COMBINATORIAL PROCESS FOR PREPARING SUBSTITUTED INDANE LIBRARIES

Abstract: This invention relates to a novel solid phase process for the preparation of indane combinatorial librairies (1). These libraries have use for drug discovery and are used to form wellplate components (3) of novel assay kits, as illustrated in the figure.

Description: TITLE COMBINATORIAL PROCESS FOR PREPARING SUBSTITUTED INDANE LIBRARIES Field of the Invention This invention relates to the preparation of libraries of substituted indane compounds by combinatorial processes. These libraries are useful for discovery of lead compounds for drug development and improved assay kits. Background of the Invention Traditional chemical synthesis for drug discovery is done by individually creating, isolating, and identifying candidate compounds. Companies have long relied on their historical collections of compounds and compound collections from exchange agreements as sources of diverse structures for generating lead pharmaceutical compounds. All of these historical approaches have drawbacks. Corporate collections of compounds may have a certain bias and medicinal chemists using traditional synthetic techniques cannot synthesize hundreds or thousands of diverse compounds to find promising leads. Combinatorial chemistry is a relatively new technique for chemical synthesis. It fills the long felt need for a method to quickly generate highly diverse non-peptide compound libraries. Generally, diverse libraries containing a common scaffold which are substituted with a great variety of substituents. More recently, modern drug discovery has used the methods of combinatorial chemistry to generate large numbers (viz., about 10^ to 10^) of compounds with common scaffolds generically referred to as "libraries." Combinatorial chemistry may be performed in a manner where libraries of compounds are generated as mixtures with complete identification of individual compounds postponed until after positive screening results are obtained. However, a preferred form of combinatorial chemistry is "parallel array synthesis" where individual reaction products (most often individual compounds) are synthesized together, but are retained in separate vessels. For example, the library compounds are held in the individual wells of 96 well microtiter plates. Use of standardized microtiter plates or equivalent apparatus is advantageous because such apparatus is readily manipulated by programmed robotic machinery. Generally, combinatorial chemistry is conducted on a solid phase support, normally a polymer. A selected scaffold is cleavably tethered to the solid support by a chemical linker. Reactions are carried out to modify the scaffold while tethered to the solid support. In a final step, the product is cleaved and released from the solid support. Combinatorial chemistry evidences its utility by commercial success. Millions of dollars have been spent for recent purchases or cooperative associations of major pharmaceutical companies with small companies specializing in combinatorial chemistry (e.g., Glaxo's acquisition of Affymax, Marion Merrell Dow's purchase of Selectide, Proctor & Gamble with Houghten, Astra with Alanex, Pfizer with Oxford Asymmetry, Sandoz with Pharmacopeia, Solvay with Arqule, CIBA with Chiron, and Eli Lilly with Sphinx Pharmaceutical) . To continue exploration of new libraries for pharmaceutical and agricultural lead compounds it is necessary to develop new chemistries which permit chemical novel scaffolds to be functionalized with highly diverse groups. Summary of the Invention This invention is an improved combinatorial process for making a library of indane compounds. This invention is also a combinatorial library of indane compounds. This invention is also a library of intermediate substituted solid supported indane library compounds. This invention is also the individual indane compounds in the indane combinatorial library of the invention. This invention is also a novel wellplate apparatus containing the novel indane library compounds of the invention. This invention is also an assay kit for identification of pharmaceutical lead indane compounds, said kit comprising (i) wellplate apparatus, and (ii) biological assay reagents, said wellplate apparatus having a combinatorial library compound in each well; wherein the improvement comprises using as a wellplate a combinatorial indane wellplate apparatus where each well contains a indane compound prepared by the process of the invention. Brief Description of the Drawing FIG. 1 is a top view of a wellplate apparatus. Detailed Description of the Invention I. Definitions: The following terms have the meaning defined below when used in this specification of the invention: "Assay kit" means an assemblage of two cooperative elements, namely, (i) a wellplate apparatus, and (ii) biological assay materials. "Biological assay materials" are materials necessary to conduct a biological evaluation of the efficacy of any library compound in a screen relevant to a selected disease state. "Directed Library" is a collection of compounds created by a combinatorial chemistry process for the purpose of optimization of the activity of a lead compound, wherein each library compound has a common scaffold, and the library, considered in its entirety, is a collection of closely related homologues or analogs to the lead compound (compare to "Diverse library"). "Diverse library" means a library where the substituents on the combinatorial library scaffold are highly variable in constituent atoms, molecular weight, and structure and the library, considered in its entirety, is not a collection of closely related homologues or analogs (compare to "Directed library") . "Electrophile" means an electron seeking reagent. "Lead compound" means a compound in a selected combinatorial library for which the Assay kit has revealed significant activity relevant to a selected disease state. "Leaving group" means a group capable of substitution by a nucleophile. "Library" is a collection of compounds created by a combinatorial chemical process, said compounds having a common indane scaffold with one or more variable substituents. "Library compound" means an individual reaction product (usually a single compound) in a library produced by the method of the invention. "Parallel array synthesis" means a method of conducting combinatorial chemical synthesis of libraries wherein the individual combinatorial library reaction products are separately prepared and stored without prior or subsequent intentional mixing. "Reaction zone" means the individual vessel location where the combinatorial chemical library compound preparation process of the invention is carried out and individual library compounds synthesized. Suitable reaction zones are the individual wells of a wellplate apparatus. "Scaffold" means the invariant region (viz., indane core) of the compounds which are members of a library. "Simultaneous synthesis" means making of library of compounds within one production cycle of a combinatorial method (not making all library compounds at the same instant in time) . "Solid support" means a functional resin such as a carboxyl functional resin, represented by the symbols, "Substituents" are chemical radicals (excluding hydrogen) which are bonded