Abstract:
The present invention relates to novel substituted diamine derivatives for the formula  
                         
 
     wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , A, Y and n are as described in the specification, pharmaceutical compositions containing them and intermediates used in their manufacture. More particularly, the compounds of the invention are motilin receptor antagonists useful for the treatment of associated conditions and disorders such as gastrointestinal reflux disorders, eating disorders leading to obesity and irritable bowel syndrome.

Description:
CROSS REFERENCE TO RELATED APPLICATION  
       [0001]     This is a divisional application of and claims priority to U.S. application Ser. No. 11/386,960 filed Apr. 26, 2006, which is a divisional application of and claims priority to U.S. application Ser. No. 11/066,202 filed Feb. 25, 2005, which is a divisional application of and claims priority to U.S. application Ser. No. 10/291,133, filed Nov. 8, 2002, now issued as U.S. Pat. No. 6,967,199, which is a divisional application of U.S. application Ser. No. 09/829,767, filed Apr. 10, 2001, now issued as U.S. Pat. No. 6,511,980, which claims priority from U.S. provisional application Ser. No. 60/202,131, filed May 5, 2000, the contents of each are hereby incorporated by reference. 
     
    
     FIELD OF THE INVENTION  
       [0002]     The present invention relates to novel substituted diamine derivatives, pharmaceutical compositions containing them and intermediates used in their manufacture. More particularly, the compounds of the invention are motilin receptor antagonists useful for the treatment of associated conditions and disorders such as gastrointestinal reflux disorders, eating disorders leading to obesity and irritable bowel syndrome.  
       BACKGROUND OF THE INVENTION  
       [0003]     In mammals, the digestion of nutrients and the elimination of waste are controlled by the gastrointestinal system. Within this system, there are a number of natural peptides, ligands, enzymes, and receptors which play a vital role and are potential targets for drug discovery. Modifying the production of, or responses to these endogenous substances can have an effect upon the physiological responses such as diarrhea, nausea, and abdominal cramping. One example of an endogenous substance which affects the gastrointestinal system is motilin.  
         [0004]     Motilin is a peptide of 22 amino acids which is produced in the gastrointestinal system of a number of species. Although the sequence of the peptide varies from species to species, there are a great deal of similarities. For example, human motilin and porcine motilin are identical; while motilin isolated from the dog and the rabbit differ by five and four amino acids respectively. Motilin induces smooth muscle contractions in the stomach tissue of dogs, rabbits, and humans as well as in the colon of rabbits. Apart from local gastrointestinal intestinal tissues, motilin and its receptors have been found in other areas. For example motilin has been found in circulating plasma, where a rise in the concentration of motilin has been associated with gastric effects which occur during fasting in dogs and humans. Itoh, Z. et al.  Scand. J. Gastroenterol.  11:93-110, (1976); Vantrappen, G. et al.  Dig. Dis Sci  24, 497-500 (1979). In addition, when motilin was intravenously administered to humans it was found to increase gastric emptying and gut hormone release. Christofides, N. D. et al.  Gastroenterology  76:903-907, 1979.  
         [0005]     Aside from motilin itself, there are other substances which are agonists of the motilin receptor and which elicit gastrointestinal emptying. One of those agents is the antibiotic erythromycin. Even though erythromycin is a useful drug, a great number of patients are affected by the drug&#39;s gastrointestinal side effects. Studies have shown that erythromycin elicits biological responses that are comparable to motilin itself and therefore may be useful in the treatment of diseases such as chronic idiopathic intestinal pseudo-obstruction and gastroparesis. Weber, F. et al.,  The American Journal of Gastroenterology,  88:4, 485-90 (1993).  
         [0006]     Although motilin and erythromycin are agonists of the motilin receptor, there is a need for antagonists of this receptor as well. The nausea, abdominal cramping, and diarrhea which are associated with motilin agonists are unwelcome physiological events. The increased gut motility induced by motilin has been implicated in diseases such as Irritable Bowel Syndrome and esophageal reflux. Therefore researchers have been searching for motilin antagonists.  
