COMBINATORIAL PROCESS FOR PREPARING HYDROFUROQUINOLINE LIBRARIES

Abstract: This invention relates to a novel diverse combinatorial library of hydrofuroquinoline compounds and to an apparatus providing a readily accessible source of individual members of the library. The apparatus can be used in assay kits and as a replaceable element in automated assay machines.

Description: COMBINATORIAL PROCESS FOR PREPARING HYDROFUROQUINOLINE LIBRARIES This application claims the benefit of U.S. Provisional Patent Application Serial No. 60/033,665, filed December 18, 1996. Field of the Invention The present invention relates to diverse libraries of hydrofuroquinoline compounds, methods of making such libraries, and an apparatus for storing and providing a readily accessible source of diverse hydrofuroquinoline compounds . The apparatus harboring the present combinatorial libraries is a useful component of assay systems for identifying compounds for drug development. Background of the Invention Research and development expenses account for a large outlay of capital in the pharmaceutical industry. Synthesis of compounds is an expensive and time consuming phase of research and development. Historically, research chemists individually synthesized and analyzed high purity compounds for biological screening to develop pharmaceutical leads. Although such methods were successful in bringing new drugs to the market, the limitations of individual synthesis and complete compound characterization considerably slowed the discovery of new pharmaceutically active compounds. The need for more rapid and less expensive drug discovery methodology is increasingly important in today's competitive pharmaceutical industry. Recently, modern drug discovery has utilized combinatorial chemistry to generate large numbers (10^ - 10°) of compounds generically referred to as "libraries". An important objective of combinatory chemistry is to generate a large number of novel compounds that can be screened to generate lead compounds for pharmaceutical research. Theoretically the total number of compounds which may be produced for a given library is limited only by the number of reagents available to form substituents on the variable positions on the library's molecular scaffold. The combinatorial process lends itself to automation, both in the generation of compounds and in their biological screening, thereby greatly enhancing the opportunity and efficiency of drug discovery. Combinatorial chemistry may be performed in a manner where libraries of compounds are generated as mixtures with complete identification of the 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 are simultaneously synthesized, but are retained in separate vessels. For example, the individual library compounds can be prepared, stored, and assayed in separate wells of a microtiter plate, each well containing one member of the parallel array. The use of standardized microtiter plates or equivalent apparatus, is advantageous because such an apparatus is readily accessed by programmed robotic machinery, both during library synthesis and during library sampling or assaying. Typically, completion of the solution phase reactions in combinatorial chemistry schemes are ensured by selecting high yielding chemical reactions and/or by using one reagent in considerable excess. When one reagent is used in excess, completion of the reaction produces a soluble product with at least one soluble unreacted reagent. Combinatorial chemistry may be used at two distinct phases of drug development. In the discovery phase diverse libraries are created to find lead compounds. In a second optimization phase, strong lead compounds are more narrowly modified to find optimal molecular configurations . The preparation of selected hydrofuroquinoline compounds by the reaction of dihydrofuran with imines derived from the condensation of anilines with aldehydes have been described by Jose Cabral, et al . , Tetrahedron Letters, Vol. 29, pp. 547-550, (1988); Jose Cabral, et al, Tetrahedron Let ters, Vol. 30, pp. 7237-7238, (1989); and Kametani, et al . , Syntheti c Communications , Vol. 15, pp. 499-505, (1985). Those authors describe the use of protic acids and Lewis acids in catalyzing the cyclization reaction and the effects of various solvents and catalysts on the ratio of the stereoisomers in the reaction of benzylideneaniline with dihydrofuran, dihydropyran, and ethylvinyl ether The method of the present invention is based on the preparation of a novel diverse library of hydrofuroquinolines useful in the identification of new lead compounds. The library is created, stored, and used as an apparatus comprising of a two-dimensional array of reservoirs, each reservoir containing a predetermined library compound differing from those in adjacent reservoirs . Summary of the Invention The present invention provides combinatorial libraries of structurally related hydrofuroquinoline library compounds having the general formula (I): wherein Ri, Ri ' are substituents derived from an optionally substituted aniline of the formula: Nih R2 is hydrogen or an organic moiety derived from an aldehyde of the formula R2CHO, and R3 is hydrogen or an organic moiety derived from an optionally substituted dihydrofuran of the formula: The invention further provides a method for preparing hydrofuroquinoline libraries generally in accordance with Scheme 1 as set forth below. Another embodiment of the present invention provides an assay kit for the identification of pharmaceutical lead hydrofuroquinoline compounds, said kit comprising assay materials and a well plate apparatus or equivalent apparatus providing a two-dimensional array of defined reservoirs. The well plate apparatus provides a diverse combinatorial library, wherein each well (reservoir) contains a unique reaction product of the hydrofuroquinoline library. The well plate apparatus is used to provide multiple reaction zones for making the library, to store the library and to provide a readily accessible source of library compounds. Brief Description of the Drawings Fig. 1 is a top view of a well plate in accordance with this invention. Fig. 2 is a side view of a well plate apparatus for use in the process of this invention. Detailed Description of the Invention The term "assay kit" as used in accordance with the present invention refers to an assemblage of two cooperative elements, namely (1) a well plate apparatus and (2) 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. A "library" is a collection of compounds created by a combinatorial