METHOD OF SYNTHESIZING BARBITURIC ACID DERIVATIVES AND THEIR USE FOR THE SYNTHESIS OF CHEMICAL LIBRARIES

Abstract: A support template of Formula (1).

Description: Description METHOD OF SYNTHESIS OF COMPOUNDS OF FORMULA 1 AND THEIR USE FOR THE SYNTHESIS OF CHEMICAL LIBRARIES Field of the Invention The present invention relates to method of synthesis of compounds of Formula 1 (referred to herein as support templates) as follows: Formula 1 where x, R 2 , R 3 , R 11 , X 3 , and X 4 are as defined below, the use of Formula 1 for the synthesis of chemical libraries, and cleavage of the heterocycle compounds of the libraries to provide compounds of therapeutic use. Table of Abbreviations Alloc allyloxycarbonyl BOC tert-butyloxycarbonyl CBZ benzyloxycarbonyl Fmoc 9-fluorenylmethyloxycarbonyl g gram h hour LC liquid chromatography MS mass spectroscopy ml milliliter mmole millimole min minute M molar Ph phenyl rt room temperature Background of the Invention As is known, solid support synthesis is carried out on a substrate made of a polymer, cross-linked polymer, functionalized polymeric pin, or other insoluble material. These polymers or insoluble materials have been described in the literature and are known to those who are skilled in the art of solid phase synthesis (see, Stewart JM, Young J.D., Solid Phase Peptide Synthesis, 2nd Ed, Pierce Chemical Company, Rockford, Illinois, United States of America, 1984). Some of the supports are based on polymeric organic substrates such as polyethylene, polystyrene, polypropylene, polyethylene glycol, polyacrylamide, and cellulose. Additional types of supports include composite structures such as grafted copolymers and polymeric substrates such as polyacrylamide supported within an inorganic matrix such as kieselghuhr particles, silica gel, and controlled pore glass. Such polymers are substituted with linkers that modulate the stability of the linkage to the support resin. The linkers incorporate reactive functionalities (e.g. amino, hydroxy, oximo, phenolic, silyl, etc.) for loading of monomers suitable for carrying out a plurality of further reactions to synthesize the desired products (see, Hemkens, P. H. H., Ottenheijm, H. C. J., and Rees, D., Tetrahedron Lett., 1996, Vol. 52, pp. 4527-4554). Examples of well known support resins and linkers are given in various reviews (see, Barany, G. and Merrifield, R.B., "Solid Phase Peptide Synthesis", The Peptides - Analysis, Synthesis, Biology, Vol. 2, [Gross, E. and Meienhofer, J., Eds.], Academic Press, Inc., New York, 1979, pp. 1-284, and Backes, B. J. and Ellman, J. A., Curr. Opin. Chem. Biol. 1997, Vol. 1 , p. 86) and in commercial catalogs (see, Advanced ChemTech, Louisville, Kentucky, United States of America and Novabiochem, San Diego, California, United States of America). Some examples of particularly well known functionalized resin/linker combinations that are meant to be illustrative and not limiting in scope include hydroxymethyl polystyrene resin, Wang resin, hydroxymethylbenzoic acid resin (HMBA resin), hydroxymethylphenoxy functionalized Tentagel™ resin, Argogel™ resin, oxime resin, 4-hydroxymethyl-3-methoxyphenoxybutyric acid-BHA resin (HPPB-BHA resin), and polyethylene glycol type A resin (PEGA resin). Also, well known is a type of solid phase synthesis method referred to as the "pin method", which was developed by Geysen et al. and is useful for combinatorial solid-phase peptide synthesis (see, Geysen et al., J. Immunol. Meth., 1987, Vol. 102, pp. 259-274). According to this method, a series of 96 polymeric pins are mounted on a block, in an arrangement and a spacing which correspond to a 96-well microtiter reaction plate, and the surface of each polymeric pin is functionalized (also referred to as derivatized) to contain a terminal functional group linker. The polymeric pin block is then lowered into the 96-well microtiter reaction plate to immerse the pins in the wells of the plate where coupling (i.e., linking) with a compound occurs at the terminal functional group linkers. Next, a plurality of further reactions are carried out in a similar fashion on each compound by having reagents varying in their substituent groups occupy the wells of the plate in a predetermined array, in order to achieve as ultimate products, a unique product on each pin. Each product is then cleaved from each polymeric pin. By using different combinations of substituents, one achieves a large number of different products with an array of central core structures. A related known method of synthesis uses porous polyethylene bags (colloquially referred to as the tea bag method) containing the functionalized solid phase resins referred to above (see, Houghton, R.A., et al., Nature, Vol. 354, pp. 84-86, 1991). These tea bags of resin can be moved from one reaction vessel to another in order to undergo a series of reaction steps for the synthesis of libraries of products. Also known is the use of solubilizable resins that can be rendered insoluble during the synthesis process as solid phase supports. This may be achieved by attachment of linkers to resins that can be solubilized under certain solvent and reaction conditions and rendered insoluble for isolation of reaction products from reagents, for instance, by use of high molecular weight polyethyleneglycol as a solubilizable polymeric support (see, Vandersteen, A. M., Han, H., and Janda, K. D., Molecular Diversity, 1996, Vol. 2, pp. 89-96). Additionally, solid support synthesis is known to provide several advantages over solution chemistry, as shown by the ease of purification and