CA2191203A1 - Systematic modular production of aminimide- and oxazolone- based molecules having at least two structural diversity elements - Google Patents

Abstract

Aminimide- and oxazolone-based molecules, and arrays thereof, having at least two structural diversity elements are made via systematic modular production. A combinatorial library of aminimide- and oxazolone-based molecules is made via systematic modular production.

Description

W0 95/32184 2 1 9 i 2 0 3 I ~/u~
SYST13~TIC J~OD~ AR PRUWu~Luh OF AMTrirTMTnE- AND OXAZOr~ONE-BASED r~r.r!CZ7r.~.q ~IAVING AT I,E~AST TWO
b~uL.~u~AIl DIVERSrTy ETEME~7TS

The present invention relates to the modular development of ~m;n;m;~-based and oxazolone-derived synthetic organic molecules, possessing selected properties for a particular application. This invention involves: a) the synthesis of an 10 array of different --~ ?s generated from base modules of ~m;n;m;fle-forming, oxazolone, oxazolone-forming and/or oxazolone-derived molecules containing a chosen set of substituent groups which confer structural diversity; and/or the reactiOn of these modules with other appropriate reactive groups 15 to produce an array of molecules possessing a chosen set of diverse structural moieties; and, b) the screening of some or all of the molecules in the array for the desired set of properties in a target application. The iterative application of this invention enables molecules to be produced, having an zO optimum balance of properties for the particular application.
BAl_h~j~ulJNL~ OF THE lNV~;N'l'l~N
The discovery of new molecules has traditionally f ocused in two broad areas, biologically active molecules, which are 25 used as drugs for the treatment of life-threatening fl;c~cfc, and new materials, which are used in f ~:ial, and ~cr~ 1lY, in high technological applications. In both areas, the strategy used to discover new molecules has involved two basic operations: (i) a more or less random choice of a molecular 30 candidate, prepared either via chemical synthesis or isolated from natural sources; and, (ii) the testing of the molecular candidate for the ~JLVp(:L ~y or properties of interest. This discovery cycle is repeated indefinitely until a molecule possessing the desirable property, i.e., "lead molecule", is 35 located. This "lead molecule" discovery process has been inherently ~ hoc in nature and is ~ nrJ, laborious, unpredictable and costly.

21912~3 WO 95/3218~ "J ,~C
..
Once a candidate lead molecule has been det~rm;ned, the synthetic chemist must subsequently find ways to synthesize structural variants of this molecule to optimize its properties in the desired application. In the case where the lead molecule 5 is a synthesized organic species or a natural product, the chemist is usually limited to certain struct~al and synthetic reaction schemes. These schemes are dict~ed largely by the structural composition of the lead molecule and by the requirements of the specific application. For example, in cases 10 where the lead molecule pocct~st~ a functionally important aromatic ring, various electrophilic and nucleophilic substitutions may be carried out on the ring to produce variants . Each such case ~ must be approached as a specif ic ; n,lt~rt~nrlf~nt design and synthesis problem, starting each time 15 from the beginning, because of the lack of availability of an appropriate chemistry to simply alter the structure of the lead uu~ Juu~d to produce the variant.
Recently, some attempts have been made to modularize certain synthetic organic reaction schemes to facilitate 20 modification and transformation of a lead or base ~ _ ~ (see, for example, 1993 Proc. Natl. Acad. Sci. USA, 90, 6909).
However, the molecules which can be l.)L u~uued by such attempts are t"L~L~ -ly limited in their achievable diversity and are still bounded by factors dictated by the choice of specific 25 structural themes. In the case where the "lead molecule" is a naturally occurring biological molecule, such as a peptide, a protein, an oligonucleotide or a carbohydrate, simple synthetic point-modifications to the lead molecule to produce variants are quite difficult to achieve.
A brief account of the strategies and tactics used in the discovery of new molecules is described below. The emphasis is on biologically interesting molecules; however, the technical problems encountered in the discovery of biologically active molecules as outlined here are also illustrative of the problems 35 encountered in the discovery of molecules which can serve as b~ tlin~ blocks for the devt~lt ~ of new tools and materials for a variety of high tet~hnt~logical applications. Furth- e, -Wo 9i/32184 ~ 0 3 - r~ s ~ -as discussed below, these problems are also illustrative o~ theproblems encountered in the development of fabricated structures and materials for high technological applications.
Druq Desiqn ~ odern theories of biological activity state that biological activities, and therefore physiological states, are lO the result of molecular recognition events. For example, nucleotides can f orm complementary base pairs so that complementary single-stranded molecules hybridize resulting in double- or triple-helical structures that appear to be involved in regulation of gene expression. In another example, a 15 biologically active molecule, referred to as a ligand, binds with another molecule, usually a macromolecule referred to as ligand-acceptor (e.g., a receptor, an enzyme, etc. ), and this binding elicits a chain of molecular events which ultimately gives rise to a physiological state, e.g., normal cell growth 20 and differentiation, :~lhnr~ l cell growth leading to car~ ;n~g,~n,~ , blood-pressure regulation, nerve-impulse-generation and -propagation, etc. The binding between ligand and ligand-acceptor is geometrically characteristic and extraordinarily specific, involving c.~,pL~,~Liate three-25 dimensional structural aLlt~n~ -nts and t.~hr~ ;t~l interactions.
A currently favored strategy for the development of agents which can ~e used to treat diseases involves the discovery of forms of ligands of biological receptors, enzymes, or related macromolecules, which mimic such ligands and either boost, i.e., 30 agonize, or suppress, i.e., antagonize, the activity of the ligand. The discovery of such desirable ligand forms has traditionally been carried out either by random screening of molscules (~Lo~luced through chemical synthesis or isolated from natural sources), or by using a so-called "rational" approach 35 involving identification of a lead-structure, usually the structure of the native ligand, and optimization of its properties through numerous cycles of s~lu~LuLtll redesign and Wo 95r32181 ~ 2 ~ 3 ~ C
biological testing. since m~st use~ul drugs have been discovered not through th~s,~ra~tionalN approach but through the screening of randomly--chosen ~ ~)UII~S, a hybrid approach to drug discovery has recently emerged which is based on the use 5 of combinatorial chemistry to construct huge libraries of randomly-built l~h~m;c~l structures which are screened for specific biological activities. (S. Brenner and R. A. Lerner, 1992, Proc. Natl. Acad. sci~ USA 89:53, 81) Nost lead-structures which have been used in the UrationalN
10 drug design approach are native polypeptide ligands of receptors or enzymes. The majority of polypeptide ligands, ~sp~ 11y the small ones, are relatively unstable in physiological fluids, due to the tendency of the peptide bond to undergo facile hydrolysis in acidic media or ln-the presence of peptidases. Thus, such 15 ligands are decisively inferior in a pharr~c~k;n~tic sense to non-peptidic compounds, and are not favored as drugs. An additional limitation of small peptides as drugs is their low affinity for ligand acceptors. This ~h-- is in sharp contrast to the affinity fl LL~ted by large, folded 2 0 po lypept ides , e . g ., proteins , f or speci f i c acceptors , e . g ., receptors or enzymes, which can be in the sub-nanomolar range.
For peptides to become effective drugs, they must be transformed into non-peptidic organic ~Llu-:LuLes, i.e., peptide mimetics, which bind tightly, preferably in the nanomolar range, and can 25 withstand the chemical and biochemical rigors of coexistence with biological tissues and f luids .
Despite numerous in~:L ~ Lal advances in the art of pepT ;~ ;T ;o design, no general solution to the problem of converting a polypeptide-ligand structure to a pepT id: ir ~ic 30 has been defined. At present, "rationalN peptidomimetic design is done on an ad hoc basis. Using numerous redesign-synthesis-screening cycles, peptidic ligands belonging to a certain biorhc~T~;c~l class have been converted by groups of organic chemists and pharmacologists to specific pepT ;fl~m;r Lics;
35 however, in the majority of cases, results in one biochemical area, e.g., peptidase inhibitor design using the enzyme substrate as a lead, cannot be transf erred f or use in another 2lsl2a3 r q W095/3218S P~ x~r~7 ~
area , e. g., tyrosine-kinase inhibitor design using the kinase substrate as a lead.
In many cases, the pept;~om;m~tics that result from a peptide structural lead using the "rational" approach comprise 5 unnatural alpha-amino acids. Many of these mimetics exhibit several of the troublesome features of native peptides (which also comprise alpha-amino acids) and are, thus, not favored for use as drugs. Recently, fundamental research on the use of non-peptidic scaffolds, such as steroidal or sugar structures, to 10 anchor specific receptor-binding groups in fixed geometric rela~;nnchirs have been described (see for example Hirschmann, R. et al., 1992 J. Am. Chem. Soc. 114:969g-9701; Hirschmann, R. et al., 1992 J. Am. Chem, Soc., 114:9217-9218); however, the success of this approach remains to be seen.
In an attempt to accelerate the identif ication of lead-structures, and also the identification of useful drug candidates through screening of randomly chosen c ~ u~Lds, researchers have developed automated methods for the generation of large combinatorial libraries of peptides and certain types 20 of peptide mimetics, e.g., "peptoids", which are screened for a desirable biological activity. For example, the method of H.
M. Geysen, (1984 Proc. Natl. Acad. Sci. USA 81:3998) employs a modification of the Merrifield peptide synthesis, wherein the C-terminal amino acid residues of the peptides to be synthesized 25 are linked to solid-support particles shaped as polyethylene pins; these pins are treated individually or collectively in sequence to introduce additional amino-acid residues forming the desired peptides. The peptides are then screened for activity without removing them from the pins. Houghton, ~1985, Proc.
30 Natl. ~cad. Sci. USA 82:5131; and U. S. Patent No. 4,631,211) utilizes individual polyethylene bags ("tea bags") containing C-l-rrm;n;~l amino acids bound to a solid support. These are mixed and coupled with the requisite amino acids using solid phase synthesis techniques. The peptides produced are then 35 recovered and tested individually. Fodor et al., (l991, Sci~ence 251:767) described light-directed, spatially addressable parallel-peptide synthesis on a silicon wafer to generate large _ _ _ _ _ _ . . . _ .. _ _ . . . . .. _ _ _ _ .

WO 95/32184 ~ ` ~ 2 1 9 1 2 0 3 . ~ r - ~
arr2ys of addressable peptides that can be directly tested for binding to biological targets. These workers have also developed recombinant DNA/genetic engineering methods for expressing huge peptide libraries on the surface of phages (Cwirla et al., 1990, Proc. ~ Natl. Acad. Sci.~ USA 87 6378) .
In another combinatorial approach, V ~ Huebner and D. V.
Santi (U. S. Patent~No. 5,182,366) u~lized functionalized polystyrene beads divided into portions each of which was acylated with a desired amino acid; the bead portions were mixed 10 together, then divided into portions each of which was re-subjected to acylation with a second desirable amino acid producing dipeptides, using the techniaues of solid phase peptide synthesis. By using this synthetic scheme, exponentially increasing numbers of peptides were produced in 15 uniform amounts which were then separately screened for a biological activity of interest. Another method of producing libraries of organic compounds based on dipeptides, hydantioins and benzodiazepines using a polystyrene based solid support is described by DeWitt et al. (1993, Proc. Natl. Acad. sci. USA, 20 90:6909). Bunin et al. (1992, J. Am. Chem. SQc. 114:10997) describe a method for the combinatorial synthesis of large libraries of peptides. According to Bunin, 2-amino benzorh-~n( nP-:
are attached to a poly~yL-~.e solid support and converted into various 1,4 benzodiazepine derivatives, which can then be 25 screened for specific receptor or enzyme activity.
Z-~rk~rl--n et al., (1992, Int. J. Pel~tide Pro~ln Res. 91:1 and 1993, StrucfllrAl BioloaY. 3:580~ also have developed similar methods for the synthesis of peptide libraries and applied these methods to the automation of a modular synthetic che_istry for 30 the production of libraries of, for example, N-alkyl glycine peptide derivatives, called "peptoids~, which are screened for activity against a variety of biochemical targets. (See also, Symon et al., 1992, Proc. Natl. Acad. Sci. USA 89:9367).
Encoded combinatorial rh.omicAl syntheses have been described 35 recently (S. Brenner and R. A. Lerner, 1992, Proc. Natl. Acad.
Sci. YSA 89:5381).

~ WO 95/32184 2 1 9 1 2 0 3 P~ c -The focus of these structural diversity activities on peptide synthesis chemistry is a direct result of the fact that the ability to generate structural diversity requires, as-its starting point, the access to practical stepwise sequential 5 synthesis chemistries which allow the incorporation of varied structural elements with orthogonal reactivities. To date, the6e have only been worked out for the Merrifield synthesis of peptides and the Carruthers synthesis of oligonucleotide8.
Thus, there remains a need for an improved method for the l0 6tructure-directed generation and screening of organic compounds to determine which may be suitable in a particular application.
SI~ RY OF T~T~ INVENTIC)~ -The present invention relates to compounds having selected 15 properties for a particular application which are made by forming base modules having at least two structural diversity elements. Such base modules are formed by reaction of a first reactive group, with a compound having at least one structural diversity element and a second reactive group. The first and 20 second reactive groups can be combined by an addition reaction to produce a first array of molecules when at least one of the structural diver6ity elements of the compounds is varied when producing the base modules. This array can be screened to determine a first suitable compound for a particular =:=
25 application.
If desired, this method can be repeated by producing a fiecond array of molecules through the formation of base modules having structural diversity elements that are dif f erent from those of the f irst array of molecules, and acreening the second 30 array of molecules to determine a second suitable compound for the particular application. The second array can be produced by f orming base modules having at least two structural diversity elements in the same manner as the first array, except that the structural diversity elements are modified from those of the 35 first suitable, -'. The steps of producing and screening an array of molecules can be repeated as of ten as necessary to ach~eve an optimum compound for the particular application.

