AU3223200A - Method of synthesizing barbituric acid derivatives and their use for the synthesis of chemical libraries - Google Patents

Description

WO 00/46211 PCTIUSOO/02998 -1 Description METHOD OF SYNTHESIS OF COMPOUNDS OF FORMULA 1 AND THEIR USE FOR THE SYNTHESIS OF CHEMICAL LIBRARIES 5 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: 10 X3 X4 x N R R 3 R 2 0 15 Formula 1 where x, R 2 , R 3 , R", 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. 20 Table of Abbreviations Alloc allyloxycarbonyl BOC tert-butyloxycarbonyl CBZ benzyloxycarbonyl 25 Fmoc 9-fluorenylmethyloxycarbonyl g gram h hour WO 00/46211 PCT/USOO/02998 -2 LC liquid chromatography MS mass spectroscopy ml milliliter mmole millimole 5 min minute M molar Ph phenyl rt room temperature 10 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 15 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 20 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 25 functionalities (e.g. amino, hydroxy, oximo, phenolic, silyl, etc.) for loading of WO 00/46211 PCT/USOO/02998 -3 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 5 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, 10 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), 15 hydroxymethylphenoxy functionalized Tentagel T M resin, Argogel T M 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 20 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 25 contain a terminal functional group linker. The polymeric pin block is then WO 00/46211 PCT/USOO/02998 -4 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 5 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. 10 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 15 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 20 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 25 advantages over solution chemistry, as shown by the ease of purification WO 00/46211 PCT/USOO/02998 -5 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, 5 C.C., Acc. 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). 10 Summary and Objects of the Invention The present invention provides a support template comprising a compound of Formula 1 as follows: x3 x4 0 ? 0 III x -y N N"R" 15 R R 0 15 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 20 template, and x and the remainder of the template comprise a chemical library, where:

R

2 , R 3 , and R" are the same or different and are selected from: WO 00/46211 PCT/USOO/02998 -6 (a) H, (b) mono-, di- and tri-substituted aryl, and (c) CC10 alkyl, C1C10 substituted alkyl, C-CO substituted alkyl-aryl, C1C10 substituted alkenyl, and CrC10 5 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, Cr1C10 alkyloxy, Cr0l-O alkyloxy aryl, C-C 10 aminoalkyl, C-C10 alkylamino, CI-C1o aminoalkyl aryl, CrC10 aminocarbonyl, Cr1C10 aminocarbonylalkyl-aryl, Cr0j-0 thioalkyl, Cr 10 C10 thioalkyl-aryl, C1C10 alkylsulfoxide, C1C10 alkylsulfone, C-CO alkylsulfonamide, C-C10 alkylsulfonamide aryl, C-C1O alkylsulfoxide aryl, C C10 alkylsulfone aryl, Cr1C10 alkyl, aminocarbonylamino C1C-10 alkyl, C1C10 alkyl aminocarbonylamino Cl-C1o alkyl aryl, CI-C1o alkyloxycarbonyl C-C1o alkyl, C-CI alkyloxycarbonyl Cr1C10 alkyl aryl, Cr-CO carboxyalkyl, C-C1O 15 carboxyalkyl aryl, C-C 10 carbonylalkyl, C-C1o carbonylalkyl aryl, CIC1o alkyloxycarbonylamino alkyl, CIC1o alkyloxycarbonylamino alkyl aryl, guanidino, C0I-o alkylCOOH, CrC10 alkylCONH 2 , CrC10 alkenylCOOH, C C1o alkenyl CONH 2 , and where the aryl group of (b) and (c) is selected from: 20 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 25 X 3 and X 4 are the same or different and are selected from: WO 00/46211 PCTUSOO/02998 -7 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: x 3

X

4 -1KN Y NR1 5 RR 0 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 10 template, and x and the remainder of the template comprise a chemical library, where:

R

2 , R 3 , and R" are the same or different and are selected from: (a) H, 15 (b) mono-, di- and tri-substituted aryl, and (c) C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 substituted alkyl-aryl, C 1

