This application claims the benefit of provisional application serial number 60/255,092 filed on December 12,2000. The entire disclosure is incorporated herein by reference.

FIELD OF THE INVENTION This invention relates to a novel method for preparing monocyclic N- acyl-aminolactam compounds and combinatorial libraries thereof.

BACKGROUND The design and synthesis of conformationally constrained mono or polycyclic peptidomimetics is an important approach toward developing potent, selective and metabolically stable drug candidates from endogenous peptide hormones, neurotransmitters, receptor ligands and other peptidic lead molecules (Olson, G. L. et al., J. Med. Chem. 36,3039 (1993)). A major objective in the development of these low molecular weight, nonpeptidic peptidominetics is the close reproduction of the so-called"bioactive topology" which is derived from the putative"bioactive conformation". Small, polyfunctional, conformationally constrained, mono-or polycyclic"molecular scaffolds"which can be substituted by the essential pharmacophores are ideal for this purpose. Indeed, these kinds of peptidomimetic molecular scaffolds have been successfully incorporated into a number of drug candidates with potent enzyme inhibitory or receptor antagonistic activities (e. g. Sugihara, H. et al., J. Med. Chem. 41,489 (1998)). There are also potential applications of such peptidomimetics as antigen constraints to improve immune response to protein epitopes (Long, R. D.; Moeller, K. D. J. Am. Chem. Soc. 119,12394 (1997)). 1,4-Benzodiazepin-3-one system is one of the most widely used "molecular scaffold" (peptitomimetics).

The 2-ketopiperazine moiety can also be used as a p-turn mimics of a dipeptide and has been incorporated into a cyclic peptide as potential active site mimic of lipase which shows lipase-like activity (Uchida et al., Chem.

Pharm. Bull. 45,1228 (1997)).

2-Ketopiperazines are important pharmacophores that have been reported in a number of marketed drugs or drug candidates under development. Examples include enkephalin analogues which contain 5,6- unsubstituted 2-ketopiperazines (Piercy, M. F. et al., Brain Res. 74,385 (1986), glycoprotein Ilb/llla angtagonists (Takada, S. et al. ; Pharm. Res. 14,1146 (1997); Sugihara, H. et al., J. Med. Chem. 41,489 (1998)) and substance P antagonists (Wright, et al., J. Med. Chem. 11,390 (1968)). Antihelminthic drug Praziquantel contains a 2-ketopiperazine moiety that is fused to an aromatic ring.

1,4-Perhydrodiazepin-2-one derivatives have been described as novel conformation constrained y-turn mimetic of a dipeptide in the literature (Weitz, I. S. et al., J. Org. Chem. 62,2527 (1997); Czaplewski, C. et al., Pol. J. Chem.

68,2589 (1994)). The 1,4-perhydrodiazepin-2-one structure has also been found in some naturally occurring antibiotics such as Liposidomycins B and C (Isono, K. et al., J. Antibiot. 38,1617 (1985); Ubukata, M et al., J. Am. Chem.

Soc. 110,4416 (1985)). The synthesis of 1,4-diazepin-2-ones reported in the literature. involved a multi-step synthesis, typically five-to seven-step for simple 1,4-perhydrodiazepin-2-one compounds starting from an amino acid derivative, and in the solution phase.

1,4-Perhydrodiazepin-5-one derivatives are described as factor IXa inhibitors (Scarborough, R. M.; Zhu, B.-Y. W09846628) and interleukin-1 b converting enzyme inhibitors (Bemis, G. W et al., US 5847135) among others.

The discovery of new pharmaceutical active compounds for a given indication involves the screening of all compounds from available compound collections. The combinatorial synthesis, or parallel synthesis, of large arrays of single compounds is now an important component of modern drug discovery method. Although such compounds as monocyclic N-acyl-aminolactams, or, <BR> <BR> <BR> <BR> monocyclic N-acyl-alpha-aminoacetamide and N-acyl-beta-aminopropanamide compounds are useful and important dipeptidomimetics, it is not practical to use these reported solution phase methodologies to prepare a large set of these compounds. The multiple component condensation (MCC) reactions are particularly attractive for rapid access to large numbers of structural analogs in a single step. There has thus been recent interest in the application of the Ugi four component condensation (Ugi, I., Angew. Chem. Int Ed. Engl. 1,8 (1962))

and other multiple component condensations to the solid phase thereby simplifying work up and enabling reactions to be driven to completion by using reagent excesses subsequently removed by filtration. In the realm of combinatorial drug-like library synthesis, success has been achieved through post Ugi four component condensation which resulted in several interesting type of scaffolds such as pyrrole (Keating, T. A.; Armstrong, R. W. J. Am.

