Abstract:
The invention relates to methods of synthesizing libraries of diverse and complex 2-substituted azole compounds of the general formula (I) or (II)                            
     wherein X, R 2  and the ring components                            
     are as described herein, novel intermediates useful for synthesizing such substituted azole compounds and methods for identifying and isolating the compounds.

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application claims the priority of U.S. provisional application serial No. 60/209,730 filed Jun. 5, 2000, the contents of which are hereby incorporated by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention is directed to a method of synthesizing libraries of diverse and complex 2-substituted azole derivatives and novel intermediate compounds. The invention is further directed to methods for synthesizing the libraries on solid supports. 
     BACKGROUND OF THE INVENTION 
     Compounds having biological activity can be identified by screening diverse collections of compounds (i.e., libraries of compounds) produced through synthetic chemical techniques. 
     The generation of chemical libraries on and off solid resins have proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs using high throughput screening (HTS) techniques. In creating the libraries, the compounds are ideally synthesized in situ in solution phase or on a solid support. However, relatively simple synthetic methods to produce a diverse collection of such derivatives in situ are often not available. 
     Such screening methods include methods wherein each member of the library is tagged with a unique identifier tag to facilitate identification of compounds having biological activity or where the library comprises a plurality of compounds synthesized at specific locations on the surface of a solid substrate wherein a receptor is appropriately labeled to identify binding to the compound, e.g., fluorescent or radioactive labels. Correlation of the labeled receptor bound to the substrate with its location on the substrate identifies the binding compound. Using these techniques, the development of efficient high throughput screening has greatly enhanced the pharmaceutical industry&#39;s ability to screen large numbers of compounds for biological activity. 
     Central to these methods is the screening of a multiplicity of compounds in the library and the ability to identify the structures of the compounds that have a requisite biological activity. Preferably, in order to facilitate synthesis and identification, the compounds in the library are typically formed on solid supports wherein the compound is covalently attached to the support via a cleavable or non-cleavable linking arm. In this regard, libraries of diverse compounds are prepared and then screened to identify “lead compounds” having good binding affinity to the receptor. 
     Pharmaceutical drug discovery relies heavily on studies of structure-activity relationships wherein the structure of “lead compounds” is typically altered to determine the effect of such alteration on activity. Alteration of the structure of the lead compounds permits evaluation of the effect of the structural alteration on activity. 
     Thus, libraries of compounds derived from a lead compound can be created by including derivatives of the lead compound and repeating the screening procedures. In this manner, compounds with the best biological profile, i.e., those that are most active and which have the most ideal pharmacologic and pharmacokinetic properties, can be identified from the initial lead compound. 
     Recently, 2-substituted oxazoles were found to be potent as MMP inhibitors (Sheppard, et al,  in Bioorg Med Chem Lett  8(22), 3251 (1998)); 2-substituted imidazoles were found to produce local anesthetic effects (Colombo, et al.,  Rev Farmacol Clin Exp,  4(1), 41-47 (1987); and 2-substituted thiazoles were found to be selective inhibitors of 5-lipoxygenase (Bird, et al., 5 th    Int Conf Inflamm Res Assoc (September  23-27 Whit Haven) Abst 85, 1990). 
     Synthesis of substituted nitrogen containing heteroaryls using solution phase chemistry has been previously described. Khristich et al., in  Khimia Geterotsiklicheskikh Soedineii,  8, 1136-36 (1983) describe the solution phase synthesis of α-(1-methyl-2-benzimidazolyl)benzyl benzoates. Roe et al., in  JCS  p 2195 (1963) describe the thermal condensation of imidazoles with carbonyl compounds. Papadopolous, in  J. Org. Chem.,  42 (24) 3925-29, (1977) describes reaction of imidazoles with isocyanates, while Papadopolous et al., in  J. Org. Chem.,  44(1) 99-104 (1979) describe reactions of azoles with isocyanates. Cleavage of the silicon-carbon bond of 2-trimethylsilyl-1-methylimidazole and 2-trimethylsilyl-1-benzimidazole to yield 2-substituted imidazoles and 2-substituted benzimidazoles is described by Pinkerton, F. H. and Thames, S. F., in  J. Heterocycl. Chem.  9(1), 67-72 (1972). Dondoni et al., in  J. Org. Chem.,  53, 1748-61 (1988) describe the synthesis of (trimethylsilyl)thiazoles which are reacted with carbonyl compounds to prepared highly substituted thiazoles. 
     These methods however, do not permit for rapid synthesis of large libraries with diverse substitution patterns. Thus there exists a need for a solid phase method for synthesis of highly substituted azole compounds. 
     Accordingly, in order to develop new pharmaceutical drugs to treat various disease conditions, it would be highly desirable to be able to generate such libraries of substituted azole derivatives and novel intermediate compounds optionally attached to a solid support. Thus, there is a need for a facile in situ method for the generation of a multiplicity of substituted azole derivatives and novel intermediate compounds. 
     SUMMARY OF THE INVENTION 
     The present invention is directed to a process for assembly of diverse, 2-substituted azole derivatives and novel intermediate compounds using available azoles as starting materials. The rapid synthesis of such highly complex drug-like molecules is unexpected and surprising. 
     Accordingly, the invention is directed to a method of synthesizing highly substituted azole derivatives having the formula (I) or (II):                           
     wherein 
     X is selected from the group consisting of NH, NR A  and S;                           
     represents a 5 membered aromatic ring structure; optionally containing one to two additional heteroatoms selected from the group consisting of N, O and S; 
     provided that the additional heteroatoms are not at the attachment point of the R 2  group (i.e. the R 2  group is always attached to a ring carbon); 
     provided that the 5 membered ring remains aromatic in nature; 
     wherein the 5 membered ring is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO 2 R and —CONR B R C ; wherein the amine substituents are independently selected from alkyl, cycloalkyl, aryl or aralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be further optionally substituted with one or more substituent is independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano or nitro;                           
     represents a 9 membered ring structure, wherein the five membered portion of the ring structure—                          
     — is aromatic and the six membered portion of the ring structure —                          
     — is saturated, partially unsaturated, or aromatic; 
     wherein the 5 membered portion of the ring structure is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO 2 R and —CONR B R C ; wherein the amine substituents are independently selected from alkyl, cycloalkyl, aryl or aralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be further optionally substituted with one or more substituent is independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano or nitro; 