Wo 9~/3218~ 2 ~ 9 1 2 0 3 P~ C -- --Preferably, the first ~ ulld is produced by forming an oxa201e ~ ~ '' having at least one structural diversity element attached thereto and reac1~ing it with a nucleophile or carbonyl compound which cont~s at least one structural 5 diversity element to form a~ base module having one of the following structures:
\1--7~= H~
N~ O
wherein at least two of the unconnected lines can be connected to structural diversity elements.
Alternatively, it is also preferred to provide the first compound as an ~minimicje-forming ~ ' having at least one structural diversity element attached thereto and to react it with an oxazolone or other ~ ~_ulld which contains at least one structural diversity element to form a base module having one 2 5 of the f ollowing ~ LL UL: LUL l:S:
e. g , O \1/
O H ¦ H ~ N~N~

~minimN1P-forming reagent oY~7ol~nP-derived ~minimirlP
wherein at least two of the unconnected lines are connected to sN_lu~ Lulc-l diversity elementS.
Advantageously, the first and second ~LLU~:LUL~1 diversity elements can be any of the following; (a) an amino acid derivative of the form (Aa)ll; (b) a nucleotide derivative of the ~¦ W0 95/3218~ 219 12 ~13 F~~
form (NUC~) n; (c) a carbohydrate derivative o8 the form (CH) n;
(d) an organic moiety of an alkyl, carboxycyclic, aryl, alkylaryl, aralkyl, alkaryl group or a substituted or heterocyclic derivative thereof; (e) of a naturally occurring 5 or synthetic organic structural motif, optionally containing a reporter element, an electrophilic group, a nucleophilic group or a polymerizable group; or, -(f) a macromolecular r nrnr~nent If desired, at lea8t one of the first and second compounds can be provided with two or more structural diversity elements, lO two of which can form a ring structure. Thus, a wide varlety o~ compounds can be made. Various combinations of the8e compounds can be placed into arrays which represent another embodiment of the invention.
These arrays are useful in a method for obtaining compounds 15 having selected properties for a particular application by producing a first structurally diverse array of molecules having at least two orthogonal reactivity elements wherein a f irst orthogonal reactivity element is held con8tant for each molecule and a second orthogonal reactivity element i8 varied. The array 20 is screened to determine a first suitable compound for the intended application. Further modifying t~e first suitable compound can form a second structurally diverse array of molecules. Preferably, the first 8uitable compound has at least two orthogonal reactivity elements, 80 that the first suitable 25 compound can be modified by holding a first orthogonal reactivity element constant while varying the second orthr~ n~l reactivity element to produce a second structurally diverse array which can be screened to determine a second suitable compound for the ;nt~n~pd application. The modifying and 30 screening steps can be repeated as often as necessary to achieve the optimum compound for the ' nt~-n~lPd application .
The variou6 base compounds represent another aspect of the present invention. These compounds include those which have any of the following structures:

W095132181 219 12 0 3 PCTIUS95/06tO8 o ~[ ~

N~3 ~ O
(~CHCH2 N~--N--C~) V
lS Q H
N [ ]~f N ~
o ~ H 0 2 5 (~ - O ~ 0~) wherein A, B, C, D, E, F, G, H, I, J, K, L and, M are 6tructured diversity elements o~ the types mentioned 3 0 above;
Y is an oxygen, sul~ur or nitrogen atom;
Z is Q~3 Jl, n WOss13218~ 21~312 0 3 r~ ,5r or (~) (~ III

and; n can be any integer from l to four, inclusive.
A wide variety of molecular arrays can thus be generated for use in screening to determine which compounds would be lO suitable for a particular application.
The f irst structurally diverse array of molecules is advantageOusly produced by reacting either an oxazolone or an ;lm;nim;df, compound, or combinations thereof, with the first and second components which provide the orthogonal reactivity 15 elements. It is useful for the first structurally diverse array of molecules to have one of the specific structures disclosed herein. These structures may include ~-nmrnnr~nts such as an amino acid derivative, a nucleotide derivative, a carbohydrate derivative, an organic structural motif, a reporter element, a 20 polymerizable moiety, or a macromolecular component.
This method is useful for a wide variety of applications, ;ncl~l~l;n~ the development of new bio~h~-ceutical agents, new ic species for the modular construction of separations tools, ;n~l11r9;ng chiral selectors, industrial detergents and 25 additives, and for the development of modular chemical intermediates for the production of new materials and polymers.
Specifically, the method relates to the selection of molecular modules containing appropriate ~LLU~ULr11 diversity and reactivity elements, the connecting of these modules together 30 v a facile high-yield addition r~ct;nn~ which produce discrete, highly pure molecules in microscopic ( less than or equal to milligram) to macroscopic quantities (greater than l milligram) in a manner such that the properties of these molecules are det~rm i nr~rl by the contributions of the individual building 35 modules. The molecular modules of the invention may be chiral, and can be used to synthesize new compounds, structures and materials which are able to reco~Jni~e biological receptors, _ _ _ _ . . . , . _ _ . . _ _ _ _ _ . .

W0 95t32184 ~ ~ 9 ~ 2 ~ J~
enzymes, genetic materials, and other chiral molecules, and are thus of great interest in the f ields of biopharmaceuticals, separation industrial and materials science.
5 DETAII,ED PES~RTPTIQN QF THE INVENTT~N
For the purposes of this irny~ion the f ollowing terms are defined to clearly delineate the'scope of the present invention;
The term "addition reaction" is c~n~i rlPred to be any reaction in which the number of original atoms or bonds in a lO compound is increased after~ such reaction has occurred.
"Compartments" is defined as any structure in, or on which a discrete amount of a L~ r is situated. This term is considered to Pnl~nmrA~f: structures which have classically been considered to be .:, Llilents such as sample vials and test 15 tubes, as well as no~craditional compartments, such as, for example, silicon wafers, gelatin, polystyrene or other macromolecular media.
A base module is a set of molecules which is common to a group of larger molecules in an array of said larger molecules, 20 where said larger molecules have one or more structural diversity elements. The term "base module" is equivalent to the term "molecular scaffolding" for the present invention.
Structural diversity elements are any organic or inorganic atom(s), molecule(s), or bond(s) which adds to or changes the 25 structure of a base module.
A reactive group is a molecule(s) capable of forming a structural diversity element.
When a numerical variable is specified as a part of any structure or f ormula, such numerical variable is intended to 30 represent each P~hofl;r-nt of the subject -~L;l-:~UL~: or formula that would correspond to each numerical value that said variable could be.
The present invention is able to generate a number of different molecules for screening purposes by first forming a 35 base module that contains at least two structural diversity elements attached thereto. These modules are formed by reacting f irst and second - _ _ ", each of which has at least one J~ Wo 95/3218~ r~ ),,,sr structural diversity element and a re~ctive group. The reactive groups of the f irst and second compounds are such that they react with each other to f orm the base module by an additional reaction. By fixing one of the positions and structures of the 5 structural diversity elements and by varying at least one of the others, an array of different molecules is easily generated.
These molecules can then be screened to determine which are suitable for a particular application or target use. Once a suitable compound is identified, it can be selected for lO generating a further array of molecules. This is done by modifying the particular structural diversity elements that are found to be suitable, or by combining the chosen structural diversity element with an ~r~nded or different set of second compounds or elements. This process can be repeated as often as 15 necesE:Ary to develop the optimum compound f or the particular use .
The particular base module chosen for use in accordance with the present invention is not critical and can be any one of a wide variety of structures. It has been found, however, 2 0 that two particular structures which are known in the art are highly useful as such base modules, these known cu...~,L,u-.ds being the oxazolones and ~m;n;m;tl~s, Thus, it is preferred to utilize Cu~Juu~ldS which are zlm;nim;~ forming, oxazolone forming, oxazolone or oxazolone-derived molecules for use as the base 25 module. D~r~n(1ing upon the specific structure and feature selccted, these base modules can have between two and nine structural diversity elements. The specif;~- chemistry of these molecules, as well as an identification of the structural diversity elements and reactivity groups, follows.

~191203 Wo 9513218~ PCTiUS95l06208 OxazolQnes ~
Oxazolones, or azlactones, are structures of the general f ormula: 4 3 N--(C H2)n `~ . ~
0 A~
where A, R, and R' are functional groups, and n is an integer between 0 and 3.
Oxazolones may possess up to two substituents at the 5-position, represented by R and R'. When these substituents are 5 not e~uivalent , that is when R ~ R', the carbon atom at the 5-position is asymmetric and two non-superimposable oxazolone structures (azlactones) result as shown below:
2 0 Ay~O Ay~ O
~R2 N R2 Rl R

Chiral oxazolones possessing a single, non-hydrogen substituent at the 5-position (also known as 5(4H)-oxazolones), derived from chiral natural amino acid derivatives, int~.3~tfl;n~
30 activated acylamino acyl structures, have been prepared and isolated in the pure, crystalline state (Bodansky, M.; ~1 I.lcnf~r, Y. S.; Ondetti, M. A. in "Peptide Synthesis", Second Edition, John Wiley & Sons, New York, 1976, p. 14 and references cited therein). The facile, base-catalyZed racemization of several 35 of these oxazolones has been studied in connection with investigations of the serious racemization problem confronting peptide synthesis (see Kemp, D. S. in '`The Peptides, Analysis, W0 95132184 219 1~ 0 3 r~ C ~ 8 Synthesis, and Biology", Vol. 1, Gross, E. & Meienhofer, J.
editors, 1979, p. 315).
Racemization during peptide synthesis becomes very extensive when the desired peptide is produced by aminolysis of 5 activated peptidyl carboxyl, as in the case of peptide chain extension from the amino t~rm;ntl~, e.g., I - VI shown below (see Atherton, E.; Sheppard, R. C. "Solid Phase Peptide Synthesis, A Practical Approach, " IRL Press at Oxford University Press, 1989, pages 11 and 12) . An extensively studied r- ' ~n;cm 10 describing this racemization involves conversion of the activated acyl derivative (II) to an oxazolone (III) followed by facile base-catalyzed racemization of the oxazolone via a resonance-stabilized int~-rm~ te (IV) and aminolysis of the racemic oxazolone (V) producing racemic peptide products (VI).

WO 9~/3ZI84 219 12 0 3 14 I ~ .'r ~, O <~}N=C--N{~
O R2 H "aCtiVatiOIl"

~N~ ~>~0~ N~4~H
15 ~ Jo O~
H R N n Dono 2 0 Base f f N ~ ~--~ Pro~o r ~ /~) IV
2 5 ~ H "~ ~ minolysis ~ , / , .
N~ ~ N Go2 W095~32184 2191,~n~ r~.l/l)~,S'C
Extensive research on the trapping of oxazolones III (or of their activated acyl precursorS II) to give acylating agents which undergo little or no racemization upon aminolysis has been carried out. Successeg in this area (such as the use of N-5 hydroxybenzotriazole) have greatly advanced the art of peptidesynthesis (Kemp, D. S. in "The Peptides, Analysis, Synthesis/
and Biology," Vol. 1, Gross, E. & Meienhofer, J. editors, 1979, p. 315). I~owever, the control of such racemization is difficult, and at times unpredictable. Thus, attempts to deal 10 with the racemization problem in peptide synthesis have involved suppressing or avoiding the formation of oxazolone intermediates altogether .
Oxazolones having at least one hydrogen substituent at the 5-position can also undergo a variety of rearrangements and 15 side-reactions (cf., 1967 Tetrahedron 23, 3363), which may interfere with other desired transformations. This is illustrated for the case of the oxazolone formed from the cyclization of N-acryloyl glycine through a 1,5-hydrogen shift, (a [5,1] sigmatropic rearrangement) from the corrP~rnn~;n~ mono-20 substituted vinyl ~ ctnnc~
~0 ~ ' o 2 5 ( ~ H N
H H
oxazolones containing no ll~dLoge,- substituents at the five position (e.g., where R and R' are alkyl substituents, or where an exo-olefin protrudes from the oxazolone ring at this position) are ~LLu~ LuL~lly precluded from undergoing these racemizations and side-reactions. These di-substituted 35 oxazolones may be obtained chirally pure and may be subjected to the transformations, which are the subject of this invention, with retention of the chirality at this position.

_ _ _ _ . .. . _ ... _ . . .