Chem. Soc. 118,2574 (1996); Strocker, A. M. et al., Tetrahedron Lett. 37,1149 (1996); Mjalli, A. M. M. ; et al., Tetrahedron Lett. 37,2943 (1996)), imidazole (Zhang, C. et al., Tetrahedron Lett. 37,751 (1996)), diketopiperazine (Szardenings, A. K. et al., Tetrahedron, 53,6573 (1997); Hulme, C. et al., Tetrahedron Lett. 39,1113 (1998)), and 1,4-benzodiazepine-2,5-dione (Keating, T. A.; Armstrong, R. W. J. Org. Chem. 61,8935 (1996)).

SUMMARY OF THE INVENTION We have developed a novel solid-phase methodology which constructs a large number of monocyclic N-acyl-aminolactam compounds of the formula (I) without tedious workup process. This method rapidly provides libraries to the combinatorial drug discovery, and as such is invaluable in speeding drug discovery. Such compounds have been shown to be useful as pharmaceutical agents.

0 DETAILED DESCRIPTION OF THE INVENTION This description is not intended to be exhaustive or to limit the invention to the precise details or examples disclosed. Details and examples have been chosen to illustrate the invention to others skilled in the art.

The methods of this invention described herein and in the claims, may be performed in several ways. Preferred methodologies are described as follows.

This invention provides a method for preparing a monocyclic N-acyl- aminolactam compound of the formula (I) :

comprising the steps of: i) reacting the following reagents: (a) an isocyanide of the formula R1 NC, (b) a ketone of the formula R2COR3 or aldehyde of the formula R2CHO, (c) a protected amino acid chosen from the formulae R4CH (NHP) COOH or R9CH (NHP) CH (R8) COOH, (d) a protected a-or ß-aminoaldehyde of the formula NH2 (CH2) nCH (OR7) 2, wherein said isocyanide or said ketone or aldehyde is bound to a polymer via an acid-labile linkage, to produce a polymer-bound acetal compound of the formula (II) (11) ii) reacting said polymer-bound acetal compound of the formula 11 with an acetal-deprotecting reagent to afford a polymer-bound aldehyde compound of the formula (III) : (III) iii) reacting said polymer-bound aldehyde. compound of the formula (III) with a base reagent to afford a polymer-bound amino aldehyde compound of the formula (IV) :

iv) reacting said polymer-bound amino aldehyde compound (IV) with a carboxylic acid of the formula R5COOH and an isocyanide of the formula R6NC to afford a polymer-bound monocyclic N-acyl-aminolactam compound of the formula (V): (V) and, v) reacting said polymer-bound monocyclic N-acyl-aminolactam compound of the formula (V) with an acid to afford the monocyclic N-acyl- aminolactam compound of the formula (I), wherein Ri is an organic moiety derived from an isocyanide of the formula R1NC, R2 and R3 represent hydrogen, or an organic moiety derived from a ketone of the formula R2COR3, or an aldehyde of the formula of R2CHO, R4 is a substitutent of a protected a-amino acid of the formula R4CH (NHP) COOH, R5 is an organic moiety derived from a carboxylic acid of the formula R5COOH, R6 is an organic moiety derived from an isocyanide of the formula R6NC, R7 is alkyl or cyclic alkyl, R8 and Rg are substitutents of a protected amino acid of the formula R9CH (NHP) CH (R8) COOH,

P is a base-labile protecting group of an amino functional group, n is 1 or 2, Z is chosen from R4CH or RsCHCH (R8) Preferably, said isocyanide reagent of the formula RIC is bound to a polymer via an acid-labile linkage. Preferably, said acid in the step v) is trifluoroacetic acid (TFA).