         [0007]     One such antagonist is OHM-11526. This is a peptide derived from porcine motilin which competes with both motilin and erythromycin for the motilin receptor in a number of species, including rabbits and humans. In addition, this peptide is an antagonist of the contractile smooth muscle response to both erythromycin and motilin in an in vitro rabbit model. Depoortere, I. et al.,  European Journal of Pharmacology,  286, 241-47, (1995). Although this substance is potent in that model (IC 50  1.0 nM) it is a peptide and as such offers little hope as an oral drug since it is susceptible to the enzymes of the digestive tract. Zen Itoh,  Motilin , xvi (1990). Therefore it is desirable to find other non-peptidic agents which act as motilin antagonists. The compounds of this invention are such agents.  
         [0008]     The compounds of this invention are non-peptidyl motilin antagonists with potencies and activities comparable to known peptidyl motilin antagonists. These compounds compete with motilin and erythromycin for the motilin receptor site in vitro. In addition, these compounds suppress smooth muscle contractions induced by motilin and erythromycin with activities and potencies comparable to OHM 11526 in an in vitro model.  
       SUMMARY OF THE INVENTION  
       [0009]     The present invention is directed to compounds of the formula (I):  
                         
 
         [0010]     wherein  
         [0011]     R 1  is selected from the group consisting of hydrogen, aryl, aralkyl, heterocyclyl, diarylalkyl, heterocyclyl-alkyl, and lower alkyl; wherein the alkyl, aryl or heterocyclyl moieties in the foregoing groups may be substituted with one or more substituents independently selected from halogen, hydroxy, nitro, carboxy, cyano, amino, dialkylamino, lower alkoxy, lower alkyl, tri-halomethyl, alkylamino, carboxy and alkoxycarbonyl;  
         [0012]     R 2  is selected from the group consisting of aryl, aralkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclyl-alkyl, diarylalkyl, aminoalkyl, tri-halomethyl, arylamino and lower alkyl; wherein the alkyl, aryl, heterocyclyl-alkyl, heterocyclyl, or amino moieties in the foregoing groups may be substituted with one or more substituents independently selected from halogen, hydroxy, nitro, cyano, amino, dialkylamino, lower alkoxy, lower alkyl, tri-halomethyl, alkylamino, phenyl, carboxy, carboxyalkyl and alkoxycarbonyl;  
         [0013]     X 1 , X 2 , X 3  and X 4  are independently absent or selected from the group consisting of CO and SO 2 ; provided that at least one of X 1  or X 2  and at least one of X 3  or X 4  is CO or SO 2 ;  
         [0014]     alternatively R 1 , R 2  and X 1  can be taken together (with the amine nitrogen) to form a monocyclic or fused bicyclic or tricyclic secondary amine ring structure; wherein the monocyclic or fused bicyclic or tricyclic secondary amine ring structure may be optionally substituted with one or more substituents independently selected from halogen, oxo, nitro, cyano, amino, alkylamino, dialkylamino, trialkylamino, lower alkoxy, lower alkyl, tri-halomethyl, carboxy, acetyloxy, alkoxycarbonyl, aryl, aralkyl andr heterocyclyl;  
         [0015]     A is selected from the group consisting of lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, cycloalkenyl, cycloalkenyl-alkyl, alkyl-cycloalkenyl, alkyl-cycloalkyl-alkyl; alkyl-aryl-alkyl, alkyl-aryl, aryl-alkyl and phenyl; where, in each case, the A group may optionally be substituted with one or more substituents selected from R 7 ;  
         [0016]     where R 7  is selected from alkyl, tri-halomethyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclyl-alkyl, diarylalkyl, aminoalkyl, or arylamino; wherein the alkyl, aryl, heterocyclyl-alkyl, heterocyclyl, or amino moieties in the foregoing groups may be substituted with one or more substituents independently selected from halogen, hydroxy, nitro, cyano, amino, dialkylamino, lower alkoxy, lower alkyl, tri-halomethyl, alkylamino, phenyl, carboxy and alkoxycarbonyl;  
         [0017]     provided that A is not -1,3-cyclopentyl-1-ene-alkyl;  
         [0018]     R 3  is selected from the group consisting of hydrogen, aryl, heterocyclyl, aralkyl, diarylalkyl, heterocyclo-alkyl, tri-halomethyl, alkylamino, arylamino and lower alkyl; wherein the aryl, heterocyclyl, aralkyl, diarylalkyl, heterocyclyl-alkyl, alkylamino, arylamino or lower alkyl group may be substituted with one or more substituents independently selected from halogen, nitro, cyano, amino, dialkylamino, lower alkoxy, lower alkyl, tri-halomethyl, carboxy and alkoxycarbonyl;  
         [0019]     Y is selected from the group consisting of —O—, —NH—, —S— and —SO 2 —;  
         [0020]     n is an integer from 0 to 5;  
         [0021]     R 4  is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, N-alkyl-N-aralkyl-amino, trialkylamino, dialkylaminoalkoxyalkyl, heterocyclyl, heterocyclyl-alkyl, oxo-substituted heterocyclyl and lower alkyl-substituted heterocyclyl;  
         [0022]     R 5  is selected from the group consisting of hydrogen, halogen, nitro, cyano, amino, alkylamino, dialkylamino, trialkylamino, lower alkoxy, lower alkyl, tri-halomethyl, carboxy and alkoxycarbonyl;  
         [0023]     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0024]     Relative to the above generic description, certain compounds of the general formula are preferred.  