WO 9~/32184 2 1 9 1 2 ~ 3 P~
The formation of these substituted vinyl azlactones containing no ~1y~lL oy~1- substituents at the 5-position can be produced through the cyclization of N-acryloyl glycine (where R is a hydrogen atom~ or an es~uivalent reagent (e.g., where R
5 an alkyl group) in the presence of a carbonyl-containing reagent (e.g., an aldehyde or ketone compound1 as shown below:
lO R ` ~
The substituent at the 2-position can be capable of lS undergoing addition reactions, as in the case of the substituted vinyl group (where R can be a i1yd~ ~y~11 or other substituent) .
Chemical modifications may be carried out with retention of the chirality at the 5-pos~tion to produce new oxazolones. This is shown for the ~ichael-type addition of the reagent A'Xi1 to the 20 alkenyl oxazolone as follows:
R R
~ \~ A'X~ G
A'XH + N~R2 N~R2 Functional groups that are capable of this i~ichael-type transformation without opening of the azlactone ring under appropriate conditions are, for example, mercaptans (where X =
S) or secondary amines (where X = NR, and R can be a structural diversity element that:does not adver5ely affect the outcome of 35 the desired reaction). In both cases, A' can be a structural diversity group that does not adversely affect the formation of the molecular scaffold, as shown below:

Wo 95/3218~ 219 12 0 3 F~~

`~~_ = A'--X~Jl~ N~
Rl where Y is a hetero-atom capable of opening the azlactone ring 10 to form the molecular scaffold unit, and B' is a structural diversity element.
SYnthesis of Oxazolones The compounds of the present invention can be synthesized by many routes. It is well known in the art of organic synthesis that many different synthetic protocols can be used to prepare a given ~ ~ ~u~ld. Different routes can involve more or less expensive reagents, easier or more difficult separation 24 or purification procedures, straightforward or ~ ulllb~ls ? scale-up, and higher or lower yield. The skilled synthetic organic chemist knows well how to balance the competing characteristics of synthetic strategies. Thus the ~u..~uul~ds of the present invention are not limited ~y the choice of synthetic strategy, 25 and any synthetic strategy that yields the ~ ~ - u.lds describcd above can be used.
Oxazolones may be prepared from the appropriate amino acid using any of a number of standard acylation and cyclization techniques well-known to those skilled in the art, e.g.:
Rj~RZ ~ R~jR2 ACOCI + H2N C02H A N CO2H
H
~c ~ Ac20 R~

Wo9SI32184 219120 3 ~ Sl~ --The size of the azlactone ring, as well as the geometric 5 configuration of the structural diversity/ elements Q, T, ~, V, W and Z will be dictated by the choice ~,o~: ~the amino-carboxylic acid containing reagent, e.g. ~
ACO R~R2 Ac20 A ~0~Go Cl + H2N C02H N~R2 where n = o R
R1 R2 Ac20 A~0 0 ACOC~ t H2N~X~C02H N~ ~ ~R2 where n = 1 ~ z ACOCI t ~ ~ R2 where n = 2 W Z ~ U~ R1 ACOCI + H N~ , A~~
where n = 4 Q T W z N
T U V
The features of the ~LLU~;LUr ~1 diversity elements, R~ and R2, as well as Q, T, U, V, W, and Z will be dictated by the amino-carboxylic acid containing reagent. The diversity elements R~ and RZ could also be added onto the azlactone module (e.g., alpha-alkylation of the carbonyl in the presence of a non-nucleophilic base like DBU (1,8-diazobicyclo[5.4.0]undec-7-ene~ and an alkylated agent, similar to the ones described below) .

4 2 1 91 2 0 3 r~-,u~ o~
These oxazolonQs may be i~olated in the pure state or may be generated in-situ from the acyl amino acid by treatment, for example, with equivalent amounts of triethyl amine and ethyl chloroformate in benzene. Following the evolution of carbon 5 monoxide and the removal of the triethyl ammonium chloride formed by filtration, the solution of the oxazolone may be utilized directly for subsequent transformations.
0 R ~R
(~COR H2N~C02H
R = OH, OAlkyl, Cl ( Et)3 N ~
R2 R1 CICO2E~ ~
(~ N C 02H CR HTG R~

For the purposes of this invention a ~LU~:LULal diversity element can be any organic or inorganic atom, molecule or bond 25 which adds to or changes the ~ u~LuLe of a base module.
Examples of structural diversity elements, are for example, any linear or hr~n~h.ocl chain alkyl group that is substituted or unsubstituted, any substituted or unsubstituted carbocyclic compound and any substituted or unsubstituted aryl group.
Further, the b-LU~:LULàl diversity elements preferably do not interfere or adversely affeçt the formation of the azlactone module. While the structural diversity element is broadly defined above, diversity element A can be, ~or example, straight or branched chain alkyl groups such as methyl, ethyl, propyl, 35 butyl including n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc., and their variants, straight and branch chain alkenyl chains such as ethenyl, propenyl, 21~1203 Wo 95/32184 ~ 8 butenyl, pentenyl, hexenyl, heptenyl, octenyl, etc., and their variants, straight and branch chain alkynyl chains such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, etc., and their variants, for example, aryl, aralkyl, 5 alkaryl, cycloalkyl, cycloalkylalkyl a~,d heterocycles.
Funct; nn~ ed diversity elements (e.g., 2-~2~romoethyl) and their variants, functionalized surfaces such~ as films, membranes, wafers, resins and beads may also be used.
Preferred reagents for the synthesis of structural lo diversity element A are ~ '~ such as straight and branch chain alkyl carboxylic acids such as formic acid, acetic acid, propanoic acid, butanoic acid including n-butanoic acid, sec-butanoic acid, iso-butanoic acid, tert-butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, etc., aryl 15 carboxylic acids, aralkyl carboxylic acids, alkaryl carboxylic acids, cycloalkyl carboxylic acids, cycloalkylalkyl carboxylic acids and their variants, heterocyclic acids, N-protected amino acids, peptides and proteins such as N,S-Di-CBZ-L-Cysteine, N, N ' -bi s ( t -BOc ) -L-cystine, N-t-Butoxycarbony l -S-pheny ~ n; n l~, 2 o N-t-Butoxycarbonyl-R-phenyl ~ l ~n; n~, etc ., other carboxylic acid6 such as 3-Am;n~-h~n70ir acid, 4-~minoh~on~oic acid, 2-Aminoisobutyric acid, cis-4-(Am;- -thyl)cyclrh~Y~n~ ylic acid, t~ans-4-(~m;nl thyl)cyclrhloy~n~r~rboxylic acid, 5-Aminovaleric acid, B-l --et;c acid, 3-BLI ~Lol,ionic acid, 25 Cyclohexanecarboxylic acid, Diphenylacetic acid, Ethylc~n~ m;n~tetraacetic acid, 2-Formylphenoxyacetic acid, 4-Formylphenoxyacetic acid, EIippuric acid, TC~n;r~cQtic acid, (R)-(-)-Mandelic acid, (S)-(+)-M~n~ l ;r acid, (+)-2-Methylbutyric acid, D-Tartaric acid, ~-Tartaric acid, Thiosalicylic acid, 30 Trifluoroacetic acid, esters and acid halides listed below.
Reaction~ of ~Y~7olones Rinq-o~Qn; nn Addition Oxazolones may be subjected to ring opening reactions with a variety of nucleophiles, as shown below:

~ WO 95/32184 2 1 9 1 2 0 3 F-IIL~
;~R2 In the structure above, Y represents a hetero-atom, such as an oxygen, sulfur, or nitrogen atom. Rl and R2 differ from one another, and taken alone, each signifies one of the 10 following: alkyl including carbocyclic and substituted forms thereof; aryl, aralkyl, alkaryl, and substituted or heterocyclic versions thereof.
The above ring-opening reaction can be carried out either in an organic solvent such as methylene chloride, ethyl acetate, 15 dimethyl formamide (DMF) or in water at room or higher temperatures, in the presence or absence of acids, such as carboxylic acids, other proton or Lewis-acids, or bases, such as tertiary amines or hydroxides, serving as catalysts.
This reaction may be used to generate an array of adducts, 20 po~s~;n~ combinations of the structural diversity elements A
and C, as shown:
` ~ R2 (~ o ~) The reagents for the synthesis of diversity element B may 30 be, for instance, straight or branched chain alkyl amines such as methyl amine, ethyl amine, propyl amine, butyl amine including n-butyl amine, sec-butyl amine, iso-butyl amine, tert-butyl amine, pentyl amine, hexyl amine, heptyl amine, octyl amine , etc ., aryl amines , aralkyl amines , alkaryl amines , 35 cycloalkyl amines, cycloalkylalkyl amines, heterocyclic amines and their variants, other amines such as l-A~Ar~nti~n^- L.hylamine, 4'-Aminoacetophenone, 3_A1n;nOh~?n~9;C
. . . . .. . _ ... ~

WO 95/32184 2 ~ 9 1 2 ~ 3 J~
acid, 4-Aminnbt~n7~ic acid, 4-Amino-1-benzylpiperidine, 4-Amino-1-butanol, 4-Aminobutyraldehyde diethyl acetal, DL-a:-Amino-~-caprolactam, 1-Amino-2, 6-dimethylpiperidine, Aminodiphenylmethane, 4- (2-Aminoethyl) morpholine, 2- (2-5 Aminoethyl) -l-methylpyrrole, 2- (2-Aminoethyl) -1-methylpyrrolidine, 2-(2-Aminoethyll~pyridine~ 1-(2-Aminoethyl)pyrrolide, 1-Aminohomopi~èridine, 1-Amino-4-(2-llydL."~yethyl)piperazine, 2-Aminoiso~tyric acid, 1-Amlnoindan, (R) - ( + ) -1-Amino-2 - (meth~.~y y l ) pyrrolidine, ( S ) - ( -) -1-Amino-2 -10 ( m e t h o x y m e t h y 1 ) p y r r o l i d i n e, t r a n s - 4 -(Aminomethyl) cyclohexanecarboXYliC acid, 2- (2-Aminomethylphenylthio) benzyl alcohol, 1-Amino-4-methylpiperazine, 3-(Aminomethyl)pyridine, 4-~m;n~ ~rpholine, 2-Amino-1-phenylethanol, 2- (4-Aminophenyl) ethylamine, 1-15 Aminopiperidine, (R) - (-) -1-Amino-2-propanol, (S) - (+) -1-Amino-2-propanol, (R)-(-)-2-Amino-1-propanol, (S)-(+)-2-Amino-l-propanol, 3-Amino-1-propanol, 3-~m;nnrhnrl~n;nt~, N-Amino-l,2,3,4-tetrahydroisoslll; nnl; nt~, 4-Amino-1, 2, 4-triazole, r-Aminovaleric acid, 8enzylamine, Cyclohexylamine, Dehydroabiethylamine, 20 Diacetone acrylamine, Diethylamine, N,N-Diethylethylt~nt~ ?m;nt~, N, N ' -Diethylethyl-~nt~ m; nt~, N, N-Diethylethylenetriamine, 2, 4-Difluorobenzylamine, Diisopropylamine, N,N-Diisopropylethylamine, 2,2-Dimethoxypropane, 3-Dimethylaminopropylamine, N~N-Dimethylethylt~nt~ Am;nt~ 1,1-25 Dimethylhydrazine, 2,2-Diphenylethylamine, Ethanolamine, 2-Ethoxybenzylamine, Fur~urylamine, Histamine, Hydrazine, 2-Methoxybenzylamine, 3-MethoxybenZylamine, 4-Methoxybenzylamine, 2-Methoxyphenethylamine, 3-Methoxyphenethylamine, 4-Methoxyphenethylamine, Methyl 3-~m;nc.~t~nzoate, Methyl 4-30 aminobenzoate, (R)-(+)-~-Methylbezylamine, 1-Methyl-3-phenylpropylamine, 1-Na~hthalenemethylamine, (S)-(-)_~_ Methylbezylamine, Phenethylamine, 4-Phenylbutylamine, 3-Phenyl-l-propylamine, Tetrally~lL oruL ruL y lamine, 1, 2, 3, 4 -Tetrahydro-1-naphthylamine, 2 - (p-Tolyl ) ethylamine, 35 Tris(Hydroxymethyl)aminomethane, Tryptamine, Tyramine, V;n~m;nt~; straight and branch chain alkyl mercaptans such as methyl r ~ u., Ethanethiol, propyl r .,l~-dn, butyl r~ ~Ldn Wo 95/32184 2 i g 1 2 0 ~ P~ J .,5 C
including n-butyl mercaptanl sec-butyl mercaptan, isobutyl mercaptan, tert-butyl mercaptan, pentyl mercaptan, hexyl mercaptan, heptyl mercaptan, octyl mercaptan, etc., aryl mercaptans, alkaryl mercaptans, aralkyl mercaptans, cycloalkyl 5 mercaptans, cycloalkylalkyl mercaptans, heterocyclic mercaptans and their variants, other thiols, such as 4-Acetamidothiophenol, 2-(2-Aminomethylphenylthio)benZyl alcohol, 3-Chloro-l-propanethiol, DL-Dithiothreitol, Methyl (methylthio)acetate, Methyl 3 - (methylthio ) prop ionate, 5 -Methyl-l, 3, 4 -th i ~ 7 Ole-2 -lO thiol, Methyl thioglycolate, Methyl th;os~l ;rylatel 4-(Methylthio) benzaldehyde, 2- (Methylthio) ethanol, 3-(Methylthio)propionaldehyde, l-Phenyl-l}~-tetrazole-5-thiol, l-Thio-B-D-glucose, 2-Thionaphthol, 2-Thiorh--n.o-~rboYP,l~ hyde, Th;o~l;cylic acid, Benzyl mercaptan, 2 l1~1.ia~obenzothiazole, 15 2-Mercaptoeth~n( l, 2-Mercaptopyridine; straightandbranchchain alkyl alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol including n-butyl alcohol, sec-butyl alcohol, iso-butyl alcohol, tert-butyl alcohol, pentyl alcohol, hexyl alcohol , heptyl alcohol , octyl alcohol , etc., aryl 20 alcohols, alkaryl alcohols, aralkyl alcohols, cycloalkyl alcohols, cycloalkylalkyl alcohols, heterocyclic ~lcnhnl~: and their variants, other alcohols such as 4-Aret~mi-lnthiophenol, ~-Amino-l-butanol, 2-(2-Am;n~ thylphenylthio)benzyl alcohol, 2-Amino-l-phenylethanol, (R)-(-)-l-Amino-2-propanol, (S)-(+)-l-25 Amino-2-propanol, (R)-(-)-2-Amino-l-propanol, (S)-(+)-2-Amino-l-propanol, 3-Amino-l-propanol, 2-Bromoethanol, N-t-Butoxycarbonyl-(S)-phenyl~l~n;nnl, N-t-Butoxycarbonyl-(R)-phenyl~l~n;nnl, (R)-(-)-Fr;n~rh7-ine, (S)-(+)-Epinephrine, Ethanolamine, Glycerol, Glycidol, 2-Mercaptoethanol, (R)-2-3o Methylglycidol, (S) -2-MethylglycidOl, 2- (Methylthio) ethanol, Phenol, (R)-(-)-2-PhenylglycinOl, (S)-(+)-2-Phenylglycinol, 2-Thionaphthol, 4-(Trifluoromethyl)benZyl alcohol, and 2-(TrifluuL~ yl)phenethyl alcohol.
In a preferred embodiment of the present invention the 35 above described ~LU~;~ULal diversity ~l~ s are substituents on the following general structure:

