Background of the Invention 1,4-benzodiazepine-2,5-diones are an important class of biologically actives compound. This class of compound has been identifie as having platelet aggregation inhibitor activity, anticonvulsant activity, anxiolytic activity and as anti tumor agents (Mc Dowell, R. S. et al., J. Am. Chem. Soc., 1994, 116,5077; Cho, N. S. et al., J Heterocycl. Chem., 1989,26,1807; Wright, W. B. et al., J. Med. Chez., 1978,21,1087; Jones; G. B. et al., Anti-Cancer Drug Des. 1990,5,249).

Diketopiperazines are known to be ligands of neurokinin-2 receptors and neurokinin-3 receptors (Gordon, D. W.; Steele, J. Bioorg. Med. Chem. Lett., 1995,5,47. (b) Terrett, N. K.; Garder, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J., Tetrahedron, 1995, 51, 8135) and are useful in the treatment of asthma, inflammation, Parkinsons disease, anxiety, psychosis, epilepsy and pain.

Reports of the biological utility of ketopiperazines have appeared in several areas, including applications as antagonists of the platelet glycoprotein IIb-IIIa (Takada, S.; Kurokawa, T.; Miyazaki, K.; Iwasa, S.; Ogawa, Y. Pharm. Res. 1997,14,1146), and substance P (Wright, H. B.; Martin, D. L. J. Med.

Chem.. 1968,11,390) and as hypocholesteremic agents (Piercey, M. F.; Moon, M. W.; Blinn, J. R.

Brain Res., 1986,385,74).

Reports of the biological utility of dihydroquinoxalinones (also known as benzopiperazinones) have appeared in several areas, including applications as inhibitors of aldose reductase (Sarges, R.; Lyga, J. W. J. Heterocycl. Chem. 1988,25,1474), partial agonists ofthe g-aminobutyric acid (GABA)/benzodiazepine receptor complex (Tenbrink, R. E.; Im, W. B.; Sethy, V. H.; Tang, A. H.; Carter, D. B. J. Med. Chem. 1994,37,758), angiotensin 11 receptor antagonists (Kim, K. S.; Qian, L.; Bird, J. E.; Dickinson, K. E.; Moreland, S.; Schaeffer, T. R.; Waldron, T. L.; Delaney, C. L.; Weller, H. N. ; Miller, A. V. J. Med. Chem. 1993, 36, 2335) and are known to possess antiviral activity as associated with HIV (Meichsner, C.; Riess, G.; Kleim, J. P.; Roesner, M.; Paessens, A.; Blunck, M. Eur. Pat. Appl. EP 657166 A 1 950614).

Early work pioneered by Freidinger (Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org. Chem.

1982,47,104) showed y-lactams to be a useful new type of conformational contraint in peptides and useful in the synthesis of LHRH (Samenen, J.; Hempel, J. C.; Narindray, D.; Regoli, D. Peptides.

Chemistry and Biology', Proc. IOth Am. Peptide Symp. 1988, 137), angiotensin II (Douglas, A. J.; Mulholland, G.; Walker, B.; Guthrie, D. J. S.; Elmore, D. T.; Murphy, R. F. Biochem. Soc. Trans. 1988,16, 175), pentagastrin (Piercey, M. F.; Moon, M. W.; Blinn, J. R.; Dobry-Schreur, P. J. K. Brain Res. 1986,385, 74), and substance P analogues. The lactams described herein, in particular those produced via cyclization of a primary amine, result in potential ATP competitive kinase inhibitors possessing functionality that may mimic the N I-N6 interaction of ATP binding to a relevant kinase (Myers, M. R. ; He, W.; Hulme, C. Curr. Phare. Design. 1997,3,473).

Benzodiazepines have been to shown to have utility as GPIIb/IIIa receptor antagonists (Ku, T.

W.; Miller, W. H.; Bondinell, W. E.; Erhard, K. F.; Keenan, R. M.; Nicols, A. J.; Peishoff, C. E.; Samenen, J. M.; Wong, A. S.; Huffman, W. F. J. Med. Chem. 1995, 38, 9-12) and may be useful for the treatment of acute myocardial infarction, unstable angina, or thrombotic stroke. Recent developments have extended the therapeutic utility of this class of molecule to include integrin åntagonists (for example antagonists of the vitronectin receptor), useful for the stimulation of bone formation and treatment of bone fractures, osteoporosis and other bone-related disorders (Drake, F. H. W098115278- A 1,1997).

Dihydroimidazoles (or imidazolines) have been shown to have biological utility as anti- depressants and additionally imidazoline receptors are widely distributed in both the peripheral and central nervous system playing potential roles in the regulation of several physiological effects (Piciiii, M.; Bousquet, P.; Carotti, A.; Dontenwill, M.; Gianella, M.; Moriconi, R.; Piergentili, A.; Quaglia, W.; Tayebati, S. K.; Brasili, L.; Bioorg. Med. Chem. 1997,5,833; Harfenist, M.; Heuser, D. J.; Jouer, C. T.; Batchelor, J. F.; White, H. L.; J. Med. Chem. 1996,39,1857; Jackson, H. C.; Griffin, I. J.; Nutt, D. J.; Br. J.

Pharmacol. 1991, 104,258; and Tibirica, E.; Feldman, J.; Mermet, C.; Gonon, F.; Bousquet, P. J.

Pharmacol. 1987, 134, 1). The imidazoline moiety has also been extensively studied as an amide bond replacement in biologically active peptides (Gilbert, I.; Rees, D. C.; Richardson, R. S. Tetrahedron Lett.

1991,32,2277; and Jones, R. C. F.: Ward, G. J. Tetrahedron Lett. 1988,29,3853).

Pressures on the pharmaceutical industry have increased significantly to meet the economic challenges of the 1990s. As a consequence, efforts in both industrial and academic sectors are now being directe at new technologies for attacking drug discovery in a more efficient and cost-effective manner.

As such, with the recent development of combinatorial chemistry and high speed parallel synthesis within the Lead Discovery arena, the multi-component rection (MCR) has witnessed a resurgence of interest. From a practical consideration one-pot rections, such as the Ugi and Passerini rections, are easily automate and production of diverse or directe libraries of small organic molecules is thus both facile and high-throughput. Despite this tremendous synthetic potential, the Ugi rection is limited by producing products that are flexible and peptidic-like, often being classifie as'non-drug-like'and suffering from bioavailability problems. Interestingly several novel intramolecular derivatives of this

versatile rection have recently been reporte where constrained products are achieved by intercepting the intermediate nitrilium ion of the Ugi rection. An altennative approach and the one described in this application is to constrain the Ugi product via a so-called secondary rection after initial formation of the classical Ugi product. Production of the derivatives described herein is facile and amenable to automate high throughput production, allowing production of vast arrays of biologically relevant molecules (in the range of at least 10,000 molecules/template revealed in good purity).

Summary of the Invention The present invention relates to a method for preparing an N- [ (aliphatic or aromatic) carbonyl)]- 2-aminoacetamide compound of the formula

wherein R, is

R. is hydrogen, optionally substituted aliphatic or optionally substituted aromatic; Rb is hydrogen, optionally substituted aliphatic or optionally substituted aromatic; <BR> <BR> k. and Flb are independently hydrogel.. optionally substituted aliphatic or optionally substituted aromatic;

Rd is Rd, is optionally substituted aliphatic or optionally substituted aromatic; and

R, a is substituted with a primary or secondaly protected amine that upon deprotection can react with the *ab or *db carbon, or at least one of Rb, Rca or Rcb where each is at least substituted with an activated carboxylic acid to form a 5-7 membered cyclic ring; or Rb is substituted with a primary or secondary protected amine that upon deprotection can react with the *ab or *db carbon, or at least one of Raa, RCD or Rcb where each is at least substituted with an activated carboxylic acid to form a 5-7 membered cyclic ring; or l,. and RCb are independently substituted with a primary or secondary protected amine that upon deprotection can react with the *ab or *db carbon, or at least one of Raya, Rb, Rca, Rcb or Rrla where each is at least substituted with an activated carboxylic acid to form a 5-7 membered cyclic ring; or Rda is substituted with a primary or secondary protected amine that upon deprotection can react with at least one of R, ,, or RCI) where each is at least substituted with an activated carboxylic acid to form a 5-7 membered cyclic ring, provided that when Raa is substituted with a primary or secondary protected amine that upon deprotection can react with Izb at least substituted with an activated carboxylic acid, then Raa is other than substituted aliphatic, comprising reacting the following four compound: an carbonyl compound of formula an amine compound of formula NH2Rb, an isonitrile compound of formula

NCRda,and an acid compound of formula RaCO2H, to produce the N- [ (aliphatic or aromatic) carbonyl)]-2-aminoacetamide compound, and the N- [ (aliphatic or aromatic) carbonyl)]-2-aminoacetamide compound. The invention is also directe to a method for cyclizing N- [ (aliphatic or aromatic) carbonyl)]-2-aminoacetamide compound to a cyclic compound selected from the group consisting of a 1,4-benzodiazepine-2, 5-dione derivative, diketopiperazine derivative, ketopiperazine derivative, lactam derivative, 1,4-benzodiazapine derivative and dihydroquinoxalinones derivative, and the cyclized compound.

DETAILED DESCRIPTION As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:- "Acid bioisostere"means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21, p. 283"Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993,33, p. 576-579 "Application Of Bioisosterism To New Drug Design" ; Zhao, Huaxue Tongbao, 1995, p. 34-38 "Bioisosteric Replacement And Development Of Lead Compound In Drug Design" ; Graham, Theochem, 1995,343, p. 105-109"Theoretical Studies Applied To Drug Design: ab initio Electronic Distributions In Bioisosteres"). Examples of suitable acid bioisosteres include:-C (=O)-NHOH,-C (=O)- CH20H,-C (=O)-CH2SH,-C (=O)-NH-CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, 3-hydroxy-3-N-methoxycarbamoyl, cyclobutene-1,2-dione, 3, 5-dioxo-1, 2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl.

"Acidic functional group"means a group with an acidic hydrogen within it. The"corresponding protected derivatives"are those where the acidic hydrogen atom has been replace with a suitable protecting group, to block or protect the acid functionality while the rections involving other functional sites of the compound are carried out. Such protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U. S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. For suitable protecting groups see T. W. Green and P. G. M. Wuts in "Protective Groups in Organic Chemistry"John Wiley and Sons, 1991. Exemplary acidic functional

groups include carboxyl (and acid bioisosteres), hydroxy, mercapto and imidazole. Examples of carboxylic acid protecting groups include esters such as methoxymethyl, methylthiomethyl, tetrahydropyranyl, substituted and unsubstituted phenacyl, 2,2,2-trichloroethyl, tert-butyl, cinnamyl, dialkylaminoalkyl (e. g., dimethylaminoethyl and the like), trimethylsilyl, and the like, and amides and hydrazides including N,N-dimethyl, 7-nitroindolyl, hydrazide, N-phenylhydrazide, C I to C8 loweralkyl (e. g., methyl, ethyl or tertiary butyl and the like); and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; alkanoyloxyalkyl groups such as pivaloyloxymethyl or propionylo. xymethyl and the like; aroyloxyalkyl, such as benzoyloxyethyl and tille like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl and the like; alkoxycarbonyloxyalkyl, such as t-butyloxycarbonyloxymethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like ; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo- 1,3-dioxolen-4-yl) alkyl, such as (5-t-butyl-2-oxo-1, 3-dioxolen-4-yl) methyl and the like; and (5-phenyl-2- oxo-1,3-dioxolen-4-yl) alkyl, such as (S-phenyl-2-oxo-1, 3-dioxolen-4-yt) methyl and the like.

"Acyl"means an H-CO-or alkyl-CO-group wherein the alkyl group is as herein described.

Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2- methylpropanoyl, t-butylacetyl, butanoyl and palmitoyl.

"Aliphatic"means a radical derived from a non aromatic C-H bond by removal of the hydrogen atom.

The aliphatic radical may be further substituted by additional aliphatic or aromatic radicals as defined serein. Representative aliphatic groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkyloxyalkyl, aralkyloxycarbonylalkyl, aralkyl, aralkynyl, aralkyloxyalkenyl, heteroaralkenyl, heteroaralkyl, heteroaralkyloxyalkenyl, heteroaralkyloxyalkyl, heteroaralkynyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, and the like as described herein, which are optionally substituted including to a solid support (resin) directly or through a linker attache to the to the solid support. including to a solid,"Aliphatic", as used herein, also encompasses the residual, non-carboxyl portion of natural and unnatural amino acids as defined herein.

"Aromatic" means a radical derived from an aromatic C-H bond by removal of the hydrogen atom. Aromatic inclues both aryl and heteroaryl rings as defined herein. The aryl or heteroaryl ring may be further substituted by additional aliphatic or aromatic radicals as defined herein. Representative aromatic groups include aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused

heterocyclenylheteroaryl, fused heterocyclylheteroaryl, and the like, as described herein, which are optionally substituted including to a solid support (resin) directly or through a linker attache to the to the solid support.

"Acylamino"is an acyl-NH-group wherein acyl is as defined herein.

"Alkenoyl"means an alkenyl-CO-group wherein alkenyl is as defined herein.

"Alkenyl"means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which ma be straight or branche shaving about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain and more preferably about 2 to about 5 carbon atoms in the chain. Branche means that one or more lower alkyl groups such as methyl, ethyl or propyl are attache to a linear alkenyl chain."Lower alkenyl"means about 2 to about 4 carbon atoms in the chain which may be straight or branche. The alkenyl group may be substituted with one or more "alkenyl group substituents"which may be the same or different, and include halo, alkenyloxy, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaralkyloxy, heterocyclyl, heterocyclylalkyloxy, alkoxycarbonyl, aralkoxycarbonyl, <BR> <BR> heteroaralkyloxycarbonyl or yly2N-, Y'Y2NCO-or yly2NS02-, wherein Y'and y2 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or for where the substituent is Y'Y2N-, then one of Y'and <BR> <BR> Y2 mamy be acyl or aroyl as defined herein and the other of Y'and y2 is as defined previously, or for<BR> <BR> where the substituent is Y1Y2NCO- or Y1Y2NSO2, Y'and y2 may also be taken together with the N atom<BR> <BR> <BR> <BR> through which Y'and y2 are linked to form a 4 to 7 membered heterocyclyl or heterocyclenyl.

Exemplary alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl. Exemplary alkenyl groups include ethenyl, propenyl, rr-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

"Alkenyloxy"means an alkenyl-O- group wherein the alkenyl group is as herein described.

Exemplary alkenyloxy groups include allyloxy and 3-butenyloxy.

"Alkenyloxyalkyl" means alkenyl-O-alkyl group wherein the alkyl and alkenyl groups are as described herein.

"Alkoxy"means an alkyl-O- group wherein the alkyl group is as herein described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.

"Alkoxyalkyl"means an alkyl-O-alkyl-group wherein the alkyl groups are independent as herein described. Exemplary alkoxy groups include methoxyethyl, ethoxymethyl"Z-butoxymethyl and cyclopentylmethyloxyethyl.

"Aminoiminomethyl" means a NH2C (=NH)- group. It is known that this moiety may be mono or di-protected to afford, for example (alkoxycarbonylamino) iminomethyl and (alkoxycarbonylamino)alkoxycarbonyliminomethylgroups.

"Alkoxycarbonyl"means an alkyl-O-CO-group, wherein the alkyl group is as herein defined.

Exemplary alkoxyzarbonyl groups include methoxycarbonyl, ethoxycarbonyl, and t-butyloxycarbonyl.

"Alkoxycarbonylalkyl"means an alkyl-O-OC-alkyl-group wherein the alkyl groups are as herein defined. Preferred groups include methoxy-and ethoxy-carbonylmethyl and carbonyl ethyl.

"Alkyl"means an aliphatic hydrocarbon group which may be straight or branche having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branche means that one or more lower alkyl groups such as methyl, ethyl or propyl are attache to a linear alkyl chain."Lower alkyl"means about I to about 4 carbon atoms in the chain which may be straight or branche. The alkyl may be substituted with one or more"alkyl group substituents"which may be the same or different, and include halo, alkenyloxy, cycloalkyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulphonyl, alkylsulphonyl, alkylphosphonate, heteroaralkyloxy, heterocyclyl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused heteroarylheterocyclyl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, (alkoxycarbonylamino) iminomethyl, alkoxycarbonylamino)alkoxycarbonyliminomethyl, heteroaralkyloxycarbonyl or Y'YZN-, Y'Y'-NCO-or <BR> <BR> Y'YZNS02-, wherein Y'and y2 are independently hydrogen, alkyl, aryl, heteroaroyl, aralkyl or<BR> <BR> <BR> <BR> <BR> <BR> <BR> heteroaralkyl, or for where the substituent is yly2N-, then one of Y'and y2 may be acyl, alkoxycarbonyl<BR> <BR> <BR> <BR> <BR> <BR> or aroyl as defined herein and the other of Y'and y2 is as defined previously, or for where the substituent<BR> <BR> <BR> <BR> <BR> is Y'Y2NCO-or Y'Y2NSO2, Y'and y2 may also be taken together with the N atom through which Y'<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> and y2 are linked to form a 4 to 7 membered heterocyclyl or heterocyclenyl. Exemplary alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, u-propyl, i-propyl, n- butyl, t-butyl, n-pentyl, n-nonyl, decyl, 3-pentyl, methoxyethyl) carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl. Preferred alkyl group substituents are fused arylcycloalkenyl, cyano, fused arylcycloalkyl, aralkylthio, Y1Y2N-, Y1Y2NCO-, fused arylheterocyclenyl, fused arylheterocyclyl, hydroxy, heterocyclyl, aralkoxy, alkoxycarbonyl, alkylthio, aryloxy, aroyl, heteroaroyl, arylsulphonyl, heteroarylthio alkylphosphonate, alkylsulphonyl,

(alkoxycarbonylamino) iminomethyl, (alkoxycarbonylam ino) alkoxycarbonyl iminomethyl, and cycloalkyl.

"Alkylcarbamoyl"is an alkyl-NH-CO-group wherein the alkyl group is herein defined.

"Alkylphosphonate" means an (alkylO)2P=O- group wherein the alkyl groups are independent of each other are herein defined.

"Alkylsulfinyl"means an alkyl-SO-group wherein the alkyl group is as defined above.

Preferred groups are those wherein the alkyl group is lower alkyl.

"Alkylsulfonyl"means an alkyl-SO2-group wherein the alkyl group is as defined above.

Preferred groups are those wherein the alkyl group is lower alkyl.

"Alkylsulphonylcarbamoyl"means an alkyl-SO2-NH-C(=O)- group wheren the alkyl group is as herein described. Preferred alkylsulphonylcarbamoyl groups are those wherein the alkyl group is Cl, alkyl.

"Alkylthio"means an alkyl-S-group wherein the alkyl group is as herein described. Exemplary alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.

"Alkynyl"means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branche having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain ; and more preferably about 2 to about 4 carbon atoms in the chain. Branche means that one or more lower alkyl groups such as methyl, ethyl or propyl are attache to a linear alkynyl chain."Lower alkynyl"means about 2 to about 4 carbon atoms in the chain which may be straight or branche. The alkynyl group may be substituted with one or more "alkynyl group substituents" which may be the same or different, and include halo, alkenyloxy, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaralkyloxy, heterocyclyl, heterocyclylalkyloxy, alkoxycarbonyl, aralkoxycarbonyl, <BR> <BR> heteroaralkyloxycarbonyl or Y'YZN-, YYZNCO-or Y'Y'NS02-, wherein Yt and y2 are independently hydrogen, alkyl, aryl. aralkyl or heteroaralkyl, or for where the substituent is Y'Y2N-, then one of Y'and <BR> <BR> <BR> y mamy be acyl or aroyl as defined herein and the other of Y'and y2 iS as defined previously, or for<BR> <BR> <BR> <BR> <BR> <BR> where the substituent is Y1Y2NCO- or Y1Y2NSO2, Y'and y2 may also be taken together with the N atom<BR> <BR> <BR> <BR> <BR> <BR> <BR> through which Y'and y2 are linked to form a 4 to 7 membered heterocyclyl or heterocyclenyl.

Exemplary alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, t-butyl,n-pentyl,3-pentyl,methoxyethyl,carboxymethyl,n-butyl , methoxycarbonylethyl, Exemplarypyridylmethyloxycarbonylmethyl.

alkynyl groups include ethynyl, propynyl, r-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl.

"Alkynyloxy"means an alkynyl-O-group wherein the alkynyl group is as herein described.

Exemplary alkynyloxy groups include propynyloxy and 3-butynyloxy.

"Amino acid"means an amino acid selected from the group consisting of natural and unnatural amino acids as defined herein. Preferred amh1o acids are those possessing an a-amino group. The amino acids may be neural, positive or negative depending on the substituents in the side chain.

"Neutral amino acid"means an amino acid containing uncharged side chain substituents. Exemplary neutral amino acids include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine and cysteine."Positive amino acid"means an amino acid in which the side chain substituents are positively charged at physiological pH. Exemplary positive amino acids include lysine, arginine and histidine. "Negatie amino acid"means an amino acid in which the side chain substituents bear a net negative charge at physiological pH. Exemplary negative amino acids include aspartic acid and glutamic acid. Preferred amino acids are a-amino acids. Exemplary natural amino acids are isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cystine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid and glutamic acid.

"Unnatural amino acid"means an amino acid for which there is no nucleic acid codon.

Examples of unnatural amino acids inclue, for example, the D-isomers of the natural a-amino acids as indicated above; Aib (aminobutyric acid), ßAib (3-amh1oisobutyric acid), Nva (norvaline), ß-Ala, Aad (2-aminoadipic acid), ßAad (3-aminoadipic acid), Abu (2-aminobutyric acid), Gaba (y-aminobutyric acid), Acp (6-aminocaproic acid), Dbu (2,4-diaminobutryic acid), a-aminopimelic acid, TMSA (trimethylsilyl-Ala), aIle (allo-isoleucine), Nle (norleucine), tert-Leu, Cit (citrulline), Orn, Dpm (2,2'- diaminopimelic acid), Dpr (2,3-diaminopropionic acid), a-or final, Cha (cyclohexyl-Ala), hydroxyproline, Sar (sarcosine), and the like; cyclic amino acids; N-a-alkylated amino acids such as MeGly (N-a-methylglycine), EtGly (N-a-ethylglycine) and EtAsn (N-a-ethylasparagine); and amino acids in which the a-carbon bears two side-chain substituents. The names of natural and unnatural amino acids and residues thereof used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature as set out in"Nomenclature of a-Amino Acids (Recommendations, 1974)" Biochemistry, 14 (2), (1975). To the extent that the names and abbreviations of amino acids and residues thereof employed in this specification and appende claims differ from those noted, differing names and abbreviations will be made clear.

