Abstract:
The present invention is directed to a series of novel substituted aminoalkylamide derivatives, pharmaceutical compositions containing them and their use in the treatment of reproductive disorders and affective conditions. Further, the compounds of the invention are antagonists of follicle stimulating hormone, a hormone associated with the human reproductive system.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS  
       [0001]    This application claims priority from U.S. provisional application Ser. No. 60/173,139, filed Dec. 27, 1999, the contents of which are hereby incorporated by reference. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    This invention relates to novel substituted aminoalkylamide derivatives, pharmaceutical compositions containing them and their use in the treatment of reproductive disorders and affective conditions. The compounds of the invention are antagonists of follicle stimulating hormone, a hormone associated with the human reproductive system.  
         BACKGROUND OF THE INVENTION  
         [0003]    Follicle stimulating hormone (FSH) belongs to a family of glycoprotein hormones, which includes lutenizing hormone (LH), thyrotropin (TSH) and chorionic gonadotropin (CG). Each of these hormones is composed of two different non-covalently bound subunits termed α and β. Within a species the amino acid sequence of the α subunits for these different hormones is identical, while the hormone specific β subunits exhibit different amino acid sequences (Combarnous, Endocrine Review, 13:670-691 (1992).  
           [0004]    In females, follicle stimulating hormone (FSH) stimulates follicular granulosa cell proliferation in the ovary and impacts synthesis of estrogen, a hormone which is integral to follicular maturation and ovulation. An antagonist of FSH therefore acts to limit proliferation of follicular granulosa cells in the ovary, acting as a contraceptive. The FSH antagonist may also delay the maturation of follicles within the ovary, thereby postponing the maturation of a limited number of follicles in women. Such treatments have the potential for increasing the possibility of natural fertilization and pregnancy later in life.  
           [0005]    Because of the controlling function of FSH on estrogen synthesis, an FSH antagonist may also be effective in the treatment of estrogen related disorders such as uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer.  
           [0006]    An added advantage for an FSH antagonist would be its specific action on ovarian tissue without impact on peripheral tissues containing estrogen receptors. This would be expected to reduce the side effects associated with estrogen receptor antagonists.  
           [0007]    Because the proliferation of follicular granulosa cells also impacts the health and development of the oocyte, FSH antagonists may be useful in preventing depletion of oocytes, a common side effect of chemotherapy or similar treatments designed to treat rapidly dividing cells.  
           [0008]    In males, follicle stimulating hormone (FSH) is involved in the maturation of sperm cells. More specifically, FSH action in males is directed at the Sertoli cells, which are a recognized target of the hormone and which support the process of sperm maturation (spermatogenesis). FSH antagonists will therefore inhibit sperm maturation without affecting the production of androgens produced from Leydig cells under the control of luteinizing hormone (LH). In addition, FSH receptors have been reported in the epididymis in the male reproductive tract. Thus an FSH antagonist would be expected to affect the viability and motility of sperm by controlling functions of the epididymis.  
           [0009]    FSH antagonists also have the potential to modify the rate of germ cell division in males. Because chemotherapy is known to deplete rapidly dividing cells such as spermatocytes, an FSH antagonist may be useful in a planned chemotherapy regimen to prevent spermatocyte depletion.  
           [0010]    An FSH antagonist used as a female contraceptive could be used in contraceptive formulations alone or in combination with known contraceptive agents such as progesterone receptor modulators, estrogen receptor modulators, or androgen receptor modulators. An FSH antagonist used as a male contraceptive could be used alone or in combination with androgen receptor modulators, progesterone receptor modulators, or with estrogen receptor modulators. In addition, agents that affect the viability or motility or fertilizability of sperm by acting within the female genital tract may also be used in combination with FSH antagonists concomitantly, or as scheduled in a kit that prevents fertilization during the administration of an FSH antagonist. An example of such an agent is nonoxynol-9.  
           [0011]    In recent years, peptide (based) FSH agonists and antagonists have been discovered and developed. Bono, G., et. al., in WO 97/12038 disclose novel amino acid residue peptide useful in stimulating FSH enhancement.  
           [0012]    Amino acid based sulfonamide derivatives have also been developed for the treatment of a variety of conditions and disorders. Dumont, R. in WO 93/05014 discloses sulfonamide derivatives useful as inhibitors of Ca +2  dependent enzymes.  
           [0013]    The compounds of the present invention are non-peptide antagonists of FSH useful in the treatment of estrogen related disorders such as uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer; prevention of depletion of oocytes (a common side effect of chemotherapy or similar treatment); female and male contraception; and prevention of spermatocyte depletion.  
           [0014]    Additionally, the generation of chemical libraries on and off solid resins has proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs using high throughput screening (HTPS) 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.  
           [0015]    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.  
           [0016]    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.  
         SUMMARY OF THE INVENTION  
         [0017]    The present invention is directed to compounds of the formula (I)  
                         
 
           [0018]    wherein  
           [0019]    R 1  and R 2  are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 perhaloalkyl, phenyl, phenylC 1 -C 6 alkyl-, phenylcarbonyl-, pyridyl, pyridylC 1 -C 6 alkyl-, pyridylcabonyl-, thienyl, thienylC 1 -C 6 alkyl- and thienylcarbonyl, wherein the phenyl, pyridyl or thienyl is optionally substituted with one to three substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy or NO 2 ;  
           [0020]    R 3  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl, where the C 1 -C 6 alkyl is optionally substituted with a phenyl, pyridyl, thienyl or furyl, wherein the phenyl, pyridyl, thienyl or furyl is optionally substituted with one to three substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy or NO 2 ;  
           [0021]    R 4  is selected from the group consisting of —C 2 -C 6 alkyl-, -cyclopentyl-, -cylcohexyl-, -cyclohexyl-CH 2 —, —CH 2 -cyclohexyl-CH 2 —, —CH 2 -phenyl-CH 2 —, —C(O)—CH 2 -phenyl-CH 2 —, —C(O)—C 1 -C 6 alkyl- and -cyclohexyl-CH 2 -cyclohexyl-;  
           [0022]    where the R 4  substituent is inserted into the compound of formula (I) from left to right, as defined;  
           [0023]    alternately, R 2 , R 3 , and R 4  can be taken together with the two N atoms of  
                         
 
           [0024]    the diamine portion of the molecule to form  
           [0025]    alternately, R 3  can be taken together with R 2  as —C 2 -C 3 alkyl-, provided that R 4  is —C 2 -C 6 alkyl-;  
           [0026]    L is selected from the group consisting of —C 3 -C 6 cycloalkyl (wherein the cycloalkyl is substituted with R 5  and R 6 ), a bicyclic compound of the form  
                         
 
           [0027]    wherein the point of the attachment of the bicyclic compound is any carbon atom of the alkyl portion and wherein the aromatic portion of the bicyclic compound is optionally substituted with one to three substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, NO 2 , acetamido, —NH 2 , —NH(C 1 -C 6 alkyl) or —N(C 1 -C 6 alkyl) 2 ), and —(CH 2 ) m -CR 8 R 5 R 6 ;  
           [0028]    m is 0 to 3;  
           [0029]    R 5  is selected from the group consisting of phenyl, naphthyl, (wherein the phenyl and naphthyl may be optionally substituted with one to three substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, NO 2 , acetamido, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkylcarbonylamino or C 1 -C 6 alkylsulfonylamino), bicyclo[4.2.0]octa- 1,3 ,5-trienyl, 2,3-dihydro- 1H-indolyl, N-methylpyrrolidinyl, 3,4-methylenedioxyphenyl, C 3 -C 6 cyloalkenyl, (wherein the cycloalkenyl group contains one or two double bonds), a six membered heteroaryl (wherein the six membered heteroaryl contains one to three N atoms), and a five membered heteroaryl (wherein the five membered heteroaryl contains one sulfur, oxygen or nitrogen, optionally contains one to three additional nitrogen atoms); wherein the point of attachment for the five or six membered heteroaryl is a carbon atom; and wherein the five or six membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy or NO 2 ;  
           [0030]    R 6  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxy and phenyl, (wherein the phenyl may be optionally substituted with one to three substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl or trifluoromethoxyl); provided that R 6  may be phenyl only when R 5  is phenyl;  
           [0031]    R 8  is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;  
           [0032]    Z is selected from the group consisting of —SO 2 —, —C(═O)—, and —C(═O)NH—;  
           [0033]    p is 0 to 1; 
                         
 
           [0034]    is selected from the group consisting of phenyl, naphthyl, quinolinyl, thienyl, and furyl;  
           [0035]    X is selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, NO 2 , acetamido, —NH 2 , —NH (C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl) 2 ;  
           [0036]    n is 0 to 3;  
           [0037]    Y is selected from the group consisting of phenyl, —O—phenyl, —NH—phenyl, naphthyl, (wherein the phenyl or naphthyl is optionally substituted with one to three substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, NO 2 , cyano, methylthio, acetamido, formyl, -amino, -aminocarbonyl, —NH—C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —COOH, —COO(C 1 -C 6 alkyl), —COO(C 1 -C 6 alkylphenyl), C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylaminocarbonyl, di(C 1 -C 6 alkyl)aminocarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl or di(C 1 -C 6 alkyl)aminosulfonyl), biphenyl, 3,4-methylenedioxyphenyl, dianthrenyl, dibenzothienyl, phenoxathiinyl, a six membered heteroaryl (wherein the six membered heteroaryl contains one to three nitrogen atoms), and a five membered heteroaryl (wherein the five membered heteroaryl contains one sulfur, oxygen or nitrogen atom, optionally contains one to three additional nitrogen atoms); wherein the point of attachment for the five or six membered heteroaryl is a carbon atom; and wherein the five or six membered heteroaryl is optionally substituted with one to three substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, trifluoromethyl, trifluoromethoxy, formyl, NO 2 , cyano, methylthio, acetamido, -amino, -aminocarbonyl, —NH C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —COOH, —COO(C 1 -C 6 alkyl), or —COO(C 1 -C 6 alkylphenyl));  
           [0038]    q is 0 to 1;  
           [0039]    provided that when q is 1, n is 0;  
           [0040]    and stereoisomers and pharmaceutically acceptable salts or esters thereof.  
         DETAILED DESCRIPTION OF THE INVENTION  
         [0041]    The compounds of formula (I) that comprise this invention may be prepared using a process wherein the compound is synthesized on a solid support resin, followed by cleavage of the compound from the resin support, as a final isolation step. The various substituents described in formula (I) may be present initially on the reagents employed to prepare the compounds of formula (I). In some instances they may be conveniently added following cleavage. In those cases where the substituents are present on the reagents, care must be taken in the selection of the resin to insure that the substituents are compatible with the selected resin.  
           [0042]    One method for producing the compounds of formula (I) involves synthesis, on resin, of three intermediates, followed by cleavage of the resin to yield the desired product, as outlined in Scheme 1. 
                         
 
           [0043]    The solid support resin, herein represented by the symbol          is typically polystyrene, and is terminated with a reactive functional group. There are a number of commercially available resins, with a variety of terminating groups. Suitable examples of support resins for preparation of compounds of formula (I) include: Wang resin (Wang, S. S., J. Am. Chem. Soc., 95,1328 (1973); Kiselov, A. S. and Amstrong, R. W., Tetrahedron Letter, 318, 6163 (1997)), [wherein the terminating group is —(p-phenyl)—CH 2 —O—(p-phenyl)—CH 2 —OH]; RAPP Tentagel SAM resin (Rotte, B., et.al., Collect. Czech. Chem. Commun., 61, 5304 (1996)), [wherein the terminating group is —(p-phenyl)—CH 2 —O—(p-phenyl)—CH 2 —NH 2 ]; vinylsulfonyl resin (Kroll, F. E., et. al., Tetrahedron Lett., 38, 8573, 1997), [wherein the terminating group is —(p-phenyl)—CH 2 —SO 2 —CH═CH 2 ]; rink amide resin (Rink, H., Tetrahedron Lett., 28, 3787,1987; Brown, E. G. and Nuss, J. M., Tetrahedron Lett., 38, 8457, 1997), [wherein the terminating group is —CH 2 —O—(p-phenyl)—CH 2 (NH—Fmoc)-(2,4-dimethoxyphenyl)]; FMPB resin (4-(4-formyl-3-methoxyphenoxy)butyryl AM resin) (Bilodeau, M. T. &amp; Cunningham, A. M., J. Org. Chem., 63, 2800,1998; Kearny, P. T., et. al., J. Org. Chem., 63,196,1998) [wherein the terminating group is an aldehyde]; and the like. The appropriate selection of solid support resin and terminating group is based on the synthesis steps, reaction conditions and final compound substituents; and may be determined by one skilled in the art.  
           [0044]    The selected resin and appropriate reactants are employed to prepare resin bound, substituted diamines of formula (II):  
                         
 
           [0045]    Broadly, there are three approaches described herein to obtain the resin bound substituted diamines of formula (II). In the first approach a commercial resin capable of direct coupling reactions to an appropriately substituted diamine is purchased and reacted to produce the compound of formula (II). In the second approach, a commercial resin is suitably activated to react with an appropriately substituted diamine. This approach is advantageously employed in those cases where the purchased resin is not amine terminated. In the third approach, a commercially available amine terminated resin is reacted with a substituted and protected amine alcohol to form the resin substituted diamine of formula (II). In this third approach, the terminal amine of the selected resin is incorporated into the end product compound.  
           [0046]    Specifically, compounds of formula (II) wherein R 2  and R 3  are hydrogen; wherein R 2  and R 3  are taken together as —C 2 -C 3 alkyl and R 4  is other than C(O)—CH 2 -phenyl-CH 2 — or C(O)—C 1 -C 6 alkyl-; and wherein R 2 , R 3  and R 4  are taken together with the two N atoms of the diamine portion of the molecule to form  
                         
 
           [0047]    may be prepared as outlined in Scheme 2 below:  
                         
 
           [0048]    According to Scheme 2, a commercially available, OH terminated resin is coupled with 4-nitrophenyl chloroformate, in an organic solvent such as DCM, DCE, and the like, preferably DCM, in the presence of an amine base, such as pyridine, N-methylmorpholine (NMM), triethylamine (TEA), diisopropylethylamine (DIEA), and the like, preferably N-methylmorpholine (NMM), preferably at room temperature, to incorporate the —C(O)—O—(p-nitrophenyl)— group into the resin, to form the corresponding p-nitrophenol carbonate terminated resin.  
           [0049]    The p-nitrophenol group on the p-nitrophenol carbonate terminated resin is next displaced with a suitably substituted linear diamine of formula (V), a suitably substituted cyclic diamine of formula (VI), or a suitably substituted bicyclic heterocyclyl diamine of formula (VIl), in an organic solvent such as DMF, DMAC, DCM, DCE, and the like, preferably at room temperature, to form the corresponding resin bound substituted diamine of formula (IIa), (IIb) or (IIc), respectively.  
           [0050]    Alternately, compounds of formula (II), wherein R 2  and R 3  are hydrogen may be prepared according to the process outlined in Scheme 3. 
                         
 
           [0051]    Accordingly, a commercially available, vinylsulfonyl terminated resin is coupled with a suitably substituted linear diamine of formula (V), in an organic solvent such as DMF, overnight, at room temperature, to produce the resin bound substituted diamine of formula (IId). In this approach, the amine group is coupled directly to the terminal methylene group of the vinylsulfonyl terminated resin.  
           [0052]    Compounds of formula (II) wherein R 3  is hydrogen and R 4  is selected from C(O)—CH 2 -phenyl-CH 2 — or C(O)—C 1 -C 6 alkyl- may be prepared according to the process outlined in Scheme 4. 
                         
 
           [0053]    When R 2  is other than hydrogen, a commercially available amine terminated resin is reacted with a suitably substituted aldehyde of formula (VIII), in an organic solvent such as DCM, DCE, and the like, in the presence of a catalyst such as sodium cyanoborohydride, sodium triacetoxyborohydride and the like, preferably sodium triacetoxyborohydride, preferably at room temperature, to produce the corresponding substituted amine terminated resin of formula (IX).  
           [0054]    The substituted amine terminated resin of formula (IX) is coupled with a suitably substituted Fmoc-protected amine alcohol, a compound of formula (X), in an organic solvent such as DMF, DMAC, DCM, and the like, preferably DMF, preferably at room temperature, to produce the corresponding resin bound Fmoc-protected, substituted diamine of formula (XI). The Fmoc protecting group on the resin bound substituted diamine of formula (XI) is then removed using 20% piperidine in DMF, preferably at room temperature, to produce the corresponding resin bound, substituted diamine of formula (lie).  
           [0055]    Compounds of formula (II) wherein R 3  is other than hydrogen may be prepared according to the process outlined in Scheme 5. 
                         
 
           [0056]    A resin bound substituted diamine of formula (IIe) is coupled with a suitably substituted aldehyde of formula (XII), in the presence of a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydide, and the like, preferably triacetoxyborohydride, in an organic solvent such as DCM, DCE, and the like, preferably DCE, preferably at room temperature, to produce the corresponding resin bound substituted diamine of formula (II).  
           [0057]    The resin bound, substituted diamines of formula (II) are next reacted with suitably substituted reagents to produce the corresponding resin bound, substituted secondary amine of formula (III):  
                         
 
           [0058]    In a general approach to producing the resin bound substituted triamine of formula (III), bromoacetic acid is initially coupled to the diamine for formula (II), followed by coupling of a suitably substituted amine.  
           [0059]    More specifically, in this approach, compounds of formula (III) may be prepared according to the process outlined in Scheme 6. This approach is also particularly advantageous in the preparation of compounds of formula (I) wherein L is —C 3 -C 6 cycloalkyl.  
                         
