formylarabinoses, and further contemplated suitable sugars include those listed under the section "Contemplated Sugars". Moreover, it should be appreciated that while it is preferred that the aldehyde group is located on the Ci-carbon atom of the appropriate sugar, various alternative position for the aldehyde group also deemed suitable and include all non-glycosidic carbon atoms (especially C₂, C₃, and C₅). With respect to the first set of reagents, it is contemplated that all known primary amines are suitable for use herein and will have the general structure R-NH₂, wherein R may be hydrogen, a functional group, 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 be appreciated that all or almost all of such primary amines are commercially available, and where a particular primary amine is not commercially available, it should be recognized that such amines may readily be synthesized from commercially available precursors following procedures 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 Classics in Total Synthesis: Targets, Strategies, Methods, by K. C. Nicolaou, E. J. Sorensen; John Wiley & Son Ltd; ISBN: 3527292314).

With respect to the second set of reagents, it is contemplated that all known carboxylic acids are suitable for use herein, and will have the general structure R-COOH, wherein R may be hydrogen, a functional group, 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 be appreciated that all or almost all of such carboxylic acids are commercially available, and where a particular carboxylic acid is not commercially available, it should be recognized that such carboxylic acid may readily be synthesized from commercially available precursors following procedures well known in the art (supra).

Furthermore, numerous substituted and unsubstituted alkynyls are contemplated suitable for use herein and appropriate alkynyls will have the general formula R-C≡C-R', wherein R and R' are independently hydrogen, a functional group, 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 be appreciated that all or almost all of such alkynyls are commercially available, and where a particular alkynyl is not commercially available, it should be recognized that such alkynyl may readily be synthesized from commercially available precursors following procedures well known in the art (supra). With respect to the cyclohexylene isocyanate, the same considerations as described above apply.

Thus, it should be recognized that such contemplated nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 11 with a first set of substituents A, Ri, R₂, Ei, and E₂, wherein another one of the at least two library compounds has a structure according to Formula 11 with a second set of substituents A, Ri, R₂, Ei, and E₂:

Formula 11

wherein A is a protected or unprotected sugar that is covalently bound to a solid phase, Ri, R₂, Ei, and E₂ are independently hydrogen, a functional group, 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, and wherein not all of the substituents A, R_1} R₂, Ei, and E₂ in the first set are the same as the substituents A, Ri, R₂, Ei, and E₂ in the second set.

Consequently, it should be recognized that contemplated compounds may have a structure according to formula 11 (supra), wherein A is a protected or unprotected sugar, and Ri, R₂, Ei, and E₂ are independently hydrogen, a functional group, 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. Substituted C-Dihvdropyrimidine Nucleoside Libraries

The inventors also discovered that nucleoside analog libraries can be prepared in a reaction sequence comprising a multiple component condensation that forms a substituted C-dihydropyrimidine heterocyclic base, and one particularly preferred aspect is described below.

Scheme 12 depicts a general synthetic approach for a substituted C- dihydropyrimidine nucleoside library, in which (an optionally protected) sugar aldehyde (here: l'-formylribofuranose) is coupled via the C5'-atom to a solid phase. The Ci aldehyde group then serves as an electrophilic group that is used to react with urea and at least one mono- or disubstituted substrate (having R and Ri substituents) in an MCC reaction to form a C-dihydropyrimidine heterocyclic base. Further reaction of the C-dihydropyrimidine heterocyclic base with a second substrate (substituted primary amine, having an R₂ substituent) will then lead to a substituted C-dihydropyrimidine nucleoside library. The sugar is then cleaved from the solid phase. It should be particularly appreciated that all combinations of R, Ri, and R₂ in the first and second set of substrates will potentially be represented in the so generated library.

Scheme 12

With respect to (the optional protecting groups,) the solid phase and coupling conditions of the 1 '-aldehyde sugar to the solid phase the same considerations as described above for the substituted C-pyrrole apply. It should further be appreciated that suitable sugars need not be limited to the Ci-formylribofuranose, and numerous alternative sugars are also contemplated. Particularly preferred alternative sugars include various substituted Ci-formylribofuranoses and substituted and unsubstituted Ci-formylarabinoses, and further contemplated suitable sugars include those listed under the section "Contemplated Sugars". Moreover, it should be appreciated that while it is preferred that the aldehyde group is located on the Ci-carbon atom of the appropriate sugar, various alternative position for the aldehyde group also deemed suitable and include all non-glycosidic carbon atoms (especially C₂, C₃, and C₅).

With respect to the first set of reagents, it is contemplated that all known beta-oxo- carboxylic acids and acid esters of the general formula Rι-C(O)-CH₂-COOR are suitable for use herein, wherein R and Ri may independently be hydrogen, a functional group, 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 be appreciated that many of such beta-oxo- carboxylic acid esters are commercially available, and where a particular beta-oxo- carboxylic acid ester is not commercially available, it should be recognized that such beta- oxo-carboxylic acid esters may readily be synthesized from commercially available precursors (e.g., beta-oxo-carboxylic acids) following procedures 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 Classics in Total Synthesis: Targets, Strategies, Methods, by K. C. Nicolaou, E. J. Sorensen; John Wiley & Son Ltd; ISBN: 3527292314).

With respect to the second set of reagents, it is contemplated that all known primary amines are suitable for use herein and will have the general structure R-NH₂, wherein R may be hydrogen, a functional group, 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 be appreciated that all or almost all of such primary amines are commercially available, and where a particular primary amine is not commercially available, it should be recognized that such amines may readily be synthesized from commercially available precursors following procedures well known in the art (supra).

Similarly, it is contemplated that the urea may be replaced with various diamines, in ' which the amino groups are terminal amino groups, and wherein at least one of the amino groups may further be substituted. For example, suitable alternative compounds include thiourea, and N-substituted urea.

Thus, it should be recognized that such contemplated nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 12 with a first set of substituents A, Ri, and R₂ wherein another one of the at least two library compounds has a structure according to Formula 12 with a second set of substituents A, R_ls and R Formula 12

wherein A is a protected or unprotected sugar that is covalently bound to a solid phase, and Ri and R₂ are independently hydrogen, a functional group, 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, and wherein not all of the substituents A, Ri, and R₂ in the first set are the same as the substituents A, Ri, and R₂ in the second set.

Consequently, it should be recognized that contemplated compounds may have a structure according to formula 12 (supra), wherein A is a protected or unprotected sugar, and Ri and R₂ are independently hydrogen, a functional group, 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.