automation of solid support synthesis of peptides (see, Atherton, E. and Sheppard, RC, Solid Phase Peptide Synthesis: A Practical Approach, IRL Press at Oxford University Press, Oxford, 1989) as well as by the ease of purification and automation of non-peptide-based molecules (see, Lenzoff, C.C, Ace. Chem. Res., 1978, Vol. 11, pp. 327-333). Moreover, solid support synthesis of combinatorial libraries has yielded many biologically active compounds (see, Moos, W. H. et al., Annu. Rep. Med. Chem., 1993, Vol. 28, pp. 315-324, and Terrett, N.K., Gardner, M., Gordon, D. W., Kobylecki, R. J., and Steele, J., Tetrahedron, 1995, Vol. 51 , pp. 8135-8173). Summary and Objects of the Invention The present invention provides a support template comprising a compound of Formula 1 as follows: where: of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where: R 2 , R 3 , and R 11 are the same or different and are selected from: (a) H, (b) mono-, di- and tri-substituted aryl, and (c) C1-C10 alkyl, Cι-Cι 0 substituted alkyl, C 1 -C 10 substituted alkyl-aryl, C1-C10 substituted alkenyl, and C 1 -C 10 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C 1 -C 10 alkyloxy, C 1 -C 10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C-C 1 0 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C- 1 -C 1 0 thioalkyl, d- C 1 0 thioalkyl-aryl, C1-C10 alkylsulfoxide, C 1 -C 1 0 alkylsulfone, C 1 -C 1 0 alkylsulfonamide, C 1 -C 1 0 alkylsulfonamide aryl, Cι-C 10 alkylsulfoxide aryl, d- C 10 alkylsulfone aryl, d-do alkyl, aminocarbonylamino C 1 -C 1 0 alkyl, C 1 -C 1 0 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C 1 0 alkyloxycarbonyl C 1 -C 1 0 alkyl, C 1 -C 1 0 alkyloxycarbonyl C Cι 0 alkyl aryl, C- 1 -C 1 0 carboxyalkyl, C 1 -C 1 0 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C1Q carbonylalkyl aryl, CirCio alkyloxycarbonylamino alkyl, C 1 -C 10 alkyloxycarbonylamino alkyl aryl, guanidino, d-Cio alkylCOOH, d-C 10 alkylCONH 2 , d-C 10 alkenylCOOH, d- C 1 0 alkenyl CONH 2 , and where the aryl group of (b) and (c) is selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X 3 and X 4 are the same or different and are selected from: H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine. Also, the present invention provides a method of making a support template comprising a compound of Formula 1 as follows: where: φ of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where: R 2 , R 3 , and R 11 are the same or different and are selected from: (a) H, (b) mono-, di- and tri-substituted aryl, and (c) C1-C10 alkyl, C1-C10 substituted alkyl, d-C 10 substituted alkyl-aryl, C1-C1 0 substituted alkenyl, and C1-C1 0 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, Ci-do alkyloxy, C-i-do alkyloxy aryl, C1-C10 aminoalkyl, d-do alkylamino, C1-C10 aminoalkyl aryl, C1-C10 aminocarbonyl, C 1 -C 10 aminocarbonylalkyl-aryl, d-Cι 0 thioalkyl, d- C10 thioalkyl-aryl, C Cι 0 alkylsulfoxide, d-C 10 alkylsulfone, d-Cio alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C 1 -C 1 0 alkylsulfoxide aryl, Cr C 10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C 1 -C 1 0 alkyl, C1-C 1 0 alkyl aminocarbonylamino C 1 -C 1 0 alkyl aryl, C 1 -C- 10 alkyloxycarbonyl C 1 -C 1 0 alkyl, C 1 -C 1 0 alkyloxycarbonyl C1-C10 alkyl aryl, C 1 -C 1 0 carboxyalkyl, C 1 -C 1 0 carboxyalkyl aryl, C 1 -C10 carbonylalkyl, C 1 -C 1 0 carbonylalkyl aryl, C 1 -C- 1 0 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, C 1 -C10 alkylCOOH, C1-C10 alkylCONH 2 , C C 10 alkenylCOOH, d- C10 alkenyl CONH 2 , and where the aryl group of (b) and (c) is selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X 3 and X 4 are the same or different and are selected from: H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine where said method comprises: (1 ) coupling a functionalized polymer support #-x-H with a N- protected alpha-amino acid of Formula A as follows: where R 4 and R 5 are the same or different and are selected from: H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ, in the presence of an amide-bond forming reagent, (2) amine-deprotecting the resultant by replacing R 5 with H, and reacting the deprotected resultant with an amine R 11 NH 2 or an isocyanate R 11 NCO under urea-forming reaction conditions to provide a urea-bound solid support resin of Formula 4 as follows: (3) treating the urea-bound solid support resin of Formula 4 with an acid, followed by cyclization to achieve ring closure of the ring with the two N, to provide the template of Formula 1. Hence, it is an object of the invention to provide certain novel solid support templates, chemical libraries produced therewith, and cleaved heterocycle compounds of the libraries. Some of the objects of the invention having been stated above, other objects will become evident as the description proceeds, when taken in connection with the Laboratory Examples as best described below. Detailed Description of the Invention The present invention relates to carbonyl-esters or carbonyl-amides linked to insoluble materials as depicted in Formula 1 , and methods for producing chemical libraries generated through a plurality of chemical reactions utilizing support templates of Formula 1. Formula 1 where x, R 2 , R 3 , R 11 , X 3 , and X 4 are as defined below. Optionally, R 2 and R 3 in Formula 1 may be joined together to form cyclic compounds of Formula 1a with ring size of 3-8 as follows: Formula 1a For instance, the ring system may be selected from: (a) mono-, di-, tri-, or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, (b) mono-, di-, tri-, or tetra-substituted