to the scaffold through the combinatorial synthesis process. The different functional groups account for the diversity of molecules throughout the library and are selected to impart diversity of biological activity to the scaffold in the case of diverse libraries, and optimization of a particular biological activity in the case of directed libraries. "Reagent" means a reactant, any chemical compound used in the combinatorial synthesis to place substituents on the scaffold of a library. "Wellplate apparatus" means a structure capable of holding a plurality of library compounds in dimensionally fixed and defined positions. "Indane" is a synonym for "indan" and is the nucleus represented by the structural formula: II. General description of the indane combinatorial library: The indane library of the invention is preferably a diverse combinatorial library comprising individual substituted indane library compounds represented by the general formula (I) : wherein Ei and E2 are the same or different electrophilic group. The sources for diversity in the indane library compounds of the invention are the groups Ei and E2. The indane library compounds of this invention are non- peptide, substantially non-naturally occurring molecules having a molecular weight range of from about 100 to about 800. Preferred libraries contain indane library compounds wherein; Ei and E2 are the same or different electrophilic groups preferably derived from an electrophilic reagent having a molecular weight of from about 30 to about 600 selected from the group consisting of; organic halides, acyl halides, sulfonic acid esters, organohaloformates, organosulfonyl halides, organic isocyanates, and organic isothiocyanates . Electrophilic groups for Ei and E2 include, but are not limited to C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, Ci- C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C2-C12 alkoxyalkyl, C1-C6 alkylsulfinyl, C1-C10 alkylsulfonyl, - (CH2)m~0- (C1-C10 alkyl) , aryl, substituted aryl, substituted alkoxy, fluoroalkyl, aryloxyalkyl, carbocyclic radical, substituted carbocyclic radical, heterocyclic radical, substituted heterocyclic radical, and nitroalkyl; where m is from 1 to 8. Preferred electrophilic groups Ei and E2 groups derived from electrophilic reagents are independently selected from groups represented by the following structural formulae: A diverse library of indane compounds (compounds diversely substituted at specific sites on an indane scaffold) was created by parallel array synthesis for its general utility in drug candidate screening, agricultural candidate screening, structure activity relationship studies, and/or clinical investigation (as well as other specific utilities described herein) . III. Process of Making the Indane Libraries of the Invention: Combinatorial chemistry may be used at two distinct phases of drug development. In the discovery phase highly diverse libraries are created to find lead compounds. In a second optimization phase, strong lead compounds are much more narrowly modified to find optimal molecular configurations. The method of this invention has applicability for making both diverse libraries of indane compounds useful for finding new lead compounds and directed libraries of indane compounds useful for optimizing a particular desired biological activity. The compounds of formula (I) comprise the products of a multiple component combinatorial parallel array synthesis derived from multiple reactants comprising; a first reactant containing electrophilic group Ei; a second reactant containing electrophilic group E2; and a third reactant having an indane scaffold. Generally, the third reactant remains constant for all compounds prepared in the library. The sole source of diversity for the indane scaffold is the first and second reactants. The electrophilic group containing first and second reactants: Electrophiles react with the amine nitrogen atoms pendant on the indane ring of Formula (I) . Alkylation and acylation reactions are suitable. Electrophilic reactants suitable for use in this step have a molecular weight of from abut 15 to 600 and are selected from organic halides, acyl halides, sulfonic acid esters, organohaloformates, organosulfonylhalides, organic isocyanates, and organic isothiocyanates. Suitable electrophilic reagents for practice of this process step of the invention are set out below: Acyl Halides -- 3,5-bis(trifluoromethyl)benzoyl chloride benzoyl chloride 2-bromobenzoyl chloride 2-fluorobenzoyl chloride pentafluorobenzoyl chloride 2, 4-difluorobenzoyl chloride 2,6-difluorobenzoyl chloride 2-chlorobenzoyl chloride 2,4-dichlorobenzoyl chloride 2, 6-dichlorobenzoyl chloride o-acetylsalicyloyl chloride 2-methoxybenzoyl chloride 2, 6-dimethoxybenzoyl chloride 2-(trifluoromethyl)benzoyl chloride o-toluoyl chloride 3-bromobenzoyl chloride 3-fluorobenzoyl chloride 3-chlorobenzoyl chloride 3,4-dichlorobenzoyl chloride m-anisoyl chloride 3,4-dimethoxybenzoyl chloride 3,4,5-trimethoxybenzoyl chloride 3, 5-dimethoxybenzoyl chloride 3-ethoxybenzoyl chloride isophthaloyl chloride trimesoyl chloride 3- (trifluoromethyl)benzoyl chloride m-toluoyl chloride 3- (chloromethyl) benzoyl chloride 4-bromobenzoyl chloride 4-fluorobenzoyl chloride 4-chlorobenzoyl chloride p-anisoyl chloride 4-ethoxybenzoyl chloride 4-n-butoxybenzoyl chloride 4-n-hexyloxybenzoyl chloride 4-heptyloxybenzoyl chloride 4-biphenylcarbonyl chloride terephthaloyl chloride 4- (trifluoromethyl)benzoyl chloride 4-tert-butylbenzoyl chloride p-toluoyl chloride 4-ethylbenzoyl chloride 4-n-propylbenzoyl chloride 4-butylbenzoyl chloride 4-pentylbenzoyl chloride 4-hexylbenzoyl chloride 4-n-heptylbenzoyl chloride methyl oxalyl chloride ethyl oxalyl chloride heptafluorobutyryl chloride 2-acetoxyisobutyryl chloride pivaloyl chloride 3-chloropivaloyl chloride 2-bromopropionyl chloride 2, 3-dibromopropionyl chloride 2, 3-dichloropropionyl chloride o-acetylmandelic acid chloride itaconyl chloride methacryloyl chloride isobutyryl chloride 2-ethylhexanoyl chloride acetyl chloride bromoacetyl chloride chloroacetyl chloride phenoxyacetyl chloride 4-chlorophenoxyacetyl chloride methoxyacetyl chloride phenylacetyl chloride 3,3-dimethylacryloyl chloride cinnamoyl chloride fumaryl chloride ethyl malonyl chloride tert-butylacetyl chloride isovaleryl chloride undecanoyl chloride lauroyl chloride myristoyl chloride palmitoyl chloride heptadecanoyl chloride stearoyl chloride propionyl chloride 3-bromopropionyl chloride 3-chloropropionyl chloride hydrocinnamoyl chloride succinyl chloride 3-carbomethoxypropionyl chloride ethyl succinyl chloride butyryl chloride 4-bromobutyryl chloride 4-chlorobutyryl chloride valeryl chloride 5-chlorovaleryl chloride adipoyl chloride hexanoyl chloride 6-bromohexanoyl chloride pimeloyl chloride heptanoyl chloride suberoyl chloride octanoyl chloride 10-undecenoyl chloride 2-chloro-2, 2-diphenylacetyl chloride dichloroacetyl chloride alpha-chlorophenylacetyl chloride 2-chloropropionyl chloride 2-iodobenzoyl chloride 4-iodobenzoyl chloride eyelopropanecarbonyl chloride trans-2-phenyl-1-eyelopropanecarbonyl chloride cyclobutanecarbonyl chloride cyclopentanecarbonyl chloride 3-cyclopentylpropionyl chloride cyclohexanecarbonyl chloride 4-cyanobenzoyl chloride 2-furoyl chloride 1-naphthoyl chloride 