-C

10 substituted alkenyl, and C1-C1O substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: 20 H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aryl, CI-C1o aminoalkyl, C1-CO alkylamino, C1-C1o aminoalkyl aryl, Ci-Co aminocarbonyl, C1-C10 aminocarbonylalkyl-aryl, C1-C1o thioalkyl, C1 C10 thioalkyl-aryl, C1-C10 alkylsulfoxide, C1-C10 alkylsulfone, C1-C10 WO 00/46211 PCT/USOO/02998 ~ -8 alkylsulfonamide, C1C10 alkylsulfonamide aryl, CrC10 alkylsulfoxide aryl, C C10 alkylsulfone aryl, C-CO alkyl, aminocarbonylamino Cr1C10 alkyl, C-C10 alkyl aminocarbonylamino C-C10 alkyl aryl, C1C10 alkyloxycarbonyl CrC-10 alkyl, C-C10 alkyloxycarbonyl C1C10 alkyl aryl, C1C-10 carboxyalkyl, C1-C10 5 carboxyalkyl aryl, C1C10 carbonylalkyl, Cr1C10 carbonylalkyl aryl, Cl-Cia alkyloxycarbonylamino alkyl, CI-C1o alkyloxycarbonylamino alkyl aryl, guanidino, C-C1o alkylCOOH, C-CO alkylCONH 2 , C1C10 alkenylCOOH, C C1o alkenyl CONH 2 , and where the aryl group of (b) and (c) is selected from: 10 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 15 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: 20 R3 R2 R 5 O,'VY 1H

R

4 0 where

R

4 and R 5 are the same or different and are selected from: WO 00/46211 PCT/US0O/02998 -9 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, 5 (2) amine-deprotecting the resultant by replacing R 5 with H, and reacting the deprotected resultant with an amine R'NH 2 or an isocyanate R 1 NCO under urea-forming reaction conditions to provide a urea-bound solid support resin of Formula 4 as follows: 10 xR R N.R O H H (3) treating the urea-bound solid support resin of Formula 4 with an acid, followed by cyclization to achieve ring closure of the 15 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 20 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 WO 00/46211 PCT/USOO/02998 -10 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. 5 X3 X4 x RN N Formula 1 where x, R 2, R 3, R", X3 , and X4 are as defined below. 10 Optionally, R 2 and R 3 in Formula 1 may be joined together to form cyclic compounds of Formula 1 a with ring size of 3-8 as follows: 3 2 RR R 15 Formula 1a For instance, the ring system may be selected from: (a) mono-, di-, tri-, or tetra-substituted cyclopropyl, cycl o b utyl, c yclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, WO 00/46211 PCT/USOO/02998 -11 (b) mono-, di-, tri-, or tetra-substituted cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di-, tri-, or tetra-substituted heterocyclic ring 5 system, where 0, 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 10 (f) CrC10 substituted alkyl, Cr-C1o -substituted alkyl-aryl C CIO substituted alkenyl, and CI-C1o substituted alkenyl aryl, where the substituents of (e) and (f) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, CrC10 alkyloxy, C1C10 alkyloxy aryl, CrC10 aminoalkyl, CrC10 alkylamino, CrC10 aminoalkyl 15 aryl, Cl-C 10 aminocarbonyl, CrC-10 aminocarbonylalkyl-aryl, CrC10 thioalkyl, CC10 thioalkyl-aryl, CC10 alkylsulfoxide, CC10 alkylsulfone, CrC10 alkylsulfonamide, CrC-10 alkylsulfonamide aryl, CrC-10 alkylsulfoxide aryl, C C10 alkylsulfone aryl, C0-O alkyl, aminocarbonylamino Cr-CO alkyl, CrC10 alkyl aminocarbonylamino CrC10 alkyl aryl, CI-C10 alkyloxycarbonyl CrC10 20 alkyl, C-C1o alkyloxycarbonyl C1C10 alkyl aryl, C-C1o carboxyalkyl, CI-C1o carboxyalkyl aryl, C-C1o carbonylalkyl, CrC10 carbonylalkyl aryl, CrC10 alkyloxycarbonylamino alkyl, C-CO alkyloxycarbonylamino alkyl aryl, guanidino, Ci-C1o alkylCOOH, CI-CIO alkylCONH 2 , CI-C1o alkenylCOOH, and C1C10 alkenyl CONH 2 , and the like, 25 and where the aryl groups of (e) and (f) are selected from: WO 00/46211 PCT/USOO/02998 -12 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, 5 benthiazolyl, and benzoxazolyl, and the like. Support templates of Formula 1 were synthesized according to Scheme 1 below, x' H + Formula 2 amide-bond R RR O H formation 0 H H' 2<NR5 Formula 3 1) Deprotection Formula A F 2) (Urea Formation) R 1

NH

2 or RNCO Formula acid condensation, R3 R20 cyclization 0 H H Formula 4 10 Scheme 1 where x, R 2 , R 3 , R 5 , R", X 3 , and X 4 are as defined below. In general, Scheme 1 is performed as follows. As represented by @, 15 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 WO 00/46211 PCTUSOO/02998 -13 literature that is described above), functionalized with xH (such as amino, hydroxy, oximo, phenolic, or silyl) where x is a linker (such as NH, 0, CHNO, PhO, or SiH 2 , respectively), provided a functionalized polymer support as shown in Formula 2 (i.e., the functionalized * also may be any of the 5 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 10 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 1