For purposes of illustration, when n equals 1, Z is R4CH, said monocyclic N-acyl-aminolactam compound may also be referred to as a 2-ketopiperazine and is represented by the following formula (VI) : When n equals 2, Z is R4CH, said monocyclic N-acyl-aminolactam compound may also be referred to as a 1,4-perhydrodiazepin-2-one and is represented by the following formula (Vll) : When n equals 1, Z is RgCHCH (R8), said monocyclic N-acyl- aminolactam compound may also be referred to as a 1,4-perhydrodiazepin-5- one and is represented by the following formula (XIII) : When n equals 2, Z is RgCHCH (R8), said monocyclic N-acyl- aminolactam compound may also be referred to as a 1,5-diazocan-2-one and is represented by the following formula (IX) :

The invention also provides an N-acyl-aminolactam compound of the formula (I) and a combinatorial library of N-acyl-aminolactam compounds.

For purposes of illustration, when n equals 1, Z is R4CH, said monocyclic N-acyl-aminolactam compound is represented by the formula (VI). When n equals 2, Z is R4CH, said monocyclic N-acyl-aminolactam compound is represented by the formula (VII). When n equals 1, Z is R9CHCH (R8), said monocyclic N-acyl-aminolactam compound is represented by the formula (XIII).

When n equals 2, Z is R9CHCH (R8), said monocyclic N-acyl-aminolactam compound is represented by the formula (IX).

Preferably, R1 represents alkyl, aryl, heterocyclcyl, or heteroaryl groups.

R2 represents hydrogen, alkyl, aryl, heterocyclcyl, or heteroaryl groups. R3 represents hydrogen, alkyl, aryl, heterocycicyl, or heteroaryl groups. More preferably, R3 represents hydrogen. R4 represents hydrogen, alkyl, aryl, heterocyclcyl, or heteroaryl groups. R5 represents hydrogen, alkyl, aryl, heterocyclcyl, or heteroaryl groups. R6 represents alkyl, aryl, heterocycicyl, or heteroaryl groups. R8 represents hydrogen, alkyl, aryl, heterocyclcyl, or heteroaryl groups. More preferably, R8 represents hydrogen. Rg represents hydrogen, alkyl, aryl, heterocycicyl, or heteroaryl groups. More preferably, Rg represents hydrogen.

The reaction described in the specification is conducted in the solid phase. Either isocyanide or ketone or aldehyde is linked to a solid support via an acid-labile linkage before it is used to react with other three reagents in the four component condensation reaction. Preferably, the isocyanide of the formula R4NC is linked to a solid support. Reagents in the first reacting step of

this method are mixed in a solvent and reaction is performed at room temperature for 48 to 72 hours.

Examples of this synthetic route described in the specification are performed individually or in parallel in either manual or automated operation.

The parallel reaction is typically performed in a 96 well titer plate and the final product N-acyl-aminolactams are directly transferred into a 96 well titer plate for high throughput screening.

An acid, trifluoroacetic acid (TFA) is used to cleave the product from a solid support. After removal of the solvent and the acid, the N-acyl- aminolactam compound is preferably obtained in pure form directly.

Alternatively, a conventional purification procedure can be used.

DEFINITIONS As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

"Acetal deprotecting reagent", as used herein, means any reagent that can remove the acetal protecting group as in a-or ß-aminoaldehydel diethyl acetal without affecting other functional groups or protecting groups in the molecule. An acetal group can be removed using an organic acid or an inorganic acid or an Lewis acid. Examples of these acetal deprotecting reagents include but not limited to, hydrochloric acid, trifluoroacetic acid and titanium chloride. More examples can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2nd Ed. John Wiley & Sons, (1991).

"Acid-labile linkage", as used herein, means the link between an organic molecule and a solid support (or polymer, resin) can be removed or cleaved by treatment with an acid while remaining stable to other reagents. Examples of acid labile linkage include ether or ester bond on Wang resin (Wang, S.-S. J.

Am. Chem. Soc. 95,1328 (1973)), amide bond on Rink resin (Rink, H., Tetrahedron Lett. 28,3787 (1987)), or acetal functionality on a polymer.

Preferred acids to cleave the product from these polymers (resins) are trifluoroacetic acid (TFA) or HF.

"Acyl", as used herein, means an H-CO-or alkyl-CO-, aryl-CO-, heteroaryl-CO, heterocyclyl-CO-groups wherein alkyl, aryl, heteroaryl, heterocyclyl groups are as herein described.

"Alkyl", as used herein, means a cyclic, branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, pentyl, and adamantyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents, e. g., halogen, alkoxy, acyloxy, amino, cyano, nitro, hydroxyl, mercapto, carboxy, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group. Alkyl groups can be saturated or unsaturated (e. g., containing - C=C-or-C-C-subunits), at one or several positions. Typically, alkyl groups will comprise 1 to 12 carbon atoms, preferably 1 to 10, and more preferably 1 to 8 carbon atoms. Lower alkyl generally means the alkyl group with less than four carbon atoms in it.