     wherein the 6-membered portion of the ring structure may further optionally containing one to four additional heteroatoms selected from the group consisting of N, O and S; 
     wherein the 6-membered portion of the ring structure may further be optionally substituted with one to four substituents independently selected from the group consisting of halogen, hydroxy, alkyl, halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano, nitro, —COOR, —COR, —SO 2 R and —CONR B R C ; wherein the amine substituents are independently selected from alkyl, cycloalkyl, aryl or aralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be further optionally substituted with one or more substituent independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano or nitro; 
     R 2  is selected from the group consisting of                           
     Z is selected from the group consisting of hydrogen, —OH, —OR, —NR A R B , N(R A )OR B,  —SR, —CN, —N 3 , and                           
     wherein                           
     represents a three to eight membered heterocyclyl group bound at the N atom, wherein the heterocyclyl group is saturated, partially unsaturated or aromatic; when the heterocyclyl group is a saturated six to eight membered heterocyclyl, the heterocyclyl group may optionally contains a group selected from O, CHR, NR, S, SO, or SO 2 , provided that that the group is separated from the N atom by at least two carbon atoms; and wherein the heterocylcyl group is optionally substituted with one or more substituents independently selected from R; 
     R 3  is selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, fluorinated alkyl, —COR, —COOR and —CONR B R C ; wherein the aralkyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono- or di-substituted amino, cyano or nitro; 
     R 4  is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, fluorinated alkyl, alkenyl, alkynyl, —COOR, —COR, —CONCND, -alkyl-COOR, heterocycle and                           
     wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocycle may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, aryl, alkoxy, aryloxy, amino, mono-or di-substituted amino, cyano or nitro; wherein Y is selected from the group consisting of O, S and NR A ; 
     where R is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocycle; wherein the alkyl, aryl, aralkyl or heterocycle may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano or nitro; 
     where R A  is selected from the group consisting of hydrogen, —R, —COOR, —COR, —SO 2 R and —CONR B R C  and                           
     where R B  and R C  are independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano or nitro; or are joined together to form a 4 to 8 membered heterocyclyl ring structure; 
     which method comprises: 
     a) preparing a compound of the formula (III) or (V) on a solid support resin,                           
     wherein R 3  and R 4  are as described above; 
     b) cleaving the compound from the solid support resin by nucleophilic substitution to yield the corresponding compound of formula (I) or (II); 
     c) optionally further substituting the compound of formula (I) or (II) via alkylation reactions in solution phase. 
     DETAILED DESCRIPTION OF THE INVENTION 
     As used herein, the term “alkyl” whether used alone or as part of a substituent group, shall denote straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, “lower” when used with alkyl means a carbon chain composition of 1 to 4 carbon atoms. Similarly, as used herein, the term “alkenyl”, whether used alone or as part of a substituent group, shall denote straight and branched chain alkene radicals, i.e. straight of branched chains containing at least one double bond. For example, alkenyl radicals include allyl, vinyl, and the like. Similarly, as used herein, the term “alkynyl”, whether used alone or as part of a substituent group, shall denote straight and branched chain alkyne radicals, i.e., straight or branched chains containing at least one triple bond. For example, alkynyl radicals include —CCH, —CH 2 CCH (propargyl), —CH 2 CCCH 3 , and the like. 
     As used herein, unless otherwise noted, “alkoxy” shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. 
     As used herein, “halogen” shall mean chlorine, bromine, fluorine and iodine. 
     As used herein, unless otherwise noted, “aryl” shall refer to carbocyclic aromatic groups such as phenyl, naphthyl, and the like. Similarly, the term “aryloxy” shall denote the oxygen ether radical of the above described aryl group, i.e. —O-(aryl). Suitable examples include phenyloxy, naphthyloxy, and the like. 
     As used herein, unless otherwise noted, “aralkyl” shall mean any lower alkyl group substituted with an aryl group such as phenyl, naphthyl and the like. Suitable examples of aralkyls include benzyl, 1-(phenyl)ethyl, naphthylmethyl, and the like. 
     As used herein, the term “cycloalkyl” shall denote any monocyclic three to eight membered, saturated carbocyclic ring structure. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloocytyl. 
     As used herein, unless otherwise noted, the terms “heterocycle”, “heterocyclyl” and “heterocyclo” shall denote any five or six membered monocyclic, nine or ten membered bicyclic or thirteen or fourteen membered tricyclic ring structure containing at least one heteroatom selected from the group consisting of N, O and S, optionally containing one to four additional heteroatoms, wherein the ring structure is saturated, partially unsaturated, aromatic or partially aromatic. The heterocyclyl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. 
     Exemplary monocyclic heterocyclic groups can include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropryanyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, triazinyl, triazolyl and the like. 
     Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl), or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisoth iazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl and the like. 
     Exemplary tricyclic heterocylclic groups include phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl, phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the like. 
     In the definition of Z, suitable examples of the                           
     group include pyrazol-1-yl, imidazol-1-yl, pyrrol-1-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl, aziridin-1-yl, pyrrolidin-1-yl, piperidin-1yl, piperazin-1-yl, morpholin-1-yl, 4-methyl-diazepin-1-yl, azepin-1-yl, diazepin-1-yl, 4-methyl-piperazin-1yl, and the like. 
     When a particular group is “substituted” (e.g., cycloalkyl, aryl, heterocyclyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents. 
     With reference to substituents, the term “independently” means that when more than one of such substituents is possible, such substituents may be the same or different from each other. 
     Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenylalkylaminocarbonylalkyl” substituent refers to a group of the formula                           
     The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. 
     The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. 
     As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. 
     For the purposes of this invention, the term “chemical library” means a collection of molecules prepared by the method of the invention based on logical design by means of simultaneous or parallel chemical reactions. Each species of molecule in the library is referred to as a member of the library. 
     Abbreviations used in the specification, particularly the Schemes and Examples, are as follows: 
     
