PATENT 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.

PATENT DESCRIPTION
CROSS REFERENCE TO RELATED APPLICATIONS 
     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 
     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 
     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). 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     Pharmaceutical drug discovery relies heavily on studies of structure-activity relationships wherein the structure of “lead compounds” is typically altered to determine the effect of such alteration on activity. Alteration of the structure of the lead compounds permits evaluation of the effect of the structural alteration on activity. 
     Thus, libraries of compounds derived from a lead compound can be created by including derivatives of the lead compound and repeating the screening procedures. In this manner, compounds with the best biological profile, i.e., those that are most active and which have the most ideal pharmacologic and pharmacokinetic properties, can be identified from the initial lead compound. 
     SUMMARY OF THE INVENTION 
     The present invention is directed to compounds of the formula (I)                           
     wherein 
     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 ; 
     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 ; 
     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-; 
     where the R 4  substituent is inserted into the compound of formula (I) from left to right, as defined; 
     alternately, R 2 , R 3 , and R 4  can be taken together with the two N atoms of the diamine portion of the molecule to form                           
     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-; 
     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                           
     (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 ; 
     m is 0 to 3; 
     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 ; 
     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; 
     R 8  is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; 
     Z is selected from the group consisting of —SO 2 —, —C(═O)—, and —C(═O)NH—; 
     p is 0 to 1;                          
     is selected from the group consisting of phenyl, naphthyl, quinolinyl, thienyl, and furyl; 
     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 ; 
     n is 0 to 3; 
     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)); 
     q is 0 to 1; 
     provided that when q is 1, n is 0; 
     and stereoisomers and pharmaceutically acceptable salts or esters thereof. 
     DETAILED DESCRIPTION OF THE INVENTION 
     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. 
     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.                          
     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. 
     The selected resin and appropriate reactants are employed to prepare resin bound, substituted diamines of formula (II):                           
     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. 
     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                           
     may be prepared as outlined in Scheme 2 below:                           
     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. 
     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 (VII), 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. 
     Alternately, compounds of formula (II), wherein R 2  and R 3  are hydrogen may be prepared according to the process outlined in Scheme 3.                          
     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. 
     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.                          
     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). 
     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 (IIe). 
     Compounds of formula (II) wherein R 3  is other than hydrogen may be prepared according to the process outlined in Scheme 5.                          
     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). 
     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):                           
     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. 
     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.                           
     Accordingly, a resin bound, substituted diamine of formula (II) is coupled with bromoacetic acid, using a coupling agent such as diisopropyl carbodiimide, 1,1′-carbonyldiimidazole, 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). 
     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). 
     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):                           
     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. 
     More particularly, in the first process, the resin bound compound of formula (IV) is prepared as outlined in Scheme 7.                          
     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). 
     The second process is particularly advantageous for preparation of compounds of formula (I) wherein Z is sulfonyl, n is 0, q is 1 and the                           
     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                           
     In the second process, the resin bound compound of formula (IV) is prepared via the process outlined in Scheme 8.                          
     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). 
     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). 
     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). 
     A resin bound compound of formula (IVa) may alternatively be further reacted with a suitably substituted compound of formula (XX) and/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.                          
     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). 
     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). 
     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.                          
     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). 
     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). 
     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). 
     Compounds of formula (I), wherein R 1  and/or R 2  is alkylcarbonyl may be prepared according to the process outlined in Scheme 11.                          
     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). 
     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. 
     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. 
     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. 
     As used herein the terms “aromatic and aryl” shall denote phenyl and naphthyl. 
     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. 
     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. 
     As used herein, unless otherwise noted, “halogen” shall denote chlorine, bromine, fluorine and iodine. 
     As used herein, unless otherwise noted, “*” represents the presence of a stereogenic center. 
     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                           
     In a preferred embodiment of the present invention are compounds of the formula (I) wherein 
     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 
     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). 
     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. 
     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. 
     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                           
     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 . 
     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. 
     Preferred L substituents include -cyclopropyl-, cyclohexyl-, (wherein the cylcopropyl or cyclohexyl is substituted with R 5  and R 6 ),                           
     and (CH 2 ) m —CR 8 R 5 R 6 . 
     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. 
     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. 
     Preferred R 8  substituents include hydrogen and C 1 -C 3 alkyl. 
     Preferably Z is selected from the group consisting of SO 2 , C(═O) and —C(═O)—NH—. 
     Preferred                           
     substituents include phenyl, naphthyl, quinolinyl and thienyl. 
     Preferably n is 0 to 2. 
     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. 
     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. 
     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-methoxyphenyl 
                 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-trifluoromethoxy 
               
               
                 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-phenyl)-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 
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 Cmpd # 
                 Stereo 
                 Y 
               
               
                   
                   
               
               
                   
                 497 
                 R 
                 2-chlorophenyl 
               
               
                   
                 498 
                 R 
                 2-methylphenyl 
               
               
                   
                 499 
                 R 
                 3-fluorophenyl 
               
               
                   
                 500 
                 S 
                 2-chlorophenyl 
               
               
                   
                   
               
               
                   
                 and stereolsomers and pharmaceutically acceptable salts or esters thereof.  
               