WO 9513218~ ~19 ~ 2 0 3 F~ ,,SlC ~
o (~ / [ Z ~Y\~ I
wherein where A and,~B~are structured diversity elements of the t~y~es mentioned above;
Y is an oxygen, sulfur or nitrogen atom;
Z is selected from '3 ~

or (~) m n can ~e any integer from l to four, inclusive 25 with the proviso that when n=l, A is a nitrogen group, Z is a compound according to :~LU~iLUL~: III ana Y is an oxygen atom, B
is not a resin bead. In another preferred ~mho~l;r L of the present invention the substituents on f ormula I are such that when n=l, Z is a ., ~ '' according to structure III, C and D
3 0 are hydrogen atoms, A is a carbon atom bonded to: ( a ) a secondary amine; (b) a hydrogen atom; and, (c) another carbon atom which is bonded to a substituted or unsubstituted aminal.
still another preferred ~mhoS;r L is when formula I is substituted such that when n=l, Z is a , . 1 according to 35 structure III, C and D are hy~Lou,t:l! atoms, and A is a carbon atom bonded to 2 1.ydLu~el- atoms and a primary or s~ . y amine .

~ Wo 95/3218~ 219 12 0 3 r~ r In addition, by appropriate selection o~ the Rl and RZ
groups, two additional diversity elements can be provided in those positions. Thus, the compound shown can have from two to four structural diversity elements attached to the base module 5 as desired.
Carbor3Yl A~18; tion When both substituents in the 5-position are hydrogen, i.e., the oxazolone is formed from cyclization of an acyl lO glycine, the ring may undergo a high yield condensation addition reaction with aldehydes or ketone-containing structural groups through an Aldol-type condensation (e.g., the Erlenmeyer azlactone synthesis). This reaction may be used to generate an array of adducts, possessing combinations of the structural 15 diversity elements A, B and E, as shown:
+

Again, as noted above, the C and D groups can be selected to be diversity elements to provide an additional structural diversity group on the oxazolone molecule.
When D is a hydrogen, diversity element C can be, for 30 example, straight or branched chain alkyl aldehydes such as Formaldehyde, ethanal, propanal, butanal including n-butyl aldehyde, sec-butyl aldehyde, iso-butyl aldehyde, pentanal, hexanal , heptanal , octanal , etc ., aryl aldehydes , alkaryl aldehydes, aralkyl aldehydes, cycloalkyl aldehydes, 35 cycloalkylalkyl aldehydes, heterocyclic aldehydes and their variants, other aldehydes such as o-An;2:Al-l-ohyde, m-An;cAld.~hyde, p--An;~:Altl~hyde, B~n7~ldc~hyde~ 1~4--R~n70rl;~v~n--6--.. . . ... _ .. . . _ _ . _ _ _ _ _ 21 912~3 .r' Wo 9sl32184 carboxaldehyde~ 3-senzyloxybenzaldehyde, 4-Benzyloxybenzaldehyde, 4-Biphenylcarboxaldehyde, 3, 5-Bis (trifluoromethyl) benzaldehyde, 4-Bromobenzaldehyde, 3- (4-tert-Butylphenoxy)b~n7~ hyde, 4-CarboxybQn.~A1~1~hyde, 2-5 Chlorob~n7~ hyde, 3-chlorob~n7~ Qhyde~ 4-Chlorob-~n.~ hyde, trans-Cinnamaldehyde, (S) - (-)~Citronellal, CyClnh~YAn~'CArbnYAl dehyde, CyclopropAn~cAr~oxaldehyde~ 3--(3, 4--Dichlorophenoxy)b~n7~1fl~hyde, 2,3-Difl~o~h~nzAl~ hyde~ 2,4-Difluorobenzaldehyde, 2,5-Difluor`obenzaldehyde, 2,6-lO Difluorobenzaldehyde, 3,4-Difluorobenzaldehyde, 3,5-Dif luorobenzaldehyde, 2, 3 -Dimethoxybenzaldehyde, 2, 4-Dimethoxybenzaldehyde, 2, 5-Dimethoxybenzaldehyde, 4-(Dimethylamino)benzaldeyde, Diphenylacetaldehyde, 2-Ethoxyb~-n 7A 1 d,~hyde, 4-Ethoxybenzaldehyde, 4-Ethylbenzaldehyde, 15 3-Fluoro-p-anisaldehyde, 2-Fluorobenzaldehyde, 3-Fluorobenzaldehyde, 4-Fluorobenzaldehyde, 3-Fluoro-2-methylbenzaldehyde, 2-Fluoro-3-trifluuL,- I_~ylh~n7Al~Rhyde, Formaldehyde, 4-Formyl-1,3-benzPn~fl;~111fonic acid, 4-Formylhc-nzPn~ lfonic acid, 5-Formyl-2-furansuifonic acid, 2-20 Formylphenoxyacetic acid, 4-Formylphenoxyacetic acid, trans-trans-2,4-T~ ;~nAl, 4-Hydroc-innAr~ hyde~ HY~1LU~Y1~ hYde, Indole-3-carboxaldehyde, 4-Isopropylbenzaldehyde, Isovaleraldehyde, 2-Methoxy-l-pyrrr~ 9;npl-Arh-~yAlcl~hyde~ 3-Methyl-p-A n; F:A 1 ~ohyde, 3 - ( 4 -Methylphenoxy) benzaldehyde, 4 -25 (Methylthio)bF~n7~1l1ehyde, 3-(Methylthio)propionaldehyde, l-Naphthaldehyde, 2-Naphthaldehyde, 2-NitrohPn7A1d~hyde, 5-Norbornene-2-carboxaldehyde, 3-Phenoxybenzaldehyde, 4-Phenoxybenzaldehyde, Phenylar~tAldphyde~ 3-Phenylbutyraldehyde, Phenylpropionaldehyde, 4-Propoxybenzaldehyde, Piperonal, 2-30 Pyridinecarboxaldehyde, 3-Pyridinecarboxaldehyde, 4-Pyridinecarboxaldehyde, Pyrrole-2-carboxaldehyde, Stilbenecarboxaldehyde, 2-Thiophenecarboxaldehyde, o-Tolualdehyde, m-Tolualdehyde, p-Tolualdehyde, 3-( Tr i f lu o r om etho xy ) ben z a l d ehy d e , 4 -35 ( T r i f l u o r o m e t h o x y ) b e n z a l d e h y d e, 3 - [ 3 -(Trifluoromethyl)phenoxy]b~n~ hyde, ~ -Trifluoro-o-wO 95/32184 2 1 9 1 ~ ~ 3 P~ c -tolualdehyde, a,~ Trifluoro-m-tolualdehyde, r,~ Trifluoro-p-tolualdehyde, and Valeraldehyde.
Where D is not Hydrogen, either of the diversity elements C and D can be, for example, generated from reagents such as 5 straight or branched chain alkyl ketones such as propanone, 2-butanone, 3-butanone, pentanone, hexanone, heptanone, octanone, etc., aryl aryl ketones, alkyl aryl ketones, aryl alkyl ketones, cycloalkyl ketones, cycloalkylalkyl ketones, heterocyclic ketones and their variants, other ketones such as 5- ( 2 -10 Adamantylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione, 4'-Aminoacetophenone~ Benzophenone, Cyclopropyl phenyl ketone, Diacetone acrylamine, 2, 2-Dimethyl-1, 3-dioxane-4, 6-dione, 10-Methyl-9 (10~) -acridone, l-Methyl-2-pyrazol ;~l;n~mP, and 3-Methyl-3 -pyrazolin-5-one .
Combi n~tion Qf the T~o Reactions The resulting adduct may subsequently undergo a high yield ring-opening addition reaction with a wide variety of nucleophiles, such as reagents ~ ns, amino groups and 20 alcohols. This reaction sequence may, thus, be used to generate an array of adducts, possessing combinations of the structural diversity elements A, B, C and D, as shown:

~~ ~
~ O ~
Again, as noted above, the A, C and D groups can be 35 R~ cte~ to be diversity ~ s to provide additional structural diversity groups on the oxazolone molecule. And the diversity element B can be selected to provide additional _ _ _ .. _ _ .. .... . , . . _ _ . _ . . _ . . .. ... .... .. .. _ _ _ _ .

Wo 9s/32184 219 ~ 2 0 3 r~llL~s~
structural diversity on the oxazolone-based molecule that is formed after ring opening in the presence of a nucleophile.
This is illustrated for~ the case of the in-si~u generation of the oxazolone from hippuric acid, followed by removal of the 5 triethylammonium chloride by filtration, the addition of benzaldehyde to form the unsaturated adduct and the ring opening addition of benzylamine to give the trllphenyl substituted adduct shown. In this specific case, ;t~e reagents have been chosen such that the diversity element~A is a phenyl ring, as o generated from the azlactone module, diversity element C is a phenyl ring and diversity element D is a hydrogen atom, as generated by benzaldehyde, and the diversity element B is a benzyl group, as generated by the nucleophilic opening of the azlactone by benzylamine:

o Step I
2 0 ¢~ N C 02H ClCOz E t ~ + C 0 Cs H6 N
RT ~ / H-' H
-- (Et),NHCI / Step 2 filtr~tio~
Addition ~~G 60 C/10 minuteS
N~
~--H

~I WO95/32184 ~1~12 ~ 3 PCTrUSs~/06208 ~NH2 Step3 ~ Addition ~n c/3(~ minutes ~NJ~3 ~ he ability of these various reactions to be carried out in a stepwise sequential process using modules chosen in a structure-directed manner allows the production of t~LLu~:LuLally 30 directed thematic diversity libraries, having structural elements systematically varied around a basic motif.
Am;n;m;~
Am;nim;~c are Zwitterionic structures described by the 35 r~l n~nce hybrid of the two energet; ~l ly comparable Lewis structures shown below:

WO95/32184 21912~3 r~

0 _ R3 ~ R1--C_ N--Nl+--R4 The tetrasubstituted nitrogen of the aminimide group can be asy}m[letric, rendering Am;n;m;rlDc chiral as shown by the two 10 enantiomers below:
O R2 3 ~ R