cyclopropenyl, cyclobutenyl, cyciopentenyl, cyclohexenyi, cycloheptenyl and cyclooctenyl, and (c) mono-, di-, tri-, or tetra-substituted heterocyclic ring system, where O, S, SO, SO 2 , NH, or substituted N is inserted in the ring system, where the subtituents in (a), (b), and (c) are selected from: (d) H, (e) mono di- and tri-substituted aryl, and (f) C1-C10 substituted alkyl, C1-C10 -substituted alkyl-aryl d- C10 substituted alkenyl, and C1-C10 substituted alkenyl aryl, where the substituents of (e) and (f) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, d-C 10 alkyloxy, d-do alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C1-C10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C-1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, Cι-C 10 alkylsulfone, C1-C10 alkylsulfonamide, d-C o alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, d- C10 alkylsulfone aryl, Cι-C 10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C-1-C10 alkyloxycarbonyl C1-C10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C1 0 carbonylalkyl, C1-C1 0 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C 1 -C 10 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH 2 , C1-C10 alkenylCOOH, and d-Cio alkenyl CONH 2 , and the like, and where the aryl groups of (e) and (f) are selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl, and the like. Support templates of Formula 1 were synthesized according to Scheme 1 below, on) 1 NCO acid condensation, 2O Formula 1 R .R X. 11 N 'R cyclization • N^ O H H Formula 4 Scheme 1 where x, R 2 , R 3 , R 5 , R 11 , X 3 , and X 4 are as defined below. In general, Scheme 1 is performed as follows. As represented by φ, a material suitable for a support (which may be any of the polymers suitable for a support, which may be a solid support, as mentioned in the referenced literature that is described above), functionalized with xH (such as amino, hydroxy, oximo, phenolic, or silyl) where x is a linker (such as NH, O, CHNO, PhO, or SiH 2 , respectively), provided a functionalized polymer support as shown in Formula 2 (i.e., the functionalized φ also may be any of the funtionalized polymer supports, which may be solid supports, as mentioned in the referenced literature that is described above), which was then reacted with a N-protected alpha-amino acid of Formula A (defined below and in Provisional U.S. Patent Application Serial No. 60/116,915, which was filed on January 22, 1999 and which is the priority application of International PCT Application No. , which was filed on January 21, 2000) using standard amide bond forming reactions (described below) to create a polymer-bound amide as shown in Formula 3. Deprotection of the amine moiety of Formula 3 using standard conditions, followed by reaction with an amine (R 11 NH 2 ) or an isocyanate (R 11 NCO), under urea-forming standard reaction conditions, provided a urea-bound support resin as shown in Formula 4 (see, Buckman, B. O. et al, Tet. Lett., 1996, Vol. 37, p. 4439). Reaction of a compound of Formula 4 with an acid, followed by cyciization to achieve ring closure, provided a polymer-bound support template of Formula 1 , which may be a polymer-bound solid support template. More particularly, N-protected alpha-amino acids of Formula A have one or two substituents (R 2 and/or R 3 ) at the alpha position and are defined as follows: Formula A where: R 2 and R 3 are the same or different and are selected from: (a) H, (b) mono-, di- and tri-substituted aryl, and (c) Ci-do alkyl, C1-C10 substituted alkyl, C- 1 -C 1 0 substituted alkyl-aryl, C 1 -C 1 0 substituted alkenyl, and C 1 -C 10 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, CrC 10 alkyloxy, C1-C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, Cι-C 10 aminocarbonyl, C 1 -C 10 aminocarbonylalkyl-aryl, CrC 10 thioalkyl, C 1 -C 1 0 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C 1 -C10 alkylsulfonamide, C1-C-10 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, Ci- do alkylsulfone aryl, C 1 -C 1 0 alkyl, aminocarbonylamino C- 1 -C 1 0 alkyl, C 1 -C 10 alkyl aminocarbonylamino C 1 -C 1 0 alkyl aryl, C 1 -C 1 0 alkyloxycarbonyl C 1 -C 10 alkyl, C- 1 -C 1 0 alkyloxycarbonyl C 1 -C 1 0 alkyl aryl, C Cι 0 carboxyalkyl, C 1 -C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, Cι-C 10 carbonylalkyl aryl, C 1 -C 1 0 alkyloxycarbonylamino alkyl, C 1 -C 10 alkyloxycarbonylamino alkyl aryl, guanidino, C 1 -C10 alkylCOOH, C C 10 aikylCONH 2 , d-Cι 0 alkenylCOOH, d- C 1 0 alkenyl CONH 2 , and the like, and where the aryl group of (b) and (c) is selected from: phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and the like, and where: R 4 and R 5 are the same or different and are selected from: H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ and the like. Optionally, R 2 and R 3 in Formula A are joined together to form cyclic compounds of Formula Aa with a ring size of 3-8 as follows: Formula Aa For instance, the ring system may be selected from substituted- cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl as shown in compounds of Formulae Ab and Ac as follows: Formula Ab Formula Ac selected from substituted- cyciopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl as in compounds of Formula Ad as follows: Formula Ad where R 6 and R 7 , R 6 and R 10 , or R 9 and R 10 may be joined together as a ring to form a fused system with the cyclopentene ring, where the aryl and its substituents are as defined below vis-a-vis (e) and (f), or selected from substituted heterocyclic compounds, where A is O, S, SO, SO 2 , NH, SO 2 NHR 8 , NCONHR 8 , NCOOR 8 , or NR 8 inserted