Substituted Tetrazole Nucleoside Libraries

The inventors still further discovered that substituted tetrazole nucleoside analog libraries can be prepared in a reaction sequence comprising a multiple component condensation that forms a substituted tetrazole heterocyclic base, and one particularly preferred aspect is described below.

Scheme 13 depicts a general synthetic approach for a substituted tetrazole nucleoside library, in which a protected Cl'-amino-N-formyl sugar (here: l'-amino-N- formylribofuranose) is converted into the corresponding (partially) protected 1 '-isocyano sugar, which is subsequently coupled to a solid phase via the C5' atom of the ribose. The isocyano group then serves as a reactive group that is (directly and/or indirectly) reacted with (sodium) azide, a disubstituted ketone (having substituents Ri and R₂), and a secondary amine (having substituents R₃ and R₄) in an MCC reaction to form a substituted tetrazole nucleoside. The sugar is then cleaved from the solid phase. It should be particularly appreciated that all combinations of Ri, R₂, R₃, and R₄ in the disubstituted ketone and the secondary amine will potentially be represented in the so generated library.

MeNH,

•≤ 5-- R„

HO -δH ⁴

Scheme 13

, With respect to the protecting groups, the solid phase and coupling conditions of the Cl'-amino-N-formyl sugar to the solid phase the same considerations as described above apply. The C -amino-N-formyl sugar can be prepared following procedures well known in the art. It should further be appreciated that suitable sugars need not be limited to Cl'- amino-N-formyl ribofuranose, and numerous alternative sugars are also contemplated. Particularly preferred alternative sugars include various substituted Cl'-amino-N-formyl ribofuranoses and substituted and unsubstituted C -amino-N-formylarabinoses, and still further contemplated suitable sugars include those listed under the section "Contemplated Sugars". Moreover, it should be appreciated that while it is preferred that the amino-N- formyl group is located on the Ci-carbon atom of the appropriate sugar, various alternative position for the aldehyde group also deemed suitable and include all non-glycosidic carbon atoms (especially C₂, C , and C₅).

With respect to the first set of reagents, it is contemplated that all known disubstituted ketones of the general formula Rι-C(O)- R₂ are suitable for use herein, wherein Ri and R₂ may be independently hydrogen, a functional group, 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 be appreciated that many of such disubstituted ketones are commercially available, and where a particular disubstituted ketone is not commercially available, it should be recognized that such disubstituted ketones may readily be synthesized from commercially available precursors following procedures 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 Classics in Total Synthesis: Targets, Strategies, Methods, by K. C. Nicolaou, E. J. Sorensen; John Wiley & Son Ltd; ISBN: 3527292314).

With respect to the second set of reagents, it is contemplated that all known secondary amines are suitable for use herein and will have the general structure R NHR^ wherein R₃ and R-i may be independently hydrogen, a functional group, 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 be appreciated that numerous secondary amines are commercially available, and where a particular secondary amine is not commercially available, it should be recognized that such amines may readily be synthesized from commercially available precursors following procedures well known in the art (supra). Similarly, it is contemplated that the sodium azide may be replaced with various alternative N₃ ^" donors, and suitable N₃ ^" donors include e.g., KN₃ or NaN₃.

Thus, it should be recognized that such contemplated nucleoside libraries with at least two library compounds can be prepared in which one of the at least two library compounds has a structure according to Formula 13 with a first set of substituents A, Ri, R₂, R , and wherein another one of the at least two library compounds has a structure according to Formula 13 with a second set of substituents A, Ri, R₂, R₃, and R₄

Formula 13

wherein A is a protected or unprotected sugar that is covalently bound to a solid phase, and Ri, R₂, R₃, and R₄ are independently hydrogen, a functional group, 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, and wherein not all of the substituents A, Ri, R₂, R₃, and R in the first set are the same as the substituents A, Ri, R , R , and R₄U1 the second set.

Consequently, it should be recognized that contemplated compounds may have a structure according to Formula 13 (supra), wherein A is a protected or unprotected sugar, and Ri, R₂, R₃, and R-i are independently hydrogen, a functional group, 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.

Uses of contemplated libraries and compounds hi one preferred aspects, it is contemplated that the libraries according to the inventive subject matter may be used to facilitate structure-activity analysis of nucleoside- type compounds. For example, where it is known that an enzyme employs a nucleoside as substrate/co-substrate, and where an inhibitor or alternative substrate for the enzyme is desired, contemplated libraries will provide a researcher with rapid information on the impact of a particular substituent in a particular position of the library compound. In a further example, it is contemplated that libraries according to the inventive subject matter will exhibit a significant source of revenue for a seller since in most cases purchase of a library of nucleosides, nucleoside analogs, nucleotides, and/or nucleotide analogs will be less costly to a user than individual synthesis of these compounds.

In yet another example, the library compounds may serve as in vitro and/or in vivo substrates or inhibitors with particularly desirable physicochemical and/or biological properties. Among other uses, the library compounds may act as inhibitors of DNA and/or RNA for various nucleoside-using enzymes, and especially polymerases, reverse transcriptases, and ligases. Therefore, contemplated nucleosides will exhibit particular usefulness as in vitro and/or in vivo antiviral agent, antineoplastic agent, or immunomodulatory agent. 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 (RSN), hepatitis B virus (HBN), hepatitis C virus (HCN), herpes simplex type 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (H1N), influenza A virus, Hanta virus (hemorrhagic fever), human papilloma virus (HPN), 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 apH 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 of the specification to provide numerous formulations for a particular route of administration. In particular, 5. contemplated nucleosides may be modified to render them more soluble in water or other vehicle, which for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.) that are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present 0 compounds for maximum beneficial effect in a patient.

h certain pharmaceutical dosage forms, prodrug forms of contemplated nucleosides may be formed to for various purposes, including reduction of toxicity, increasing the organ or target cell specificity, etc. One of ordinary skill in the art will recognize how to readily modify the present compounds to pro-drug forms to facilitate delivery of active compounds 5 to a target site within the host organism or patient (see above). One of ordinary skill in the art will also take advantage of favorable pharmacokinetic parameters of the pro-drug forms, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect of the compound.