As a result of the polarity of their structures but lack of net charge, simple Aminim;rlDc are freely soluble in both water and organic solvents.
Dilute aqueous solutions of ~m~n;m;dDc are neutral and of very low conductivity; the conjugate acids of simple Am;n;m;(lDc are weakly acidic, with a pKa of about 4.5. A striking ~L~ Ly of Am;n;m;flDc is their hydrolytic stability, under acidic, basic, or enzymatic conditions. For example, boiling trimethyl 25 amine bDn7Amid~ in 6 N NaO}~ for 24 hrs leaves the Am;n;m;dD
unchanged. Upon thermolytic treatment, at t~ ~LUL~:S
DYCDD~l;n~ 180 C, Am;n;m;dDc de ,ose to give isocyanates as follows:
3 o R2 R2 R1--C=N_N+--R4 ~ R1--N--C=0 + N_R4 35 SYnthetic Rou~es to Pm;n;mi~Dc Aminimides can be synthesized in a variety of dif f erent ways. It is well known in the art of organic synthesis that lg~20~
WO95/3218~ 1~ ","
many different synthetic protocols aan be used to prepare a given ~ Different routes can involve more or less expensive reagents, easier or more difficult separation or purification procedures, straight forward or cumbersome scale-5 up, and higher or lower yields. The skilled synthetic organicchemist knows well how to balance the competing characteristics of different strategies. Thus, the ~u L~uul~ds of the present invention are not limited by the choice of synthetic strategy.
Any synthetic strategy that yields the ~Iuu.-ds described can 10 be used.
Am;n;m;d~s via Alkylatign of ~,N-Di-substitUtÇd HYdrazides .
Alkylation of a hydrazide followed by neutralization with a base produces an ;-m; n; m;

(2) neutralization d ~
This alkylation is carried out in a suitable solvent, such as a protic solvent, e.g., water, ethanol, isopropyl alcohol or 25 a dipolar aprotic solvent, e.g., DNF, DNSû, acetonitrile, usually with heating. An example of this reaction is the synthesis of the trifluoroacyl-analide dipeptide elastase inhibitor mimetics shown in the examples below.
The synthesis of hydrazides is well known. For example, 30 hydrazides can be generated from the reaction of hydrazines with acid chlorides. The diversity elements E and F may be, for example, derived from reagents containing di-substituted hydrazines. The ~LLU~UL~11 diversity element H may be, for example, derived from reagents such as acid halides and reagents 3s that are capable of being converted to acid halides, such as carboxylic acids and esters as described below.

woss/32l84 2~ 9~ 2~ r~l"~
Diversity ~lement G may be, for example, straight or branched chain alkyl L~L~ such as bLI thane, bromoethane, 1-bL ~ ~L u~ane, 2 -BL . ~ u~ane, bL, ' [.ane including l-bromobutane, 2-Bromobutane, l-Bromo-2-methylpropane~ sec-butyl 5 bromide, iso-butyl bromide, ~L~ ntane, }.~ Ys~n~, LIL- h~rtane~ bromooctane, etc., aryl bL- . ~P~, alkaryl bromides, aralkyl bromides, cycloalkyl bromides ,~ cycloalkylalkyl bromides and their variants, other bL- i~ such as Benzyl bromide, 2-Bromoacetamide, Bromoacè~ic acid, 4-10 ~L. hPn7Al~ hyde~ l-Bromo-2,2-~ U~u~y~Lu~ e, 2-Bromoethanol, 2- (2-Bromoethyl) -1, 3-dioxane, (2-Bromoethyl) benzene, 3-(BL. ~lly1)-2,4,10-tri (~YAA ~Ar- ntane, 3-~L' L U~/ ionic acid, tert-Butyl bromoacetate, carbon tetrabromide, Cinnamyl bromide, Methyl bL- etate, ~ethyl 3-bromopropionate, straight and 15 branch chain alkyl chlorides such as chloromethane, chloro ethane, 1- chl uL U~L u~,ane, 2 - chl c~I Upl uyane, chlorobutane including l-chlorobutane, 2-chlorobutane, sec-butyl chloride, iso-butyl chloride, chloropentane, chlorohexane, chloroheptane, chlorooctane, etc., aryl chlorides, alkaryl chlorides, aralkyl 20 chlorides, cycloalkyl chlorides, cycloalkylalkyl chlorides and their variants, other chlorides such as Benzyl chloride, 2-Chloroethyl methyl sulfide, 3-Chloro-l-propanethiol, 1,2-Dichloroethane, straight and branch chain alkyl iodides such as iodomethane, iodoethane, 1-iodu~Lupal~, 2-iodopropane, 25 iodobutane including l-iodobutane, 2-iodobutane, sec-butyl iodide, iso-butyl iodide, iodopentane, ;ot9rlh.oYAn~, iodoheptane, iodooctane , etc ., aryl iodides , alkaryl iodides , aralkyl iodides, cycloalkyl iodides, cycloalkylalkyl iodides and their variants, other iodides such as Benzyl iodide, substituted 30 alcohols (e.g., mesitylated or tosylated derivatives) for the alcohols such as those previously listed.
~n;m;tlF~s via AcYlatiQn of ~ -TrialkYl HYdrazinillm Salts Acylation of a suitable trialkyl hydrazinium salt by an 35 acyl derivative or isocyanate in the presence of a strong base in a suitable organic solvent, e.g., dioxane, ether, acetonitrile, etc., produces good yields of Am;n;mil1e~.

WO ~5/32184 21~12 ~3 3 r~ c (~3N+--NH2 X- + ~ ~N+--5 (~3 O
The formation of the hydraziniUm salt is well known. For example, alkylation of a di-substituted hydrazine with an alkyl halide will generally alkylate the hydrazine on the more lO substituted nitrogen, thus forming the hydrazinium salt. The structural diversity elements E and F may be generated from reagents that contain a di-substituted hydrazine, as those described above. The ~LLu~LuL~l diversity element G may be generated from reagents capable of alkylation, also described 15 as above for the alkylation of hydrazides.
Diversity element H may be any diversity element such as those defined above. In particular, H can be derived from reagents such as straight or branched chain alkyl esters, such as alkyl formate, alkyl acetate, alkyl propionate, alkyl 20 butanoate including alkyl n }JuLal~oa~e~ alkyl sec buLcl~oate, alkyl iso-L,uL~1~Oa~e, alkyl pentanoate, alkyl hexanoate, alkyl heptanoate, alkyl octanoate, etc., alkaryl esters, aralkyl esters, cycloalkylalkyl esters, heterocyclic esters and their variants, other esters such as Diethyloxalate, Dimethyl L-25 Tartrate, Ethyl 3,4-di11y1Lu~y11y1Lu~;nn ;Ir- te, Ethyl 2,3-E,UO~ybU~yLdte~ Ethylhydroc;nn;~r~te~ EthylN-~lydLu-~y~cetimidate, Ethyl ;~:nn;r~cQtate, Ethyl 2-methyl-4-pentenoate, Ethyl 4-methyl-s-imidazOlecarboxylate, Ethyl (+)-nipecotate, Ethyl ( )-3-phenylglycidate, Ethyl l-piperA~;n~c~rboxylate, Ethyl l-30 piper;~l;n~ncetate, Ethyl o-tolylacetate, Methyl acetate, Methyl 3-~m;nnhF-n~oate, Methyl 4-i~m;nnhc-n~onte, Methyl benzoate, Methyl l-benzyl-s-oxo-3-pyrrol ;~;n~c~rhnxylate, Methyl bL. - -etate, Methyl 3-bL1 ~ u~,ionate, Methyl butyrate, Methyl caproate, Methyl trans-cinnamate, Methyl cyr-lnh-~Y~n~r~rboxylate, Methyl 35 cyclnh~Y~nF-rropionate, Methyl cyclohexylacetate, Methyl cycloprop~n,~rboxylate, Methyl 2,5-dichlorobenzoate, Methyl 2,4-di11ydLu~y}.~l~zoate, Methyl 3,5-~;r Ulu~ybel~zoate, Methyl 2,2-wo gs/32l84 2 1 9 1 2 ~ 3 1 ~ ,5.~ ~
dimethyl-3 -l~ydL U~y~ .,pionate , Methyl 3, 3 -dimethyl-4 -pentenoate , Methyl diphenylacetate, Methyl 1olll-Epoxy~ln~ Ano;lte~ Methyl 4-fluorobenzoylacetate~ Methyl 4-formylbenzoate, Methyl 2-furoate, Methyl 3-lly~3.Lu~ybu~lzoate~ Methyl 4-lly-llu~ybenzoate, 5 Methyl 2 hy~lLu~Lyisobutyrate, Methyl 4-hy~Luxyll~ethylbenzoate~
Methyl 3- (4-hydroxyphenyl) propion~?, Methyl 4-llydLu~y~henylacetate, Methyl isobutyrat~ethyl isonicotinate, Methyl (S~ - (-) -lactate, Methyl ~ t+) : ntl~l Ate, Methyl me~hAn~slll fonate, Methyl methoxyacetate, Methyl 2-10 methoxybenzoate, Methyl 4-methoxybenzoate, Methyl trans- (+) -3-(4-methoxyphenyl) glycidate, Methyl 4-methoxyphenylacetate, Methyl 2-methylbenzoate, Methyl 3-methylbenzoate, Methyl 4-methylbenzoate, (+)-Methyl 2-methylbutyrate, Methyl 2-methyl-3-furancarboxylate, Methyl 6-methylnicotinate, Methyl o-15 Methylpodacarpate, Methyl 1-methyl-2-pyrroleacetate, Methyl (methylthio)acetate, Methyl 3-(methylthio)propionate, Methyl 1-naphthaleneacetate, Methyl nicotinate, Methyl 2-oxocyclopentalle~ ~,.LLu,Lylate~ Methyl phenoxyacetate, Methyl 2-phenyl-4-q~;nr,l ;n~cs~rboxylate~ Methyl propionate, Methyl 3-20 pyridyl~ L~, Nethyl salicylate, Methyl thioglycolate, Methyl thiosalicylate, Methyl trifluoroacetate, Methyl trimethylacetate, Methyl valerate, Nethyl vanillate, Nethylphenylacetate, straight and branch chain acid halides such as formoyl halide, Acetyl halide, Propionyl halide~, butyryl 25 halide ;nclll~;n~ n-butyryl halide, sec IJU~YLY1 halide, Isobutyryl halide, pentionyl halide, Isovaleryl halide, hexionyl halide, heptionyl halide, octionyl halide, Palmitoyl chloride, etc., aryl acid halides such as Benzoyl chloride, alkaryl acid halides, aralkyl acid halides such as 4-Biphenylcarbonyl 30 chloride, cycloalkylalkyl acid halides such as Cycloh~ n-~ ..l,ullyl chloride, Cyclopentane~;c,Ll,ullyl chloride, Cycloprop~nec.Arbonyl chloride and their variants, other acid halides such as, Acryloyl chloride, l-Adamantanecarbonyl chloride, Bromoacetyl bromide, 3-BL~ ~ u~ionyl chloride, 35 Diphenylacetyl chlorl~l~, 2-Furoyl chloride, Eydrocinn: yl chloride, Iminodibenzyl-5-carbonyl chloride, 2-Nesityl ~n~ l fonyl chloride, Nethacryloyl chloride, 219~20~
WO95/3218~ . J/C
Methanesulfonyl chloride, 4-Morpholinecarbonyl chloride, Nicotinoyl chloride, 3-Nitrobenzoyl chloride, 4-Nitrobenzoyl chloride, Oxalyl chloride, Phenylacetyl chloride, Piperonyloyl chloride, Terephthaloyl chloride, Valeryl chloride, straight and 5 branch chain alkyl haloformates, a 6uch as Ethyl chloroformate, and Isobutyl chloroformate, aryl haloformates, alkaryl haloformates, aralkyl haloformatcs, cycloalkyl haloformates, cycloalkylalkyl haloformates and their variants, the carboxylic acids, previously described, that can be converted to esters l0 ( e . g ., propionic acid in the presence of boron trif luoride etherate ln methanol will form methyl propionate) or acid halides (e. g ., propionic acid in the presence of thionyl chloride will yield propionyl chloride).
15 Aminimidçs via the ~Ydrazine-EPoxide-Ester Reaction A very useful and versatile synthesis of ;~m;nimi~l~c involves the one-pot reaction of an epoxide, an asymmetrically di-substituted hydrazine, and an ester in a protic solvent, usually water or an alcohol, which is allowed to proceed usually 20 at room temperature over several hours to several days.
(~ C ~--C H2 ~} C O O R
Q
30 ~}CH CH2 N+--N--C--~) + ROH
O H