in the ring systems as in compounds of Formulae Ae and Af as follows: FFoorrmmuullaa AAee Formula Af where the substituents R 4 and R 5 in Formulae Aa-Af are as defined above and where the substituents (R 6 , R 7 , R 8 , R 9 , and R 10 ) in Formulae Aa-Af are the same or different and are selected from: (d) H, (e) mono-, di-, and tri-substituted aryl, and (f) C1-C10 substituted alkyl, C1-C10 substituted alkyl-aryl, C 1 -C 10 substituted alkenyl, and C1-C10 substituted alkenyl aryl, where the substituents of (e) and (f) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, Cι-C 10 alkyloxy, C1-C10 alkyloxy aryl, d-do aminoalkyl, C1-C10 alkylamino, C 1 -C 10 aminoalkyl aryl, C1-C-10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C 10 thioalkyl, C1-C-10 thioalkyl-aryl, Cι-C 10 alkylsulfoxide, C1-C10 alkylsulfone, C 1 -C1 0 alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, d- C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C1 0 alkyl, C 1 -C 10 alkyl aminocarbonylamino C-1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C 10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C 0 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C1 0 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, d-C 10 alkylCOOH, C1-C10 alkylCONH 2 , C1-C10 alkenylCOOH, d- C 10 alkenyl CONH 2 , and the like, and where the aryl group of (e) and (f) is selected from: phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and the like. Compounds of Formula A are synthesized according to the following reaction mechanism: R 4 NC NH 2 -CHR-COOH R 3 -CO-R 2 convertible isocyanide chiral auxiliary ketone or aldehyde ned the same Formula B 1) aryl amine cleavage/hydrolysis, R 3 R 2 including catalytic hydrogenation o 2) amide cleavage or hydrolysis * , and - Formula A 3) amine protection with R 5 * lt is noted that when proceeding from Formula B to Formula A, 1 ) may be performed prior to 2), 2) may be performed prior to 1), or 1 ) and 2) may be performed concurrently. Reaction of an appropriate aldehyde or ketone (such as but not limited to phenylacetaldehyde or cyclohexanone) with an amino acid/removable chiral auxiliary or salt thereof (such as but not limited to phenyl glycine, i.e., R is phenyl) and an appropriate convertible isocyanide (such as but not limited to R 4 is phenyl-, cyclohexenyl-, cyclohexyl-, or t- butyl-) utilizing an appropriate solvent and reaction conditions (such as but not limited to R 1 OH is methanol, ethanol, or isopropanol, at about -80°C to 220°C) provided compounds of Formula B. The desired alpha-amino acid of Formula B has a removable amino acid/chiral auxiliary and preferably is selected from compounds where R is mono, di-, tri-, tetra- or penta-substituted aryl, where the aryl is selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, and the like, and the substituents are selected from: H, cyano, amino, C1-C 10 alkyl, C 1 -C 10 alkyloxy, d-do alkyloxy aryl, d-C 10 aminoalkyl, C1-C10 alkylamino, C 1 -C 10 aminoalkyl aryl, and the like. Then, after cleavage of both the chiral auxiliary amine and the amide portions, compounds of Formula B provided the corresponding alpha-amino acids and their derivatives of Formula A. For the attachment of the acid group of Formula A, many reagents are known to be suitable (see, Stewart, J.M. and Young, J.D., Solid Phase Peptide Synthesis, 2nd Ed, Pierce Chemical Company, Rockford, Illinois, United States of America, 1984). Among the many reagents available are: dialkylcarbodiimide with an additive such as 1-hydroxybenzotriazole; especially diispropylcarbodiimide/1 -hydroxy-7-azabenzotriazole (DIC/HABT); benzotriazol-1 -yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP); O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU); bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP); and Fmoc amino acid fluorides (see for instance, Carpino, L.A., et al., "9-Fluorenylmethyloxycarbonyl Amino Acid Fluorides, Convenient New Peptide Coupling Reagents Applicable to the Fmoc/Tert-Butyl Strategy for Solution and Solid-Phase Synthesis", J. Am. Chem.Soc, 1990, Vol. 112, pp. 9651-9652). The degree of steric hindrance, reactivity of the amine, and other factors may determine which reagent will be most suitable for a particular substrate, but many of the reagents will give a suitable result for most reactions. As is conventional, the amine group (NHR 5 of Formula 3) should stay protected (i.e., R 5 should not be H in the group) until it is to be utilized in a reaction sequence. Those skilled in the art will appreciate that any of the wide variety of available amino protecting groups for R 5 may be used such as tert-butyloxycarbonyl (BOC), fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (CBZ), and the like. The choice of a particular protecting group will depend on the specific nature of the substituents and reactions contemplated. Also, more than one type of protecting group may be necessary at any given point in the synthesis (see, e.g., Green, T. and Wuts, P. G. M., Protective Groups In Organic Synthesis 2 nd Ed, Wiley, 1991, and references cited therein). Last, deprotecting of the amine group (NHR 5 of Formula 3) was conducted with standard conditions, and then, the resultant was reacted with an amine (R 11 NH 2 ) or an isocyanate (R 11 NCO), where R 11 is defined the same as R 2 and/or R 3 , to provide the urea-bound support resin (which may be a solid support) of Formula 4, which was then treated with an acid (such as 1 ,3-dichloropropionic acid, malonic acid, their derivatives, and the like) followed by cyclization in the presence of a condensation