In addition, contemplated compounds may be administered alone or in combination 0 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 iήgredient(s) and pharmaceutically active agents may be administered separately or together and when administered separately this 5 may occur simultaneously or separately in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Among other contemplated agents for combination with contemplated compounds, it is especially preferred that such agents include interferon, and particularly IFN-alpha or IFN-beta (or 0 fragments thereof). Examples

Ribofuranosylimidazole Nucleoside Libraries (Scheme 1)

To a solution of beta-D-ribofuranose-1 -acetate (5 g, 9.91 mmol) in 50 ml of dimethylformamide was added 0.97 g of sodium azide (14.87 mmol). The mixture was stirred at 115 °C for 16 hours under argon and then evaporated. The residue was extracted by chloroform and dried over sodium sulfate. The intermediate 1 was obtained in 82 % yield. To a solution of 2,2-dimethoxypropane (7.0 ml, 57.2 mmol) and p-toluenesulfonate (0.8 g, 4.3 mmol) in 20 ml of dry acetone was added 1 (1.0 g, 5.71 mmol) in 10 ml of dry acetone. The mixture was stirred at room temperature overnight under argon. After evaporation the residue was purified by column chromatography on silica gel eluted with 10% methanol in dichloromethane to give the intermediate 2 in 87 % yield.

Carboxypolystyrene resin (1.0 g, 2.0 mmol/g substitution) was treated with thionyl chloride (0.6 ml, 8.0 mmol) in 8.0 ml of benzene at 80 °C for 6 hours under nitrogen. The resin was filtered and washed with dry benzene three times and dried on vacuum. To the resin in 10 ml of dichloromethane was added of 2 (0.65 g, 3.0 mmol), 0.41 ml of triethylamine (3.0 mmol) and 24.4 mg of dimethylaminopyridine (0.2 mmol). The mixture was stirred for 24 hours at room temperature. The resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum. The intermediate 3 was given in 90 % yield. To the resin 3 (0.91 g) was added 5 ml of THF, 0.5 ml of water and 8.64 ml of 1.0 M trimethylphosphine in THF. The mixture was shaken at room temperature overnight. The resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum. The intermediate 4 was given in 95 % yield.

To the resin 4 (100 mg) was added 0.17 ml of 1.0 M phenylglyoxal hydrate in THF, 0.21 ml of 1.0 M isobutyric acid in methanol, 85 μl of 1.0 M zinc chloride in diethyl ether and 0.17 ml of 1.0 M cyclohexyl isocyanide. The mixture was shaken at room temperature for two days. Then the resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum. The intermediate 5 was given in 74 % yield. To the resin 5 (66 mg) was added 3.0 ml of 4.0 M ammonium acetate. The mixture was shaken at 100 °C for fourteen hours. The resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum to give the intermediate 6. The intermediate 6 was treated with 3.0 ml of 80 % acetic acid in water at 50 °C for four hours. The resin was filtered and washed with dimethylformamide three time, methanol three times, dichloromethane three times and dried on vacuum. To the dried resin was added 1.5 ml of a solution of triethylamine, diethylamine, tetra-butylamine and dichloromethane. The mixture was shaken at room temperature for eighteen hours. Then, the resin was filtered. The filtrate was evaporated to give 12 mg of product 7.

Ribofuranosylimidazole C-Nucleoside Libraries (Scheme 1A)

To a solution of 2,2-dimethoxypropane (7.0 ml, 57.2 mmol) and p-toluenesulfonate (0.8 g, 4.3 mmol) in 20 ml of dry acetone was added beta-D-ribofuranose-1 -carboxylic acid 8 (9.91 mmol) in 10 ml of dry acetone. The mixture was stirred at room temperature overnight under argon. After evaporation the residue was purified by column chromatography on silica gel eluted with 10% methanol in dichloromethane to give the intermediate 9 in 87 % yield.

Carboxypolystyrene resin (1.0 g, 2.0 mmol/g substitution) was treated with thionyl chloride (0.6 ml, 8.0 mmol) in 8.0 ml of benzene at 80 °C for 6 hours under nitrogen. The resin was filtered and washed with dry benzene three times and dried on vacuum. To the resin in 10 ml of dichloromethane was added of 9 (0.65 g, 3.0 mmol), 0.41 ml of triethylamine (3.0 mmol) and 24.4 mg of dimethylaminopyridine (0.2 mmol). The mixture was stirred for 24 hours at room temperature. The resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum. The intermediate 10 was given in 90 % yield.

To the resin 10 (0.91 g) was added 5 ml of THF, 0.5 ml of water and 8.64 ml of 1.0 M trimethylphosphine in THF. The mixture was shaken at room temperature overnight. The resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum. The intermediate 11 was given in 95 % yield. To the resin 11 (100 mg) was added 0.17 ml of 1.0 M phenylglyoxal hydrate in THF, 0.21 ml of 1.0 M isobutyric acid in methanol, 85 μl of 1.0 M zinc chloride in diethyl ether and 0.17 ml of 1.0 M cyclohexyl isocyanide. The mixture was shaken at room temperature for two days. Then the resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum. The intermediate 12 was given in 74 % yield.

To the resin 12 (66 mg) was added 3.0 ml of 4.0 M ammonium acetate. The mixture was shaken at 100°C for fourteen hours. The resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum to give the intermediate. The intermediate was treated with 3.0 ml of 80 % acetic acid in water at 50 °C for four hours. The resin was filtered and washed with dimethylformamide three time, methanol three times, dichloromethane three times and dried on vacuum. To the dried resin was added 1.5 ml of a solution of triethylamine, diethylamine, tetra-butylamine and dichloromethane. The mixture was shaken at room temperature for eighteen hours. Then, the resin was filtered. The filtrate was evaporated to give 12 mg of product 13.

Ribofuranosylbenzodiazepine Libraries (Scheme 2)

To the resin 3 (26.0 g) was added 50 ml of THF, 2.0 ml of water and 105.3 ml of 1.0 M trimethylphosphine in THF. The mixture was shaken at room temperature for four hours. The resin was filtered and washed with dimethylformamide three times methanol three times, dichloromethane three times and dried on vacuum. The intermediate 4 was given in 96 % yield and 1.34 mmol/g substitution. To the resin 4 (225 mg) was added 0.5 ml of dichloromethane, 0.9 ml of 1.0 M phenylglyoxal hydrate in THF, 0.9 ml of 1.0 M Bocanthranilic acid in methanol, 0.15 ml of 1.0 M zinc chloride in diethyl ether and 0.9 ml of 1.0 M benzyl isocyanide. The mixture was shaken at room temperature for two days.