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 DCE = 
                 1,2-Dichloroethane 
               
               
                   
                 DCM = 
                 Dichloromethane 
               
               
                   
                 DIPEA = 
                 Diisopropylethylamine 
               
               
                   
                 DMF = 
                 N,N-Dimethylformamide 
               
               
                   
                 Et 2 O = 
                 Diethyl ether 
               
               
                   
                 ID# = 
                 Compound ID number 
               
               
                   
                 MeOH = 
                 Methanol 
               
               
                   
                 Pd(PPh 3 ) 4  = 
                 Palladium, tetrakis(triphenylphosphine)- 
               
               
                   
                 TEA = 
                 Triethylamine 
               
               
                   
                 TFA = 
                 Trifluoroacetic acid 
               
               
                   
                 THF = 
                 Tetrahydrofuran 
               
               
                   
                 THP = 
                 Tetrahydropyran 
               
               
                   
                   
               
             
          
         
       
     
     The compounds of formula (I) wherein R 2  is                           
     may be prepared on solid resin according to the process outlined in Scheme 1.                           
     More specifically, a solid resin support of formula (VII), a resin support terminated with a carbonyl chloride functional group, a known compound or compound prepared by known methods (e.g. polystyrene-carbonylchloride resin from T. M. Fyles, C. C. Leznoff, J. Weatherston,  Can. J. Chem.  1978, 56, 1031 and Meyers, at al., Molecular Diversity, 1, 13 (1995); or Reaction of NovaSyn® TG carboxy Resin from Calbiochem-Novabiochem Corp with oxalyl chloride;) is reacted with a compound of formula (VIII), a known compound or compound prepared by known methods, 
     and then reacted with a compound of formula (IX), in a non-protic solvent such as acetonitrile, dioxane, THF, and the like, in the presence of a base such as TEA, and the like, at a temperature in the range of about 0° C. to about reflux, to form the corresponding compound of formula (X). 
     Where Z is a moiety other than H, the compound of formula (X) is then reacted with a compound of formula (XI), in the presence of an acid such as TFA, and the like, in a non-protic solvent such as acetonitrile, dioxane, THF, and the like, at a temperature in the range of about 0° C. to about reflux, resulting in cleavage of the resin support, to form the corresponding compound of formula (Ia). 
     When in the compound of formula (Ia) Z is H, the compound of formula (X) is reduced by transfer hydrogenation with a metal catalyst such as Pd(PPh 3 ) 4 , and the like, in the presence of a source of transfer hydrogen such as triethylammonium formate, ammonium formate, and the like, wherein the source of transfer hydrogen is present in an amount equal to about 2 to 20 equivalents, preferably about 5 equivalents, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of about 40-110° C., preferably at about reflux temperature, to form the corresponding compound of formula (Ia). 
     Compounds of formula (II) wherein R 2  is                           
     may be similarly prepared on solid resin according to the process outlined in Scheme 1, with appropriate substitution of a compound of formula (XII)                           
     for the compound of formula (VIII), to yield the corresponding compound of formula (IIa).                           
     The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter. 
    