The structural diversity elements E, F and ~I may be any structural diversity element. In particular, E, F and ~ may be _ _ _ _ _ _ _ _ . . , . .. _ ... _ .. , 219120~ .
Wo 9Sl32184 r~ s;c derived from reagents containing substituents such as alkyl, carbocyclic, cycloalkyl, aryl or alkaryl, and those carboxylates as described above. The :,Llu~:LuL~Il diversity element J may be selected from reagents containing a tf~rm;n~l epoxide, for 5 example ethylene oxide, prQpylene oxide and styrene oxide.
other oxiranes are listed in preferred~examples set forth for ~:LUL~l diversity elements J, K a~ L.
The rates for the above reacti~n increase with increasing electrophilicity of the ester component. Generally, a mixture 10 of 0.1 mole of each of the reactants in 50-100 mL of an appropriate solvent is stirred for the required period at room t~ _L~.LULe (the reaction may be monitored by thin layer chromatography). At the end of this period, the solvent is removed in vacuo to give the crude product.
Any of the various structural diversity elements illustrated in all of these Am;n;mide and aminimide-forming structures may be selected to be a structural diversity element.
The ability of these various reactions to be carried out using modules chosen in a structure-directed manner allows the 20 production of structurally directed thematic diversity libraries, having structural elements systematically varied around a basic motif.
Other methods of producing Am;n;m;do~ are detailed in an article entitled "Chemistry of ~m;nim;r1~c", Stanley Wawzonek, 25 Ind. Eng. Chem. Prod. Res. Dev., Volume 19, pages 338-349, 1980, herein specifically incoLyoL~Led by reference. Further detail6 on the reaction possibilities for the subject oxazolone and aminimide ~ ~ .ullds can be found in PCT applications, PCT/US93/12591 and PCT/USs3/12612, each filed on December 28, 30 1993, and entitled Nodular Design And Synthesis Of Oxazolone-Derived Molecules and Modular Design And synthesis of l~m;n;m;~
Derived Molecules, respectively. The content of each of those applications is expressly incorporated herein by reference thereto to the extent ne~ sAry to understand the metes and 35 bounds of this invention. ~
Mixed ~minimide-oxazQlones --21~12~3 WO 95J32184 ~ ) .,5 ~
A particularly useful ~mho~;r~nt of the invention is the synthesis of mixea Am;n;m;~ oxazolone molecules, as shown below. q his scenario allows the incorporation of multiple structural diversity elements as indicated:
1l ,o ~ ~>G
N H H Step 1 N~
15 ~--NHz + (~cH--cH2 ~ N+ -- Step3 (~ O Step Z 1 ~N-H
N t~/
o ,L~ HO
W
The diversity element A represents that diversity element from the module azlactone, the diversity elements C and D L~:~L~Sa1.L
those for the carbonyl-derived diversity element of the 30 azlactone module, the diversity elements E and F I~Lesel-L
diversity elements derived from an ull~y LLic, 1,1-disubstituted hydrazine, and the diversity element J represents diversity ele~ents derived from a funct; tm ~ "1 oxirane, in this example, a t~rminill oxirane.
The oxirane used in the formation of the hydrazinium ion in the example shown above can be di-substituted or tri-substituted. In the case where a tri-substituted oxirane is _ .... _ . . . , . _ _ Wo 95132184 2 1 9 i 2 ~ 3 . ~"~
used, an additional two structural diversity elements, K and L, can be introduced.
Some preferred reagents for the synthesis of the diversity element J, K and L may be epoxides such as straight and branch 5 chain oxiranes such as ethylene oxide, Propylene oxide, 1, 2-Epoxybutane, c~s-2,3-E~u~cybu-ane, trans-2,3-E~u~sy},uLane, 1,2-Epoxypentane, 2, 3-Epoxypentane, 1, 2-Epoxyhexane, 2,3-Epoxyhexane, 3, 4 -Epoxyhexane, Epoxyheptane ,~Epoxyoctane, etc ., aryl ,~p,~ c, alkaryl F~rrnr;~9~c, aralkyl~èpoxides, cycloalkyl 10 epoxides, cycloalkylalkyl epoxides, heterocyclic epoxides and their variants, other oxiranes such as (+) -l, 3-Butadiene diepoxide, Butyl glycidyl ether, 4-Chlorophenyl glycidyl ether, Cyclohexene oxide, Cyclooctene oxide, Cyclopentene oxide, Ethyl (+)-3-phenylglycidate, 2-Ethylhexyl glycidyl ether, Glycidol, 15 (+)-Glycidyl 2-methylphenyl ether, (+)-Glycidyl isopropyl ether, (+) -Limonene oxide, Methyl trans- (+) -3- (4-methoxypheny l ) g lyc idate, ( R) - 2 -Methylg lyc ido l, ( S ) - 2 -Methylglycidol, a-Pinene oxide, Styrene oxide, 4-tert-Butylphenyl 2,3-~:~U~-y~LU~yl ether, Epichlorohydrin, (+)-1,2-20 Epoxy-3-pheno,,y~Lup~ el 1, 2-Epoxy-5-hexene, 1, 2-Epoxyhexane, exo-2, 3 -Epoxynorbornane, ( + J - ( 2, 3 -EYU1~Y~IL u~y 1 ) benzene, 2, 3 -EP~I~Y~LU~Y1 4-methoxyphenyl ether, Ethyl 2,3-E~u~ybu~yL~te, Methyl lolll-E~u~y~ T~c~n~lzlte.
Fur~h ~:, the hydroxyl group can be modified to 25 ac~ '~te yet another structural diversity element, represented by M. The structural diversity element M may be derived from those reagents described for the structural diversity element G. Thus, a total of nine diversity elements can be provided on the mixed aminimide-oxa~olone base module as 30 shown below.
3s (~ \ / (~

W09sl32l84 21912 0 3 ~ ~I/U~. ~.r - -Strucl~u~al Dive~sitY Elements Any of a wide variety of structural diversity elements can be used. These elements would include:
1. ) Amino acid derivatives of the form (AA) nl which would include, for example, natural and synthetic amino acid residues (n=1) including all of the naturally occurring alpha amino acids, such as alanine, arginine, asparagnine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, 10 isoleucine, leucine, lysine, methionine, phenyl~lAn;n~, proline, serine, threonine, tryptophan, tyrosine, etc.; the naturally occurring di-substituted amino acids, such as amino isobutyric acid, and isovaline, etc.; a variety of synthetic amino acid residues, including alpha-disubstitUted variants, species with 15 olefinic substitution at the alpha position, species having derivatives, variants or mimetics of the naturally occurring side chains; N-Substituted glycine residues; natural and synthetic species known to functionally mimic amino acid residues, such as statine, bestatin, etc. Peptides (n = 2-3~) 20 constructed from the amino acids listed above, such as angiot~n~; nr~gen and its family of physiologically ; L~.IL
angiotensin hydrolysis products, as well as derivatives, variants and mimetics made from various combinations and permutations of all the natural and synthetic residues listed 25 above. Polypeptides (n = 31-70), such as big endothelin, pancreastatin, human growth hormone releasing factor and human pancreatic polypeptide. Proteins (n > 70) in~ d;ng structural proteinS such as collagen, functional proteins such as hemoglobin, regulatory proteins such as the dt~p~m;nR and 3 o thrombin receptors .
2. ) Nucleotide derivatives of the form (NUCL)n, which includes natural and synthetic nucleotides (n=1) such as adenosine, thymine, gilAn;fl;nF-, uridine, cystosine, derivatives of these and a variety of variants and mimetics of the purine 35 ring, the sugar ring, the phosphate linkage and combinations of some or all of these. Nucleotide probes (n=2-25) and oligonucleotides (n>25) including all of the various possible ~ . _ _ _ .. ... ... _ _ . .. _ . . _ _ . _ _ . . _ .

21912~3 "~
wo 95/3218 homo and hetero~ynthetiC combinations and permutations of the naturally occurring nucleotides, derivatives and variants containing synthetic purine or pyrimidine species or mimics of these, various sugar ring mimetics, and a wide variety of 5 alternate backhone analogs including but not limited to phosphodiester, phosphorothionate, phosphorodithionate, r~nramidate, alkyl phosphotries-tër, sulfamate, 3~-thioformacetal, methylene(methyll~mino), 3-N-carbamate, morpholino carbamate and peptide nùcleic acid analogs.
3. ) CaLlJollydLate derivatives of the form (CH)n, including natural physiologically active carbohydrates such as glucose, galactose, sialic acids, beta-D-glucosylamine and nojorimycin which are both inhibitors of glucosidase; pseudo sugars, such as 5a-carba-2-D-galactopyranose, which is known to inhibit the 15 growth of Klebsiella pneumonia (n=1), synthetic ~ bully-lL~Le residues and derivatives of these (n=1) and all of the complex oligomeric permutations of these as found in nature, including high mannose oligosaccharides, the known antibiotic streptomycin (n>l) .
4 . ) A naturally occurring or synthetic organic structural motif . This term is def ined as meaning an organic molecule having a specific structure that has biological activity, such as having a complementary structure to an enzyme, for instance.
This term includes any of the well known base structures of 25 pharmaceutical ~ u~l-ds including pharmacophores or metabolites thereof. These motifs include beta-lactams, such as penicillin, known to inhibit bacterial cell wall biosynthesis;
~;h~n7~7~rines~ known to bind to CNS receptors, used as antidepressants; polyketide macrolides, known to bind to 30 bacterial ribosymes, etc. These structural motifs are generally known to have specific desirable binding properties to ligand acceptors .
5. ) A reporter element, such as a natural or synthetic dye or a residue capable of photographic amplification which 35 p~ ss-~c reactive groups which may be synthetically incorporated into the oxazolone structure or reaction scheme, and may be attached through the groups without adversely ~ WO 95/32184 2 1 9 12 0 3 r ~ i7~1c '~
interfering with the reporting functionality of the group.
Preferred reactive groups are amino, thio, hydroxy, carboxylic acid, carboxylic acid ester, particularly methyl ester, acid chloride, isocyanate alkyl halides, aryl halides and oxirane 5 groups.

6. ) An organic moiety containing a polymerizable group such as a double bond or other functionalities capable of undergoing rrnflPnc~tion polymerization or co-polymerization.
Suitable groups include vinyl groups, oxirane groups, carboxylic 10 acids, acid chlorides, esters, amides, lactones and lactams.
Other organic moiety such as those defined for R and R' may also be used.

7. ) A macromolecular ~ rn~nt, such as a macromolecular surface or structures which may be attached to the oxazolone 15 modules v a the various reactive groups outlined above in a manner where the binding of the attached species to a ligand-receptor molecule is not adversely affected, and the interactive activity of the attached functionality is det~rm;n~d or limited by the macromolecule. This includes porous and non-porous 20 inorganic macromolecular ~nmrrn~nts~ 6uch as, but not limited to silica, alumina, zirconia, titania and the like, as commonly used for various applications, such as normal and reverse phase chromatographic separations, water purification, pigments for paints , eto .; porous and non-porous organic macromolecular 25 components, ;nrll~tq;ng synthetic _ -n~nts such as styrene-divinyl benzene beads, various methacrylate beads, PVA beads, and the like, commonly used for protein purification, water softening and a variety of other applications, natural components such as native and functirn~ ed celluloses, such 30 as, for example, agarose and chitin, sheet and hollow fiber membranes made from nylon, polyether sulfone or any of the materials mentioned above. The molecular weight of these macromolecules may range from about l000 Daltons to as high as possible. They may take the form of nanoparticles (dp = 100-35 1000 Any~,L~ ), latex particles (dp 5 1000-5000 Any~L~ ), porous or non-porous beads (dp = 0.5-1000 microns), membranes, W0 95132184 2 1 9 ~ ~ 0 ~ C
gels, macroscopic surfaces or funct;~m~li7ed or coated versions or composites of these.

8) A structural moiety selected from the group including cyano, nitro, halogen, oxygen, hydroxy, alkoxy, thio, straight 5 or branched chain alkyl, carbocyclic aryl and substituted or heterocyclic derivatives thereof.
As used herein, the phrase linear chain br branched chained alkyl groups means any substituted or unsubstituted acyclic carbon-containing ~_ _ '-, including àlkanes, alkenes and 10 alkynes. Alkyl groups having up to 30 carbon atoms are preferred. Examples of alkyl groups include lower alkyl, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl; upper alkyl, for example, octyl, nonyl, decyl, and the like; lower alkylene, for example, ethylene, propylene, lS propyldiene, butylene, butyldiene; upper alkenyl such as 1-decene, 1-nonene, 2,6-aimethyl-5-octenyl, 6-ethyl-5-octenyl or heptenyl, and the like; alkynyl such as l-ethynyl, 2-butynyl, 1 p~ y~lyl and the like. The ordinary skilled artisan is familiar with numerous linear and branched alkyl groups, which 20 are within the scope of the present invention.
In addition, such alkyl group may also contain various substituents in which one or more hydrogen atoms has been replaced by a functional group. Functional groups include but are not limited to hydroxyl, amino, carboxyl, amide, ester, 25 ether, and halogen lfluorine, chlorine, bromine and iodine), to mention but a few. Specific substituted alkyl groups can be, for example, alkoxy such as methoxy, ethoxy, butoxy, pentoxy and the like, polyhydroxy such as 1, 2-dillydL U~y~L u~y 1, 1, 4-dihydroxy-1-butyl, and the like; methylamino, ethylamino, 30 dimethylamino, diethylamino, triethylamino, cyclopentylamino, benzylamino, dibenzylamino, and the like; propanoic, butanoic or pentanoic acid groups,-and the like; formamido, acet~m;(90, but~n~m;d~, and the like, methoxycarbonyl, ethu~yuc~L~u..yl or the like, chloroformyl, bromoformyl, 1,1-chloroethyl, bromo ethyl, 35 and the like, or dimethyl Qr diethyl ether groups or the like.
As used herein, substituted and unsubstituted ~c~L~ouy.:lic groups of up to about 2~ carbon atoms means cyclic carbon-W095/32184 21gl203 r. ."J~.,r~ ~r containing compounds, including but not limited to cyclopentyl,cyclohexyl, cycloheptyl, admantyl, and the like. such cyclic groups may also contain various substituents in which one or more hydrogen atoms has been replaced by a f unctional group .
5 Such functional groups include those described above, and lower alkyl groups as described above. The cyclic groups of the invention may further comprise a heteroatom. For example, in a specific F.mhnr1i --lt, R2 is cycnb~nnl.
As used herein, substituted and unsubstituted aryl qroups 10 means a hydrocarbon ring bearing a system of conjugated double bonds, usually comprising an even number of 6 or more pi-bond electrons. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anisyl, toluyl, xylenyl and the like.
According to the present invention, aryl also includes aryloxy, 15 aralkyl , aralkyloxy and heteroaryl groups , e . g ., pyrimidine , morpholine, piperazine, piperidine, benzoic acid, toluene or thiophene and the like. These aryl groups may also be substituted with any number of a variety of functional groups.
In addition to the functional groups described above in 20 connection with substituted alkyl groups and ~:~L~o~,y~lic groups, functional groups on the aryl groups can be nitro groups.
As mentioned above, these structural moieties can also be any combination of alkyl, carbocyclic or aryl groups, for example, 1-cyclohexylpropyl, benzylcyclohexylmethyl, 2-25 cyclohexyl-propyl, 2, 2-methylcyclohexylpropyl, 2, 2-methylphenylpropyl, 2,2-methylphenylbutyl, and the like.
In one preferred r~Tnhod;T t of the present invention one or more of the structural diversity elements; A, B, C, D, E, F, G, H, J, K, L and M are reactive groups that are capable of 30 further reactions to produce a base module or an orthogonal reactive group. For example, the present invention is directed to structural diversity groups that may themselves be capable of further reaction to form base modules as described herein.
For example, a structural diversity element that is an oxazolone 35 based reactive group that upon further reaction can form an m;n;m;df. base module. Such ring opening reactions are described in PCT applications, PCT/US93/12591 and PCT/US93/12612, each _ _ _ , .. . . _ _ ... _ .