reagent (such as acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, 1 ,1'- carbonyldiimidazole, and the like) to result in Formula 1. Support templates of Formula 1 (which may be solid support templates) may be reacted with plurality of chemical transformations followed by cleavage from the support φ of the desired heterocycle compounds under appropriate conditions (such as by trichloroacetic acid/dichloromethane). Some examples of these transformations provided desired heterocycle compounds of Formulae B-J, which are referred to as "libraries" prior to cleavage from the support φ, as shown below in Scheme 2. B H Scheme 2 where each of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 is d-C 10 alkyl, C 1 -C 10 aryl, or C1-C10 alkyl-aryl. For example, reaction of Formula 1 with an acid chloride (R 12 COCI, or equivalent) or an alkyl halide (R 12 Br, R 12 CI, R 12 F, or equivalent) using standard conditions followed by cleaving the product from the support (under standard conditions described above) provided compounds of Formula A and Formula C, respectively, after cleavage from the support. Moreover, cyclization of Formula B (prior to cleavage from the support) with an amine (where R 12 = R 14 -CH-NH-R 18 ) followed by cleavage provided compounds of Formula H, after cleavage from the support. On the other hand, reaction of compounds of Formula B (prior to cleavage from the support) with a hydrazine (R 13 NHNH 2 ) provided compounds of Formula G, after cleavage from the support. Also, reaction of Formula 1 with an alpha-halomethyl ketone (R 15 COCH 2 Br, R 15 COCH 2 CI, or R 15 COCH 2 F, or equivalent) provided compounds of Formula E, after cleavage from the support. Additionally, reaction of Formula E (prior to cleavage from the support) with a hydrazine (R 13 NHNH 2 ) provided compounds of Formula D, after cleavage from the support. When R 7 in Formula B was -CH(CH 2 NHR 17 )NHR 16 , compounds of Formula F were obtained, after cleavage from the support. Furthermore, selective amine deprotection (R 16 , R 17 ) of Formula F and cyclization provided compounds of Formula I and Formula J, after cleavage from the support. It is noted that in Formulae B through J, linker x was amine resulting in the pendent moiety NH 2 ; however, if linker x was O, for instance, the result would be the pendent moiety OH. Laboratory Examples General Methods of Synthesis: Compounds of Formula 1 were prepared according to the general process outlined below in Scheme 1. Scheme 1 More specifically, a N-protected alpha-amino acid of Formula A (defined as above) was attached to the solid support of Formula 2 (described above) in the presence of a coupling reagent such as N,N'- diisopropylcarbodiimide to produce compounds of Formula 3. Deprotection of the amino moiety in standard conditions, followed by reaction with either an isocyanate (R 11 NCO) or 4-nitrophenyl chloroformate and a primary amine (R 11 NH 2 ), provided a urea-bound solid support resin of Formula 4. Compounds of Formula 1 were obtained by condensation of Formula 4 with a malonic acid derivative of Formula 6. Formula 6 where X 1 = halogen, hydroxy, alkoxy, acyloxy; X 2 = halogen, alkoxy, or acyloxy; and preferably, X 1 + X 2 = OC(CH 3 ) 2 O to provide an intermediate compound of Formula 5. In carrying out the condensation, either reactivity of the amide nitrogen in Formula 4 is enhanced by treatment with N,O-bis(trimethylsilyl)acetamide or instead the carbonyl moiety in Formula 6 is activated by formation of chloroanhydrides, mixed anhydrides, or active esters. Ring closure occurs via an intermediate compound of Formula 5, which may be isolated, if desired. Compounds of Formula 5 were cyclized in the presence of a condensation reagent, such as acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, or 1 ,1'- carbonyldiimidazole, to provide compounds of Formula 1. Compounds of Formula 1 underwent a variety of chemical transformations and cleavage of the library from φ, to yield diverse derivatives, i.e., the desired heterocycle compounds, of Formula 7 Formula 7 where x = O; R 2 , R 3 , and R 11 are as defined above; X 3 = H, alkyl, arylalkyl, acyl, or N,N'-substituted amidine; X 4 = H, alkyl, arylalkyl, acyl, or N,N'-substituted amidine; and when both X 3 and X 4 are not H, preferably X 3 + X 4 = carbocycle or heterocycle. More specifically, provided were the following acids of Formula 7 as per EXAMPLES 1-12 below. EXAMPLE 1 1 -(1 -carboxy-2-phenyl)ethyl-3-propylbarbituric acid N-Fmoc-phenylalanyl-Wang resin (1 g, loading 1.0 mmol/g, Wang resin supplied by NovaBiochem) was treated with piperidine/dimethylformamide (1 :1 ) for 3 h. The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The resulting resin was swelled in dichloromethane/tetrahydrofuran (1 :1 ), treated with 4-nitrophenyl chloroformate (1.039 g, 5 mmol) and N,N-diisopropylethylamine (0.348 ml, 2 mmol), and stirred at rt for 45 min. The resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol). Propylamine (0.411 ml, 5 mmol) was then added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times). The resulting resin was dried in vacuum. A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1 :1 ) for LC/MS analysis: m/z 251 (M+H) + . N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-(propylcarbamoyl)phenylalanine on Wang resin. The slurry was heated at 50°C for 5 h. The resulting resin was filtered and washed with 1 ,2-dichloroethane. 