Then the resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum. The intermediate 14 was given in 82 % yield.

To the resin 14 (88 mg) was added 25 % trifluoroacetic acid in dichloromethane. The mixture was shaken at room temperature for two hours. Then the resin was filtered and washed with dimethylformamide three times methanol three times, dichloromethane three times and dried on vacuum. The intermediate 15 was given in 90 % yield. To the resin 15 (70 mg) was added 3.0 ml of a solution of diethylamine, triethylamine, tetra-butylamine and dichloromethane (1 : 1 : 1 : 1). The 25 % trifluoroacetic acid in dichloromethane. The mixture was shaken at room temperature for fourteen hours. The resin was filtered. The filtrate was evaporated to give 7 mg of the product 16 with > 70 % purity.

The following 10 isocyanides were used as building blocks for generation of ribofuranosyl 1,4-benzodiazepine and ribofuranosyl imidazole nucleoside library: lH-benzotriazol-1-ylmethyl isocyanide, p-toluenesulfonyhnethyl isocyanide, 2,6- dimethylphenyl isocyanide, 1,1,3,3-tetramethylbutyl isocyanide, 2-morpholinoethyl isocyanide, tert-butyl isocyanide, cyclohexyl isocyanide, n-butyl isocyanide, benzyl isocyanide and iso-propyl isocyanide.

The following 18 α-ketoaldehydes were used as building blocks for generation of ribofuranosyl 1,4-benzodiazepine and ribofuranosyl imidazole nucleoside library: 4- cyclohexylphenyl glyoxal, 4-biphenyl glyoxal, 2-naphthyl glyoxal, 4-fluorophenyl glyoxal, 4-chlorophenyl glyoxal, 4-bromophenyl glyoxal, 4-methylphenyl glyoxal, 4-hydroxyphenyl glyoxal, 4-methoxyphenyl glyoxal, 2-thiophenyl glyoxal, 3,4-methylenedioxyphenyl glyoxal, 4-nitrophenyl glyoxal, 4-morphlinophenyl glyoxal, 2,4-difluorophenyl glyoxal, 3-carbomethoxy-4-hydroxyphenyl glyoxal, phenyl glyoxal, and methyl glyoxal.

The following 16 carboxylic acids were used as building blocks for generation of ribofuranosyl imidazole nucleoside library: 4-methoxycyclohexanecarboxylic acid, cycloheptanecarboxylic acid, 1-cyclopentene-l -acetic acid, cyclopropanecarboxylic acid, 2-methylcyclopanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclopentylacetic acid, 3-cyclopentylpropionic acid, cyclohexanecarboxylic acid, cyclohexylacetic acid, 3-cyclohexylpropionic acid, 4-methyl-l -cyclohexanecarboxylic acid, 4-methylcyclohexaneacetic acid and tetralιydrofuran-2-carboxylic acid.

The following 8 Boc-2-aminobenzoic acid derivatives were used as building blocks for generation of ribofuranosyl 1,4-benzodiazepine nucleoside library: Boc-2-aminobenzoic acid, 5-bromo-Boc-2-aminobenzoic acid, 4-bromo-Boc-2-aminobenzoic acid, 5-chloro- Boc2-aminobenzoic acid, 5-fluoro-Boc-2-aminobenzoic acid, 3,5-dimethyl-Boc-2- aminobenzoic acid, 3-methoxy-Boc-2-aminobenzoic acid and 5-methyl-Boc-2- aminobenzoic acid.

S',2',5',1 '-Imidazole Substituted Libraries (Scheme 3)

As described above, to the amino-substituted nucleoside attached on the solid support (100 mg) was added 0.17 ml of 1.0 M phenylglyoxal hydrate in THF, 0.21 ml of 1.0 M isobutyric acid in methanol, 85 μl of 1.0 M zinc chloride in diethyl ether and 0.17 ml of 1.0 M cyclohexyl isocyanide. The mixture was shaken at room temperature for two days. Then the resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum. To the dried resin (66 mg) was added 3.0 ml of 4.0 M ammonium acetate. The mixture was shaken at 100 °C for fourteen hours. The resin was filtered and washed with dimethylformamide three times, methanol three times, dichloromethane three times and dried on vacuum. The dried resin was treated with 3.0 ml of 80 % acetic acid in water at 50 °C for four hours. The resin was filtered and washed with dimethylformamide three time, methanol three times, dichloromethane three times and dried on vacuum. To the dried resin was added 1.5 ml of a solution of triethylamine, diethylamine, tetra-butylamine and dichloromethane. The mixture was shaken at room temperature for eighteen hours. Then, the resin was filtered. The filtrate was evaporated to give 12 mg of product.

Dihydropyrimidine N/C Libraries (Scheme 4)

A mixture of 1 '-Amino-2',3 '-diprotected ribose attached on the solid support, isocyanate or isothiocyanate (1 equip) in DMF was shaken for 24 h. The resin was washed 3 times with DMF and dichloromethane. To the dried resin was added 1 equivalent of aldehyde and 1 equivalent of alkene with an electron-withdrawing group in DMF. The mixture was shaken for 24 h at 60 C, and washed with DMF, Methanol and dichloromethane. The resin was subjected to the TFA to cleave the product off the resin. The filtrates were collected to the 96 different vials. The samples were dried and analyzed by LC-MS spectrometry. 3 ',2',5',1 '-Heterocyclic Libraries (A) (Scheme 5)

A mixture of 3'-aminonucleoside attached on solid support and potassium thiocyanate (1 equiv) in methanol was heated at 60 C for 1 hour. Aldehyde or ketone (1 equiv) and isocyanide (1 equiv) were added sequentially. The mixture was shaken at rt for 24 h and the resin was washed with DMF, methanol and dichloromethane. The dried resin was subjected to TFA to cleave the product off the resin. The filtrates from 96 reaction vessels were collected to the 96 different vials. The samples were dried and analyzed by LC-MS spectrometry.

3 ',2',5 ',1 '-Heterocyclic Libraries (B) (Scheme 6)

A mixture of 3 '-aminonucleoside attached on the solid support, mercapto-carboxylic acid and aldehyde was shaken at 80 C for 24 hours. The resins in the 96 reaction vessels were washed with DMF, methanol, and dichloromethane. The dried resins were subjected to the TFA to cleave the products from the solid supports. The samples were dried and analyzed by LC-MS spectrometry.