2-naphthoyl chloride indane-2-carbonyl chloride 2-thiopheneacetyl chloride trimellitic anhydride chloride 2, 6-pyridinedicarboxylic acid chloride 2-quinoxaloyl chloride 2-nitrobenzoyl chloride 3-nitrobenzoyl chloride 3, 5-dinitrobenzoyl chloride 4-nitrobenzoyl chloride 3, 4-dimethoxyphenylacetyl chloride 3-methyladipoyl chloride 3, 5-dichlorobenzoyl chloride 2, 5-difluorobenzoyl chloride 3, 4-difluorobenzoyl chloride 9-fluorenone-4-carbonyl chloride 3, 5-difluorobenzoyl chloride (s) -(-)-n-(trifluoroacetyl)prolyl chloride benzyloxyacetyl chloride acetoxy acetyl chloride 3-cyanobenzoyl chloride 2,5-dimethoxyphenylacetyl chloride 3-methoxyphenylacetyl chloride iminodibenzyl-5-carbonyl chloride 2,4,6-trimethylbenzoyl chloride tetrafluorosuccinyl chloride perfluorooctanoyl chloride diphenylacetyl chloride alpha-methyl valeroyl chloride methyl malonyl chloride ethyl glutaryl chloride 5-bromovaleryl chloride methyl adipyl chloride 3-cyclohexenecarbonyl chloride 3-isocyanato benzoyl chloride 2,4,6-triisopropylbenzoyl chloride fluoroacetyl chloride 2-ethoxybenzoyl chloride piperonyloyl chloride 2,4-dimethoxybenzoyl chloride 2,3,5, 6-tetrachloroterephthaloyl chloride 5-(dimethylsulfamoyl)-2-methoxybenzoyl chloride 2-(4-chlorobenzoyl)benzoyl chloride 2,2-bis(chloromethyl)propionyl chloride cinnamylidenemalonyl chloride 2-phenoxypropionyl chloride 2-phenylbutyryl chloride 2-ethylbutyryl chloride p-tolylacetyl chloride gamma-methylvaleroyl chloride 3,3-dichloropivaloyl chloride 1-methyl-l-cyclohexanecarboxylic acid chloride 2-(2,4,5-trichlorophenoxy)acetyl chloride 4-chloro-3-nitrobenzoyl chloride 4-methyl-3-nitrobenzoyl chloride 2,3-dichlorobenzoyl chloride morpholine-4-carbonyl chloride p-chlorophenylacetyl chloride bicyclo[2.2.l]heptane- -carbonyl chloride d(-)-alpha-formyloxy-alpha-phenylacetyl chloride d(-)-alpha-phenylglycine chloride hydrochloride trifluoroacetyl chloride pentafluoropropionyl chloride hexafluoroglutaryl chloride 2-chlorocinnamoyl chloride o-methoxycinnamyl chloride 5-nitro-2-furoyl chloride 2-chlorobutyryl chloride 4-phenylazobenzoyl chloride 4-n-aιrtyloxybenzoyl chloride 4-decylbenzoyl chloride 4-octylbenzoyl chloride dl-2-methylbutyryl chloride linolenoyl chloride linolelaidoyl chloride llh-eicosafluoroundecanoyl chloride 9h-hexadecafluorononanoyl chloride 2,3-difluorobenzoyl chloride 2-(benzoyloxymethyl)benzoyl chloride 2,2-dimethylvaleroyl chloride 3,5,5-trimethylhexanoyl chloride phenothiazine-10-carbonyl chloride 3,4-dimethyl benzoyl chloride (+)-p-(2-methylbutyl)benzoyl chloride 2,4-dichlorophenoxyacetic chloride pe tadecanoyl chloride nonadecanoyl chloride neoheptanoyl chloride 9-anthracenecarbonyl chloride 2-ethoxy-1-naphthoyl chloride indane carbonyl chloride m- (chlorosulfonyl)benzoyl chloride 2-n-propyl-n-valeroyl chloride 2-chloro-4-nitrobenzoyl chloride 2-phenoxybutyryl chloride 2-chloronicotinyl chloride 6-chloronicotinyl chloride 4- (trifluoromethoxy)benzoyl chloride 2- (trifluoromethoxy) enzoyl chloride 2, 6-dichloropyridine-4-carbonyl chloride 3-chlorobenzo[b]indane-2-carbonyl chloride 4-chloromethylbenzoyl chloride neodecanoyl chloride (phenylthio)acetyl chloride 4-carbethoxyhexafluorobutyryl chloride octafluoroadipoyl chloride 2-diazo-3,3, 3-trifluoropropionylchloride 2-bromobutyryl chloride arachidoyl chloride cis-vaccenoyl chloride 11-eicosenoyl chloride behenoyl chloride petroselinoyl chloride palmitoleoyl chloride tridecanoyl chloride 2-chloro-5-nitrobenzoyl chloride 3-methylthiopropionyl chloride methyl 4-chlorocarbonylbenzoate anthraquinone-2-carbonyl chloride carbazole-n-carbonyl chloride 2-nitrophenoxyacetyl chloride 2-bromo-2-methylpropionyl chloride 2-fluoro-3- (trifluoromethyl)benzoyl chloride 2-fluoro-4- (trifluoromethyl)benzoyl chloride 2-fluoro-5- (trifluoromethyl)benzoyl chloride 3-fluoro-5- (trifluoromethyl)benzoyl chloride 4-fluoro-2- (trifluoromethyl)benzoyl chloride 4-fluoro-3- (trifluoromethyl)benzoyl chloride 2-fluoro-6-(trifluoromethyl)benzoyl chloride 2,3, 6-trifluorobenzoyl chloride 2,4, 5-trifluorobenzoyl chloride 2, 4-di(trifluoromethyl)benzoyl chloride 2, 6-di (trifluoromethyl)benzoyl chloride 3- (trifluoromethoxy)benzoyl chloride m- (fluorosulfonyl)benzoyl chloride trans-1, 2-cyclobutanedicarboxylic acid chloride 3-cyclohexylpro ionyl chloride 4-ethyl-2,3-dioxo-l-piperazinecarbonylchloride isoxazole-5-carbonyl chloride bromodifluoroacetyl chloride erucoyl chloride 2, 4, 6-trifluorobenzoyl chloride dichlorochrysanthemic acid chloride isononanoyl chloride 1-adamantanecarbonyl chloride 2, 5-bis (trifluoromethyl)benzoyl chloride 2, 3, 4-trifluorobenzoyl chloride 2,3,4, 5-tetrafluorobenzoyl chloride 2,4,6-trichlorobenzoyl chloride 2, 4-dichloro-5-fluorobenzoyl chloride 4-methoxyphenylacetyl chloride trans-3- (trifluoromethyl) cinnamoyl chloride 3- (dichioromethyl) benzoyl chloride 4-isocyanato benzoyl chloride heneicosanoyl chloride 2-chloroisobutyryl chloride trans-4-nitrocinnamoyl chloride 3, 4, 5-trifluorobenzoyl chloride 5-fluoro-2- (trifluoromethyl)benzoyl chloride 2, 3, 5-trifluorobenzoyl chloride 2-chloro-4-fluorobenzoyl chloride (-) -alpha-chlorophenylacetyl chloride 2- (para-tolylsulfonyl)acetyl chloride 4-methyl-4-nitrohexanoyl chloride l-chloro-4-fluorosulfonyl-2-naphthoyl chloride 2,3-dibromo-3-phenylpropionyl chloride 2-menthoxyacetyl chloride 2-phenyl-2- (phenylsulfonyl)acetyl chloride 4, 4, 4-trifluorocrotonyl chloride 4,4,4-trifluorobutyryl chloride 3, 4-dichloro-2, 5-thiophenedicarbonyl chloride pentachlorobenzoyl chloride 4, 4,7,7-tetranitrosebacoyl chloride alpha,alpha' -dimethylsuccinyl chloride alpha-bromoisovaleryl chloride benzoyl chloride oleoyl chloride methyl suberyl chloride gamma-linolenoyl chloride (-) -camphanic acid chloride 4,4' -stilbenedicarbonyl chloride chlorinated benzoyl chloride (lr) -(+) -camphanic chloride 2- (4-nitrophenoxy) tetradecanoyl chloride 7- [ (chlorocarbonyl)methoxy] -4-methylcoumarin n,n-bis (2-chloroethyl)carbamoyl chloride (s) - (-)-2-acetoxypropionyl chloride linoleoyl chloride 3-chlorotetrafluoropropionyl chloride 3, 4-dichloropentafluorobutyryl chloride 7h-dodecafluoroheptanoyl chloride 5h-octafluoropentanoyl chloride perfluorononanoyl chloride 3h-tetrafluoropropionyl chloride 2-bromo-2,3,3,3-tetrafluoropropanoyl chloride arachidonoyl chloride pentachloropropionyl chloride 4-decenoyl chloride tridecafluoroheptanoyl chloride undecafluorocyclohexanecarbonyl chloride 4-n-nonylbenzoyl chloride 3- (trichlorogermyl)propionylchloride 3,4, 5-triiodobenzoyl chloride 2- (phenylthio)propionyl chloride 2,2,2-triphenylacetyl chloride d(-) -alpha-azido-phenyl acetyl chloride 4-azido-benzoyl chloride difluoroacetyl chloride 5-chloropyrazine-2-carbonyl chloride n- (1-naphthalenesulfonyl) -1-phenylalanyl chloride n- (4-nitrophenylsulfonyl) -1-phenylalanyl chloride n- (p-toluenesulfonyl) -1-phenylalanyl chloride dimethylmalonyl chloride methyl sebacoyl chloride 2, 5-dichloropyridine-3-carbonyl chloride 3- (2, 5 xylyloxy) propionyl chloride. Organic Halides — benzyl bromide alpha-bromo-o-xylene alpha-bromo-m-xylene 4- (tert-butyl)benzyl bromide alpha-bromo-p-xy1ene tert-butyl bromoacetate methyl bromoacetate benzyl bromoacetate ethyl bromoacetate 2-bromoacetophenone 2-bromo-2 ' -methoxyacetophenone 2-bromo-2 ' , 4 '-dimethoxyacetophenone 2-bromo-2 ' , 5 ' -dimethoxyacetophenone 3-methoxyphenacyl bromide 