chemical process, said compounds having a common scaffold with one or more variable substituents . The scaffold of the present invention is a hydrofuroquinoline . A "library compound" is an individual reaction product, a single compound or a mixture of isomers, in a combinatorial library. A "Lead compound" is a library compound in a selected combinatorial library for which the assay kit has revealed significant activity relevant to a selected disease state. A "diverse library" means a library where the substituents on the combinatorial library scaffold or core structure, are highly variable in constituent atoms, molecular weight, and structure, and the library, considered in its entirety, is not a collection of closely related homologues or analogues (compare to "directed library"). A "directed library" is a collection of compounds created by a combinatorial chemical 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 analogues to the lead compound (compare with "diverse library"). The term "scaffold" as used in accordance with the present invention refers to the invariable region (a hydrofuroquinoline core in the present invention) of the compounds which are members of the combinatorial library. "Substituents" are chemical radicals which are bonded to or incorporated onto the hydrofuroquinoline scaffold through the combinatorial synthesis process. The different functional groups account for the diversity of the molecules throughout the library and are selected to impart diversity of biological activity to the scaffold in the case of diverse libraries, and optimization of a particular biological activity in the case of directed libraries. "Reagent" means a reactant, any chemical compound used in the combinatorial synthesis to place substituents on the scaffold of a library. "Parallel array synthesis" refers to the method of conducting combinatorial chemical synthesis of libraries wherein the individual combinatorial library compounds are separately prepared and stored without prior and subsequent intentional mixing. "Simultaneous synthesis" means making of library compounds within one production cycle of a combinatorial method (not making all library compounds at the same instant in time) . The "reaction zone" refers to the individual vessel location where the combinatorial chemical library compound preparation process of the invention is carried out and where the individual library compounds are synthesized. Suitable reaction zones are the individual wells of a well plate apparatus. "Well plate apparatus" refers to the structure capable of holding a plurality of library compounds in dimensionally fixed and defined positions. "Non-interfering substituents" are those groups that do not significantly impede the process of the invention and yield stable hydrofuroquinoline library compounds. "Aryl" means one or more aromatic rings, each of 5 or 6 ring carbon atoms and includes substituted aryl having one or more non-interfering substituents. Multiple aryl rings may be fused, as in naphthyl, or unfused, as in biphenyl. "Alkyl" means straight or branched chain or cyclic hydrocarbon having 1 to 20 carbon atoms. "Substituted alkyl" is alkyl having one or more non- interfering substituents. "Halo" means chloro, fluoro, iodo or bromo . "Heterocycle" or "heterocyclic radical" means one or more rings of 5, 6 or 7 atoms with or without unsaturation or aromatic character, optionally substituted, and at least one ring atom which is not carbon. Preferred heteroatoms include sulfur, oxygen, and nitrogen. Multiple rings may be fused, as in quinoline or benzofuran, or unfused as in 4- phenylpyridine . "Substituted heterocycle" or "Substituted heterocyclic radical" is heterocycle having one or more non-interfering substituents. Suitable radicals for substitution on the heterocyclic ring structure include, but are not limited to halo, Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, C1-C10 alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, di (Ci- C10) -alkylamino, C2-C12 alkoxyalkyl, C1-C6 alkylsulfinyl, Cl-Cio alkylsulfonyl, arylsulfonyl , aryl, hydroxy, hydroxy (C1-C10) alkyl, aryloxy (C1 . -C10 ) alkyl , C1-C10 alkoxycarbonyl , aryloxycarbonyl, C1-C10 alkanoyloxy, aryloyloxy, substituted alkoxy, fluoroalkyl, nitro, cyano, cyano (C1-C10) alkyl, C1-C 0 alkanamido, aryloylamido, arylaminosulfonyl, sulfona ido, heterocyclic radical, nitroalkyl, and - (CH2 )m ~z_ (C1-C10 alkyl), where m is 1 to 8 and Z is oxygen or sulfur. "Organic moiety" means a substituent comprising a non-interfering substituent covalently bonded through at least one carbon atom. Suitable radicals for substitution onto the connecting carbon atom include, but are not limited to hydrogen, halo, Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, C1-C10 alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, di (Ci- Cio) -alkylamino, C2-C12 alkoxyalkyl, Cχ-C6 alkylsulfinyl, Cl-Cio alkylsulfonyl, arylsulfonyl, aryl, hydroxy, hydroxy (C1-C10) alkyl, aryloxy (C1-C10 ) lkyl, C1-C10 alkoxycarbonyl , aryloxycarbonyl, C1-C10 alkanoyloxy, aryloyloxy, substituted alkoxy, fluoroalkyl, nitro, cyano, cyano (Ci-Cio ) alkyl, C1-C10 alkanamido, aryloylamido, arylaminosulfonyl, sulfonamido, heterocyclic radical, nitroalkyl, and - (CH2 )m~ z_ (Cl-Cio alkyl), where m is 1 to 8 and Z is oxygen or sulfur. "Optionally substituted aniline" means aniline or aniline having at least one non-interfering substituent covalently bound to the benzene ring. Suitable radicals for substitution on the benzene ring include, but are not limited to halo, Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, Cl-Cio alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, di (Ci-Cio ) -alkylamino, C2-C12 alkoxyalkyl, C1-C6 alkylsulfinyl, C1-C10 alkylsulfonyl, arylsulfonyl , aryl, hydroxy, hydroxy (Ci- C10) alkyl, aryloxy (C1-C10 ) alkyl, C1-C10 alkoxycarbonyl, aryloxycarbonyl, C1-C10 alkanoyloxy, aryloyloxy, substituted alkoxy, fluoroalkyl, nitro, cyano, cyano (Ci- Cχo) lkyl, C1-C10 alkanamido, aryloylamido, arylaminosulfonyl, sulfonamido, heterocyclic radical, nitroalkyl, and - (CH2 )m~Z- (Cχ-Cιo alkyl), where m is 1 to 8 and Z is oxygen or sulfur. "Optionally substituted dihydrofuran" means dihydrofuran or dihydrofuran having at least one non- interfering substituent covalently bound to the furan ring. Suitable radicals for substitution on the benzene ring include, but are not limited to halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, C1-C10 alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, di (C1-C10 ) -alkylamino, C2-C12 alkoxyalkyl, Cχ-C6 