3 ',2 ',5 ',1 '-Thiadiazolinone Libraries (Scheme 7)

A mixture of 3'-azidonucleoside attached on solid support and isothiocyanate (1 equiv) was shaken at 60 C for 24 hours, following the addition of isocyanate (10 equiv). After heating for 24 h at elevated temperature, the 96 resins were washed and dried. The resins were subjected to TFA to cleave the products from the solid support and collected to 96 different vials. The samples were dried and analyzed by LC-MS spectrometry.

3 ',2 ',5 '-Substituted Amino Libraries (A) (Scheme 8)

A mixture of 3'-aminonuceloside attached on the solid support and the electrophiles as listed in Scheme 9 in DMF was shaken at 60 C for 24 hours. The resins were washed with DMF, methanol and dichloromethane. The dried resins were subjected to the TFA to cleave the products from the solid support. The filtrates from the 96 reaction vessels were collected to the 96 different vials. The samples were dried and analyzed by LC-MS spectrometry. ^■ 3 ',2 ',5 '-Substituted Amino Libraries (B) (Scheme 9)

A mixture of 3'-aminonucleoside attached on the solid support, isocyanide and aldehyde in DMF was shaken at 60 C for 24 hours. The resins were washed with DMF, methanol, and dichloromethane. The 96 resins were subjected to the TFA to cleave the products off the resins. The samples were dried and analyzed by LC-MS spectrometry.

N-substituted Benzodiazepine Nucleoside Libraries (Scheme 10)

Synthesis of l-formaldehyde-2, 3-isopropyledine-β-E⁾-ribofuranose: To a solution of 2,5-anhydro-D-mannose (16.2 g, 100 mmol) in DMF (50 ml) and 2,2'-dimethoxypropane (20 ml) was added toluenesufonic acid ( 0.5 g). The mixture was stirred at room temperature for 16 h and partitioned between NaHCO and EtOAc. The aqueous solution was extracted with EtOAc. The organic phase was washed with water, dried and purified on silica gel column to give 16.9 g product (83 %).

Attachment of the sugar to the carboxypolystyrene: Benzoic acid-functionalized polystyrene-2% divinylbenzene resin was converted to polymer-bound benzoyl chloride by treatment with SOCl₂ (DMF, reflux, 2-3 h). Suspend the polymer-bound benzoyl chloride resin in DCM (10 ml/g resin). Add 1.5 equivalents (based on starting resin substitution) of l-formaldehyde-2, 3-isopropyledine-β-D-ribofuranose. Add 1.5 equivalents (based on starting resin substitution) of triethylamine and 0.1 equivalent of DMAP. The mixture was shaken with a mechanical shaker at room temperature for 24 h. The resin was filtered and washed with DCM, then with 50% (v/v) DCM/methanol, finally with methanol. The resin was dried in vacuo to a constant weight.

Solid-phase synthesis of benzodiazepine derivatives using Ugi reaction: Ninety-six individual reactions were performed in a single 96-well microtiter plate to produce one product per well. For the reaction, 0.014 mmol of the ester-styrene resin per well in MeOH/DCM (1 :2) served as the aldehyde input, and an appropriate isocyanide (10 equiv) as a single input. Twelve amines (10 equivalents) in column 1-12 and eight carboxylic acid (10 equiv) in rows A-H were used for the construction of the library as follows. The esterstyrene resin (1.2 g, 1.5 mmol g) was partitioned equally into a 96-well polyethylene microtiter plate. The eight carboxylic acid (1 M in MeOH, 138 μl, 10 equiv) and twelve amines (1 M in MeOH, 138 μl, 10 equivalents) were each added to the appropriate wells. After 30 min the isocyanide (1 M in DCM, 138 μl, 10 equiv) was added to all the wells. The plate was capped and shaken at room temperature for 24 h and rinsed with DCM (200, μl) and MeOH (200 μl). A 10 % solution of AcCl in MeOH (0.18 ml each) was added and the mixture was heated at 55 °C for 1-6 h. The resin was rinsed with DCM (200 μl) and MeOH (200 μl). A solution of 80% acidic acid was added to all the wells (1.5 ml each). The plate was heated at 90 °C for 16 h. The resin was filtered and washed liberally with MeOH and DCM. The products were removed from the resin, washed into a second 96- well plate with 10 % methylamine in MeOH (0.5 ml, 50 °C for 1 h), and then rinsed with DCM (200 μl) and MeOH (200 μl). The solvents were removed in a reduced-pressure centrifuge.

Substituted C-Pyrrole Nucleoside Libraries (Scheme 11)

Ninety-six individual reactions were performed in a single 96-well microtiter plate to produce one product per well. For the reaction, 0.014 mmol of the ester-styrene resin per well in MeOH/DCM (1 :2) served as the aldehyde input, and an appropriate isocyanide (10 equivalents) as a single input. Twelve amines (10 equivalents) in column 1-12 and eight carboxylic acids (10 equiv) in rows A-H were used for the construction of the library as follows. The ester-styrene resin (0.88 g, 1.5 mmol g) was partitioned equally into a 96-well polyethylene microtiter plate. The eight carboxylic acids (1 M in MeOH, 138 μl, 10 equiv) and twelve amines (1 M in MeOH, 138 μl, 10 equiv) were each added to the appropriate wells. After 30 min the isocyanide (1 M in DCM, 138 μl, 10 equivalents) was added to all the wells. The plate was capped and shaken at room temperature for 24 h and rinsed with DCM (200 μl), MeOH (200 μl) and toluene (200 μl). Appropriate disubstituted acetylene (1 M in toluene, 0.07 mmol, 5 equiv) was added followed by HC1 (3 eqiv as a 1.0 M solution in anhydrous ether). The plate was capped and shaken at 100 °C for 16 h. The resin was rinsed with DCM (200 μl) and MeOH (200 μl). A solution of 80% acidic acid was added to all the wells (1.5 ml each). The plate was heated at 90 °C for 16 h. The resin was washed liberally with MeOH and DCM. The products were removed from the resin, washed into a second 96-well plate with methylamine in MeOH (0.5 ml, 50 °C for 1 h), and then rinsed with DCM (200 μl) and MeOH (200 μl ). The solvents were removed in a reduced-pressure centrifuge.