2-bromo- ' -methoxyacetophenone 2-bromo-4 ' -phenylacetophenone 2-bromo-4 ' -methylacetophenone ethyl bromopyruvate 1-bromopinacolone l-bromo-2-butanone l-bromo-2,2-dimethoxypropane 1-bromo-2,2-dimethylpropane bromoacetaldehyde dimethyl acetal bromoacetaldehyde diethyl acetal l-bromo-2-methylpropane l-bromo-2-ethylbutane 2-ethylhexyl bromide 1-bromodecane 1-bromoundecane 2-bromoacetamide iodoacetamide 4-(bromomethyl)phenylacetic acid phenacyl ester isopropyl bromoacetate 5-bromo-2-methyl-2-pentene 3,4-difluorobenzyl bromide 2,5-difluorobenzyl bromide 3,5-bis(trifluoromethyl)benzyl bromide 2-bromo-2 '-nitroacetophenone 3,5-difluorobenzyl bromide 2,4-bis(trifluoromethyl)benzyl bromide 8-bromo-l-octanol 4-(bromomethyl)phenylacetic acid methyl (r)-(+)-3-bromo-2-methylpropionate 4-iodobutyl acetate 7-acetoxy-4-bromomethylcoumarin 4-bromomethyl-6,7-dimethoxycoumarin 2,4-difluorobenzyl bromide methyl 2-(bromomethyl)acrylate 3-bromopropionaldehyde dimethyl acetal (r)-(-)-3-bromo-2-methyl-1-propanol Sulfonic Acid Esters -- ethyl trifluoromethanesulfonate 2,2,2-trifluoroethyl p-toluenesulfonate 2-chloroethyl-p-toluenesulfonate 1,3-propane sultone 5'-tosyladenosine 1, 4-butane sultone cyanomethyl benzenesulfonate hexadecyl methanesulfonate ethyl methanesulfonate 2-chloroethyl methanesulfonate ethyl p-toluenesulfonate trans-2-hydroxycyclohexyl p-toluenesulfonate (2r) -(-) -glycidyl tosylate (s) - (+) -2-methylbutyl methanesulfonate (s) - (+) -2-methylbutyl p-toluenesulfonate (s) - (+) -1-phenyl-l,2-ethanediol 2-tosylate (2r) - (-) -glycidyl 3-nitrobenzenesulfonate propargyl benzenesulfonate 2, 2-dimethyl-l,3-dioxolan-4-ylmethyl p-toluenesulfonate (r) - (-)-2,2-dimethyl-l, 3-dioxolan-4-ylmethyl p- toluenesulfonate (s) - (+) -2,2-dimethyl-l,3-dioxolan-4-ylmethyl p- toluenesulfonate 1,2:5, 6-di-o-isopropylidene-3-o- (methylsulfonyl) -alpha- d-glucofuranose ethyl 1-2- ( (methylsulfonyl) oxy)propionate (2s) -(+) -glycidyl tosylate (2s) - (+) -glycidyl 3-nitrobenzenesulfonate 3-o-acetyl-6-o-benzoyl-5-o- (methylsulfonyl) -1, 2-o- isopropylidene-alpha-d-glucofu (r) - (-) -1-benzyloxy-3- (p-tosyloxy) -2-propanol (s) - (+) -1-benzyloxy-3- (p-tosyloxy) -2-propanol ethyl 1-2- ( (trifluoromethylsulfonyl)oxy)propionate 2- (2-chloroethoxy) ethyl methanesulfonate 1-cyanoethyl p-toluenesulfonate Organohaloformates 9-fluorenyImethy1 chloroformate phenyl chloroformate 4-chlorophenyl chloroformate methyl chloroformate benzyl chloroformate vinyl chloroformate isobutyl chloroformate 2-ethylhexyl chloroformate ethyl chloroformate 2-bromoethyl chloroformate 2-chloroethyl chloroformate 1-chloroethyl chloroformate allyl chloroformate n-propyl chloroformate butyl chloroformate n-hexyl chloroformate octyl chloroformate 2,2,2-trichloro-l, 1-dimethylethyl chloroformate 2,2,2-trichloroethyl chloroformate cholesteryl chloroformate 4-nitrophenyl chloroformate 4-nitrobenzyl chloroformate (-)-menthyl chloroformate 4-t-butylcyclohexyl chloroformate cetyl chloroformate (+)-1-(9-fluorenyl)ethyl chloroformate isopropyl chloroformate 3-chlorocyclohexyl chloroformate decyl chloroformate oleyl chloroformate octadecyl chloroformate butenediol bischloroformate 2-chlorobenzyl chloroformate 4-chlorobutyl chloroformate (+)-menthyl chloroformate 4,5-dimethoxy-2-nitrobenzyl chloroformate cyclopentyl chloroformate t-butylcyclohexyl chloroformate menthylchloroformate p-tolyl chloroformate 4-bromophenyl chloroformate 4-fluorophenyl chloroformate 4-methoxyphenyl chloroformate 2-nitrophenyl chloroformate 4-methoxycarbonylphenyl chloroformate l-chloro-2-methylpropyl chloroformate (+/-) -1,2,2,2-tetrachloroethyl chloroformate 2, 2-dichloroethyl chloroformate myristyl chloroformate cyclohexyl chloroformate chloromethyl chloroformate. Organosulfonylhalides — 1-naphthalenesulfonyl chloride dansyl chloride 2-naphthalenesulfonyl chloride 2-acetamido-4-methyl-5-thiazolesulfonyl chloride 2-thiophenesulfonyl chloride 8-quinolinesulfonyl chloride benzenesulfonyl chloride pentafluorobenzenesulfonyl chloride 2, 5-dichlorobenzenesulfonyl chloride 2-nitrobenzenesulfonyl chloride 2, 4-dinitrobenzenesulfonyl chloride 3, 5-dichloro-2-hydroxybenzenesulfonyl chloride 2,4, 6-triisopropylbenzenesulfonyl chloride 2-mesitylenesulfonyl chloride 3-nitrobenzenesulfonyl chloride p-bromobenzenesulfonyl chloride 4-fluorobenzenesulfonyl chloride 4-chlorobenzenesulfonyl chloride 4-chloro-3-nitrobenzenesulfonyl chloride pipsyl chloride 4-nitrobenzenesulfonyl chloride 4-methoxybenzenesulfonyl chloride 4-tert-butylbenzenesulfonyl chloride p-toluenesulfonyl chloride trifluoromethanesulfonyl chloride trichloromethanesulfony1 chloride isopropylsulfonyl chloride methanesulfonyl chloride alpha-toluenesulfonyl chloride trans-beta-styrenesulfonyl chloride 2,2,2-trifluoroethanesulfonyl chloride 1-hexadecanesulfonyl chloride ethanesulfonyl chloride 2-chloroethanesulfonyl chloride 1-propanesulfonyl chloride 3-chloropropanesulfonyl chloride 1-butanesulfonyl chloride methyl 2-(chlorosulfonyl)benzoate 2-nitro-4-(trifluoromethyl)benzenesulfonyl chloride 3-(trifluoromethyl)benzenesulfonyl chloride 1-octanesulfonyl chloride 4- (trifluoromethoxy)benzenesulphonyl chloride (lr)-(-)-10-camphorsulfonyl chloride d- (+) -10-camphorsulfonyl chloride (+/-) -10-camphorsulfonyl chloride 2-nitro-alpha-toluenesulfonyl chloride. Isocyanate Reagents -- trans-2-phenylcyclopropyl isocyanate phenyl isocyanate 2-bromophenyl isocyanate 2-fluorophenyl isocyanate 2,4-difluorophenyl isocyanate 2, 6-difluorophenyl isocyanate 2-chlorophenyl isocyanate 2,3-dichlorophenyl isocyanate 2, -dichlorophenyl isocyanate 2, 5-dichlorophenyl isocyanate 2,6-dichlorophenyl isocyanate 2-methoxyphenyl isocyanate 2, -dimethoxyphenyl isocyanate 2,5-dimethoxyphenyl isocyanate 2-ethoxyphenyl isocyanate 2- (trifluoromethyl)phenyl isocyanate o-tolyl isocyanate 2, 6-dimethylphenyl isocyanate 2-ethylphenyl isocyanate 3-bromophenyl isocyanate 3-fluorophenyl isocyanate 3-chlorophenyl isocyanate 3, 4-dichlorophenyl isocyanate 3-methoxyphenyl isocyanate 3- (trifluoromethyl)phenyl isocyanate m-tolyl isocyanate 4-bromophenyl isocyanate 4-fluorophenyl isocyanate 4-chlorophenyl isocyanate 4-methoxyphenyl isocyanate ethyl 4-isocyanatobenzoate 4- (trifluoromethyl)phenyl isocyanate p-tolyl isocyanate n- (chlorocarbonyl) isocyanate benzoyl isocyanate tert-butyl isocyanate (s) - {-) -alpha-methylbenzyl isocyanate isopropyl isocyanate methyl isocyanate ethyl isocyanatoacetate octadecyl isocyanate ethyl isocyanate 2-chloroethyl isocyanate allyl isocyanate n-propyl isocyanate butyl isocyanate cyclohexyl isocyanate 1-naphthyl isocyanate (r) - (-)-1- (1-naphthyl)ethyl isocyanate 4-fluoro-3-nitrophenyl isocyanate 2-nitrophenyl isocyanate 3-nitrophenyl isocyanate 4-nitrophenyl isocyanate 2, 6-diisopropylpheny1 isocyanate benzyl isocyanate 3-chloropropyl isocyanate ethoxycarbonyl isocyanate 3, 5-bis (trifluoromethyl)phenyl isocyanate 2,4, 6-tribromophenyl isocyanate 2, 5-difluorophenyl isocyanate 2,4, 5-trichlorophenyl isocyanate 2, 4, 6-trichlorophenyl isocyanate 2-methoxycarbonylphenyl isocyanate 2-ethoxycarbonylphenyl isocyanate 2-isopropylphenyl isocyanate 2,3-dimethylphenyl isocyanate 4-methoxy-2-methylphenyl isocyanate 2, 4-dimethylpheny1 isocyanate 2, 5-dimethylphenyl isocyanate 2-ethyl-6-methylphenyl isocyanate 3-cyanophenyl isocyanate 5-chloro-2, 4-dimethoxyphenyl isocyanate 