alkylsulfinyl, Ci-Cio alkylsulfonyl, arylsulfonyl, aryl, hydroxy, hydroxy (C1-C10 ) alkyl , aryloxy (Ci- C10) alkyl, C1-C10 alkoxycarbonyl, aryloxycarbonyl, C1-C10 alkanoyloxy, aryloyloxy, substituted alkoxy, fluoroalkyl, nitro, cyano, cyano (Cl-Cio ) alkyl , Cχ-Cιo alkanamido, aryloylamido, arylaminosulfonyl, sulfonamido, heterocyclic radical, nitroalkyl, and - (CH2 )m _z_ (C1-C10 alkyl) , where m is 1 to 8 and Z is oxygen or sulfur. A diverse library of hydrofuroquinolines is provided in accordance with the present invention. The hydrofuroquinoline library embodied as an apparatus of this invention serves as a readily accessible source of diverse hydrofuroquinoline compounds for use in identifying new biologically active hydrofuroquinoline compounds through pharmaceutical and agricultural candidate screening assays, for use in studies defining structure/activity relationships, and/or for use in clinical investigation. The library provided in accordance with the present invention includes hydrofuroquinoline compounds of the formula (I) : wherein Ri and Ri ' are independently hydrogen or non- interfering substituents derived from an optionally substituted aniline of the formula: R2 is hydrogen or an organic moiety derived from an aldehyde of the formula R2CHO, and R3 is hydrogen, or an organic moiety derived from an optionally substituted dihydrofuran of the formula: In another embodiment of the present invention there is provided a library of compounds of Formula I above, wherein Ri and Ri ' are independently selected from hydrogen and non-interfering substituents, R2 is alkyl, substituted alkyl, or aryl, and R3 is hydrogen, alkyl, substituted alkyl, or aryl. In another embodiment of this invention there is provided a library of compounds of Formula I above, wherein Ri and Ri ' are independently selected from hydrogen and non-interfering substituents, R2 is Cχ-Cιo alkyl, substituted (Cχ-Cιo alkyl), or aryl, and R3 is hydrogen . In still another embodiment of the present invention there is provided a library of compounds of Formula I above, wherein Ri and Ri ' are independently hydrogen or non-interfering substituents selected from the group consisting of halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, Cl-Cio alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, di (C1-C10 ) -alkylamino, 2-C12 alkoxyalkyl, C1-C6 alkylsulfinyl , Ci-Cio alkylsulfonyl, arylsulfonyl , aryl, hydroxy, hydroxy (Ci- C10) alkyl, aryloxy (C1-C10 ) lkyl, C1-C10 alkoxycarbonyl, aryloxycarbonyl, C1-C10 alkanoyloxy, aryloyloxy, substituted alkoxy, fluoroalkyl, nitro, cyano, cyano (Cι~ Cio) alkyl, Cι_-Cιo alkanamido, aryloylamido, arylaminosulfonyl, sulfonamido, heterocyclic radical, nitroalkyl, or - (CH2 )m _ Z- (Ci-Cio alkyl), where m is 1 to 8 and Z is oxygen or sulfur; R2 is Cl-Cio alkyl, substituted (Cl-Cio alkyl), or aryl; and R3 is hydrogen, Cl-Cio alkyl, or substituted (Ci-Cio alkyl) . The present invention also provides a method for preparing the library of hydrofuroquinoline compounds of Formula I using combinatorial chemistry in a parallel array synthesis technique illustrated in the following reaction scheme: Scheme 1 . The method comprises the steps of preparing substituted imine intermediates by reacting series of optionally substituted anilines with series of optionally substituted aldehydes, and then further reacting each intermediate with optionally substituted dihydrofuran in the presence of a Lewis acid to prepare a library of hydrofuroquinoline compounds with four sites of diversity, Ri, Ri ' , R2 and R3 , each derived respectively from the aniline reagent, the aldehyde reagent, and the dihydrofuran reagent. Each compound is prepared in a separate reaction zone (i.e. parallel array synthesis), and the predetermined product compound is identified by the plate and reaction well number. The aniline, aldehyde, and dihydrofuran reagents are either commercially available or prepared from commercially available starting materials. Anilines for the use in accordance with this invention are compounds of the formula: NH 2 wherein Ri and Ri ' are non-interfering groups, i.e., substituents which do not interfere with the reaction with the aldehyde and cyclopentadiene . Typically the aniline reactants have a molecular weight of about 100 to about 600. Illustrative of suitable anilines for use in preparation of the hydrofuroquinoline library of this invention include, but are not intended to be limited to, the following: 3-Methoxy-5- ( trifluoromethyl) aniline 3 , 5-Bis (trifluoromethyl ) aniline 4-Cyclohexylaniline 3-Amino-4-methoxybenzoic acid 5-Aminoisophthalic acid Nl- (4, 5-dimethyloxazol-2-yl) sulfanilamide Sulfathiazole Nl- (6-indazolyl) sulfanilamide 3 , 4-methylenedioxyaniline N- (4-amino-2-methylphenyl) -4-chlorophthalimide Sulfadiazine 4-Morpholinoaniline 6-Aminonicotinic acid 6-Aminonicotinamide -Aminoquinoline -Aminoquinaldine 5-Aminoquinoline 5-Amino-6-nitroquinoline 6-Aminoquinoline 8-Aminoquinoline 3 , 4-Ethylenedioxyaniline 5-Aminoisoquinoline 2-Bromo-4, 6-dinitroaniline 6-Chloro-2 , 4-dinitroaniline 2 , 6-Dinitroaniline 2,4, 6-Trinitroaniline 2 , 4-Dinitro-5-fluoroaniline 2 , 4-Dinitroaniline 4-Methoxy-2-nitroaniline 4~Ethoxy-2-nitroaniline 4-Amino-3-nitrobenzotrifluoride 2, 6-Dinitro-4-methylaniline 2-Methoxy-5-nitroaniline 4-Nitroanthranilic acid 3 , 5-Dinitroaniline 2 , 5-Dimethoxy-4-nitroaniline 2-Amino-5-nitrobenzonitrile 2-Methoxy-4-nitroaniline 2 -Amino-5-nitrobenzophenone 2 -Amino-5-nitrobenzotrifluoride 4-Methoxymetanilyl fluoride 4-Aminobenzhydrazide Aniline o-Arsanilic acid 2 -Aminobenzonitrile 2-Bromoaniline 2 , 4-Dibromoaniline 2,4, 6-Tribromoaniline 2-Bromo-4-methylaniline 2 , 5-Dibromoaniline 3 -Amino-4-bromobenzotrifluoride , 6-Dibromoaniline , 6-Dibromo-4-nitroaniline , 6-Dibromo-4-methylaniline -Fluoroaniline ,3,4,5, 6-Pentafluoroaniline ,3,5, 6-Tetrafluoroaniline -Amino-2 ,3,5, 6-tetrafluorobenzonitrile , 4-Difluoroaniline ,4, 5-Trifluoroaniline ,4, 6-Trifluoroaniline , 5-Difluoroaniline -Fluoro-5-nitroaniline -Amino-4-fluorobenzotrifluoride -Fluoro-5-methylaniline , 6-Difluoroaniline -Chloroaniline , 3 -Dichloroaniline ,3,5, 6-Tetrachloroaniline -Bromo-2-chloroaniline , 4-Dichloroaniline ,4, 5-Trichloroaniline ,4, 6-Trichloroaniline , 4-Dichloro-6-nitroaniline -Chloro-4-nitroaniline -Chloro-4-methylaniline , 5-Dichloroaniline -Chloro-5-nitroaniline -Amino-4-chlorobenzoic acid - ( 3 -Amino-4-chlorobenzoyl) benzoic acid -Amino-4-chlorobenzotrifluoride -Chloro-5-methylaniline , 6-Dichloroaniline , 6-Dichloro-3-methylaniline , 6-Dichloro-4-nitroaniline -Chloro-6-methylaniline -Amino-3 , 5-diiodobenzoic acid , 6-Diiodo-4-nitroaniline 4-Amino-3 , 5-diiodobenzoic acid 2-Nitroaniline 2 -Aminophenol 2-Amino-5-nitrophenol 6-Amino-m-cresol 2-Amino-4-chlorophenol 2-Amino-4-nitrophenol 3-Amino-4-hydroxybenzoic acid 2-Amino-4-tert-butylphenol 2-Amino-p-cresol 3-Hydroxyanthranilic acid 2 -Aminobiphenyl 2 -Aminothiophenol Orthanilic acid 2- (Phenylsulfonyl) aniline 2- (2-Chloro-l, 1, 2-trifluoroethylthio) aniline 2- (Methylmercapto) niline Methyl anthranilate Ethyl 2-aminobenzoate Anthranilic acid 2-Aminobenzotrifluoride 2-Isopropenylaniline 2-Isopropylaniline o-Toluidine p-Toluidine 2-Methyl-3-nitroaniline 2 , 3 -Dimethylaniline 2-Methyl-4-nitroaniline 4-Methoxy-2-methylaniline 4-Amino-3-methylbenzoic acid 2 , 4-Dimethylaniline 4, 6-Dimethyl-2-nitroaniline 2,4, 6-Trimethylaniline 2-Methyl-5-nitroaniline 3-Amino-4-methylbenzoic acid 2 , 5-Dimethylaniline 2-Methyl-6-nitroaniline -Amino-3-methylbenzoic acid -Isopropyl-6-methylaniline , 6-Dimethylaniline -Aminobenzyl alcohol -Benzylaniline -Ethylaniline -Ethyl-6-methylaniline 2 , 6-Diethylaniline -Aminophenethyl alcohol 3-Aminobenzonitrile 3-Bromoaniline 3 -Fluoroaniline 3 -Fluoro-2 -methylaniline 3 , 4-Difluoroaniline 3 -Fluoro-4-methylaniline 3 , 5-Difluoroaniline 5-Fluoro-2 -methylaniline 3 -Chloroaniline 3 -Chloro-2-methylaniline 3 -Chloro-4-fluoroaniline 3 , 4-Dichloroaniline 3,4, 5-Trichloroaniline 4, 5-Dichloro-2-nitroaniline 3 -Chloro-p-anisidine 4-Amino-2-chlorobenzoic acid 3-Chloro-4-methylaniline 3 , 5-Dichloroaniline 5-Chloro-2-nitroaniline 5-Chloro-o-anisidine 2-Amino-4-chlorobenzoic acid 5-Chloro-2 -methylaniline 3 -Nitroaniline m-Anisidine 3-Benzyloxyaniline m-Phenetidine 3 -Aminophenol 3-Amino-o-cresol Phenyl aminosalicylate 4-Aminosalicylic acid 5-Phenyl-o-anisidine 3-Aminothiophenol 3- (Methylmercapto) aniline Ethyl 3-aminobenzoate 3-Aminobenzoic acid 3 ' -Aminoacetophenone 3 -Aminobenzotrifluoride 3- (1-Hydroxyethyl) aniline m-Toluidine 2-Amino-6-methylbenzoic acid 3 , 4-Dimethylaniline 4, 5-Dimethyl-2-nitroaniline 3 , 5-Dimethylaniline 5-Methyl-2-nitroaniline 2-Methoxy-5-methylaniline 2-Amino-4-methylbenzophenone 3-Aminobenzyl alcohol 3-Ethylaniline 4-Aminobenzonitrile 4-Bromoaniline 2-Amino-5-bromobenzoic acid 4-Bromo-2 -methylaniline 4-Bromo-2 , 6-dimethylaniline 5-Amino-2-bromobenzotrifluoride 4-Bromo-3 -methylaniline 4-Fluoroaniline 4-Fluoro-2-nitroaniline 2-Amino-5-fluorobenzotrifluoride 4-Fluoro-2 -methylaniline 4-Fluoro-3-nitroaniline 5-Amino-2-fluorobenzotrifluoride 4-Chloroaniline 4-Chloro-2-nitroaniline Methyl 2-amino-5-chlorobenzoate 2-Amino-5-chlorobenzoic acid 2-Amino-5-chlorobenzophenone 2-Amino-2 ' , 5-dichlorobenzophenone 2 -Amino-5-chlorobenzotrifluoride 4-Chloro-2 -methylaniline 4-Chloro-3-nitroaniline 5-Amino-2-chlorobenzoic acid 5-Amino-2-chlorobenzotrifluoride 4-Chloro-2-methoxy-5-methylaniline 2-Iodoaniline 3-Iodoaniline 4-Iodoaniline 2-Amino-5-iodobenzoic acid P-Phenylazoaniline 4-Nitroaniline 4 ' -Amino-n-methylacetanilide n, n-Dimethyl-p-phenylenediamine n,n-Diethyl-p-phenylenediamine 4-Phenoxyani1ine p-Anisidine p-Phenetidine 4-Butoxyaniline 4-Pentyloxyaniline 4-Hexyloxyani1ine 4-Aminophenol 2-Amino-5-hydroxybenzoic acid 4-Amino-m-cresol 4-Amino-2 , 5-dimethylphenol 4-Amino-2 , 6-dibromophenol 4-Amino-2 , 6-dichlorophenol 4-Amino-2-nitrophenol 5-Aminosalicylic acid 4-Aminobipheny1 4-Aminothiophenol 4-Amino-4 ' -nitrodiphenyl sulfide 4-Aminodibenzenesulfonamide Sulfanilic acid 4-Hexadecylsulfonylaniline 4- (Methylmercapto) aniline Methyl 4-aminobenzoate Ethyl 4-aminobenzoate 4-Aminobenzoic acid 4-Aminobenzophenone 4-Aminoacetophenone 4-Aminobenzotrifluoride hydrochloride 4-Tritylaniline 4-Tert-butylaniline 4-Isopropylaniline 4-Methyl-2-nitroaniline 4-Aminotoluene-3-sulfonic acid 2-Amino-5-methylbenzoic acid 4-Methyl-3-nitroaniline 5-Amino-2-methylbenzenesulfonic acid 4-Aminophenylacetonitrile Diethyl 4-aminobenzylphosphonate 2 , 5-Dimethoxy-4 ' -a inostilbene 4-Aminophenylacetic acid P-Decylaniline P-Dodecylaniline 4-Hexadecylaniline 4-Ethylaniline 4-Aminophenethyl alcohol 4-n-Propylaniline 4-n-Butylaniline 4-n-Amylaniline 4-n-Hexylaniline 4-n-Heptylaniline p-Octylaniline 2 -Aminobenzenesulfonamide 4-Amino-6-chloro-l, 3 -benzenedisulfonamide Sulfanilamide 2 -Aminobenzamide 3 -Aminobenzamide 4-Aminobenzamide 4-Amino-2 ,3,5, 6-tetrafluorobenzamide 4-Amino-3 , 5-dinitrobenzamide 2 , 5-Dimethoxyaniline 2 , 4-Dimethoxyaniline 3 , 5-Dimethoxyaniline 3,4, 5-Trimethoxyaniline 3 , 4-Dimethoxyaniline Methyl 3,4, 5-trimethoxyanthranilate Dimethyl aminoterephthalate Dimethyl 5-aminoisophthalate 2 , 6-Diisopropylaniline 2-Bromo-4, 6-difluoroaniline Methyl 3 -aminothiophene-2 -carboxylate 2-n-Propylaniline p-Tetradecylaniline n- (4-Aminobenzoyl) -beta-alanine 5-methoxy-2-methyl-4-nitroaniline 2 , 3 -dimethyl-6-nitroaniline n, n-Dimethyl-4 , 4 ' -azodianiline 4-Bromo-2 -fluoroaniline 5-Amino-2-methoxyphenol 4-Sec-butylaniline 2 , 3 -Difluoroaniline 3-Aminosalicylic acid 2 -Amino-4-chloro-5-nitrophenol 2 , 5-Di-tert-butylaniline 4-Chloro-2 -fluoroaniline 4- (4-Nitrophenylsulfonyl) aniline Methyl 3 , 5-dibromoanthranilate Methyl 4-amino-3 , 5-diiodobenzoate 2 -Amino-3 -nitrophenol 4, 5-Difluoro-2-nitroaniline 2,4, 6-Tri-tert-butylaniline 2-Amino-4 , 5-dimethoxybenzoic acid 2,3, 4-Trifluoroaniline 2-Fluoro-4-iodoaniline 4-Amino-n-methylphthalimide 2 , 4-Dibromo-6-nitroaniline 4-Bromo-2 ,3,5, 6-tetrafluoroaniline 2,3, 6-Trifluoroaniline 2-Bromo-3 , 4, 6-trifluoroaniline 2,4, 6-Triphenylaniline 4-Aminophenylarsine oxide Aniline hydrochloride o-Toluidine hydrochloride 6-Chloro-m-anisidine hydrochloride 3-Aminobenzoic acid hydrochloride 3 -Aminobenzamidine dihydrochloride n, n-Dimethyl-p-phenylenediamine sulfate n, n-Diethyl-p-phenylenediamine sulfate 4-Aminoazobenzene hydrochloride 4-Benzyloxyaniline hydrochloride 4-Aminophenol hydrochloride Ethyl 4-aminobenzoate hydrochloride 4-Aminobenzamidine dihydrochloride 4-Amino-3-nitrobenzonitrile 2-Bromo-4, 5, 6-trifluoroaniline 4-Bromo-2 , 6-difluoroaniline 5-Amino-2-nitrobenzotrifluoride 2 -Amino-6-fluorobenzonitrile 4-Amino-3-methoxybenzoic acid 2-Amino-4, 5-dimethoxyacetophenone 2-Amino-5-nitrobenzoic acid 3 , 5-Dibromoanthranilic acid 3 , 5-Dichloroanthranilic acid 4-Amino-3-hydroxybenzoic acid 2-Amino-3 , 5-dimethylbenzoic acid Butyl 4-aminobenzoate 2,3,4, 5-Tetrafluoroaniline 2-Amino-4-tert-amylphenol 2-Aminotoluene-5-sulfonic acid l-Butyl-3-sulfanilylurea 5-Tert-butyl-o-anisidine 4-Amino-2 , 6-diphenylphenol 2-Amino-5-diethylaminotoluene monohydrochloride 6-Amino-2 , 4-dichloro-3-methylphenol hydrochloride