Substituted C-Tetrahydropyrimidine Nucleoside Libraries (Scheme 12)

Ninety-six individual reactions were performed in a single 96-well microtiter plate to produce one product per well. For the reaction, 0.014 mmol of the ester-styrene resin per well in THF/BTF (1:2) served as the aldehyde input (BTF: benzotrifluoride). Twelve /?-keto ester (10 equiv) and twelve volatile amines (20 equiv) in column 1-12 and eight substituted or non-substituted ureas (10 equiv) in rows A-H were used for the construction of the library as follows. The ester-styrene resin (0.88 g, 1.5 mmol g) was partitioned equally into a 96- well polyethylene microtiter plate. The eight substituted ureas (1 M in THF, 138 μl, 10 equiv) and twelve yS-keto ester (1 M in THF, 138 μl, 10 equiv) were each added to the appropriate wells. A 15 % HC1 solution (10. μl) was added to all the wells. The plate was capped and shaken at 50 °C for 3 days. The resin was rinsed with DCM (200 μl) and MeOH (200 μl). A solution of 80% acidic acid was added to all the wells (1.5 ml each). The plate was heated at 90 °C for 16 h. The resin was washed with MeOH and DCM (3x 0.5 ml) and twelve amines (20 equiv) were added to column 1-12. The plate was capped and heated at 50 °C for 16 h. The products were removed from the resin, washed into a second 96-well plate with methylamine in MeOH (0.5 ml, 50 °C for 1 h), and then rinsed with DCM (200 μl) and MeOH (200 μl ). The solvents were removed in a reduced-pressure centrifuge.

Substituted Tetrazole Nucleoside Libraries (Scheme 13)

5-0- (t-Butyldimethylsilyl)-2,3-O-isopropylidene-β--D-ribofuranosylisocyanide: To a solution of 5-O- (t-Butyldimethylsilyl)-N-formyl-2,3-Ο-isopropylidene-β-£>-ribofuranosyl- amine (3.5 g, 14.9 mmol) in dry CHC1 (70ml) diisopropylamine (5.6 ml) and phosphorus oxychloride (2.1 ml) were added at °C and the mixture stirred at this temperature for 30 min. After a further 16 h at 25 °C the mixture was poured into a solution of Na₂CO₃ (5 g) in water (500 ml) and stirred for 15 min. After workup the oily product was purified by chromatography on silica gel (petroleum ether : ethyl acetate : triethylamine = 50:50:3) to give a colorless oil (2.44 g, 70%). 2,3-O-isopropylidene-β-E>-ribofuranosylisocyanide: To a solution of 5-0- (t- Butyldimethylsilyl)-2, 3-O-isopropylidene-β-E)- ribofuranosylisocyanide (2.40 g, 8.1 mmol) in THF (50ml) was added 1.0 M solution of TBAF in THF (8.91 ml, 8.91 mmol). The mixture was stirred at room temperature for 1 h and evaporated to give an oil. The product was purified by chromatography on silica gel (EtOAc:MeOH, 18:1) to give a colorless oil (1.32g, 82%).

Attachment of the sugar to the carboxypolystyrene: Suspend the polymer-bound benzoyl chloride resin in DCM (10 ml g resin). Add 1.5 equivalents (based on starting resin substitution) of 2, 3-O-isopropylidene-β--D-ribofuranosylisocyanide in Py (1 M) and 0.1 equivalent of DM AP. The mixture was shaken with a mechanical shaker at room temperature for 24 h. The resin was filtered and washed with DCM, then with 50% (v/v) DCM/methanol, finally with methanol. The resin was dried in vacuo to a constant weight.

Solid-phase synthesis of tetrazole derivatives: Ninety-six individual reactions were performed in a single 96-well microtiter plate to produce one product per well. For the reaction, 0.014 mmol of the ester-styrene resin per well in MeOH DCM (1 :2) served as the isocyanide input, and hydrazoic acid (10 equivalents) as a single input. Twelve amines (10 equiv) in column 1-12 and eight aldehydes (10 equiv) in rows A-H were used for the construction of the library as follows. The ester-styrene resin bound isocyanide (0.88 g, 1.5 mmol/g) was partitioned equally into a 96-well polyethylene microtiter plate. The eight aldehydes (1 M in MeOH, 138 μl, 10 equiv) and twelve amines (1 M in MeOH, 138 μl, 10 equiv) were each added to the appropriate wells. Hydraozic acid (108 μl, 5.5 % in benzene, 10 equiv) was each added to all wells. The plate was capped and shaken at room temperature for 16 h. The resin was rinsed with DCM (200 μl) and MeOH (200 μl). A solution of 80% acidic acid was added to all the wells (1.5 ml each). The plate was heated at 90 °C for 16 h. The resin was washed liberally with MeOH and DCM. The products were removed from the resin, washed into a second 96-well plate with methylamine in MeOH (0.5 ml, 50 °C for 1 h), and then rinsed with DCM (200 μl) and MeOH (200 μl ). The solvents were removed in a reduced-pressure centrifuge.

Thus, specific embodiments and applications of substituted MCC libraries and MCC library compounds have been disclosed. It should be apparent, however, to those skilled in the art that many more modifications besides those akeady described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the 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, hi 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 having at least two library compounds, wherein each of the library compounds comprises a heterocyclic base covalently bound to a sugar, and wherein the heterocyclic base is formed by a multiple component condensation.

2. The nucleoside library of claim 1 wherein the heterocyclic base comprises a structure selected from the group consisting of an imidazole, an imidazoline, a thiazolidine, a benzodiazepine, and a dihydropyrimidine.

3. The nucleoside library of claim 2 wherein the heterocyclic base is 1 '-N- glycosidically or l'-C-glycosidically bound to the sugar portion.

4. The nucleoside library of claim 2 wherein the heterocyclic base is 3'-N- glycosidically or 3'-C-glycosidically bound to the sugar.

5. The nucleoside library of claim 1 wherein one of the at least two library compounds has a structure according to Formula 1 or Formula 1A with a first set of substituents A, Ri, R₂, and R₃, wherein another one of the at least two library compounds has a structure according to Formula 1 or Formula 1A with a second set of substituents A, Ri, R₂, and R₃;

Formula 1 Formula 1A

wherein A is selected from the group consisting of R , a protected sugar that is covalently bound to a solid phase, and an unprotected sugar that is covalently bound to a solid phase;

Ri, R₂, R₃, and R₄ are independently selected from the group consisting of hydrogen, a functional group, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted alkynyl, an unsubstituted alkynyl, a substitu- ted aryl, an unsubstituted aryl, a substituted alkaryl, an unsubstituted alkaryl, a 5- membered heterocycle, a 6-membered heterocycle, and a fused heterocycle;

with the proviso that when A is R₄, then one of Ri, R₂, and R₃ is a protected sugar that is covalently bound to a solid phase or an unprotected sugar that is covalently ^' bound to a solid phase; and

wherein not all of the substituents A, Ri, R₂, and R₃ in the first set are the same as the substituents A, Ri, R₂, and R₃ in the second set.