"Amino acid side chains"means the substituent found on the carbon between the amino and carboxy groups in a-amino acids. For examples of"corresponding protected derivatives"of amino acid

side chains, see T. W. Green and P. G. M. Wuts in"Protective Groups in Organic Chemistry"John Wiley and Sons, 1991.

"Amine protecting group"means an easily removable group which is known in the art to protect an amino group against undesirable rection during synthetic procedures and to be selectively removable.

The use of amine protecting groups is well known in the art for protecting groups against undesirable rections during a synthetic procedure and many such protecting groups are known, cf, for example, T. H.

Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991), incorporated herein by reference. Preferred amine protecting groups are acyl, including formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like. and acyloxy including methoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2- trifluoroethoxycarbonyl, 2-trimethylsilylethaoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, t- butyloxycarbonyl (BOC), l, l-dimethylpropynyloxycarbonyl, benzyloxycarbonyl (CBZ), p- nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, and the like.

"Acid labile amine protecting group"means an amine protecting group as defined above which is readily removed by treatment with acid while remaining relatively stable to other reagents. Preferred acid labile amine protecting groups include tert-butoxycarbonyl (BOC), 2- (4-biphenyl)-isopropoxy carbonyl.

"Base labile amine protecting group"means an amine protecting group as defined above which is readily removed by treatment with base while remaining relatively stable to other reagents. Preferred base labile amine protecting groups include 9-fluoroenylmethoxycarbonyl (FMOC).

"Hydrogenation labile amine protecting group"means an amimie protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile amine protecting group is benzyloxycarbonyl (CBZ).

"Hydrogenation labile acid protecting group''means an acid protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile acid protecting group is benzyl.

"Analogue"means a compound which comprises a chemically modifie form of a specific compound or class thereof, and which maintins the pharmaceutical and/or pharmacological activities characteristic of said compound or class.

"Aralkenyl"means an aryl-alkenyl-group wherein the aiyl and alkenyl are as herein described.

Preferred aralkenyls contain a lower alkenyl moiety. An exemplary aralkenyl group is 2-phenethenyl.

"Aralkoxy"means an aralkyl-O-group wherein the aralkyl groups is as herein described.

Exemplary aralkoxy groups include benzyloxy and 1-or 2-naphthalenemethoxy.

"Aralkoxyalkyl"means an aralkyl-O-alkyl group wherein the aralkyl and alkyl groups are as herein described. An exemplary aralkyloxyalkyl group is benzyloxyethyl.

"Aralkoxycarbonyl"means an aralkyl-O-CO-group wherein the aralkyl groups is as herein described. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.

"Aralkoxycarbonylalkyl"means an aralkyl-OOC-alky-group wherein the alkyl and aralkyl groups are as herein described. Preferred groups include benzyloxy-methyl and ethyl.

"Aralkyl"means an alkyl group substituted by one or more aryl groups, wherein tille aryl and alkyl are as herein described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2,2-diphenylethyl, 2, 2-diphenylmethyl, 2-phenethyl and naphthlenemethyl.

"Aralkylamino"means an aryl-alkyl-NH-group wherein aryl and alkyl are as defined herein.

"Aralkyloxyalkenyl"means an aralkyl-O-alkenyl grou wherein the aralkyl and alkenyl groups are as herein described. An exemplary aralkyloxyalkenyl group is 3-benzyloxyallyl.

"Aralkylsulfonyl"means an aralkyl-SO,-group wherein the aralkyl group is as herein described.

"Aralkylsulfinyl"means an aralkyl-SO-group wherein the aralkyl group is as herein described.

"Aralkylthio"means an aralkyl-S-group wherein the aralkyl group is as herein described. An exemplary aralkylthio group is benzylthio.

"Aroyl"means an aryl-CO-group wherein the aryl group is as hereh1 described. Exemplary groups include benzoyl and 1-rand 2-naphthoyl.

"Aroylamino"is an aroyl-NH-group wherein aroyl is as defined herein.

"Aryl"means an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms, preferably of about 6 to about 10 carbon atoms. The aryl is optionally substituted with one or

more"ring system substituents" which may be the same or different, and are as defined herein.

Representative aryl groups include phenyl or naphthyL or phenyl substituted or naphthyl substituted groups. Preferred aryl groups are phenyl or naphthyl.

"Aralkenyl" means an aryl-alkenyl- group wherein the aryl and alkenyl moiety are as described herein. Preferred alkenyl groups contain a C2-12 alkenyl moiety. Exemplary arylalkenyl groups include styryl, 4-phenyl-1,3-pentadienyl, 2,5-dimethyl-2-phenyl-4-hexenyl, "Aralkynyl" means an aryl-alkynyl-group wherein the aryl and alkynyl moiety are as described herein. Exemplary arylalkynyl groups include phenylacetylene and 3-phenylbut- 2-ynyl.

'Aryldiazo"means an aryl-azo- group wherein the aryl and azo groups are as defined herein.

"Arylcarbamoyl"is an aryl-NHCO-group, wherein the aryl group is as defined herein.

"Fused ar lcycloalkenyl"means a fused aryl and cycloalkenyl as defined herein. Preferred fused arylcycloalkenyls are those wherein the aryl thereof is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atomes. A fused arylcycloalkenyl as a variable may be bonded through any atom of the ring system thereof capable of such. The fused arylcycloalkenyl may be optionally substituted by one or more ring system substituent, wherein the"ring system substituent"is as defined herein. Representative fused arylcycloalkenyl include 1, 2-dihydronaphthylene, indene, and the like.

"Fused arylcycloalkyl"means a fused aryl and cycloalkyl as defined herein. Preferred fused arylcycloalkyls are those wherein the aryl thereof is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. A fused arylcycloalkyl as a variable may be bonded through any atom of the ring system thereof capable of such. The fused arylcycloalkyl may be optionally substituted by one or more ring system substituent, wherein the"ring system substituent"is as defined herein. Representative fused arylcycloalkyl inclues 1,2,'3,4-tetrahydronaphthyl, 5,6,7,8-tetrahydronaphth-1-yl, and the like. Preferred fused arylcycloalkyl include indanyl, "Fused arylheterocyclenyl" means a fused aryl and heterocyclenyl as defined herein. Preferred fused arylheterocyclenyls are those wherein the aryl thereof is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. A fused arylheterocyclenyl as a variable may be bonded through any atom of the ring system thereof capable of such. The designation of the aza, oxa or thia as a prefix before heterocyclenyl portion of the fused arylheterocyclen l define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused arylheterocyclenyl may be optionally substituted by one or more ring system substituent, wherein the'ring system substituent"is as defined herein. The

nitrogen atom of a fused arylheterocyclenyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused arylheterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Representative fused arylheterocyclenyl include 3H- indolinyl, 1H-2-oxoquinolyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl, indazolyl, 1, 2-dihydroisoquinolinyl, benzotriazolyl,, 3,4-dihydroisoquinolinyl, and the like.

"Fused arylheterocyclyl"means a fused aryl and heterocyclyl as defined herein. Preferred fused arylheterocyclyls are those wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. A fused arylheterocyclyl as a variable may be bonded through any atom of the ring system thereof capable of sucs. The designation of the aza, oxa or thia as a prefix before heterocyclyl portion of the fused arylheterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused arylheterocyclyl may be optionally substituted by one or more ring system substituent, wherein the"ring system substituent"is as defined herein. The nitrogen atom of a fused arylheteroaryl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heterocyclyl portion of the fused arylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S- oxide or S, S-dioxide. Representative preferred fused aryllheterocyl ring systems include indolinyl, phthalimide,,1, 2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroisoindol-2-yl, 2,3-dihydrobenz [flisoindol-2-yi, I., 2,3, 4-tetrahydrobenz[g]isoquinolin-2-yl, 1,3-benzodioxole, and the like.

"Aryloxy"means an aryl-O-group wherein the aryl group is as defined herein. Exemplary groups include phenoxy and 2-naphthyloxy.

"Aryloxyalkyl"means an aryl-O-alkyl-group wherein the aryl or alkyl groups are as herein described. An exemplary aryloxyalkyl groups is phenoxypropyl.

"Aryloxyalkenyl"means an aryl-O-alkenyl-group wherein the aryl or alkenyl groups are as serein described. An exemplary aryloxyalkenyl groups is phenoxyallyl.

"Aryloxycarbonyl"means an aryl-O-CO-group wherein the aryl group is as defined herein.

Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

"Aryloxycarbonylalkyl" means an aryl-O-OC-alky-group. Preferred groups include phenoxycarbonyl-methyl and ethyl.

"Aryisulfonyl"means an aryl-SO2- group wherein the aryl group is as defined herein.

"Arylsulfinyl" means an aryl-SO-group wherein the aryl group is as defined herein.

"Arylthio"means an aryl-S-group wherein the aryl group is as herein described. Exemplary arylthio groups include phenylthio and naphthylthio.

"Basic nitrogen atom"means an sp2 or Sp3 hybridized nitrogen atom having a non-bonde pair of electrons which is capable of being protonated. Examples of basic nitrogen atoms include optionally substituted imino, optionally substituted amino and optionally substituted amidino groups.

"Carbamoyl"is an NH2-CO-group.

"Carboxy"means a HO (O) C- (carboxylic acid) group.

"Carboxyalkyl"means an HOOC-alkyl-group wherein the alkyl group is as defined herein.

Preferred groups include carboxymethyl and carboxyethyl.

"Compounds of the invention", and equivalent expressions, are meant to embrace compound of general formula (I), and compound of formula (II), as hereinbefore described, which expression inclues the prodrugs, the pharmaceutically acceptable salts, and the solvates, e. g. hydrates, where the context so ermites. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permit. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permit.

"Cycloalkoxy"means an cycloalkyl-O-group wherein the cycloalkyl group is as herein described. Exemplary cycloalkoxy groups include cyclopentyloxy and cyclohexyloxy.

"Cycloalkyl"means a non-aromatic mono-or multicyclic ring system of about 3 to about 10 carbon atoms. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The cycloalkyl is optionally substituted with one or more 4'ring system substituents"which may be the same or different, and are as defined herein. Representative monocyclic cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Representative multicyclic cycloalkyl inclue 1- decalin, norbornyl, adamant-(1-or 2-) yl, 6,6-dimethylbicyclo [3.1.1] heptane, and the like. Preferred ring system substituents for a cycloalkyl are alkyl, aralkoxy, amidino, hydroxy, or Y'Y'N-as defined herein.

"Cycloalkylcarbonyl''means a cycloalkyl-CO-group, wherein cycloalkyl is as hereinbefore defined. Exemplary cycloalkylcarbonyl groups include cyclopropylcarbonyl.

"Cycloalkenyl"means a non-aromatic mono-or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms, and which contains at least one carbon- carbon double bond. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The cycloalkenyl is optionally substituted with one or more'ring system substituents' which may be the same or different, and are as defined herein. Representative monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. A representative multicyclic cycloalkenyl is norbornylenyl. Preferred ring system substituents for a cycloalkyl are amidino or Y1Y2N- as defined herein "Derivative"means a chemically modifie compound wherein the modification is considered routine by the ordinary skilled chemist, such as an ester or an amide of an acid, protecting groups, such as a benzyl group for an alcohol or thiol, and tert-butoxycarbonyl group for an amine.

"Diazo"means a bivalent-N=N-radical.

"Effective amount"is means an amount of a compound/composition according to the present invention effective in producing the desired therapeutic effect.

"Electron donating group"shall designate a group that will release or donate electrons more than hydrogen would if it occupied the same position in the molecule. See J. March, Advanced Organic Chemistry, 3rd Ed., John Wiley & Sons p. 238 (1985). These types of groups are well known in the art.

Examples include alkyl, aralkyl, cycloalkyl, heteroaralkyl, heteroaryl, or heterocyclyl.

"Formulations suitable for nasal or inhalational administration"means formulations which are in a form suitable to be administered nasally or by inhalation to a patient. The formulation may contain a carrier, in a powder form, having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.) Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhaleras.<BR> <BR> <P> "Formulations suitable for oral administration"means formulations which are in a form suitable to be administered orally to a patient. The formulations may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-

water liquid-emulsion or a water-in-oil liquid mulsion. The active ingredient may also be presented as a bolus, electuary or paste.

'Formulations suitable for parenteral administration"means formulations which are in a form suitable to be administered parenterally to a patient. The formulations are sterile and include mulsions, suspensions, aqueous and non-aqueous injection solutions, which may contain suspending agents and thickening agents and anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic, and have a suitably adjusted pH, with the blood of the intended recipient.

"Formulations suitable for rectal administrations"means formulations which are in a form suitable to be administered rectally to a patient. The formulation is preferably in the form of suppositories which can be prepared by mixing the compound of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.

"Formulations suitable for systemic administration"means formulations which are in a form suitable to be administered systemically to a patient. The formulation is preferably administered by injection, including transmuscular, intravenous, intraperitoneal, and subcutaneous. For injection, the compound of the invention are formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the compound may be formulated in solid form and redissolved or suspende immediately prior to use. Lyophilized forms are also included.

Systematic administration also can be by transmucosal or transdermal means, or the compound can be administered orally. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and inclue, for example, bile salts and fusidic acid derivatives for transmucosal administration. In addition, detergents may be used to facilitate permeation. Transmucosal administration may be through use of nasal sprays, for example, or suppositories. For oral administration, the compound are formulated into conventional oral administration forms such as capsules, tables, and tonics.

"Formulations suitable for topical administration"means formulations which are in a form suitable to be administered topically to a patient. The formulation may be presented as a topical ointment, salves, powders, sprays and inhalant, gels (water or alcohol based), creams, as is generally known in the art, or incorporated into a matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrie. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

Formulations suitable for topical administration in the eye include eye drops wherein the active

ingredient is dissolve or suspende in a suitable carrier, especially an aqueous solvent for the active ingredient. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

"Formulations suitable for vaginal administration"means formulations which are in a form suitable to be administered vaginally to a patient. The formulation may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

"Halo"means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro.

"Heteroaralkenyl"means an heteroaryl-alkenyl- group wherein the heteroaryl and alkenyl are as herein described. Preferred heteroaralkenyls contain a lower alkenyl moiety. An exemplary aralkenyl group is 4-pyridylvinyl, thienylethenyl, pyridylethenyl, imidazolylethenyl and pyrazinylethenyl.

"Heteroaralkyl"means a heteroaryl-alkyl- group wherein the heteroaryl and alkyl are as herein described. Preferred heteroaralkyls contain a lower alkyl moiety. Exemplary heteroaralkyl groups may contain thienylmethyl, pyridylmethyl, imidazolylmethyl and pyrazinylmethyl.

"Heteroaralkyloxy"means an heteroaralkyl-0-orroup wherein the heteroaralkyl group is as herein described. An exemplary heteroaralkyloxy group is 4-pyridylmethyloxy.

"Heteroaralkyloxyalkenyl"means an heteroaralkyl-O-alkenyl group wherein the heteroaralkyl and alkenyl groups are as herein described. An exemplary heteroaralkyloxyalkenyl group is 4- pyridylmethyloxyallyl.

"Heteroaralkyloxyalkyl"means an heteroaralkyl-O-alkyl group wherein the heteroaralkyl and alkyl groups are as herein described. An exemplary heteroaralkyloxy group is 4-pyridylmethyloxyethyl.

"Heteroaralkynyl" means an heteroaryl-alkynyl-group wherein the heteroaryl and alkynyl are as herein described. Preferred heteroaralkynyls contain a lower alkynyl moiety. Exemplary heteroaralkynyl groups are pyrid-3-ylacetylenyl and quinolin-3-ylacetylenyl and 4-pyridylethynyl.

"Heteroaroyl"means an means an heteroaryl-CO-group wherein the heteroaryl group is as herein described. Exemplary groups include thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl and 1- and 2- naphthoyl and pyridinoyl.

"Heteroaryl"means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, preferably about 5 to about 10 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element (s) other than carbon, for example nitrogen, oxygen or sulfur.

Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The"heteroaryl" may also be substituted by one or more"ring system substituents"which may be the same or different, and are as defined herein. The designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen oxygen or sulfur atom is present respectively as a ring atom. A nitrogen atom of an heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N- oxide. Representative heteroaryl and substituted heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyi, isothiazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1, 2, 4-thiadiazolyl, pyridaziny (, quinoYalinyl, phthalazinyl, imidazo [1,2- a] pyridine, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1,2, 4-triazinyl, Preferred heteroaryl groups include pyrazinyl, thienyl, pyridyl, pyrimidinyl, quinolinyl, tetrazolyi, imidazolyl, thiazolyl, benzothienyl, isoxazolyl and isothiazolyl. aheteroaryl-alkenyl-groupwhereintheheteroaryl"Heteroarylalke nyl"means and alkenyl moities are as described herein. Preferred heteroarylalkenyl groups contain a C2., 2 alkenyl moiety. Exemplary heteroarylalkenyl groups include pyridylpentenyl, pyridylhexenyl and pyridylheptenyl.

"Heteroarylalkynyl"means an aryl-alkynyl- group wherein the heteroaryl and alkynyl moiety are as herein described. Preferred heteroarylalkynyl groups contain a C2-12 alkynyl moiety. Exemplary heteroarylalkynyl groups include 3-pyridyl-but-2-ynyl and pyridylpropynyl.

"Heteroaryldiazo"means an heteroaryl -azo- group wherein the heteroaryl and azo groups are as defined herein.

"Fused heteroarylcycloalkenyl"means a fused heteroaryl and cycloalkenyl as defined herein.

Preferred fused heteroarylcycloalkenyls are those wherein the heteroaryl thereof is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. A fused heteroarylcycloalkenyl as a variable may be bonded through any atom of the ring system thereof capable of such. The designation of the aza, oxa

or thia as a prefix before heteroaryl portion of the fused heteroarylcycloalkenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylcycloalkenyl may be optionally substituted by one or more ring system substituent, wherein the"ring system substituent"is as defined herein. The nitrogen atom of a fused heteroarylcycloalkenyl may be a basic nitrogen atom. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkenyl may also be optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkenyl include 5, 6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-lH-benzimidazolyl, 4,5-dihydrobenzoxazolyl, and the like.

"Fused heteroarylcycloalkyl"means a fused heteroaryl and cycloalkyl as defined serein.

Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. A fused heteroarylcycloalkyl as a variable ma be bonded through any atom of the ring system thereof capable of such. The desirnation of the aza, oxa or thia as a prefix before heteroaryl portion of the fused heteroarylcycloalkyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylcycloalkyl may be optionally substituted by one or more ring system substituent, wherein the "ring system substituent"is as defined herein. The nitrogen atom of a fused heteroarylcycloalkyl may be a basic nitrogen atom. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkyl may also be optionally oxidized to the corresponding N-oxide.

Representative fused heteroarylcycloalkyl include 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8- tetrahydroisoquinolyl, 5,6.7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro- lH-benzimidazolyl, 4,5, 6,7-tetrahydrobenzoxazolyl, 1H-4-oxa-1,5-diazanaphthalen-2-onyl, 1,3- dihydroimidizole- [4.5]-pyridin-2-onyl, and the like.

"Fused heteroarylheterocyclenyl"means a fused heteroaryl and heterocyclenyl as defined herein.

Preferred fused heteroarylheterocyclenyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms. A fused heteroarylheterocyclenyl as a variable may be bonded through any atom of the ring system thereof capable of such. The designation of the aza, oxa or thia as a prefix before the heteroaryl or heterocyclenyl portion of the fused heteroarylheterocyclenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclenyl may be optionally substituted by one or more ring system substituent, wherein the"ring system substituent"is as defined herein. The nitrogen atom of a fused heteroarylazaheterocyclenyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heteroaryl portion of the fused heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide S-oxide or S, S-dioxide. Representative fused heteroarylheterocyclenyl include 7,8-dihydro [1,7] naphthyridinyl, 1, 2-dihydro [2,7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4, 5-c] pyridyl,

1, 2-dihydro-1, 5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl, 1,2-dihydro-1,7-naphthyridinyl, 1,2- dihydro-I, 8-naphthyridinyl, 1,2-dihydro-2,6-naphthyridinyl, and tille like.

"Fused heteroarylheterocyclyl" means a fused heteroaryl and heterocyclyl as defined herein.

Preferred fused heteroarylheterocyclyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms. A fused heteroarylheterocyclyl as a variable may be bonded through any atom of the ring system thereof capable of such. The designation of the aza, oxa or thia as a prefix before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclyl may be optionally substituted by one or more ring system substituent, wherein the "ring system substituent"is as defined herein. The nitrogen atom of a fused heteroarylheterocyclyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heteroaryl portion of the fused heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Representative fused heteroarylheterocyclyl include 2,3-dihydro-lH pyrrol [3,4-b) quinolin- 2-yl, 1, 2,3, 4-tetrahydrobenz [b] [1,7] naphthyridin-2-yl, 1,2,3,4-tetrahydrobenz [b] [1,6]naphthyridin-2-yl, 1,2,3,4-tetrahydro-9H-pyrido [3, 4-b] indol-2yl, 1,2,3,4-tetrahydro-9H-pyrido [4,3-bJindol-2y1,2,3,- dihydro-1 H-pyrrolo [3,4-b] indol-2-yl, 1H-2, 3,4,5-tetrahydroazepino [3, 4-b] indol-2-yl, 1H-2, 3,4,5- tetrahydroazepino [4,3-b] indol-3-yl, 1 H-2,3,4,5-tetrahydroazepino [4,5-b] indol-2 yl, 5,6,7,8- tetrahydro [1,7] napthyridinyl, 1,2,3,4-tetrhydro [2,7] naphthyridyl, 2,3-dihydro [1,4] dioxino [2,3-b] pyridyl, 2,3-dihydro [1,4] dioxino [2, 3-b]pyridyl, 3,4-dihydro-2H-I-oxa [4,6] diazanaphthalenyl, 4,5,6,7-tetrahydro- 3H-imidazo [4,5-c] pyridyl, 6,7-dihydro [5, 8] diazanaphthalenyl, 1, 2,3,4-tetrahydro [1,5] napthyridinyl, 1,2,3,4-tetrahydro [1,6] napthyridinyl, 1,2,3,4-tetrahydro [1,7] napthyridinyl, 1,2,3,4- tetrahydro [1,8] napthyridinyl, 1,2,3,4-tetrahydro [2,6) napthyridiny (, and the like.