    
     EXAMPLE A 
                              To a suspension of polystyrene-carbonylchloride resin (prepare from carboxypolystyrene by treatment with thionyl chloride, T. M. Fyles, C. C. Leznoff, J. Weatherston,  Can. J. Chem.  1978, 56, 1031,) in THF is added 10 equivalents each of 1-benzylimidazole benzaldehyde, and then N,N-diisopropylethylamine. The mixture is shaken at room temperature far one to five days and washed five times with THF. The product resin is dried under vacuum overnight. 
     EXAMPLE B 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared in as Example 1, in tetrahydrofuran, is added 20 equivalents of water and 5 equivalents of trifluoroacetic acid. The mixture is shaken one to five days at 65° C. and after cooling to room temperature is washed five times with tetrahydrofuran. The washes are concentrated to afford the product. The product is used as is or is purified by flash chromatography on silica eluted with methanol:methylene chloride mixtures to yield the purified product. 
     EXAMPLE C 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 1, in tetrahydrofuran, is added 20 equivalents of anhydrous methanol and 5 equivalents of trifluoroacetic acid. The mixture is shaken one to five days at 65° C. and after cooling to room temperature is washed five times with tetrahydrofuran. The washes are concentrated to afford the product. The product is used as is or is purified by flash chromatography on silica eluted with methanol:methylene chloride mixtures to yield the purified product. 
     EXAMPLE D 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 1, in tetrahydrofuran, is added 20 equivalents of absolute ethanol and 5 equivalents of trifluoroacetic acid. The mixture is shaken one to five days at 65° C. and after cooling to room temperature is washed five times with tetrahydrofuran. The washes are concentrated to afford the product. The product is used as is or is purified by flash chromatography on silica eluted with methanol:methylene chloride mixtures to yield the purified product. 
     EXAMPLE E 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 1, in tetrahydrofuran, is added 20 equivalents of acetamide and 5 equivalents of trifluoroacetic acid. The mixture is shaken one to five days at 65° C. and after cooling to room temperature is washed five times with tetrahydrofuran. The washes are concentrated to afford the product. The product is purified by flash chromatography on silica eluted with methanol:methylene chloride mixtures to yield the purified product. 
     EXAMPLE F 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 1, in tetrahydrofuran, is added 20 equivalents of methanesulfonamide and 5 equivalents of trifluoroacetic acid. The mixture is shaken one to five days at 65° C. and after cooling to room temperature is washed five times with tetrahydrofuran. The washes are concentrated to afford the product. The product is purified by flash chromatography on silica eluted with methanol:methylene chloride mixtures to yield the purified product. 
     EXAMPLE G 
     
       
                 
         
             
             
         
      
     
     To a suspension of polystyrene-carbonylchloride resin (prepare from carboxypolystyrene by treatment with thionyl chloride, T. M. Fyles, C. C. Leznoff, J. Weatherston,  Can. J. Chem.  1978, 56, 1031.) in THF is added 10 equivalents each of 1-methylbenzimidazole, benzaldehyde, and then N,N-diisopropylethylamine. The mixture is shaken at room temperature for one to five days and washed five times with THF. The resin product is dried under vacuum overnight. 
     EXAMPLE H 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 7, in tetrahydrofuran, is added 20 equivalents of water and 5 equivalents of trifluoroacetic acid. The mixture is shaken one to five days at 65° C. and after cooling to room temperature is washed five times with tetrahydrofuran. The washes are concentrated to afford the product. The product is used as is or is purified by flash chromatography on silica eluted with methanol:methylene chloride mixtures to yield the purified product. 
     EXAMPLE I 
     
       
                 
         
             
             
         
      
     
     To a suspension of polystyrene-carbonylchloride resin (prepare from carboxypolystyrene by treatment with thionyl chloride, T. M. Fyles, C. C. Leznoff; J, Weatherston,  Can. J. Chem.  1979, 56, 1031.) in THF is added 10 equivalents each of thiazole, benzaldehyde, and then N,N-diisopropylethylamine. The mixture is shaken at room temperature for one to five days and washed five times with THF. The resin product is dried under vacuum overnight. 
     EXAMPLE J 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 9, in tetrahydrofuran, is added 20 equivalents of water and 5 equivalents of trifluoroacetic acid. The mixture is shaken one to five days at 65° C. and after cooling to room temperature is washed five times with tetrahydrofuran. The washes are concentrated to afford the product. The product is purified by flash chromatography on silica eluted with methanol:methylene chloride mixtures to yield the purified product. 
     EXAMPLE 1 
     
       
                 
         
             
             
         
      
     
     Method A: 
     To a suspension of polystyrene-carboxylate resin (2 g, loading 1.24 mmol/g from NovaBiochem) in dichloromethane (40 mL) was added oxalyl chloride (0.55 mL, 6.2 mmol) and DMF (0.5 mL) under nitrogen. The mixture was refluxed for 6 hours with a reflux condenser. After cooling to room temperature, the resin was washed five times with DCM to yield the title product, the polystyrene-carbonylchloride resin A. 
     Method B: 
     To a suspension of polystyrene-carboxylate resin (2 g loading 1.24 mmol from NovaBiochem) in toluene (40 mL) was added oxalyl chloride (0.55 mL, 6.2 mmol) under nitrogen. The mixture was heated for 6 hours at 60° C. with a reflux condenser. After cooling to room temperature, the resin was washed two times with toluene and three times with DCM to yield the title compound, the polystyrene-carbonylchloride resin A. 
     EXAMPLE 2 
     
       
                 
         
             
             
         
      
     