NH

2 ) or an isocyanate (R 1 NCO), under urea-forming standard 15 reaction conditions, provided a urea-bound support resin as shown in Formula 4 (see, Buckman, B. 0. et al, Tet. Lett., 1996, Vol. 37, p. 4439). Reaction of a compound of Formula 4 with an acid, followed by cyclization to achieve ring closure, provided a polymer-bound support template of Formula 1, which may be a polymer-bound solid support template. 20 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: WO 00/46211 PCTIUSOO/02998 -14

R

3

R

2 RN O'H R H Formula A where: 5 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) CC10 alkyl, C-C 10 substituted alkyl, CC10 substituted alkyl-aryl, C-C 10 substituted alkenyl, and C0-IO 10 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, CrC10 alkyloxy, C1C10 alkyloxy aryl, CC10 aminoalkyl, Cl-C1o alkylamino, CrIC1o aminoalkyl aryl, CrC-10 aminocarbonyl, CriC1o aminocarbonylalkyl-aryl, CC10 thioalkyl, 15 CrC10 thioalkyl-aryl, CC10 alkylsulfoxide, C-C10 alkylsulfone, CIC1o alkylsulfonamide, CIC-o alkylsulfonamide aryl, Cl-C1o alkylsulfoxide aryl, C C10 alkylsulfone aryl, CrC-10 alkyl, aminocarbonylamino CC10 alkyl, Cr-CO alkyl aminocarbonylamino CC10 alkyl aryl, Cr-CO alkyloxycarbonyl Cr-C1o alkyl, C1C10 alkyloxycarbonyl C-C10 alkyl aryl, C1C10 carboxyalkyl, CICO 20 carboxyalkyl aryl, Cr-C1o carbonylalkyl, CC10 carbonylalkyl aryl, CI-C10 alkyloxycarbonylamino alkyl, Cl-CO alkyloxycarbonylamino alkyl aryl, guanidino, CrC10 alkylCOOH, C-C1o alkylCONH 2 , C-C1o alkenylCOOH, Ci C1o alkenyl CONH 2 , and the like, and where the aryl group of (b) and (c) is selected from: WO 00/46211 PCT/USOO/02998 -15 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, 5 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. 10 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: N' H R4 0 Formula Aa 15 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:

R

9

R

6

R

10

R

9 R 10 R 7 R R 7 R, Os R N O' H 5-N H

R

4 R Formula Ab Formula Ac WO 00/46211 PCTUSOO/02998 -16 selected from substituted- cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl as in compounds of Formula Ad as follows: 5

R

6 Rio R7 R RN OH 4 0 Formula Ad where R 6 and R 7 , R 6 and RI 0 , or R 9 and Ri 0 may be joined together as a ring to form a fused system with the cyclopentene ring, where the aryl and its 10 substituents are as defined below vis-a-vis (e) and (f), or selected from substituted heterocyclic compounds, where A is 0, S, SO, S02, NH, SO 2 NHR", NCONHR , NCOOR , or NR 8 inserted in the ring systems as in compounds of Formulae Ae and Af as follows: RIO A R6 R6 A R 1 R7 RR O R R

R

5 -N H R 'H '44 R R0 15 Formula Ae Formula Af where the substituents R 4 and R 5 in Formulae Aa-Af are as defined above and where the substituents (R , R 7 , R", R 9 , and RI 0 ) in Formulae Aa-Af are the same or different and are selected from: WO 00/46211 PCT/USOO/02998 ~ -17 (d) H, (e) mono-, di-, and tri-substituted aryl, and (f) CC10 substituted alkyl, Cr1C10 substituted alkyl-aryl, CI-CI substituted alkenyl, and C1C10 substituted alkenyl aryl, 5 where the substituents of (e) and (f) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1C10 alkyloxy, C1C10 alkyloxy aryl, CrC10 aminoalkyl, C1C10 alkylamino, C1C10 aminoalkyl aryl, Cr-CO aminocarbonyl, C-C1o aminocarbonylalkyl-aryl, Cl-C1o thioalkyl, C1C10 thioalkyl-aryl, C1C10 alkylsulfoxide, CICO alkylsulfone, CC10 10 alkylsulfonamide, Cr-C1o alkylsulfonamide aryl, CC10 alkylsulfoxide aryl, C C10 alkylsulfone aryl, Cr-CO alkyl, aminocarbonylamino Cr-CO alkyl, Cr-CO alkyl aminocarbonylamino C-CO alkyl aryl, Cr1C10 alkyloxycarbonyl Cr-C1o alkyl, C-CO alkyloxycarbonyl C-C10 alkyl aryl, Cr-C1o carboxyalkyl, Cr-C10 carboxyalkyl aryl, CrC-10 carbonylalkyl, CrC10 carbonylalkyl aryl, CrC10 15 alkyloxycarbonylamino alkyl, CI-C10 alkyloxycarbonylamino alkyl aryl, guanidino, CrC-10 alkylCOOH, C-C10 alkylCONH 2 , CrC10 alkenylCOOH, C CO 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, 20 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 25 reaction mechanism: WO 00/46211 PCTUSOO/02998 ~ -18 R4NC + NH 2 -CHR-COOH + R 3