 
           [0060]    Accordingly, a resin bound, substituted diamine of formula (II) is coupled with bromoacetic acid, using a coupling agent such as diisopropyl carbodiimide, 1,1′-carbonyidiimidazole, N,N′-dicyclohexylcarbodiamide, and the like, preferably diisopropylcarbodiamide, in a solvent such as DMF, DMAC, and the like, preferably DMF, preferably at room temperature, to form the corresponding resin bound, bromoacetylated alkylcarbonyl diamine of formula (XIII).  
           [0061]    The bromine on the resin bound, bromoacetylated alkylcarbonyl diamine of formula (XIII) is then displaced with a suitably substituted amine of formula (XIV), in a solvent such as DMSO, preferably at room temperature, to form the corresponding resin bound, substituted secondary amine of formula (III).  
           [0062]    The resin bound, substituted secondary amine of formula (III) is subsequently reacted with suitably substituted reagents to produce the corresponding resin bound, compound of formula (IV):  
                         
 
           [0063]    The resin bound compound of formula (IV) may be prepared via two processes. In the first process, the resin bound, substituted secondary amine of formula (III) is directly coupled with a suitably substituted sulfonyl chloride, suitably substituted carbonyl chloride or suitably substituted isocyanate reagent to prepared the end product compound. In the second process, the resin bound, substituted secondary amine of formula (III) is first coupled with a halogen substituted aryl or heteroaryl sulfonyl chloride, followed by displacement of the halogen with a suitably substituted aryl or heteroaryl substituted boronic acid, to yield the end product compound.  
           [0064]    More particularly, in the first process, the resin bound compound of formula (IV) is prepared as outlined in Scheme 7. 
                         
 
           [0065]    According to the first process, the resin bound, substituted secondary amine of formula (III) is coupled with a suitably substituted chloride of formula (XV), or a suitably substituted isocyanate of formula (XVI), in a solvent such as DCM, DCE, chloroform, and the like, preferably DCM, in the presence of an amine base such as pyridine, N-methylmorpholine (NMM), triethyl amine (TEA), diisopropylethylamine (DIEA), and the like, preferably pyridine, preferably at room temperature, to form the corresponding resin bound compound of formula (IV).  
           [0066]    The second process is particularly advantageous for preparation of  
           [0067]    compounds of formula (I) wherein Z is sulfonyl, n is 0, q is 1 and the  
                         
 
           [0068]    substituent is phenyl, napthyl, thienyl or furyl. The second process is also particularly advantageous for preparation of compounds of formula (I) wherein R 2  and R 3  are taken together as C 2 -C 3 alkyl and Z is sulfonyl; and wherein R 2 , R 3 , and R 4  are taken together with the two N atoms of the diamine portion of the molecule to form  
                         
 
           [0069]    In the second process, the resin bound compound of formula (IV) is prepared via the process outlined in Scheme 8. 
                         
 
           [0070]    The resin bound, substituted secondary amine of formula (III) is coupled with a suitably substituted aryl or heteroaryl sulfonyl chloride of formula (XVII), wherein A represents a halogen selected from chlorine, bromine or iodine, preferably bromine, in a solvent such as DCM, DCE, chloroform, and the like, preferably DCM, in the presence of an amine base such as pyridine, N-methylmorpholine, triethylamine (TEA), diisopropylethylamine (DIEA), and the like, preferably pyridine, preferably at room temperature, to form the corresponding resin bound, substituted sulfonyl compound of formula (XVIII).  
           [0071]    On the resin bound, substituted sulfonyl of formula (XVIII), the halogen represented by A is next displaced with a suitably substituted boronic acid of formula (XIX), using Suzuki conditions (in a solvent such as dimethoxyethane (DME), dioxane, and the like, in the presence of a base such as 2M sodium carbonate, tetramethylguanadine (TMG), and the like, under a N 2  atmosphere, at a temperature in the range of about 80-100° C., in the presence of a catalyst, such as palladium tetrakistriphenylphosphine), to form the corresponding resin bound, substituted sulfonamide formula (IVa).  
           [0072]    The resin bound compound of formula (IV), may next be treated to yield the corresponding compound of formula (I) by cleaving the solid support resin, using a cleaving cocktail, such as 90:10 TFA:water, preferably at room temperature, to produce the corresponding compound of formula (I).  
           [0073]    A resin bound compound of formula (IVa) may alternatively be further reacted with a suitably substituted compound of formula (XX) and I or formula (XXI), wherein J is bromine or iodine, to incorporate R 1  and R 2  substituents, wherein R 1 =R 2  and are other than hydrogen. For this process, the preferred resin is the vinylsulfonyl terminated resin, R 4  is other than —C(O)—CH 2 -phenyl- or —C(O)-C 1 -C 6 alkyl-, and the R 1  and R 2  substituents are incorporated according to the process outlined in Scheme 9. 
                         
 
           [0074]    Accordingly, a resin bound compound of formula (IVa) is reacted with a suitably substituted compound of formula (XX) and/or formula (XXI), wherein J is bromine or iodine, preferably at room temperature, to produce the corresponding resin bound, quaternary amine of formula (XXII).  
           [0075]    The resin bound quaternary amine of formula (XXVI) is then treated to yield the desired corresponding compound of formula (I) by cleaving the solid support resin, using a cleaving cocktail, such as 20% DIEA in DMF, preferably at room temperature, to produce the corresponding compound of formula (I).  
           [0076]    In an alternative scheme for producing compounds of formula (I) wherein R 1  and/or R 2  are other than hydrogen, the R 1  and R 2  substituents may be introduced following cleavage of the resin bound compound of formula (IV). More particularly, such a process is as outlined in Scheme 10. 
                         
 
           [0077]    A compound of formula (Ia), wherein R 1  and R 2  are hydrogen, is treated with a suitably substituted aldehyde of formula (XXIII), preferably in the amount of at least one molar equivalent, in an organic solvent such as TMOF, and the like, in the presence of a reducing agent such as sodium triacetoxyborohydride, and the like, preferably at room temperature, and then with a suitably substituted aldehyde of formula (XXIV), preferably in the amount of at least one molar equivalent, in an organic solvent such as TMOF, and the like, in the presence of a reducing agent such as sodium triacetoxyborohydride, and the like, preferably at room temperature, to produce the corresponding compound of formula (I).  
           [0078]    In an alternative method of Scheme 10, compounds of formula (I), wherein R 1  and R 2  are the same and other than hydrogen, are produced by treating the compound of formula (Ia) with at least two molar equivalents of a suitably substituted aldehyde of formula (XXIII) or (XXIV), to produce the corresponding product of formula (I).  
           [0079]    In another alternative method of Scheme 10, compounds of formula (I), wherein one of R 1  or R 2  is hydrogen, the compound of formula (Ia) is treated with at least one molar equivalent of a suitably substituted aldehyde of formula (XXIII) or (XXIV), to yield the desired corresponding compound of formula (I).  
           [0080]    Compounds of formula (I), wherein R 1  and/or R 2  is alkylcarbonyl may be prepared according to the process outlined in Scheme 11. 
                         
 
           [0081]    Accordingly, a suitably substituted compound of formula (Ia), wherein R 1  and R 2  are each hydrogen, is treated with a suitably substituted acid chloride of formula (XXV), preferably in the amount of at least one molar equivalent, in an organic solvent such as chloroform, DCM, and the like, in the presence of a organic base such as TEA, and the like, preferably at room temperature, to yield the corresponding compound of formula (Ib). Alternatively, a suitably substituted compound of formula (Ia), wherein R 1  and R 2  are each hydrogen, is treated with a suitably substituted carboxylic acid of formula (XXVI), preferably in the amount of at least one molar equivalent, in an organic solvent such as DMF, and the like, in the presence of a coupling agent such as DIC, and the like, preferably at room temperature, to yield the corresponding compound of formula (Ib).  
           [0082]    As used herein, unless otherwise noted, “alkyl” whether used alone or as part of a substituent group, shall include straight and branched chains containing 1 to 6 carbon atoms. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-methyl-3-butyl, hexyl and the like. Similarly, the term “cycloalkyl” shall include saturated alkyl ring structures containing 3 to 6 carbon atoms. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl and cylcohexyl.  
           [0083]    As used herein, unless otherwise noted, “alkenyl” and “alkynyl” shall include straight and branched chain alkene and alkyne having 1 to 6 carbon atoms, for example allyl, vinyl, 2-propenyl, 2-propynyl, and the like.  
           [0084]    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, propoxy, sec-butoxy, t-butoxy, 2-methyl-3-bytoxy and the like.  
           [0085]    As used herein the terms “aromatic and aryl” shall denote phenyl and naphthyl.  
           [0086]    Suitable “six membered heteroaryls containing one to three nitrogen atoms” include pyridyl, pyridizanyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl.  
           [0087]    Suitable “five membered heteroaryl containing one sulfur, oxygen or nitrogen atom, optionally containing one to three additional nitrogen atoms” include thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and the like.  
           [0088]    As used herein, unless otherwise noted, “halogen” shall denote chlorine, bromine, fluorine and iodine.  
           [0089]    As used herein, unless otherwise noted, “*” represents the presence of a stereogenic center.  
           [0090]    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 “phenylC 1 -C 6 alkylamidoC 1 -C 6 alkyl” substituent refers to a group of the formula  
                         
 
           [0091]    In a preferred embodiment of the present invention are compounds of the formula (I) wherein  
           [0092]    R 1  and R 2  are independently selected from the group consisting of hydrogen, methyl, ethyl, methylcarbonyl, trifluoromethyl, phenyl, benzyl, phenylcarbonyl, pyridyl, pyridylcarbonyl, thienyl, thienylmethyl and thienylcarbonyl (where the phenyl, pyridyl or thienyl is optionally substituted with one to two substituents independently selected from halogen, C 1 -C 3 alkyl, C 1 —C 3 alkoxy, trifluoromethyl, trifluoromethoxy or nitro); and  
           [0093]    R 3  is selected from the group consisting of hydrogen, methyl, —CH═CH— (optionally substituted with phenyl, pyridyl or thienyl; wherein the phenyl, pyridyl or thienyl is further optionally substituted with one to two substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy and nitro), —C≡C—, (optionally substituted with phenyl, pyridyl or thienyl; wherein the phenyl, pyridyl or thienyl is further optionally substituted with one to two substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy and nitro).  
           [0094]    More preferably, R 1 , R 2 , and R 3  are the same; most preferably R 1 , R 2  and R 3  are the same and are hydrogen.  
           [0095]    In another preferred embodiment of the present invention are compounds of the formula (I) wherein R 2  and R 3  are taken together as C 2 -C 3 alkyl, more preferably 1,2-ethyl; and R 4  is C 2 -C 6 alkyl, more preferably 1,2-ethyl or 1,3-n-propyl.  
           [0096]    In another preferred embodiment of the present invention are compounds of the formula (I) wherein R 2 , R 3 , and R 4  are taken together with the two N atoms of the diamine portion of the molecule to form  
                         
 
           [0097]    Preferred R 4  substituents include —C 2 -C 6 alkyl, -cyclohexyl, —CH 2 -cyclohexyl—CH 2 , -cyclohexyl—CH 2 -cyclohexyl and —CH 2 -phenyl—CH 2 .  
           [0098]    In another preferred embodiment of the invention are compounds of the formula (I) wherein R 2 , R 3 , and R 4  may be taken together with the two N atoms of the diamine portion of the molecule to form 4,4′-bipiperidinyl.  
           [0099]    Preferred L substituents include -cyclopropyl-, cyclohexyl-, (wherein the cylcopropyl or cyclohexyl is substituted with R 5  and R 6 ),  
                         
 
           [0100]    and (CH 2 ) m —CR 8 R 5 R 6 .  
           [0101]    Preferred R 5  substituents include phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, methylcarbonylamino, methylsulfonylamino, nitro, acetomido, amino, C 1 -C 3 alkylamino or di(C 1 -C 3 alkyl)amino), N-methylpyrrolidinyl, 3,4-methylenedioxyphenyl, bicyclo[4.2.0]octa-1,3,5-trienyl, 2,3-dihydro-1H-indolyl, C 3 -C 6 cycloalkenyl (wherein the cycloalkenyl contains one or two double bonds), thienyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl and triazinyl.  
           [0102]    Preferred R 6  substituents include hydrogen, C 1 -C 3 alkyl, cyclopropyl, cyclobutyl, cyclohexyl, C 1 -C 3 alkoxy, hydroxy and phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl or trifluoromethoxy); provided that R 6  is phenyl only when R 5  is phenyl.  
           [0103]    Preferred R 8  substituents include hydrogen and C 1 -C 3 alkyl.  
           [0104]    Preferably Z is selected from the group consisting of SO 2 , C(═O) and —C(═O)—NH—.  
           [0105]    Preferred  
                         