"Heteroarylsulphonylcarbamoyl" means a heteroaryl-SO2-NH-C (=O)-group wherein the heteroaryl group is as herein described.

"Heterocyclenyl"means a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 13 carbon atoms, preferably about 5 to about 13 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element (s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclenyl may be optionally substituted by one or more ring system substituent, wherein the"ring system substituent"is as defined herein. The nitrogen atom of an heterocyclenyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the

heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oside or S, S-dioxide.

Representative monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydrol1ydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1, 2,3,6-tetrahydropyridine, 1,45, 6-tetrahydropyrimidine, 2- pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 1, 4,4a, 5a, 6,9,9a, 9b-octahydro-dibenzofuran, and the like. Exemplary oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. Preferred is diliydrofuranyl. An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo [2.2. 1] heptenyl. Preferred monocyclic thiaheterocycleny rings include dihydrothiophenyl and dihydrothiopyranyl; more preferred is dihydrothiophenyl. Preferred ring system substituents inclue amidino, halogen, hydroxy, alkoxycarbonylalkyl, carboxyalkyl or Y'Y'N-as defined herein.

"Heterocyclyl"means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoîns, in which one or more of the carbon atoms in the ring system is/are hetero element (s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclyl may be optionally substituted by one or more"ring system substituents"which may be the same or different, and are as defined herein.

The nitrogen atom of an heterocyclyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oside or S, S-dioxide.

Representative monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1, 3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2- thioxo-4-thiazolidinonyl, tetrahydrothiopyranyl, and the like. Preferred heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidyl, Preferred heterocyclyl group substituents include alkyl, aralkyl, amidino, halogen, hydroxy, aralkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl or Y1Y2N- as defined herein.

"Heterocyclylalkyl"means an heterocyclyl-alkyl-group wherein the heterocyclyl and alkyl are as herein described. Preferred heterocyclylalkyls contain a lower alkyl moiety. An exemplary heteroaralkyl group is tetrahydropyranylmethyl.

"Heterocyclylalkyloxyalkyl"means an heterocyclyl-alkyl-O-alkyl- group wherein the heterocyclyl and alkyls groups independently are as herein described. An exemplary heteroaralkyl group is tetrahydropyranylmethyloxymethyl.

"Heterocyclyloxy"means a heterocyclyl-O-group in which the heterocyclyl group is as previously described. Exemplary heterocyclyloxy groups include quinuclidyloxy, pentamethylenesulfideoxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy,

tetrahydrofuranyloxy or 7-oxabicyclo [2.2. 1] heptanyloxy, hydroxytetrahydropyranyloxy and hydrory-7- oxabicyclo [2.2. I Iheptanyloxy.

"Hydrate" means a solvate wherein the solvent molecule (s) is/are H. O.

"Hydroxyalkyl" means a HO-alkyl-group wherein alkyl is as herein defined. Preferred hydroxyalkyls contain lower alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 2- hydroxyethyl.

"Hygroscopicity"means sorption, implying an acquired amount or state of water sufficient to affect the physical or chemical properties of the substance (Eds. J. Swarbrick and J. C. Boylan, Encyclopedia of Pharmaceutical Technology, Vol. 10, p. 33).

"Liquid dosage form"means the dose of the active compound to be administered to the patient is in liquid form, for example, pharmaceutically acceptable mulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in tille art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcool, isopropyl alcool, ethyl carbonate, ethyl acetate, benzyl alcool, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcool, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

"Modulate" refers to the ability of a compound to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of a ligand from a precursor) induce expression of gene (s) maintained under hormone control, or to repress expression of gene (s) maintained under such control.

"Patient"includes both human and other mammals.

"Pharmaceutical composition"refers to a composition comprising a compound of formula (1). a compound of formula (il), or a compound of formula (III), and at least one component selected from the group comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillersz disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.

Examples of suspending agents include ethoxylated isostearyl alcools, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured

by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonge absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin. Examples of suitable carriers, diluent, solvents or vehicles include water, ethanol, polyols, suitable mixtures thereof. vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, dicalcium phosphate phosphate. Examples of disintegrating agents include starch, alginic acids and certain complex silicates.

Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols.

"Pharmaceutically acceptable"means it is, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and lower animales without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.

'Pharmaceutically acceptable dosage forms"refers to dosage forms of the compound of the invention, and inclues, for example, tables, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalant tables, lozenges, mulsions, solutions, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and fonmulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA. latest edition.

"Pharmaceutically acceptable ester"refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups inclue, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters inclues formates, acetates, propionates, butyates, acrylates and ethylsuccinates.

"Pharmaceutically acceptable prodrugs"as used herein refers to those prodrugs of the compound of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic fonns, where possible, of the compound of the invention. The term "prodrug"refers to compound that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compound of this invention. They inclue, but are not limited to such groups as alkanoyl (such as

acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzol), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl-and triethysilyl), monoesters formed with dicarboxylic acids (such as succinyl), and the like. Because of the ease with which the metabolically cleavable groups of the compound of this invention are cleaved in vivo, the compound bearing such groups act as pro-drugs. The compound bearing the metabolically cleavable groups have the avantage that they may exhibit improved bioavailability as a result of enhanced solubilit and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion is provided in Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in Enzymology,. K. Widder et al, Ed., Academic Press, 42, p. 309-396, 1985 ; A Textbook of Drug Design and Developement, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5 ;"Design and Applications of Prodrugs"p. 113-191, 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p. 1-38, 1992 ; Journal of Pharmaceutical Sciences, 77, p. 285, 1988; Chem.

Pharm. Bull., N. Nakeya et al, 32, p. 692,1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A. C. S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

"Pharmaceutically acceptable salts"refers to the relatively llon-toxic, inorganic and organic acid addition salts, and base addition salts, of compound of the present invention. These salts can be prepared in situ during the final isolation and purification of the compound. In particular, acid addition salts can be prepared by separately reacting the purifie compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate. acetate, oxalate, valerate, oleate, palmitate, stearate. laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulphamates, malonates, salicylates, propionates, methylene-bis-ßhydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinateslaurylsulphonate salts, and the like. (See, for example S. M. Berge, et al., "Pharmaceutical Salts,"J. Pharm. Sci., 66: p. l-l9 (1977) which is incorporated herein by reference.) Base addition salts can also be prepared by separately reacting the purifie compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts. The sodium and potassium salts are preferred. Suitable inorganic base addition salts are prepared from metal bases which include sodium hydrie, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide. Suitable amine base addition salts are prepared from amines which have sufficient basicity to form a stable salt, and preferably include those amines which are frequently used in medicinal chemistry because of their low

toxicity and acceptability for medical use. ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, N,N'-dibenzylethylenediamine,chloroprocaine,diethanolamine,p rocaine,choline, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N- ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamhze, trimethylamine, ethylamine, basic ai-lino acids, e. g., lysine and arginine, and dicyclohexylamine, and the like.

"Solid dosage form"means the dosage form of the compound of the invention is solid form, for example capsules, tables, pills, powders, dragees or granules. In such solid dosage forms, the compound of the invention is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compound, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, (j) opacifying agents, (k) buffering agents, and agents which release the compound (s) of the invention in a certain part of the intestinal tract in a delayed manner.

"Solvate"means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid."Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates, and the like.

"dring system substituents"mean substituents attache to aromatic or non-aromatic ring systems inclusive of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryldiazo, heteroaryldiazo, amidino, YYN-, Y1Y2N-alkyl-, Y1Y2NCO- or Y1Y2NSO2-, wherein Y'and are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or for where the substituent is Y1Y2N-, then one of Y'and YZ may be acyl or aroyl as

defined herein and the other of Y'and YZ is as defined previously, or for where the substituent is<BR> <BR> <BR> <BR> Y1Y2NCO- or Y1Y2NSO2-, Y'and y2 may also be taken together with the N atom through which Y'and Y-are linked to form a 4 to 7 membered heterocyclyl or heterocyclenyl. Preferred ring system substituents are alkoxycarbonyls alkoxy, halo, aryl, aralkoxy, alkyl, hydroxy, aryloxy, nitro, alkylsulfonyl, heteroaryh Y'Y2N-. Most preferred ring system substituents are selected from alkoxycarbonyl, halo, aryl, aralkoxy, aralkyl, alkyl, hydroxy, aryloxy, Y1Y2N-, oxo, cyano, nitro, and arylsulfinyl,. When a ring system is saturated or partially saturated, the"ring system substituents" further inclue, methylene (H2C=), oxo (O=), thioxo (S=).

"Solid support"means a substrate which is inert to the reagents and rection conditions described herein, as well as being substantially insoluble in the media used. Representative solid supports include inorganic substrats 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 supporte 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). In addition,"solid support"includes a solid support as described above which is affixed to a second inert support such as the pins described herein which comprise a detachable polyethylene-or polyproylene-base head grafted with an amino functionalized methacrylate copolymer and an inert stem. In addition,"solid support"includes polymeric supports such as-té polyethylene glycol supports described by Janda et al., Proc. Natal. 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.

"Resin"means a solid support as defined above which is chemically modifie as is known in the art to incorporate a plurality of reactive groups, such as hydroxyl, amino or isocyanate moities. groups are covalently bound directly to the solid support or attache to the solid support by covalent bonds through a linking group. The resins used in this invention are designated as which designates a solid support optionally bearing a linking group which can be directly bound or through the liking group thereof to a rection component in the method according to the invention.

"YIY2N-"means a substituted or unsubstituted amino group, wherein Y and Y2 are as herein described. Exemplary groups include amino (H2N-) methylamino, dimethylamino, diethylamino, pyrrolidine, piperidine, benzylamino, or phenethylamino.

"YIY2NCO-"means a substituted or unsubstituted carbamoyl group, wherein Y I and Y2 are as herein described. Exemplary groups are carbamoyl (H2NCO-) and dimethylaminocarbamoyl (Me2NCO-).

"Y1Y2NSO2-" means a substituted or unsubstituted sulfamoyl group, wherein Y I and Y2 are as herein described. Exemplary groups are aminosulfamoyl (H2NS02-) and dimethylaminosulfamoyl (Me2NS02-).

"Primary or secondary protected amine"means a group of the following formula YaYbN- wherein one of Ya and Yb is Pa a nitrogen protecting group and the other of Ye and Yb is hydrogen, alkenyl, alkyl, aralkyl, aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloall : yl, fused heteroarylheterocyclenyl, fused heteroarylheterocyclyl, heterocyclenyl or heterocyclyl.

"Activated carboxylic acid"means a group of the following formula LO-CO-wherein L is aliphatic, aromatic or a resin moiety.

In a specific embodiment. the term"about"or"approximately"means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

Preferred Embodiments One particular aspect of the present invention is directe to a method for preparing a cyclyzed compound selected from group of formulae consisting of 1,4-benzodiazepine-2,5-dione derivatives of general formulae (I), and (VII), diketopiperazine derivatives of general formula (II), ketopiperazine derivatives and dihydroqtiinoxalinone derivatives of general formula (III) and (VIII), dihydroimidazole derivatives of general formula (IV), lactam derivatives of general formula (V), 1,4-benzodiazepine-2,5- dione diketopiperazine derivatives of formula (VI), and ketopiperazine derivatives of formula (XLII):-.

wherein: n I or 2; 0or1;m= p 2; R'and R9 independently represent hydrogen, alkenyl, alkyl, aralkenyl, aralkyl, aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkenyl, heteroaralkyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused heteroarylheterocyclyl, heterocyclenyl, or heterocyclyl; R2 represents hydrogen, alkenyl, alkyl, aralkyl, aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused heteroarylheterocyclyl, heterocyclenyl or heterocyclyl;

R3 represents hydrogen, alkenyl, alkyl, aralkyl, aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused orheterocyclyl.heteroarylheterocyclyl,heterocyclenyl Ra or RS independently represent hydrogen, alkenyl, alkyl, aryl, alkynyl, aralkenyl, aralkynyl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaralkenyl, heteroaralkynyl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused heteroarylheterocyclyl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or R4 and R5 taken together with the carbon atom through which R4 and R5 are linked form a 3 to 7 membered cycloalkyl or cycloalkenyl; R6, R',RsandRgindependently represent hydrogen, alkenyl, alkenyloxy, alkoxy, alkyl, aryl, alkylsulfinylcarbamoyl, alkynyl, alkynyloxy, aralkenyl, aralkylsulfonyl, aralkynyl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, aryloxycarbonyl, cycloalkyloxy, heteroaralkenyl, heteroaralkyloxy, heteroaralkynyl, heteroaroyl, fused heteroaryleycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused heteroarylheterocyclyl, heteroalylsulphonylcarbamoyl, heterocyclyloxy, heteroalyl, aralkyl, heteroaralkyl, hydroxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryldiazo, heteroaryldiazo, amidino, Y1Y2N-, <BR> <BR> Y1Y2NCO- or Y1Y2NSO2-, wherein Y'and y2 are independently hydrogen, alkyl, aryl, aralkyl or<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> heteroaralkyl, or where the substituent is Y'Y2N-, then one of Y'and y2 may be acyl or aroyl and the<BR> <BR> <BR> <BR> <BR> <BR> <BR> other of Y'and y2 iS as defined previously, or where the substituent is Y1Y2NCO- or Y1Y2NSO2-, Y'and<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> Y2 mamy also be taken together with the N atom through which Y'and y2 are linked form a 4 to 7 membered heterocyclyl or heterocyclenyl, or R3 and R8 taken together with the nitrogen atom and carbon atoms through which R3 and R8 are linked form a 5 to 7 membered heterocyclyl or heterocyclenyl, or two adjacent substituents selected from the substituents R6, R7, R8 and R8 taken together with the aryl carbon atoms through which the two adjacent substituents are linked form a 5 to 7 membered cycloalkyl or a cycloalkenyl. heterocyclyl or heterocyclenyl, or 6 membered aryl or 5 to 6 membered heteroaryl; R14, R15, R10 and R"independently represent hydrogen, alkenyl, alkyl, aryl, alkynyl, aralkenyl, aralkynyl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaralkenyl, heteroaralkynyl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused

heteroarylheterocyclenyl, fused heteroarylheterocyclyl, heteroarylsulphonylcarbamoyl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or when n=1, R"and R14 are absent and R10 and R15 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; or when n=1, R'o and R'5 taken together with the adjacent carbon atoms through which they are linked form a 5 to 7 membered cycloalkyl or a cycloalkenyl, heterocyclyl or heterocyclenyl; or when n=2, adjacent R"and R14 are absent and R'° and adjacent R15 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; or when n=2, R'° and adjacent R'5 taken together with the adjacent carbon atoms through which they are linked form a 5 to 7 membered cycloalkyl or a cycloalkenyl, heterocyclyl or heterocyclenyl; or when n or p =2, adjacent R14 and R14 are absent and adjacent R'S and R'S taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; or when n or p =2, adjacent R'5 and R's taken together with the adjacent carbon atoms through which they are linked form a 5 to 7 membered cycloalkyl or a cycloalkenyl, heterocyclyl or heterocyclenyl; or when m=1, R"and R14 are absent and R10 and R'5 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl; or when m=1, R'° and R"taken together with the adjacent carbon atoms through which they are linked form a 5 to 7 membered cycloalkyl or a cycloalkenyl, heterocyclyl or heterocyclenyl; R12 represents alkenyl, alkyl, aralkyl, aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused heteroarylheterocyclyl, heterocyclyl;or R16 represents hydrogen, alkenyl, alkyl, aralkyl, aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, heteroaralkenyl, fused arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroarylcycloalkenyl,fusedheteroarylcycloalkyl,fusedhetero arylheterocyclenyl,heteroaryl,fused fused heteroarylheterocyclyl, heterocyclenyl or heterocyclyl.

In one aspect, this invention is directe to a solution phase synthesis of a compound of formula (I) via a '3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962,1,8) combining reacting a nitrogen-protected amino acid of formula (XIV), with an aldehyde or ketone of formula (XV), an amine of formula (XVI), and a non resin bound isonitrile of formula (IX) to form an intermediate compound of formula (XVII) and nitrogen- deprotection of the intermediate compound and cyclization to form the compound of formula (1). Hulme, C.; Tang, S-Y.; Bures, C. J.; Morize, I. ; Labaudiniere, R. J, Org, Chem. 1998, 63, 8021.

In another aspect, this invention is directe to a solid phase synthesis of a compound of formula (I) via a'3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, 1., Angew. Chem. Int. Ed. Engl., 1962, 1, 8) combining reacting a nitrogen-protected amino acid of formula (XIV), with an aldehyde or ketone of formula (XV), an amine of formula (XVI), and a resin bound isonitrile selected from (luxa) or (XVIII) to form the respective intermediate resin bound compound and nitrogen-deprotection of the intermediate compound and cyclization to form the compound of formula (I).

In another aspect, this invention is directe to a solution phase synthesis of a compound of formula (II) via a'3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962,1,8) combining reacting a nitrogen-protected amino acid of formula (XXII) with an aldehyde or ketone of formula (XV), an amine of formula (XVI), and a non resin bound isonitrile of formula (IX) to form an intermediate compound of formula (XXIII) and nitrogen- deprotection of the intermediate compound and cyclization to form the compound of formula (il).

Hulme, C.; Morrissette, M. M.; Volz, F. A.; Bures, C. J. Tetrahedron Lett. 1998,39,113.

In another aspect, this invention is directe to a solid phase synthesis of a compound of formula (II) via a'3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962,1.8) combining reacting a nitrogen-protected amino acid of formula (XXII) with an aldehyde or ketone of formula (XV), an amine of formula (XVI), and a resin bound isonitrile selected from (IXa) or (XVIII) to form the respective intermediate resin bound compound and nitrogen-deprotection of the intermediate compound and cyclization to form the compound of formula (II).

In another aspect, this invention is directe to a solution phase synthesis of a compound of fonnula (III) via a'3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962,1,8) combining reacting an acid of formula (XXVI) with an aldehyde or ketone of formula (XV), an diamine of formula (XXVII), and a non resin bound isonitrile of formula (IX) to form an intermediate compound of formula (XXVIII) and nitrogen-deprotection of the intermediate compound and cyclization to form a compound of formula (III). Hulme, C.; Peng, J.; Lourdas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron Lett. 39,7227.

In another aspect, this invention is directe to a solid phase synthesis of a compound of formula (III) via a'3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962,1.8) combining reacting an acid of formula (XXVI) with an aldehyde or ketone of formula (XV), a diamine of formula (XXVII), and a resin bound isonitrile selected from (luxa) or (XVIII) to form the respective intermediate resin bound compound and nitrogen- deprotection of the intermediate compound and cyclization to form the compound of formula (ici).

In another aspect, this invention is directe to a solution phase synthesis of a compound of formula (IV) via a'3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Envi.., 1962,1,8) combining reacting an nitrogen-protected amino aldehyde of formula (XXXIII) with acid of formula (XXVI), an amine of formula (XVI), and a non resin bound isonitrile of formula (IX) to form an intermediate compound of formula (XXXIV) and nitrogen- deprotection of the intermediate compound and cyclization to form a compound of formula (IV). The non-cyclized amines were removed via a solution phase scavenging step with the simultaneous addition of PS-DIEA or PS-tris (2-aminoethyl) amine (6 equiv.) and PS-NCO (3 equiv.) in dichloroethane. (Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997,119,4882. Flynn, D. L.; Cric, J. Z.; Devraj, R. V.; Hockerman, S. L. Parlow, J. J.; South, M. S.; Woodward, S. J. Anz Chem. Soc. 1997, 119, 4874.

Purchased from Argonaut technologies (PS-DIEA-polystyrene bound disopropylethylamine)).

In another aspect, this invention is directe to a solution phase synthesis of a compound of formula (VI) via a'3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962,1,8) combining reacting compound of formula (XXXVII), with an acid of formula (XIV), an amine of formula (XVI), and a non resin bound isonitrile of formula (IX) to form an intermediate compound of formula (XXXVIII) and nitrogen-deprotection of the intermediate compound and cyclization to form a compound of formula (VI).

In another aspect, this invention is directe to a solid phase synthesis of a compound of formula (V) via a'3-step. one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962,1,8) combining reacting a nitrogen-protected amino aldehyde or ketone of formula (XXXV), an amine of formula (XVI), an acid of formula (XXVI) and a resin bound isonitrile selected from (luxa) or (XVIII) to form the respective intermediate resin bound compound and nitrogen-deprotection of the intermediate compound and cyclization to form the compound of formula (V).

In another aspect, this invention is directe to a solution phase synthesis of a compound of formula (VI) via a'3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. vint. Ed. Engl., 1962,1,8) combining reacting an nitrogen-protected amino acid of formula (XIV) with an aldehyde or ketone of formula (XXXVII), an amine of formula (XVI), and a non resin bound isonitrile of formula (IX) to form an intermediate compound of formula (XXXVIII) and nitrogen-deprotection of the intermediate compound and cyclization to form a compound of formula (VI).

In another aspect, this invention is directe to a solid phase synthesis of a compound of formula (VI) via a'3-step. one pot'procedures employh1g the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962,1.8) combining reacting an nitrogen-protected amino acid of formula (XIV) witl1 an aldehyde or ketone of formula (XXXVII), an amine of formula (XVI), and a resin bound isonitrile of formula (XVIII) to form an intermediate compound and nitrogen-deprotection of the intermediate compound and cyclization to form a compound of formula (VI).

In another aspect, this invention is directe to a solution phase synthesis of a compound of formula (VII) via a'3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Vint. Ed. Engl., 1962,1,8) combining reacting nitrogen-protected amino acid of formula (XIV), a suitable non-rein bound α-amino ester, a non-rein bound isonitrile (IX), and an aldehyde or ketone of formula (XV), to fonn an intermediate compound and nitrogen-deprotection of the intermediate compound and cyclization to form a compound of formula (VIII).