3-chloro-4-methylphenyl isocyanate 3, 5-dichlorophenyl isocyanate 5-chloro-2-methoxyphenyl isocyanate 3,4, 5-trimethoxyphenyl isocyanate 3, 5-dimethoxyphenyl isocyanate 3- (methylthio)phenyl isocyanate 3-ethoxycarbonylpheny1 isocyanate 3-acetylphenyl isocyanate 3, 4-dime hylphenyl isocyanate 3, 5-dimethylphenyl isocyanate 2-methoxy-5-methylphenyl isocyanate 3-ethylphenyl isocyanate 4-chloro-2-methoxyphenyl isocyanate 4-chloro-2-trifluoromethylphenyl isocyanate 4-chloro-3-trifluoromethylphenyl isocyanate 4-iodophenyl isocyanate 4-phenoxypheny1 isocyanate 4-ethoxyphenyl isocyanate 4- (methylthio)phenyl isocyanate 4-acetylphenyl isocyanate 4-isopropylphenyl isocyanate 4-ethylphenyl isocyanate 4-n-butylphenyl isocyanate 3- (dichloromethylsilyl)propyl isocyanate octyl isocyanate 4-methyl-3-nitrophenyl isocyanate 4-chloro-2-nitrophenyl isocyanate 2-methyl-4-nitrophenyl isocyanate 4-methyl-2-nitrophenyl isocyanate 2-fluoro-5-nitrophenyl isocyanate 2-methyl-5-nitrophenyl isocyanate 3-bromopropyl isocyanate 2,4, 6-trimethylpheny1 isocyanate 2-isopropyl-6-methylphenyl isocyanate 2, 6-diethylphenyl isocyanate 5-chloro-2-methylphenyl isocyanate 4-chloro-2-methylphenyl isocyanate 4- (trifluoromethoxy)phenyl isocyanate 4-trifluoromethylthiophenylisocyanate 2, 4-dibromophenyl isocyanate 2, 6-dibromo-4-ethylphenyl isocyanate 2, 3,4,5-tetrachlorophenyl isocyanate 2-chloro-5-trifluoromethylpheny1 isocyanate 2-chloro-6-methylphenyl isocyanate 2-n-carbobutoxyphenyl isocyanate 2,4, 5-trimethylphenyl isocyanate 2-methyl-6- (t-butyl)phenyl isocyanate 2-ethyl-6-isopropylphenyl isocyanate 3-chloro-2-methoxyphenyl isocyanate 3-chloro-2-methylphenyl isocyanate 3-chloro-4-fluorophenyl isocyanate 4-cyanophenyl isocyanate 4-bromo-2-methylphenyl isocyanate 4-bromo-2, 6-dimethylphenyl isocyanate 2, 6-dibromo-4-fluorophenyl isocyanate 4-n-butoxyphenyl isocyanate 4-butoxycarbonylphenyl isocyanate phenethyl isocyanate 2-methyl-3-nitrophenyl isocyanate hexyl isocyanate hexadecyl isocyanate methylene bis (o-chlorophenyl isocyanate) 4-chloro-3-nitrophenyl isocyanate 2-chloro-4-nitrophenyl isocyanate 4, 5-dimethyl-2-nitrophenyl isocyanate 2-chloro-5-nitrophenyl isocyanate 2-methoxy-4-nitrophenyl isocyanate 3-fluoro-4-methylphenyl isocyanate 5-fluoro-2-methylphenyl isocyanate 3, 5-dicarbomethoxyphenyl isocyanate 2,4-dichlorobenzyl isocyanate 2- (methylthio)phenyl isocyanate n- (methoxycarbonyl) isocyanate n- (phenoxycarbonyl) isocyanate 2-biphenylyl isocyanate 3-iodophenyl isocyanate 4-phenylphenyl isocyanate tetrahydro-2-pyranyl isocyanate 4- (tert-butyl)phenylisocyanate 1- (4-bromophenyl)ethyl isocyanate isocyanatoacetic acid n-butyl ester dodecyl isocyanate 6,7-methylenedioxy-4-isocyanate-methylcoumarin (r) - (+) -alpha-methylbenzyl isocyanate (+/-) -1- (1-naphthyl)ethyl isocyanate (s) - (+)-1- (1-naphthyl)ethyl isocyanate 3, 4-difluorophenyl isocyanate 2-methoxy-5-nitrophenyl isocyanate undecyl isocyanate ethyl 2-isocyanato-4-methyl valerate ethyl 6-isocyanatohexanoate ethyl 2-isocyanato-4-methylthiobutyrate ethyl 2-isocyanatopropionate ethyl 3-isocyanatopropionate ethyl 2-isocyanato-3-methylbutyrate tert-butyl 3-isothiocyanatopropionate ethyl 2-isocyanato-3-phenylpropionate 1, 3-bis (isocyanatomethyl)cyclohexane 2- (trifluoromethoxy)phenyl isocyanate 4- (chloromethyl) phenyl isocyanate 1-adamantyl isocyanate 1, 3-bis(2-isocyanato-2-propyl)benzene n-amyl isocyanate n-heptyl isocyanate 2-chloroethyl isocyanate, [ethyl-1, 2-14c] 1, 1, 3, 3-tetramethylbutyl isocyanate 3, 5-dinitrophenyl isocyanate Organic Isothiocyanates — cyclohexyl isothiocyanate 1-naphthyl isothiocyanate trimethylsilyl isothiocyanate phenyl isothiocyanate 2-bromophenyl isothiocyanate 2-fluorophenyl isothiocyanate 2-chlorophenyl isothiocyanate o-tolyl isothiocyanate 3-bromophenyl isothiocyanate 3-fluorophenyl isothiocyanate 3-chlorophenyl isothiocyanate m-tolyl isothiocyanate 4-bromophenyl isothiocyanate 4-fluorophenyl isothiocyanate 4-chlorophenyl isothiocyanate p-tolyl isothiocyanate ethoxycarbonyl isothiocyanate benzoyl isothiocyanate tert-butyl isothiocyanate tert-octyl isothiocyanate methyl isothiocyanate benyl isothiocyanate ethyl isothiocyanate phenethyl isothiocyanate allyl isothiocyanate The indane scaffold containing third reactant: The indane scaffold containing reactant may be prepared by a process which comprises the following sequential steps: (1) Nitrating an indanone to give a nitoindanone major product; (2) Reducing the product of step 1 to give the corresponding alcohol; (3) Reacting product of step 2 in an acid catalyzed dehydration to give an indene; (4) Oxidizing the double bond of the product of step 3 to give an epoxide; (5) Reacting the product epoxide of step with ammonium hydroxide to give an amino alcohol; and (6) Protecting the amino alcohol of step 5 with a conventional protecting group. A specific illustrative reaction scheme illustrating steps for forming the indane combinatorial library scaffold is shown below (as steps 1 to 6) : 1-lndanone major 90% 91% over 2 steps The invention provides a method of making a diverse library of compounds having an indane scaffold, which comprises the sequential steps of: A) contacting a polymer bearing a carboxylic acid functionality with a protected indane of the following formula: (protective group) B) coupling the reactants of step (A) ; C) deprotecting the product of step (B) resulting in an amine functional indane bound to a resin support; D) acylating the product of step (C) to attach a first diverse group, Ei; E) reducing the product of step (D) to give the corresponding aniline; F) again acylating the product of step (E) ' to attach a second diverse group, E2; G) cleaving with a base of the product of step (F) from the resin support to give a product characterized by the formula (I) , as described above. The present invention describes a method of making a diverse library of compounds having an indane scaffold, said library compounds having the formula (I) , supra; said method comprising conducting a sequence of chemical depicted in the following reaction scheme (steps 6 to 12) : 1. Pyridine (16 Eq.), DMAP (0.15 Eq-). CH 2 CI 2 2. E + , eg. RCOCI ( 6.5 Eq.) 1. Pyridine (16 Eq.), DMAP (0.15 Eq.), CH 2 CI 2 2.E + , eg. R'COCI (6.5 Eq.) where PS is a polystyrene resin and R and R' are electrophilic groups. Indane library compounds are formed on a solid polymer support as illustrated by the following 12 process steps (with reference to the preceding reaction scheme: The abbreviations used have the following definitions LC - liquid chromatography mCPBA - meta-chloro perbenzoic acid THF - tetrahydrofuran DMAP - dimethyl amino pryidine DMF - dimethyl formamide 1. To a solution of 1-indanone (25 g, 0.189 mol) in concentrated H 2 SO 4 (84 ml) at 0°C was added a solution of KNO3 (8.33 g, 0.0824 mol) in H 2 S0 (40 ml) to maintain an internal temperature below 15°C. After stirring at 0°C for 1 hour, the reaction mixture was poured into crushed ice and stirred vigorously for 30 min. The suspension was then filtered, air dried, and purified by LC (5% ethyl acetate/toluene) to provide 1 (18.90 g, 56%) as a pale yellow solid. 