 
           [0106]    substituents include phenyl, naphthyl, quinolinyl and thienyl.  
           [0107]    Preferably n is 0 to 2.  
           [0108]    Preferred X substituents include halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, trifluoromethyl, trifluoromethoxy, nitro, acetamido, amino, C 1 -C 3 alkylamino and di(C 1 -C 3 alkyl)amino.  
           [0109]    Preferred Y substituents include phenyl, naphthyl, (wherein the phenyl or naphthyl is optionally substituted with one to three substituents independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, formyl, nitro, cyano, methylthio, acetamido, amino, aminocarbonyl, C 1 -C 3 alkylamino, di(C 1 -C 3 alkyl)amino, carboxy, —COO(C 1 -C 3 alkyl), —COO(C 1 -C 3 alkylphenyl), C 1 - 4 alkylaminosulfonyl, C 1 -C 4 alkylcarbonylamino), biphenyl, 3,4-methylenedioxyphenyl, dianthryl, dibenzothienyl, phenoxathiinyl, a five membered heteroaryl (wherein the five membered heteroaryl contains one nitrogen, oxygen or sulfur atom and optionally contains an additional nitrogen or oxygen atom) and a six membered heteroaryl (wherein the six membered heteroaryl contains one nitrogen atom and optionally contains an additional nitrogen or oxygen atom); wherein the five or six membered heteroaryl is optionally substituted with one to two substituents independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, formyl, nitro, cyano, methylthio, acetamido, amino, aminocarbonyl, C 1 -C 3 alkylamino or di(C 1 -C 3 alkyl)amino; and wherein the point of attachment for the five or six membered heteroaryl is a carbon atom.  
           [0110]    Particularly preferred compounds of the present invention are listed in Table 1, below.  
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 TABLE 1                                                                                  Cmpd #   m   R 5     R 6     Stereo   p   Y               336   1   2-methoxyphenyl   H   —   0   2-methylphenyl       337   1   2-methoxyphenyl   H   —   0   2-chlorophenyl       338   1   2-methoxyphenyl   H   —   0   2-methoxyphenyl       339   1   2-methoxyphenyl   H   —   0   2,4-dichlorophenyl       340   0   2-methoxyphenyl   H   —   0   2-methylphenyl       341   0   2-methoxyphenyl   H   —   0   2-chlorophenyl       342   0   2-methoxyphenyl   H   —   0   2-methoxyphenyl       343   0   2-methoxyphenyl   H   —   0   2,4-dichlorophenyl       384   1   phenyl   CH 3     R   0   2-methylphenyl       385   1   phenyl   CH 3     R   0   2-chlorophenyl       386   1   phenyl   CH 3     R   0   3-fluorophenyl       387   1   phenyl   CH 3     S   0   2-methylphenyl       388   1   phenyl   CH 3     S   0   2-chlorophenyl       389   1   phenyl   CH 3     S   0   3-fluorophenyl                                                                           344   1   2-methoxyphenyl   H   —   0   2-methylphenyl       345   1   2-methoxyphenyl   H   —   0   2-chlorophenyl       346   1   2-methoxyphenyl   H   —   0   2-methoxyphenyl       347   1   2-methoxyphenyl   H   —   0   2,4-dichlorophenyl       348   0   2-methoxyphenyl   H   —   0   2-methyl       349   0   2-methoxyphenyl   H   —   0   2-chlorophenyl       350   0   2-methoxyphenyl   H   —   0   2-methoxyphenyl       351   0   2-methoxyphenyl   H   —   0   2,4-dichlorophenyl       390   1   phenyl   CH 3     R   0   2-methylphenyl       391   1   phenyl   CH 3     R   0   2-chlorophenyl       392   1   phenyl   CH 3     R   0   3-fluorophenyl       393   1   phenyl   CH 3     S   0   2-methylphenyl       394   1   phenyl   CH 3     S   0   2-chlorophenyl       395   1   phenyl   CH 3     S   0   3-fluorophenyl                                                                               Cmpd #   m   Y                       74   0   2-methylphenyl           75   0   3-thienyl           76   0   2-methoxyphenyl           77   0   4-fluorophenyl           78   0   2,3-dimethoxyphenyl           79   0   4-methoxyphenyl           80   0   4-methylphenyl           81   0   1-napthyl           82   0   2-chlorophenyl           83   0   3-pyridyl           84   0   2-thienyl           85   0   3-aminocarbonylphenyl           86   0   phenyl           87   0   4-chlorophenyl           88   0   4-[3,5-dimethylisoxazolyl]           89   0   2-furyl           90   0   4-cyanophenyl           91   0   4-pyridyl           92   0   3-methoxyphenyl           93   0   4-aminophenyl           94   1   2-methylphenyl           95   1   3-thienyl           96   1   2-methoxyphenyl           97   1   4-fluorophenyl           98   1   2,3-dimethyoxyphenyl           99   1   4-methoxyphenyl           100   1   4-methylphenyl           101   1   1-napthyl           102   1   2-chlorophenyl           103   1   3-pyridyl           104   1   2-thienyl           105   1   3-aminocarbonylphenyl           106   1   phenyl           107   1   4-chlorophenyl           108   1   4-[3,4-dimethylisoxazolyl]           109   1   2-furyl           110   1   4-cyano phenyl           111   1   4-pyridyl           112   1   3-methoxyphenyl           113   1   4-aminophenyl                                                                                   Cmpd #   m   R 5     R 6     Y                       1   0   2-methoxyphenyl   H   4-chlorophenyl           2   0   2-methoxyphenyl   H   3-trifluoromethylphenyl           3   0   2-methoxyphenyl   H   2-chlorophenyl           4   0   2-methoxyphenyl   H   2-methylphenyl           5   0   2-methoxyphenyl   H   2-methoxyphenyl           6   0   2-methoxyphenyl   H   2,4-dichlorophenyl           7   0   2-methoxyphenyl   H   3,5-di(trifluoromethyl)                           phenyl           8   0   2-methoxyphenyl   H   3-chloro-4-fluorophenyl           9   0   2-methoxyphenyl   H   4-methoxyphenyl           20   0   3-methoxyphenyl   H   3-trifluoromethylphenyl           21   0   3-methoxyphenyl   H   2-methoxyphenyl           22   0   3-methoxyphenyl   H   2,4-dichlorophenyl           23   0   3-methoxyphenyl   H   3-fluorophenyl           24   0   3-methoxyphenyl   H   3-methoxyphenyl           25   0   3-methoxyphenyl   H   4-methylphenyl           26   0   3-methoxyphenyl   H   4-fluorophenyl           27   0   3-methoxyphenyl   H   3-chloro-4-fluorophenyl           28   0   3-methoxyphenyl   H   4-methoxyphenyl           29   1   2-methoxyphenyl   H   3-trifluoromethyl phenyl           30   1   2-methoxyphenyl   H   3-nitrophenyl           31   1   2-methoxyphenyl   H   2-chlorophenyl           32   1   2-methoxyphenyl   H   2-methylphenyl           33   1   2-methoxyphenyl   H   2-methoxyphenyl           34   1   2-methoxyphenyl   H   2,4-dichlorophenyl           35   1   2-methoxyphenyl   H   phenyl           36   1   2-methoxyphenyl   H   3-chlorophenyl           37   1   2-methoxyphenyl   H   4-fluorophenyl           38   1   2-methoxyphenyl   H   2-trifluoromethyl phenyl                                                                                                           Cmpd #   R 5     R 6     p                                 X               39   2-methoxyphenyl   H   0   phenyl   —       40   2-methoxyphenyl   H   0   2-thienyl   5-chloro       41   2-methoxyphenyl   H   0   1-phenyl   3-trifluoromethyl       42   2-methoxyphenyl   H   0   1-phenyl   2-trifluoromethyl       43   2-methoxyphenyl   H   0   1-phenyl   3-chloro       44   2-methoxyphenyl   H   0   1-phenyl   3,4-dichloro       45   2-methoxyphenyl   H   0   2-napthyl   —       46   2-methoxyphenyl   H   0   1-phenyl   2-chloro       47   2-methoxyphenyl   H   0   1-phenyl   4-chloro       48   2-methoxyphenyl   H   0   3-thienyl   2,5-dichloro       49   2-methoxyphenyl   H   0   1-phenyl   2,4-dichloro       50   2-methoxyphenyl   H   0   1-phenyl   2,6-dichloro       51   2-methoxyphenyl   H   0   1-phenyl   3,5-dichloro       52   2-methoxyphenyl   H   0   1-phenyl   2,5-dichloro       53   2-methoxyphenyl   H   0   1-phenyl   2,3-dichloro       54   2-methoxyphenyl   H   1   phenyl   —       55   2-methoxyphenyl   H   0   1-phenyl   4-methyl       56   2-methoxyphenyl   H   0   1-phenyl   4-methoxy       57   2-methoxyphenyl   H   0   1-napthyl   —       58   2-methoxyphenyl   H   0   1-phenyl   4-fluoro       59   2-methoxyphenyl   H   0   1-phenyl   3,4-dimethoxy       60   2-methoxyphenyl   H   0   1-phenyl   2,5-dimethoxy       61   2-methoxyphenyl   H   0   1-phenyl   2-nitro       62   2-methoxyphenyl   H   0   1-phenyl   4-nitro       63   2-methoxyphenyl   H   0   1-phenyl   3-nitro       64   2-methoxyphenyl   H   0   1-phenyl   4-iodo       65   2-methoxyphenyl   H   0   1-phenyl   4-tert-butyl       66   2-methoxyphenyl   H   0   1-phenyl   2-nitro-4-methoxy       67   2-methoxyphenyl   H   0   1-phenyl   3-methyl-4-methoxy       68   2-methoxyphenyl   H   0   1-phenyl   2-nitro-4-                           trifluoromethyl       69   2-methoxyphenyl   H   0   1-phenyl   3-fluoro       70   2-methoxyphenyl   H   0   1-phenyl   2-fluoro       71   2-methoxyphenyl   H   0   1-phenyl   4-trifluoromethyl       72   2-methoxyphenyl   H   0   1-phenyl   4-trifluoromethoxy       402   2-methoxyphenyl   H   0   1-phenyl   2,3-dichloro       403   3,4-methylene   H   0   8-quinolinyl   —           dioxyphenyl                                                                               Cmpd #   Stereo   Y                       372   R   2-methylphenyl           373   R   2-chlorophenyl           374   R   3-fluorophenyl           375   S   2-methylphenyl           376   S   2-chlorophenyl           377   S   3-fluorophenyl                                                                                                           Cmpd #   R 5     R 6     Stereo                                 Y               10   2-methoxyphenyl   H   —   1,4-phenyl   3-nitrophenyl       11   2-methoxyphenyl   H   —   1,4-phenyl   2-chlorophenyl       12   2-methoxyphenyl   H   —   1,4-phenyl   2-methylphenyl       13   2-methoxyphenyl   H   —   1,4-phenyl   2-methoxy                           phenyl       14   2-methoxyphenyl   H   —   1,4-phenyl   3-fluorophenyl       15   2-methoxyphenyl   H   —   1,4-phenyl   phenyl       16   2-methoxyphenyl   H   —   1,4-phenyl   3-methoxy                           phenyl       17   2-methoxyphenyl   H   —   1,4-phenyl   4-fluorophenyl       18   2-methoxyphenyl   H   —   1,4-phenyl   2-trifluoro                           methylphenyl       19   2-methoxyphenyl   H   —   1,4-phenyl   3-chloro-4-                           fluorophenyl       197   phenyl   H   R   1,4-phenyl   phenyl       207   phenyl   H   S   1,4-phenyl   phenyl       208   phenyl   H   S   1,4-phenyl   2-chlorophenyl       209   phenyl   H   S   1,4-phenyl   3-chlorophenyl       210   phenyl   H   S   1,4-phenyl   2-methoxyphenyl       211   phenyl   H   S   1,4-phenyl   3-methoxyphenyl       212   phenyl   H   S   1,4-phenyl   4-methoxyphenyl       213   phenyl   H   S   1,4-phenyl   3-fluorophenyl       214   phenyl   H   S   1,4-phenyl   4-fluorophenyl       215   phenyl   H   S   1,4-phenyl   2-methylphenyl       216   phenyl   H   S   1,4-phenyl   4-methylphenyl       217   2-methoxyphenyl   H   —   1,2-phenyl   2-thienyl       218   2-methoxyphenyl   H   —   1,2-phenyl   2-methylphenyl       219   2-methoxyphenyl   H   —   1,2-phenyl   3-thienyl       220   2-methoxyphenyl   H   —   1,2-phenyl   2-methoxyphenyl       221   2-methoxyphenyl   H   —   1,2-phenyl   4-fluorophenyl       222   2-methoxyphenyl   H   —   1,2-phenyl   4-methoxyphenyl       223   2-methoxyphenyl   H   —   1,2-phenyl   4-methylphenyl       224   2-methoxyphenyl   H   —   1,2-phenyl   1-napthyl       225   2-methoxyphenyl   H   —   1,2-phenyl   4-chlorophenyl       226   2-methoxyphenyl   H   —   1,2-phenyl   3-methoxy                           phenyl       227   2-methoxyphenyt   H   —   1,2-phenyl   3-aminophenyl       228   2-methoxyphenyl   H   —   1,2-phenyl   3-fluorophenyl       229   2-methoxyphenyl   H   —   1,2-phenyl   2-fluorophenyl       230   2-methoxyphenyl   H   —   1,2-phenyl   1-(3,4-methylene                           dioxyphenyl)       232   2-methoxyphenyl   H   —   1,2-phenyl   phenyl       233   2-methoxyphenyl   H   —   1,2-phenyl   4-(3,5-dimethyl                           isoxazole)       234   2-methoxyphenyl   H   —   1,2-phenyl   4-cyanophenyl       235   2-methoxyphenyl   H   —   1,2-phenyl   4-pyridyl       236   2-methoxyphenyl   H   —   1,2-phenyl   2,3,4-                           trimethoxyphenyl       237   2-methoxyphenyl   H   —   1,2-phenyl   3-cyanophenyl       238   2-methoxyphenyl   H   —   1,2-phenyl   2,5-dimethoxy                           phenyl       239   2-methoxyphenyl   H   —   1,2-phenyl   2,4-dichloro                           phenyl       240   2-methoxyphenyl   H   —   1,2-phenyl   3-trifluoro                           methylphenyl       241   2-methoxyphenyl   H   —   1,2-phenyl   4-trifluoro                           methylphenyl       242   2-methoxyphenyl   H   —   1,2-phenyl   2-trifluoro                           methylphenyl       243   2-methoxyphenyl   H   —   1,2-phenyl   3-methylphenyl       244   2-methoxyphenyl   H   —   1,3-phenyl   2-methylphenyl       245   2-methoxyphenyl   H   —   1,3-phenyl   3-thienyl       246   2-methoxyphenyl   H   —   1,3-phenyl   2-methoxyphenyl       247   2-methoxyphenyl   H   —   1,3-phenyl   4-fluorophenyl       248   2-methoxyphenyl   H   —   1,3-phenyl   4-methoxyphenyl       249   2-methoxyphenyl   H   —   1,3-phenyl   4-methoxyphenyl       250   2-methoxyphenyl   H   —   1,3-phenyl   1-napthyl       252   2-methoxyphenyl   H   —   1,3-phenyl   3-pyridyl       253   2-methoxyphenyl   H   —   1,3-phenyl   4-chlorophenyl       254   2-methoxyphenyl   H   —   1,3-phenyl   3-methoxyphenyl       255   2-methoxyphenyl   H   —   1,3-phenyl   3-aminophenyl       256   2-methoxyphenyl   H   —   1,3-phenyl   3-fluorophenyl       257   2-methoxyphenyl   H   —   1,3-phenyl   2-fluorophenyl       258   2-methoxyphenyl   H   —   1,3-phenyl   1-(3,4-methylene                           dioxyphenyl)       259   2-methoxyphenyl   H   —   1,3-phenyl   3-chlorophenyl       260   2-methoxyphenyl   H   —   1,3-phenyl   phenyl       261   2-methoxyphenyl   H   —   1,3-phenyl   4-(3,5-dimethyl                           isoxazole)       262   2-methoxyphenyl   H   —   1,3-phenyl   4-cyanophenyl       263   2-methoxyphenyl   H   —   1,3-phenyl   4-pyridyl       264   2-methoxyphenyl   H   —   1,3-phenyi   2,3,4-                           trimethoxyphenyl       265   2-methoxyphenyl   H   —   1,3-phenyl   4-cyanophenyl       266   2-methoxyphenyl   H   —   1,3-phenyl   2,5-dimethoxy                           phenyl       267   2-methoxyphenyl   H   —   1,3-phenyl   3-trifluoro                           methylphenyl       268   2-methoxyphenyl   H   —   1,3-phenyl   4-trifluoro                           methylphenyl       269   2-methoxyphenyl   H   —   1,3-phenyl   2-trifluoro                           methylphenyl       270   2-methoxyphenyl   H   —   1,3-phenyl   3-methylphenyl       271   2-methoxyphenyl   H   —   2,5-thienyl   2-thienyl       272   2-methoxyphenyl   H   —   2,5-thienyl   2-methylphenyl       273   2-methoxyphenyl   H   —   2,5-thienyl   3-thienyl       274   2-methoxyphenyl   H   —   2,5-thienyl   2-methoxyphenyl       275   2-methoxyphenyl   H   —   2,5-thienyl   4-fluorophenyl       276   2-methoxyphenyl   H   —   2,5-thienyl   4-methoxyphenyl       277   2-methoxyphenyl   H   —   2,5-thienyl   4-methylphenyl       279   2-methoxyphenyl   H   —   2,5-thienyl   2-chlorophenyl       280   2-methoxyphenyl   H   —   2,5-thienyl   3-pyridyl       281   2-methoxyphenyl   H   —   2,5-thienyl   4-chlorophenyl       282   2-methoxyphenyl   H   —   2,5-thienyl   3-methoxyphenyl       283   2-methoxyphenyl   H   —   2,5-thienyl   3-aminophenyl       284   2-methoxyphenyl   H   —   2,5-thienyl   3-fluorophenyl       285   2-methoxyphenyl   H   —   2,5-thienyl   2-fluorophenyl       287   2-methoxyphenyl   H   —   2,5-thienyl   3-chlorophenyl       288   2-methoxyphenyl   H   —   2,5-thienyl   phenyl       289   2-methoxyphenyl   H   —   2,5-thienyl   4-(3,5-dimethyl                           isoxazole)       290   2-methoxyphenyl   H   —   2,5-thienyl   4-cyanophenyl       291   2-methoxyphenyl   H   —   2,5-thienyl   4-pyridyl       292   2-methoxyphenyl   H   —   2,5-thienyl   2,3,4,-                           trimethoxyphenyl       293   2-methoxyphenyl   H   —   2,5-thienyl   3-cyanophenyl       294   2-methoxyphenyl   H   —   2,5-thienyl   2-furyl       295   2-methoxyphenyl   H   —   2,5-thienyl   2,5-dimethoxy                           phenyl       296   2-methoxyphenyl   H   —   2,5-thienyl   2,4-dichloro                           phenyl       297   2-methoxyphenyl   H   —   2,5-thienyl   3-trifluoro                           methylphenyl       298   2-methoxyphenyl   H   —   2,5-thienyl   4-trifluoro                           methylphenyl       299   2-methoxyphenyl   H   —   2,5-thienyl   2-trifluoro                           methylphenyl       300   2-methoxyphenyl   H   —   2,5-thienyl   3-methylphenyl                                                                                                   Cmpd #   p   m                                 X               114   0   1   2-thienyl   5-chloro       115   0   1   phenyl   3-trifluoromethyl       116   0   1   phenyl   2-trifluoromethyl       117   0   1   phenyl   3-chloro       118   0   1   phenyl   3,4-dichloro       119   0   1   2-napthyl   —       120   0   1   phenyl   2-chloro       121   0   1   phenyl   2,5-dimethoxy       122   0   1   phenyl   2,4-dichloro       123   0   1   phenyl   2,6-dichloro       124   0   1   phenyl   2,5-dichloro       125   0   1   phenyl   3,5-dichloro       126   0   1   2-thienyl   4,5-dichloro       127   1   1   phenyl   —       128   0   1   phenyl   4-methoxy       129   0   1   1-napthyl   —       130   0   1   phenyl   4-fluoro       131   0   1   phenyl   3-fluoro       132   0   1   phenyl   2-fluoro       133   0   1   phenyl   3,4-dimethoxy       134   0   1   phenyl   2-nitro       135   0   1   phenyl   3-nitro       136   0   1   phenyl   4-nitro       137   0   1   phenyl   4-iodo       138   0   1   phenyl   4-t-butyl       139   0   1   phenyl   2-nitro-4-methoxy       140   0   1   phenyl   2-methoxy-5-methyl       141   0   1   2-thienyl   4-nitro-5-chloro       142   0   1   phenyl   2-nitro-4-trifluoro methyl       143   0   1   phenyl   4-trifluoromethyl       144   0   1   phenyl   4-trilluoromethoxy       147   0   1   2-thienyl   —       148   0   1   phenyl   4-methyl       149   0   1   phenyl   4-chloro       150   0   1   phenyl   —       404   0   0   1-phenyl   2,3-dichloro                                                                                               Cmpd #   R 5                                   Y               73   2-methoxyphenyl   2,-thienyl   5-(2-methylthio-pyrimidyl)       405   3,4-methylene   8-quinolinyl   —           dioxyphenyl                                                                                                           Cmpd #   R 6     R 5     Stereo   Z                                 Y               145   2-methoxy   