In another aspect, this invention is directe to a solid phase synthesis of a compound of formula (Vil) via a'3-step, one pot'procedure, employing the Ugi multi-component reaction (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962,1,8) combining reacting a nitrogen-protected amino acid of formula (XIV), a resiii bound a-amino ester of formula (XXXIX), and a non-rein bound isonitrile (IX) and an aldehyde or ketone of formula (XV), to form the intermediate resin bound compound (XL) and nitrogen- deprotection of the intermediate compound and cyclization to form the compound of formula (VII).

In another aspect, this invention is directe to a solution phase synthesis of a compound of formula (VIII) via a'3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Vint. Ed. Engl., 1962,1,8) combining reacting an acid of formula (XXVI) with (XXXVII), a diamine of formula (XXVII), and a non resin bound isonitrile of formula (IX) to form an intermediate compound of formula (XLI) and nitrogen-deprotection of the intermediate compound and cyclization to form a compound of formula (VIII).

In another aspect, this invention is directe to a solid phase synthesis of a compound of formula (VIII) via a'2-step one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, l., Angew. Chem. Int. Ed. Engl., 1962,1,8) combining reacting an acid of formula (XXVI) with (XXXVII), a diamine of formula (XXVIIa), and a resin bound isonitrile of formula (luxa) or (XVIII) to form an intermediate and cyclization to fonn a compound of formula (VIII), wherein R12 represents the resin bound isonitrile derivative.

In another aspect, this invention is directe to a solution phase synthesis of a compound of formula (VIII) via a '2-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chez. Int. Ed. Engl., 1962,1,8) combining reacting an acid of formula (XXVI) with

(XXXVII). a diamine of formula (XXVIIa), and a non resin bound isonitrile of formula (IX) to form an intermediate compound of formula (XLI) and cyclization to form a compound of formula (VIII).

In another aspect, this invention is directe to a solid phase synthesis of a compound of formula (VIII) via a'3-step. one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962, 1,8) combining reacting an acid of formula (XXVI) with (XXXVII), a diamine of formula (XXVII), and a resin bound isonitrile of formula (IXa) or (XVIII) to form an intermediate and nitrogen-deprotection of the intermediate compound and cyclization to form a compound of formula (VIII), wherein R12 represents the resin bound isonitrile derivative.

In another aspect, this invention is directe to a solid phase synthesis of a compound of formula (XLII) via a 3-step, one pot'procedure, employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Envol., 1962,1,8) combining reacting a nitrogen-protected amino acid of formula (XLIII), a resin bound a-amino ester of formula (XXXIX), and a non-rein bound isonitrile (IX) and an acid of formula (XXVI), to form the intermediate resin bound compound (XLIX) and nitrogen- deprotection of the intermediate compound and cyclization to form the compound of formula (XLII).

In another aspect, this invention is directe to the preparation of 1,4-benzodiazepine-2,5-dione derivatives of general formulae (I) and (VI), diketopiperazine derivatives of general formula (II), ketopiperazine derivatives and dihydroquinoxalinone derivatives of general formula (III) and (VIII), dihydroimidazole derivatives of general formula (IV), lactam derivatives of general formula (V), by solid phase synthesis employing the Ugi multi-component rection (MCR) (Ugi, I., Angew. Chem. Int. Ed. Engl., 1962,1,8) using an isonitrile functionalized polymer resin linker (luxa) as described herein, followed by amine deprotection, cleavage from the resin and cyclization. The alkoxide and hydroxide safety-catch clipping strategy and subsequent solution phase cyclization offers similar avantages to a traceless linker (Plunkett, M. J.; Liman, J. A. J. Org. Chem. 1995,60,6006 ; Hulme, C.; Peng, J.: Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998,39,) in that no constant functionality derived from clipping remains at the end of the synthetic protocol.

In another aspect, this invention is directe to the preparation of ketopiperazine derivatives of general formula (XLII) and 1,4-benzodiazepine-2,5-dione derivatives of general formula (VII), by solid phase synthesis employing the Ugi multi-component rection (MCR) (Ugi, 1., Angew. Chem. Int. Ed.

Engl., 1962,1,8) using an amino ester bound polymer resin linker (XXXIX) as described herein, followed by amine deprotection, cleavage from the resin and cyclization.

In another aspect, this invention is directe to the preparation and use of a novel resin bound isonitrile (IXa), deployed as a novel safety catch linker (Backes, B. J., Virgilio, A. A., Ellman, J. A. J.

Am. Chem. Soc. 1996,118,3055; Kenner, G. W., McDermott, J. R., Sheppard, R. C. J. Chem. Soc.,

Chem. Commun. 1971, 636.) in the preparation of 1,4-benzodiazepine-2,5-dione derivatives of general fonnulae (I), (VI) and (VII), diketopiperazine derivatives of general formula (II), ketopiperazine derivatives and dihydroquinoxalinone derivatives of general formula (III) and (VIII), dihydroimidazole or imidazoline derivatives of general formula (IV), and lactam derivatives of general formula (V).

A preferred aspect of the compound of the invention are those wherein: 1or2.n= A preferred aspect of the compound of the invention are those wherein: m 0 or 1.

A preferred aspect of the compound of the invention are those wherein: R'is aralkyl, alkyl, aryl, heteroaryl, cycloalkyl, aralkenyl, heterocyclenyl or heterocyclyl.

A preferred aspect of the compound of the invention are those wherein: R'is hydrogen or alkyl.

A preferred aspect of the compound of the invention are those wherein: R2 represents heteroaralkyl, aralkyl, alkyl, fused arylcycloalkyl, cycloalkyl, heterocyclyl) aryl, fused arylheterocyclenyl, or fused arylheterocyclyl.

A preferred aspect of tille compound of the invention are those wherein: R3 represents hydrogen, alkyl, aralkyl, aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclyl,cycloalkyl,cycloalkenyl,heteroaralkyl,heter oary,fusedarylheterocyclenyl,fused heteroarylcycloakenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused heteroarylheterocyclyl, heterocyclenyl, or heterocyclyl A preferred aspect of the compound of the invention are those wherein: R4 and R5 independently represents hydrogen, alkyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, heterocyclenyl or heterocyclyl.

A preferred aspect of the compound of the invention are those wherein:

R6, R7 R8 and R8' independently represents hydrogen, alkenyl, alkyl, aryl, aralkyl, heteroaralkyl, hydroxy, aryloxy, alkoxy, aralkoxy, halo, nitro, cyano, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, fused aiylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused heteroarylheterocyclyl, Y1Y2N-,orY1Y2NSO2-.heteroarylsulphonylcarbamoyl,heteroaryl, A preferred aspect of the compound of the invention are those wherein: R'5 is absent and R3 and R14 taken together with the nitrogen atom and carbon atom through which R3 and R'4 are linked to form a 6 membered aryl or 5 to 6 membered heteroaryl.

A preferred aspect of the compound of the invention are those wherein: R4 and R5 taken together with the carbon atom through which R4 and R5 are linked form a 3 to 7 membered cycloalkyl or cycloalkenyl.

A preferred aspect of the compound of the invention are those wherein: two adjacent substituents selected from the substituents R6, R', Rs and Rs taken together with the aryl carbon atoms through which the two adjacent substituents are linked form a 5 to 7 membered cycloalkyl or a cycloalkenyl, heterocyclyl or heterocyclenyl, or 6 membered aryl or 5 to 6 membered heteroaryl.

A preferred aspect of the compound of the invention are those wherein: R10, R11, R14 and R'5 independently represent hydrogen, alkyl, heteroaralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aralkyl.or A preferred aspect of the compound of the invention are those wherein: n=l, R"and R14 are absent and R10 and R15 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl.

A preferred aspect of the compound of the invention are those wherein: n=l, R'° and R'5taken together with the adjacent carbon atoms through which they are linked form a 5 to 7 membered cycloalkyl or a cycloalkenyl, heterocyclyl or heterocyclenyl.

A preferred aspect of the compound of the invention are those wherein n=2, adjacent R"and R'4 are absent and R'° and adjacent R'5 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl.

A preferred aspect of the compound of the invention are those wherein

n=2, R'° and adjacent R'5 taken together with the adjacent carbon atoms through which they are linked form a 5 to 7 membered cycloalkyl or a cycloalkenyl, heterocyclyl or heterocyclenyl.

A preferred aspect of the compound of the invention are those wherein n or p =2, adjacent R14 and R14 are absent and adjacent R15 and R15 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl.

A preferred aspect of the compound of the invention are those wherein n or p =2, adjacent R15 and R15 taken together with the adjacent carbon atoms through which they are linked form a 5 to 7 membered cycloalkyl or a cycloalkenyl, heterocyclyl or heterocyclenyl.

A preferred aspect of the compound of the invention are those wherein m=1, R"and R'4 are absent and R'° and R5 taken together with the adjacent carbon atoms through which they are linked form a 6 membered aryl or 5 to 6 membered heteroaryl.

A preferred aspect of the compound of the invention are those wherein m=l, R'° and R'5 taken together with the adjacent carbon atoms through which they are linked form a 5 to 7 membered cycloalkyl or a cycloalkenyl, heterocyclyl or heterocyclenyl.

A preferred aspect of the compound of the invention are those wherein: R16 represents hydrogen, alkenyl, alkyl, aralkyl, aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, heteroaralkenyl, fused arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused arylcycloalkyl, fused heteroarylheterocyclyl, heterocyclenyl or heterocyclyl.

A preferred aspect of the compound of the invention are those wherein: Rl6 represents alkenyl, alkyl, aralkyl, aryl, fused arylcycloalkenyl, fused arylcycloalkyl, heteroaralkenyl, fused arylheterocyclenyl, fused arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, fused heteroarylcyc (oalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, fused orheterocyclyl.heteroarylheterocyclyl,heterocyclenyl A more preferred aspect of the compound of the invention are those wherein: n = 1.

A more preferred aspect of the compound of the invention are those wherein: n=2.

A more preferred aspect of the compound of the invention are those wherein:

m =0.

A more preferred aspect of the compound of the invention are those wherein: <BR> <BR> <BR> in 1.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> A more preferred aspect of the compound of the invention are those wherein: hydrogen.R9is A more preferred aspect of the compound of the invention are those wherein: alkyl.R9is A more preferred aspect of the compound of the invention are those wherein: R'is aralkyl, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl.

A more preferred aspect of the compound of the invention are those wherein: R2 represents aralkyl, alkyl, fused arylheterocyclenyl, or fused arylheterocyclyl.

A more preferred aspect of the compound of the invention are those wherein: R'represents hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkenyl, heteroaralkyl or heterocyclenyl, heterocyclyl.

A more preferred aspect of the compound of the invention are those wherein: R'represents hydrogen.

A most preferred aspect of the compound of the invention are those wherein: R4 and R5 independently represents alkyl, aralkyl, heteroaralkyl, heterocyclyl, or cycloalkyl.

A more preferred aspect of the compound of the invention are those wherein: R6, R7 R8 and R8, independently represents hydrogen, halo, alkoxy, alkyl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, fused heteroarylcycloalkenyl, fused heteroarylcycloa (kyl, fused heteroarylheterocyclenyl, fused heteroarylheterocyclyl, or heteroaryl.

A more preferred aspect of the compound of the invention are those wherein: R10, R", R14 and R15 independently represent hydrogen, alkyl, or aralkyl.

A more preferred aspect of the compound of the invention are those wherein: R12 represents alkyl, aralkyl, aryl, cycloalkyl, or heterocyclyl.

A more preferred aspect of the compound of the invention are those wherein: R16 represents alkyl, fused arylheterocyclyl, aralkyl, cycloalkyl, heteroaryl, aryl, heteroaralkyl, alkenyl, heteroaralkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused heteroarylcycloalkenyl, fused orheterocyclyl.heteroarylheterocyclyl,heterocyclenyl A preferred compound according to the invention is selected from the group of formulae consisting of:

for R=H, or CH3

It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.

It is a further object of the invention to provide kits having a plurality of active ingredients (with or without carrier) which, together, may be effectively utilized for carrying out the novel combination therapies of tille invention.

It is another object of the invention to provide novel pharmaceutical compositions which is effective, in and of itself, for utilization in a beneficial combination therapy because it inclues a plurality of active ingredients which may be utilized in accordance with the invention.

The compound of the invention optionally are supplie as salts. Those salts which are pharmaceutically acceptable are of particular interest since they are useful in administering the foregoing

compound for medical purposes. Salts which are not pharmaceutically acceptable are useful in manufacturing processes, for isolation and purification purposes, and in some instances, for use in separating stereoisomeric forms of the compound of this invention. The latter is particularly true of amine salts prepared from optically active amines.

Where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form.

Also, where the compound of the invention contains a basic group, or a sufficiently basic bioisostere, acid addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.

The foregoing compound of the invention may also be mixed another therapeutic compound to form pharmaceutical compositions (with or without diluent or carrier) which, when administered, provide simultaneous administration of a combination of active ingredients resulting in the combination therapy of the invention.

While it is possible for the compound of the invention to be administered alone it is preferably to present them as phamwaceutical compositions. The pharmaceutical compositions, both for veterinary and for human use. of the present invention comprise at lease one compound of the invention, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.

In certain preferred embodiments, active ingredients necessary in combination therapy may be combine in a single pharmaceutical composition for simultaneous administration.

The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observe in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combine with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tables. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluent such as sucrose. ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

The oily phase of the mulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.

Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) make up the emulsifying wax, and the way together with the oil and fat make up the emulsifying ointment base which forms the oily disperse phase of the cream formulations. Emulgents and mulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Sang 80, cetostearyl alcool, benzyl alcool, myristyl alcool, glyceryl mono-stearate and sodium lauryl sulfate.

If desired, the aqueous phase of the cream base may inclue, for example, a least 30% w/w of a polyhydric alcool, i. e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1, 3-dol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.

The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affecte areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branche chain, mono- or dibasic alkyl esters such as di-isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2- ethylhexyl palmitate or a blend of branche chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Solid compositions of may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.

The pharmaceutical compositions can be administered in a suitable formulation to humans and animals by topical or systemic administration, including oral, inhalational, rectal, nasal, buccal, sublingual, vaginal, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. It will be appreciated that the preferred route may vary with for example the condition of the recipient.

The formulations can be prepared in unit dosage font by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compresse tables may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.

If desired, and for more effective distribution, the compound can be microencapsulated in, or attache to, a slow release or targeted delivery systems such as a biocompatible, biodegradable polymer matrices (e. a. poly (d, l-lactide co-glycolide)), liposomes, and microspheres and subcutaneously or intramuscularly injecte by a technique called subcutaneous or intramuscular depot to provide continuos slow release of the compound (s) for a period of 2 weeks or longer. The compound may be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating sterilizina agents in the form of sterile solid compositions which can be dissolve in sterile water, or some other sterile injectable medium immediately before use.

Actual dosage levels of active ingredient in the compositions of the invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors.

Total daily dose of the compound of this invention administered to a host in single or divided doses may be in amonts, for example, of from about 0.001 to about 100 mg/kg body weight daily and preferably 0.01 to 10 mg/kg/day. Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the body

weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.

The amount of each component administered is determined by the attending clinicians taking into consideration the etiology and severity of the disease, the patient's condition and age, the potency of each component and other factors.

The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Preparation of Compound of the Invention The starting materials and intermediates of compound of the invention may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.

Compound of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

In the rections described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the rections. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Green and P. G. M. Wuts in"Protective Groups in Organic Chemistry"John Wiley and Sons, 1991; J. F. W. McOmie in"Protective Groups in Organic Chemistry"Plenum Press, 1973.

General methodology for the preparation the isonitrile resin linker (IXa)

Reagents and Conditions:- (i) Wang resin, 4-nitrophenylchloroformate (5 equiv.), n-methyl morpholine (10 equiv.). THF. (ii) 2- (4 amino phenyl) ethylamine (5 equiv.), DMF. (iii) Formic acid (excess), acetic anhydride (excess), CH, CIz (iv) Ph3P ( equiv.), CC14 (5 equiv.), Eut, N (5 equiv.), CH2Cl2.

Experimental Procedures Nitrocarbonate Resin (XI): Wang resin (X) (100.0 g, 109.0 mmol) was swelled in anhydrous THF (1500 ml).

N-methyl morpholine (119.8 ml, 1090.0 mmol) and 4-nitrophenyl chloroformate (109.86 g, 545 mmol) were added sequentially. The rection was cooled in an ice bath for several minutes to quench the slightly exothermic rection. The ice bath was then removed and the rection was allowed to warm to RT. It was mixed on an orbital shaker at RT overnight. The rection solution was drained off and the resin was washed with THF (5X), 20% H2O in DMF (5X), DMF (5X), THF (5X), and Et, O (5x). The resin product (XI) was then placed in a vacuum oven at RT overnight to dry. IR analysais showed two sharp peaks at 1520 cm-1 and 1350 cm-1 for the NOZ group.

Aniline Resin (XII) The nitrocarbonate resin (XI) (115.0 g, 125.35 mmol) was swelled in anhydrous DMF (1250 ml). 2- (4- Aminophenyl) ethylamine (82.6 ml, 626.75 mmol) was added to the resin slurry. The rection was mixed on an orbital shaker at RT overnight. The rection solution was drained off and the resin was washed with DMF (8X). The still swollen resin was suspende in anhydrous DMF (1000 ml) and a second coupling of the amine (82.6 ml) was run overnight. After draining and washing with DMF (8X) a third coupling was run overnight. The final rection solution was drained off and the resin product (XII) was washed with DMF (I OX), THF (I OX), and Et2O (I OX). The resin was then dried in a vacuum oven at RT overnight. IR analysis showed loss of the NO2 peaks.

Formamide Resin (XIII) : The aniline resin (XII) (109.0 g, 86.1 mmol) was swelled in anhydrous CH2Cl2 (1000 ml). Formic acid (500 ml) and acetic anhydride (500 ml) were combine and the resulting exothermic rection was cooled in an ice bath. Once at RT, the resulting solution was allowed to sit at RT for 40 minutes. This mixed anhydride solution was then added to the resin slurry. The rection was mixed on an orbital shaker at RT overnight. The rection solution was drained off and the resin was washed with CH2CI2 (10X). To remove any remaining acetic acid, the resin was washed with 20% H2O in THF (6X) until the washings were neutral to litmus paper. The resin product (XIII) was finally washed with THF (10X) and Et2O (8X) and then dried in a vacuum oven at RT overnight. IR analysis showed a strong carbonyl stretch for the formamide at 1698 cm-1.

Isonitrile Resin (luxa):

The formamide resin (XIII) (50. 0 g, 44.5 mmol) was swelled in anhydrous CH2CI2 (500 moi).

Triphenylphosphine (58.4 g, 222.5 mol), carbon tetrachloride (21.5 ml, 222. 5 mmol), and triethylamine (31. 0 ml, 22'. 5 mmol) were added sequentially at RT. The rection was mixed on an orbital shaker for 4.5 hours at RT. The rection solution was drained off and the resin product (luxa) was washed with CH2CI2 (20X), THF (1 ou), and Et, O (I OX). The resin was then placed in a vacuum oven at RT overnight to dry. IR analysis showed a sharp peak for the isonitrile at 2121 cm-1.

General methodolog, v for the preparation of 1 *4-Benzodiazepine-2*5-diones (1)

In general terms, compound of formula (1) wherein R', R2, R3, R8, R6, R7, R8 and R9 are hereinbefore defined, may be synthesized by reacting a compound of formula (XIV) wherein R, R, R, R7 and R8 are hereinbefore defined and Z'is a suitable amimie protecting group, with a compound of formula (XV) wherein R'and R9 are hereinbefore defined, a compound of formula (XVI) wherein R2 is hereinbefore defined, and a compound of formula (IX) wherein Rl2 represents alkyl, aralkyl, aryt, fused arylcycloalkyl, fused arylheterocyclyl, cycloalkyl, heteroaralkyl, heteroaryl, fused heteroarylcycloalkyl, fused heteroarylheterocyclyl, heterocyclyl; in a suitable solvent at about room temperature, to afford the intermediate compound (XVII), wherein R', R2, R3, R8', R6, R7, R8, R9, Rl2 and Z1 are hereinbefore defined. The general rection is illustrated in scheme I below: R8 o R OH O R9 RZ-NHy Rg R3 W) WI) R8 O t s (XIV) (i) solvent R'N, Rtz 2 R O 12 R8*, R12NC (XVII) (IX)

Scheme I There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the rection or on the reagents involved (See Waki et al. J. Am. Chem. Soc., 1977, 6075-6077). Examples of suitable solvents include: alcools, such as methanol, 1-butanol, phenol, trifluoroethanol, hexafluoro-2-propanol ; hydrocarbons, such as benzene and toluene ; amides, such as dimethyl acetamide, dimethylformamide; halides, such as dichloromethane, dichloroethane ; and ethers, such as tetrahydrofuran and dioxane; other solvents include water, 1-methyl-2-pyrrolidine, diethyl

phosphite, tetramethylsulphone, dimethyl sulphoxide, acetonitrile and pyridine. Of these solvents, the alcools are preferred.

There is no restriction on the isonitrile (IX) used in the rection scheme I above, provided that it has no adverse effect on the rection involved. Examples of suitable isonitriles inclue, 1- isocyanocyclohexene, benzyl isocyanide, n-butyl isocyanide, diethyl isocyanomethyl phosphonate, cyclohexyl isocyanide, 2,6-dimethylphenyl isocyanide, methyl isocyanoacetate, isopropyl isocyanide and 1,1,3,3-tetramethylbutyl isocyanide. Preferable isonitriles include the isonitrile functionalized polymer resin (IXa) or (XVIII), 1-isocyanocyclohexene (IXb), benzyl isocyanide, n-butyl isocyanide, diethyl isocyanomethyl phosphonate. More preferably, isonitriles used in the rection are isonitrile functionalized polymer resin (IXa) or the isonitrile functionalized polymer resin (XVIII) (A. Piscopio, ORG Poster 232, American Chemical Society Meeting, Las Vegas, NV, 7-10 Sept., 1997): (XVIII) or(IXb): The use of resin bound isonitriles (luxa) or (XVIII) in the synthesis of compound of the formula (1), (11), (111) or (V), is advantageous over other non-rein bound isonitriles. The use of the resin bound isonitriles allow excess amount of reagents to be used in the rection to drive the Ugi rection forward.