"Amino acid", as used herein, means any of the naturally occurring amino acids, as well as optical isomers (enantiomers and diastereomers), racemic mixtures, synthetic analogs and derivatives thereof. a-Amino acids comprise a carbon atom to which is bonded an amino group, a carboxyl group, a hydrogen atom, and a distinctive group referred to as a side chain. ß-Amino acids comprise an amino group and a carboxylic acid group that is separated from the amino group by two carbons. The Fmoc protected a-or (3-amino acid refers to an a-or P-amino acid in which the amino group is protected temporarily with a Fmoc group which would be removed in an appropriate reaction step.

"Aryl", as used herein, means a monovalent unsaturated aromatic carbocyclic group having a single-ring (e. g., phenyl) or multiple condensed rings (e. g., naphthyl or anthryl), which can be optionally unsubstituted or substituted with amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, aryl, nitro, halo, mercapto, and other substituents.

"Base-labile protecting group", as used herein, means a protecting group of an amino group that can be removed by a base reagent. For example, an Fmoc group is used in the protection of an amino group and it can be removed under a basic condition. Fmoc stands for Fluorenylmethyl carbonyl group and is used to temporarily protect an amino group, especially in an aminoacid molecule. Fmoc group can be removed using an amine base such as piperidine, piperazine, morpholine, dicyclhexylamine, dimethylaminopyridine, diisopropyethylamine or tertiary butylaminum fluoride. Other protecting groups

such as carbamate, cyclic imide are also useful for protecting an amino group and they can be removed under basic conditions. And more examples can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2"d Ed.

John Wiley & Sons, (1991).

"Base reagent", as used herein, means a base that can be used to deprotect a base-labile protecting group without affecting the other functionalities in the molecule. For examples, the base reagent that can be used to deprotect a base-labile protecting group such as Fmoc includes piperidine, piperzine, morpholine, dicyclhexylamine, dimethylaminopyridine, diisopropyethylamine or tertiary butylaminum fluoride. Other protecting groups such as carbamate and cyclic imide can also be removed by a base reagent.

More examples on deprotection of a protecting group with a base reagent can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2nd Ed.

John Wiley & Sons, (1991).

"Combinatorial library", as used herein, means a collection of compounds created by a combinatorial chemical method, and these compounds have a common scaffold with one or more variable substituents.

The combinatorial libraries described in the invention have an N-acyl- aminolactam, or more specifically, an N-acyl-alpha-aminoacetamide or N-acyl- beta-propanamide scaffold. The libraries with N-acyl-alpha-aminoacetamide scaffold include 2-ketopiperazine and 1,4-perhydrodiazepin-2-one sublibraries.

Similarly, the libraries with N-acyl-beta-aminopropanamide scaffold include 1,4- diazepin-5-one and 1,5-diazocan-2-one sublibraries.

"Derived from", as used herein, means any acceptable organic group that is part of a molecule bearing a distinct functional group such as carboxylic acid (COOH), isocyanide (NC), aldehyde (CHO) or ketone (CO). These functional groups react as skilled artisan would expect.

"Diverse collection"or"diverse library", as used herein, mean a library where the substituents on the combinatorial library scaffold or core structure, are highly variable in constituent atoms, molecular weight, and structure, and the library, considered in its entirety, is not a collection of closely related homologues or analogues.

"Heteroaryl", as used herein, means a monovalent unsaturated aromatic carbocyclic group having a single ring (e. g., pyridyl or furyl) or multiple

condensed rings (e. g., indolizinyl or benzothienyl) and having at least one hetero atom, such as N, O, or S, within the ring, which can optionally be unsubstituted or substituted with amino, cyano, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, aryl, halo, mercapto, and other substituents.

"Heterocyclyl", as used herein, means radical heterocycles which are saturated, or unsaturated and non-aromatic. These may be substituted or unsubstituted, and are attached to other via any available valence, preferably any available carbon. More preferred heterocycles are of 5 or 6 members. In six membered non-aromatic monocyclic heterocycles, the heteroatom (s) are from one to three Ns, and wherein when the heterocycle is five membered and non-aromatic, preferably it has one or two heteroatoms selected from O, N, or S.