-CO-R

2 convertible isocyanide chiral auxiliary ketone or aldehyde

R

1 0H H R3 2 OR R0H 4,R N ORi where R 1 is defined the same 0 H 0 as R 2 and/or R 3 Formula B 1) aryl amine cleavage/hydrolysis, R3 R2 including catalytic hydrogenation 0 H H 0 2) amide cleavage or hydrolysis*, and Formula A 3) amine protection with R 5 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 10 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 15 not limited to R 1 OH is methanol, ethanol, or isopropanol, at about -800C to 220 0 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 WO 00/46211 PCT/USOO/02998 -19 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-C1o alkyl, CI-C1o alkyloxy, C 1

-C

10 alkyloxy aryl, CI-C 10 aminoalkyl, C 1

-C

10 alkylamino, C 1

-C

10 5 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 10 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); 15 benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP); O-benzotriazol-1 -yl-N,N,N',N'-tetramethyluronium hexafluoro phosphate (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 20 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 25 most reactions.

WO 00/46211 PCT/USOO/02998 -20 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 5 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, 10 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'NH 2 ) or an isocyanate (R 1 NCO), where R" is defined the 15 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' 20 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 0 of the desired heterocycle compounds under appropriate conditions (such as by trichloroacetic 25 acid/dichloromethane). Some examples of these transformations provided WO 00/46211 PCT/USOO/02998 -21 desired heterocycle compounds of Formulae B-J, which are referred to as "libraries" prior to cleavage from the support 1, as shown below in Scheme 2. R 17 HN NHR 16 R o2 0 0 oj o 0 NH 0 NH O O N OO N NHOO NNH

H

2 N N N 1 1

H

2 N R N N R1 H N NR R YRxR 2Y H 2 N R X R 2 00 0 B I

R

15 R15 R12 / NH 0 O

N-R

1 3

H

2 N N NsRl H 2 N N

H

2 N N N R O O C D E R 17 HN R1 N 0 Ra2 R1 RHO-NR 0 0 Y 0 N- N-0R 1 8

H

2 N N N....R N 1 H 2 N N N Ri1 H 2 N N N R 0 0 0 5 F G H Scheme 2 WO 00/46211 PCT/USOO/02998 ~ -22 where each of R", R 12 , R 13 , R 14 , R 1 5 , R 16 , R 1 7 , and R 18 is C1-C1o alkyl, C1-C1o aryl, or C1-C10 alkyl-aryl. For example, reaction of Formula I 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 5 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 10 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 15 (R' 5

COCH

2 Br, R' 5

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. 20 When R 7 in Formula B was -CH(CH 2

NHR

7

)NHR

6 , 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.

WO 00/46211 PCTIUSOO/02998 ~ -23 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 0, for instance, the result would be the pendent moiety OH. 5 Laboratory Examples General Methods of Synthesis: Compounds of Formula 1 were prepared according to the general process outlined below in Scheme 1. 10 x H + H Formula 2 x______ R 5 0

R

3

R

2 H HO R 5 Formula 3

R

3

R

2 Formula A Formula 1 0 H0 x R~X "- O0 W 3 N Rma RRH

R

3

R

2 FormulaF 5 0 0 Formula 5 Scheme 1 15 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'- WO 00/46211 PCT/USOO/02998 ~ -24 diisopropylcarbodiimide to produce compounds of Formula 3. Deprotection of the amino moiety in standard conditions, followed by reaction with either an isocyanate (R 1 NCO) or 4-nitrophenyl chloroformate and a primary amine

(R

1

NH

2 ), provided a urea-bound solid support resin of Formula 4. 5 Compounds of Formula 1 were obtained by condensation of Formula 4 with a malonic acid derivative of Formula 6. O O X X2 Formula 6 10 where X 1 = halogen, hydroxy, alkoxy, acyloxy; X2 = halogen, alkoxy, or acyloxy; and preferably, X1 + X2 = OC(CH 3

)

2 0 to provide an intermediate compound of Formula 5. In carrying out the condensation, either reactivity of the amide nitrogen in Formula 4 is 15 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 20 acetic anhydride, N,N'-diisopropylcarbodiimide, oxalyl chloride, or 1,1' carbonyldiimidazole, to provide compounds of Formula 1.