Also, unlike solution phase procedures, these reagents can be easily removed by subsequent washing of the rein, leaving the Ugi product clean and resin bound The reaction can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 1 50°C, preferably from room temperature to about 1 00°C, more preferably at about room temperature. The time required for the rection may also vary widely,

depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

The intermediate compound of the formula (XVII) thus prepared may be recovered from the rection mixture by conventional means. For example, the compound may be recovered by distilling off the solvent in vacuo from the rection mixture or, if necessary after distilling off the solvent from the rection mixture pouring the residue into water followed by extraction with a water-immiscible organic solvent and distilling off the solvent from the extract. Additionally, the product can, if desired, be further purifie by various well techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.

The intermediate compound is preferably recovered from the rection mixture by distilling offthe solvent in vacuo.

The intermediate compound (XVII) may be converted to a compound of formula (I) by reacting with acid and optionally base, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group (Z'), followed by cyclization. This rection is illustrated in Scheme 2. R8 O R Rs H R8 0R2 N' N-Rz (i) acid R' w N R' 2 R8 R3 R R3 1 3 R R (XVII) (I) Scheme 2 This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z'and cyclization, may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the rection can also be generated in situ, for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

In addition to carrying out the rection in scheme 2 in the presence of acid, a rection step involving basic conditions can also be optionally carried out so as to facilitate the removal of the amine protecting group Z', wherein Z is a base labile amine protecting group. There is no particular restriction on the nature of the base to be used in this rection, and any base conventionally used to facilitate

removal of a base labile amine protecting group Z', may equally be used here, provided that it has no adverse effect on other parts of tille molecule. Examples of suitable bases include: organic bases such as ammonia, piperidine, morpholine, etlianolamine and diethylamine.

In situations where acidic conditions are used to remove the amine protecting group in (XVII) it may also be necessary to treat the deprotected intermediate, which is present as an acid salt, with base so as to convert the acid addition salt to its corresponding free base. There is no particular restriction on the nature of the base to be used. A base conventionally used to convert an acid addition salt to its corresponding free base form may be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include ammonia, piperidine, morpholine, ethanolamine, diethylamine, polystyrene bound di-isopropylethylamine or basic DOWEX. Preferably diethylamine, basic DOWEX or polystyrene bound di-isopropylethylamine.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

There is no particular restriction on the amine protecting group (Z') employed. However, amino acid protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Examples of amine protecting groups include both acid labile amine protecting groups and base labile protecting groups.

Preferred acid labile amine protecting aroup include tert-butoxycarbonyl (BOC) and 2- (4-biphenylyl)- isopropoxy carbonyl (BPOC). Preferred base labile amine protecting group include 9-fluoroenylmethyl carbamate (FMOC).

The use of the novel resin bound isonitrile (luxa) in the synthesis of compound of the formula (I), wherein R'-is the novel resin bound isonitrile derivative (luxa), is advantageous over other non-rein bound isonitriles. However, use of (luxa) in the synthesis of (I) h1volves activation of the resin linker to facilitate cleavage of the resin linkage and cyclization to afford (I). An illustration of the use of the novel resin bound isonitrile (IXa) in the synthesis of the interrnediate formula (XIX) is illustrated in Scheme 3.

Rs O OH Rs i N_Z RR9 RZ-NHZ R8 R3 (XV) (XVI) Re O (XIV (1 SOIVCIit R X'N 93 R6<N-Z1 < CNlo eRZ o I CN R R N3 Z H I/ N 0' H (xi) (XIX) (IXa) (XIX) Scheme 3 Activation of the benzamide carbonyl of (XIX) to give the intermediate (XX), wherein Z'is a carbamate protective group promotes facile cleavage from the resin. Examples of carbamate protective groups which may activate the benzamide group, provided that they no adverse effect on the rection involved are, for example, t-butyl-O-CO- (BOC), benzyl-O-CO- (CBZ), Cl3CCH2-O-CO- (Troc), (CH3) 3SiCH2CH2-O-CO- (TEOC), I-methyl-I- (4-biphenylyl) ethyl-O-CO- (BPOC) and cycloalkyl-O- CO-. Other carbamate protective groups include those described in'Protecting groups in Organic Synthesis'Greene, 1981, p. 223-49. An eaample of the activation of the benzamide group is illustrated in Scheme 4, wherein Z2X a suitable carbamate protective group ragent, for example (BOC) 2O.

Scheme 4 The rection conditions and reagents used in the activation of the benzamide, are ones that are known in the art of for the conversion of an amine to a carbamate group. This sort of rection is usually carried out in dichloromethane, in the presence of a base, for example Et3N, and a catalytic amount of DMAP. (For other rection conditions, see'Protecting groups in Organic Synthesis'Greene, 1981, p. 223-49).

The resin'safety catch"linker is then cleaved, to facilitate the removal of the resin, by reacting the activated benzamide compound (XX) with an appropriate alkoxide, or hydroxide, to afford the corresponding alkyl ester or carboxylic acid derivative (XXI) respectively, wherein R13 is, for example, H, alkyl, phenyl or cycloalkyl (Mjalli, A. M. M., Sarshar, S., Baiga, T. J. Tetrahedron Lett. 1996,37,2943 ; Flynn, D. L., Zelle, R. E., Grieco, P. A. J. Org. Chem. 1983,48,2424.). An example of the cleavage from the resin is illustrated in rection Scheme 5:

Scheme 5 The intermediate compound (XXI) may be converted to a compound of formula (I) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group (Z'), followed by cyclization. This rection is illustrated in Scheme 6. RB O Ri Rs Re Rz | l n2 A l I k RZ 0 R6o YN-Z ; (ii) Heat R6 I N-R9 Re. i Re, i s O R3 R (XXI) Scheme 6 This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z1 and cyclization, may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the rection can also be generated in situ, for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

In addition to carrying out the rection in scheme 6 in the presence of acid, a rection step involving basic conditions can also be optionally carried out so as to facilitate the removal of the amine protecting group Z', wherein Z'is a base labile amine protecting group. There is no particular restriction on the nature of the base to be used in this rection, and any base conventionally used to facilitate removal of an base labile amine protecting group Z', may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include: organic bases such as ammonia, piperidine, morpholine, ethanolamine and diethylamine.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 1 SO°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However,

provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

There is no particular restriction on the amimie protecting group (Z') employed. However, amino acid protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Examples of amine protecting groups include both acid labile amine protecting groups and base labile protecting groups.

Preferred acid labile amine protecting group include tert-butoxycarbonyl (BOC) and 2-(4-biphenylyl)- isopropoxy carbonyl (BPOC). Preferred base labile amine protecting group include 9-fluoroenylmethyl carbamate (FMOC).

In situations where acidic conditions are used to remove the amine protecting group in (XXI) it may also be necessary to treat the deprotected intermediate, which is present as an acid salt, with base so as to convert the acid addition salt to its corresponding free base. There is no particular restriction on the nature of the base to be used. A base conventionally used to convert an acid addition salt to its corresponding free base form may be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases inclue ammonia, piperidine, morpholine, ethanolamine, diethylamine, polystyrene bound di-isopropylethylamh1e or basic DOWEX. Preferably diethylamine, basic DOWEX or polystyrene bound di-isopropylethylamine.

Similarly, solid phase synthesis of a compound of formula (I) can be carried out using the resin bound isonitrile of formula (XVIII) using rection conditions similar to those described for scheme I and scheme 2.

General methodolow for the preparation of diketopiperazines (II) Compound of formula 11 may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, or by methods according to this invention herein.

In general terms, compound of formula (II) wherein R', R2, R3, R4 R5 and R9 are hereinbefore defined and Z'is a suitable amine protecting group, may be synthesized by reacting an amino acid of

formula (XXII), wherein R', R', R and Z'are hereinbefore defined, with compound of formula (XV) wherein R'and R9 are hereinbefore defined, (XVI) wherein RZ is hereinbefore defined, and (IX) wherein R'Z is hereinbefore defined, in a suitable solvent at about room temperature, to afford the intermediate compound (XXIII). This rection is illustrated in Scheme 7 below: 0 Rs O RW Rs Rz_NHz Z R4 RS'OH (XV) (XVI) 3 0 1 SOV2Ilt. N x'N. tz (XXII) R12NC R4 Rs R2 Õ (IX) (XXIII) Scheme 7 The rection conditions used for the synthesis of (XXIII), illustrated in Scheme 7, are similar to those described for tille synthesis of (XVII) illustrated in Schème 1.

The intermediate compound (XXIII) may be converted to a compound of formula (II) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group (Z'), followed by cyclization. This rection is illustrated in Scheme 8 below. R R9 H (i) acid RF Z. NN.N. R2 Z,, N, <, 2y N 12 4 N, (XXIII) 0 (11) Scheme 8 This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z'and cyclization, may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the rection can also be generated in situ, for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

In addition to carrying out the rection in scheme 8 in the presence of acid, a rection step involving basic conditions can also be optionally carried out so as to facilitate the removal of the amine protecting group Z', wherein Z'is a base labile amine protecting group. There is no particular restriction on the nature of the base to be used in this rection, and any base conventionally used to facilitate removal of an base labile amine protecting group Z', may equally be used here, provided that it has no

adverse effect on other parts of the molecule. Examples of suitable bases include: organic bases such as ammonia, piperidine, morpholine, ethanolamine aud diethylamine.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 1 50°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffixe.

There is no particular restriction on the amine protecting group (Z') employed. However, amine protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Examples of amine protecting groups include both acid labile amine protecting groups and base labile protecting groups.

Preferred acid labile amine protecting group include tert-butoxycarbonyl (BOC) and 2-(4-biphenylyl)- isopropoxy carbonyl (BPOC). Preferred base labile amine protecting group include 9-fluoroenylmethyl carbamate (FMOC).

In situations where acidic conditions are used to remove the amine protecting group in (XXII) it may also be necessary to treat the deprotected intermediate, which is present as an acid salt, with base so as to convert the acid addition salt to its corresponding free base. There is no particular restriction on the nature of the base to be used. A base conventionally used to convert an acid addition salt to its corresponding free base form may be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include ammonia, piperidine, morpholine, ethanolamine, diethylamine, polystyrene bound di-isopropylethylamine or basic DOWEX. Preferably diethylamine, basic DOWEX or polystyrene bound di-isopropylethylamine.

The use of the novel resin bound isonitrile (luxa) in the synthesis of compound of the formula (XXII), wherein Rl2 is the novel resin bound isonitrile derivative, is advantageous over other non-rein bound isonitriles. However, use of (IXa) in the synthesis of (II) involves activation of the resin linker to facilitate cleavage of the rein linkage and cyclization to afford (il). An illustration of the use of the novel resin bound isonitri (e (IXa) in the synthesis of the intermediate of the formula (XXIII) is illustrated in Scheme 9. R3 O O z1 o tOH R1 Jk R9 R3 O i s (XXII) 2_ (i) solvent . N Z R4 R5 N Rz l O i CN I H 1 I N 0' H (XXIII) (luxa)

Scheme 9 The rection conditions, and isolation of the product, of the rection illustrated in Scheme 9 are similar to those described for the synthesis of compound (XIX) illustrated in Scheme 3 above.

The benzamide compound (XXIII) is then activated for nucleophilic cleavage by conversion to intermediate (XXIV) under similar conditions to that described for synthesis ofthe intermediate (XX).

The conversion of (XXIII) to (XXIV) is illustrated in Scheme 10.

Scheme 10 The resin "safety catch"linker is then cleaved, to facilitate the removal of the resin, by reacting the activated benzamide compound (XXIV) with an appropriate alkoxide, or hydroxide, affording the corresponding alkyl esters or carboxylic acids derivative (XXV) respectively, wherein R''is, for example, H, alkyl, phenyl or cycloalkyl (Mjalli, A. M. M., Sarshar, S., Baiga, T. J. Tetrahedron Lett. 1996, 37,2943; Flynn, D. L., Zelle, R. E., Grieco, P. A. J. Org. Chen1. I983,48,2424). An example of the cleavage from the resin is illustrated in rection Scheme 11:

Scheme 1 l The intermediate compound (XXV), may be converted to a compound of formula (II) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group (Z') and, wherein R3 is an amine protecting group, removal of this amine protecting group also.

The deprotected intermediate is then cyclized. This rection is illustrated in Scheme 12.

0 R R9Rs1) acid RUS : 4-5 N"-2Y 3. N R O (ii) Heat R R9 o (XXV) (II) Scheme 12 The rection conditions and reagents used for the synthesis of (II), illustrated in Scheme 12, are similar to those described for the synthesis of (1) illustrated in Scheme 6.

In situations where acidic conditions are used to remove the amhze protecting group in (XXV) it may also be necessary to treat the deprotected intermediate, which is present as an acid sali, with base so as to convert the acid addition salt to its corresponding free base. There is no particular restriction on the nature of the base to be used. A base conventionally used to convert an acid addition salt to its corresponding free base form may be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include ammonia, piperidine, morpholine, ethanolamine, diethylamine, polystyrene bound di-isopropylethylamine or basic DOWEX. Preferably diethylamines basic DOWEX or polystyrene bound di-isopropylethylamine.

General methodologv for the preparation of ketopiperazines and dihydroquinoxalinones derivatives of general formula (ICI):-.

Compound of formula (III) may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, or by methods according to this invention herein.

In general terms, compound of formula (III) wherein n, R', R3, R9, Rl°, R", R14, R15 and R16 are hereinbefore defined, may be synthesized via a '3-step, 1-pot' procedure by reacting a compound of formula (XXVI) wherein R16 is hereinbefore defined, with a compound of formula (XXVII) wherein n, R3, R10, R", R14 and R15 are hereinbefore defined and Z'is a suitable amine protecting group, (XV)

wherein R'and R9 are hereinbefore defined, and (IX) wherein R'z is hereinbefore defined, in a suitable solvent at about room temperature, to afford the intermediate compound (XXVIII), wherein n, R', R3, R9, R10, R11, R12, R14, R15, R16 and Z'are hereinbefore defined. The general rection is illustrated in Scheme 13 below: 0 0 RsH RR9 R (R-N_R12 (XXVI) (XV) R16lk N y N-R _y (i) solvent i Ro R R12-NC nRo zl N n NH2 (IX) R3-N'z R14 R15 (XXVIII) (XXVII)

Scheme 13 The rection conditions used for the synthesis of (XVIII), illustrated in Scheme 13, are similar to those described for the synthesis of (XVII) illustrated in Scheme 1.

The intermediate compound (XXVIII) may be converted to a compound of formula (III) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group (Z'), followed by cyclization. This rection is illustrated in Scheme 14 below. o 0 Ri R9 RUZ R (i) acid R9 N Rt Rtt II N Ra/ -wv (ii) Heat IIW5 n Rs Ro Rm R 3N, zi (XXVIII) (ICI)

Scheme 14 This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z'and cyclization, may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the rection can also be generated in situ, for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

In addition to carrying out the rection in scheme 14 in the presence of acid, a rection step involving basic conditions can also be optionally carried out so as to facilitate the removal of the amil1e protecting group Z', wherein Z'is a base labile amine protecting group. There is no particular restriction on the nature of the base to be used in this rection, and any base conventionally used to facilitate removal of an base labile amine protecting group Z', may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include: organic bases such as ammonia, piperidine, morpholine, ethanolamine and diethylamine.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

There is no particular restriction on the amine protecting group (Z') employed. However, amine protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Examples of amine protecting groups include both acid labile amine protecting groups and base labile protecting groups.

Preferred acid labile amine protecting group include tert-butoxycarbonyl (BOC) and 2-(4-biphenylyl)- isopropoxy carbonyl (BPOC). Preferred base labile amine protecting group include 9-fluoroenylmethyl carbamate (FMOC).

In situations where acidic conditions are used to remove the amine protecting group in (XXVIII) it may also be necessary to treat the deprotected intermediate, which is present as an acid salt, with base so as to convert the acid addition salt to its corresponding free base. There is no particular restriction on the nature of the base to be used. A base conventionally used to convert an acid addition salt to its corresponding free base form may be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include ammonia, piperidine, morpholine, ethanolamine, diethylamine, polystyrene bound di-isopropylethylamine or basic DOWEX. Preferably diethylamine, basic DOWEX or polystyrene bound di-isopropylethylamine.

The use of the novel resin bound isonitrile (luxa) in the synthesis of compound of the formula (XXVIII) wherein Rl2 novel resin bound isonitrile derivative is advantageous over other non-rein bound isonitriles. However, use of (luxa) in the synthesis of (ils) involves activation of the resin linker to facilitate cleavage of the resin linkage and cyclization to afford (III). An illustration of the use of the novel resin bound isonitrile (luxa) in the synthesis of the intermediate of the formula (XXIX) is illustrated in Scheme 15 belon.

0 0 RispH RR9 O R R9 H 1I/H (XXVI) x RsN/N O R3 Ro R" (i) solvent R R, s R"o i H CN C I R°, ztwN4NH2 < 0 3'NZtRt° ° Rta Rts H O i. : (XXIX) (IXa) Scheme 15 The rection conditions, and isolation of the product, of the rection illustrated in Scheme 15 are similar to those described for the synthesis of compound (XIX) illustrated in Scheme 3 above.

The benzamide compound (XXIX) is then activated for nucleophilic cleavage by conversion to intermediate (XXX) under similar conditions to that described for synthesis of the intermediate (XX).

The conversion of (XXIX) to (XXX) is illustrated in Scheme 16.

Scheme 16 The resin"safety catch"linker is then cleaved, to facilitate the removal of tulle resin, by reacting the activated benzamide compound (XXX) with an appropriate alkoxide, or hydroxide, affording the corresponding alkyl esters or carboxylic acids derivative (XXXI) respectively, by the same procedure as described for the synthesis of (XXV) above. An illustration of the cleavage from the resin is illustrated in rection Scheme 17:

Scheme 17 The intermediate compound (XXXI), may be converted to a compound of formula (111) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group (Z') and, wherein R'is an amine protecting group, removal of this amine protecting group also. The deprotected intermediate is then cyclized to afford the product (ils). This rection is illustrated in Scheme 18. O Rt R9 0 is R13 R R, R N » O1 acid R N, NI R (//--al \ I/-R'° (ii) Heats/ N_6o fiR n R R R (X3CXI) (III) Scheme 15 The rection conditions and reagents used for the synthesis of (ici), illustrated in Scheme 18, are similar to those described for the synthesis of (1) illustrated in Scheme 6.

In situations where acidic conditions are used to remove the amine protecting group in (XXXI) it may also be necessary to treat the deprotected intermediate, which is present as an acid salt, with base so as to convert the acid addition salt to its corresponding free base. There is no particular restriction on the nature of the base to be used. A base conventionally used to convert an acid addition salt to its corresponding free base form may be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include ammonia, piperidine, morpholine, ethanolamine, diethylamine, polystyrene bound di-isopropylethylamine or basic DOWEX. Preferably diethylamine. basic DOWEX or polystyrene bound di-isopropylethylamine.

The use of the resin bound isonitrile (XVIII) in the synthesis of compound of the formula (XXVIII), wherein R'Z is the resin bound isonitrile derivative (XVIII), is advantageous over other non- resin bound isonitriles. However, use of (luxa) in the synthesis of (ici) involves activation of the resin linker to facilitate cleavage of the resin linkage and cyclization to afford (ils). An illustration of the use of the novel resin bound isonitrile (XVIII) in the synthesis of the intermediate of the formula (XXXII) is illustrated in Scheme 19. 0 o, RisH RR9 OII R R H- OH RFk9 V N 0 (XXVI) (XV) R'N-- (i) solvent (, R Rp o R » n R, o ZN4NH2 R3oN>z1 7J paps NC (XXXII) (XXVII) (XVIII)

Scheme 19 The rection conditions used for the synthesis of (XXXII), illustrated in Scheme 19, are similar to those described for the synthesis of (XVII) illustrated in Scheme 1.

The intermediate compound (XXXII) may be converted to a compound of formula (ils) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of tille amine protecting group. followed by cyclization. This rection is illustrated in Scheme 20. O R R9 R s RsNN'J O) Acid NR t R R » R N R4l n Ro (ii) Heat 's/ R3'N, zl R R'O R" (XXXII) (III) Scheme 20 This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z'and cyclization, may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the rection can also be generated in situ, for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

In addition to carrying out the rection in scheme 20 in the presence of acid, a rection step involving basic conditions can also be optionally carried out so as to facilitate the removal of the amine protecting group Z', wherein Z'is a base labile amine protecting group. There is no particular restriction on the nature of the base to be used in this rection, and any base conventionally used to facilitate removal of an base labile amine protecting group Z', may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include: organic bases such as ammonia, piperidine, morpholine, ethanolamine and diethylamine.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

There is no particular restriction on the amine protecting group (Z') employed. However amine protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Examples of amine protecting groups include both acid labile amine protecting groups and base labile protecting groups.

Preferred acid labile amine protecting group include tert-butoxycarbonyl (BOC) and 2-(4-biphenylyl)- isopropoxy carbone ( (BPOC). Preferred base labile amine protecting group include 9-fluoroenylmethyl carbamate (FMOC).

In situations where acidic conditions are used to remove the amine protecting group in (XXXII) it may also be necessary to treat the deprotected intermediate, which is present as an acid salt, with base so as to convert the acid addition salt to its corresponding free base. There is no particular restriction on the nature of the base to be used. A base conventionally used to convert an acid addition salt to its corresponding free base form may be used here, provided that it has no adverse effect on other parts of the molecute : Examples of suitable bases include ammonia, piperidine, morpholine, ethanolamine, diethylamine, polystyrene bound di-isopropylethylamine or basic DOWEX. Preferably diethylamine, basic DOWEX or polystyrene bound di-isopropylethylamine.