6. A nucleoside having a structure according to Formula 1 or Formula 1 A

Formula 1A

wherein A is selected from the group consisting of R , a protected sugar, and an unprotected sugar;

Ri, R₂, R₃, and R₄ are independently selected from the group consisting of hydrogen, a functional group, 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;

with the proviso that when A is R , then one of Ri, R₂, and R₃ is a protected sugar or an unprotected sugar.

7. The nucleoside 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, and wherein the sugar is in a D-configuration or in an L-configuration.

8. The nucleoside of claim 7 wherein the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to an atom selected from the group consisting of a Ci' atom of the sugar, a C₂' atom of the sugar, a C₃' atom of the sugar, and a carbon atom of R₄.

9. The nucleoside library of claim 1 wherein one of the at least two library compounds has a structure according to Formula 2 with a first set of substituents A, Ri, R₂, and R₃, wherein another one of the at least two library compounds has a structure according to Formula 2 with a second set of substituents A, Ri, R₂, and R₃;

Formula 2

with the proviso that when A is R , then one of Ri, R₂, and R₃ is a protected sugar that is covalently bound to a solid phase or an unprotected sugar that is covalently bound to a solid phase; and

wherein not all of the substituents A, Ri, R₂, and R₃ in the first set are the same as the substituents A, R_1} R₂, and R₃ in the second set.

10. A nucleoside having a structure according to Formula 2

Formula 2

wherein A is selected from the group consisting of R₄, a protected sugar, and an unprotected sugar;

Ri, R₂, R , and R are independently selected from the group consisting of hydrogen, a functional group, 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

11. The nucleoside of claim 10 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.

12. The nucleoside of claim 11 wherein the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to an atom selected from the group consisting of a Ci' atom of the sugar, a C₂' atom of the sugar, a C₃' atom of the sugar, and a carbon atom of R .

13. The nucleoside library of claim 1 wherein one of the at least two library compounds has a structure according to Formula 3 with a first set of substituents B^PG, Ar, Ri, R₂, and R , wherein another one of the at least two library compounds has a structure according to Formula 3 with a second set of substituents B^PG, Ar, Ri, R₂, and R₃;

Formula 3

C¹ wherein B is a protected or unprotected heterocyclic base, and Ar is selected from the group consisting of a substituted aryl, an unsubstituted aryl, a substituted heterocycle, and an unsubstituted heterocycle;

Ri is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, O- alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, and S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl;

R₂ and R₃ are independently selected from the group consisting of hydrogen, a functional group, 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 of the substituents B , Ar, Ri, R₂, and R₃ in the first set are the same as the substituents B^PG, Ar, Ri, R₂, and R₃ in the second set, and wherein • comprises a solid phase.

14. A nucleoside having a structure according to Formula 3 A

Formula 3A

wherein B is a heterocyclic base, and Ar is selected from the group consisting of a substituted aryl, an unsubstituted aryl, a substituted heterocycle, and an unsubstituted heterocycle;

Ri is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, O- alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, and S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; R₂ and R₃ are independently selected from the group consisting of hydrogen, a functional group, 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.

15. The nucleoside library of claim 1 wherein one of the at least two library compounds has a structure according to Formula 4 or Fonnula 4A with a first set of substituents A, E, X, Ri, R , and R₃, wherein another one of the at least two library compounds has a structure according to Formula 4 or Formula 4A with a second set of substituents A, E, X, R_1} R₂, and R₃;

Formula 4 Formula 4A

wherein A is selected from the group consisting of a protected sugar covalently bound to a solid phase, and an unprotected sugar covalently bound to a solid phase;

E is an electron withdrawing group, and X is O or S;

Ri, R₂, and R₃ are independently selected from the group consisting of hydrogen, a functional group, 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 of the substituents A, E, X, Ri, R₂, and R₃ in the first set are the same as the substituents A, E, X, Ri, R₂, and R₃ in the second set.

16. A nucleoside having a structure according to Formula 4 or Formula 4A

Formula 4 Formula 4A

wherein A is selected from the group consisting of a protected sugar, and an unprotected sugar;

E is an electron withdrawing group, and X is O or S; and

Ri, R₂, and R₃ are independently selected from the group consisting of hydrogen, a functional group, a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, ah 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.

17. The nucleoside of claim 16 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.

18. The nucleoside of claim 17 wherein the bond in the N-A covalent bond couples the nitrogen atom of the N-A bond to an atom selected from the group consisting of a Ci' atom of the sugar, a C₂' atom of the sugar, a C₃' atom of the sugar, a C₅' atom of the sugar, and a carbon atom of R₄.

19. The nucleoside library of claim 1 wherein one of the at least two library compounds has a structure according to Formula 5 with a first set of substituents B^PG, Ri, R₂, R₃, and R₄ wherein another one of the at least two library compounds has a structure according to Formula 5 with a second set of substituents B^PG, Ri, R₂, R₃ and R_4; Formula 5

wherein B^P is a protected or unprotected heterocyclic base;

R₂, R₃, and are independently selected from the group consisting of hydrogen, a functional group, 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 of the substituents B^PG, Ri, R , R₃, and R₄ in the first set are the same as the substituents B^PG, Ri, R₂, R₃, and R₄ in the second set, and wherein • comprises a solid phase.

20. A nucleoside having a structure according to Formula 5A

Formula 5A

wherein B is a heterocyclic base; Ri is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, O- alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH,

and S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; and

R₂, R₃, and R are independently selected from the group consisting of hydrogen, a functional group, 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.

21. The nucleoside library of claim 1 wherein one of the at least two library compounds has a structure according to Formula 6 with a first set of substituents B , R_1} R₂, and R₃, wherein another one of the at least two library compounds has a structure according to Formula 6 with a second set of substituents B^PG, Ri, R , and R₃:

Formula 6

wherein B is a protected or unprotected heterocyclic base;

R₂ and R are independently selected from the group consisting of hydrogen, a functional group, 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 of the substituents B^PG, Ri, R₂, and R₃ in the first set are the same as the substituents B^PG, Ri, R₂, and R₃ in the second set, and wherein • comprises a solid phase.