p-Toluidine hydrochloride n, n-Diethyl-p-phenylenediamine hydrochloride 2-Phenoxyani1ine 4-Amino-2-chlorotoluene-5-sulfonic acid 2-Amino-4- (ethylsulfonyl) phenol 4-Amino-2-chlorobenzonitrile 2-Amino-4-chlorobenzonitrile 4-Amino-5-chloro-2-methoxybenzoic acid 2-Sec-butylaniline 2-Fluoro-4-methylaniline 4- (Trifluoromethoxy) aniline 2, 6-Dibromo-4-fluoroaniline 3- (Trifluoromethoxy) aniline 3 -Phenoxyani1ine n, n-Dimethyl-p-phenylenediamine oxalate 3-Chloro-2 , 4-difluoroaniline 2 , 4-Dibromo-6-fluoroaniline 3- (1, 1, 2 , 2-Tetrafluoroethoxy) aniline 2 -Bromo-4-fluoroaniline 3 -Amino-4-methoxybenzotrifluoride 2 -Chloro-4-fluoroaniline 3 -Amino-4-mercaptobenzotrifluoride hydrochloride 2,3, 4-Trichloroaniline 4-Azidoaniline hydrochloride 3-Chloro-6-methyl-4-nitroaniline 2-Chloro-4, 6-dimethylaniline Aniline-2 ,3,4,5, 6-d5 , and the like. Other suitable anilines for use in preparation of the hydrofuroquinoline library of this invention include, but are not intended to be limited to, illustrated by the following formulas, wherein Li and L2 are hydrogen: The aldehyde reagents for use in the process for preparing the present library are represented by the general formula R2CHO, wherein R2 is hydrogen, or an organic moiety. Typically, aldehyde reagents have a molecular weight ranging from about 50 to about 600. Illustrative of suitable aldehydes for use in preparation of the hydrofuroquinoline library of this invention include, but are not intended to be limited to, the following: Ethyl 2-formyl-1-cyclopropanecarboxylate Cyclohexanecarboxaldehyde 1,2,3, 6-Tetrahydrobenzaldehyde Diphenylacetaldehyde 2-Phenylpropionaldehyde 2 , 3 -Dimethylvaleraldehyde Isobutyraldehyde 2 , 6-Dimethyl-5-hepten-1-al 2 -Methylbutyraldehyde 2 -Ethylbutyraldehyde 2 -Methylpentanal 2 -Ethylhexanal 2 -Methylundecanal Phenylacetaldehyde Isovaleraldehyde 7-Methoxy-3 , 7-dimethyloctanal Undecanal Dodecanal Tridecanal Tetradecyl aldehyde Propionaldehyde 3-Phenylpropionaldehyde 3- (Methylthio) propionaldehyde Butyraldehyde Cis-4-decen-l-al N-valeraldehyde Hexanal Heptaldehyde Octanal Nonanal Decanal Undecylenic aldehyde Cis-11-hexadecenal Cis-13-octadecenal Cis-9-hexadecenal 2 , 5-Dimethoxy-3-tetrahydrofurancarboxaldehyde 3,5, 5-Trimethylhexanal Succinic semialdehyde (+/-) -3-Phenylbutyraldehyde 2,6, 6-Trimethyl-l-cyclohexene-l-acetaldehyde Cyclopropanecarboxaldehyde 3 -Cyclohexylpropionaldehyde Hydroxycitronellal Cis-4-heptenal Cis-6-nonen-l-al Tetrahydrocitral Cis-7-decen-l-al Cis-8-undecen-l-al 3, 5, 6-Trimethyl-3-cyclohexene-l-carboxaldehyde Lyral (r) Bis (2-chlorophenyl) acetaldehyde 2 -Thioglyceraldehyde 3- (4-Isopropylphenyl) isobutyraldehyde 2 -Ethyl-3 -methylbutanal 2-Ethylcaprylaldehyde 3 -Methylvaleraldehyde 3-Phenyl-3- (p-tosyl) propionaldehyde 3-Hexenal 3- (Methylthio) butanal Veltonal Citronellal 2- (Trifluoromethyl) propionaldehyde 3 , 3 -Dimethylbutyraldehyde Campholene aldehyde 2-Formylpropionic acid methyl ester 5-Hydroxypentanal p-Methylphenylacet ldehyde Omega-ketoheptanoic acid 4-Chlorophenylcyanoacetaldehyde Hexadecanal Methyl 7-oxoheptanoate Diethyl formyl succinate 4-Pregnene-20-beta-carboxaldehyde-3-one Cis-7-tetradecenal Cyclopentylmethanal 3 , 4-Dimethyl-3-cyclohexenylmethanal 2,4, 6-Trimethyl-3-cyclohexen-l-carboxaldehyde Adipic semialdehyde methyl ester Cis-14-methyl-8-hexadecenal Cis-3-hexen-l-al Trans-4-decen-l-al 2 , 2-Dichlorooctadecanal 2 , 2 -Dichlorotetradecanal 2 , 2-Dichlorooctanal 2 , 2 -Dichlorohexanal (r) - (+) -Citronellal 8-Methyl-7-nonenal 2- (p-Tolyl) propionaldehyde Aldehyde C-ll MOA (2-methyldecanal) Alpha-methylhydrocinnamaldehyde (s) - (-) -Citronellal 4-Hydroxybutanal 4-Oxobutyric acid methyl ester 3,3,4,4,5,5,5-Hept fluoropentanal 3-Methylbutanal-l-13c 6-Methyl-3-cyclohexene-l-carboxaldehyde 4- (4-Methyl-2 -pentenyl) -3-cyclohexene-l- carboxaldehyde 3-Pentyn-l-al 3-Pyridylacetaldehyde n-oxide 2 , 3-Dihydro-5-methoxy-3-phenyl-2- indolecarboxaldehyde 2, 4-Diphenyl-3-oxobutyraldehyde 3,3, 3-Triphenylpropionaldehyde 2-Bromo-n- (3-formyl-1-methylpropyl) benzamide 3 - ( Phenylthio) butyraldehyde Diethyl 2- (diethoxymethyl) -3-formylsuccinate 2-Chloro-3- (4-nitrophenyl ) -propionaldehyde 2 -Acetoxypropionaldehyde 2-Methyl-4-phenylpentanal (lr, 2s, 3r, 4s) - (+) -2 -Benzyloxy-3-formyl-oxybornane 5- (4 ' -Chlorophenoxy) -1-pentanal Boc-ala-CHO Boc-leu-CHO Boc-phe-CHO Boc-tyr (OBzl) -CHO Boc-tyr (OMe) -CHO Boc-val-CHO 4-Pentenal l-Formyl-6- (dimethylamino) fulvene 1, 4-Dioxaspiro (4.5) decane-7-acetaldehyde Alpha-citronellal Diethyl 2-Acetamido-2- (2-formylethyl)malonate 3,4,4,5,5, 5-Hexafluoro-3- (trifluoromethyl) pent nal 3,4,4, 4-Tetrafluoro-3- (heptafluoropropoxy) butanal 3,4,4, 4-Tetrafluoro-3- (trifluoromethoxy) butanal 3,4,4, 4-Tetrafluoro-3- (trifluoromethyl) butanal 3,3,4,4,5,5,6,6,7,7,8,8, 8-Tridecafluorooctanal 3,3, 3-Trifluoropropanal Beta, beta-dimethylhydrocinnamaldehyde 5-Norbornene-2-carboxaldehyde Chrysanthal 9-Decenal Decyl aldehyde, [l-14c] 4,4, 4-Trifluorobutyraldehyde 3 -Methyl-3 -butenal 3- (5-Methyl-2-furyl) butanal 3-Phenyl-4-pentenal Trans-2 -dodecenal 9 , 10-Dihydro-9 , 10-ethanoanthracene-ll-carboxaldehyde Methyl hexyl acetaldehyde 2 , 3-Dihydro-2-oxo-lH-imidazol-4-carboxaldehyde N-Acetylmuramic acid, and the like. Particularly suitable aldehydes useful for forming the imine intermediates in preparation of the present hydrofuroquinoline libraries are further illustrated by the following formulas, wherein L is -CHO: r Cl OH H j C & The optionally substituted dihydrofuran reactants are also either commercially available, or they can be synthesized using commercially available starting materials. Preferably the substituent R3 is either hydrogen, alkyl or substituted alkyl. Most typically, R3 is hydrogen, C1-C10 alkyl or substituted C1-C10 alkyl wherein the substituent is a non-interfering group. Exemplary of the groups R3 other than hydrogen are methyl, ethyl, propyl, butyl, isopropyl, 2-methoxy ethyl, 2-chloropropyl, benzyl, and 4-bromobenzyl . The preparation of the hydrofuroquinoline library compounds of Formula I above comprises a two-step process wherein an imine intermediate is first formed and subsequently reacted with an optionally substituted dihydrofuran in the presence of acid, typically a protic acid and/or a Lewis acid, for example, trifluoroacetic acid and ferric chloride. The progress/completion of the reactions can be determined by a number of conventional techniques including thin layer chromatography (TLC) . In the first step of the process for preparing the present library compounds, equivalent amounts of an optionally substituted aniline