     To a suspension of polystyrene-carbonylchloride resin A (prepared as in Example 1) in tetrahydrofuran was added 5 equivalents of methylimidazolyl, 10 equivalents benzaldehyde, and then 10 equivlanets of N,N-diisopropylethylamine. The mixture was shaken at room temperature for 24 hours and washed with DCM. The product resin B was dried under vacuum overnight. 
     EXAMPLE 3 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 2, in tetrahydrofuran were added 20 equivalents of water and 10 equivalents of trifluoroacetic acid. The mixture was shaken for 24 hours at 65° C. and after cooling to room temperature was washed with tetrahydrofuran, DCM and methanol. The washes were concentrated to afford the product. The product was purified by flash chromatography on silica eluted with methanol:ethyl acetate mixtures to yield the purified product. 
     LC/MS (ESP) m/z 189 (MH + ) 
     EXAMPLE 4 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 2, in DMF, was added 10 equivalents of NaN 3  and 5 equivalents of BF 3 .Et 2 O. The mixture was shaken for 24 hours at 70° C. and after cooling to room temperature was washed with DCM and methanol. The washes were concentrated to afford the product. The product was purified by flash chromatography on silica eluted with methanol:ethyl acetate mixtures to yield the purified product. 
     LC/MS (ESP) m/z 214 (MH + ) 
     EXAMPLE 5 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 2, in tetrahydrofuran were added 10 equivalents of aniline and 6 equivalents of trifluoroacetic acid. The mixture was shaken for 24 hours at 65° C. and after cooling to room temperature was washed five times with tetrahydrofuran, DCM and MeOH. The washes were concentrated to afford the product. The product was purified by flash chromatography on silica eluted with ethyl acetate and hexane mixtures to yield the purified product. 
     LC/MS (ESP) mlz 264 (MH + ). 
     EXAMPLE 5 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 2, in tetrahydropyran, were added 10 equivalents of piperidine, 9 equivalents of trifluoroacetic acid and 1.5 equivalents of BF 3 .Et 2 O. The mixture was shaken 24 hours and after cooling to room temperature was washed with tetrahydrofuran, DCM and MeOH. The washes were concentrated to afford the product. 
     LC/MS (ESP) mlz 256 (MH + ). 
     EXAMPLE 7 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared in as Example 2, in tetrahydrofuran, were added 20 equivalents of methanol and 10 equivalents of trifluoroacetic acid. The mixture was shaken 24 hours at 65° C. and after cooling to room temperature was washed with DCM and MeOH. The washes were concentrated to afford the product. 
     LC/MS (ESP) m/z 203 (MH + ). 
     EXAMPLE 8 
     
       
                 
         
             
             
         
      
     
     To a suspension of the resin prepared as in Example 2, in tetrahydropyran, were added 10 equivalents of morpholine, 9 equivalents of trifluoroacetic acid and 1.5 equivalents of BF 3 .Et 2 O. The mixture was shaken 24 hours at 70° C. and after cooling to room temperature was washed with tetrahydrofuran, DCM and MeOH. The washes were concentrated to afford the product. 
     LC/MS (ESP) m/z 258 (MH + ). 
     EXAMPLES 9-13 
     Following the procedures described in Examples 3 to 8 above, selected compounds of the present invention were prepared as listed in Table 1 
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 Measured Mass 
               
               
                   
                 ID # 
                 Z 
                 R 4   
                 spec (MH + ) 
               
               
                   
                   
               
               
                   
                  9 
                 phenyloxy 
                 phenyl 
                 265 
               
               
                   
                 10 
                 4-methyl-piperazin-1-yl 
                 phenyl 
                 271 
               
               
                   
                 11 
                 methoxyamino 
                 phenyl 
                 218 
               
               
                   
                 12 
                 (2-hydroxyethyl)thio 
                 phenyl 
                 249 
               
               
                   
                 13 
                 (2-hydroxyethyl)amino 
                 phenyl 
                 232 
               
               
                   
                   
               
             
          
         
       
     
     EXAMPLE 14 
     
       
                 
         
             
             
         
      
     
     To a polystyrene-carbonylate resin loaded in ACT 496 MOS blocks (Advanced Chem Tech, Louisville, Ky., USA) was added 5 equivalents of oxalyl chloride in toluene. The mixtures were shaken at about 40° C. for 20 hours. The reaction well was emptied, and washed with toluene and dichloromethane to yield the polystyrene-carbonylchloride resin. 
     To the well loaded with the polystyrene-carbonylchloride resin, 6 equivalents of 4-chlorobenzaldehyde in dichloromethane, 3 equivalents of 1-benzylimidazole and 6 equivalents of N,N-diisopropylethylamine in dichloromethane were added consecutively. The mixture was shaken at room temperature for 48 hours and washed with DCM to yield the title compound, the polystyrene-carbonylate resin C. 
     EXAMPLE 15 
     
       
                 
         
             
             
         
      
     
     To the resin prepared as in Example 8 above were added 5 equivalents of phenol in tetrahydropyran, 4 equivalents of trifluoroacetic acid and 1.5 equivalents of BF 3 .Et 2 O in tetrahydropyran. The mixture was shaken 24 hours at 50° C. and after cooling to room temperature was washed with tetrahydrofuran, DCM and methanol. The washes were concentrated to yield the title product as a solid. MS (ESP) MH +  376. 
     EXAMPLE 16-127 
     Following the procedures described in Examples 14 and 15 above, selected compounds of the present invention were prepared using the ACT 496 MOS robot (Advanced Chem Tech, Louisville, Ky., USA) as listed in Table 2 and 3. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                 ID # 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Z 
                 R 4   
                 Meas. MW 
               
               
                   
               
             
          
           
               
                 16 
                 1-benzyl-imidazol-2-yl 
                 Piperidin-1-yl 
                 4-chlorophenyl 
                 281 (M +  loss of C 5 H 10 N) 
               
               
                 17 
                 1-benzyl-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 4-chlorophenyl 
                 381 
               
               
                 18 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-morpholin-1-yl 
                 4-chlorophenyl 
                 239 (M +  loss of C 4 H 8 ON) 
               
               
                 19 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 4-chlorophenyl 
                 339 
               