22. A nucleoside having a structure according to Formula 6 A

Formula 6A

wherein B is a heterocyclic base;

Ri is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, O- alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, and S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; and

R₂ and R₃ are independently selected from the group consisting of hydrogen, a functional group, 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.

23. The nucleoside library of claim 1 wherein one of the at least two library compounds has a structure according to Formula 7 with a first set of substituents B , Ri, R₂, and R₃, wherein another one of the at least two library compounds has a structure according to Formula 7 with a second set of substituents B , Ri, R₂, and R _; Formula 7

wherein B C¹ is a protected or unprotected heterocyclic base;

Ri is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, O- alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH , =O, and S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl;

R₂ and R₃ are independently selected from the group consisting of hydrogen, a functional group, a substituted alkyl, an unsubstituted alkyl, a substitμted 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 of the substituents B , Ri, R₂, and R₃ in the first set are the same as f the substituents B , Ri, R₂, and R₃ in the second set, and wherein • comprises a solid phase.

24. A nucleoside having a structure according to Formula 7A

Formula 7A

wherein B is a heterocyclic base; Ri is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, O- alkyl, O-aryl, O-alkenyl, O-alkynyl, OH, protected OH, =CH₂, =O, and S-R, wherein R is alkyl, aryl, alkenyl, and alkynyl; and

R and R₃ are independently selected from the group consisting of hydrogen, a functional group, 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.

25. A nucleoside library having at least two library compounds, wherein each of the library compounds comprises a moiety covalently bound to a sugar, and wherein the moiety is formed by a multiple component condensation.

26. The nucleoside library of claim 25 wherein one of the at least two library compounds has a structure according to Formula 8 with a first set of substituents B^PG, Ri, R₂, and R₃, wherein another one of the at least two library compounds has a structure according to Formula 8 with a second set of substituents B^PG, Ri, R₂, and R _;

Formula 8

R₃-N Ri R₂

wherein B^PG is a protected or unprotected heterocyclic base;

R₂ is selected from the group consisting of COW, CSW, SO₂W, CONHW, CSNHW, and W, and R₃ is hydrogen or W;

wherein W is selected from the group consisting of hydrogen, a functional group, 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 of the substituents B^PG, Ri, R₂, and R₃ in the first set are the same as the substituents B^PG, Ri, R₂, and R₃ in the second set, and wherein • comprises a solid phase.

27. A nucleoside having a structure according to Formula 8A

R₃-N ^"Ri Formula

R₂

wherein B is a heterocyclic base;

R₂ is selected from the group consisting of COW, CSW, SO₂W, CONHW, CSNHW, and W, and R₃ is hydrogen or W; and

wherein W is selected from the group consisting of a substituted alkyl, an unsubstituted alkyl, a substituted alkenyl, an unsubstituted alkenyl, a substituted aryl, an unsμbstituted aryl, a substituted heterocycle, and an unsubstituted heterocycle.

28. A nucleoside library having at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 9 with a first set of substituents B^PG, Ri, R₂, and R₃, wherein another one of the at least two library compounds has a structure according to Formula 9 with a second set of substituents B^PG, R,, R₂, and R_3; Formula 9

wherein B^PG is a protected or unprotected heterocyclic base;

29. A nucleoside having the structure according to Formula 9A

Formula 9A

30. A nucleoside comprising a heterocyclic base covalently bound to a sugar, wherein the heterocyclic base is formed by a multiple component condensation.

31. A nucleoside library having at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 10 with a first set of substituents A, Ri, R₂, and R₃, wherein another one of the at least two library compounds has a structure according to Formula 10 with a second set of substituents A, Rι, R₂, and R₃

Formula 10

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

Ri, R₂, and R₃ are independently hydrogen, a functional group, 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; and

wherein not all of the substituents A, Ri, R₂, and R₃ in the first set are the same as the substituents A, R R₂, and R₃ in the second set.

32. A nucleoside having a structure according to Formula 10

Formula 10

wherein A is a protected or unprotected sugar; and

Ri, R₂, and R₃ are independently hydrogen, a functional group, 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.

33. A nucleoside library having at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 11 with a first set of substituents A, Ri, R , Ei, and E₂, wherein another one of the at least two library compounds has a structure according to Formula 11 with a second set of substituents A, Rι, R₂, Eι, and E₂

Formula 11

wherein A is a protected or unprotected sugar that is covalently bound to a solid phase; Ri, R₂, E_ls and E₂ are independently hydrogen, a functional group, 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; and wherein not all of the substituents A, Ri, R₂, Ei, and E₂ in the first set are the same as the substituents A, Ri, R₂, Ei, and E₂ in the second set.

34. A nucleoside having a structure according to Formula 11

Formula 11

wherein A is a protected or unprotected sugar; and

Ri, R₂, Ei, and E₂ are independently hydrogen, a functional group, 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.

35. A nucleoside library having at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 12 with a first set of substituents A, Ri, and R₂ wherein another one of the at least two library compounds has a structure according to Formula 12 with a second set of substituents A, Ri, and R₂

Formula 12

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

Ri and R₂ are independently hydrogen, a functional group, 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; and '

wherein not all of the substituents A, Rj, and R₂ in the first set are the same as the substituents A, Ri, and R₂ in the second set.

36. A nucleoside having a structure according to Formula 12

* Formula 12

wherein A is a protected or unprotected sugar; and

Ri and R₂ are independently hydrogen, a functional group, 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.

37. A nucleoside library having at least two library compounds, wherein one of the at least two library compounds has a structure according to Formula 13 with a first set of substituents A, Ri, R₂, R₃, and » wherein another one of the at least two library compounds has a structure according to Formula 13 with a second set of substituents A, Ri, R₂ R₃, and R4

Formula 13

wherein A is a protected or unprotected sugar that is covalently bound to a solid phase; Ri, R₂, R₃, and R₄ are independently hydrogen, a functional group, 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; and

wherein not all of the substituents A, Ri, R₂, R₃, and R₄ in the first set are the same as the substituents A, Ri, R₂, R₃, and R₄ in the second set.

38. A nucleoside having a structure according to Formula 13

Formula 13

wherein A is a protected or unprotected sugar; and

Ri, R₂, R₃, and ₄ are independently hydrogen, a functional group, 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.