1 M solution of Meldrum's acid in 1 ,2- dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1 :1) for LC/MS analysis: m/z 337 (M+H) + . N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on Wang resin (500 mg) was swelled in 1 M acetic anhydride/1 ,2- dichloroethane (10 ml). The resulting mixture was agitated by bubbling of nitrogen overnight. The resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. 1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1 :1) for 1 h. LC/MS analysis: m/z 319 (M+H) + . EXAMPLE 2 1-(1-carboxy-2-phenyl)ethyl-3-(4-methylbenzyl)barbituric acid N-Fmoc-phenylalanyl-Wang resin (1 g, loading 1.0 mmol/g, NovaBiochem) was treated with piperidine/dimethylformamide (1 :1 ) for 3 h. The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The resulting resin was swelled in dichloromethane/tetrahydrofuran (1 :1), treated with 4-nitrophenyl chloroformate (1.039 g, 5 mmol) and N,N- diisopropylethylamine (0.348 ml, 2 mmol), and then stirred at rt for 45 min. The resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol). 4-methylbenzylamine (0.656 ml, 5 mmol) was added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times) and dichloromethane (5 times). The resulting resin was dried in vacuum. A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1) for LC/MS analysis: m/z 313 (M+H) + . N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-((4-methylbenzyl)carbamoyl)phenylalanine on Wang resin. The slurry was heated at 50°C for 5 h. The resulting resin was filtered and washed with 1 ,2-dichloroethane. 1 M solution of Meldrum's acid in 1 ,2-dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1 :1) for LC/MS analysis: m/z 399 (M+H) + . N-(carboxymethylcarbonyl)-N-((4-methylbenzyl)carbamoyl)phenylala- nine on Wang resin (500 mg) was swelled in 1 M acetic anhydride/1 ,2- dichloroethane (10 ml). The resulting mixture was agitated by bubbling of nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then suspended in 1 M acetic anhydride/1 ,2-dichloroethane (10 ml). The resulting mixture was again agitated by bubbling of nitrogen overnight, washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. The resulting product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1 :1 ) for 1 h. LC/MS analysis: m/z 381 (M+H) + . EXAMPLE 3 1 -(1 -carboxy)ethyl-3-propylbarbituric acid N-Fmoc-alanyl-Wang resin (1 g, loading 1.0 mmol/g, NovaBiochem) was treated with piperidine/dimethylformamide (1:1 ) for 3 h. The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The resulting resin was swelled in dichloromethane/tetrahydrofuran (1 :1), treated with 4- nitrophenyl chloroformate (1.039 g, 5 mmol), and N,N-diisopropylethylamine (0.348 ml, 2 mmol), and then stirred at rt for 45 min. The resulting resin was washed with dichloromethane (4 times) and swelled in 10 ml of dimethylformamide and N,N-diisopropylethylamine (0.348 ml, 2 mmol). Propylamine (0.411 ml, 5 mmol) was added to the resulting mixture. The reaction mixture was stirred for 40 min, and the resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times). The resulting resin was dried in vacuum. A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1 :1) for LC/MS analysis: m/z 175 (M+H) + . N,O-bis(trimethylsilyl)acetamide (2.5 ml) and tetrahydrofuran (2.5 ml) were added to obtained N-(propylcarbamoyl)alanine on Wang resin. The resulting slurry was heated at 50°C for 5 h. The resulting resin was filtered and washed with 1 ,2-dichloroethane. 1 M solution of Meldrum's acid in 1 ,2- dichloroethane (10 ml) was added, and the reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane (1:1) for LC/MS analysis: m/z 261 (M+H) + . N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)alanine on Wang resin (500 mg) was swelled in 1 M acetic anhydride/1 ,2-dichloroethane (10 ml). The resulting mixture was agitated by bubbling of nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then suspended in 1 M acetic anhydride/1 ,2-dichloroethane (10 ml). The resulting mixture was again agitated by bubbling of nitrogen overnight, washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. 1-(1-Carboxy)ethyl-3-propylbarbituric acid was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1 :1) for 1 h. LC/MS analysis: m/z 243 (M+H) + . EXAMPLE 4 1 -(1 -carboxy-2-phenyl)ethyl-3-propylbarbituric acid N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on Wang resin (50 mg) was swelled in 1 ml of 1 M solution of 1 ,1'- carbonyldiimidazole in 1 ,2-dichloroethane. The resulting mixture was agitated by bubbling of nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. 1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1 :1 ) for 1 h. LC/MS analysis: m/z 319 (M+H) + . EXAMPLE 5 5,5-dibenzyl-1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid 1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml tetrahydrofuran. The resulting suspension was treated with 1 M tetrabutylammonium tetrafluoroborate (0.2 ml) for 2 h. After addition of 1 M benzyl bromide in tetrahydrofuran (1 ml), the reaction was continued for another 2 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. 5,5-dibenzyl-1 -(1 -carboxy-2-phenyl)ethyl-3-propylbarbituric acid was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1) for 1 h. LC/MS analysis: m/z 499 (M+H) + . EXAMPLE 6 1 -(1 -carboxy-2-phenyl)ethyl-5-propionyl-3-propylbarbituric acid 1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml pyridine. 1 M propionyl chloride in pyridine (0.25 ml) was dissolved in 1-methyl-2-pyrrolidinone (1 ml). Suspension of the resulting resin in pyridine and solution of propionyl chloride were combined. The resulting reaction mixture was allowed to stand for 0.5 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1 :1 ) for 1 h. LC/MS analysis: m/z 375 (M+H) + . EXAMPLE 7 1 -(1 -carboxy-2-phenyl)ethyl-5-(2-butenoyl)-3-propylbarbituric acid 1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml pyridine. 