WO 00/46211 PCTIUSOO/02998 -25 Compounds of Formula 1 underwent a variety of chemical transformations and cleavage of the library from *, to yield diverse derivatives, i.e., the desired heterocycle compounds, of Formula 7 O 0 0 x j RN N s' R H R 3 R 2 0 5 Formula 7 where x = 0; R 2 , R 3 , and R" are as defined above; X3 = H, alkyl, arylalkyl, acyl, or N,N'-substituted amidine; X4 = H, alkyl, arylalkyl, acyl, or N,N'-substituted amidine; 10 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. 15 EXAMPLE 1 1 -(1 -carboxy-2-phenyl)ethyl-3-propylbarbituric acid OH041 01r OHO O N N IIZ11O WO 00/46211 PCTIUSOO/02998 ~ -26 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 5 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 10 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 15 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. 20 The slurry was heated at 500C 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 25 vacuum.

WO 00/46211 PCT/USOO/02998 -27 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 5 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 10 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 15 OHO O N N OO 0 I N-Fmoc-phenylalanyl-Wang resin (1 g, loading 1.0 mmol/g, NovaBiochem) was treated with piperidine/dimethylformamide (1:1) for 3 h. 20 The resulting resin was washed with dimethylformamide (3 times), methanol (3 times), and dichloromethane (3 times), and then dried in vacuum. The WO 00/46211 PCT/USOO/02998 ~ -28 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 5 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. 10 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 500C for 5 h. The resulting resin was 15 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. 20 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 25 nitrogen overnight. The resulting resin was washed with dimethylformamide WO 00/46211 PCT/USOO/02998 -29 (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 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)*. 10 EXAMPLE 3 1 -(1 -carboxy)ethyl-3-propylbarbituric acid OHO 0 O O N N 15 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 20 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).

WO 00/46211 PCT/USOO/02998 ~ -30 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. 5 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 500C for 5 h. The resulting resin was filtered 10 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. 15 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. 20 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 25 in vacuum. 1-(1-Carboxy)ethyl-3-propylbarbituric acid was cleaved from the WO 00/46211 PCTIUSOO/02998 -31 dried resin by treatment with trifluoroacetic acid/dichloromethane (1:1) for I h. LC/MS analysis: m/z 243 (M+H)*. EXAMPLE 4 5 1 -(1 -carboxy-2-phenyl)ethyl-3-propylbarbituric acid OHO 'O N N O N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on 10 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. 15 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 20 5,5-dibenzyl-1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid WO 00/46211 PCTUSOO/02998 -32 0 0 OH O N Y N 1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml tetrahydrofuran. The resulting suspension was 5 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. 10 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 15 1-(1-carboxy-2-phenyl)ethyl-5-propionyl-3-propylbarbituric acid WO 00/46211 PCTUSOO/02998 -33 0 O 0 OH O N N 1-(1-carboxy-2-phenyl)ethyl-3-propylbarbituric acid on Wang resin (50 mg) was swelled in 1 ml pyridine. I M propionyl chloride in pyridine (0.25 5 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. 10 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 15 1 -(1 -carboxy-2-phenyl)ethyl-5-(2-butenoyl)-3-propylbarbituric acid WO 00/46211 PCTIUSOO/02998 -34 o 0 0 OH O N N OO 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) 5 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. 10 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 15 1 -(1 -carboxy-2-phenyl)ethyl-5-(3-phenyl-2-((9-fluorenylmethoxycarbonyl) amino)pro-pionyl)-3-propylbarbituric acid WO 00/46211 PCT/USOO/02998 -35 0 0 N O H

O

0 0 OHO N yN 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 5 (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 10 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 15 phenyl)ethyl-3-propylbarbituric acid WO 00/46211 PCT/USOO/02998 -36

NH

2 H 0 N 0 O OxO OH ;): 0 NyN 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 5 N"-(tert-butyloxycarbonyl)-N"-(9-fluorenylmethoxycarbonyl)propionic acid and 1,3-diisopropylcarbodiimide in 1 ml I-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 10 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 15 acid WO 00/46211 PCTUSOO/02998 -37 0 00 0 H N N 2-(4-formyl-3-methoxyphenoxy)ethy polystyrene (100 mg, loading 0.5 mmol/g, Novabiochem) was mixed with triethyl orthoformate (1 ml) and 1 M 5 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 10 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 15 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)*.