H   —   SO 2     2,5-thienyl   2-pyridyl           phenyl       146   2-methoxy   H   —   SO 2     2,5-thienyl   5-(2-methylthio-           phenyl                   pyrimidyl)       198   phenyl   CH 3     R   SO 2     1,4-phenyl   2-chlorophenyl       199   phenyl   CH 3     R   SO 2     1,4-phenyl   3-chlorophenyl       200   phenyl   CH 3     R   SO 2     1,4-phenyl   2-methoxyphenyl       201   phenyl   CH 3     R   SO 2     1,4-phenyl   3-methoxyphenyl       202   phenyl   CH 3     R   SO 2     1,4-phenyl   4-methoxyphenyl       203   phenyl   CH 3     R   SO 2     1,4-phenyl   3-fluorophenyl       204   phenyl   CH 3     R   SO 2     1,4-phenyl   4-fluorophenyl       205   phenyl   CH 3     R   SO 2     1,4-phenyl   2-methylphenyl       206   phenyl   CH 3     R   SO 2     1,4-phenyl   4-methylphenyl       231   2-methoxy   H   —   SO 2     1,2-phenyl   3-chlorophenyl           phenyl       251   2-methoxy   H   —   SO 2     1,3-phenyl   2-chlorophenyl           phenyl       278   2-methoxy   H   —   SO 2     2,5-thienyl   1-naphthyl           phenyl       286   2-methoxy   H   —   SO 2     2,5-thienyl   1-(3,4-methylene           phenyl                   dioxyphenyl)       301   phenyl   CH 3     R   SO 2     1,4-phenyl   2-fluorophenyl       302   phenyl   CH 3     R   SO 2     1,4-phenyl   2,6-dichlorophenyl       303   phenyl   CH 3     R   SO 2     1,4-phenyl   2,4-dichlorophenyl       304   phenyl   CH 3     R   SO 2     1,4-phenyl   2-trifluoromethyl                               phenyl       305   phenyl   CH 3     R   SO 2     1,4-phenyl   2,4,6-trimethyl                               phenyl       306   phenyl   CH 3     S   SO 2     1,4-phenyl   2-fluorophenyl       307   phenyl   CH 3     S   SO 2     1,4-phenyl   2,6-difluorophenyl       308   phenyl   CH 3     S   SO 2     1,4-phenyl   2,4-dichlorophenyl       309   phenyl   CH 3     S   SO 2     1,4-phenyl   2-trifluoromethyl                               phenyl       310   phenyl   CH 3     S   SO 2     1,4-phenyl   2,4,6-                               trimethylphenyl       311   phenyl   CH 3     Mix   SO 2     1,4-phenyl   2-methylphenyl       312   phenyl   CH 3     Mix   SO 2     1,4-phenyl   2-chlorophenyl       313   phenyl   CH 3     Mix   SO 2     1,4-phenyl   3-fluorophenyl       314   4-chloro   CH 3     Mix   SO 2     1,4-phenyl   2-methylphenyl           phenyl       315   4-chloro   CH 3     Mix   SO 2     1,4-phenyl   2-chlorophenyl           phenyl       316   4-chloro   CH 3     Mix   SO 2     1,4-phenyl   3-fluorophenyl           phenyl       317   4-chloro   cyclo-   —   SO 2     1,4-phenyl   2-methylphenyl           phenyl   propyl       318   4-chloro   cyclo-   —   SO 2     1,4-phenyl   2-chlorophenyl           phenyl   propyl       319   4-chloro   cyclo-   —   SO 2     1,4-phenyl   3-fluorophenyl           phenyl   propyl       323   phenyl   H   —   SO 2     1,4-phenyl   2-methylphenyl       324   phenyl   H   —   SO 2     1,4-phenyl   2-chlorophenyl       325   phenyl   H   —   SO 2     1,4-phenyl   3-fluorophenyl       412   phenyl   CH 3     R   SO 2     1,4-phenyl   phenyl       413   phenyl   CH 3     R   SO 2     1,4-phenyl   3-nitrophenyl       414   phenyl   CH 3     R   SO 2     1,4-phenyl   4-fluorophenyl       415   phenyl   CH 3     R   SO 2     1,4-phenyl   2-methylphenyl       416   phenyl   CH 3     R   SO 2     1,4-phenyl   3-trifluoromethyl                               phenyl       417   phenyl   CH 3     R   SO 2     1,4-phenyl   4-trifluoromethyl                               phenyl       418   phenyl   CH 3     R   SO 2     1,4-phenyl   3-chlorophenyl       419   phenyl   CH 3     R   SO 2     1,4-phenyl   3-methoxy phenyl       420   phenyl   CH 3     R   SO 2     1,4-phenyl   2-trifluoromethyl                               phenyl       421   phenyl   CH 3     R   SO 2     1,4-phenyl   2-methoxy phenyl       422   phenyl   CH 3     R   SO 2     1,4-phenyl   4-trifluoro                               methoxyphenyl       423   phenyl   CH 3     R   SO 2     1,4-phenyl   3-fluorophenyl       424   phenyl   CH 3     R   SO 2     1,4-phenyl   2-naphthyl       425   phenyl   CH 3     R   SO 2     1,4-phenyl   3-chloro-4-                               fluorophenyl       426   phenyl   CH 3     R   SO 2     1,4-phenyl   3-bromophenyl       427   phenyl   CH 3     R   SO 2     1,4-phenyl   4-chlorophenyl       428   phenyl   CH 3     R   SO 2     1,4-phenyl   3,5-dichloro                               phenyl       429   phenyl   CH 3     R   SO 2     1,4-phenyl   2,4-dichloro                               phenyl       430   phenyl   CH 3     R   SO 2     1,4-phenyl   3,5-ditrifluoro                               methylphenyl       432   phenyl   CH 3     R   SO 2     1,4-phenyl   2-benzofuryl       433   phenyl   CH 3     R   SO 2     1,4-phenyl   2-(t-butylamino                               sulfonyl)phenyl       434   phenyl   CH 3     R   SO 2     1,4-phenyl   4-cyanophenyl       435   phenyl   CH 3     R   SO 2     1,4-phenyl   3-cyanophenyl       436   phenyl   CH 3     R   SO 2     1,4-phenyl   3-carboxyphenyl       437   phenyl   CH 3     R   SO 2     1,4-phenyl   2[(di-i-propyl)                               aminocarbonyl]                               phenyl       438   phenyl   CH 3     R   SO 2     1,4-phenyl   4-(3,5-dimethyl)                               isoxazolyl       439   phenyl   CH 3     R   SO 2     1,4-phenyl   2-methoxy-5-                               formylphenyl       440   phenyl   CH 3     R   SO 2     1,4-phenyl   4-pyridyl       441   phenyl   CH 3     R   SO 2     1,4-phenyl   2,3,4-tri                               methoxyphenyl       442   phenyl   CH 3     R   SO 2     1,4-phenyl   phenoxathiinyl       443   phenyl   CH 3     R   SO 2     1,4-phenyl   2-(5-formyl)furyl       444   phenyl   CH 3     R   SO 2     1,4-phenyl   2-(4-methyl)                               thienyl       446   phenyl   CH 3     R   SO 2     1,4-phenyl   dibenzothienyl       447   phenyl   CH 3     R   SO 2     1,4-phenyl   dianthrenyl       448   phenyl   CH 3     R   SO 2     1,4-phenyl   dibenzothienyl       449   phenyl   CH 3     R   SO 2     1,4-phenyl   3-benzothienyl       450   phenyl   CH 3     R   SO 2     1,4-phenyl   3,4-dimethoxy                               phenyl       451   phenyl   CH 3     R   SO 2     1,4-phenyl   2-fluorophenyl       452   phenyl   CH 3     R   SO 2     1,4-phenyl   1-naphthyl       453   phenyl   CH 3     R   SO 2     1,4-phenyl   4-methoxy phenyl       454   phenyl   CH 3     R   SO 2     1,4-phenyl   3-fluoro-4-                               chlorophenyl       455   phenyl   CH 3     R   SO 2     1,4-phenyl   2-nitrophenyl       456   phenyl   CH 3     R   SO 2     1,4-phenyl   3-biphenyl       457   phenyl   CH 3     R   SO 2     1,4-phenyl   2-(t-butylcarbonyl                               amino)-3-methoxy                               phenyl       458   phenyl   CH 3     R   SO 2     1,4-phenyl   2-(t-butyl carbonyl                               amino)-5-methoxy                               phenyl       459   phenyl   CH 3     R   SO 2     1,4-phenyl   2-(5-formyl)furyl       460   phenyl   CH 3     R   SO 2     1,4-phenyl   2,5-dimethoxy                               phenyl       461   phenyl   CH 3     R   SO 2     1,4-phenyl   2-(di(i-propyl)                               aminocarbonyl)-3-                               methoxyphenyl       462   phenyl   CH 3     R   SO 2     1,4-phenyl   4-methylthio                               phenyl       463   phenyl   CH 3     R   SO 2     1,4-phenyl   2,4,6-tri                               methylphenyl       464   phenyl   CH 3     R   SO 2     1,4-phenyl   3-methylphenyl       465   phenyl   CH 3     R   SO 2     1,4-phenyl   4-methylphenyl       466   phenyl   CH 3     R   SO 2     1,4-phenyl   3-pyridyl       467   phenyl   CH 3     R   SO 2     1,4-phenyl   3-aminophenyl       468   phenyl   CH 3     R   SO 2     1,4-phenyl   3-methylcarbonyl                               aminophenyl       477   phenyl   CH 3     R   C(O)   1,4-phenyl   2-chlorophenyl       478   phenyl   CH 3     R   C(O)   1,4-phenyl   2-methylphenyl       479   phenyl   CH 3     R   C(O)   1,4-phenyl   3-fluorophenyl       480   phenyl   CH 3     R   C(O)   1,4-phenyl   2-bromophenyl       481   phenyl   CH 3     R   C(O)   1,4-phenyl   2,5-dichloro                               phenyl       521   phenyl   CH 3     R   SO 2     1,4-phenyl   2-methyl-3-                               chlorophenyl       522   phenyl   CH 3     R   SO 2     1,4-phenyl   2-chloro-5-                               methylphenyl       523   phenyl   CH 3     R   SO 2     1,4-phenyl   2-methyl-5-                               chlorophenyl       524   phenyl   CH 3     R   SO 2     1,4-phenyl   3-chloro-4-                               methylphenyl       525   phenyl   CH 3     R   SO 2     1,4-phenyl   2-chloro-6-                               methylphenyl       526   phenyl   CH 3     R   SO 2     1,4-phenyl   2-chloro-4-                               methylphenyl       550   3-trifluoro   H   —   SO 2     1,4-phenyl   phenyl           methyl           phenyl       590   phenyl   CH 3     R   C(O)NH   1,4-phenyl   phenyl       591   phenyl   CH 3     S   C(O)NH   1,4-phenyl   phenyl                                                                           Cmpd #   R 4     m   R 5     R 6     Stereo   Y               378   1,5-n-pentyl   1   phenyl   CH 3     R   2-methylphenyl       379   1,5-n-pentyl   1   phenyl   CH 3     R   2-chlorophenyl       380   1,5-n-pentyl   1   phenyl   CH 3     R   3-fluorophenyl       381   1,5-n-pentyl   1   phenyl   CH 3     S   2-methylphenyl       382   1,5-n-pentyl   1   phenyl   CH 3     S   2-chlorophenyl       383   1,5-n-pentyl   1   phenyl   CH 3     S   3-fluorophenyl       352   1,5-n-pentyl   1   2-methoxyphenyl   H   —   2-methylphenyl       353   1,6-n-hexyl   1   2-methoxyphenyl   H   —   2-chlorophenyl       354   1,6-n-hexyl   1   2-methoxyphenyl   H   —   2-methoxyphenyl       355   1,6-n-hexyl   1   2-methoxyphenyl   H   —   2,4-dichlorophenyl       356   1,6-n-hexyl   0   2-methoxyphenyl   H   —   2-methylphenyl       357   1,6-n-hexyl   0   2-methoxyphenyl   H   —   2-chlorophenyl       358   1,6-n-hexyl   0   2-methoxyphenyl   H   —   2-methoxyphenyl       359   1,6-n-hexyl   0   2-methoxyphenyl   H   —   2,4-dichlorophenyl       396   1,6-n-hexyl   1   phenyl   CH 3     R   2-methylphenyl       397   1,6-n-hexyl   1   phenyl   CH 3     R   2-chlorophenyl       398   1,6-n-hexyl   1   phenyl   CH 3     R   3-fluorophenyl       399   1,6-n-hexyl   1   phenyl   CH 3     S   2-methylphenyl       400   1,6-n-hexyl   1   phenyl   CH 3     S   2-chlorophenyl       401   1,6-n-hexyl   1   phenyl   CH 3     S   3-fluorophenyl                                                                                                   Cmpd #   R 4     R 5                                   X               406   1,4-n-butyl   2-methoxyphenyl   1-phenyl   2,3-dichloro       407   1,6-n-hexyl   2-methoxyphenyl   1-phenyl   2,3-dichloro       408   1,4-n-butyl   3,4-methylene   8-quinolinyl   —               dioxyphenyl       409   1,6-n-hexyl   3,4-methylene   8-quinolinyl   —               dioxyphenyl                                                                               Cmpd #   m   Y                       151   1   2-methylphenyl           152   1   3-thienyl           153   1   2-methoxyphenyl           154   1   4-fluorophenyl           155   1   2,4-dimethoxyphenyl           156   1   4-methoxyphenyl           157   1   4-methylphenyl           158   1   1-napthyl           159   1   2-chlorophenyl           160   1   3-pyridyl           161   1   2-thienyl           162   1   3-acetamidophenyl           163   1   phenyl           164   1   4-chlorophenyl           165   1   4-[3,5-dimethylisoxazolyl]           166   1   3-chlorophenyl           167   1   4-cyanophenyl           168   1   4-pyridyl           169   1   3-methoxyphenyl           170   1   3-aminophenyl           171   1   3-fluorophenyl           172   1   2-fluorophenyl           173   1   3,4-methylenedioxyphenyl           174   0   2-methylphenyl           175   0   3-thienyl           176   0   2-methoxyphenyl           177   0   4-fluorophenyl           178   0   2,4-dimethoxyphenyl           179   0   4-methoxyphenyl           180   0   4-methylphenyl           181   0   1-napthyl           182   0   2-chlorophenyl           183   0   3-pyridyl           184   0   2-thienyl           185   0   3-acetamidophenyl           186   0   phenyl           187   0   4-chlorophenyl           188   0   4-[3,5-dimethylisoxazolyl]           189   0   3-chlorophenyl           190   0   4-cyanophenyl           191   0   4-pyridyl           192   0   3-methoxyphenyl           193   0   3-aminophenyl           194   0   3-fluorophenyl           195   0   2-fluorophenyl           196   0   3,4-methylenedioxyphenyl                                                                                                   Cmpd #   R 5                                   X               410   2-methoxyphenyl   1-phenyl   2,3-dichloro       411   3,4-methylenedioxyphenyl   8-quinolinyl   —                                                                               Cmpd #   Stereo   Y                       366   R   2-methylphenyl           367   R   2-chlorophenyl           368   R   3-fluorophenyl           369   S   2-methylphenyl           370   S   2-chlorophenyl           371   S   3-fluorophenyl                                                                               Cmpd #   Y               320   2-methylphenyl       321   2-chlorophenyl       322   3-fluorophenyl                                                                           Cmpd #   Stereo   n   X               431   R   1   4-n-butyl       445   R   0   —       469   R   1   4-bromo       470   S   1   4-bromo       551   R   1   4-methoxy       552   R   1   4-trifluoromethyl       553   R   1   4-isopropyl       554   R   1   4-n-propyl       555   R   1   4-t-butyl       556   R   1   4-n-pentyl       557   R   1   3-methoxy       558   S   1   4-methoxy       559   S   1   4-trifluoromethyl       560   S   1   4-isopropyl       561   S   1   4-n-propyl       562   S   1   4-t-butyl       563   S   1   4-n-pentyl       564   S   1   3-methoxy                                                                           Cmpd #   R 1     R 2     Stereo   Y               471   methyl   methyl   R   2-chlorophenyl       472   ethyl   ethyl   R   2-chlorophenyl       473   H   methylcarbonyl   R   2-chlorophenyl       474   methyl   methyl   S   2-methylphenyl       475   ethyl   ethyl   S   2-methylphenyl       476   H   methylcarbonyl   S   2-methylphenyl                                                                           Cmpd #   R 4     L               483   —CH 2 —(1,4-phenyl)—CH 2 —   4-methyoxyphenylethyl       484   —CH 2 —(1,4-phenyl)—CH 2 —   3,6-dimethoxyphenylethyl       485   —CH 2 —(1,4-phenyl)—CH 2 —   2,3-dimethoxyphenylethyl       486   —CH 2 —(1,4-phenyl)—CH 2 —   1-cyclohexenylethyl       487   —CH 2 —(1,4-phenyl)—CH 2 —   3-bromo-4,5-dimethylphenylethyl       488   —CH 2 —(1,4-phenyl)—CH 2 —   2-chlorphenylethyl       489   —CH 2 —(1,4-phenyl)—CH 2 —   3-chlorophenylethyl       490   —CH 2 —(1,4-phenyl)—CH 2 —   2,4-dichlorophenylethyl       491   —CH 2 —(1,4-phenyl)—CH 2 —   2,6-dichlorophenylethyl       492   —CH 2 —(1,4-phenyl)—CH 2 —   2-trifluoromethylphenylethyl       493   —CH 2 —(1,4-phenyl)—CH 2 —   3,4-dimethylphenylethyl       494   —CH 2 —(1,4-phenyl)—CH 2 —   3,5-dimethylphenylethyl       495   —CH 2 —(1,4-phenyl)—CH 2 —   3-methoxyphenylethyl       496   —CH 2 —(1,4-phenyl)—CH 2 —   3-(2-chlorophenyl)-4,5-               dimethoxyphenylethyl       501   n-hexyl   3,4-dimethoxyphenylethyl       502   n-hexyl   4-methoxyphenylethyl       503   n-hexyl   2,3-dimethoxyphenylethyl       504   n-hexyl   3-bromo-4,5-               dimethoxyphenylethyl       505   n-hexyl   2-chlorophenylethyl       506   n-hexyl   3-chlorophenylethyl       507   n-hexyl   2,4-dichlorophenylethyl       508   n-hexyl   2,6-dichlorophenylethyl       509   n-hexyl   3,5-dimethoxyphenylethyl       510   n-hexyl   3-methoxyphenylethyl       511   n-hexyl   2,5-dimethoxyphenylethyl       512   n-hexyl   1-cyclohexenylethyl       513   n-hexyl   3-(2-chlorophenyl)-3,4-               dimethoxyphenylethyl       514   n-hexyl   2-fluorophenylethyl       515   n-hexyl   2-trifluoromethylphenylethyl       527   —CH 2 —(1,4-phenyl)—CH 2 —   2-nitrophenylethyl       528   —CH 2 —(1,4-phenyl)—CH 2 —   2-aminophenylethyl       529   —CH 2 —(1,4-phenyl)—CH 2 —   2-dimethylaminophenylethyl       530   —CH 2 —(1,4-phenyl)—CH 2 —   2-(methylcarbonylamino)               phenylethyI       531   —CH 2 —(1,4-phenyl)—CH 2 —   2-(methylsulfonylamino)               phenylethyl       532   —CH 2 —(1,4-phenyl)—CH 2 —   CH 2 —C(CH 3 ) 2 -phenyl       533   —CH 2 —(1,4-phenyl)—CH 2 —   CH 2 —C(OCH 3 )-phenyl       534   —CH 2 —(1,4-phenyl)—CH 2 —   CH 2 —CH(CH 3 )-(2-methoxyphenyl)       535   —CH 2 —(1,4-phenyl)—CH 2 —   bicyclo[4.2.0]octa-1,3,5-triene       536   —CH 2 —(1,4-phenyl)—CH 2 —   CH 2 —CH(cyclohexyl)-phenyl       537   —CH 2 —(1,4-phenyl)—CH 2 —   CH 2 —CH(cyclobutyl)-phenyl       538   —CH 2 —(1,4-phenyl)—CH 2 —   CH 2 —CH(ethyl)-phenyl       539   —CH 2 —(1,4-phenyl)—CH 2 —   2,3-dihydro-1H-indene       540   —CH 2 —(1,4-phenyl)—CH 2 —   CH(phenyl) 2         541   —CH 2 —(1,4-phenyt)—CH 2 —   2-methylphenylethyl       542   —CH 2 —(1,4-phenyl)—CH 2 —   3-fluorophenylethyl       543   —CH 2 —(1,4-phenyl)—CH 2 —   3,4-methylenedioxyphenyl       544   —CH 2 —(1,4-phenyl)—CH 2 —   2-pyridylethyl       545   —CH 2 —(1,4-phenyl)—CH 2 —   2-thienylethyl       546   —CH 2 —(1,4-phenyl)—CH 2 —   2-(N-methyl)-pyrrolidinylethyl       547   —CH 2 —(1,4-phenyl)—CH 2 —   phenylpropyl       548   —CH 2 —(1,4-phenyl)—CH 2 —   2-ethoxyphenylethyl       549   —CH 2 —(1,4-phenyl)—CH 2 —   3,4-dichlorophenylethyl       572   n-hexyl   CH 2 —CH(OCH 3 )-phenyl       573   n-hexyl   CH 2 —CH(CH 3 )—(2-methoxyphenyl)       574   n-hexyl   bicyclo[4.2.0]octa-1,3,5-triene       575   n-hexyl   CH 2 —CH(cyclohexyl)-phenyl       576   n-hexyl   CH 2 —CH(cyclobutyl)-phenyl       577   n-hexyl   CH 2 —CH(ethyl)-phenyl       578   n-hexyl   2,3-dihydro-1H-indene       579   n-hexyl   CH 2 —CH(phenyl) 2         580   n-hexyl   2-methylphenylethyl       581   n-hexyl   3-fluorophenylethyl       582   n-hexyl   3,4-methylenedioxyphenyl       583   n-hexyl   2-pyridylethyl       584   n-hexyl   2-thienylethyl       585   n-hexyl   2-(N-methylpyrrolidinyl)ethyl       586   n-hexyl   phenylpropyl       587   n-hexyl   2-ethoxyphenylethyl       588   n-hexyl   3,4-dichlorophenylethyl       589   n-hexyl   3-trifluoromethylphenylethyl               TABLE 1                                                                               Cmpd #   Stereo   Y                       497   R   2-chlorophenyl           498   R   2-methylphenyl           499   R   3-fluorophenyl           500   S   2-chlorophenyl                                  
 