"Library compound", as used herein, means an individual reaction product, a single compound or a mixture of isomers, in a combinatorial library.

"Non-interfering substituent", as used herein, means an organic group that does not significantly impede the method of the invention and yield desired N-acyl-aminolactams, that is, N-acyl-alph-aminoacetamide or N-acyl-beta- aminopropanamide library compound.

"Organic moiety", as used herein, means a substituent comprising a non-interfering substituent covalently bonded through at least one carbon atom.

Suitable radicals for substitution onto the connecting carbon atom include, but are not limited to, hydrogen, alkyl, haloalkyl, aryl, heterocyclyl, and heteroaryl radicals.

"Parallel synthesis", as used herein, means the method of conducting combinatorial chemical synthesis of libraries wherein the individual combinatorial library compounds are separately prepared and stored without prior and subsequent intentional mixing."Protected a-or ß-aminoaldehyde", as used herein, means an a-or p-aminoa) dehyde in which the carbonyl group is protected with, typically an acetal (ketal) group. Examples of protecting group of a carbonyl functional group can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2nd Ed. John Wiley & Sons, (1991).

"Protecting group", as used herein, means a chemical group that exhibits the following characteristics: (I) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected

reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality ; and 3) is removable in good yield by reagents compatible with the other functional group (s) generated in such protected reactions. Example of protecting groups used in the invention included Fmoc, which is used for amino group protection, especially for an amino group in amino acids as described in the invention, and diethyl acetal as in a-or ß-aminoaldehydel diethyl acetal in the invention. More examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2nd Ed. John Wiley & Sons, (1991).

"Reagent", as used herein, means a reactant, any chemical compound used in the combinatorial synthesis to place substituents on the scaffold of a library.

"Solid-phase synthesis", as used herein, means a heterogeneous reaction in which one of reactants is covalently connected to a solid support (polymer or resin, etc.). Other reactants are dissolved in an organic solvent or solvents and the product is obtained through a cleavage step from the solid support.

"Solid support", as used herein, means a substrate which is inert to the reagents and reaction conditions described herein, as well as being substantially insoluble in the media used. Representative solid supports include inorganic substrates such as kieselguhr, silica gel, and controlled pore glass ; organic polymers including polystyrene, polypropylene, polyethylene glycol, polyacrylamide, cellulose, and the like ; and composite inorganic/polymeric compositions such as polyacrylamide supported within a matrix of kieselguhr particles. See J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd. Ed., Pierce Chemical Co. (Chicago, IL, 1984). A polymer is preferably used in this invention. In addition,"solid support"includes polymeric supports such as the polyethylene glycol supports described by Janda et al., Proc. Natl.

Acad. Sci. USA, 92,6419-6423 (1995) and S. Brenner, WO 95/16918, which are soluble in many solvents but can be precipitated by the addition of a precipitating solvent. The solid support is designated as # in this specification.

"Solvent", as herein used, means a liquid that can dissolve other compound and has no adverse effect on the reaction or on the reagents involved. Examples of suitable solvents include alcohols (methanol, 1-butanol, phenol, trifluoroethanol, hexafluoro-2-propanol, etc.), hydrocarbons (benzene, toluene, etc.), amides (dimethyl acetamide, dimethylformamide, etc.), halides (dichloromethane, dichloroethane, etc.), and ethers (tetrahydrofuran, dioxane, etc.). Other solvents include water, 1-methyl-2-pyrrolidine, diethyl phosphite, tetramethaylsulphone, dimethyl sulphoxide, acetonitrile and pyridine.

"Substituents", as used herein, mean chemical radicals which are bonded to or incorporated onto the N-acyl-alph-aminoacetamide or N-acyl- beta-aminopropanamide scaffolds through the combinatorial synthesis method.

The different functional groups account for the diversity of the molecules throughout the library and are selected to impart diversity of biological activity to the scaffold in the case of diverse libraries, and optimization of a particular biological activity in the case of directed libraries.