and an aldehyde, each typically in ' solution in a suitable organic solvent, are combined in a reaction zone and reacted overnight, preferably at ambient temperature and thereafter for about 4 hours at ~ 50°C. Suitable organic solvents are those in which each of the reactants are soluble and which do not interfere with the imine-forming condensation reaction. Suitable solvents include alcohols, such as methanol or ethanol; ethers, such as diethyl ether; esters, such as ethyl acetate; and halogenated hydrocarbon solvents, such as methylene chloride, chloroform or 1 , 2-dichloroethane . The reaction temperature is not critical; however, good results have been obtained by carrying out the reaction at about 25°C to about 50 °C. The progress of the imine-forming reaction can be monitored by, for example, thin layer chromatography . Following completion of the imine-intermediate forming step, the reaction mixture is evaporated by vacuum to provide an intermediate product including an intermediate imine in each reaction zone. The imine intermediate in each reaction zone is then dissolved in a halogenated hydrocarbon solvent, preferably methylene chloride, and reacted with a 2 , 3 -dihydrofuran, typically in solution at a 10-30% molar excess relative to the imine intermediate, in the presence of catalytic amounts of trifluoroacetic acid (TFA) and ferric chloride (FeCl3) . The TFA and FeCl3 are typically added in an amount corresponding to about 1 to about 20% of the molar equivalent amount based on the amount of imine intermediate. Other strong protic acids and/or Lewis acids can be used, for example, trifluromethane sulfonic acid, polyphosphoric acid, chlorosulfonic acid, aluminum chloride and boron trifluoride. The reaction is typically carried out with shaking at room temperature for about 24 hours. The progress of the reaction can be followed by thin layer chromatography or other suitable art recognized analytical techniques. The reaction is typically complete after about 24 hours at room temperature. Following completion of the reaction about 90 mg of a 3:1 mixture of neutral alumina/Siθ2 is added to each reaction zone with additional solvent, and after about 24-40 hours each reaction mixture is filtered into a clean reservoir. The reaction zone and the filtered alumina/Siθ2 are rinsed with methylene chloride, and the washes are added to the respective filtrate. Evaporation with vacuum of the combined filtrate and washes provide a library compound in each reservoir. A sample of each library compound can be submitted for analysis by chromatographic, preferably combined chromatographic/mass spectral analysis. The process of the present invention utilized in preparation of a library of hydrofuroquinolines of Formula I above may be carried out in any vessel capable of holding the liquid reaction medium. In one embodiment, the process of the invention is carried out in containers adaptable to parallel array synthesis. In particular, the hydrofuroquinoline library of this invention can be formed in a 96-well plate as illustrated in Figures 1 and 2. That apparatus provides multiple reaction zones most typically in a two-dimensional array of defined reservoirs, wherein one member of the hydrofuroquinoline library of this invention is prepared in each reservoir. Thus the diverse hydrofuroquinoline library of the present invention comprises a plurality of reservoir arrays (e.g. well plates), each reservoir or well containing a library compound of the hydrofuroquinoline library. Accordingly the library compounds are typically identified by reference to their well plate number and their X column and Y row well plate coordinates . Following simultaneous preparation of the library member compounds in the reservoir array, the compounds can be transferred in whole or in part to other reservoir arrays (e.g. well plates), to prepare multiple copies of the library apparatus or to subject the library to additional reaction conditions. Copies of the library apparatus (daughter well plates, each comprising a 2- dimensional array of defined reservoirs with each reservoir containing a predetermined member of the library) are useful as replaceable elements in automated assay machines. The apparatus of this invention allows convenient access to a wide variety of structurally related hydrofuroquinoline compounds. One preferred reservoir array for use in making and using this invention is a multi-well titer plate, typically a 96- well microtiter plate. Figure 1 illustrates the top surface of a well plate apparatus of the present invention. The well plate (1) is a plastic plate with 96-wells (depressions) capable of holding liquids for parallel array synthesis. Individual reaction products are prepared in each well and are labeled by the well plate coordinates. For example, the library compound at location (2), is identified by the alpha numeric coordinate, "A6". Figure 2 illustrates a side view of a modified well plate apparatus for use in preparation of the library of the present invention. Well plate (3) contains wells (4) with a filter (5), a retaining frit (6), and a liquid reaction medium used in carrying out the process (7) . The wells have an outlet at the bottom which is sealed by gasket (8) held in place by a top cover (9) and bottom cover (10) maintained in position by clamps (11) . Such well plates are typically prepared using standard 96-well plates. A hole is drilled in the bottom of each well in the plates and a porous frit is placed in the bottom of each well. The plate is then placed in the clamp assembly to seal the bottom of the wells . Synthesis is initiated by adding reagents to their individual wells according to their assigned plate coordinates. The plate is then capped and tumbled to mix the reagents . Following completion of the reaction to form the respective imine intermediates, a dihydrofuran is added with acid catalyst and ferric chloride to each reaction zone followed by further mixing. Finally, neutral alumina/silicon oxide is added to each reaction zone after completion of the reaction. After sufficient reaction time, the contents of each well containing a product library compound is filtered. The filtrate is collected in another 96-well plate. The reaction products are then analyzed, for example, by thin layer chromatography, mass spectrometry and/or nuclear magnetic resonance spectrometry. In one embodiment of the present invention is an assay kit for the identification of pharmaceutical lead compounds. The assay kit comprises as essential parts, (1) a well plate apparatus (containing one of the hydrofuroquinoline compounds in each of its individual wells), and (2) biological assay materials. The biological assay materials are generally 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 assays known in the art, including, but not intended to be limited to: In vi tro assays such as: Enzymatic inhibition, Receptor-ligand binding, Protein-Protein interaction, Protein-DNA interaction, and the like; Cell based, functional assays such as: Transcriptional regulation, Signal transduction/Second messenger, Viral Infectivity, and the like; and Add, Incubate, & Read assays such as: Scintillation Proximity Assays, Angiotensin II IPA receptor binding assay, Endothelia converting enzyme [125j gp^ assay, HIV proteinase [125j] gp^ enzyme assay, Cholesteryl ester transfer (CETP) [^H] SPA assay, Fluorescence Polarization Assays, Fluorescence Correlation Spectroscopy, Colorimetric biosensors, Ca2 + - EGTA for Cell-based assays, Receptor Gene Constructs for cell based assays, Cellular reporter assays utilizing reporters such as luciferase, green fluorescent protein, Beta- lactamase, and the like; Electrical cell impedance sensor assays, and the like. Example 1. Hydrofuroquinoline Library Plates: General Procedure. A different aniline reagent (100 μL of a 0.5 M solution in EtOH) was added to the wells of each row of a (several) 96-well glass titer plate (well volume of 1 mL) , with care taken that all liquid was added to the bottom of the wells and with minimum splattering. A different aldehyde (100 μL of a 0.5 M solution in EtOH) was then added to the wells of each column in the plate (s) . The wells were capped and the plates shaken at ambient temperature overnight followed by 4 hours incubation at ~50_C. The solvent was then evaporated by vacuum overnight (5-10 in/Hg, ambient temperature) . The residue in each well was then dissolved in methylene chloride (0.3 mL) . A solution of 2,3- dihydrofuran (100 μL of a 0.6 M solution in methylene chloride) was then added to all the wells of a plate(s). Different substituted dihydrofurans may be added to the wells of different plates to create diversity at R3 in Formula I. Trifluoroacetic acid was then added (100 μL of a 25 mM solution) followed by FeCl3 (lOOμL of a 50 mM solution in methylene chloride) to each well. The plate (s) was quickly capped and shaken for twenty four hours at ambient temperature. The plate was uncapped and a 3:1 mixture of neutral alumina/Siθ2 (~90 mg) was added to each well followed by additional methylene chloride (300 μL) . The plate(s) was capped and occasionally shaken at ambient temperature for two days. The plates were uncapped and the contents filtered into clean titer plates. The wells and alumina/Siθ2 were rinsed with methylene chloride and the washes added to the respective filtrate (2 x 0.5 L per well) . The solvent was evaporated at ambient temperature by speed-vac overnight. This process afforded plates containing about 40 μmol of a library compound per well. Prior to final drying, samples of solution are taken from each well and submitted for thin layer chromatography and/or mass spectral analysis. Example 2. d, 1-2 , 3 , 3a, 4 , 5.9b-Hexahvdro-8-chloro-4- (p- methoxyphenyl ) furo T3 , 2-cl quinoline : The procedure in Example 1 was used to produce d, 1- 2,3, 3a, 4,5, 9b-hexahydro-8-chloro-4- (p- methoxyphenyl) furo [3 , 2 -c] quinoline. 4-Chloroaniline (100 μL of a 0.5 M solution in EtOH) and 4-methoxybenzaldehyde (100 μL of a 0.5 M solution in EtOH) were reacted overnight at ambient temperature, followed by 4 hours incubation at ~50_C. The solvent was then evaporated by vacuum overnight (5-10 in/Hg, ambient temperature). The residue was then dissolved in methylene chloride (0.3 mL) , and 2 , 3 -dihydrofuran (100 μL of a 0.6 M solution in methylene chloride) was added to the reaction zone. Trifluoroacetic acid was then added (100 μL of a 25 mM solution) followed by FeCl3 (lOOμL of a 50 mM solution in methylene chloride) . The well was capped and shaken for twenty four hours at ambient temperature. The well was uncapped and a 3:1 mixture of neutral alumina/Siθ2 (-90 mg) was added to the well followed by additional methylene chloride (300 μL) . The well was capped and occasionally shaken at ambient temperature for two days. The well was uncapped and the contents filtered into a well in a fresh titer plate. The well and alumina/Siθ2 were rinsed with methylene chloride and the washes added to the filtrate (2 x 0.5 mL per well) . The solvent was evaporated at ambient temperature by speed-vac overnight. Prior to final drying, a sample of solution was taken from the well and submitted for low resolution mass spectrometry, which confirmed an m/e for C19H20CINO2 of 329 (M + τ , 4), and 331 (M+2 , 2 Example 3. d, 1 -2 .3 , 3a , 4 , 5 , 9b-Hexahvdro-8-cvclohexyl-4- (p-cvanophenyl) furo [3 , 2-cl quinoline: The procedure in Example 1 was used to produce d, 1- 2 , 3 , 3a, 4, 5, 9b-hexahydro-8-cyclohexyl-4- (p- cyanophenyl) furo [3 , 2-c] quinoline. 4-Cyclohexylaniline (100 μL of a 0.5 M solution in EtOH) and 4- cyanobenzaldehyde (100 μL of a 0.5 M solution in EtOH) were reacted overnight at ambient temperature, followed by 4 hours incubation at ~50_C. The solvent was then evaporated by vacuum overnight (5-10 in/Hg, ambient temperature) . The residue was then dissolved in methylene chloride (0.3 mL) , and 2 , 3 -dihydrofuran (100 μL of a 0.6 M solution in methylene chloride) was added to the reaction zone. Trifluoroacetic acid was then added (100 μL of a 25 mM solution) followed by FeCl3 (lOOμL of a 50 mM solution in methylene chloride) . The well was capped and shaken for twenty four hours at ambient temperature. The well was uncapped and a 3:1 mixture of neutral alumina/Siθ2 (-90 mg) was added to the well followed by additional methylene chloride (300 μL) . The well was capped and occasionally shaken at ambient temperature for two days. The well was uncapped and the contents filtered into a well in a clean titer plate. The well and alumina/Siθ2 were rinsed with methylene chloride and the washes added to the filtrate (2 x 0.5 mL per well) . The solvent was evaporated at ambient temperature by speed-vac overnight. Prior to final drying, a sample of solution was taken from the well and submitted for low resolution mass spectrometry, which confirmed an m/e for C24H26N20 of 358 (M + , 11) . Example 4. d, 1-2 , 3 , 3a, 4 , 5 , 9b-Hexahydro-4- (p- benzyloxyphenyl ) -8-chloro-6-phenylcarbonylfuro [3,2- cl quinoline : The procedure in Example 1 was used to produce d, l - 2,3, 3a, 4,5, 9b-hexahydro-4- (p-benzyloxyphenyl ) -8-chloro-6- phenylcarbonylfuro [3 , 2-c] quinoline . 