                         
 
 where p and t are integers from 1-6. More preferably, R 4  is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 2-oxo-pyrrolidin-1-yl, 2-(1-methylpyrrolidinyl), 1-piperazinyl, 1-piperidinyl, di(methyl)aminoethyloxyethyl, N-methyl-N-benzyl-amino, di(methyl)amino and diethylamino. More preferably still, R 4  is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, di(methyl)amino and di(ethyl)amino. More referably still, R 4  is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl and di(methyl)amino. Most preferably, R 4  is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl and 1-piperidinyl; 
 
         [0025]     Preferably R 5  is selected from the group consisting of hydrogen and lower alkyl. More preferably R 5  is selected from the group consisting of hydrogen and methyl.  
         [0026]     In a preferred embodiment of the present invention are those compounds of general formula (I) wherein:  
         [0027]     R 1  is selected from the group consisting of hydrogen, aralkyl, heterocyclyl and heterocyclyl-alkyl; where the aralkyl, heterocyclyl or heterocyclyl-alkyl may be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkoxy, tri-halomethyl, hydroxy or nitro;  
         [0028]     R 2  is selected from the group consisting of alkyl, tri-halomethyl, aryl, aralkyl, arylamino, biphenyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl; where the aryl, aralkyl or heterocyclyl group may be substituted with one or more substituents independently selected from halogen, lower alkoxy, nitro, carboxy, carboxyalkyl, hydroxy, phenyl, diphenylmethyl, tri-halomethyl or trihaloalkylacetyl;  
         [0029]     X 1 , X 2 , X 3  and X 4  are independently absent or selected from the group consisting of CO and SO 2 ; such that at least one of X 1  or X 2  and at least one of X 3  or X 4  is CO or SO 2 ;  
         [0030]     A is selected from the group consisting of lower alkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, -cycloalkyl, -cycloalkenyl-, cycloalkenyl-alkyl- and -aryl-alkyl-; where the alkyl moiety in the foregoing groups may be substituted with one or more substituents independently selected from aralkyl or cycloalkyl;  
         [0031]     provided that A is not -1,3-cyclopentyl-1-ene-alkyl;  
         [0032]     R 3  is selected from the group consisting of hydrogen, aryl, aralkyl and arylamino; where the aryl or aralkyl group may be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkoxy or tri-halomethyl;  
         [0033]     Y is —O—;  
         [0034]     n is an integer from 0 to 3;  
         [0035]     R 4  is selected from the group consisting of hydrogen, heterocyclyl, oxo-substituted heterocyclyl, lower alkyl-substituted heterocyclyl, di(lower alkyl)amino, N-lower alkyl-N-aralkyl-amino and di(lower alkyl)amino alkoxy alkyl;  
         [0036]     R 5  is selected from the group consisting of hydrogen and lower alkyl;  
         [0037]     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
         [0038]     In a preferred embodiment are compounds of the general formula (I) wherein:  
         [0039]     R 1  is selected from the group consisting of hydrogen, phenyl(C 1 -C 6 ) alkyl-, naphthyl(C 1-6 )alkyl and heterocyclyl(C 1 -C 6 )alkyl- where the heterocyclyl group is selected from pyridyl and where the phenyl, naphthyl or heterocyclyl moiety is optionally substituted with one to three substituents selected from halogen, lower alkyl, lower alkoxy, tri-halomethyl, hydroxy and nitro;  