219120~ p~ ,5,'C' WO 95/32l84 filed on December 28, 1993, and entitled Modular Design And Synthesis Of Oxazolone-Derived Molecules and Modular Design And synthesis Of Aminimide-Derived Molecules, respectively. The content of each of those applications i8 expressly incorporated 5 herein by reference thereto to th'e extent necessary to understand the metes and bounds of t~ii6 invention.
~, ~
Orthoqonal Reactiviti es - ~-A key element of the present method is the presence of at 10 least two c u--ds, each having a reactive group capable of forming an addition _ 1 with the other and carrying at least one of the structural diversity groups. These compounds are used to form the aminimide and the oxazolone base modules.
These compounds may take the form of either a) multiple reactive 15 groups which are capable of being "turned on" independently of each other, or b) groups with multiple states with di~fering reactivities which may be addressed or brought into being at different times or under different conditions in a reaction sequence. It is highly desirable, although not absolutely .20 nPc~ssAry, that each individual reaction be a high-yielding addition reaction without possible interfering side-reactions, so that isolation and purification steps are not n~c.o5~ry, or, at least, are held to a minimum.
Specif ically preferred reactive groups to generate the 25 ;lmin;mi~l~ and oxazolone structures and the resulting base modules are listed below in tables 1, 2 and 3. The bonds in the structureS in these f igures represent potential points of attA~' ~ for the att~l' L of the ~LLU~:~U1a1 diversity elements to the fir6t and second _I-Jul-ds and to the base 3 o modules .

O 95/3218~ r~
Table 1. Oxazolone Modules Reactivity Groups Base Module y~ _ HY-- J~ N ~ \
(y = N, S, O) H
O O
Yo~ + )=O y~ -, 0~ (Y _ N, S, O) J~ N~ \
O O
--C02HICI y,~_ H2N CO2H (ClCO2Et/Et3N) o 0~ + (X - S-, N\ ) ~X' y~--(Z = CH2=CH-, etc.) O
Repres~n~s po~en~ial points or altacllmen~ ror stmctural div~rsity ~l~ments ~ 47 --SUBSTITUTE SHEET (F~ULE 26) -WO 95/32184 219 12 0 3 r~~ ,A -- --Tahle 2. Alllininliae Modules Reaclivity GroDps Base M()~ s -- COOH H2Ni< -- CONHI~<
--NCO H2NN< --NH~QNHN~
--OCOCI H2NN< --O CONHN~
--~SCOCI H2NN< --SCONHN~
--CONHi`< -- X --CONN--(neutr.) --CONHi~ ~7 --CONI~/
_ x I+
--NHCONH~ neutr.) -- NHCONN----NHcoNH~ ~ -- NHCONN~/
o ¦ OH
--OCONH~< (neutr.) --ocoNN---OCONHN~ ~ ~ --OCON~
O I OH
--SCONHN~ -- X --SCONN--(neutr.) --SCONHN~ ~ --SCONI~
o ¦ OH
Rel~rcsell~s l~olen~ oints Or ~ cll~ncnl ~or slmc~-lral di-lcrsi(y clcmcn~
~, _ SUBSTITUTE SHEET (RULE 26) Table 2. Contil~ued - Amil1imide Mod~lles Reactivity Gloups Base Modules 5 2 \ (neutr.) H2NN< ~7 HNN/~
. i ¦ + OH
._ - I +

HN~ -- cooR --CONN--HNN~ -- COOR --CONI~
OH I + OH
X~ ~ ~+N~

HN~ ~ \ ~N~

Rep~esents polemi;ll poin~s Or 2llachlll~n~ ~()I strucillral ~livcrsily ~Iclncms 21912~3 wo 95/3218~ r~l~u.,,s.c ~able 3. Aminimide-oxazolone Modules Reaclivity Ciroups ~ ~, Bas~ Modulc~
H N ~ 0 ~ 0 N N
o H2NN-- o. ~< O H N
(Base) Rellrc~ell~s l~o~e~ oillls Or ~ lCllnlcll~ ror slruclurlll (~ivcrsily clcmcl~ls SUBSTITUTE SHEET (RULE ~6) 219~20~

9~/3218~ l~"l C
EXA~PLES
In order to exemplify the results achieved using the methods and compounds of the present invention, the f ollowing 5 examples are provided without any intent to limit the scope of the instant invention to the discussion therein, all parts and percentages are by weight unless otherwise indicated.
EXRMPLE 1.
This example describes the generation of a matrix of 16 molecules around the following aryl-heterocycle-alicyclic amine structural theme.
Tlleme ¦ArylGroup ¦~N~ AcyclicAmillc ¦
He~erocYcle I
The 2-phenyl and 2- (2-naphthyl~ -5-oxazolones (produced by reacting the lithium salt of glycine with the aryl acid 25 chlorides, followed by cyclization with ethyl chloroformate at 0 C) were reacted with 2-furfural, 3-furfural, 2-thiophenal and 3-thiophenyl to produce the oxazolones funct;f~nAl;7ed at the 5-position. This reaction was followed by subsequent ring-opening addition of 4-(3-aminopropylmorpholine and 1-(3-aminopropyl)-2-30 pipicoline to form the adducts shown. The reactions werecarried out in individual vials such that each vial contained one pure final ~ _ a as follows:
1) equimolar quantities of the oxazolone and the aldehyde dissolved in dry benzene (25 mL/gm reactants) were heated to 75 35 C for 15 minutes; 2) the reaction mixture was cooled to 10 C, and the amine was added dropwise with stirring; 3) the mixture WO 95/32184 2 1 9 1 2 0 3 i ~
waEi re-heated to 75 oc ~or 20 minutes and 4 ) the Lolvent was removed in vacuo to ~lve the crude solid product.
~CH0 ~?
J~ ~~N
A r ~f ~--Nl WO 95/32184 2 1 ~ 1 2 0 3 P~ 5 ~
Ar X / Isomer R / Y
Ph O 2- H O

10 Ph S 2- H O
Ph O 2- CH3 CH2 Ph 5 2- CH3 CH2 15 Naphthyl O 2- H O
Naphthyl S 2- H O
Naphthyl O 2- CH3 CH2 Naphthyl S 2- CH3 CH2 Ph O 2- H O
Ph S 2- H O
Ph O 2- CH3 CH2 25 Ph S 2- CH3 CH2 Naphthyl O 2- H O
Naphthyl S 2- H O
30 Naphthyl o 2- CH3 CH2 Naphthyl $ 2- CH3 CH2 Wo95/32181 21912~3 P~l/v~ol ~
EXA~PLE 2.
The following example outlines the generation of a matrix 5 of 16 molecules around the basic structural theme of a hydroxy-proline transition state mimetic inhibitorifor proteases:
Structural Theme: ~
,~ ' ¦ PHENYLALANINEI ¦ PROLINE ~
I ALANINE MIMETIC ~ MIMETIC ¦
-OH
This mimetic was synthesized oy reacting styrene oxide or propylene oxide, ethyl acetate or methyl benzoate with four commercially available cyclic hydrazines (as mimetics of proline) in isopropanol in 16 individual sample vials, as shown 2 O in f igure l .
\~ R2COOR=~ N~
N~
¦ X=CHI ¦ ¦ X. I~Mc ~ ~ X=O ¦ ¦X=CHICH2I
3 0 ¦ R~ Rl ¦ ¦ Rl n' ¦ ¦ R R~ ¦ ¦ R Rl ¦
rh Me rll Me Ph Me Ph Mc Ph rh 1'1~ Ph Ph Ph Ph Pll 3 5 Me Me Me Me Me Me Me Me Me Ph Mc rh Me Ph Mc Pi, ~ 54 ~

W0 95132184 ~ 1 9 1 ~ 0 3 p~ ~", ,5:~
These 16 materials were isolated in essentially ~uantitative yield on removal of the reaction solvent by evaporatiOn and purif ied samples were obtained as crystalline 5 solids after recrystallization from ethyl acetate and characterized by lH-N~R, FTIR and other analytical techniques.
The set of molecules where X = CH2 was tested as competitive inhibitors of the enzyme chymotrypsin in a standard assay using a BTEE substrate. The results found for K~ were 200 uM for R~
10 = Ph, R2= Ne; 130 uM for Rl = lle, R2 = Ph; 500 uM for Rl = Ph, R2 = Ph; and Rl = Me, R2 = ~e was found to not be an inhibitor.
These results indicate a preference of the enzyme in this assay for one phenyl and one methyl, with the phenyl being preferred in the R~ position. Based on these results, a second array was 15 synthesized using phenyl groups in this position having a variety of different substituent groups for further testing against the enzyme.
From the f oregoing, it is seen that various arrays of molecules can be prepared. These arrays can be generated in the 20 desired size to facilitate the screening of a large number of molecules at one time. In Example 2, 4 x 4 arrays of molecules were ~L~paLed, but the invention is not to be limited to that specific embodiment. For example, standard trays having 96 compartments in an 8 x 12 array can be used where any number of 25 ~ - i Ls contain different molecules, while the other can contain controls or duplicate samples. It is possible, and preferred, to include 16 controls and 80 different samples in the array. After an initial screening identifies molecules having certain beneficial or desirable properties, a second tray 30 containing, e.g., 20 samples of each of 4 different molecules, again with 16 controls, samples, can be used to confirm the original results. The samples can be placed in columns of the same material, or a completely random array can be generated to have a completely blind analysis.
In view of these variations, one of ordinary skill in the act und~l=.L~.,d:, that any m x p array of molecules can be generated, where n and p are integers, m being greater than o ... _ . .. . . _ _ _ _ 219~203 Wo 95132184 ~ C -and p being greater than l. There is no upper limit to m and p other than the capabilities of the testing or screening equipment. A6 noted above, an 8 x 12 array would be typical, but of compounds can be tested from arrays where m or p is as 5 high as 25 or more; of being the total of m times p. At this time, it is specifically preferred that m and p be integers of between 3 and 15, and that a few contrQ~ molecules be included so that q is less than the product of~ m and p. However, this invention contemplates that~ use of an~`y integer for m or n, with lO each integer or combination of m x p integers relied upon as representing a useful embodiment.
As noted above, the molecules used in the array would be generated from one or more of the base molecules described herein. In this manner, combinatorial libraries of r different 15 compounds, where r is any integer, can be made. Typically, r will be greater than 5, other 25 or greatex. As noted, r can be as high as 80 or 96 using available trays, or can even be higher using specifically designed trays. Although for convenience, linear arrays are described, the specific 20 arrangement of the molecules and tray compartments can be circular, staggered or in any other configuration which can have a completely blind analysis.
In view of these variations, one of ordinary skill in the art understands that any m x p array of molecules can be 25 generated, where n and p are integers, m being greater than o and p are integers, me being greater than o and p being greater than l. There is no upper limit to m and p other than the cAr~hi 1 i ties of the testing or screening equipment. As noted above, an 8 x 12 array wouId be typical, but of compounds can 30 be testéd from arrays where m or p is as high as 25 or more; of being the total of m times p. At this time,-i~ is specifically preferred that m and p be integers of between 3 and 15, and that a few control molecules be ; nr~lllrqprl so that q is less than the product of m and p. However, this invention contemplates the 35 use of any integer for m or n, with each integer or combination of m x p integers relied upon as Le~l~st~ ing a useful ~mhQ~ i r t .