               
                 20 
                 4-benzyl-1,2,4-triazol-3-yl 
                 4-morpholin-1-yl 
                 4-chlorophenyl 
                 381 (M Na + ) 
               
               
                 21 
                 4-benzyl-1,2,4-triazol-3-yl 
                 4-methyl-piperazin-1-yl 
                 4-chlorophenyl 
                 404 (M Na + ) 
               
               
                 23 
                 thiazol-2-yl 
                 4-morpholin-1-yl 
                 4-chlorophenyl 
                 317 (M Na + ) 
               
               
                 24 
                 thiazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 4-chlorophenyl 
                 208 (M +  loss of C 5 H 11 N 2 ) 
               
               
                 25 
                 4-methyl-5-vinyl-thiazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 4-chlorophenyl 
                 248 (M +  loss of C 5 H 11 N 2 ) 
               
               
                 26 
                 1-benzyl-imidazol-2-yl 
                 4-morpholin-1-yl 
                 4-methoxyphenyl 
                 364 
               
               
                 27 
                 1-benzyl-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 4-methoxyphenyl 
                 377 
               
               
                 28 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-morpholin-1-yl 
                 4-methoxyphenyl 
                 235 (M +  loss of C 4 H 8 ON) 
               
               
                 29 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 4-methoxyphenyl 
                 335 
               
               
                 32 
                 thiazol-2-yl 
                 4-morpholin-1-yl 
                 4-methoxyphenyl 
                 204 (M +  loss of C 4 H 8 ON) 
               
               
                 33 
                 thiazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 4-methoxyphenyl 
                 304 
               
               
                 34 
                 4-methyl-5-vinyl-thiazol-2-yl 
                 4-morpholin-1-yl 
                 4-methoxyphenyl 
                 331 
               
               
                 35 
                 4-methyl-5-vinyl-thiazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 4-methoxyphenyl 
                 344 
               
               
                 36 
                 1-benzyl-imidazol-2-yl 
                 4-morpholin-1-yl 
                 vinyl 
                 284 
               
               
                 37 
                 1-benzyl-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 vinyl 
                 297 
               
               
                 38 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-morpholin-1-yl 
                 vinyl 
                 242 
               
               
                 39 
                 4-benzyl-1,2,4-triazol-3-yl 
                 4-morpholin-1-yl 
                 vinyl 
                 285 
               
               
                 40 
                 4-benzyl-1,2,4-triazol-3-yl 
                 4-methyl-piperazin-1-yl 
                 vinyl 
                 298 
               
               
                 43 
                 thiazol-2-yl 
                 4-morpholin-1-yl 
                 vinyl 
                 211 
               
               
                 44 
                 thiazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 vinyl 
                 224 
               
               
                 45 
                 4-methyl-5-vinyl-thiazol-2-yl 
                 4-morpholin-1-yl 
                 vinyl 
                 251 
               
               
                 46 
                 4-methyl-5-vinyl-thiazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 vinyl 
                 264 
               
               
                 47 
                 1-benzyl-imidazol-2-yl 
                 4-morpholin-1-yl 
                 2-pyridyl 
                 248 (M +  loss of C 4 H 8 ON) 
               
               
                 48 
                 1-benzyl-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 2-pyridyl 
                 348 
               
               
                 49 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-morpholin-1-yl 
                 2-pyridyl 
                 206 (M +  loss of C 4 H 8 ON) 
               
               
                 50 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 2-pyridyl 
                 206 (M +  loss of C 5 H 11 N 2 ) 
               
               
                 51 
                 4-benzyl-1,2,4-triazol-3-yl 
                 4-morpholin-1-yl 
                 2-pyridyl 
                 358 (M Na + ) 
               
               
                 52 
                 4-benzyl-1,2,4-triazol-3-yl 
                 4-methyl-piperazin-1-yl 
                 2-pyridyl 
                 349 
               
               
                 53 
                 thiazol-2-yl 
                 4-morpholin-1-yl 
                 1-methylpyrrol-2-yl 
                 286 (M Na + ) 
               
               
                 54 
                 thiazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 1-methylpyrrol-2-yl 
                 299 (M Na + ) 
               
               
                 55 
                 1-benzyl-imidazol-2-yl 
                 4-morpholin-1-yl 
                 thiophen-3-yl 
                 340 
               
               
                 56 
                 1-benzyl-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 thiophen-3-yl 
                 353 
               
               
                 57 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-morpholin-1-yl 
                 thiophen-3-yl 
                 398 
               
               
                 58 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 thiophen-3-yl 
                 311 
               
               
                 59 
                 4-benzyl-1,2,4-triazol-3-yl 
                 4-morpholin-1-yl 
                 thiophen-3-yl 
                 341 
               
               
                 60 
                 4-benzyl-1,2,4-triazol-3-yl 
                 4-methyl-piperazin-1-yl 
                 thiophen-3-yl 
                 254 (M +  loss of C 5 H 11 N 2 ) 
               
               
                 63 
                 thiazol-2-yl 
                 4-morpholin-1-yl 
                 thiophen-3-yl 
                 180 
               
               
                 64 
                 thiazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 thiophen-3-yl 
                 280 
               
               
                 67 
                 thiazol-2-yl 
                 4-morpholin-1-yl 
                 phenylethynyl 
                 285 
               
               
                 68 
                 4-methyl-5-vinyl-thiazol-2-yl 
                 4-morpholin-1-yl 
                 phenylethynyl 
                 325 
               