             
          
         
       
     
     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 
               
               
                   
               
               
                 and stereoisomers and pharmaceutically acceptable salts or esters thereof.  
               
             
          
         
       
     
     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 
               
               
                   
               
             
          
         
       
     
     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: 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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 
               
               
                   
               
             
          
         
       
     
     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. 
     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. 
     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. 
     Physiologically tolerable carriers are well known in the art. Carriers may be divided into liquid and solid carriers. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Optically Pure Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     Compounds 301-310 were prepared according to the above procedure with appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E. 
     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. 
     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. 
     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. 
     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. 
     Compounds 522-526 were similarly prepared according to the procedure above, with appropriate selection and substitution of reagents. 
     EXAMPLE 2 
     COMPOUND #272 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin. 
     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. 
     B. Coupling of Bromoacetic acid. 
     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. 
     C. Preparation of the Secondary Amine on Resin 
     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. 
     D. Preparation of Sulfonamide Resin 
     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. 
     E. Preparation of Substituted Phenylsulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin. 
     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. 
     B. Coupling of Bromoacetic acid. 
     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. 
     C. Preparation of the Secondary Amine 
     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. 
     D. Preparation of Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin. 
     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. 
     B. Coupling of Bromoacetic Acid. 
     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. 
     C. Preparation of the Secondary Amine 
     (Displacement of Bromide by 2-(2-methoxy)phenethylamine) 
     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. 
     D. Preparation of Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Secondary Amine on Resin 
     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. 
     D. Preparation of 2-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Substituted Phenylsulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin. 
     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. 
     B. Coupling of Bromoacetic Acid. 
     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. 
     C. Preparation of the Secondary Amine 
     (Displacement of Bromide by 2-(2-methoxy)phenethylamine) 
     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. 
     D. Preparation of Sulfonamide Resin 
     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. 
     E. Cleavage of the Resin Support 
     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. 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Optically Pure Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Substituted Phenylsulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin. 
     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. 
     B. Coupling of Bromoacetic Acid. 
     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. 
     C. Preparation of the Secondary Amine 
     (Displacement of Bromide by 2-(2-methoxy)phenethylamine) 
     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. 
     D. Preparation of Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Secondary Amine on Resin 
     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. 
     D. Preparation of Sulfonamide Resin 
     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. 
     E. Preparation of Substituted Phenylsulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin. 
     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. 
     B. Coupling of Bromoacetic Acid. 
     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. 
     C. Preparation of the Secondary Amine 
     (Displacement of Bromide by 2-(2-methoxy)phenethylamine) 
     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. 
     D. Preparation of Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Substituted Phenylsulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Optically Pure Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Substituted Phenylsulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Optically Pure Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Substituted Phenylsulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Optically Pure Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Piperazino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Substituted Phenylsulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Piperazino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Substituted Phenylsulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Bipiperidino Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Optically Pure Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin. 
     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. 
     B. Coupling of Bromoacetic Acid. 
     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. 
     C. Preparation of the Secondary Amine 
     (Displacement of Bromide by 2-methoxybenzylamine) 
     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. 
     D. Preparation of Sulfonamide Resin 
     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. 
     E. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin. 
     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. 
     B. Coupling of Bromoacetic Acid. 
     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. 
     C. Preparation of the Secondary Amine 
     (Displacement of Bromide by 2-methoxybenzylamine) 
     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. 
     D. Preparation of Sulfonamide Resin 
     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. 
     E. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Dimethylation of Compound #198. 
     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. 
     B. Purification of Product. 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Acetylation of Compound #198. 
     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. 
     B. Purification of Product. 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Optically Pure Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Bromophenylsulfonamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Optically Pure Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Biphenylurea Resin 
     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. 
     E. Cleavage of the Resin Support 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     A. Preparation of Amino Carbamate Resin 
     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. 
     B. Coupling of Bromoacetic Acid 
     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. 
     C. Preparation of the Optically Pure Secondary Amine on Resin 
     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. 
     D. Preparation of 4-Iodobenzamide Resin 
     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. 
     E. Preparation of Sulfonamide Resin 
     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. 
     F. Cleavage of the Resin Support 
     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. 
     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 
     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.). 
     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 
     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 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). 
     Preparation of Test Compound 
     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 
     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  
       
     
     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 
     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.). 
     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 
     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). 
     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 
     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. 
     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 . 
     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 
     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 
     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 
     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 
     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 
     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 
               
               
                   
               
             
          
         
       
     
     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.