WO 9513218~ 2 1 ~ 12 ~ 3 r~ "~
As noted above, the molecules used in the array would be generated from one or more of the base molecules described herein. In this manner, combinatorial libraries of r different compounds, where r is an integer, can be made. Typically, r will 5 be greater than 5, often 25 or greater. As noted, r can be as high as 80 or 56 using available trays. Although for convenience, linear arrays are described, the specific arrangement of the molecules and tray compartments can be circular, rectangular, staggered or in any configuration which lO can be analyzed by the testing or screening device used.
The relevant portions of all cited patents, patent applications and other publications are specifically incorporated herein by reference.
The scope of the following claims is intended to encompass 5 all obvious changes in the details, materials and arrangement of parts that will occur to one of ordinary skill in the art .

Claims (30)

The Claims We claim;

1. A compound having a structure according to formula I;
I
wherein n = 1 - 4;
A, B, C and D are structural diversity elements which can include but are not limited to set of:
- methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, octyl, nonyl, decyl, ethylene, propylene, propyldiene, butylene, butyldiene, 1-decene, 1-nonene, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, heptenyl, 1-ethynyl, 2-butynyl, 1-pentynyl, hydroxyl, amino, carboxyl, amide, ester, ether, and halogen (fluorine, chlorine, bromine and iodine), methoxy, ethoxy, butoxy, pentoxy, 1,2-dihydroxypropyl, 1,4-dihydroxy-1-butyl, methylamino, ethylamino, dimethylamino, diethylamino, triethylamino, cyclopentylamino, benzylamino, dibenzylamino, propanoic, butanoic or pentanoic acid groups, formamido, acetamido, butanamido, methoxycarbonyl, ethoxycarbonyl, chloroformyl, bromoformyl, 1,1-chloroethyl, bromo ethyl, dimethyl or diethyl ether groups, cyclopentyl, cyclohexyl, cycloheptyl, admantyl, phenyl, naphthyl, anisyl, toluyl, xylenyl, aryloxy, aralkyl, aralkyloxy, heteroaryl groups(pyrimidine, morpholine, piperazine, piperidine, thiophene), 1-cyclohexylpropyl, benzylcyclohexylmethyl, 2-cyclohexyl-propyl, 2,2-methylcyclohexylpropyl, 2,2-methylphenylpropyl, 2,2-methylphenylbutyl, and Y = O, S or N; and Z is II
or III

2. A compound according to claim 1 with the proviso that when n=1, A is a nitrogen group, Z is a compound according to structure III and Y is an oxygen atom, B is not a resin bead.

3. A compound according to claim 1 with the proviso that when n=1, Z is a compound according to structure III, C and D
are hydrogen atoms, A is a carbon atom bonded to: (a) a secondary amine; (b) a hydrogen atom; and, (c) another carbon atom which is bonded to a substituted or unsubstituted aminal.

4. A compound according to claim 1 with the proviso that when n=1, Z is a compound according to structure III, C and D
are hydrogen atoms, and A is a carbon atom bonded to 2 hydrogen atoms and a primary or secondary amine.

5. A compound according to claim 1 wherein n is an integer greater than 1.

6. A compound according to claim 1 wherein n is 1.

7. A compound according to claim 1 wherein Z is II

8. A compound according to claim 1 wherein Z is III

9. A compound according to claim 1 wherein structural diversity elements A, B, C and D are the same or different and are selected from substituted or unsubstituted, branched or straight chain alkyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted aryl.

10. A, compound according to claim 1 wherein structural diversity element A, B, C and D are the same or different and are selected from amino acid derivatives, nucleotide derivatives, carbohydrate derivatives, naturally occurring or synthetic organic structural motifs, reporter elements, organic moieties containing a least one polymerizable group, or macromolecular components.

11. A compound according to claim 1 wherein C and D are the same.

12. A compound according to claim 1 wherein C and D are different.

13. A compound having a structure according to formula IV:
IV
wherein E, F, G and H are structural diversity elements whieh can include but are not limited to set of: methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl, octyl, nonyl, decyl, ethylene, propylene, propyldiene, butylene, butyldiene, 1-decene, 1-nonene, 2,6-dimethyl-5octenyl, 6-ethyl-5-octenyl, heptenyl, 1-ethynyl, 2-butynyl, 1-pentynyl, hydroxyl, amino, carboxyl, amide, ester, ether, and halogen (fluorine, chlorine, bromine and iodine), methoxy, ethoxy, butoxy, pentoxy, 1,2-dihydroxypropyl, 1,4-dihydroxy-1-butyl, methylamino, ethylamino, dimethylamino, diethylamino, triethylamino, cyclopentylamino, benzylamino, dibenzylamino, propanoic, butanoic or pentanoic acid groups, formamido, acetamido, butanamido, methoxycarbonyl, ethoxycarbonyl, chloroformyl, bromoformyl, 1,1-chloroethyl, bromo ethyl, dimethyl or diethyl ether groups, cyclopentyl, cyclohexyl, cycloheptyl, admantyl, phenyl, naphthyl, anisyl, toluyl, xylenyl, aryloxy, aralkyl, aralkyloxy, heteroaryl groups (pyrimidine, morpholine, piperazine, piperidine, thiophene), 1-cyclohexylpropyl, benzylcyclo-hexylmethyl, 2-cyclohexyl-propyl, 2,2-methylcyclohexylpropyl, 2,2 methylphenylpropyl, 2,2-methylphenylbutyl, with the proviso that no more than one of E, F, and G is an alkoxy group.

14. A compound according to claim 13 wherein structural diversity element E, F, G and H are the same or different and are selected from amino acid derivatives, nucleotide derivatives, carbohydrate derivatives, naturally occurring, or synthetic organic structural motifs, reporter elements, organic moieties containing a least one polymerizable groups or macromolecular components.

15. A compound having a structure according to formula V;
V
wherein E, F, J and EI are structural diversity elements which can include but are not limited to set of: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, octyl, nonyl, decyl, ethylene, propylene, propyldiene, butylene, butyldiene, 1-decene, 1-nonene, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, heptenyl, 1-ethynyl, 2-butynyl, 1-pentynyl, hydroxyl, amino, carboxyl, amide, ester, ether, and halogen (fluorine, chlorine, bromine and iodine), methoxy, ethoxy, butoxy, pentoxy, 1,2-dihydroxypropyl, 1,4-dihydroxy-1-butyl, methylamino, ethylamino, dimethylamino, diethylamino, triethylamino, cyclopentylamino, benzylamino, dibenzylamino, propanoic, butanoic or pentanoic acid groups, formamido, acetamido, butanamido, methoxycarbonyl, ethoxycarbonyl, chloroformyl, bromoformyl, 1,1-chloroethyl, bromo ethyl, dimethyl or diethyl ether groups, cyclopentyl, cyclohexyl, cycloheptyl, admantyl, phenyl, naphthyl, anisyl, toluyl, xylenyl, aryloxy, aralkyl, aralkyloxy, heteroaryl groups(pyrimidine, morpholine, piperazine, piperidine, thiophene), 1-cyclohexylpropyl, benzylcyclo-hexylmethyl, 2-cyclohexyl-propyl, 2,2-methylcyclo-hexylpropyl, 2,2-methylphenylpropyl, 2,2-methylphenylbutyl..

16. A compound according to claim 16 wherein structural diversity elements E, F, J and H are the same or different and are selected from amino acid derivatives, nucleotide derivatives, carbohydrate derivatives, naturally occurring or synthetic organic structural motifs, reporter elements, organic moieties containing a least one polymerizable group or macromolecular component.

17. A compound having a structure according to formula VI;
VI
wherein A, C, D, E, F and J are structural diversity elements which can include but are not limited to set of: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, octyl, nonyl, decyl, ethylene, propylene, propyldiene, butylene, butyldiene, 1-decene, 1-nonene, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, heptenyl, 1-ethynyl, 2-butynyl, 1-pentynyl, hydroxyl, amino, carboxyl, amide, ester, ether, and halogen (fluorine, chlorine, bromine and iodine), methoxy, ethoxy, butoxy, pentoxy, 1,2-dihydro-xypropyl, 1,4-dihydroxy-1-butyl, methylamino, ethyl-amino, dimethylamino, diethylamino, triethylamino, cyclopentylamino, benzylamino, dibenzylamino, propanoic, butanoic or pentanoic acid groups, formamido, acetamido, butanamido, methoxycarbonyl, ethoxycarbonyl, chloroformyl, bromoformyl, 1,1-chloroethyl, bromo ethyl, dimethyl or diethyl ether groups, cyclopentyl, cyclohexyl, cycloheptyl, admantyl, phenyl, naphthyl, anisyl, toluyl, xylenyl, aryloxy, aralkyl, aralkyloxy, heteroaryl groups(pyrimidine, morpholine, piperazine, piperidine, thiophene), 1-cyclohexylpropyl, benzylcyclo-hexylmethyl, 2-cyclohexyl-propyl, 2,2-methylcyclohexylpropyl, 2,2-methylphenylpropyl, 2,2-methylphenylbutyl.;
Z is II

or III
where n = 1 - 4.

18. A compound having a structure according to formula VII;
VII
wherein A, C, D, E, F, J, K, L and M are structural diversity elements which can include but are not limited to set of: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, octyl, nonyl, decyl, ethylene, propylene, propyldiene, butylene, butyldiene, 1-decene, 1-nonene, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, heptenyl, 1-ethynyl, 2-butynyl, 1-pentynyl, hydroxyl, amino, carboxyl, amide, ester, ether, and halogen (fluorine, chlorine, bromine and iodine), methoxy, ethoxy, butoxy, pentoxy, 1,2-dihydroxypropyl, 1,4-dihydroxy-1-butyl, methyl amino, ethylamino, dimethylamino, diethylamino, triethylamino, cyclopentylamino, benzylamino, dibenzylamino, propanoic, butanoic or pentanoic acid groups, formamido, acetamido, butanamido, methoxycarbonyl, ethoxycarbonyl, chloroformyl, bromoformyl, 1,1-chloroethyl, bromo ethyl, dimethyl or diethyl ether groups, cyclopentyl, cyclohexyl, cycloheptyl, admantyl, phenyl, naphthyl, anisyl, toluyl, xylenyl, aryloxy, aralkyl, aralkyloxy, heteroaryl groups (pyrimidine, morpholine, piperazine, piperidine, thiophene), 1-cyclohexylpropyl, benzylcyclohexyl-methyl, 2-cyclohexyl-propyl, 2,2-methylcyclohexyl-propyl, 2,2-methylphenylpropyl, 2,2-methylphenyl-butyl.;
Z is II
or III
and, n = 1 - 4.

19. An m x p array of molecules comprising molecules having at least one of the following structures:

I
IV
V
VI
VII
wherein A, B, C, D, E, F, G, H, J, K, L and M are structural diversity elements;
Z is II
or III
wherein at least q molecules in said array have at least one different structural diversity group; and n = 1 - 4;
m is an integer greater than 0;
p is an integer greater than 1;
p is greater than m;
and q is an integer greater than 1.

20. An m x p array of molecules according to claim 21 wherein m and p are integers between 1 and 25 and q is equal to m multiplied by p.

21. An m x p array of molecules according to claim 21 wherein m and p are integers between 1 and 25 and q is an integer less than m multiplied by p.

22. An m x p array of molecules according to claim 21 wherein m and p are integers between 3 and 15 and q is an integer less than m multiplied by p.

23. An m x p array of compartments containing molecules, wherein said molecules have at least one of the following structures:
I
IV

V
VI
VII

wherein A, B, C, D, E, F, G, H, J, K, L and M are structural diversity elements;
Z is II
or III

wherein at least q molecules in said array have at least one different structural diversity group; and n = 1 - 4;
m is an integer greater than 0;
p is an integer greater than 1;

p is greater than m;
and, q is an integer greater than 1.

24. An m x p array of compartments containing molecules according to claim 25 wherein m and p are integers between 1 and 25 and q is equal to m multiplied by p.

25. An m x p array of compartments containing molecules according to claim 25 wherein m and p are integers between 1 and 25 and q is an integer less than m multiplied by p.

26. An m x p array of compartments containing molecules according to claim 25 wherein m and p are integers between 3 and 15 and q is an integer less than m multiplied by p.

27. A combinatorial library of compounds comprising r different compounds, wherein each of the compounds has a base module selected from the following structures;
I
IV
V
VI

VII
wherein A, B, C, D, E, F, G, H, J, K, L and M are structural diversity elements;
Z is II
or III
n = 1 - 4;
r is an integer greater than 1.

28. A combinatorial library of compounds according to claim 29 wherein r is an integer greater than 5.
29. A combinatorial library of compounds according to

claim 29 wherein r is an integer greater than 25.

30. A compound according to any one of claims 1, 13, 16, 19 and 20 wherein one or more structural diversity elements defined as A, B, C, D, E, F, G, H, J, K, L and M is capable of further reactivity to form a base module.