               
                 69 
                 4-methyl-5-vinyl-thiazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 phenylethynyl 
                 338 
               
               
                 70 
                 1-benzyl-imidazol-2-yl 
                 phenyloxy 
                 4-chlorophenyl 
                 375 
               
               
                 71 
                 1-benzyl-imidazol-2-yl 
                 Piperidin-1-yl 
                 4-methoxyphenyl 
                 368 
               
               
                 72 
                 1-benzyl-imidazol-2-yl 
                 2-pyridylamino 
                 4-chlorophenyl 
                 375 
               
               
                 73 
                 thiazol-2-yl 
                 2-hydroxy ethylthio 
                 4-chlorophenyl 
                 285 
               
               
                 74 
                 1-benzyl-imidazol-2-yl 
                 phenyloxy 
                 4-methoxyphenyl 
                 371 
               
               
                 75 
                 1-benzyl-imidazol-2-yl 
                 Piperidin-1-yl 
                 4-methoxyphenyl 
                 362 
               
               
                 76 
                 1-benzyl-imidazol-2-yl 
                 2-hydroxy ethylthio 
                 4-methoxyphenyl 
                 277 (M +  loss of C 2 H 6 NS) 
               
               
                 77 
                 1-benzyl-imidazol-2-yl 
                 2-pyridylamino 
                 4-methoxyphenyl 
                 371 
               
               
                 78 
                 thiazol-2-yl 
                 Piperidin-1-yl 
                 2-pyridyl 
                 260 
               
               
                 79 
                 thiazol-2-yl 
                 2-pyridylamino 
                 2-pyridyl 
                 269 
               
               
                 80 
                 1-benzyl-imidazol-2-yl 
                 phenyloxy 
                 1-methylpyrrol-2-yl 
                 344 
               
               
                 81 
                 1-benzyl-imidazol-2-yl 
                 phenyloxy 
                 thiophen-3-yl 
                 347 
               
               
                 82 
                 1-benzyl-imidazol-2-yl 
                 Piperidin-1-yl 
                 thiophen-3-yl 
                 338 
               
               
                 83 
                 1-benzyl-imidazol-2-yl 
                 2-hydroxy ethylthio 
                 thiophen-3-yl 
                 253 (M +  loss of C 2 H 6 NS) 
               
               
                 84 
                 1-benzyl-imidazol-2-yl 
                 2-pyridylamino 
                 thiophen-3-yl 
                 347 
               
               
                 85 
                 thiazol-2-yl 
                 phenyloxy 
                 thiophen-3-yl 
                 274 
               
               
                 86 
                 thiazol-2-yl 
                 2-hydroxy ethylthio 
                 thiophen-3-yl 
                 257 
               
               
                 87 
                 1-benzyl-imidazol-2-yl 
                 phenyloxy 
                 3,5-di(trifluoro methyl)phenyl 
                 477 
               
               
                 88 
                 1-benzyl-imidazol-2-yl 
                 Piperidin-1-yl 
                 3,5-di(trifluoro methyl)phenyl 
                 468 
               
               
                 89 
                 1-benzyl-imidazol-2-yl 
                 2-hydroxy ethylthio 
                 3,5-di(trifluoro methyl)phenyl 
                 383 
               
               
                 90 
                 1-benzyl-imidazol-2-yl 
                 2-pyridylamino 
                 3,5-di(trifluoro methyl)phenyl 
                 477 
               
               
                 91 
                 thiazol-2-yl 
                 phenyloxy 
                 1-methylindol-3-yl 
                 321 
               
               
                 92 
                 thiazol-2-yl 
                 2-pyridylamino 
                 1-methylindol-3-yl 
                 321 
               
               
                 93 
                 1-benzyl-imidazol-2-yl 
                 phenyloxy 
                 4-biphenyl 
                 417 
               
               
                 94 
                 1-benzyl-imidazol-2-yl 
                 Piperidin-1-yl 
                 4-biphenyl 
                 323 
               
               
                 95 
                 1-benzyl-imidazol-2-yl 
                 2-hydroxy ethylthio 
                 4-biphenyl 
                 323 
               
               
                 96 
                 1-benzyl-imidazol-2-yl 
                 2-pyridylamino 
                 4-biphenyl 
                 417 
               
               
                 97 
                 1-benzyl-imidazol-2-yl 
                 phenyloxy 
                 1-phenylpyrazol-4-yl 
                 407 
               
               
                 98 
                 1-benzyl-imidazol-2-yl 
                 Piperidin-1-yl 
                 1-phenylpyrazol-4-yl 
                 398 
               
               
                 99 
                 1-benzyl-imidazol-2-yl 
                 2-hydroxy ethylthio 
                 1-phenylpyrazol-4-yl 
                 313 (M +  loss of C 2 H 6 NS) 
               
               
                 100 
                 1-benzyl-imidazol-2-yl 
                 2-pyridylamino 
                 1-phenylpyrazol-4-yl 
                 407 
               
               
                 101 
                 thiazol-2-yl 
                 phenyloxy 
                 1-phenylpyrazol-4-yl 
                 334 
               
               
                 102 
                 thiazol-2-yl 
                 Piperidin-1-yl 
                 1-phenylpyrazol-4-yl 
                 240 (M +  loss of C 5 H 10 N) 
               
               
                 103 
                 thiazol-2-yl 
                 2-hydroxy ethylthio 
                 1-phenylpyrazol-4-yl 
                 317 
               