2. A solution of 1 (18.90 g, 0.107 mol) in methanol (300ml) was cooled to 0°C and NaBH 4 (4.04g.0.107 mol) was added in several small portions. The reaction was then stirred overnight at 25°C. The solution was quenched at 0°C with methanolic HCl (200 ml) , concentrated under reduced pressure, redissolved in CH2CI2, washed with H 2 O, and the organic layer reconcentrated to provide the crude alcohol as a brown solid. 3. To a solution of crude alcohol in toluene (300 ml) was added a catalytic amount of p-toluenesulfonic acid and the reaction was refluxed for 1 hour using a Dean Stark trap to remove the H2O. The organic layer was washed with saturated NaHC0 3 (3 x 200 ml), dried over MgSθ 4 , solvent removed under vacuum, and the product recrystallized from methanol to afford 3 (13.41g, 78% over two steps) as a tan solid. 4. To a solution of 3 (10.53g, 0.0653 mol) in dichloromethane (350ml) at 0°C was added mCPBA (29g, 0.0924 mol) in small amounts over the course of 1 hour. After stirring overnight at 25°C, the mixture was washed with saturated a S03 (2 x 200 ml), saturated NaHC0 3 ( 2 x 200ml), filtered through a cotton plug, and concentrated under vacuum. 5. A suspension of 4 in concentrated NH 4 OH (250 ml) was heated overnight in an oil bath at 45°C. The next day H 2 O was added and the basic aqueous layer was saturated with NaCl. The cloudy reaction mixture was extracted with THF until no more product could be seen by TLC. Organic layers were combined, dried over MgSθ 4 , concentrated , and recrystallized from ethyl acetate to give 5 (11.54 g, 91% over two steps) as a fluffy tan solid. 6. To a solution of 5 (8.34g, 0.0429 mol) in THF (200 ml) was added a solution of di-tert-butyldicarbonate (11.25g, 0.0515 mol) in THF (50 ml). After stirring 1 hour at 25°C, the solvent was removed under reduced pressure and the resulting solid was recrystallized from ethyl acetate to afford 6 (11.37g, 90%) as a white solid. 7. Under an 2 atmosphere a 3 liter three-necked round bottomed flask equipped with an overhead stirrer and addition funnel was charged with carboxylated polystyrene resin (70 g, 2.77 mmol C0 2 H/g resin), anhydrous dichloromethane (1000ml) , and anhydrous DMF (10 ml) . Next, oxalyl chloride (50.75 ml, 0.582 mol) was added via a slow dropwise addition from an addition funnel. After reluxing overnight under N 2 , the solvent was removed under vacuum using a gas dispersion tube. The resin was subsequently washed with anhydrous dichloromethane (3 x 500 ml) . Once the last wash was complete, the resin was dried under vacuum for 2-3 hours. At this time, the polymer was resuspended in dry THF (1000 ml) followed by the addition of dry pyridine (314 ml, 3.88 mol), DMAP (11.85 g, 0.0970 mol), and 6 (85.62 g, 0.291 mol) . The mixture was refluxed for 10 days under an inert atmosphere. The solvent was removed by vacuum filtration and the resin was washed with THF ( 3 x 300 ml) , CH 2 CI 2 ( 3 x 300 ml) , and dried overnight in a vacuum oven to provide 7 (122.18 g) as a tan resin. 8. Into a round bottomed flask equipped with a stir bar was placed 7 (28mg, 0.02827 mmol), 0.500 ml dichloromethane, and TFA (0.109 ml, 0.14135 mmol). The reaction mixture was stirred at 25°C overnight, resin collected by filtration, resuspended in 10%TEA/CH 2 Cl 2 , stirred for 15 min., filtered again, and finally washed with dichloromethane to afford 8. 9. Into a 10 ml round bottomed flask was placed 7 (0.02827 mmol) followed by 0.5 ml of a solution of pyridine (0.03659 ml, 0.4524 mmol) and DMAP (0.518 mg, 0.004241 mmol) in dichloromethane. Next, a IM solution of an electrophile in dichloromethane (0.1838 ml, 0.1838 mmol) was added and the resulting mixture was stirred overnight at 25°C. At this time the solvent was removed by vacuum filtration and the resin was washed with CH 2 CI 2 , DMF, methanol, DMF, methanol, and CH2CI2 • 10. To a solution of 9 (0.02827 mmol) in DMF (0.625 ml) was added SnCl 2 2 H 2 O (102 mg, 0.4524 mmol) . Upon stirring at 25°C for 48 hours, the resin was isolated by filtration and washed with CH 2 CI 2 / DMF, methanol, DMF, methanol, and CH 2 C1 2 • 11. Into a 10 ml round bottomed flask was placed 10 (0.02827 mmol) followed by 0.5 ml of a solution of pyridine ( 0.03659 ml, 0.4524 mmol) and DMAP (0.518 mg, 0.004241 mmol) in dichloromethane. Next, a IM solution of an electrophile in dichloromethane (0.1838 ml, 0.1838 mmol) was added and the resulting mixture was stirred overnight at 25°C. At this time the solvent was removed by vacuum filtration and the resin was washed with CH 2 CI 2 , DMF, methanol, DMF, methanol, and CH2CI2. 12. To a flask containing 11 (0.02827 mmol) was added a IM solution of NaOH in methanol (0.375 ml, 0.375 mmol) and THF ( 0.400 ml) . After overnight stirring at 25°C, the reaction was neutralized with 4M HCl in methanol (0.100ml, 0.400 mmol), resin filtered, and the filtate was concentrated under reduced pressure to provide 12. Indane Library Process Methodolody: Reaction Medium - The reaction medium may be any liquid which is non-reactive with the reactants used in the library synthesis and is a non-solvent for the solid support. It is generally advantageous to have the electrophilic reagent soluble in the reaction medium. Typical reaction media useful in the processes of the invention are methanol, chloroform, dimethylacetamide, tetrahydrofuran, dimethylformamide, methylene chloride, and acetonitrile. The Reaction Zone - the process of the invention may be carried out in any vessel capable of holding the liquid reaction medium and having inlet and outlet means. Preferably the process of the invention is carried out in containers adaptable to parallel array syntheses. Most preferably, the indane library is formed in an 8 by 12 matrix of reaction vessels such as glass tubes is a dimensionally stable holder or the wells of standard wellplates, such as the 96 well wellplate illustrated in Fig.l. Each well may be filled by multiple delivery apparatus, automated or robotic apparatus, any of which may be either manually or computer controlled. The diverse indane library of this invention may take the form of a plurality of wellplates, each wellplate having wells containing a separate reaction product (library compound) . In such cases, the library compounds are conveniently identified by their wellplate number and "x" column and "y" wellplate row coordinates. A preferred technique for practicing the process of the invention is parallel array synthesis. With parallel array synthesis individual reaction products are prepared in each of multiple reaction zones. The amount of electrophilic reagent introduced into each reaction zone will depend on the desired amount of each library compound that is needed for conducting biological assays, archival storage and other related needs. Typically, the desired amount of individual reaction product is from 1 microgram to 50 milligrams. The reaction zone is maintained at a temperature and for a time sufficient to permit substantial reaction of the solid phase indane compound and the electrophilic reagent(s). The time, temperature, and pressure of the combinatorial reaction zones used for the creation of library compounds are not critical aspects of the invention. Reaction times for a single step of the reaction are generally from 0.1 seconds to 72 hours, with times of 1 hour to 24 hours being most often used. The temperature of the reaction may be any temperature between the freezing point and the boiling point of the liquid reaction