           [0111]    In a particularly preferred embodiment of the present invention are compounds of the formula (I) as enumerated in Table 2 below:  
                         TABLE 2                       (Structure and Compound #)                                                                                                                    #14    208                                                                                       #16   #213                                                                                       #24   #215                                                                                       #26    #311                                                                                       #31   #352                                                                                       #32   #353                                                                                       #33   #390                                                                                        #198   #392                                                                                       #203   #397                          
 
           [0112]    For the compounds listed in Table 3 below, as well as all compounds listed in Table 1 and 2 above, structures were confirmed via molecular weight determination using an electro-spray mass spectrometer in positive mode and via HPLC retention time on a reversed phase column.  
                                     TABLE 3                           Meas MW   HPLC RT       Cmpd #   MH +     (min)                                39   460.47           40   500.13, 502.10       41   528.56, 530.27       42   528.48, 530.28       43   494.43, 496.16       44   528.05, 530.16       45   510.29       46   494.32, 496.16       47   494.23, 496.16       48   534.05, 536.12       49   528.07, 530.11       50   528.07, 530.12       51   528.07, 530.13       52   528.07, 530.14       53   528.07, 530.15       54   474.62, 476.30       55   474.62, 476.31       56   490.62, 492.37       57   510.57, 512.37       58   478.66, 480.23       59   520.45, 522.37       60   520.56, 522.33       61   505.3       62   505.3       63   505.3       64   586.45       65   516.7       66   535.41       67   504.67, 506.39       68   573.51       69   478.68, 480.35       70   478.68, 480.36       71       3.325       72       3.348       73       3.315       74   52.45, 524.28       75   514.34, 516.29       76   538.47, 540.32       77   526.58, 528.32       78   568.03       79   538.42, 540.36       80   522.57, 524.34       81   558.56, 560.31       82   542.26, 544.13       83   509.14       84   514.16       85   565.5, 567.30       86   508.47, 510.29       87   542.19, 544.07       88   527.44, 530.22       89       3.206       90   533.40, 535.30       91   509.14       92   538.46, 540.34       93   523.16       94   536.54       95   528.31, 530.28       96   552.48, 55434       97   540.44, 542.34       98   582.07       99   552.67, 554.32       100   536.53, 538.37       101   572.43, 574.23       102   556.25, 558.04       103   523.16       104   528.3       105       3.158       106   522.42       107   556.20, 558.01       108   541.34, 543.37       109       3.293       110   547.22       111   523.2       112   552.37       113   537.18       114   508.0, 510.0       115   536.1       116   536.1       117   502.1, 504.1       118   536.0, 538.0       119   518.1       120   502.1, 504.1       121   528.1       122   536.0, 538.0       123   536.0, 538.1       124   536.0, 538.2       125   536.0, 538.3       126   541.9, 543.9       127   482.2       128   498.2       129   518.1       130   486.2       131   486.2       132   486.2       133   528.1       134   513.1       135   513.1       136   513.1       137   594       138   524.2       139   543.1       140   512.2       141       2.946       142   581       143   536.1       144   552       145   551       146   598.1       147   474.1       148   482.2       149   502.1, 504.1       150   468.1       151   508.2       152   500.1       153   524.1       154   512.1       155   554.1       156   524.1       157   508.2       158   544.1       159   528.1, 530.1       160   495.2       161   500.1       162   551.1       163   494.2       164   528.1       165   513.1       166   528.1, 530.0       167   519.1       168   495.2       169   524.1       170   509.1       171   512.1       172   512.1       173   538.1       174   494.2       175   486.1       176   510.1       177   498.1       178   540.1       179   510.1       180   494.2       181   530.1       182   514.1, 516.2       183   481.1       184   486.1       185   537.1       186   480.2       187   514.1, 516.0       188   499.1       189   514.1, 516.0       190   505.1       191   481.1       192   510.1       193   495.2       194   498.1       195   498.1       196   524.1       197   528.2       198   562.1, 564.0           562.4, 564.4       199   562.1, 564.1       200   558.1       201   558.1       202   558.1       203   546.1       204   546.1       205   542.1       206   542.1       207   528.1       208   562.1, 564.0       209   562.1, 564.1       210   558.1       211   558.1       212   558.1       213   546.1       214   546.1       215   542.1, 542.5       216   542.1       217       3.418       218       3.509       219       3.403       220       3.413       221       3.450       222       3.465       223       3.539       224       3.575       225   578.1, 580.1       226   574.1       227   559.1       228   562.1       229   562.1       230   588.1       231   578.1, 580.1       232   544.1       233   563.1       234   569.1       235   545.1       236   634.3       237   569.1       238   604.2       239   612.1, 614.1       240   612.2       241   612.2       242   612.2       243   558.1       244   558.2       245   550.1       246   574.2       247   562.1       248   574.2       249   558.2       250   594.2       251   578.1, 580.1       252   545.2       253   578.1, 580.1       254   574.2       255   559.2       256   562.1       257   562.1       258   588.2       259   578.1       260   544.2       261   563.2       262   569.2       263   545.2       264   534.4       265   569.1       266   604.3, 605.3       267   612.3       268   612.3       269   612.3       270   558.2       271   554.0, 556.1       272   564.1       273   556.1       274   580.2       275   568.1       276   580.2       277   564.1       278   600.2       279   584.1, 586.1       280   551.1       281   584.1, 586.1       282   580.2       283   565.1       284   568.1       285   568.1       286   594.2       287   584.1, 586.1       288   550.1       289   569.1       290   575.1       291   551.1       292   640.4       293   575.1       294       3.315       295   610.2       296       4.021       297   618.3       298   618.2       299   618.2       300   564.1       301   546       302   564       303   595.9, 597.9       304   596       305   570       306   546       307   564       308   595.9, 597.9       309   596       310   570       311   542       312   561.9, 563.9       313   546       314   576.0, 578.0       315   595.9, 597.9       316   579.9, 581.9       317   588.0, 590.0       318   608.0, 610.0       319   592.0, 594.0       320   540       321   559.9, 561.9       322   544       323   528       324   548.0, 549.9       325   532       336   564.1       337   584.1, 586.1       338   580.1       339   618.1, 620.1       340   550.1       341   570.0, 572.0       342   566.1       343   604.1, 606.1       344   558.1       345   578.0, 580.0       346   574.1       347   612.1, 614.1       348   544.1       349   564.0, 566.0       350   560.1       351   598.0, 600.0       352   538.2, 538.2       353   558.1, 560.1           558.1, 560.1       354   554.1       355   592.0, 594.0       356   524.2       357   544.1, 546.1       358   540.1       359   578.0, 580.0       366   574.2       367   594.1, 596.1       368   578.1       369   574.1       370   594.1, 596.1       371   578.1       372   548.2       373   568.1, 570.1           568.1, 570.1       374   552.1       375   548.2       376   568.1, 570.0       377   552.1       378   508.2       379   526.1       380   512.1       381   508.2       382   528.1, 530.1       383   512.1       384   548.2       385   568.1, 570.0       386   552.1       387   548.1       388   568       389   552.1       390   542.1, 542.1       391   564       392   546, 546.0       393   542.1       394   562.0, 564.0       395   546       396   522.2, 522.2       397   542.1, 544.1           542.1, 544.1       398   526.1, 526.1       399   522.2       400   542.1, 544.1       401   526.1       402   528.1, 530.2.       412   528.2       413   573.1       414   546.1       415   542.2       416   596.1       417   596.1       418   562.1       419   558.1       420   596.1       421   558.1       422   612.1       423   546.1       424   578.1       425   580       426   606       427   562       428   596       429   596       430   664       431   508.1       432   568.1       433   663       434   553.1       435   553.1       436   572       437   655.1       438   547.1       439   586       440   529.1       441   618.1       442   650       443   532       444   548.1       445   452.1       446   634.1       447   666       448   634.1       449   584       450   588.1       451   546.1       452   578.1       453   558.1       454   580       455   573       456   604.1       457   657.1       458   657.1       459   546.1       460   588.1       461   685.2       462   574       463   570.1       464   542.2       465   542.1       466   539.2       467   543.2       468   585.1       469   530.31, 532.31       470   530.31, 532.32       471   590.54, 592.54       472   618.59, 620.57       473   604.52, 606.54       474   570.59       475   598.64       476   584.57       477   526.5, 528.5       478   506.6       479   510.6       480   606.5, 608.5       481   614.5, 616.5       483   578.5, 580.4       484   608.5, 610.5       485   608.5, 610.5       486   552.5, 554.5       487   686.5, 688.5       488   582.4, 584.4       489   582.4, 584.4       490   616.5, 618.5       491   616.5, 618.4       492   616.5, 618.5       493   622.6, 624.6       494   608.5, 610.5       495   578.4, 580.4       496   718.6, 720.6       497   636.7       498   616.7       499   620.9       500   636.7       501   602.6, 604.5       502   558.5, 560.5       503   588.5, 590.5       504   666.6, 668.6       505   562.4, 564.4       506   562.4, 564.4       507   596.4, 598.4       508   596.5, 598.5       509   588.5, 590.5       510   558.5, 560.5       511   588.5, 560.5       512   532.5, 534.5       513   698.7, 700.7       514   546.5. 548.5       515   596.5, 598.5       521   576.5, 578.5       522   576.5, 578.5       523   576.5, 578.6       524   576.5, 578.7       525   576.5, 578.8       526   576.5, 578.9       527   592.9, 594.9       528   563.0, 565.5       529   590.9, 592.9       530   604.9, 606.9       531   640.9, 642.9       532   576.0, 577.9       533   578.0, 580.0       534   592.0, 594.0       535   560.0, 562.0       536   616.0, 618.0       537   587.9, 589.9       538   576.0, 578.0       539   560.0, 562.0       540   623.9, 625.9       541   562.0, 564.0       542   566.0, 567.9       543   591.9, 593.9       544   549.0, 551.0       545   554.0, 555.9       546   555.0, 557.0       547   562.0, 564.0       548   591.9, 593.9       549   615.8, 617.8       550   582.6       551   482.6       552   520.5       553   494.6       554   494.6       555   508.6       556   522.6       557   482.6       558   482.6       559   520.5       560   494.5       561   494.6       562   508.6       563   522.6       564   482.5       572   558.4, 560.0       573   572.0, 574.0       574   540.5, 542.1       575   596.4, 598.0       576   569.2, 571.0       577   557.0, 559.1       578   540.5, 542.1       579   604.3       580   542.4, 544.1       581   547.1, 549.0       582   572.0, 574.0       583   529.0, 531.0       584   534.0, 536.0       585   535.1, 537.1       586   542.5, 544.1       587   572.0, 574.0       588   596.0, 597.9       589   596.3, 597.9       590   507.6       591   507.6                  
 
           [0113]    The salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:  
           [0114]    acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.  
           [0115]    The pharmaceutically acceptable esters of the novel compounds of the present invention include such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,43, Column 9, line 61 ot Column 12, line 51, which is incorporated herein by reference. Included within such pharmaceutically acceptable esters are those hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and those described I detail in U.S. Pat. No. 4.479.947, which is incorporated herein by reference.  
           [0116]    The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.  
           [0117]    Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.  
           [0118]    Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.  
           [0119]    It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.  
           [0120]    Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:  
                   TABLE 4                       Abbreviation   Definition                   BOC =   Butoxycarbonyl       Cmpd # =   Compound Number       DCE =   Dichloroethane       DCM =   Dichloromethane       DIEA =   Diisopropylethylamine       DMAC =   Dimethylacetamide       DMAP =   4-Dimethylaminopyridine       DMF =   Dimethylformamide       DMSO =   Dimethylsulfoxide       EDTA =   Ethylenediamine-N,N,N″,N″-tetraacetic acid       Fmoc =   9-Fluorenyl methoxycarbonyl       h-FSHR =   human Follicle Stimulating Hormone Receptor       FMPB =   4-(4-Formyl-3-methoxyphenyoxy)butyryl       HATU =   2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium           hexafluorophosphate       HPLC RT =   High Pressure Liquid Chromatography           Retention Time       Mol. Wt. =   Measured Molecular Weight       PBF =   2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl       Stereo =   Optical Configuration of Stereogenic Center       TMOF =   Trimethylorthoformate                  
 