1 M crotonyl chloride in pyridine (0.25 ml) was dissolved in 1-methyl-2-pyrrolidinone (1 ml). Suspension of the resulting resin in pyridine and solution of crotonyl chloride were combined. The resulting reaction mixture was allowed to stand for 0.5 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1) for 1 h. LC/MS analysis: m/z 387 (M+H) + . EXAMPLE 8 1 -(1 -carboxy-2-phenyl)ethyl-5-(3-phenyl-2-((9-fluorenylmethoxycarbonyl) amino)pro-pionyl)-3-propylbarbituric acid 1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was treated with 0.025 M symmetric anhydride prepared in situ from N- (9-fluorenylmethoxycarbo-nyl)phenylalanine and 1 ,3-diisopropylcarbodiimide in 1 ml 1-methyl-2-pyrrolidinone for 4.5 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1 :1 ) for 1 h. LC/MS analysis: m/z 688 (M+H) + . EXAMPLE 9 5-(2-amino-3-((9-fluorenylmethoxycarbonyl)amino)propionyl)-1-(1-carboxy-2- phenyl)ethyl-3-propylbarbituric acid 1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was treated with 0.025 M symmetric anhydride prepared in situ from N α -(tet -butyloxycarbonyl)-N ω -(9-fluorenylmethoxycarbonyl)propionic acid and 1 ,3-diisopropylcarbodiimide in 1 ml 1-methyl-2-pyrrolidinone for 4.5 h. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1 :1 ) for 1 h. LC/MS analysis: m/z 627 (M+H) + . EXAMPLE 10 5-acetyl-3-benzyl-1-(1-(2-Phenylethylaminocarbonyl)-2-phenyl)ethylbarbituric acid 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene (100 mg, loading 0.5 mmol/g, Novabiochem) was mixed with triethyl orthoformate (1 ml) and 1 M 2-phenylethylamine in 1 ,2-dichloroethane (1 ml). Nitrogen was bubbled into the resulting slurry for 2 h. The resulting solution was removed by suction, and the resulting resin was treated with 1 M sodium cyanoborohydride in tetrahydrofuran (1 ml) and 1% acetic acid in N,N-dimethylformamide (1 ml) overnight under nitrogen. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. The resulting resin was treated with 0.25 M symmetric anhydride prepared in situ from N-(9- fluorenylmethoxycarbonyl)phenylalanine and 1 ,3-diisopropylcarbodiimide in 3 ml 1-methyl-2-pyrrolidinone overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried. A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for LC/MS analysis: m/z 491 (M+H) + . The resin was treated with piperidine/dimethylformamide (1:1 ) for 3 h, then washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. 1 M benzyl isocyanate in 1 ,2-dichloroethane (3 ml) was added to the resulting resin. The resulting mixture was agitated for 4h. The resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried. A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichioromethane/triethylsilane (25:75:1) for LC/MS analysis: m/z 402 (M+H) + . N,O-bis(trimethylsilyl)acetamide (1 ml) and tetrahydrofuran (1 ml) were added to the obtained resin. The resulting slurry was heated at 50°C for 5 h. The resulting resin was filtered and washed with 1 ,2-dichloroethane. 1 M solution of Meldrum's acid in 1 ,2-dichloroethane (3 ml) was added to the resulting resin. The reaction mixture was allowed to stand overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. A sample of the dried resin (5 mg) was cleaved by trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1) for LC/MS analysis: m/z 488 (M+H) + . The resin was swelled in 1 M acetic anhydride/1 ,2-dichloroethane (3 ml). The resulting mixture was agitated by bubbling of nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1 ) for 1 h. LC/MS analysis: m/z 512 (M+H) + . EXAMPLE 11 1-(1-carboxy-2-phenyl)ethyl-3-propyl-5-(N,N'-diisopropylamidino)barbituric acid N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on Wang resin (50 mg) was treated with 1 M N,N'-diisopropyicarbodiimide in 1- methyl-2-pyrrolidinone under nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and dichloromethane (5 times), and then dried in vacuum. The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1 ) for 1 h. LC/MS analysis: m/z 445 (M+H) + . EXAMPLE 12 5-acetyl-3-benzyl-1-(1-(2-phenylethylaminocarbonyl)-2-phenyl)ethylbarbituric acid hydrazone 5-acetyl-3-benzyl-1 -(1 -(2-phenylethylaminocarbonyl)-2-phenyl) ethylbarbituric acid on resin (50 mg) (see Example 11 ) was treated with 0.7 M hydrazine hydrate in 1-methyl-2-pyrrolidinone under nitrogen overnight. The resin was washed with dimethylformamide (5 times), methanol (5 times) and dichloromethane (5 times) and dried under vacuum. The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1) for 1 h. LC/MS analysis: m/z 526 (M+H) + . EXAMPLE 13 3-benzyl-1-(1-(4-methylbenzylaminocarbonyl))ethyl-5,5-bis(phenacyl)bar- bituric acid 3-benzyl-1 -(1 -(4-methylbenzylaminocarbonyl))ethylbarbituric acid on the resin (50 mg) was swelled in 1 ml tetrahydrofuran. The suspension was treated with 1 M tetrabutylammonium tetrafluoroborate (0.2 ml) for 2 h. After addition of 1 M 2-bromoacetophenone in tetrahydrofuran (1 ml), the reaction was continued for another 2 h. The resin was washed with dimethylformamide (5 times), methanol (5 times) and dichloromethane (5 times) and dried under vacuum. The product was cleaved from the dried resin by treatment with trifluoroacetic acid/dichloromethane/triethylsilane (25:75:1) for 1 h. LC/MS analysis: m/z 630 (M+H) + . It will be understood that various details of the invention may be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation — the invention being defined by the claims.