The following abbreviations have the indicated meanings: Bn = benzyl CDC13= deutered chloroform CD30D= deutered methanol CH2CI2 = dichloromethane CSA = camphor sulfonic acid DIPEA = diisopropylethyl amine DMAP= 4- (dimethylamino)-pyridine DMF= N, N-dimethylformamide DMSO = dimethylsulfoxide eq = equivalent EtOAc = ethyl acetate Fmoc = 9-Fluorenylmethoxycarbonyl HCI = hydrochloric acid HF = hydrofluoric acid HPLC = high performance liquid chromatography MeOH = methanol MgSO4 = magnesium sulfate

MS = mass spectrometry Ph = phenyl TFA = trifluoroacetic acid THF= tetrahydrofuran TLC = thin layer chromatography The following alkyl group abbreviations are used.

Me = methyl Et = ethyl n-Bu = normal butyl t-Bu = tertiary butyl i-Pr = isopropyl n-Pr = normal propyl c-Hexyl = cyclic hexyl EXAMPLES To further illustrate this invention, the following examples are included.

The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.

Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, manufacturing methods, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the invention.

Scheme 1. Example scheme for synthesis of 2-ketopiperazines (n = 1, Z = RiO-n on a solid support

0 OR7 + R2 H + H2N + CN-R CHCI3/MeOH (2 : 1) ) FmocHN X XI XI I XI I I 1) 1N HCI in TNF N Nu2 0 NH FmocHN ° 2) 20% piperidine OR7 FIV fiv 0 R H 0 R2 H R5COOH, ZINC R4 Rp 20% TFA 4\4N4 (R O CHCI3/MeOH (2: 1) 5y CH2CI2 R5 yN 0 0 0 NH N H 0 R6 XVI Vl Polymer 1) Preparation of polymer-bound isocyanide (XIII) Cesium carbonate (24.7 g, 84 mmol) was added to the suspension of brominated Wang resin (1.4 mmol/g, 20 g) and N- (p- hydroxylphenylethyl) formamide (13.86g, 84 mmol) in DMF (150 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at the temperature for 14 hours. The resin was filtered and washed with DMF, methanol, dichloromethane repeatedly and dried up under vacuum to give the resin bound formamide (21.87 g). Part of the resin (182.7 mg) was treated with 20% TFA to give 32.2 mg starting N- (p-hydroxylphenylethyl) formamide. The loading of the resin is therefore determined to be 1.07 mmol/g.

To the suspension of formamide resin (12g, 14.4 mmol) obtained above in dichloromethane (50 mL) was added triethylamine (6.0 mL, 43.2 mmol) followed by triphenylphosphine (11.3g, 43.2 mmol) and carbon tetrachloride (4.2 ml, 43.2 mmol). The reaction mixture was stirred under nitrogen atmosphere at room temperature for 16 hours. The solvent was drained and

the resin was washed with DMF, methanol-and dichloromethane repeatedly and dried under vacuum to give the desired isocyanide resin (XI 11, 11 g).

2) Synthesis of 2-ketopiperazines In a 5 mL fritted tube, the polymer-bound isocyanide (XIII, 150 mg, 0.1 mmol) is suspended in a mixed solvent of chloroform and methanol (2: 1; 3 mL).

A protected a-aminoaldehyde, i. e., a-aminoacetaldehyde diethyl acetal (XII, 5 eq) and an aldehyde (XI, 5 eq) are added and the mixture is shaken for 30 min before an Fmoc protected a-amino acid (X, 5 eq) is added. The suspension is shaken at room temperature for 48 h. The solvent is drained and the polymer is washed with DMF, MeOH and CH2Ct2 to give a polymer-bound intermediate (XIV). The intermediate is then treated with 1N HCI in THF followed by 20% piperidine in DMF twice, 20 min each time and washed with DMF and CH2CI2 and dried under vacuum overnight. The dried polymer-bound intermediate is suspended in CHC13/MeOH (2: 1). An isocyanide (R6NC, 5 eq) and a carboxylic acid (R5COOH, 5 eq) are added and the suspension is shaken at room temperature for 48 to 72 h. The polymer is washed, dried and cleaved with 20% TFA in CH2CI2 to give the desired product after removal of the solvents. The product is purified, if necessary, with preparative TLC.