WO 00/46211 PCT/USOO/02998 -38 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 5 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/dichloromethane/triethylsilane (25:75:1) for LC/MS analysis: m/z 402 (M+H)*. 10 N,O-bis(trimethylsilyl)acetamide (1 ml) and tetrahydrofuran (1 ml) were added to the obtained resin. The resulting slurry was heated at 500C 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 15 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)*. 20 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.

WO 00/46211 PCT/USOO/02998 -39 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)*. 5 EXAMPLE 11 1 -(1 -carboxy-2-phenyl)ethyl-3-propyl-5-(N,N'-diisopropylamidino)barbituric acid HN N O OH OH 0 N 0N 10 N-(carboxymethylcarbonyl)-N-(propylcarbamoyl)phenylalanine on Wang resin (50 mg) was treated with 1 M N,N'-diisopropylcarbodiimide in 1 methyl-2-pyrrolidinone under nitrogen overnight. The resulting resin was washed with dimethylformamide (5 times), methanol (5 times), and 15 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)*.

WO 00/46211 PCT/USOO/02998 -40 EXAMPLE 12 5-acetyl-3-benzyl-1 -(1 -(2-phenylethylaminocarbonyl)-2-phenyl)ethylbarbituric acid hydrazone

-

NH

2 00 0 N N N H 0 5 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. 10 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)*. 15 EXAMPLE 13 3-benzyl-1 -(1 -(4-methylbenzylaminocarbonyl))ethyl-5,5-bis(phenacyl)bar bituric acid WO 00/46211 PCT/USOO/02998 -41 o 0 0 0 0 N N N | 3-benzyl-1-(1-(4-methylbenzylaminocarbonyl))ethylbarbituric acid on the resin (50 mg) was swelled in 1 ml tetrahydrofuran. The suspension was 5 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. 10 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 15 foregoing description is for the purpose of illustration only, and not for the purpose of limitation-the invention being defined by the claims.

Claims (17)

1. A support template comprising a compound of Formula 1 as follows: 5 x3 4 0 01_ R3 R20 where: of the template comprises a material suitable for a support, 10 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" are the same or different and are selected from: 15 (a) H, (b) mono-, di- and tri-substituted aryl, and (c) Cl-Co alkyl, Cl-C 10 substituted alkyl, C-C 10 substituted alkyl-aryl, CrC-10 substituted alkenyl, and CrC-10 substituted alkenyl aryl, 20 where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C-C 1 o alkyloxy, Cl-C1o alkyloxy aryl, C-C 10 aminoalkyl, CI-C1o alkylamino, CI-C1o aminoalkyl aryl, C1C10 aminocarbonyl, C1C10 aminocarbonylalkyl-aryl, C0i-O thioalkyl, C- WO 00/46211 PCTUSOO/02998 -43 C10 thioalkyl-aryl, Cr1C10 alkylsulfoxide, C-C10 alkylsulfone, C-C 10 alkylsulfonamide, Cr1C10 alkylsulfonamide aryl, C1C10 alkylsulfoxide aryl, C C10 alkylsulfone aryl, C1-C10 alkyl, aminocarbonylamino C-C1o alkyl, Cl-C1o alkyl aminocarbonylamino Cr-C 10 alkyl aryl, CC10 alkyloxycarbonyl Cr0l-o 5 alkyl, Ci-C1o alkyloxycarbonyl Cl-Ci alkyl aryl, C1-C10 carboxyalkyl, CI-CO carboxyalkyl aryl, Ci-C1o carbonylalkyl, Cl-Ci carbonylalkyl aryl, C-Cio alkyloxycarbonylamino alkyl, CrC-10 alkyloxycarbonylamino alkyl aryl, guanidino, C-C1o alkylCOOH, CI-C10 alkylCONH 2 , Ci-Ci alkenylCOOH, Ci C10 alkenyl CONH 2 , 10 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, 15 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, 0, CHNO, PhO, and SiH 2 . 20