medium, but is generally between -10°C and +60°C, with 10°C to 40°C being preferred and ambient temperatures (about 20°C-30°C) being most preferred. The reactions may be conducted at subatmospheric pressure or superatmospheric pressure (viz., 60Kg./m2 - 21000 absolute) , but ambient atmospheric pressure (about 10330 Kg./m^, absolute) is most often used. Endpoint determination - The completion of the reaction may be determined by a number of conventional techniques. One method is to use thin layer chromatography. Sequence of Operation - Within each process step the addition of the reactants to the reaction zone may take place in any order. For example, the solid supported reaction product may be initially added to the reaction zone followed by addition of the electrophilic reagent containing the group Ei, then electrophilic reagent containing the group E2, or vice versa. IV. Solid Supported Intermediate Indane Libraries and Library Compounds: A library of intermediate substituted indane compounds comprising a plurality of diverse compounds, wherein each intermediate has the formula (II) is created in the process of the preceding section prior to cleavage from the resin solid support . These intermediates are themselves useful and stable compounds which may be stored and used at a later time for generating the indane library compounds of the invention. These indane intermediates are represented by formula (II) ; wherein Ei and E2 are the same or different electrophilic groups. V. Antineoplastic Activity of the Indane Library Compounds:. Neoplastic diseases, characterized by the proliferation of cells not subject to the normal control of cell growth, are a major cause of death in humans and other mammals. Clinical experience in cancer chemotherapy has demonstrated that new and more effective drugs are desirable to treat these diseases. The present invention provides a method of alleviating neoplastic diseases comprising administering to a subject an effective amount of a pharmaceutical or veterinary composition containing a library compound corresponding to formula (I) . Moreover, combination chemotherapy, chemotherapy utilizing compounds of Formula (I) in combination with other neoplastic agents, is also provided by the subject invention. In general, the dosage required for therapeutic effect will vary according to the type of use, mode of administration, as well as the particularized requirements of the individual hosts. Typically, dosages will range from about 0.001 to 1000 mg/kg, and more usually 0.01 to 10 mg/kg of the host body weight. The compound of Formula I, with or without additional anti-neoplastic agents, may be formulated into therapeutic compositions as natural or salt forms. Pharmaceutically acceptable non-toxic salts include base addition salts which may be derived from inorganic bases such as for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like. Such salts may also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as for example, hydrochloric or phosphoric acids or organic acids such as acetic, oxalic, tartaric, mandelic, and the like. Additional excipients which further the invention are provided to the skilled artisan for example in the U.S. Pharmacopeia . The compounds are screened for minimum inhibitory concentrations against KB, a human nasopharyngeal carcinoma cell line, LoVo, a human colorectal adenocarcinoma cell line. The Corbett assay, see Corbett, T.H. et al. Cvtotoxic Anticancer Druσs: Models and Concepts for Drug Discovery and Development, pp 35-87, Kluwer Academic Publishers: Norwell, 1992. see also, Valeriote, et al. Discovery and Development of Anticancer Aσents; Kluwer Academic Publishers, Norwell, 1993. The most active compounds are further evaluated for cytotoxicity against four different cell types, for example a murine leukemia, a murine solid tumor, a human solid tumor, and a low malignancy fibroblast using the Corbett assay. The compounds are further evaluated against a broad spectrum of murine and human tumors implanted in mice, including drug resistant tumors. Tumor burden (T/C) (mean tumor burden in treated animals verses mena tumor burden in untreated animals) are used as a further assessment. T/C values that are less than 42% are considered to be active by National Cancer Institute Standards; T/C values less than 10% are considered to have excellent activity and potential clinical activity by National Cancer Institute standards. While it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one compound of the invention. Such compositions contain from about 0.1 percent by weight to about 90.0 percent by weight of a present compound. As such, the present invention also provides pharmaceutical formulations comprising a compound of the invention and a pharmaceutically acceptable excipient therefor. In making the compositions of the present invention, the active ingredient is usually mixed with an excipient which can be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in a liquid medium) , and sof and hard gelatin capsules. The compounds of the invention may be delivered transdermally, if desired. Transdermal permeation enhancers and delivery systems, including patches and the like, are well known to the skilled artisan. VI. Wellplate Apparatus containing library compounds prepared bv the process of the invention: The processes of making the indane library of the invention may be conveniently carried out in a wellplate apparatus such as illustrated in Fig. 1, hereinafter described. It is particularly advantageous to carry out the method of the invention in a standard wellplate apparatus such as a plastic 96 well microtiter plate. Typically, the wellplate apparatus is in the form of a rigid or semi-rigid plate, said plate having a common surface containing openings of a plurality of vessels arranged in rows and columns. A standard form of wellplate apparatus is a rectangular plastic plate having 8 rows and 12 columns (total 96) of liquid retaining depressions on its surface. A wellplate apparatus may optionally have other elements of structure such as a top or cover (e.g., plastic or foil), a bottom in a form such as a plate or reservoir, clamping means to secure the wellplate and prevent loss of its contained compounds. VII. The wellplate apparatus of the invention: A wellplate inoculated with the novel indane library compounds of the invention is itself a new construct or apparatus which has particular utility in an assay kit used to discover lead compounds. VIII. Detailed Description of the Drawings FIG. 1 illustrates the top surface of a wellplate apparatus of the invention. The wellplate (3) is a plastic plate with 96 wells (depressions) capable of holding liquids. When used in the parallel array synthesis individual reaction products are prepared in each well and are labeled by the wellplate coordinates. The shaded circles in the Figure represent wells filled with Indane library compounds prepared by the solution phase combinatorial processes of the invention. The library compound at location (1) , for example, is identified by the alphanumeric coordinate, "A6." IX. Assay Kits using wellplates with the library compounds of the invention: This invention includes an assay kit for identification of pharmaceutical lead compounds. The assay kit comprises