Claims: CLAIMS What is claimed is: 1. A support template comprising a compound of Formula 1 as follows: where: φ of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where: R 2 , R 3 , and R 11 are the same or different and are selected from: (a) H, (b) mono-, di- and tri-substituted aryl, and (c) d-Cio alkyl, C1-C10 substituted alkyl, C1-C10 substituted alkyl-aryl, C 1 -C 1 0 substituted alkenyl, and d-C 10 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C 1 -C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C 1 -C 10 aminocarbonyl, C 1 -C 1 0 aminocarbonylalkyl-aryl, d-Cio thioalkyl, C C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C1 0 alkylsulfone, C 1 -C 10 alkylsulfonamide, C1-C10 alkylsulfonamide aryl, C1-C1 0 alkylsulfoxide aryl, d- C 10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C 1 -C1 0 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C1 0 carboxyalkyl, C 1 -C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C 1 -C1 0 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH 2 , C1-C10 alkenylCOOH, d- C 10 alkenyl CONH 2 , and where the aryl group of (b) and (c) is selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X 3 and X 4 are the same or different and are selected from: H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine. 2. The support template of claim 1 , where linker x is selected from NH, O, CHNO, PhO, and SiH 2 . 3. The solid support template of claim 1 , where the groups R 2 and R 3 are joined together to form cyclic compounds with a ring system as represented by Formula 1 a where the ring system has a ring size of 3 to 8 members. 4. The support template of claim 3, where the ring system is selected from: (a) mono-, di-, tri-, or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, (b) mono-, di-, tri-, or tetra-substituted cyciopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di-, tri-, or tetra-substituted heterocyclic ring system, where O, S, SO, SO 2 , NH, or substituted N is inserted in the ring system, where the subtituents in (a), (b), and (c) are selected from: (d) H, (e) mono di- and tri-substituted aryl, and (f) C1-C 1 0 substituted alkyl, C1-C10 -substituted alkyl-aryl d- C10 substituted alkenyl, and C 1 -C 1 0 substituted alkenyl aryl, where the substituents of (e) and (f) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C 1 0 alkyloxy, C 1 -C 1 0 alkyloxy aryl, C 1 -C 1 0 aminoalkyl, C 1 -C10 alkylamino, C1-C10 aminoalkyl aryl, C 1 -C 10 aminocarbonyl, C 1 -C 10 aminocarbonylalkyl-aryl, C 1 -C 0 thioalkyl, C1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C1 0 alkylsulfonamide, C1-C1 0 alkylsulfonamide aryl, C 1 -C 10 alkylsulfoxide aryl, d- C 10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C1 0 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C1 0 alkyl, C 1 -C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C 10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C1-C10 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH 2 , C1-C10 alkenylCOOH, and C1-C10 alkenyl CONH 2 , and where the aryl groups of (e) and (f) are selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl. 5. The chemical library cleaved from the support φ of the template of claim 1 , whereby φ is replaced with H. 6. The cleaved chemical library of claim 5, comprising a compound selected from: and 7. The cleaved chemical library of claim 5, comprising a compound selected from: and 8. A method of making a support template comprising a compound of Formula 1 as follows: where: φ of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the template, and x and the remainder of the template comprise a chemical library, where: R 2 , R 3 , and R 11 are the same or different and are selected from: (a) H, (b) mono-, di- and tri-substituted aryl, and (c) C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 substituted alkyl-aryl, C1-C1 0 substituted alkenyl, and C1-C 0 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, C1-C 10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C -C10 aminocarbonyl, C1-C1 0 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, d- C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 alkylsulfonamide, C1-C1 0 alkylsulfonamide aryl, C1-C10 alkylsulfoxide aryl, d- C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C1-C10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C 1 -C 0 alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH 2 , C1-C10 alkenylCOOH, d- C 10 alkenyl CONH 2 , and where the aryl group of (b) and (c) is selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and X 3 and X 4 are the same or different and are selected from: H, alkyl, arylalkyl, acyl, and N,N '-substituted amidine where said method comprises: (1 ) coupling a functionalized support φ-x-H with a N-protected alpha-amino acid of Formula A as follows: where R 4 and R 5 are the same or different and are selected from: H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ, in the presence of an amide-bond forming reagent, (2) amine-deprotecting the resultant by replacing R 5 with H, and reacting the deprotected resultant with an amine R 11 NH 2 or an isocyanate R 11 NCO under urea-forming reaction conditions to provide a urea-bound support resin of Formula 4 as follows: (3) treating the urea-bound support resin of Formula 4 with an acid, followed by cyclization to achieve ring closure of the ring with the two N, to provide the template of Formula 1. 9. The method of claim 8, where linker x is selected from NH, O. CHNO, PhO, and SiH 2 . 10. The method of claim 8, where the groups R 2 and R 3 are joined together to form cyclic compounds with a ring system as represented by Formula 1a where the ring system has a ring size of 3 to 8 members. 11. The method of claim 10, where the ring system is selected from: (a) mono-, di-, tri-, or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, (b) mono-, di-, tri-, or tetra-substituted cyciopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di-, tri-, or tetra-substituted heterocyclic ring system, where O, S, SO, SO 2 , NH, or substituted N is inserted in the ring system, where the subtituents in (a), (b), and (c) are selected from: (d) H, (e) mono di- and tri-substituted aryl, and (f) C1-C10 substituted alkyl, C1-C10 -substituted alkyl-aryl C1-C1 0 substituted alkenyl, and C1-C10 substituted alkenyl aryl, where the substituents of (e) and (f) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, C1-C10 aminoalkyl, C1-C10 alkylamino, C1-C10 aminoalkyl aryl, C 1 -C 10 aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C10 thioalkyl, C1-C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 alkylsulfonamide, C -C10 alkylsulfonamide aryl, C1-C1 0 alkylsulfoxide aryl, d- C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C1-C10 alkyl, C1-C10 alkyl aminocarbonylamino C1-C10 alkyl aryl, C1-C10 alkyloxycarbonyl C1-C10 alkyl, C 1 -C 10 alkyloxycarbonyl C1-C10 alkyl aryl, C1-C 10 carboxyalkyl, C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkyl, C1-C10 carbonylalkyl aryl, C1-C10 alkyloxycarbonylamino alkyl, C 1 -C 1 0 alkyloxycarbonylamino alkyl aryl, guanidino, C 1 -C 1 0 alkylCOOH, C 1 -C 1 0 alkylCONH 2 , C 1 -C 10 alkenylCOOH, and C1-C10 alkenyl CONH 2 , and where the aryl groups of (e) and (f) are selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl. 12. The method of claim 8, where in step (3), the acid is selected from 1 ,3-dichloropropionic acid, malonic acid, and their derivatives. 13. The method of claim 8, where in step (3), cyclization is conducted in the presence of a condensation reagent selected from acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, and 1 ,1 '- carbonyldiimidazole. 14. The method of claim 8, further including: (a) cleaving the chemical library from the support φ of the template, whereby φ is replaced with H. 15. The method of claim 14, wherein the cleaved chemical library comprises a compound selected from: and 16. The method of claim 14, wherein the cleaved chemical library comprises a compound selected from: and

Inventors: MJALLI ADNAN M M, MJALLI, ADNAN, M., M.
Applicants: MJALLI ADNAN M M, TRANSTECH PHARMA, MJALLI, ADNAN, M., M.
Application year: 2000
Main classification: C07D239
IPC codes: C07B61, C07D239, C07F7