         [0040]     R 2  is selected from the group consisting of (C 1 -C 6 ) branched or unbranched alkyl, phenyl, phenyl(C 1 -C 6 )alkyl-, tri-halomethyl, phenylamino-, biphenyl, diphenyl(C 1 -C 6 )alkyl-, C 5-8 cycloalkyl, C 5-8 cycloalkyl-alkyl, heterocyclyl and heterocyclyl(C 1 -C 6 )alkyl- wherein the heterocyclyl moiety is selected from naphthyl, furyl, pyridyl, pyrrolidinyl and thienyl and wherein the phenyl or heterocyclyl group may be substituted with one to four substitutuents selected from halogen, lower alkoxy, nitro, carboxy, carboxy(C 1-4 )alkyl, hydroxy, phenyl, diphenylmethyl, trihalomethyl and trihaloalkylacetyl;  
         [0041]     X 1 , X 2 , X 3  and X 4  are independently absent or selected from the group consisting of CO and SO 2 ; such that at least one of X 1  or X 2  and at least one of X 3  or X 4  is CO or SO 2 ;  
         [0042]     A is selected from the group consisting of lower alkyl, loweralkyl-cycloalkyl, cycloalkyl-loweralkyl, -cycloalkyl, -cycloalkenyl-, cycloalkenyl-loweralkyl- and -phenyl-loweralkyl- and -benzyl-loweralkyl, provided that A is not -1,3-cyclopentyl-1-ene-alkyl;  
         [0043]     R 3  is selected from the group consisting of hydrogen, phenyl, benzyl and phenylamino-; where the phenyl or benzyl moieties may be substituted with one to three substituents selected from halogen, lower alkyl, lower alkoxy and trihalomethyl;  
         [0044]     Y is -0-;  
         [0045]     n is an integer from 0 to 3;  
         [0046]     R 4  is selected from the group consisting of hydrogen, heterocyclyl, oxo substituted heterocyclyl, lower alkyl-substituted heterocyclyl, di(loweralkyl)amino, N-lower alkyl-N-aralkyl-amino and a moiety of the formula:  
                         
 
         [0047]     where p and t are integers from 1-6;  
         [0048]     R 5  is selected from hydrogen and lower alkyl;  
         [0049]     and the pharmaceutically acceptable salts esters and pro-drug forms thereof.  
         [0050]     In a more preferred embodiment of the present invention are compounds of the general formula (I) wherein  
         [0051]     R 1  is selected from the group consisting of hydrogen, benzyl, 2-(phenyl)ethyl, 4-methylbenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 4-chlorobenzyl, 2,3-dichlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 3,4-difluorobenzyl, 3-trifluoromethylbenzyl, 1-naphthyl-methyl, 2-pyridyl-methyl and 4-(1-hydroxy)pyridyl;  
         [0052]     R 2  is selected from the group consisting of methyl, ethyl, t-butyl, 2,2-dimethylpropyl, benzyl, 2-(phenyl)ethyl, 3-(phenyl)propyl, 1-(phenyl)propyl, 3-carboxy-n-propyl, 3-carboxy-3-methyl-n-butyl, 2,2-dimethyl-3-carboxy-n-propyl, trichloromethyl, trifluoromethyl, 2-naphthyl, phenylamino, 3-methoxyphenyl, 3-hydroxyphenyl, 4-fluorobenzyl, 3-carboxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-(4-methoxyphenyl)ethyl, 4-fluorophenyl, 2-(4-chlorophenyl)ethyl, 3-nitrophenyl, 3,5-di(trifluoromethyl)phenyl, 3,3,3-trifluoropropan-2-oyl, diphenylmethyl, 4-biphenyl, 3-carboxymethyl-1,2,2-tri methyl-cyclopentyl, cyclopentylethyl, (1-carboxymethyl-cyclopentyl)-methyl, 2-furyl, 2-pyridyl-(2-ethyl), 1-pyrrolidinyl-(2-ethyl), 2-theinylmethyl and 2-thienylethyl;  