as essential parts, (i) wellplate apparatus (containing in its wells the indane library compounds of the invention) , and (ii) biological assay materials. The wellplate apparatus in the kit may comprise a set of wellplate apparatus such as illustrated in Fig. 1. The library compounds contained in each wellplate may be prepared by either the indane combinatorial library forming process taught herein. Preferably the wellplate apparatus has the form of a standard 96 well microtiter plate. The assay kit also contains biological assay materials These biological assay materials are generally in vitro tests known to be predictive of success for an associated disease state. Illustrative of biological assay materials useful in the kit of this invention are those required to conduct the following assays: In vitro assays: Enzymatic Inhibition Receptor-ligand binding Protein-protein Interaction Protein-DNA Interaction Cell-based, Functional assays: Transcriptional Regulation Signal Transduction/ Second Messenger Viral Infectivity Add, Incubate, & Read assays: Scintillation Proximity Assays Angiotensin II SPA receptor binding assay Endothelin converting enzyme[ 12 5j gPA assay HIV proteinase [^ 25 I] SPA enzyme assay Cholesteryl ester transfer protein (CETP) [ 3 H] SPA assay Fluorescence Polarization Assays Fluorescence Correlation Spectroscopy Colorimetric Biosensors Ca 2+ -EGTA Dyes for Cell-based assays Reporter Gene Constructs for cell based assays Luciferase, green fluorescent protein, b-lactamase Electrical cell impedance sensor assays Strep Potentiator assay Cancer Assays Corbett assay Tumor burden (T/C) assay The utility of the indane library compounds of this invention is illustrated by their expected positive impact in at least one of the assays cited above. While the present invention has been illustrated above by certain specific embodiments, it is not intended that these specific examples should limit the scope of the invention as described in the appended claims.

Claims: We claim : 1. A library of substituted indane compounds wherein said library contains a plurality of diverse library compounds, wherein each library compound has the formula (I) ; wherein Ei and E2 are the same or different electrophilic group. 2. The library of claim 1 wherein the indane library compounds are non-peptide, substantially non-naturally occurring molecules having a molecular weight range of from about 100 to about 800 and Ei and E2 are the same or different electrophilic groups preferably derived from an electrophilic reagent having a molecular weight of from about 30 to about 600 selected from the group consisting of; organic halides, acyl halides, sulfonic acid esters, organohaloformates, organosulfonyl halides, organic isocyanates, and organic isothiocyanates. 3. The library of claim 1 wherein Ei and E2 are independently selected from groups represented by the following structural formulae: HoC 4. The individual indane library compounds of the library of claim 1. 5. A library of intermediate substituted indane compounds comprising a plurality of diverse compounds, wherein each intermediate has the formula (II) ; wherein Ei and E2 are the same or different electrophilic groups. 6. The individual intermediate indane compounds of claim 5. 7. A combinatorial process for preparing a library of substituted indane compounds, each compound having two diverse electrophilic substituents, Ei and E2, wherein said library comprises a plurality of diverse library compounds, wherein each library compound is made in a separate reaction zone and is represented by formula (I) : wherein said process comprises the steps of reacting; a) a first reactant containing electrophilic group Ei; b) a second reactant containing electrophilic group E2; and c) a third reactant having an indane scaffold. 8. A combinatorial process for preparing a library of substituted indane compounds, each compound having two diverse electrophilic substituents, wherein said library comprises a plurality of diverse library compounds, wherein each library compound is made in a separate reaction zone and is represented by formula (I) : wherein said process comprises the sequential steps of; A) contacting a polymer bearing a carboxylic acid functionality with a protected indane of the following formula: (protective group) I B) coupling the reactants of step (A) ; C) deprotecting the product of step (B) resulting in an amine functional indane bound to a resin support; D) acylating the product of step (C) with a first electrophilic reactant to attach a first diverse group, Ei; E) reducing the product of step (D) to give the corresponding aniline; F) again acylating the product of step (E) with a second electrophilic reactant to attach a second diverse group, E2; G) cleaving with a base of the product of step (F) from the resin support to give a product characterized by the formula (I) . 9. An assay kit for identification of pharmaceutical lead compounds, comprising biological assay materials and wellplate apparatus; wherein the improvement comprises using as wellplate apparatus a wellplate containing in each well the individual library compounds of a diverse combinatorial indane library prepared by the process of claim 7. 10. The assay kit of claim 9 containing biological assay materials selected from the group of assay tests; In vitro assays: Enzymatic Inhibition Receptor-ligand binding Protein-protein Interaction Protein-DNA Interaction Cell-based, Functional assays: Transcriptional Regulation Signal Transduction/ Second Messenger Viral Infectivity Add, Incubate, & Read assays: Scintillation Proximity Assays Angiotensin II SPA receptor binding assay Endothelin converting enzyme[ 125 I] gp^ assay HIV proteinase [ 12 5i] SPA enzyme assay Cholesteryl ester transfer protein (CETP) [ 3 H] SPA assay Fluorescence Polarization Assays Fluorescence Correlation Spectroscopy Colorimetric Biosensors Ca 2+ -EGTA Dyes for Cell-based assays Reporter Gene Constructs for cell based assays Luciferase, green fluorescent protein, b-lactamase Electrical cell impedance sensor assays Strep Potentiator assay Cancer Assays Corbett assay Tumor burden (T/C) assay. 11. Wellplate apparatus suitable as a replaceable element in an automated assay machine wherein the improvement comprises; using as the wellplate apparatus a diverse indane combinatorial wellplate, wherein each well contains an indane library compound prepared by the process of claim 7. 12. The apparatus of claim 11 comprising a 96 well microtiter plate.

Inventors: HOLLINSHEAD SEAN P, HUGHES PHILIP F, MENDOZA JOSE S, MITCH CHARLES H, WARD JOHN S, WILSON JOSEPH W, HOLLINSHEAD, SEAN, P., HUGHES, PHILIP, F., MENDOZA, JOSE, S., MITCH, CHARLES, H., WARD, JOHN, S., WILSON, JOSEPH, W.
Applicants: HOLLINSHEAD SEAN P, HUGHES PHILIP F, LILLY CO ELI, MENDOZA JOSE S, MITCH CHARLES H, WARD JOHN S, WILSON JOSEPH W, ELI LILLY AND COMPANY, HOLLINSHEAD, SEAN, P., HUGHES, PHILIP, F., MENDOZA, JOSE, S., MITCH, CHARLES, H., WARD, JOHN, S., WILSON, JOSEPH, W.
Application year: 1997
Main classification: C09B29
IPC codes: A61K31, A61P25, A61P43, C07B61, C07C231, C07C233, C07C235, C07C255, C07C257, C07C275, C07C311, C07D201, C07D209, C07D213, C07D215, C07D261, C07D295, C07D307, C07D333, C08F8, C08G85, C40B20, C40B30, C40B40, C40B50, C40B60, G01N33, G01N37