           [0121]    The substituted aminoalkylamide derivatives of this invention are capable of inhibiting follicle stimulating hormone (FSH) to achieve the desired pharmacological effect. With an effective amount of the substituted aminoalkylamide derivative compounds dispersed in a pharmaceutical composition as an active ingredient, the pharmaceutical composition is introduced as a unit dose into an afflicted mammal.  
           [0122]    The term “unit dosage” and its grammatical equivalent is used herein to refer to physically discrete units suitable as unitary dosages for human patients and other warm blooded mammals, each unit containing a predetermined effective, pharmacologic amount of the active ingredient calculated to produce the desired pharmacological effect in association with the required physiologically tolerable carrier, e.g., a diluent or a vehicle. The specifications for the novel unit dosage forms suitable for use herein are dictated by and are directly dependent on (a) the unique characteristics of the active ingredient, and (b) the limitations inherent in the art of compounding such an active ingredient for therapeutic use in humans and other mammals. Examples of suitable unit dosage form in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation and the like. The active ingredient is referred to herein as being dispersed in the carrier. The dispersion form can be a simple admixture, a non-settling dispersion as in the case of certain emulsions, or as an ultimate dispersion, a true solution.  
           [0123]    The amount of active ingredient that is administered in vivo depends on the age and weight of the mammal treated, the particular medical condition to be treated, the frequency of administration, and the route of administration. The dose range can be about 0.01 to about 500 milligrams per kilogram of body weight, more preferably about 0.1 to about 50 milligrams per kilogram of body weight and most preferably about 0.1 to about 25 milligrams per kilogram of body weight. The human adult dose is in the range of about 10 to about 2000 milligrams daily, given as a single dose or in 3 or 4 divided doses. Veterinary dosages correspond to human dosages with the amounts administered being in proportion to the weight of the animal as compared to adult humans. When the compounds are employed to treat FSH receptor mediated diseases or disorders the dosage range can be about 0.01 to about 200 mg/kg. The preferred dosage range is from about 0.5 to about 100 mg/kg.  
           [0124]    Physiologically tolerable carriers are well known in the art. Carriers may be divided into liquid and solid carriers.  
           [0125]    Exemplary of liquid carriers are aqueous solutions that contain no materials in addition to the substituted aminoalkylamide derivative compound, or contain a buffer such as sodium phosphate ay a physiological pH value, saline and the like. Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerin and vegetable oils such as cottonseed oil.  
           [0126]    Exemplary solid carriers (diluents) include those materials usually used in the manufacture of pills or tablets, and include corn starch, lactose, dicalcium phosphate, thickeners, such as tragacanth and methylcellulose U.S.P., finely divided SiO 2 , polyvinylpyrrolidone, magnesium stearate and the like. Antioxidants such as methylparaben and propylparaben can be present in both solid and liquid compositions, as can sweeteners such as cane or beet sugar, sodium saccharin, sodium cyclamate and the dipeptide methyl ester sweetener sold under the trademark NUTRASWEET (aspartame) by G. D. Searle Co.  
           [0127]    The pharmaceutical composition can be administered orally, topically or by injection, by means well known in the art. In preferred practice, the composition is administered orally as a tablet, capsule or aqueous dispersion. The pharmaceutical composition is maintained within the mammal until the substituted aminoalkylamide derivative compound is cleared from the mammal&#39;s body by natural means such as excretion or metabolism.  
           [0128]    Compositions for injection may be prepared in unit dosage form in ampules or in multidose containers. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents. Alternatively, the active ingredient may be in a powder form for reconstitution, at the time of delivery, with a suitable vehicle, such as sterile water. Topical formulations may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, or powders.  
           [0129]    The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.  
           [0130]    Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.  
           [0131]    Inasmuch as a pharmaceutical composition can be administered 3 to 4 times daily (per 24 hour period), the method of treating a disorder of condition mediated by FSH can include administering the pharmaceutical composition a plurality of times into the treated mammal over a time period of weeks, months and years.  
           [0132]    Disorders or conditions mediated by the FSH receptor include uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer; depletion of oocytes (a common side effect of chemotherapy or similar treatment); spermatocyte depletion; or for female and male contraception.  
           [0133]    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 1  
     COMPOUND #198  
       [0134]    [0134]                           
         [0135]    A. Preparation of Amino Carbamate resin  
         [0136]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid , 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0137]    B. Coupling of Bromoacetic Acid  
         [0138]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0139]    C. Preparation of the Optically Pure Secondary Amine on Resin  
         [0140]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL).  
         [0141]    To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0142]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0143]    The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0144]    E. Preparation of Sulfonamide Resin  
         [0145]    The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was added 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0146]    F. Cleavage of the Resin Support  
         [0147]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0148]    Compounds 301-310 were prepared according to the above procedure with appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E.  
         [0149]    Compounds 311-319 were similarly prepared according to the procedure above with appropriate selection and substitution of a racemic mixture of suitably substituted phenethylamine in Step C and appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E.  
         [0150]    Compounds 412 through 468 may similarly be prepared according to the procedure described above, with appropriate selected and substitution of a suitably substituted boronic acid in Step E.  
         [0151]    Compounds 469-470 were similarly prepared according to the procedure above, with appropriate selection and substitution of reagents. Compound 469 was prepared from the product of Step D, Compound 470 was prepared by substituting (S)-β-methylphenethylamine for (R)-β-methylphenethylamine in Step C.  
         [0152]    Compounds 483-496 were similarly prepared according to the procedure above, with appropriate selection and substitution of suitably substituted phenethylamines in step C. Compounds 527-549 were similarly prepared according to the procedure above with appropriate selection and substitution of suitably substituted phenethylamines in step C.  
         [0153]    Compounds 522-526 were similarly prepared according to the procedure above, with appropriate selection and substitution of reagents.  
       EXAMPLE 2  
     COMPOUND #272 
       [0154]    [0154]                           
         [0155]    A. Preparation of Amino Carbamate Resin.  
         [0156]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0157]    B. Coupling of Bromoacetic acid.  
         [0158]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0159]    C. Preparation of the Secondary Amine on Resin  
         [0160]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-(2-methoxy)phenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/ 10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0161]    D. Preparation of Sulfonamide Resin  
         [0162]    The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 5-bromo-2-thiophenesulfonyl chloride (5.23 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0163]    E. Preparation of Substituted Phenylsulfonamide Resin  
         [0164]    The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzeneboronic acid (0.089 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020 g, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0165]    F. Cleavage of the Resin Support  
         [0166]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0167]    Compounds 271, 273-300 were prepared according to the process above with appropriate selection and substitution of a suitably substituted boronic acid in Step E.  
       EXAMPLE 3  
     COMPOUND #205 
       [0168]    [0168]                           
         [0169]    A. Preparation of Amino Carbamate Resin.  
         [0170]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid , 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0171]    B. Coupling of Bromoacetic acid.  
         [0172]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0173]    C. Preparation of the secondary amine  
         [0174]    The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added phenethylamine (6.045 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0175]    D. Preparation of bromophenylsulfonamide Resin  
         [0176]    The resin-bound secondary amine (from C) was swelled in DCM (approximately 200 ml). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonylchloride (5.1 g, 20 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0177]    E. Preparation of Sulfonamide Resin  
         [0178]    The resin-bound secondary amine (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-methylbenzeneboronic acid (0.056 g, 0.399 millimoles). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0179]    F. Cleavage of the Resin Support  
         [0180]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0181]    Compounds 197,199-204, 206-216 and 323-325 were prepared according to the above procedure, with appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E  
         [0182]    Compounds 412 through 468 may alternatively be prepared according to the procedure described in Example 3 above, with substitution of (R)-β-methylphenylethylamine in Step C and appropriate selected and substitution of a suitably substituted boronic acid in Step E.  
       EXAMPLE 4  
     COMPOUND #245 
       [0183]    [0183]                           
         [0184]    A. Preparation of Amino Carbamate Resin.  
         [0185]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid , 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0186]    B. Coupling of Bromoacetic acid.  
         [0187]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0188]    C. Preparation of the secondary amine  
         [0189]    (Displacement of bromide by 2-(2-methoxy)phenethylamine)  
         [0190]    The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 2-(2-methoxy)phenethylamine (6.045 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0191]    D. Preparation of bromophenylsulfonamide Resin  
         [0192]    The resin-bound secondary amine (from C) was swelled in DCM (approximately 200 ml). To the suspension was added pyridine (3.19 g) followed by 3-bromophenylsulfonylchloride (5.1 g, 20 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0193]    E. Preparation of Sulfonamide Resin  
         [0194]    The 3-bromophenylsolfonamide resin (from D) was split into 30 portions, each containing 0.133 millimoles of resin. To one portion was added 2-thiopheneboronic acid (0.051 g, 0.399 millimoles). To the solution was then added palladium tetrakistriphenylphosphine (0.0154 g, 0.133 millimoles), DME (2.5 ml) and 2M sodium carbonate solution in water (0.830 ml). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0195]    F. Cleavage of the Resin Support  
         [0196]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0197]    Compounds 10-19, 145-146, 217, 219-244 and 246-270 were prepared according to the above procedure with appropriate selection and substitution of bromophenylsulfonyl chloride in step D and by appropriate selection and substitution of a suitably substituted boronic acid in step E.  
       EXAMPLE 5  
     COMPOUND #218 
       [0198]    [0198]                           
         [0199]    A. Preparation of Amino Carbamate Resin  
         [0200]    Wang p-nitrophenylcarbonate resin (4.0 millimole) was swelled in DMF (200 mL). To the suspension was added 1,4-xylenediamine (5.45 g, 40.0 millimole) dissolved in DMF (75 mL). The mixture was shaken for 24 hours. The solvent was removed by filtration. The resin was washed with 3 portions of DMF, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0201]    B. Coupling of Bromoacetic Acid  
         [0202]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0203]    C. Preparation of the Secondary Amine on Resin  
         [0204]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxyphenethylamine (6.05 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0205]    D. Preparation of 2-Bromophenylsulfonamide Resin  
         [0206]    The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 2-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0207]    E. Preparation of Substituted Phenylsulfonamide Resin  
         [0208]    The 2-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzneboronic acid (0.071 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0209]    F. Cleavage of the Resin Support  
         [0210]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
       EXAMPLE 6  
     COMPOUND #114 
       [0211]    [0211]                           
         [0212]    A. Preparation of Amino Carbamate Resin.  
         [0213]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid , 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0214]    B. Coupling of Bromoacetic acid.  
         [0215]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0216]    C. Preparation of the secondary amine  
         [0217]    (Displacement of bromide by 2-(2-methoxy)phenethylamine)  
         [0218]    The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 2-(2-methoxy)phenethylamine (6.045 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0219]    D. Preparation of Sulfonamide Resin  
         [0220]    The resin bound secondary amine (from C) was split into 36 portions each containing 0.111 millimole of resin. One portion was swelled in DCM (1.5 ml). To the suspension was added pyridine (0.089 g), followed by 5-chlorothiophene-2-sulfonyl chloride (0.121 g, 0.556 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0221]    E. Cleavage of the Resin Support  
         [0222]    The product was cleaved from the resin using a cleaving cocktail solution of 90:10 TFA:water. The cleavage solution was evaporated. The product was purified by semi-preparative reversed phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product wa lyophilized and analyzed by ES/MS and reversed phase HPLC.  
         [0223]    Compounds 115-144 and 147-150 were prepared according the above procedure with appropriate selection and substitution of a suitably substituted sulfonyl chloride in Step D.  
         [0224]    Compounds 550-564 were similarly prepared according to the procedure above with appropriate selection and substitution of suitably substituted phenethylamines in step C and appropriate selection and substitution of suitably substituted sulfonyl chlorides in step D.  
       EXAMPLE 7  
     COMPOUND #372 
       [0225]    [0225]                           
         [0226]    A. Preparation of Amino Carbamate resin  
         [0227]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-cyclohexylmethylamine (5.69 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0228]    B. Coupling of Bromoacetic Acid  
         [0229]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0230]    C. Preparation of the Optically Pure Secondary Amine on Resin  
         [0231]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0232]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0233]    The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0234]    E. Preparation of Substituted Phenylsulfonamide Resin  
         [0235]    The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-methylbenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0236]    F. Cleavage of the Resin Support  
         [0237]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0238]    Compounds 373-377 were prepared according to the procedure above with suitable selection and substitution of a suitably substituted benzeneboronic acid in Step E.  
       EXAMPLE 8  
     COMPOUND #29 
       [0239]    [0239]                           
         [0240]    A. Preparation of Amino Carbamate resin.  
         [0241]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-cyclohexylmethylamine (5.69 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0242]    B. Coupling of Bromoacetic acid.  
         [0243]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0244]    C. Preparation of the secondary amine  
         [0245]    (Displacement of bromide by 2-(2-methoxy)phenethylamine)  
         [0246]    The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 2-(2-methoxy)phenethylamine (6.045 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0247]    D. Preparation of bromophenylsulfonamide Resin  
         [0248]    The resin-bound secondary amine (from C) was swelled in DCM (approximately 200 ml). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonylchloride (5.1 g, 20 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0249]    E. Preparation of Sulfonamide Resin  
         [0250]    The 4-bromophenylsolfonamide resin (from D) was split into 30 portions, each containing 0.133 millimoles of resin. To one portion was added 3-trifluorobenzeneboronic acid (0.076 g, 0.399 millimoles). To the solution was then added palladium tetrakistriphenylphosphine (0.0154 g, 0.133 millimoles), DME (2.5 ml) and 2M sodium carbonate solution in water (0.830 ml). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0251]    F. Cleavage of the Resin Support  
         [0252]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0253]    Compounds 1-9, 20-28 and 30-38 were prepared according to the procedure above with appropriate selection and substitution of methoxybenzylamine or methoxyphenethylamine in Step C above, and appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E above.  
       EXAMPLE 9  
     COMPOUND #73 
       [0254]    [0254]                           
         [0255]    A. Preparation of Amino Carbamate Resin  
         [0256]    Wang p-nitrophenylcarbonate resin (4.0 millimole) was swelled in DMF (200 mL). To the suspension was added 1,4-cyclohexylmethylamine (5.69 g, 40.0 millimole) dissolved in DMF (75 mL). The mixture was shaken for 24 hours. The solvent was removed by filtration. The resin was washed with 3 portions of DMF, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0257]    B. Coupling of Bromoacetic Acid  
         [0258]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0259]    C. Preparation of the Secondary Amine on Resin  
         [0260]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxybenzylamine (5.226 mL, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0261]    D. Preparation of Sulfonamide Resin  
         [0262]    The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 5-bromo-2-thiophenesulfonyl chloride (5.23 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0263]    E. Preparation of Substituted Phenylsulfonamide Resin  
         [0264]    The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 5-(2-methylthiopyrimidyl)boronic acid (0.089 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0265]    F. Cleavage of the Resin Support  
         [0266]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0267]    Compounds 39-72 were similarly prepared according to the procedure above with appropriate selection and substitution of suitably substituted bromo-sulfonyl chloride in Step C above, and appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E above.  
       EXAMPLE 10  
     COMPOUND #94 
       [0268]    [0268]                           
         [0269]    A. Preparation of Amino Carbamate resin.  
         [0270]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added trans-1,4-bisaminocyclohexane (4.57 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0271]    B. Coupling of Bromoacetic acid.  
         [0272]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0273]    C. Preparation of the secondary amine  
         [0274]    (Displacement of bromide by 2-(2-methoxy)phenethylamine)  
         [0275]    The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 2-(2-methoxy)phenethylamine (6.045 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0276]    D. Preparation of bromophenylsulfonamide Resin  
         [0277]    The resin-bound secondary amine (from C) was swelled in DCM (approximately 200 ml). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonylchloride (5.1 g, 20 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0278]    E. Preparation of Sulfonamide Resin  
         [0279]    The 4-bromophenylsolfonamide resin (from D) was split into 30 portions, each containing 0.133 millimoles of resin. To one portion was added 2-methylbenzeneboronic acid (0.054 g, 0.399 millimoles). To the solution was then added palladium tetrakistriphenylphosphine (0.0154 g, 0.133 millimoles), DME (2.5 ml) and 2M sodium carbonate solution in water (0.830 ml). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0280]    F. Cleavage of the Resin Support  
         [0281]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0282]    Compounds 74-93 and 95-113 were prepared according to the procedure above with appropriate selection and substitution 2-methoxyphenethylamine or 2-methoxybenzylamine in Step C above and appropriate selection and substitution of a suitably substituted boronic acid in Step E above.  
       EXAMPLE 11  
     COMPOUND #344 
       [0283]    [0283]                           
         [0284]    A. Preparation of Amino Carbamate Resin  
         [0285]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,3-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid , 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0286]    B. Coupling of Bromoacetic Acid  
         [0287]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0288]    C. Preparation of the Secondary Amine on Resin  
         [0289]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxyphenethylamine (5.226 mL, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0290]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0291]    The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0292]    E. Preparation of Substituted Phenylsulfonamide Resin  
         [0293]    The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzeneboronic acid (0.071 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0294]    F. Cleavage of the Resin Support  
         [0295]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0296]    Compounds 345-351 were prepared according to the procedure above with appropriate selection and substitution of methoxybenzylamine or methoxyphenethylamine in Step C above and appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E above.  
       EXAMPLE 12  
     COMPOUND #392 
       [0297]    [0297]                           
         [0298]    A. Preparation of Amino Carbamate resin  
         [0299]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,3-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid , 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0300]    B. Coupling of Bromoacetic Acid  
         [0301]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0302]    C. Preparation of the Optically Pure Secondary Amine on Resin  
         [0303]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0304]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0305]    The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0306]    E. Preparation of Sulfonamide Resin  
         [0307]    The N—(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 3-fluorobenzeneboronic acid (0.056 g, 0.399 millimoles). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0308]    F. Cleavage of the Resin Support  
         [0309]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0310]    Compounds 390, 391, 393, 394 and 395 were prepared according to the procedure above with appropriate selection and substitution of a suitably substituted boronic acid in Step E.  
       EXAMPLE 13  
     COMPOUND #336 
       [0311]    [0311]                           
         [0312]    A. Preparation of Amino Carbamate Resin  
         [0313]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,3-bisaminomethylcyclohexane (5.69 g, 40 mmol) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/ 5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0314]    B. Coupling of Bromoacetic Acid  
         [0315]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0316]    C. Preparation of the Secondary Amine on Resin  
         [0317]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxybenzylamine (5.226 mL, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0318]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0319]    The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0320]    E. Preparation of Substituted Phenylsulfonamide Resin  
         [0321]    The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzeneboronic acid (0.071 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0322]    F. Cleavage of the Resin Support  
         [0323]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0324]    Compounds 337-343 were similarly prepared according to the procedure above with suitable selection and substitution of a suitably substituted benzeneboronic acid in Step E.  
       EXAMPLE 14  
     COMPOUND #384 
       [0325]    [0325]                           
         [0326]    A. Preparation of Amino Carbamate resin  
         [0327]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,3-bisaminomethylcyclohexane (5.69 g, 40 mmol) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/ 5% acetic acid , 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0328]    B. Coupling of Bromoacetic Acid  
         [0329]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0330]    C. Preparation of the Optically Pure Secondary Amine on Resin  
         [0331]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0332]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0333]    The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0334]    E. Preparation of Substituted Phenylsulfonamide Resin  
         [0335]    The N—(R)-β-methylphenethyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-methylbenzeneboronic acid (0.054 g, 0.399 mmol). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0336]    F. Cleavage of the Resin Support  
         [0337]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0338]    Compounds 385-389 were similarly prepared according to the procedure above, by appropriate selection of optically pure methylphenethylamine in Step C above, and appropriate selection and substitution of a suitably substituted boronic acid in Step E.  
       EXAMPLE 15  
     COMPOUND #379 
       [0339]    [0339]                           
         [0340]    A. Preparation of Amino Carbamate resin  
         [0341]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 15-pentanediamine (4.09 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid , 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0342]    B. Coupling of Bromoacetic Acid  
         [0343]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0344]    C. Preparation of the Optically Pure Secondary Amine on Resin  
         [0345]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0346]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0347]    The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0348]    E. Preparation of Sulfonamide Resin  
         [0349]    The N—(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0350]    F. Cleavage of the Resin Support  
         [0351]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0352]    Compounds 352, 378 and 380-383 were prepared according to the procedure above with appropriate selection and substitution of substituted benzeneboronic acid in Step E.  
         [0353]    Compounds 353-359 and 396-401 were similarly prepared according to the procedure above with substitution of 1,6-n-hexyl diamine for the 1,5-n-pentyl diamine in step B and appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E.  
       EXAMPLE 16  
     COMPOUND #151 
       [0354]    [0354]                           
         [0355]    A. Preparation of Piperazino Carbamate Resin  
         [0356]    Wang p-nitrophenylcarbonate resin (4.0 millimole) was swelled in DMF (200 mL). To the suspension was added piperazine (3.446 g, 40.0 millimole) dissolved in DMF (75 mL). The mixture was shaken for 24 hours. The solvent was removed by filtration. The resin was washed with 3 portions of DMF, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0357]    B. Coupling of Bromoacetic Acid  
         [0358]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0359]    C. Preparation of the Secondary Amine on Resin  
         [0360]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxybenzylamine (5.226 mL, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0361]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0362]    The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0363]    E. Preparation of Substituted Phenylsulfonamide Resin  
         [0364]    The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzeneboronic acid (0.071 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0365]    F. Cleavage of the Resin Support  
         [0366]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0367]    Compounds 152-173 were prepared according to the procedure above with appropriate selection and substitution of substituted boronic acid in step E.  
       EXAMPLE 17  
     COMPOUND #174 
       [0368]    [0368]                           
         [0369]    A. Preparation of Piperazino Carbamate Resin  
         [0370]    Wang p-nitrophenylcarbonate resin (4.0 millimole) was swelled in DMF (200 mL). To the suspension was added piperazine (3.446 g, 40.0 millimole) dissolved in DMF (75 mL). The mixture was shaken for 24 hours. The solvent was removed by filtration. The resin was washed with 3 portions of DMF, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0371]    B. Coupling of Bromoacetic Acid  
         [0372]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0373]    C. Preparation of the Secondary Amine on Resin  
         [0374]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxybenzylamine (5.226 mL, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0375]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0376]    The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0377]    E. Preparation of Substituted Phenylsulfonamide Resin  
         [0378]    The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzeneboronic acid (0.071 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0379]    F. Cleavage of the Resin Support  
         [0380]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0381]    Compounds 175-196 were prepared according to the procedure above with appropriate selection and substitution of substituted boronic acid in step E.  
       EXAMPLE 18  
     COMPOUND #367 
       [0382]    [0382]                           
         [0383]    A. Preparation of Bipiperidino resin  
         [0384]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 4,4′-bipiperdine (6.73 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid , 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0385]    B. Coupling of Bromoacetic Acid  
         [0386]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0387]    C. Preparation of the Optically Pure Secondary Amine on Resin  
         [0388]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0389]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0390]    The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0391]    E. Preparation of Sulfonamide Resin  
         [0392]    The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0393]    F. Cleavage of the Resin Support  
         [0394]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0395]    Compounds 366 and 368-371 were prepared according to the procedure above with appropriate selection and substitution optically pure methylphenethylamine in Step C and appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E.  
       EXAMPLE 19  
     COMPOUND #320 
       [0396]    [0396]                           
         [0397]    A. Preparation of Amino Carbamate resin  
         [0398]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0399]    B. Coupling of Bromoacetic Acid  
         [0400]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0401]    C. Preparation of the Secondary Amine on Resin  
         [0402]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 1-amino-2-phenyl-cyclopropane (5.33 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0403]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0404]    The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0405]    E. Preparation of Sulfonamide Resin  
         [0406]    The 4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-methylbenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0407]    F. Cleavage of the Resin Support  
         [0408]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0409]    Compounds 321 and 322 were prepared according to the above procedure with appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E.  
       EXAMPLE 20  
     COMPOUND #405 
       [0410]    [0410]                           
         [0411]    A. Preparation of Amino Carbamate Resin.  
         [0412]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0413]    B. Coupling of Bromoacetic acid.  
         [0414]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0415]    C. Preparation of the secondary amine  
         [0416]    (Displacement of bromide by 2-methoxybenzylamine)  
         [0417]    The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 3,4-methylenedioxy-benzylamine (6.05 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0418]    D. Preparation of Sulfonamide Resin  
         [0419]    The resin bound secondary amine (from C) was split into 36 portions each containing 0.111 millimole of resin. One portion was swelled in DCM (1.5 ml). To the suspension was added pyridine (0.089 g), followed by 8-quinolinylsulfonyl chloride (9.70 g, 0.556 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0420]    E. Cleavage of the Resin Support  
         [0421]    The product was cleaved from the resin using a cleaving cocktail solution of 90:10 TFA:water. The cleavage solution was evaporated. The product was purified by semi-preparative reversed phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product wa lyophilized and analyzed by ES/MS and reversed phase HPLC.  
         [0422]    Compounds 403, 408, 409 and 411 were prepared according the above procedure with appropriate selection and substitution of a suitable diamine in Step A.  
       EXAMPLE 21  
     COMPOUND #404 
       [0423]    [0423]                           
         [0424]    A. Preparation of Amino Carbamate Resin.  
         [0425]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0426]    B. Coupling of Bromoacetic acid.  
         [0427]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0428]    C. Preparation of the secondary amine  
         [0429]    (Displacement of bromide by 2-methoxybenzylamine)  
         [0430]    The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 2-methoxybenzylamine (5.226 mL g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0431]    D. Preparation of Sulfonamide Resin  
         [0432]    The resin bound secondary amine (from C) was split into 36 portions each containing 0.111 millimole of resin. One portion was swelled in DCM (1.5 ml). To the suspension was added pyridine (0.089 g), followed by 2,3-dichlorobenzene sulfonyl chloride (0.137 g, 0.556 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0433]    E. Cleavage of the Resin Support  
         [0434]    The product was cleaved from the resin using a cleaving cocktail solution of 90:10 TFA:water. The cleavage solution was evaporated. The product was purified by semi-preparative reversed phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product wa lyophilized and analyzed by ES/MS and reversed phase HPLC.  
         [0435]    Compounds 402, 406, 407 and 410 were prepared according the above procedure with appropriate selection and substitution of a suitable diamine in Step A.  
       Example 22  
     COMPOUND #471 
       [0436]    [0436]                           
         [0437]    A. Dimethylation of Compound #198.  
         [0438]    Compound #198, prepared as in Example 1 (100 mg, 0.178 millimoles) was dissolved in an equal mixture of TMOF and DCE (3.0 mL). To the solution were then added formaldehyde (16 mg, 0.534 millimoles), NaBH 3 CN (34 mg, 0.534 millimoles), and acetic acid (45 μL, 1.5%). The mixture was stirred for 16 h, and then the reaction was stopped by adding water. The crude product was extracted with chloroform, and the solvent removed under vacuum, to yield the product.  
         [0439]    B. Purification of product.  
         [0440]    The crude product prepared in Step A was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES + /MS and reverse phase HPLC.  
         [0441]    Compounds 472, 474, 475 were similarly prepared according to the procedure above with appropriate selection and substitution of reagents (Compound 472 was prepared by replacing the formaldehyde in Step A with acetaldehyde; Compound 474 was prepared by replacing compound 198 in Step A with compound 215; and Compound 475 by substituting compound 198 and formaldehde were in Step A with compound 215 and acetaldehyde, respectively).  
       EXAMPLE 23  
     COMPOUND #473 
       [0442]    [0442]                           
         [0443]    A. Acetylation of Compound #198.  
         [0444]    Compound #198, prepared as in Example 1, (100 mg, 0.178 millimoles) was dissolved in chloroform (3.0 mL). To the solution were added acetyl chloride (19 45 μL, 0.267 millimoles), and TEA (37 45 μL, 0.267 millimoles), and the mixture stirred for 16. The reaction was then stopped by adding water. The crude product was washed twice by 10% NaHCO 3  aqueous solution.  
         [0445]    B. Purification of product.  
         [0446]    The crude product from Step A was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES + /MS and reverse phase HPLC.  
         [0447]    Compound 476 was similarly prepared according to the procedure above, with substitution of compound 198 in Step A with compound 215.  
       EXAMPLE 24  
     COMPOUND #497 
       [0448]    [0448]                           
         [0449]    A. Preparation of Amino Carbamate resin  
         [0450]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 4,4-methylenebis(cyclohexanamine) (8.41 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0451]    B. Coupling of Bromoacetic Acid  
         [0452]    The carbamate resin (from Step A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and the mixture shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0453]    C. Preparation of the Optically Pure Secondary Amine on Resin  
         [0454]    The 2-bromoacetylated resin (from Step B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0455]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0456]    The optically pure resin-bound secondary amine resin (from Step C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0457]    E. Preparation of Sulfonamide Resin  
         [0458]    The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from Step D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was added 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution were then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0459]    F. Cleavage of the Resin Support  
         [0460]    The product from Step E was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0461]    Compounds 498 through 501 were similarly prepared according to the procedure above with appropriate selection and substitution the desired optically pure phenethylamine in Step C and appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E.  
       EXAMPLE 25  
     COMPOUND # 502 
       [0462]    [0462]                           
         [0463]    A. Preparation of Amino Carbamate resin  
         [0464]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,6-hexanediamine (4.65 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0465]    B. Coupling of Bromoacetic Acid  
         [0466]    The carbamate resin (from Step A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0467]    C. Preparation of the Secondary Amine on Resin  
         [0468]    The 2-bromoacetylated resin (from Step B) was swelled in DMSO (150 mL). To the suspension was added 4-methoxyphenethylamine (6.05 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0469]    D. Preparation of 4-Bromophenylsulfonamide Resin  
         [0470]    The optically pure resin-bound secondary amine resin (from Step C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0471]    E. Preparation of Sulfonamide Resin  
         [0472]    The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from Step D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was added 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0473]    F. Cleavage of the Resin Support  
         [0474]    The product from Step E was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0475]    Compounds 501 through 515 and 572 through 589 may be similarly prepared according to the procedure above with suitably substituted phenethylamines in Step C.  
       EXAMPLE 26  
     COMPOUND #590 
       [0476]    [0476]                           
         [0477]    A. Preparation of Amino Carbamate resin  
         [0478]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0479]    B. Coupling of Bromoacetic Acid  
         [0480]    The carbamate resin (from Step A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0481]    C. Preparation of the Optically Pure Secondary Amine on Resin  
         [0482]    The 2-bromoacetylated resin (from Step B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0483]    D. Preparation of 4-Biphenylurea Resin  
         [0484]    The optically pure resin-bound secondary amine resin from Step C (0.150 mmol) was swelled in DCE (2.0 mL). To the suspension was added 4-biphenylisocyanate (0.146 g, 0.750 mmol). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0485]    E. Cleavage of the Resin Support  
         [0486]    The product from Step D was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0487]    Compound #591 was similarly prepared according to the procedure described above with appropriate substitution of (S)-β-methylphenethylamine in Step C.  
       EXAMPLE 27  
     COMPOUND # 477 
       [0488]    [0488]                           
         [0489]    A. Preparation of Amino Carbamate resin  
         [0490]    Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 4,4-methylenebis(cyclohexanamine) (8.41 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.  
         [0491]    B. Coupling of Bromoacetic Acid  
         [0492]    The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.  
         [0493]    C. Preparation of the Optically Pure Secondary Amine on Resin  
         [0494]    The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0495]    D. Preparation of 4-lodobenzamide Resin  
         [0496]    The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-iodobenzoyl chloride (5.3 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.  
         [0497]    E. Preparation of Sulfonamide Resin  
         [0498]    Five portions of the N-(R)-β-methylphenthyl-4-iodobenzamide resin (from D), each containing 0.133 millimole of resin, were used for the next reaction. To one portion was added 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.  
         [0499]    F. Cleavage of the Resin Support  
         [0500]    The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J&#39;sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.  
         [0501]    Compounds 478-481 were similarly prepared according to the procedure above, with appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E.  
       EXAMPLE 28  
     IN VITRO TESTING: hFSH-R CHO Cells  
     Preparation of Biological Materials  
       [0502]    Minimum Essential Medium-Alpha (MEM-alpha), fetal bovine serum (FBS), penicillin, streptomycin, geneticin, trypsin-EDTA, Hanks&#39; Balanced Salt Solution (no Calcium chloride, Magnesium chloride, Magnesium sulfate, or phenol red; Ca-Mg free HBSS) were purchased from Gibco BRL (Gaithersburg, MD). The cells used for the FSH bioassay (rhFSHR-cLUC) were Chinese Hamster Ovary cells (K-1; ATCC) stably transformed with human FSH receptor (pSVK-FSHr) and a cAMP luciferase reporter gene (responsive CGα-180LUC). Follicle Stimulating Hormone (Metrodin; Fertinex) was purchased from Serono, Ltd. (Norwell, Mass.).  
         [0503]    The rhFSHR-cLUC cell cultures were maintained in MEM-Alpha supplemented with 10% heat-inactivated FBS (HIFBS), 100 U/ml penicillin, 100 μg/mL streptomycin, and included 0.1 g/L geneticin for stable cell selection.  
       HFSHR Assay Procedure  
       [0504]    Forty-eight hours after the cells were plated in sterile 96-well culture plates (Corning, Corning, N.Y.) the spent media was removed and 50 μl assay media (modified growth media with 2% HIFBS) containing 2 mM IBMX (3-isobutyl-1-methyl-xanthine) was added to the cells. Compounds (25 μl) in the appropriate concentration were added followed 5 minutes later by an EC 70  dose of FSH (25 μl; 160 ng/ml; 4.85 nM). After 10 minutes @ 22.5° C. (room temperature) the reaction was terminated by addition of 25 μL 0.5 N hydrochloric acid to each well. The amount of cAMP produced was measured by radioimmunoassay in a FlashPlate (DuPont, Boston, Mass.). To each flash plate 60 μL flash plate buffer was added followed by 40 μL acidified cell sample or cAMP standard, followed with the addition of 100 μ 1   125 l-cAMP trace. The FlashPlates were sealed, incubated overnight @ room temperature, and counted in a Packard TopCount (Packard Instrument Co., Meriden, Conn.). The cAMP radioimmunoassay results were calculated using DPM conversion and log-logit transformation of % binding (Excel program).  
       Preparation of Test Compound  
       [0505]    Test compounds were solubilized in 30% dimethyl sulfoxide (DMSO) at a concentration of 10 mM before diluting to appropriate concentrations in assay medium. The final DMSO concentration in the treated cells and in the control cells was 0.75%. The compounds were tested in the assay at a maximum final concentration of 50 μM (primary assay) and compounds that demonstrated greater than 50% inhibition or greater than 200% stimulation of cAMP production were retested in dose-ranging experiments to calculate an EC 50 .  
       Derivation and Analysis of Data  
       [0506]    For individual experiments, a set of samples were tested including a vehicle control (assay buffer), a reference compound (hFSH) at a range of concentrations designed to elicit a minimal to maximal response, and several concentrations of test compounds together with an EC 70  concentration of standard (hFSH challenge). Each compound was performed in duplicates for the primary evaluation and quadruplicates for the dose-ranging experiments. The cAMP radioimmunoassay raw data (pmol) were calculated to provide average pmol cAMP produced/ml and the percent inhibition was calculated as shown below. 
         % Inh=[1−(Avg. pmol  test compound+standard )/(Avg. pmol  standard )]×100 
         [0507]    EC 50  values were calculated from an analysis of the concentration-inhibition data using a linear analysis of the data transformed to a log-logit format.  
                                         TABLE 5                                       EC 50  hFSHR           Cmpd #   CHO cAMP (μM)                                        1   1.16           2   0.93           3   0.6           4   0.65           5   0.96           6   1.59           7   1.81           8   1.38           9   1.06           10   3.71           11   0.63           12   0.68           13   0.56           14   0.74           15   0.84           16   1.13           17   0.57           18   1.82           19   3.37           20   6.31           21   3.29           22   5.03           23   1.41           24   2.33           25   1.41           26   1.46           27   2.3           28   2.23           29   3.09           30   1.33           31   0.91           32   0.31           33   0.42           34   0.31           35   0.83           36   0.66           37   0.67           38   0.5           39   1.69           40   22.13           41   12.69           42   6.46           43   9.88           44   8.92           45   3.92           46   28.85           47   4.37           48   3.62           49   31.3           50   26.24           51   25           52   28.49           53   29.02           54   33.45           55   50           56   23.32           57   19.52           58   6.24           59   28.48           60   40.02           61   50           62   6.76           63   33.61           64   38.47           65   4.82           66   12.67           67   50           68   37.66           69   5.99           70   18.78           71   11           72   7.85           73   4.95           74   10.68           75   5.09           76   10.21           77   6.86           78   12.87           79   7.83           80   3.06           81   7.06           82   5.09           83   4.5           84   50           85   7.79           86   12.34           87   7.4           88   12.2           89   50           90   50           91   13.19           92   50           93   15.22           94   34.45           95   5.98           96   8.23           97   4.31           98   6.04           99   3.68           100   4.99           101   4.89           102   3.98           103   28.32           104   9.54           105   31.33           106   12.77           107   9.7           108   5.5           109   4.76           110   10.75           111   8.39           112   10.21           113   16.69           114   9.78           115   2.92           116   8.41           117   3.63           118   1.24           119   0.54           120   1.5           121   33.11           122   0.76           123   4.03           124   1.11           125   7.53           126   2.31           127   10.36           128   4.98           129   2.11           130   1.86           131   1.41           132   2.58           133   50           134   3.86           135   1.02           136   2.13           137   4.32           138   31.21           139   5.76           140   18.57           141   50           142   50           143   5           144   1.08           145   24.26           146   1.73           147   8.06           148   23.5           149   1.01           150   4.53           151   9.79           152   8.58           153   9.44           154   10.68           155   12.64           156   20.37           157   10.27           158   8.34           159   4.54           160   28.53           161   37.9           162   11.24           163   24.27           164   13.8           165   12.46           166   9.09           167   3.48           168   24.84           169   8.96           170   8.66           171   8.99           172   3.76           173   2.23           174   50           175   47.77           176   40.59           177   50           178   50           179   50           180   50           181   50           182   50           183   50           184   50           185   50           186   38.9           187   50           188   50           189   50           190   38.23           191   50           192   32.3           193   50           194   50           195   50           196   50           197   0.36           198   0.04           199   0.83           200   0.32           201   0.41           202   0.21           203   0.08           204   0.54           205   0.22           206   0.35           207   0.35           208   0.06           209   0.77           210   0.23           211   0.49           212   0.16           213   0.07           214   0.15           215   0.08           216   0.62           217   1.2           218   1.2           219   1.77           220   2.1           221   5.86           222   13.52           223   6.51           224   9.81           225   12.8           226   5.5           227   5.5           228   3.65           229   3.76           230   31.12           231   5.82           232   4.46           233   8.9           234   27.85           235   8.66           236   3.13           237   50           238   10.49           239   7.99           240   6.83           241   7.45           242   3.51           243   5.17           244   2.88           245   5.63           246   4.11           247   6.27           248   5.33           249   6.86           250   17.11           251   5.85           252   8.27           253   8.43           254   4.33           255   2.63           256   2.39           257   1.64           258   2.44           259   2.98           260   3.93           261   5.65           262   2.46           263   31.99           264   5.62           265   2.69           266   3.43           267   2.08           268   50           269   6.76           270   4.19           271   0.96           272   0.55           273   1.16           274   2.08           275   1.6           276   5.1           277   31.89           278   1.09           279   2.45           280   7.63           281   6.95           282   9.4           283   1.27           284   3.51           285   7.89           286   3.88           287   7.52           288   19.51           289   5.68           290   0.67           291   8.94           292   0.68           293   7.36           294   1.54           295   2.18           296   50           297   6.88           298   34.38           299   2.22           300   3.18           301   0.15           302   0.2           303   0.44           304   0.3           305   0.58           306   0.35           307   0.19           308   0.45           309   0.34           310   0.22           311   0.05           312   0.22           313   0.43           314   0.69           315   0.31           316   0.96           317   16.92           318   16.97           319   1.1           320   2.57           321   11.3           322   4.36           323   0.29           324   0.37           325   16.96           336   0.98           337   0.31           338   0.44           339   1.1           340   0.65           341   0.57           342   0.37           343   0.53           344   0.7           345   18.22           346   0.65           347   0.9           348   2.24           349   0.79           350   17.47           351   3.15           352   0.11           353   0.14           354   0.37           355   0.4           356   0.89           357   0.3           358   1.04           359   0.36           366   0.78           367   1.02           368   1.08           369   0.75           370   0.57           371   1.84           372   0.19           373   0.11           374   0.34           375   0.13           376   0.17           377   0.34           378   0.25           379   50           380   1.2           381   0.45           382   0.61           383   2.9           384   0.27           385   0.33           386   1.17           387   1.07           388   0.9           389   1.93           390   0.23           391   0.31           392   0.26           393   0.09           394   0.72           395   2.64           396   0.09           397   0.05           398   0.22           399   0.23           400   0.16           401   1.36           402   5.36           412   0.32           413   0.08           414   0.35           415   0.72           416   0.51           417   0.44           418   0.85           419   2.07           420   0.64, 0.21           421   0.55           422   0.52           423   1.38           424   18.85           425   0.42           426   0.7           427   4.75           428   &gt;50           429   3.03, 0.77           430   &gt;50           431   5.98           432   &gt;50           433   23.5           434   0.2           435   0.21           436   50           437   32.5           438   0.73           439   &gt;50           440   0.9           441   0.12           442   &gt;50           443   0.85           444   1.89           445   1.54           446   &gt;50           447   &gt;50           448   &gt;50           449   0.64           450   0.21           451   0.29, 0.52           452   0.58           453   0.37           454   0.86           455   0.23           456   3.35           457   0.58           458   20.9           459   9.05           460   0.17           461   16.3           462   1.22           463   2.14, 0.58           464   0.73           465   2.19           466   1           467   0.07           468   0.51           469   20.01           470   50           471   49.95           472   &gt;50           473   &gt;50           474   &gt;50           475   9.46           476   50           477   7.7           478   &gt;50           479   13.25           480   0.62           481   0.67           483   0.46           484   0.14           485   0.11           486   2.33           487   0.11           488   0.22           489   0.35           490   0.59           491   0.11           492   1.08           493   0.99           494   0.45           495   0.62           496   0.13           497   4.04           498   1.33           499   3.46           500   2.55           501   0.79           502   0.3           503   0.39           504   &gt;50           505   0.14           506   1.2           507   0.08           508   0.28           509   0.2           510   1.02           511   0.09           512   1.37           513   0.62           514   0.41           515   3.18           521   0.12           522   0.41           523   0.37           524   0.21           525   0.76           526   2.36           527   0.15           528   0.61           529   0.72           530   20           531   &gt;50           532   21.9           533   0.92           534   1           535   4.77           536   &gt;50           537   0.29           538   0.12           539   4.62           540   50           541   0.21           542   0.1           543   0.77           544   0.82           545   0.19           546   14.8           547   2.5           548   0.23           549   0.29           550   0.36           551   1.27           552   4.2           553   1           554   0.24           555   1.93           556   0.87           557   0.42           558   0.41           559   0.74           560   0.84           561   0.13           562   3           563   1.38           564   0.87           572   0.13           573   0.04           574   0.21           575   0.87           576   0.1           577   0.14           578   50           579   5.29           580   0.35           581   0.1           582   0.43           583   1.94           584   0.11           585   &gt;50           586   1.24           587   0.29           588   1.06           589   0.25           590   2.6           591   50                      
 