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 1a WO 00/46211 PCT/USOO/02998 -44 X3 X4 0 x N N R11 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 5 selected from: (a) mono-, di-, tri-, or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, (b) mono-, di-, tri-, or tetra-substituted cyclopropenyl, 10 cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di-, tri-, or tetra-substituted heterocyclic ring system, where 0, S, SO, S02, NH, or substituted N is inserted in the ring system, 15 where the subtituents in (a), (b), and (c) are selected from: (d) H, (e) mono di- and tri-substituted aryl, and (f) C-C1o substituted alkyl, Cr-C 10 -substituted alkyl-aryl C Ci substituted alkenyl, and Cl-C 10 substituted alkenyl aryl, 20 where the substituents of (e) and (f) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, Cl-Cia alkyloxy, C-C 1 0 alkyloxy aryl, C 1 -C 10 aminoalkyl, C-C 1 0 alkylamino, C-C10 aminoalkyl aryl, C-C 10 aminocarbonyl, C-C10 aminocarbonylalkyl-aryl, C-C 10 thioalkyl, WO 00/46211 PCT/USOO/02998 -45 CI-CI thioalkyl-aryl, Cj-C10 alkylsulfoxide, Ci-C1o alkylsulfone, C-C1o alkylsulfonamide, C-C1O alkylsulfonamide aryl, Cl-C10 alkylsulfoxide aryl, Cj C10 alkylsulfone aryl, Cj-CO alkyl, aminocarbonylamino CIC1o alkyl, CI-C1o alkyl aminocarbonylamino CrC10 alkyl aryl, Cr1C10 alkyloxycarbonyl CI-C10 5 alkyl, Cr-CO alkyloxycarbonyl CIC1o alkyl aryl, CrC10 carboxyalkyl, CC10 carboxyalkyl aryl, C-C1o carbonylalkyl, C-C1o carbonylalkyl aryl, C1C10 alkyloxycarbonylamino alkyl, CIC1o alkyloxycarbonylamino alkyl aryl, guanidino, C-C10 alkylCOOH, C1C10 alkylCONH 2 , C-C1O alkenylCOOH, and CIC1o alkenyl CONIH 2 , 10 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 15 benzoxazolyl.

5. The chemical library cleaved from the support 1 of the template of claim 1, whereby 0 is replaced with H.

6. The cleaved chemical library of claim 5, comprising a compound selected from: 20 0 0 OHO ON N WO 00/46211 PCT/USOO/02998 -46 O 0 OH N N OHO O N N OH O O N yN1 N N O 5 WO 00/46211 PCTIUSOO/02998 -47 0 O 0 OH O N N O O 0 OH;): N N O N O H O 0 0 0 NyN< 5 WO 00/462 11 PCTUSOO/02998 -48 NH 2 H 0 N 0 OH 00 000 N N H N, NH 2 0 0 0 N N H 5 WO 00/46211 PCTIUSOO/02998 -49 o 0 o 0 0 N N N Y 00 OHO OH ON N 5

7. The cleaved chemical library of claim 5, comprising a compound selected from: WO 00/46211 PCT/US0O/02998 -50 R 17 HN NHR 1 6 R 12 0 0 0 o OaO o O N NH 0 O NH H 2 N N N R H 2 N N N R H 2 N N N R O O o 0 0 R15 R O2 O R NH 13 0 0 o H O O 0 N--R O H2N NL N R H 2 N N N R 3 H2NNN NR o 00 R HN X3 X4 R12 0 R1 R"HN H 2 0: 1- 3 N- R 1 8 H2-I N NR1 H 2 N- N" > R1 H 2 N- NR 3 I 1 R xR 2 1 R xR uXR2 0 0 0 and