General methodologv for the preparation of dihydroimidazole derivatives of general formula (IV) In general terms, compound of formula (IV) wherein R2, R9, R10, R", R12 and R"are hereinbefore defined. may be synthesized via a'3-step, I-pot'procedure by reacting a compound of

formula (XXVI) wherein R'6 is hereinbefore defined with compound of formula (XXXIII) wherein R9, R'° and R"are hereinbefore defined and Z'is a amimie protecting group, (IX) wherein Rl2 is hereinbefore defined, and (XVI) wherein R2 is hereinbefore defined, in a suitable solvent at about room temperature, to afford the intermediate compound (XXXIV), wherein R2, R9, R10, R", R, Z'and R'6, are hereinbefore. The general rection is illustrated in scheme 21 below: , o RZ-NHZ Z-NH 0 R2-NC RtsOH ;golvent (XVI) 0 R" R R Z-NH R9 RZ O (XXXIV) (XXXIII) Rt° R11 Scheme 21 There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the rection or on the reagents involved (See Waki et al. J. Am. Chem. Soc., 1977, 6075-6077). Examples of suitable solvents include: alcools, such as methanol, 1-butanol, phenol, trifluoroethanol, hexafluoro-2-propanol; hydrocarbons, such as benzene and toluene; amides, such as dimethyl acetamide, dimethylformamide; halides, such as dicl1loromethane, dichloroethane; and ethers, such as tetrahydrofuran and dioxane; other solvents include water, 1-methyl-2-pyrrolidine, diethyl phosphite, tetramethylsulphone, dimethyl sulphoxide, acetonitrile and pyridine. Of these solvents, the alcools are preferred.

There is no restriction on the isonitrile used in the rection scheme 21 above. Examples of suitable isonitriles inclue, benzyl isocyanide, n-butyl isocyanide, diethyl isocyanomethyl phosphonate, cyclohexyl isocyanide, 2,6-dimethylphenyl isocyanide, methyl isocyanoacetate, isopropyl isocyanide and 1,1,3,3-tetramethylbutyl isocyanide. Preferable isocyanides inclue, benzyl isocyanide, n-butyl isocyanide, diethyl isocyanomethyl phosphonate.

The rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

The intermediate compound of the formula (XXXIV) thus prepared may be recovered from the rection mixture by conventional means. For example, the compound may be recovered by distilling off the solvent in vacuo from the rection mixture or, if necessary after distilling off the solvent from the rection mixture, pourina the residue into water followed by extraction with a water-immiscible organic solvent and distilling off the solvent from the extract. Additionally, the product can, if desired, be further purifie by various well techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.

The intermediate compound is preferably recovered from the rection mixture by distilling off the solvent in vacuo.

The intermediate compound (XXXIV) may be converted to a compound of formula (IV) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group, followed by cyclization. This rection is illustrated in scheme 22. o Z'-NH Rlo R"Rlo 0 R"N R9 (i) Acid R9 Rt2 Rz (ii) Heat R16 R2 O (XXXIV) (fiv) Scheme 22 Cyclization of the deprotected amine to dihydroimidazole proceeded an average of 66% of possible dihydroimidazole product. The remaining no-cyclized amines are removed via a solution phase scavenging step with the simultaneous addition of PS-DIEA or PS-tris (2-aminoethyl) amine (6 equiv.) and PS-NCO (3 equiv.) in dichloroethane. (Booth, R. J.; Hodges, J. C. J. Am. Chenu. Soc. 1997,119,4882.

Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M. S.; Woodward, S. J.

Am. Chenu. Soc. 1997,119,4874. Purchased from ArgonautZ technologies (PS-DIEA-polystyrene bound disopropylethylamine)).

This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z'and cyclization, may equally be used here, provided that it has no adverse effect on other parts ofthe molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the rection can also be generated in situ, for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

In addition to carrying out the rection in scheme 22 in the presence of acid, a rection step involving basic conditions can also be optionally carried out so as to facilitate the removal of the amine protecting group Z'. wherein Z'is a base labile amine protecting group. There is no particular restriction on the nature of the base to be used in this rection, and any base conventionally used to facilitate removal of an base labile amine protecting group Z', may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include: organic bases such as ammonia, piperidine, morpholine, ethanolamine and diethylamine.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 1 SO°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

There is no particular restriction on the amine protecting group (Z') employed. However, acid labile amine protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Preferred acid labile amine protecting group include tert-butoxycarbonyl (BOC) and 2-(4-biphenylyl)-isopropoxy carbonyl (BPOC).

It is also envisage that a sold phase synthesis of (IV) could be carried out using a resin bound Ugi component (XII), (IXa), (XV) or (XXXIII) using similar rection conditions as described herein.

General methodology for the preparation of lactam derivatives of general formula (V) In general terms, compound of formula (V) wherein p, R', R2, R3, R9, R14, R15 and R16 are hereinbefore defined, may be synthesized via a'3-step, I-pot'procedure by reacting a compound of

formula (XXVI) wherein R'G is hereinbefore defined, with a compound of formula (XXXV) wherein p, R3, R9, R'4, R'5 and Z'are hereinbefore defined, (XVI) wherein RZ is as hereinbefore defined, and (XVIII) in a suitable solvent at about room temperature, to afford the intermediate compound (XXXVI), wherein p, R3, R9, R'4, R'5, Rl6 and Z'are as hereinbefore defined. The general rection is illustrated in Scheme 23 below: R3 0 15 1 _zi RsxOH 2 (xXVI) O P s R (XVI) 2 (i) solvent R- RsN NH O OR Z,'iRts RZ O (XXXV) N (XXXVI) (XVIII) Scheme 23 There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the rection or on the reagents involved (See Waki et al. J. Am. Chem. Soc., 1977, 6075-6077). Examples of suitable solvents include: alcools, such as methanol, 1-butanol, phenol, trifluoroethanol, hexafluoro-2-propanol; hydrocarbons, such as benzene and toluene; amides, sucez as dimethyl acetamide, dimethylformamide; halides, such as dichloromethane, dichloroethane; and ethers, such as tetrahydrofuran and dioxane; other solvents include water, 1-methyl-2-pyrrolidine, diethyl phosphite, tetramethylsulphone, dimethyl sulphoxide, acetonitrile and pyridine. Of these solvents, the alcools are preferred.

The rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

The intermediate compound (XXXVI) may be converted to a compound of formula (V) by reacting with acid or base, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group, followed by cyclization. This rection is illustrated in scheme 24 below: R3 R N_Z R2 O pus P RsaRNR16 i Acid R N NH---O I p R 12 0 (ii) Heat/N (XXXVI) (V)

Scheme 24 This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z'and cyclization, may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the rection can also be generated in situ. for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 1 SO°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

There is no particular restriction on the amine protecting group (Z') employed. However, amine protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Examples of amine protecting groups include both acid labile amine protecting groups and base labile protecting groups.

Preferred acid labile amine protecting group include tert-butoxycarbonyl (BOC) and 2- (4-biphenylyl)- isopropoxy carbonyl (BPOC). Preferred base labile amine protecting group include 9-fluoroenylmethyl carbamate (FMOC).

Similarly. the synthesis of (V) can be carried out in solid phase using an isonitrile bound resin of fonnula (IXa) and using rection conditions similar to those described for schemes 15-18.

Similarly, the synthesis of (V) can be carried out in solution phase using a non resin bound isonitrile.

General methodology for the preparation of 1, 4-benzodiazepine-2.-dione and diketopiperazine derivatives of general formula (VI),:-.

In general terms, compound of formula (VI) wherein R1, R2, R3, R10, R11, R'2, R'4 and Rl5 are hereinbefore defined, may be synthesized by reacting a compound of formula (XIV wherein R3, R'°. R", R14 and R15 are hereinbefore defined and Z'is a suitable amine portecting group, with compound of formula (XYXVII) wherein R'and R9 are hereinbefore defined, (XVI) wherein R2 is hereinbefore defined, and tIX) wherein R12 represents hydrogen, alkyl, aroyl, aralkyl, aryl, fused arylcycloalkyl, fused arylheterocyclyl, cycloalkyl, heteroaralkyl, heteroaryl, fused heteroarylcycloalkyl. fused heteroarylheterocyclyl, heterocyclyl ; in a suitable solvent at about room temperature, to afford the intermediate compound (XXXVIII) wherein R1, R2, R3, R9, R10, R11, R12, R14, R15, and Z1 are hereinbefore defined. The general rection is illustrated in scheme 25 below: R12 NC R10 O OIW R OH Rio O O R9 R'RiH t N O R4 N-Zl SOIVerit R \N \RZ ils R u RZ O Rz-NHZ R N-Zi (XIV) R'S"'I (XXXVII) (XVI) R (XXXVIII) Scheme 25 There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the rection or on the reagents involved (See Waki et al. J. Am. Chem. Soc., 1977, 6075-6077). Examples of suitable solvents include: alcools, such as methanol, 1-butanol, phenol, trifluoroethanol, hexafluoro-2-propanol; hydrocarbons, such as benzene and toluene; amides, such as dimethyl acetamide, dimethylformamide; halides, such as dichloromethane, dichloroethane; and ethers, such as tetrahydrofuran and dioxane; other solvents include water, I-methyl-2-pyrrolidine, diethyl phosphite, tetramethylsulphone, dimethyl sulphoxide, acetonitrile and pyridine. Of these solvents, the alcools are preferred.

There is no restriction on the isonitrile (R'2-NC) used in the rection scheme above, provided that it has no adverse effect on the rection involved. Examples of suitable isonitriles inclue, benzyl isocyanide, n-butyl isocyanide, diethyl isocyanomethyl phosphonate, cyclohexyl isocyanide, 2,6- dimethylphenyl isocyanide, methyl isocyanoacetate, isopropyl isocyanide and 1,1,3,3-tetramethylbutyl isocyanide. Preferable isocyanides include cyclohexyl isocyanide, 2,6-dimethylphenyl isocyanide, isopropyl isocyanide and 1,1,3,3-tetramethylbutyl isocyanide.

The rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 1 50°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

The intermediate compound of the formula (XXXV1II) thus prepared may be recovered from the rection mixture by conventional means. For example, the compound may be recovered by distilling off the solvent in vacuo from the rection mixture or, if necessary after distilling off the solvent from the rection mixture, pouring the residue into water followed by extraction with a water-immiscible organic solvent and distilling offthe solvent from the extract. Additionally, the product can, if desired, be further purifie by various well techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.

The intermediate compound is preferably recovered from the rection mixture by distilling off the solvent in vacuo.

The intermediate compound (XXXVIII) may be converted to a compound of formula (VI) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group, followed by cyclization. This rection is illustrated in scheme 26. 0 0 O R9 Rio Rz NRiz1 ACId Rii Ri H N (ii) Heat RaR'2 N Rs mO O R5i m 13 fk3 R140) R2 1 :) (ii)HeatR14# R1^ ml O OR (XVIII) Scheme 26

This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z'and cyclization, may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the rection can also be generated in situ, for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

In addition to carrying out the rection in scheme 26 in the presence of acid, a rection step involving basic conditions can also be optionally carried out so as to facilitate the removal of the amine protecting group Z', wherein Z'is a base labile amine protecting group. There is no particular restriction on the nature of the base to be used in this rection, and any base conventionally used to facilitate removal of an base labile amine protecting group Z', may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include: organic bases such as ammonia, piperidine, morpholine, ethanolamine and diethylamine.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

There is no particular restriction on the amine protecting group (Z') employed. However, amine protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Examples of amine protecting groups include both acid labile amine protecting groups and base labile protecting groups.

Preferred acid labile amine protecting group include tert-butoxycarbonyl (BOC) and 2- (4-biphenylyl)- isopropoxy carbonyl (BPOC). Preferred base labile amine protecting group include 9-fluoroenylmethyl carbamate (FMOC). General methodology for the preparation of 1, 4-benzodiazephze-2,5-dione derivatives of general formula (VII)

Compound of formula (VII) may be prepared may be synthesized via a'3-step, l-pot procedure by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, or by methods according to this invention herein.

In general terms, compound of formula (VII) wherein R', R3, R8, R6, R7, R8, R9 R10, R"and R12 are hereinbefore defined. and Z'is a suitable amine protecting group, may be synthesized by reacting an isonitrile compound of formula (IX), wherein R'2, is hereinbefore defined, with compound of formula (XV) wherein R'and R9 are hereinbefore defined, (XIV) wherein R3, R8' R6 R7 and R8 are hereinbefore defined and amino ester bound resin compound (XXXIX) wherein R10, R"are as hereinbefore defined, R 17 and R"independently represent hydrogen, alkyl, aralkyl, aryl, fused arylcycloalkyl, fused arylheterocyclyl, aryloxy, cycloalkyl, heteroaralkyl, heteroaryl, fused heteroarylcycloalkyl, fused heteroarylheterocyclyl, or heterocyclyl, most preferably, alkyl or hydrogen; and q is 1. 2 or 3, in a suitable solvent at about room temperature, to afford the intermediate compound (XL). This rection is illustrated in scheme 27 below: Rs O O OH R RB N-Z R N \N/R2 (XIV) (xv) (i) solvent Rs I, I _ 2 RtX NH2 R12NC Rs R3 R11 R10 \ a : :', . o >., (IX) CR, e RUZ OU 9 ° R16 R17 (XXXIX) D Scheme 27 There is no restriction on the isonitrile used in the rection scheme 27 above. Examples of suitable isonitriles inclue, benzyl isocyanide, n-butyl isocyanide, diethyl isocyanomethyl phosphonate, cyclohexyl isocyanide, 2, 6-dimethylphenyl isocyanide, methyl isocyanoacetate, isopropyl isocyanide and

1,1, 3,3-tetramethylbutyl isocyanide. Preferable isonitriles include benzyl isocyanide, n-butyl isocyanide, diethyl isocyanomethyl phosphonate. More preferably l-isocyanocyclohexene.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the rection or on the reagents involved. Examples of suitable solvents include: alcools, such as methanol, I-butanol, phenol, trifluoroethanol, hexafluoro-2-propanol ; hydrocarbons, such as benzene and toluene; amides, such as dimethyl acetamide, dimethylformamide; halides, such as dichloromethane, dichloroethane : and ethers, such as tetrahydrofuran and dioxane; other solvents include water, I-methyl-2-pyrrolidine, diethyl phosphite, tetramethylsulphone, dimethyl sulphoxide, acetonitrile and pyridine. Of these solvents, the alcools are preferred.

The rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors.. notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

The intermediate compound (XL) may be converted to a compound of formula (VII) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group, followed by cyclization. This rection is illustrated in scheme 28 below: Ré 0 RU R Ri N Rs Rt H \NRt2 NW t2 o (i) Acid Re o Re/N-Z (ii) Heat R N 10 Ra R3 R Ro p Rs wN (rye (XL) (Rm R I o i. : Scheme 28 This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z'and cyclization, may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the

rection can also be generated in situ, for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

In addition to carrying out the rection in scheme 28 in the presence of acid, a rection step involving basic conditions can also be optionally carried out so as to facilitate the removal of the amine protecting group Z', wherein Z'is a base labile amine protecting group. There is no particular restriction on the nature of the base to be used in this rection, and any base conventionally used to facilitate removal of an base labile amine protecting group Z', may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include: organic bases such as ammonia, piperidine, morpholine, ethanolamine and diethylamine.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

There is no particular restriction on the amine protecting group (Z') employed. However, amine protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Examples of amine protecting groups include both acid labile amine protecting groups and base labile protecting groups.

Preferred acid labile amine protecting group include tert-butoxycarbonyl (BOC) and 2- (4-biphenylyl)- isopropoxy carbonyl (BPOC). Preferred base labile amine protecting group include 9-fluoroenylmethyl carbamate (FMOC).

Similarly, the synthesis of (VIT) can be carried out in solution phase using a non resin bound aminoester.

General methodologv for the preparation of Ketopiperazine and Dihvdroquinoxalinone derivatives of general formula (VIII)

In general terms, compound of formula (VIII) wherein n, R1, R3, R10, R", R12, R14, R15 and R16 are hereinbefore defined, may be synthesized via a'3-step, I-pot procedure by reacting a compound of formula (XXVI) wherein R16 is hereinbefore defined, with a compound of formula (XXVII) wherein n, R3, R10, R", R'4 and R'5 are hereinbefore defined and Z'is a suitable amine protecting group, (XXXVII) wherein R'and R9 are hereinbefore defined, and (IX) wherein R'Z is hereinbefore defined, in a suitable solvent at about room temperature, to afford the intermediate compound (XLI), wherein n, R', R3, R9, R10, R11, R14, R15, R16 and Z'are hereinbefore defined. The general rection is illustrated in Scheme 29 below: Q Rs RsH RR9 O RO p N-Rz (XXVI) (7 (XXVII) 1 SOIVetltR Rp i Ro R R2-NC po RsNp R14 R15 (XLI) (XXVII) Scheme 29 It is known that when the nucleophilicity of the nitrogen atom adjacent to R10 and R"is poor, the Passerini rection (See J. March, Advanced Organic Chemistry, 3rd Ed., John Wiley & Sons p. 870-871 (1985)) predominates and the yields of the desired cyclized product (VIII) is lowered. Therefore, it is preferred that at least one of R'° or R", is an electron donating group, or when n=1, R"and R14 are absent and R10 and R15 taken together with the adjacent carbon atoms through which they are linked form an electron donating 6 membered aryl or 5 to 6 membered an electron donating heteroaryl; or when n=1, R'° and R'S taken together with the adjacent carbon atoms through which they are linked form a 5 to 7 membered an electron donating cycloalkyl or an electron donating heterocyclyl; or when n=2, adjacent R"and R'4 are absent and R'° and adjacent R 15 taken together with the adjacent carbon atoms through which they are linked form a 6 membered an electron donating aryl or 5 to 6 membered an electron donating heteroaryl; or when n=2, R'° and adjacent R'5 taken together with the adjacent carbon atoms tlirough which they are linked form a 5 to 7 membered an electron donating cycloalkyl or an electron donating heterocyclyl; so as to increase the nucleophilicity of the adjacent nitrogen atom and give higher yields of the desired product (VIII).

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the rection or on the reagents involved (See Waki et al. J. Am. Chem. Soc., 1977, 6075-6077). Examples of suitable solvents include: alcools, such as methanol, 1-butanol, phenol, trifluoroethanol, herafluoro-2-propanol; hydrocarbons, such as benzene and toluene; amides, such as dimethyl acetamide dimethylformamide; halides, such as dichloromethane, dichloroethane; and ethers,

such as tetrahydrofuran and dioxane; other solvents include water, I-methyl-2-pyrrolidine, diethyl phosphite, tetramethylsulphone, dimethyl sulphoxide, acetonitrile and pyridine. Of these solvents, the alcools are preferred.

There is no restriction on the isonitrile (R'2-NC) used in the rection scheme above, provided that it has no adverse effect on the rection involved. Examples of suitable isonitriles inclue, benzyl isocyanide, n-butyl isocyanide, diethyl isocyanomethyl phosphonate, cyclohexyl isocyanide, 2, 6- dimethylphenyl isocyanide, methyl isocyanoacetate, isopropyl isocyanide and 1,1,3,3-tetramethylbutyl isocyanide. Preferable isonitriles include cyclohexyl isocyanide, 2,6-dimethylphenyl isocyanide, isopropyl isocyanide and 1,1,3,3-tetramethylbutyl isocyanide.

The rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above. a period of from 3 hours to 36 hours will usually suffice.

The intermediate compound of the formula (XLI) thus prepared may be recovered from the rection mixture by conventional means. For example, the compound may be recovered by distilling off the solvent in vacuo from the rection mixture or, if necessary after distilling off the solvent from the rection mixture, pouring the residue into water followed by extraction with a water-immiscible organic solvent and distilling off the solvent from the extract. Additionally, the product can, ifdesired, be further purifie by various well techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.

The intermediate compound is preferably recovered from the rection mixture by distilling off the solvent in vacuo.

The intermediate compound (XLI) may be converted to a compound of formula (VIII) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group, followed by cyclization. This rection is illustrated in scheme 30. O Rs 12 O O R RNH R Rs R N N-Rt2i acid 1 141 tn R10 (j ;) Heat tR16 14) n ' po Ris RR i Rs NZt (VIII) (XLI) (Vlll)

Scheme 30 This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z'and cyclization, may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the rection can also be generated in situ, for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

In addition to carrying out the rection in scheme 30 in the presence of acid, a rection step involving basic conditions can also be optionally carried out so as to facilitate the removal of the amine protecting group Z, wherein Z'is a base labile amine protecting group. There is no particular restriction on the nature of the base to be used in this rection, and any base conventionally used to facilitate removal of an base labile amine protecting group Z', may equally be used here, provided that it has no adverse effect o. l other parts of the molecule. Examples of suitable bases include: organic bases such as ammonia, piperidine, morpholine, ethanolamine and diethylamine.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours tao 36 hours will usually suffice.

There is no particular restriction on the amine protecting group (Z') employed. However, amine protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Examples of amine protecting groups include both acid labile amine protecting groups and base labile protecting groups.

Preferred acid labile amine protecting group include tert-butoxycarbonyl (BOC) and 2- (4-biphenylyl)-

isopropoxy carbonyl (BPOC). Preferred base labile amine protecting group include 9-fluoroenylmethyl carbamate (FMOC).

Alternatively, a compound formula(VIII)whereinn,R1,R10,R11,R12,R14,R15andR16arethe hereinbefore defined and R3 is hydrogen, may be prepared by'2-step, one pot'method by reacting a compound of formula (XXVI) wherein R16 is hereinbefore defined, with a compound of formula (XXVIIa) wherein n, R10, R", R14 and R15 are hereinbefore defined and R3 is hydrogen, (XXXVII) wherein R'and R9 are hereinbefore defined, and (IX) wherein R12 is hereinbefore defined, in a suitable solvent and appropriate temperature to effect cyclization and afford a compound of formula (VIII). The

general rection is illustrated in Scheme 31 below: 0 0 R1694oH R1) 9 R9 R12 ° OU 12 O (XXVI) 0 R'R3 (i) solvent o N R41 R'o R Rz-NC heat H'N4n NH2 (IX) R6 Ro Ri R14 R15 (vil) (XXVlla)

Scheme 31 The solvent and isonitrile used in this rection are similar to those used for the synthesis of (XLI) illustrated in Scheme 30. The rection temperature used in this rection is similar to that used for the cyclization of (XLI) illustrated in Scheme 30. It would also be understood by a skilled person in the art that use of a diamino compound of formula (XXVIIa) wherein R'°, R", R'4 and R'S are identical to each other would produce a single compound of-fonnula (VIII).

General methodolog, v for the preparation of ketopiperazine derivatives formula(XLII)ofgeneral

Compound of formula (XLII) may be prepared may be synthesized via a'3-step, 1-pot' procedure by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, or by methods according to this invention herein.