               
                 104 
                 1-benzyl-imidazol-2-yl 
                 phenyloxy 
                 3-benzyloxy-phenyl 
                 447 
               
               
                 105 
                 1-benzyl-imidazol-2-yl 
                 Piperidin-1-yl 
                 3-benzyloxy phenyl 
                 438 
               
               
                 106 
                 1-benzyl-imidazol-2-yl 
                 2-hydroxy ethylthio 
                 3-benzyloxy-phenyl 
                 353 (M +  loss of C 2 H 6 NS) 
               
               
                 107 
                 1-benzyl-imidazol-2-yl 
                 2-pyridylamino 
                 3-benzyloxy-phenyl 
                 447 
               
               
                 108 
                 1-benzyl-imidazol-2-yl 
                 phenyloxy 
                 4-chlorophenyl 
                 376 
               
               
                 109 
                 1-benzyl-imidazol-2-yl 
                 phenylamino 
                 4-chlorophenyl 
                 375 
               
               
                 110 
                 1-methyl-5-chloro-imidazol-2-yl 
                 phenyloxy 
                 4-chlorophenyl 
                 333 
               
               
                 112 
                 1-benzyl-imidazol-2-yl 
                 phenylamino 
                 4-methoxyphenyl 
                 370 
               
               
                 114 
                 1-benzyl-imidazol-2-yl 
                 phenylamino 
                 2-pyridyl 
                 341 
               
               
                 115 
                 1-methyl-5-chloro-imidazol-2-yl 
                 phenylamino 
                 2-pyridyl 
                 206 (M +  loss of C 6 H 6 N) 
               
               
                 117 
                 1-benzyl-imidazol-2-yl 
                 phenylamino 
                 thiophen-3-yl 
                 346 
               
               
                 118 
                 1-methyl-5-chloro-imidazol-2-yl 
                 phenyloxy 
                 thiophen-3-yl 
                 306 
               
               
                 119 
                 1-methyl-5-chloro-imidazol-2-yl 
                 phenylamino 
                 thiophen-3-yl 
                 321 
               
               
                 121 
                 4-methyl-5-vinyl-thiazol-2-yl 
                 4-morpholin-1-yl 
                 thiophen-3-yl 
                 307 
               
               
                 122 
                 4-methyl-5-vinyl-thiazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 thiophen-3-yl 
                 320 
               
               
                 123 
                 1-benzyl-imidazol-2-yl 
                 4-morpholin-1-yl 
                 phenylethynyl 
                 358 
               
               
                 124 
                 1-benzyl-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 phenylethynyl 
                 371 
               
               
                 125 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-morpholin-1-yl 
                 phenylethynyl 
                 316 
               
               
                 126 
                 1-methyl-5-chloro-imidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 phenylethynyl 
                 329 
               
               
                 127 
                 4-benzyl-1,2,4-triazol-3-yl 
                 4-methyl-piperazin-1-yl 
                 phenylethynyl 
                 272 (M +  loss of C 5 H 11 N 2 ) 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                 ID # 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Z 
                 R4 
                 Meas. MW 
               
               
                   
               
             
          
           
               
                 22 
                 1-methyl-benzimidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 4-chlorophenyl 
                 255 (M +  loss of C 5 H 11 N 2 ) 
               
               
                 30 
                 1-methyl-benzimidazol-2-yl 
                 4-morpholin-1-yl 
                 4-methoxyphenyl 
                 251 (M +  loss of C 4 H 8 ON) 
               
               
                 31 
                 1-methyl-benzimidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 4-methoxyphenyl 
                 251 (M +  loss of C 4 H 11 N 2 ) 
               
               
                 41 
                 1-methyl-benzimidazol-2-yl 
                 4-morpholin-1-yl 
                 vinyl 
                 258 
               
               
                 42 
                 1-methyl-benzimidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 vinyl 
                 271 
               
               
                 61 
                 1-methyl-benzimidazol-2-yl 
                 4-morpholin-1-yl 
                 thiophen-3-yl 
                 314 
               
               
                 62 
                 1-methyl-benzimidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 thiophen-3-yl 
                 327 
               
               
                 65 
                 1-methyl-benzimidazol-2-yl 
                 4-morpholin-1-yl 
                 phenylethynyl 
                 332 
               
               
                 66 
                 1-methyl-benzimidazol-2-yl 
                 4-methyl-piperazin-1-yl 
                 phenylethynyl 
                 345 
               
               
                 111 
                 1-methyl-benzimidazol-2-yl 
                 phenylamino 
                 4-chlorophenyl 
                 371 
               
               
                 113 
                 1-methyl-benzimidazol-2-yl 
                 phenylamino 
                 4-trifluoromethyl phenyl 
                 248 (M +  loss of C 6 H 6 N) 
               
               
                 116 
                 1-methyl-benzimidazol-2-yl 
                 phenylamino 
                 1-methylpyrrol-2-yl 
                 347 
               
               
                 120 
                 1-methyl-benzimidazol-2-yl 
                 phenylamino 
                 thiophen-3-yl 
                 365 
               
               
                   
               
             
          
         
       
     
     While some the previous examples describe the purification of reaction products by flash chromatography, these reaction products can also be purified in a high-throughput mode using high-throughput reverse-phase or high-throughput normal phase HPLC instruments, thereby, increasing the efficiency of compounds library syntheses. 
     While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.