8. A method of making a support template comprising a 5 compound of Formula I as follows: X3 )4 0 01-, ? jjj"--x R N R3 R20 WO 00/46211 PCT/USOO/02998 -51 where: 1 of the template comprises a material suitable for a support, x of the template comprises a linker for linking to the remainder of the 5 template, and x and the remainder of the template comprise a chemical library, where: R 2 , R 3 , and R" are the same or different and are selected from: (a) H, 10 (b) mono-, di- and tri-substituted aryl, and (c) CrC10 alkyl, Cr-C1o substituted alkyl, C-C 10 substituted alkyl-aryl, Cj-CO substituted alkenyl, and CC10 substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: 15 H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1C10 alkyloxy, Cr-C1o alkyloxy aryl, Cr1C10 aminoalkyl, CrC10 alkylamino, C1C10 aminoalkyl aryl, C1C10 aminocarbonyl, Cr1C10 aminocarbonylalkyl-aryl, C1C10 thioalkyl, C CO thioalkyl-aryl, C1C10 alkylsulfoxide, C1C10 alkylsulfone, CC10 alkylsulfonamide, CC10 alkylsulfonamide aryl, CC10 alkylsulfoxide aryl, C 20 CO alkylsulfone aryl, CC10 alkyl, aminocarbonylamino CIC1o alkyl, CriCO alkyl aminocarbonylamino CC10 alkyl aryl, CrCO alkyloxycarbonyl CrClo alkyl, Cr-CO alkyloxycarbonyl CrC10 alkyl aryl, CI-C1o carboxyalkyl, CC10 carboxyalkyl aryl, CC10 carbonylalkyl, Cr-CO carbonylalkyl aryl, CI-C1o alkyloxycarbonylamino alkyl, CrC10 alkyloxycarbonylamino alkyl aryl, WO 00/46211 PCT/USOO/02998 -52 guanidino, C1-C10 alkylCOOH, C1-C10 alkyICONH 2 , C1-C1o alkenylCOOH, C1 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, 5 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: 10 H, alkyl, arylalkyl, acyl, and N,N'-substituted amidine where said method comprises: (1) coupling a functionalized support *-x-H with a N-protected alpha-amino acid of Formula A as follows: R3 R2 R O,' VY 1H U H 15 R 4 0 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 20 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 1 NH 2 or an WO 00/46211 PCT/USOO/02998 -53 isocyanate R 1 NCO under urea-forming reaction conditions to provide a urea-bound support resin of Formula 4 as follows: R3 R 20 xR N N.'RU 0 H H 5 (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, 0. 10 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 3x 4 0 01- 15 0 R 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: WO 00/46211 PCT/USOO/02998 -54 (a) mono-, di-, tri-, or tetra-substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, (b) mono-, di-, tri-, or tetra-substituted cyclopropenyl, 5 cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and (c) mono-, di-, tri-, or tetra-substituted heterocyclic ring system, where 0, S, SO, S02, NH, or substituted N is inserted in the ring system, 10 where the subtituents in (a), (b), and (c) are selected from: (d) H, (e) mono di- and tri-substituted aryl, and (f) CI-C10 substituted alkyl, C-C 10 -substituted alkyl-aryl C01C10 substituted alkenyl, and C-C1o substituted 15 alkenyl aryl, where the substituents of (e) and (f) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C-C10 alkyloxy, CI-C1O alkyloxy aryl, Cj-C10 aminoalkyl, CI-C1o alkylamino, Cl-C1o aminoalkyl aryl, C-C1O aminocarbonyl, C-C1o aminocarbonylalkyl-aryl, CI-CI thioalkyl, 20 Cj-C1 thioalkyl-aryl, C-C 10 alkylsulfoxide, CI-C1O alkylsulfone, CI-C10 alkylsulfonamide, CI-C10 alkylsulfonamide aryl, C-C1o alkylsulfoxide aryl, C C1O alkylsulfone aryl, Cj-C 10 alkyl, aminocarbonylamino C-C1 alkyl, C-C1o alkyl aminocarbonylamino Cl-CI alkyl aryl, C-C1 alkyloxycarbonyl C-C10 alkyl, C-CIO alkyloxycarbonyl C-C 10 alkyl aryl, C-C1o carboxyalkyl, C-CI 25 carboxyalkyl aryl, C-C1o carbonylalkyl, Cj-C1O carbonylalkyl aryl, C-C10 WO 00/46211 PCT/USOO/02998 -55 alkyloxycarbonylamino alkyl, C1-C1O alkyloxycarbonylamino alkyl aryl, guanidino, C1-C10 alkylCOOH, C1-C10 alkylCONH 2 , C1-CI alkenylCOOH, and C1-C1O alkenyl CONH 2 , and where the aryl groups of (e) and (f) are selected from: 5 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. 10

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' 15 carbonyldiimidazole.

14. The method of claim 8, further including: (a) cleaving the chemical library from the support * of the template, whereby@ is replaced with H.

15. The method of claim 14, wherein the cleaved chemical library 20 comprises a compound selected from: OH O O N y N __ OrT O WO 00/46211 PCTUSOO/02998 -56 O ," 0 OHO N N OHO 0N N OHO O 5 N N 0 N N WO 00/46211 PCT/USOO/02998 -57 0 O 0 OH O N N O 0 0 OH N N 0 O N 0O H O 0 0 0 N~0 5 WO 00/46211 PCTIUSOO/02998 - -58 NH 2 H 0 N 0 O 00 000 N N H N, NH 2 'N' N N H 5 WO 00/46211 PCT/USOO/02998 -59 o 0 0 0 0 N N N Y 00 OH OH ON N 5

16. The method of claim 14, wherein the cleaved chemical library comprises a compound selected from: WO 00/46211 PCT/USOO/02998 -60 R' 7 HN NHR 1 6 R 12 0 0 0 0 0 NH 0 NH H 2 N R 3 RR1] H 2 N N NRR1 H 2 N N NR R 0 0 0 15 R 15 H R NH 0 H 0 0 R HN R H O O O -R1 O N N R H 2 N N N", 11 H 2 N " N 1 H 2 N R R 0 0 R

17 HN R 20 R 1 16 0 0 00 N-R 3 0 0N-R 8 N N R11 HNN Nl R1 2 N l R1 R 2 R 3 R 2f 2 R 3 R 2y 2 R 3 R 2y 0 0 0 and