In general terms. compoullds of formula (XLII) wherein R', R', R5, R9, R10, R11, R12 and R16, are hereinbefore defined, may be synthesized by reacting an isonitrile compound of formula (IX), wherein R'2, is hereinbefore defined, with compound of formula (XLIII) wherein R3, R4 R5, R9 and Z1 are hereinbefore defined, (XXVI) wherein R'6 is hereinbefore defined and amino ester bound resin <BR> <BR> compound (XXXIX) wherein R10, R"are as hereinbefore defined, R"and R"independently represent hydrogen, alkoxycarbonyl, alkyl, aralkoxycarbonyl, aralkyl, aroyl, aryl, fused arylcycloalkyl, fused arylheterocyclyl, aryloxy, aryloxycarbonyl, cycloalkyl, heteroaralkyl, heteroaroyl, heteroaryl, fused heteroarylcycloalkyl, fused heteroarylheterocyclyl, or heterocyclyl; and q is 1,2 or 3, in a suitable solvent at about room temperature, to afford the intennediate compound (XLIX). This rection is illustrated in scheme 29 below: z 0 z 1 z N R5 RsN Rs O Rs Ra Rs H R4 R5 O N-R12 (XLIII) R12-NC RsH RsN O XXVI O Solvent X g g/10 R11 R »O » p Ra R » RqXLIX) (XXXIX) Scheme 32 There is no restriction on the isonitrile used in the rection scheme 29 above. Examples of suitable isonitriles inclue, benzyl isocyanide, n-butyl isocyanide, diethyl isocyanomethyl phosphonate, cyclohexyl isocyanide, 2,6-dimethylphenyl isocyanide, methyl isocyanoacetate, isopropyl isocyanide and 1,1,3, 3-tetramethylbutyl isocyanide. Preferable isonitriles include benzyl isocyanide, n-butyl isocyanide, diethyl isocyanomethyl phosphonate. More preferably 1-isocyanocyclohexene.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the rection or on the reagents involved. Examples of suitable solvents include: alcools, such as methanol, I-butanol, phenol, trifluoroethanol, hexafluoro-2-propanol; hydrocarbons, such as benzene and toluene; amides, such as dimethyl acetamide, dimethylformamide; halides, sucez as dichloromethane, dichloroethane; and ethers, such as tetrahydrofuran and dioxane; other solvents include water, 1-methyl-2-pyrrolidine, diethyl phosphite, tetramethylsulphone, dimethyl sulphoxide, acetonitrile and pyridine. Of these solvents, the alcools are preferred.

The rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C. more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

The intermediate compound (XLIX) may be converted to a compound of formula (XLII) by reacting with acid, in a suitable solvent and appropriate temperature, to effect removal of the amine protecting group, followed by cyclization. This rection is illustrated in scheme 33 below: Z z1 R R 12 R9 N-R12 R » N R9 ruz O \- (i) Acid RoN Ruz (ii) Heat Q N R4 O (XLII) XLIX) Scheme 33 This rection is carried out in the presence of an acid. There is no particular restriction on the nature of the acid to be used in this rection, and any acid conventionally used to facilitate removal of an acid labile amine protecting group Z'and cyclization, may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable acids include: mineral acids such as hydrochloric acid or sulfuric acid; organic acids such as trifluoroacetic acid. Acids to be used in the rection can also be generated in situ, for example by the addition of acetyl chloride in methanol, to generate hydrochloric acid. Preferably, anhydrous acids are used.

In addition to carrying out the rection in scheme 29 in the presence of acid, a rection step involving basic conditions can also be optionally carried out so as to facilitate the removal of the amine protecting group Z', wherein Z'is a base labile amine protecting group. There is no particular restriction on the nature of the base to be used in this rection, and any base conventionally used to facilitate removal of an base labile amine protecting group Z', may equally be used here, provided that it has no

adverse effect on other parts of the molecule. Examples of suitable bases include: organic bases such as ammonia, piperidine, morpholine, ethanolamine and diethylamine.

This rection can take place over a wide range of temperatures, and the precise rection temperature is not critical to the invention. In general, we find it convenient to carry out the rection at a temperature of from about 0°C to about 150°C, preferably from room temperature to about 100°C, more preferably at about room temperature. The time required for the rection may also vary widely, depending on many factors, notably the rection temperature and the nature of the reagents. However, provided that the rection is effected under the preferred conditions outlined above, a period of from 3 hours to 36 hours will usually suffice.

There is no particular restriction on the amine protecting group (Z') employed. However, amine protecting groups which allow removal of the protecting group and cyclization of the deprotected intermediate, without purification or isolation of intermediates, are preferred. Examples of amine protecting groups include both acid labile amine protecting groups and base labile protecting groups.

Preferred acid labile amine protecting group include tert-butoxycarbonyl (BOC) and 2- (4-biphenylyl)- isopropoxy carbonyl (BPOC). Preferred base labile amine protecting group include 9-fluoroenylmethyl carbamate (FMOC).

Similarly, the synthesis of (XLII) can be carried out in solution phase using a non resin bound amino ester.

According to a further feature of the present invention, compound of the invention may be prepared by interconversion of other compound of the invention.

A compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XLII), including a group containing one or more nitrogen ring atoms, preferably imine (=N-), may be converted to the corresponding compound wherein one or more nitrogen ring atom of the group is oxidized to an N-oxide, preferably by reacting with a peracid, for example peracetic acid in acetic acid or m- chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.

As an example of the interconversion process, compound (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XLII), containing sulphoxide linkages may be prepared by the oxidation of correspondh1g compound containing-S-linkages. For example, the oxidation may conveniently be carried out by means of rection with a peroxyacid, e. g. 3-chloroperbenzoic acid, preferably in an inert solvent, e. g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH 5, at

temperatures between about 0°C and room temperature. This latter method is preferred for compound containing an acid-labile group.

As another example of the interconversion process, compound (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (XLII), containing sulphone linkages may be prepared by the oxidation of corresponding compound containing-S-or sulphoxide linkages. For example, the oxidation may conveniently be carried out by means of rection with a peroxyacid, e. g. 3-chloroperbenzoic acid, preferably in an inert solvent, e. g. dichloromethane, preferably at or near room temperature.

It will be understood that designation of aromaticity with respect to carbocycles and heterocycles herein inclues any highly resonant unsaturated ring structure. Alternatively, placement of double bonds, where indicated, represents one potential structure for the depicted compound but will be understood to include other resonant states of the compound as well as protonated and charged species, only one of which may be shown.

It will be appreciated that compound of the present invention may contain asymmetric centers.

These asymmetric centers may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compound of the invention may also exhibit geometrical isomerism.

It is to be understood that the present invention inclues individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compound of formula (1), a compound of formula (II), or a compound of formula (III), hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates.

For the propose herein it is understood that tautermeric forms are included in the recitation of a given group, e. g., thio/mercapto or oxo/hydroxyl.

Acid additional salts are formed with the compound of the invention in which a basic function such as an amino, alkylamino, or dialkylamino group is present. The pharmaceutically acceptable, i. e., nontoxic, acid addition salts are preferred. The salts chosen are chosen optimally to be compatible with the customary pharmaceutical vehicles and adapted for oral or parenteral administration. Acid addition salts of the compound of this invention may be prepared by rection of the free base with the appropriate acid.. by the application or adaptation of known methods. For example, the acid addition salts of the compound of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution. Some suitable acids for use in

the preparation of such salts are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, various organic carboxylic and sulfonic acids, such as acetic acid, citric acid, propionic acid, succinic acid, benzoic acid. tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, toluenesulfonic acid, fatty acids, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, cyclopentanepropionate, digluconate, dodecylsulfate, bisulfate, butyrate, lactate, laurate, lauryl sulfate, malate, hydroiodide, 2-hydroxy-ethanesulfonate, glycerophosphate, picrate, pivalate, pamoate, pectinate, persulfate, 3-phenylpropionate, thiocyanate, 2-naphthalenesulfonate, undecanoate, nicotinate, hemisulfate, heptonate, hexanoate, camphorate, camphersulfonate, and others.

The acid addition salts of the compound of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compound of the invention can be re8enerated from their acid addition salts by treatment with an alkali, e. g. aqueous sodium bicarbonate solution or aqueous ammonia solution.

Compound of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compound of the invention can be regenerated from their base addition salts by treatment with an acid, e. g. hydrochloric acid.

Base addition salts may be formed where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere. The bases which can be used to prepare the base addition salts include preferably those which produce, when combine with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharrnaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

Compound of the present invention may be conveniently prepared, or formed during the process of the invention. as solvates (e. g. hydrates). Hydrates of compound of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol. <BR> <BR> <P> EXAMPLE1<BR> Solution Phase Synthesis of Compound of Formula (I) via the'3-step. one pot'procedure emploving the Ugi multi-component rection:

Equal amounts (0. 1ml) of 0.1 M solutions of the four appropriate components compound of formulae (XIV), (XV), (XVI) and (IXb), are employed generating a theoretical 10 pmol of final 1,4- benzodiazepine-2,5-dione product (1) for 100% conversion. The 4-component condensation is performed in methanol at room temperature and the solvent evaporated at 65°C (using a SAVANTe evaporator for 2 houris). The deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane. Solvents are then evaporated at 65°C to afford the cyclized product compound of formula (I). Lc/ms analysis (liquid chromatography/mass spectrometry) is performed using a C 1$ Hypersil BDS 3m 4. 6X50mm column (UV 220 nm) with a mobile phase 0.1% TFA IN H., O/CH3CN I 0% to 100% 15 min, at a rate of 1 ml/min.

Desired products are seen as (M+ 1).

Table 5 below shows the lc/ms A% yields taken from two 96 well plates usinez the experimental procedure described above and the Ugi components listed as 1-22 below: Table 1 contains hplc retention times of the desired products from anthranilic acid 1 using a C 18 Hypersil BDS 3 m 4. 6X50mm column (UV 220 nm) with a mobile phase 0. 1% TFA in H2O/CH3CN 10% to 100%, 5 min, at a rate of I mi/min. For example, Table I indicates that anthranilic acid 1 reacted with amine 3 and aldehyde 15 affords the desired product with a retention time of 3.78, under the conditions mentioned above.

TABLE 1 56789101112131434 15 3.78 3.92 4.18 3.79 3.52 4. 14 2.82 3.26 4.63 2.86 4. 36 3.04 16 4.71 4.84 5. 15 4.67 4.58 4.97 3.70 4.14 5.46 3.61 5.15 4.0 17 4.31 4.40 4.67 4.27 4.14 4.58 3.35 3.79 5.02 3.30 4.75 3.61 18 3.61 3.79 4. 05 3.65 3.35 4.01 2.55 3.04 4.53 2.46 4.27 2.82 19 4.014.013.834.363.043.484.804.583.264.274.14 20 4.27 4. 40 4.62 4. 27 4.14 14. 1 53 3.04 3.83 4.97 3.43 4.75 3.65 21 5.11 5.20 5. 50 5. 02 4.97 5.33 4. 05 4.49 5.86 3.92 5.55 4. 36 22 3. 43 3. 74 3. 91 3.48 3.34 3.87 2. 64 3. 08 4.31 2.95 4. 18 2. 86

Table 2 contains the molecular weight of the desired products from anthranilic acid 1. Desired products are seen as (M+ 1). For example, Table 2 indicates that anthranilic acid I reacted with amine 3 and aldehyde 15 affords the desired product with a molecule weight (M+ I) of 308. 4, under the conditions mentioned above.

TABLE 2 3 4 5 6 7 8 9 10 11 12 13 14 15 308.4 322.4 302. 4 338. 4 274.4 336.4 326. 4 401.5 364.5 345.4 398.5 343.4 16 350.5 364.5 344.5 380.5 316.4 378.5 368.5 443.6 406.6 387.5 440.6 385.5 17 370.5 384.5 364.5 400.5 336.4 398.5 388.5 463.6 426.6 407.5 460.6 405.5 18 288.4324.4260.3322.4312.4387.5350.5331.4384.5329.4308.4 19 322.4 336.4 316.4 352.4 288.4 350.5 340.4 415.5 378.5 359.4 412.5 357.5 20 428.5 442.5 422.5 458.5 394.5 456.5 446.5 521.6 484.6 465.5 518. 6 463.5 21 390.5 404.6 384.6 420.6 356.5 418.6 408.5 483.6 446.6 427.6 480.7 425.6 22 378.4 392. 5 372.5 408.5 344.4 406.5 396.4 471.5 434.5 415.5 468.6 413.5

Table 3 contains hplc retention times of the desired products from anthranilic acid 2. For example, Table 3 indicates that anthranilic acid 2 reacted with amine 3 and aldehyde 15 affords the desired product with a retention time of 4.01, under the conditions mentioned above.

TABLE 3 5634 7 10111213149 15 4.01 4.09 4.45 4.01 3.79 4. 36 2.95 3.30 4.84-4.62 2.95 16 4.97 5.15 5.46 4.89 4.93 5.28 3.87 4.36 5.68 3.92 5.46 4.27 17 4.49 4.67 4.93 4.49 4.45 4.84 3.52 3.96 5.24 3.57 5.02 3.83 4.054.363.833.614.272.733.264.752.914.493.04183.83 19 4.23 4.36 4.67 4.23 4.05 4.58 3.17 3.56 5.06-4.80 3.48 20 4.36 4.62 4.84 4.36 4.40 4.71 3.43 3.92 5.06-4.97 3.70 21 5.28 5.46 5.81 5.20 5.28 5.59 4.18 4.67 6.03 3.83 5.50 4.62 3.964.233.793.574.142.773.264.392.514.403.04223.61

Table 4 contains molecular weight of the desired products from anthranilic acid 2. Desired products are seen as (M+ 1). For example, Table 4 indicates that anthranilic acid 2 reacted with amine 3 and aldehyde 15 affords the desired product with a molecule weight (M+1) of 322.4, under the conditions mentioned above.

TABLE 4 3 4 5 6 7 $ 9 10 II IZ I3 14 15 322.4 336.4 316.4 352.4 288.4 350.5 340.4 415.5 378.5 359.4 412.5 357.5 16 364.5 378.5 358.5 394.5 330.5 392.5 382.5 457.6 420.6 401.5 454.6 399.5 17 384.5 398.5 378.5 414.5 350.5 412.5 402. 5 477.6 440.6 421.5 474.6 419.5 18 308. 4 322. 4 302.4 338.4 274. 4 336.4 326.4 401.5 364.5 345. 4 398.5 343. 4 19 336.4 350.5 330.5 366.5 302.4 364.5 354.5 429. 5 392.5 373.5 426.5 371.5 20 442.5 456.5 436.5 472.5 408.5 470.6 460. 5 535. 6 498.6 479.5 532.6 477.6 21 404.6 418.6 398.6 434.6 370.5 432.6 422.6 497.7 460.7 441.6 494.7 439.6 406.5386.5422.5358.4420.5410.5485.6448.6429.5482.6427.522392 .5

Table 5, Note: For A% yields x/y: The first yield ;'x"represents that for rections with N-BOC anthranilic acid. 1. The second yield"y"represents that for N-Me-BOC anthranilic acid, 2. Row 15 represents yields of rections with aldehyde 15. Column 3 represents yields of rections with amine 3.

For example, Table 5 indicates that anthranilic acid 1 reacted with amine 3 and aldehyde 15 affords the desired product with a yield 40%, under the conditions mentioned above.

TABLE 5 3 4 5 6 7 8 10 11 12 13 14 15 40/16 40/29 40/27 54/15 40/25 39/40 26/16 18/21 41/15 1/0 39/31 47/30 16 85/87 82/72 77/64 79/72 82/69 84/67 81/73 78/67 82/74 43/10 88/74 84/73 17 88/84 85/73 89/68 92/81 92/78 88/68 90/75 82/73 84/79 39/8 76/77 85/72 18 87/80 72/52 69/43 79/70 70/41 80/51 87/63 81/64 81/70 51/25 75/60 80/62 19 45/10 37/24 39/22 36/12 34/20 33/12 41/7 28/26 44/10 9/0 37/16 39/20 20 79/49 74/61 63/51 75/12 66/53 69/54 59/10 74/61 83/67 6/0 71/49 67/64 21 89/87 86/69 88/66 85/82 89/63 85/70 90/74 83/69 86/84 38/8 84/74 88/78 86/6380/6785/8284/7585/6482/6984/6786/7527/1184/6983/612285/ 64

EXAMPLE 2 General Solid Phase Svnthesis of Compound of Fonnula (I) using the Ugi rection and resin (luxa) (60mg) of resin (IXa) is pre-swelled with THF. 0. 5M solutions of the aldehyde (XV) (10 equiv.), amine (XVI) (10 equiv.) and carboxylic acid (XIV) (10 equiv.) in THF: MeOH (1 : 1) are added sequentially to the resin (IXa) and the rection stirred at room temperature for 3 days. The resin is washed sequentially with CH2CI2, THF, DMF, THF and MeOH dried under high vacuum to yield the resin bound Ugi product (luxa) Treatment with BOC2O (10 equiv.), Et3N (10 equiv.) and DMAP in CH2Cl2 (15 hours) afforded the activated resin (XX) for cleavage. Sodium methoxide (smog) in THF: MeOH, 1: 1, is added to the resin and shaken for 20 hours. The solvent is evaporated in vacuo to give the desired methyl ester (XXI). The deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane. The samples are then evaporated in a SAVANT at room temperature for 3 hours to give the crude product of formula (I). Examples of products (examples 23 to 28) synthesized using this general methodology are indicated below and purities are determined by lc/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A% and UV A%. Lc/ms analysis is performed using a Hypersil BDS 3 m C18 4.6X50mm 0.1 % TFA in H, O/CH3N 10% to 100% CH3N 5 min, at a rate of l ml/min for 23-28. Desired products are seen as (M+ 1). Compound Retention mass ELSD UV (220 nm) time spec A% A% 23 3.36 388 >90 >90 24 3.62 402 90 >90 25 3.93 338 90 80 26 4.27 288 90 91 27 6.48 400 95 91 28 4.36 336 89 80

EXAMPLE 3 Solution Phase Senthesis of Compound of Formula (II) via the'3-step, one pot'procedure. employin= the Ugi multi-component rection: Equal amounts (0.1 ml) of 0.1 M solutions of the four appropriate components compound of formulae (XXII), (XV), (XVI) and (IXb), are employed generating a theoretical 10 pmol of final diketopiperazine product (II) for 100% conversion. The 4-component condensation is performed in methanol at room temperature and the solvent evaporated at 65 °C (using a SAVANTe evaporator for 2 hours). The deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane, and a 5% solution of diethylamine in dichloroethane [Note: 10-15 mg of N, N- (diisopropyl) amino-methylpolystyrene (PS-DIEA) is an excellent resin bound alternative to diethylamine]. Solvents are then evaporated at 65 °C to afford the cyclized products of fonnula (lui).

EXAMPLE 4 General Solid Phase Synthesis of Compound of Formula (II) using the Ugi rection and resin (luxa) (60mg) of resin (luxa) is pre-swelled with THF. 0. 5M solutions of the aldehyde (XV) (10 equiv.), amine (XVI) (10 equiv.) and carboxylic acid (XXII) (10 equiv.) in THF: MeOH (1: 1) are added sequentially to the resin (luxa) and the rection stirred at room temperature for 3 days. The resin is washed sequentially with CH, Cl,, THF, DMF, THF and MeOH dried under high vacuum to yin (d the resin bound Ugi product (XXIII). Treatment with BOC2O (10 equiv.), Et3N (10 equiv.) and DMAP in <BR> <BR> <BR> CH, C12 (15 hours) affords the activated resin bound product (XXIV) for cleavage. Sodium methoxide (smog) in THF: MeOH, 1: 1, is added to the resin and shaken for 20 hours. The solvent is evaporated in vacuo to give the desired methyl ester (XXV). The deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane, and a 5% solution of diethylamine in dichloroethane [Note: 10-15 mg of N, N- (diisopropyl) amino-methylpolystyrene (PS-DIEA) is an excellent resin bound alternative to diethylamine]. Solvents are then evaporated at 65°C to afford the cyclized product of formula (II).

Examples of products (examples 29 to 33) synthesized using this general methodology are indicated below and purities are determined by lc/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A% and W A%. Lc/ms analysis is performed using a C 18 Hypersil BDS 3 m C18 4.6X50mm 0. 1% TFA in H, O/CH, N 10% to 100% CH3N 5 min, at a rate of 1ml/min for 29-33. Desired products are seen as (M+ 1). Compound Retention Mass ELSD llV (220 nm) time spec A% A% 29 3.19 & 3.36 416 100 71 30 3.10 443 94 68 31 2.80 261 100 95 32 3.10 & 3.76 304 98 89 33 3.02 & 3.10 354 71 56

EXAMPLE 5 Solution Phase Synthesis of Compound of Formula (ICI) via the'3-step. one pot'procedure, emplovin the Ugi multi-component rection: Equal amounts (0. 1ml) of 0.1 M solutions of the four appropriate components compound of formulae (XXVI), XXVII), (XV) and (IXb), are employed generating a theoretical 10 Fmol of final product for 100% conversion. The 4-component condensation is performed in methanol at room temperature and the solvent evaporated at 65 °C (using a SAVANTs evaporator for 2 hours). The deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane, and a 5% solution of diethylamine in dichloroethane [Note: 10-15 mg of N, N- (diisopropyl) amino-methylpolystyrene (PS-DIEA) is an excellent resin bound alternative to diethylamine]. Solvents are then evaporated at 65°C to afford the cyclized product of formula (III). Examples of products (examples 34 to 45) synthesized using this

general methodology are indicated below and purities are determined by lc/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A% and UV A%.

Lc/ms analysis is performed using a C 18 Hypersil BDS 3 m 2.1 x 50 mm column (UV 220 nm) with a mobile phase of 0. 1% TFA in CH ; CN/H, O, gradient from 10% CH3CN to 100% over 5 min. HPLC is interface with APCI techniques (Atmospheric Pressure Chemical Ionization). Desired products seen as (M+ I).