2-Benzoyl-4- chloroaniline (100 μL of a 0.5 M solution in EtOH) and 4- benzyloxybenzaldehyde (100 μL of a 0.5 M solution in EtOH) were reacted overnight at ambient temperature, followed by 4 hours incubation at ~50_C. The solvent was then evaporated by vacuum overnight (5-10 in/Hg, ambient temperature) . The residue was then dissolved in methylene chloride (0.3 mL) , and 2 , 3 -dihydrofuran (100 μL of a 0.6 M solution in methylene chloride) was added to the reaction zone. Trifluoroacetic acid was then added (100 μL of a 25 mM solution) followed by FeCl3 (lOOμL of a 50 mM solution in methylene chloride) . The well was capped and shaken for twenty four hours at ambient temperature. The well was uncapped and a 3:1 mixture of neutral alumina/Siθ2 (-90 mg) was added to the well followed by additional methylene chloride (300 μL) . The well was capped and occasionally shaken at ambient temperature for two days. The well was uncapped and the contents filtered into a well in a fresh titer plate. The well and alumina/Siθ2 were rinsed with methylene chloride and the washes added to the filtrate (2 x 0.5 mL per well) . The solvent was evaporated at ambient temperature by speed-vac overnight. Prior to final drying, a sample of solution was taken from the well and submitted for low resolution mass spectrometry, which confirmed an m/e for C31H26CINO3 of 495 (M + , 7), 496 (M+l, 4), and 497 (M+2, Example 5. d, 1 -2 , 3 , 3a, 4 , 5 , 9b-Hexahvdro-4- (p- benzyloxyphenyl) -8-chloro-6-fluorofuro [3 , 2-cl quinoline: The procedure in Example 1 was used to produce d, 1- 2,3, 3a, 4,5, 9b-hexahydro-4- (p-benzyloxyphenyl ) -8-chloro-6- fluorofuro [3 , 2-c] quinoline . 2-Fluoro-4-chloroaniline (100 μL of a 0.5 M solution in EtOH) and 4- benzyloxybenzaldehyde (100 μL of a 0.5 M solution in EtOH) were reacted overnight at ambient temperature, followed by 4 hours incubation at ~50_C. The solvent was then evaporated by vacuum overnight (5-10 in/Hg, ambient temperature) . The residue was then dissolved in methylene chloride (0.3 mL) , and 2 , 3 -dihydrofuran (100 μL of a 0.6 M solution in methylene chloride) was added to the reaction zone. Trifluoroacetic acid was then added (100 μL of a 25 mM solution) followed by FeCl3 (lOOμL of a 50 mM solution in methylene chloride) . The well was capped and shaken for twenty four hours at ambient temperature. The well was uncapped and a 3:1 mixture of neutral alumina/Siθ2 (-90 mg) was added to the well followed by additional methylene chloride (300 μL) . The well was capped and occasionally shaken at ambient temperature for two days. The well was uncapped and the contents filtered into a well in a clean titer plate. The well and alumina/Siθ2 were rinsed with methylene chloride and the washes added to the filtrate (2 x 0.5 mL per well) . The solvent was evaporated at ambient temperature by speed-vac overnight. Prior to final drying, a sample of solution was taken from the well and submitted for low resolution mass spectrometry, which confirmed an m/e for C24H21FC1N02 of 409 (M + , 6), and 331 (M+2, 2).

Claims: I claim : 1. A library of hydrofuroquinoline compounds wherein said library contains a plurality of diverse library compounds of the formula (I) : wherein Ri and Ri ' are independently hydrogen or a non- interfering substituent derived from an optionally substituted aniline of the formula: R2 is hydrogen or an organic moiety derived from an aldehyde of the formula R2CHO, and R3 is hydrogen or an organic moiety derived from an optionally substituted dihydrofuran of the formula: 2. The library of claim 1 wherein Ri and Ri ' are independently selected from hydrogen and non-interfering substituents, R2 is alkyl, substituted alkyl, or aryl, and R3 is hydrogen, alkyl, substituted alkyl, or aryl. 3. The library of claim 1 wherein the optionally substituted aniline has a molecular weight of about 93 to about 600. 4. The library of claim 1 wherein the aldehyde has a molecular weight of about 44 to about 700. 5. A compound selected from the group consisting of the library compounds of the library of claim 1. 6. A process for preparing a combinatorial library of hydrofuroquinoline compounds of the formula (I): having diversity in substituent groups Ri, Rl ' , R2 - and R3 , wherein each library compound is made in a separate reaction zone, said process comprising the steps of reacting an aniline of the formula NH 2 with an aldehyde of the formula R2CHO, to form an intermediate imine compound of the formula in each reaction zone and reacting the intermediate imine in each zone with an optionally substituted 2,3- dihydrofuran of the formula in the presence of an acid, wherein in the above formulas Rl and Ri ' are independently selected from hydrogen and non-interfering substituents, R2 is hydrogen or an organic moiety, and R3 is hydrogen or an organic moiety. 7. An assay kit for identification of pharmaceutical lead compounds, said kit comprising biological assay materials and a well plate apparatus wherein each well in said apparatus contains a library compound of the library of claim 1. 8. The assay kit of claim 7 wherein the biological materials are selected for performing at least one assay test selected from the group consisting of in vi tro assays, cell based, functional assays, and add, incubate, and read assays. 9. An apparatus suitable as a replacement element in an automated assay machine as a source of individual members of a library of structurally related compounds, said apparatus comprising a 2 -dimensional array of defined reservoirs, each reservoir containing a library compound of said library, wherein said structurally related compounds are of the formula wherein Ri and Ri ' are independently hydrogen or non- interfering substituents derived from an optionally substituted aniline of the formula: R2 is hydrogen or an organic moiety derived from an aldehyde of the formula R2CHO, and R3 is hydrogen or an organic moiety derived from an optionally substituted dihydrofuran of the formula: 10. The apparatus of claim 9 wherein the library compound in each reservoir is prepared in accordance with the process of claim 6 and wherein each reservoir provides one reaction zone. 11. The apparatus of claim 9 wherein the 2- dimensional array of defined reservoirs is a multi-well microtiter plate.

Inventors: MENDOZA JOSE S, MENDOZA, JOSE S.
Applicants: LILLY CO ELI, MENDOZA JOSE S, ELI LILLY AND COMPANY, MENDOZA, JOSE S.
Application year: 1997
Main classification: C07D471
IPC codes: C07B61, C07D491