       EXAMPLE 29  
     IN VITRO TESTING: Rat Granulosa Cells  
     Preparation of Biological Materials  
       [0508]    Insulin, diethylstilbesterol, androstenedione, forskolin and DMSO were purchased from Sigma (St. Louis, Mo.). Fungizone, penicillin/streptomycin, charcoal-treated heat inactivated fetal bovine serum (CT-HI-FBS) and Dulbecco&#39;s Modified Eagle Medium:Hams F12 medium containing 15 mM Hepes and L-glutamine (DMEM:F12), were purchased from GIBCO BRL (Grand Island, N.Y.).  
         [0509]    Ovine FSH (NIADDK-oFSH-17; FSH potency=20 NIH-FSH-S1 U/mg; LH contamination=0.04 times NIH-LH-S1) was received from Ogden Bioservices Corporation, Rockville, Md. Human FSH (Fertinex), was purchased from Serono Pharmaceutical (Framingham, Mass.). Human chorionic gonadotropin (hCG) was purchased from Sigma (St Louis, Mo.).  
       Granulosa Cell Culture  
       [0510]    Immature intact female rats (Wistar-derived strain; 21-23 days old) were implanted with a single pellet (Innovative Research of America, Sarasota, Fla.) containing 2.5 mg diethylstilbesterol (DES) for 3 days. On the third day, the animals were sacrificed, the ovaries were removed, and the granulosa cells were isolated essentially as described in Haynes-Johnson et al.,  Biol. Reprod.,  61 (1), 147-153, (1999). Granulosa cells were plated at a density of 300,000 cells per ml with 0.2 ml added to each well of 96 well culture dishes (Corning, N.Y.). Cultures were incubated at 37° C. in a humidified incubator (95% air, 5% CO2) overnight (18 hours).  
         [0511]    For determination of LH-stimulated estrogen production, immature female rats, about 28 days of age, were treated with 75 IU pregnant mares serum gonadotropin (PMSG) and sacrificed 48 hours later. The granulosa cells from large follicles (not corpora lutea) were expressed into media following the procedure outlined above. Granulosa cells were plated at a density of 300,000 cells/ml with 0.2 ml of cell suspension added to each well of a 96-well plate.  
       Test Procedure  
       [0512]    Androstenedione (100,000X) was prepared by dissolving the steroid in 100% ethanol, and was subsequently diluted to a final concentration of 10 −7 M containing 0.1% ethanol in assay media. The assay media was serum-free, DES-free, insulin-free media, prepared by adding 5 mL pen-strep,1.5 mL fungizone and 5 μL androstenedione to 493.5 mL DMEM F-12 media.  
         [0513]    Test compounds were solubilized in 30% dimethyl sulfoxide (DMSO) at a concentration of 10 mM before diluting to appropriate concentrations in assay medium. The final DMSO concentration in the treated cells and in the control cells was 0.75%. The compounds were tested in the assay at a maximum final concentration of 50 μM (primary assay) and compounds that demonstrated greater than 50% inhibition or greater than 200% stimulation of cAMP production were retested in dose-ranging experiments to calculate an EC 50 .  
         [0514]    Test plates containing the granulosa cells were preincubated for 18 hours at 37° C. with 95% air, 5% CO 2 , 100% humidity. The spent media was removed and 50 μl assay media (DMEM:F12) containing 2 mM IBMX (3-isobutyl-1-methyl-xanthine) was added to the cells. Compounds (25 μl) in the appropriate concentration were added followed 5 minutes later by an EC 70  dose of FSH (25 μl; 50 ng/ml; 1.4 nM). After 30 minutes @ 22.5° C. (room temperature) the reaction was terminated by addition of 25 μL 0.5 N hydrochloric acid to each well. The amount of cAMP produced was measured by radioimmunoassay in a FlashPlate (DuPont, Boston, Mass.). To each flash plate 60 μL flash plate buffer was added followed by 40 μL acidified cell sample or cAMP standard, followed with the addition of 100 μl 125 l-cAMP trace. The FlashPlates were sealed, incubated overnight @ room temperature, and counted in a Packard TopCount (Packard Instrument Co., Meriden, Conn.). The cAMP radioimmunoassay results were calculated using DPM conversion and log-logit transformation of % binding (Excel program).  
       Progesterone and Estradiol Production  
       [0515]    The effects of the FSH antagonist on steroid production from rat granulosa cells was used to confirm that the effects on cAMP production also caused changes in progesterone and estradiol production, the biologically relevant steroids in vivo. Granulosa cells prepared as described above were incubated in the absence or presence of test compounds for intervals between 12 and 48 hours to determine the effects of compound on FSH-stimulated progesterone and estradiol production. At the end of incubation the media was aspirated (using a multichannel pipettor) into corresponding microtiter plates, and were stored at −20° C. until the concentration of estradiol and progesterone were measured by radioimmunoassay.  
       Radioimmunoassay of estradiol and progesterone  
       [0516]    Concentrations of E and P in media from the same culture wells were measured using [ 125 l]-progesterone and [ 125 l]-estradiol Coat-A-Count radioimmunoassay kits (Diagnostic Products Corp., Los Angeles, Calif.). According to the manufacturers specification sheets, the anti-progesterone antibody cross-reacts 2% with 20a-dihydroprogesterone, 2.4% with 11-deoxycortisol, 1.7% with 11-deoxycorticosterone, and 1.3% with 5b-pregnan-3,20-dione. The cross-reactivity of pregnenolone, 17a-hydroxyprogesterone, and testosterone was less than 0.4%. The assay detection limit was 0.03 ng/ml. The anti-estradiol antibody cross-reacts 10% with estrone, 4.4% with equilenin, 1.8% with estrone glucuronide, 0.3% with estriol, and less than 0.1% with other estrogens and androgens. The assay detection limit was 8 pg/ml.  
                                         TABLE 6                                       Rat Granulosa Cell           Cmpd #   EC 50  cAMP (μM)                                        1   2.42           2   0.34           3   0.21           4   0.29           5   0.27           6   0.29           7   0.83           8   0.31           9   0.47           10   1.39           11   0.40           12   0.28           13   0.48           14   1.56           15   5.55           16   0.51           17   0.49           18   0.36           19   1.67           20   0.64           21   5.30           22   0.85           24   1.07           25   1.33           26   4.30           27   1.01           28   1.81           29   2.06           30   0.49           31   1.97           32   0.16           33   0.18           34   0.17           35   0.20           36   0.49           37   0.28           38   1.07           39   0.52           40   1.92           41   0.26           42   1.45           43   0.88           44   0.72           45   2.85           46   6.37           47   0.55           48   1.08           49   2.06           50   1.20           51   3.01           52   3.50           53   3.52           54   3.22           55   12.48           56   5.16           57   1.92           58   2.15           59   2.07           60   29.35           61   7.51           62   1.27           63   3.70           64   1.46           65   1.07           66   4.58           67   25.68           68   3.89           69   5.86           70   5.01           71   3.21           72   2.19           73   1.45           74   8.23           75   0.20           76   0.94           77   0.44           78   0.57           79   1.60           80   0.23           81   25.23           82   0.12           83   0.12           84   7.66           85   0.35           86   2.64           87   0.19           88   0.14           89   1.88           90   0.90           91   0.40           92   3.08           93   0.17           94   8.91           95   0.32           96   3.09           97   0.55           98   0.43           99   0.59           100   0.32           101   25.08           102   0.17           103   0.55           104   32.88           105   8.00           106   10.22           107   1.90           108   1.45           109   3.16           110   4.89           111   1.32           112   8.63           113   0.60           114   8.97           115   1.02           117   1.16           118   2.47           119   2.95           120   1.63           122   1.53           123   10.00           124   1.01           125   2.80           126   25.11           129   1.29           131   1.35           135   1.44           197   0.06           198   0.02           199   0.06           200   0.05           201   0.15           202   0.15           203   0.06           204   0.19           205   0.05           206   0.91           208   0.04           214   0.05           215   0.01           257   1.65           271   2.80           272   0.60           275   2.15           278   0.47           358   0.11           370   0.22           373   0.11           375   0.08           377   0.09           384   0.08           400   0.03                      
 