Table I. Examples of 2-ketopiperazines No. Ri R2 R4 R5 R6 MS (m/z) 1-1 (CH2) 5COOH PhCH2CH2 Me PhCH2CH2 n-Bu 627 (M+H) 1-2 (CH2) 5COOH PhCH2CH2 Me 3-nitrophenyl n-Bu 638 (M+H) 1-3 (CH2) 5COOH i-Pr i-Pr 3-nitrophenyl t-Bu 604 (M+H) 1-4 (CH2) 5COOH i-Pr i-Pr 4-MeO2C-Ph t-Bu 617 (M+H) 1-5 (CH2) 5COOH c-Hexyl H 3-nitrophenyl Bn 636 (M+H) 1-6 (CH2) 5COOH c-Hexyl H PhCH2CH2 Bn 619 (M+H) Scheme 2. Example scheme for synthesis of 1, 4-perhvdrodiazpin-2-ones (n 2, Z = R4CH) on a solid support

0 OR ? R li + R2yH + H NOR7 + CN-R1 CHCI3/MeOH (2: 1) lOl 2 OR FmocHN X xi XVI I XI I I O R2 H 2 H N 1) 1N HCI in THF'Rp FmocHN 0 2) 20% piperidine O0 Rio XIX XVIII 0 R2 H 0 R2 o R R4NNR R5COOH, R6NC 5rN=J ° 20% TFA R N, R, CHCI3/MeOH (2: 1) 00 CH2CI2 NH NH R6 R6 xx vil Polymer General procedure for preparation of 1, 4-perhydrodiazepin-2-ones In a 5 mL frited tube, the polymer-bound isocyanide (XIII, 150 mg, 0.1 mmol) is suspended in a mixed solvent of chloroform and methanol (2: 1 ; 3 mL).- Aminopropanal diethyl acetal (XVII, 5 eq) and an aldehyde (XI, 5 eq) are added and the mixture was shaken for 30 min before an Fmoc protected a-amino acid (X, 5 eq) is added. The suspension is shaken at room temperature for 48 h.

The solvent is drained and the polymer is washed with DMF, MeOH and CH2CI2 to give a polymer-bound intermediate (XVIII). The intermediate is then treated with 1N HCI in THF followed by 20% piperidine in DMF twice, 20 min each time and washed with DMF and CH2CI2 and dried under vacuum overnight. The dried polymer-bound intermediate is suspended in CHCI3/MeOH (2: 1). An isocyanide (R6NC, 5 eq) and a carboxylic acid (R5COOH, 5 eq) are added and the suspension is shaken at room temperature for 48 to 72 h. The polymer is washed, dried and cleaved with 20% TEA in CH2CI2 to give the desired product after removal of the solvents. The product is purified, if necessary, with preparative TLC.

Table II. Examples of 1,4-perhydrodiazepin-2-ones

No. Ri R2 R4 R5 R6 MS (m/z 2-1 (CH2) 5COOH i-Pr H 3-nitrophenyl n-Bu 576 (M+H) 2-1 (CH2) 5COOH c-Hexyl H 4-MeO2C-Ph (EtO) 2P 722 (M+H) (O) CH2 2-3 (CH2) 5COOH i-Pr Me 4-n-butylphenyl n-Bu 604 (M+H) 2-4 (CH2) 5COOH c-Hexyl Me 4-bromo-n-Bu 669 (M+H) phenylmethyl 2-5 (CH2) 5COOH n-Bu Me 4-bromo-Bn 672 (M+H) phenylmethyl 2-6 (CH2) 5COOH n-Bu Me 4-AcO-Ph Bn 637 (M+H) Scheme 3. Example scheme for synthesis of 1, 4-perhydrodiazepin-5-ones (n 1, Z = R9CHCHR8) on a solid support

or + CN-R- HCI3/MeOH (2: 1) Fmoc or XXI XI XI I XI I I O R2 H O R2 H FmocHN NR, 1) 1N HCI in THF H2N Rp I I 0 2) 20% piperidine R7O/\OR xxiii XXI I XXN H N N. R N/N. R R5COOH, R6NC 20% TFA CHC13/MeOH (2 : 1) N CH2C'2 N 5 \\, R5-- N H O O R6 O O R6 XXIV Vill 9 Polymer