Compound Retention Mass UV (220 nm) time spec A% 34 77398 35 1.06 248 97 36 4.09 394 92 37 3.35 282 77 38 2.91 324 77 39 2.38 262 69 40 4.14 412 83 41 5.07 474 70 42 4.60 428 80 43 5.26 488 85 44 5.19 446 66 45 5. 14 460 30

General Procedure and 1H for compound 34 Stoichiometric amounts (2 ml) of 0.1 M solutions of the four Ugi components are combine and stirred at room temperature overnight. The solvent is evaporated in vacuo and the residue is dried under high vacuum. A 10% solution of AcCI in MeOH (8 ml) is added to the crude material and stirred at room temperature overnight. The solvent is evaporated in vacuo. A 5% solution of diethylamine in dichloroethane is then added to the crude material and the solution shaken overnight at room temperature. The solvent is evaporated in vacuo and crude material pre-absorbed onto flash silica and purifie by column chromatography to yield the desired ketopiperazine, 34, (44 mg, 55%) as a white solid: mp 188-190°C. For major conformer only:'H (CDC13) 7.90 (1H, s, NH), 7.10-7.40 (15H, m, C6H5 x 3), 5.60 (1H, s, CHCGH5), 4.78-4.83 (1H, m, CHCH2), 4.05-4.12,3.31-3.40 (2H, 2x m, CH2N), 2.98- 3.02,2.80-2.88 (2H, 2x m, Chan), 2.50-2.60 (2H, m, CH2C6H5), 1.90-2.00,2.03-2.10 (2H, Chez). For major conformer only : 13C (CDCl3) 170. 2,168.7,141.4,139.8,128.7,128.4, 128.3, 126. 7,125.8,54.5, 53.0,39.2,32. 9, 31. 7. IR (KBr disc) 3260m, 1641 s, 1620s (selected peaks only). mspec (APCI) 399 (MH+), 371.'H and'3C assignments have been obtained from 1H, 13C, DEPT, COSY, HMQC and HMBC<BR> experiments. The'H and 13C spectra show two sets of resonances throughout the spectrum. Exchange crosspeaks between major and minor forms are observe in a rotating frame Overhauser effect spectroscopy (ROESY). These resonances also show broadening at temperatures above 80°C. These experiments show that the two forms are in slow exchange under the present experimental conditions.

HMBC spectrum showed correlation between the methylene protons (H2 and H2') with the carbonyl carbon C6 confirming the ring closure.

EXAMPLE 6 General Solid Phase Synthesis of Compound of Formula (III) usine the Ugi rection and resin (luxa) (60mg) of resin (IXa) is pre-swelled with THF. 0. 5M solutions of the aldehyde (XV) (10 equiv.). diamine (XXVII) (10 equiv.) and carboxylic acid (XXVI) (10 equiv.) in THF: MeOH (1 : 1) are added sequentially to the resin (luxa) and the rection stirred at room temperature for 3 days. The resin is

washed sequentially with CH2CI2, THF, DMF, THF and MeOH dried under high vacuum to yield the resin bound Ugi product (XXX). Treatment xvith BOC2O (10 equiv.), Et3N (10 equiv.) and DMAP in CH2CI2 (15 hours) afford the activated the resin bound product (XXVII) for cleavage. Sodium methoxide (5mg) in THF: MeOH, 1: 1, is added to the resin and shaken for 20 hours. The solvent is evaporated in vacuo to cive the desired methyl ester (XXXI).''he deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane. Solvents are then evaporated at 65°C to afford the cyclized product of formula (III).

Examples of products (examples 46 to 51) synthesized using this general methodology are indicated below and purities are determined by Ic/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A% and UV A%. Lc/ms analysis is performed using a Hypersil BDS 3 m C I 8 4.6X50mm 0.1 % TFA in H2O/CH3N 10% to 100% CH3N 5 min, at a rate of Iml/min for 46-49 and 51. C 18 Hypersil BDS 3 m C 18 4. 6X50mm 0.1 % TFA in H2O/CH3N 5% to 100% CH3N 5 min, at a rate of Iml/min for 52. Desired products are seen as (M+ 1).

Compound Retention Mass ELSD A% UV (220 time spec nm) A% 46 3.54 318 100% 100% 47 3.63 368 100% 100% 48 2.80 348 100% 94% 49 4.19 380 100% 100% 50 7.55 398 100% 77% 51 5.19 446 80% 86%

EXAMPLE 7 General Solution Phase Synthesis of Compound of Formula (IV) via the'3-step one pot'procedure, emplovine the Ugi multi-component rection: Equal amounts (0.1 ml) of 0.1 M solutions of the four appropriate components compound of fonnulae (IX), (XV), (XVI) and (XXXIII) are employed generating a theoretical 10 gmot of dihydroimadazole product (IV) for 100% conversion. The 4-component condensation is performed in methanol at room temperature and the solvent evaporated at 65 OC (using a SAVANTe evaporator for 2 hours). The deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane. Solvents are then evaporated at 65 °C to afford the cyclized product of formula (IV). The non-cyclized amines were removed via a solution phase scavenging step with the simultaneous addition of PS-DIEA or PS-tris (2-aminoethyl) amine (6 equiv.) and PS-NCO (3 equiv.) in dichloroethane. (Booth, R. J.; Hodges, J. C. J. Am. Chers. Soc. 1997, 119, 4882. Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M. S.; Woodward, S. J. Am. Chem. Soc. 1997,119,4874. Purchased from Argonaute technologies (PS-DIEA- polystyrene bound disopropylethylamine)). Examples of products (examples 53 to 61) synthesized usinez this general methodology are indicated below and purities are determined by Ic/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A% and W A%.

Lc/ms analysis is performed using a C 18 Hypersil BDS in 4.6X50mm column (UV 220 nm) with a mobile phase 0. I % TFA IN H, O/CH, CN 10% to 100% 15 min, at a rate of Iml/min for 3,6,7,9,10 and 1 I. BDS Hyp. 3 m C18 4. 6X50mm 0.1% TFA IN H, O/CHCN 10% to 100% 5 min, at a rate of 1ml/min for 4,5,8. HPLC is interface with APCI techniques (Atmospheric Pressure Chemical Ionization).

Desired products are seen as (M+ 1). Compound Retention time mass spec UV (220 nm) A% 53 7.36 & 8.05 625 40 54 4.87 & 5.08 493 66 55 4.58 451 60 56 11.26 & 1.57 697 67 57 6.36 & 6.84 565 59 58 4.86 & 5.03 525 79 59 8.53 605 56 60 10.0 & 10.22 615 48 61 8.05 & 8.88 665 71 EXAMPLE 8 General Solid Phase Synthesis of Compounds of Formula (V) using the Ugi rection and resin (XVIII)

(60mg) of resin (XVIII) is pre-swelled with THF. 0. 5M solutions of the aldehyde (XV) (10 equiv.), N-BOC-amino aldehyde (XXXV) (10 equiv.) and amine (XVI) (10 equiv.) in THF: MeOH :(1 1) are added sequentially to the resin (XVIII) and the rection stirred in methanol at room temperature and the solvent evaporated at 65°C (using a SAVANT# evaporator for 2 hours). The resin is washed sequentially with CH, C12, THF, DMF, THF and MeOH dried under high vacuum to yield the resin bound Ugi product (XXXVI). The deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane. Cyclization is then effected by base treatment with a 5% solution of diethylamine in dichloroethane [Note: 10-15 iiig of N, N- (diisopropyl) amino-methylpolystyrene (PS-DIEA) is an excellent resin bound alternative to diethylamine]. Solvents are then evaporated at 65°C to afford the cyclized products. Examples of products synthesized using this general methodology are indicated below. Lc/ms (liquid charomatography/mass spectrometry) analysais is performed usina a C 18 Hypersil BDS 3 m 4.6X50mm column (UV 220 nm) with a mobile phase 0.1% TFA IN H2O/CH3CN 10% to 100% 15 min, at a rate of 1ml/min for 62. Hypersil BDS 3 m C18 4.6X50mm 0.1% TFA IN H2O/CH3CN 10% to 100% 5 min, at a rate of lml/min for 63 to 72. HPLC is interface with APCI techniques (Atmospheric Pressure Chemical Ionization). Desired products are seen as (M+ 1). Compound Retention mass spec Compound Retention mass time time spec 62 4.88 402 68 10. 75 492 63 4.34 386 69 15.79 476 64 4.30 328 70 16.59 432 65 3.33 405 71 11.22 495 66 3.47 338 72 16.86 454 67 4.56 364

Example 9 General Solution Phase Senthesis of 1, 4-benzodiazepine-2, 5-dione Compound of Formula (VI) via the 3-step one pot'procedure. emPloving the Ugi multi-component reaction: Equal amounts (0. lml) of 0.1 M solutions of the four appropriate components, ethyl glyoxalate (XXXVII), compound of formulae (XIV), (XVI) and (IX), are employed generating a theoretical 10 µmol of final 1,4-benzodiazepine-2,5-dione product (VI) for 100% conversion. The 4-component condensation is performed in methanol at room temperature and the solvent evaporated at 65 °C (using a SAVANT# evaporator for 2 hours). The deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane, and heat, to afford the cyclized products. Examples of products (examples 62 to 72) synthesized using this general methodology are indicated below and purities are determined by Ic/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A%. Lc/ms (liquid chromatography/mass spectrometry) analysis is performed using a C 18 Hypersil BDS 3 m 4.6X50mm column (UV 220 nm) with a mobile phase 0.1% TFA IN H2O/CH3CN 10% to 100% 5 min, at a rate of 1ml/min. HPLC is interface with APCI techniques (Atmospheric Pressure Chemical Ionization).

Desired products are seen as (M+ 1). Compound Retention mass spec ELSD time A% 73 4.26 419 82 74 4.93 449 83 75 4.10 427 90 76 4.06 405 89 77 3.16 317 39 78 4.00 393 27 79 4.47 411 63 80 4.30 455 60 81 3.97 399 84

Example10 General Solid Phase Svnthesis of Compound of Formula (VII) usine the Uai rection and Resin Bound Amine (XXXIX) Wang bound Fmoc-amino acids (XXXIX) (100mg : loading of 0. 70mmol/g) are treated with 20% piperidine in DMF (I ml) at room temperature for one hour and washed with DMF (x3) and CH2CI2 (. x3). To To each rection vessel containing (XXXIX) is added 0.8 mi of CH, C'2, followed by 0.1 M solutions in MeOH of aldehydes (XV) (5 equiv.), isonitriles (IX) (5 equiv.) and anthranilic acid (XIV) (5 equiv.). The rections are shaken overnight at room temperature and washed with methanol (x3) and CHZCl2 (ac3). Each resin is then treated with 10% TFA in CH2C12 at room temperature for 3 hours (1.3 ml), then washed with CHOC1, (x2). The samples are then evaporated in a SAVANT at room temperature for 3 hours to give the crude products. Examples of products (examples 82 to 93) synthesized using this general methodology are indicated below and purities are determined by Ic/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A%. Lc/ms (liquid chromatography/mass spectrometry) analysis is perfonned using a C 18 Hypersil BDS 3 in 4. 6X50mm column (UV 220 nm) with a mobile phase 0.1% TFA IN H2O/CH3CN 20% to 100% 20 min, at a rate of 1ml/min. HPLC is interface with APCI techniques (Atmospheric Pressure Chemical Ionization).

Desired products are seen as (M+ 1).

The following specific procedure is followed for compound 82 :- Wang bound Fmoc-Phenylalanine (100mg : loading of 0.70mmol/g) is treated with 20% piperidine in DMF (I m I) at room temperature for one hour and washed with DMF (x3) and CH2Cl2(x3).

To each rection vessel is added 0.8 ml of CH2CI2, followed by O. 1M solutions in MeOH of phenpropionaldehyde (46p1,5 equiv.), benzyl isocyanide (43 µl, 5 equiv.) and N-BOC anthranilic acid (83mg, 5 equiv.). The rections are shaken overnight at room temperature and washed with methanol (x3) and CH2Cl2(x3). Each resin is then treated with 10% TFA in CH, CL, at room temperature for 3 hours (1.3 ml), then washed with CH2C12 (x2). The sample is then evaporated in a SAVANT at room

temperature for 3 hours to give 20mg of crude product. Compound Retention time Mass spec ELSD A% 82 10.45 517 70 83 8.68 & 9.18 455 95 84 8.24 & 9.08 433 97 85 4.90 & 5.40 345 95 86 8.31 & 9.51 509 50 87 10.88 & 11.25 497 100 88 9.58 & 10.08 503 95 89 7.14 & 7.37 407 41 90 4.07 & 5.14 453 44 91 11.88 & 12.28 441 44 92 6.54 & 6.77 490 100 93 9.38 & 10.35 481 100

Example11 General Solid Phase Svnthesis of Acids bY HYdroxide Clipping of Resin Bound Safety Catch Linker (IXa) (60mg) of resin (luxa) is pre-swelled with THF. 0. 5M solutions of the aldehyde (XV) (10 equiv.), amine (2- (5-imidazole) ethylamine or 3- (lpyrrolidine) propylamine) (10 equiv.) and carboxylic acid (XXVI) (10 equiv.) in THF: MeOH (1: 1) are added sequentially to the resin (luxa) and the rection stirred at room temperature for 3 days. The resin is washed sequentially with CH2CI2, THF, DMF, THF and MeOH dried under high vacuum to yield the resin bound Ugi products. Treatment with BOC2O (10 equiv.), Et3N (10 equiv.) and DMAP in CHZCIz (1 S hours) afford the activated the resin bound product.

Sodium hydroxide (smog) in THF: H, O, 1: 1, is added to the resin and shaken for 20 hours. The solvent is evaporated in vacuo to afford the desired acid, where lc/ms (liquid chromatography/mass spectrometry) A% purities are judged by ELSD (evaporative light scattering detector) A%. Lc/ms analysis is performed using a Hypersil BDS 3µ C18 4.6X50mm 0.1% TFA in H2O/CH3N 5% to 100% CH3N 5 min, at a rate of 1ml/min. Desired products are seen as (M+ 1). Examples of acids synthesized using this general methodology are: Compound Retention mass ELSD time spec A% 94 4.80 485 100 95 4Z3 484 89

Example 12 General Solution Phase Svnthesis of Diketopiperazine Compound of Formula (VI) via the'3-ster), one pot'procedure, employing the Ugi multi-component rection: Equal amounts (0.1 ml) of 0.1 M solutions of the four appropriate components compound of formulae (XIV), (XXXVII), (XVI) and (IX), are employed generating a theoretical 10, umol of final I Diketopiperazine product (VI) for 100% conversion. The 4-component condensation is performed in methanol at room temperature and the solvent evaporated at 65°C (using a SAVANIe evaporator for 2 hours). The deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane, and heat, to afford the cyclized products. Examples of products (examples 96 to 112) synthesized using this general methodology are indicated below and purities are determined by lc/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A% and UV A%. Lc/ms analysis is performed using a C18 Hypersil BDS 3 m 4. 6X50mm column (UV 220 nm) with a mobile phase 0. 1% TFA IN H2O/CH3CN 10% to 100% 5 min, at a rate of I ml/min (Examples 96 to 99), or a mobile phase 5mM NH40AC. H, O/CH3CN 10% to 100% 5 min, at a rate of Iml/min (Examples 100 to 112),. HPLC is interface with APCI techniques (Atmospheric Pressure Chemical Ionization). Desired products are seen as (M+ 1). Compound UV (220 nm) ELSD Retention Mass spec A% A% Time (min) 96 80 70 4.33 421 97 75 90 3.80 379 98 81 90 4.27/4.40 419 99 80 90 3.83 379 100 86 100 3.13 303 101 86 100 4.90 495 102 84 100 4.57/4.80 469 103 92 100 433 4.60 104 72 100 329 3.53 105 83 100 357 3.80 106 81 100 475 4.53/4.77 107 82 100 343 3.67 108 88 100 449 4.39/4.49 109 95 70 499 3.89/3.96 110 80 90 3.88/4.22 521 111 70 86 3.78/3.51 476 112 63 84 3.50/3/63 538

Example 13 General Solution Phase Synthesis of Ketopiperazine Derivatives of Formula (VIII) via the'2-step, one pot'procedure, emploving the Ugi multi-component rection: Equal amounts (0. 1ml) of 0.1 M solutions of the four appropriate components compound of formulae (XXVI), (XXXVII), (XXVIIa) and (IX) are employed generating a theoretical 10 gmol of final product (VIII) for 100% conversion. The 4-component condensation is performed in methanol at room temperature followed by increased heating, to afford the cyclized products. Examples of products (examples 113 to 122) synthesized using this general methodology are indicated below and purities are determined by lc/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A% and UV A%. Lc/ms analysis is performed using a C 18 Hypersil BDS 3 m 4.6X50mm column (UV 220 nm) with a mobile phase 0.1% TFA IN H, O/CH3CN 10% to 100% 5 min, at a rate of I ml/min. HPLC is interface with APCI techniques (Atmospheric Pressure Chemical Ionization).

Desired products are seen as (M+ 1). Compound UV (220 nm) ELSD Mass spec Retention A% A% Time (min) 114 41% 90% 427 4.17 115 43% 97% 331 3.53 116 35% 96% 303 2.90 117 32% 94% 349 3.97 118 cis 41% 90% 481 4.60 118 trans 70% 99% 481 4.63 119 cis 43% 97% 385 3.36/3.83 119 trans 47% 100% 385 4.09 120 cis 35% 96% 357 3.36/3.46 120 trans 34% 100% 357 3.63 121 cis 32% 94% 403 4.37/4.54 121 trans 57% 100% 403 4.67 100%3513.2912275%

Example 14 General Solution Phase Synthesis of Ketopiperazine Derivatives of Formula (VIII) via the'3-step ! one pot'erocedureemplovin the Ugi multi-component rection: Equal amounts (0.1 ml) of 0.1 M solutions of the four appropriate components, compound of formulae (XXVI), (XXXVII), (XXVII) and (IX), are employed generating a theoretical 10 gmol of final Ketopiperazine product (VIII) for 100% conversion. The 4-component condensation is performed in methanol at room temperature and the solvent evaporated at 65 OC (using a SAVANTe evaporator for 2 hours). The deprotection/cyclization steps are performed using the intermediate (XLI) and either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane, and heat. to afford the acyclic products. MP-carbonate (3 equiv.) in dichloroethane (0. 4ml) is added to the crude product and stirred overnight. The resin is filtered and washed with dichloroethane and then the filtrate is evaporated at 65oC for 2 hours. Examples of products (examples 123 to 129) synthesized using this general methodology are indicated below and purities are determined by @c/ms (liquid

chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A% and UV A%..

Lc/ms analysis is performed using a C 18 Hypersil BDS 3 ni 6X50mm column4. (UV 220 nm) with a mobile phase :- 0.1% AQ/ACN 10% to 100%, 5 min. (Compounds 123 and 124); 0.1% AQ/ACN 0% to 100%, 10min (compound 125-128). HPLC is interface with APCI techniques (Atmospheric Pressure Chemical Ionization). Desired products are seen as (M+ 1). Compound UV (220 nm) ELSD Mass spec Retention A% A% Time (min) 123 85 100 379 4.05 124 46 78 441 4.30 125 50 77 379 3.82 126 52 31 447 4.84 127 94 100 517 4.93 128 62 79 441 4.37

Example 15 General Solution Phase Svnthesis of Dihydroquinoxalinone Derivatives of Formula (VIII) via the 3- stem one pot'procedureemplovintheUimulti-component rection: Equal amounts (0.1 ml) of 0.1 M solutions of the four appropriate components, compound of formulae (XXVI), (XXXVII), (XXVII) and (IX), are employed generating a theoretical 10 Fmol of final Dihydroquinoxalinone product (VIII) for 100% conversion. The 4-component condensation is

performed in methanol at room temperature and the solvent evaporated at 65 °C (using a SAVANT ! ; evaporator for 2 hours). The deprotection/cyclization steps are performed using either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane, and heat, to afford the cyclized products. Examples of products synthesized and further examples of other products which could be formed using this general methodology are indicated below. Examples of products (examples 129 to 131) synthesized usine this general methodology are indicated below and purities are determined by Ic/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A% and UV A%. Lc/ms analysis is performed using a C18 Hypersil BDS 3 m 4.6X50mm column (UV 220 nm) with a mobile 0.1% AQ/ACN 0% to 100%, 5 min. HPLC is interface with APCI techniques (Atmospl1eric Pressure Chemical Ionization). Desired products are seen as (M+ 1). Compound UV (220 nm) ELSD Mass spec Retention A% A% Time (min) 129 30 28 467 5.17 130 40 43 367 3.03 131 30 20 405 4.04

Example16 General Solid Phase Svnthesis of Ketopiperazine Derivatives of Formula (XLII) via the '3-step, one pot' procedureemplovina the Ugi multi-component reaction : Wanc, bound Fmoc-amino acids (XXXIX) (100mg : loading of 0.70mmol/g) is treated with 20% piperidine in DMF (I ml) at room temperature for one hour and wasled with DMF (x3) and CH2CI2 (x3).

Equal amounts (0. 1 ml) of 0.1 M solutions of the four appropriate components, compound of formulae (XXVI), (XXXIX), (XLIII) and (IX), are employed generating a theoretical 10 µmol of final Ketopiperazine product (XLII) for 100% conversion. The 4-component condensation is performed in methanol at room temperature and the solvent evaporated at 65 °C (using a SAVANT*8 evaporator for 2 hours). The deprotection/cyclization steps are performed using the intermediate (XLIX) and either a 10% solution of acetyl chloride in methanol, or a 10% solution of trifluoroacetic acid in dichloroethane, and heat, to afford the cyclized products. Examples of products synthesized using this general methodology are indicated below. Examples of products (examples 1') 2 to 139) synthesized using this general methodology are indicated below and purities are determined by lc/ms (liquid chromatography/mass spectrometry) ELSD (evaporative light scattering detector) A% and UV A%. Lc/ms analysis is performed using a C I 8 Hypersil Bd 3 m 4. 6X50mm column (UV 220 nm) with a mobile phase :- 0.1% AQ/ACN 10% to 100%, 5 min. HPLC is interface with APCI techniques (Atmospheric Pressure Chemical Ionization). Desired products are seen as (M+ 1). Compound UV (220 nm) A% ELSD Mass Spec Retention A% Time (Min) 132 57 67 607 10.14 133 48 54 621 10.35/10.78 134 62 77 573 10.15 135 59 72 523 9.54 136 29 33 675 11.47 137 37 33 573 10.21 138 47 48 613 11.07 139 30 33 635 10.81

The present invention may be embodied in other specific forms without departing from the spirit or essential attributs thereof.