       EXAMPLE 30  
     IN VIVO TESTING  
     Inhibition of FSH-stimulated Ovarian Proliferation  
       [0517]    Twenty-one day old immature female Wistar rats (Charles River) are implanted with Alzet pumps (Alza Corp.,) containing human FSH at a concentration calculated to deliver 4-8IU hFSH per day. The animals are given vehicle or test compound at a dosage level of 20 mg/kg compound (BID) dissolved in hydroxypropyl methylcellulose (HPMC). On the third or fourth day, blood samples are obtained by orbital puncture for the measurement of serum estrogen and progesterone, and immediately afterwards, ovaries and uterus are collected, weighed and prepared for histological examination. The effect of test compound is determined by measuring the weight of ovaries and uterus collected from animals treated with the test compound as compared with the weight of ovaries and uterus collected from animals treated with vehicle.  
       Interruption of 4-day Estrus Cycle  
       [0518]    The estrus cycles of mature cycling female Wistar rats (250 g) were monitored for 2 consecutive estrus cycles to select animals with regular 4-day estrus cycles. The animals were randomly assigned to treatment groups on the morning of estrus. Starting on the morning of estrus and continuing through 2 estrus cycles, the animals orally dosed with vehicle or test compound at a concentration of 20 mg/kg; BID. At the end of the second estrus cycle, blood samples were collected by orbital puncture on the morning of estrus. The animals were then sacrificed, and the number of ovulated eggs in the oviduct were counted.  
                                   TABLE 7                                       Estradiol   Progesterone   # Ovulated           Cmpd. #   Concentration   Concentration   Eggs                           198   20.1 ± 4.4   3.6 ± 0.9   14.0           215   22.2 ± 4.2   2.6 ± 0.6   16.3           Vehicle   23.8 ± 3.1   8.0 ± 2.7   16.3                      
 
       Effects on Spermatogenesis in Immature Male Rats  
       [0519]    Twenty-one day old immature male Wistar rats (Charles River) were treated with FSH antagonist at a concentration of 20 mg/kg BID for 25 days. On the penultimate day of treatment, blood samples were collected by orbital puncture immediately prior to oral dosing, and 3 hours after dosing into Vacutainers containing EDTA. On the last day of treatment, blood samples were again collected prior to time of compound administration. The concentrations of LH, FSH and testosterone were measured in the plasma. Testosterone was measured using a Coat-A-Count kit (Diagnostic Products Corp.) and luteinizing hormone and follicle stimulating hormone concentrations were measured following previously established. At the end of the treatment period, the animals were sacrificed, testes and prostates were collected and weighed, and the testes were prepared for histological examination. The presence of sperm in testes were evaluated by hematoxylin and eosin staining, and in separate slides with a BERG stain (REF, 1963).  
                               TABLE 8                       Cmpd.   Serum Testosterone   Testes   Prostate   Mating       #   (t = 3 hr, d = 25)   Weight   Weight   Sperm                   198   3.6 ± 0.6   8.8 ± 0.2   1.6 ± 0.2   3/4       215   4.9 ± 0.7   8.7 ± 0.5   1.8 ± 0.1   1/4       Vehicle   3.2 0.6   7.5 ± 1.6   1.6 ± 0.1   4/6                  
 
         [0520]    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.