General procedure for preparation of 1,4-perhvdrodiazepin-5-ones In a 5 mL frited tube, the polymer-bound isocyanide (Xttt, 150 mg, 0.1 mmol) is suspended in a mixed solvent of chloroform and methanol (2: 1; 3 mL). (3- Aminopropanal diethyl acetal (XII, 5 eq) and an aldehyde (XI, 5 eq) are added and the mixture was shaken for 30 min before an Fmoc protected (3-amino acid (XXI, 5 eq) is added. The suspension is shaken at room temperature for 48 h. The solvent is drained and the polymer is washed with DMF, MeOH and CH2CI2 to give polymer-bound intermediate (XXII). The intermediate is then treated with 1N HCl in THF followed by 20% piperidine in DMF twice, 20 min each time and washed with DMF and CH2CI2 and dried under vacuum overnight. The dried polymer-bound intermediate is suspended in CHC13/MeOH (2: 1). An isocyanide (R6NC, 5 eq) and a carboxylic acid (R5COOH, 5 eq) are added and the suspension is shaken at room temperature for 48 to 72 h. The polymer is washed, dried and cleaved with 20% TFA in CH2CI2 to give the desired product after removal of the solvents. The product is purified, if necessary, with preparative TLC.

Table lil. Examples of 1, 4-perhydrodiazepin-5-ones No. Ri R2 Rs R6 MS (m/z) 3-1 (CH2) 5COOH i-Pr 4-MeO2CPh 2-morpholinoethyl 646 (M+H) 3-2 (CH2) 5COOH i-Pr 4-MeO2CPh Me02CCH2 605 (M+H) 3-3 (CH2) 5COOH i-Pr 4-MeO2CPh 2,6- 637 (M+H) dimethylphenyl 3-4 (CH2) 5COOH n-Pr 3-nitrophenyl (EtO) 2P (O) CH2 656 (M+H) 3-5 (CH2) 5COOH n-Pr 3,5- 1,1,3,3- 577 (M+H) dimethoxyphenyl tetramethylbutyl 3-6 (CH2) 5COOH n-Pr 2-phenylethyl benzyl 579 (M+H) Scheme 4. Example scheme for synthesis of 1, 5-diazocan-2-ones (n = 2, Z = RaCHCHRs) on a solid support

O OR7 ll + H + ^ 1 CHCI3lMeOH (2: 1) FmocHN'*'OH 0 2N OR7 + XXII Xl XVII Xlil Ra H 2 H N. FmocHN'V'N'R 1) 1N HCI in THF HzN NEZ ruz N II O 2 ° 2) 20% piperidine OR7 ó R70 XXV XXVI O R2 2 R R, 20% TFA N-R, R5COOH, RsNC 20% TFA -N CHCI3/MeOH (2: 1) y CH2CI2 O O N, Rs O O H N 6 XXVII IX a Polymer

General procedure for preparation of 1. 5-diazocan-2-ones In a 5 mL frited tube, the polymer-bound isocyanide (XIII, 150 mg, 0.1 mmol) is suspended in a mixed solvent of chloroform and methanol (2: 1; 3 mL). ß- Aminopropanal diethyl acetal (XVII, 5 eq) and an aldehyde (XI, 5 eq) are added and the mixture was shaken for 30 min before a Fmoc amino acid (XXII, 3-5 eq) is added. The suspension is shaken at room temperature for 48 h. The solvent is drained and the polymer is washed with DMF, MeOH and CH2CI2 to give polymer-bound intermediate (XXV). The intermediate is then treated with 1 N HCI in THF followed by 20% piperidine in DMF twice, 20 min each time and washed with DMF and CH2CI2 and dried under vacuum overnight. The dried polymer-bound intermediate is suspended in CHCts/MeOH (2: 1). An isocyanide

(R6NC, 5 eq) and a carboxylic acid (R5COOH, 5 eq) are addecf and trie suspension is shaken at room temperature for 48 to 72 h. The polymer is washed, dried and cleaved with 20% TFA in CH2CI2 to give the desired product after removal of the solvents. The product is purified, if necessary, with preparative TLC.

Table IV. Examples of 1,5-diazocan-2-ones No. Ri R2 R5 R6 MS (m/z) 4-1 (CH2) 5COOH n-Pr 4-MeO2CPh Bn 637 M+H) 4-2 (CH2) 5COOH n-Pr S-NOs-Ph t-Bu 590 (M+H) 4-3 (CH2) 5COOH n-Pr 3-NO2-4-F-Ph t-Bu 608 (M+H) 4-4 (CH2) 5COOH n-Pr 3-NO2-Ph Bn 624 (M+H)

All patents, patent applications, and publications cited are incorporated herein by reference. The foregoing written specification is sufficient to enable one skilled in the art to practice the invention. Modifications within the scope of the claims of the above-described makes for carrying out the invention which will be apparent to those skilled in the field of chemistry or related fields are intended to be within the scope of the following claims.