         [0053]     X 1 , X 2 , X 3  and X 4  are independently absent or selected from the group consisting of CO and SO 2 ; such that one of X 1  or X 2  and one of X 3  or X 4  is CO or SO 2 ;  
         [0054]     A is selected from the group consisting of 1,2-ethyl, 1,3-propyl, 1,4-butyl, 2-methyl-1,3-propyl, 1,1,-dimethyl-(1,3-propyl), 2-cyclopentyl-1,3-n-propyl, 1S,3R-cyclopentyl-methyl, 1,2-cyclopent-1-enyl, 1,4-cyclopentyl-2-ene-methyl, methyl -1,3-cyclohexyl, 1,2-cyclohexyl-methyl-, 1,3-cyclohexyl-methyl-, 1S,3R-cyclohexyl-methyl-, 1R,3S-cyclohexyl-methyl, 1,4-cyclohexyl-methyl-, 1,2-cyclohex-4-enyl, 1,3-phenyl-methyl and 1-benzyl-methyl-;  
         [0055]     R 3  is selected from the group consisting of hydrogen, phenylamino, 4-methylphenyl, 4-fluorophenyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl and 4-trifluoromethylbenzyl;  
         [0056]     Y is selected from the group consisting of -3-O— and -4-O—;  
         [0057]     n is an integer selected from 0, 2 or 3;  
         [0058]     R 4  is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 2-oxo-pyrrolidin-1-yl, 2-(1-methylpyrrolidinyl), 1-piperazinyl, 1-piperidinyl, di(methyl)aminoethyloxyethyl, N-methyl-N-benzyl-amino, di(methyl)amino and diethylamino;  
         [0059]     R 5  is selected from the group consisting of hydrogen, 2-methyl and 6-methyl;  
         [0060]     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
         [0061]     In another preferred embodiment of the present invention are compounds of the formula (I) wherein R 1 , R 2  and X 1  are taken together (with the amine nitrogen) to form an optionally substituted, monocyclic or fused bicyclic or tricyclic secondary amine ring structure selected from the group consisting of 1-phenyl-1,2,3,4-tetrahydroisoquinolinyl, 4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl, 2-[1-benzyl-6-methoxy-1,2,3,4-tetrahydro]naphthyl, isoindole-1,3-dione, 5-t-butyl-isoindole-1,3-dione, 5-fluoro-isoindole-1,3-dione, 5-methyl-isoindole-1,3-dione, 5,6-dichloro-isoindole-1,3-dione, 4,7-dichloro-isoindole-1,3-dione, 5-bromo-isoindole -1,3-dione, 5-acetyloxy-isoindole-1,3-dione, benzo[e]isoindole-1,3-dione, 8-fluorobenzo[e]isoindole-1,3-dione, 4,4-dimethyl-piperidine-2,6-dione, 3-aza-bicyclo[3.1.0]hexane-2,6-dione and 8-aza-spiro[4.5]decane-7,9-dione; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
         [0062]     In a particularly preferred embodiment R 1 , R 2  and X 1  are taken together (with the amine nitrogen) to form 1-phenyl-1,2,3,4-tetrahydroisquinolinyl, X 2  is C(O), A is 1,3-propyl, X 3  is C(O), R 3  is 4-fluorobenzyl, Y is 3-O—, n is 2 and R 4  is 4-morpholinyl.  
         [0063]     In another preferred embodiment R 1 , R 2  and X 1  are taken together (with the amine nitrogen) to form 4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl, X 2  is C(O), A is 1,3-n-propyl, X 3  is absent, R 3  is 4-fluorophenyl, X 4  is C(O), Y is 3-O—, n is 2 and R 4  is 4-morpholinyl.  
         [0064]     In still another preferred embodiment, R 1 , R 2  and X 1  are taken together (with the amine nitrogen) to form 2-[1-benzyl-6-methoxy-1,2,3,4-tetrahydro]-naphthyl, X 2  is C(O), A is 1,3-n-propyl, X 3  is absent, R 3  is 4-fluorophenyl, X 4  is C(O), Y is 3-O—, n is 2 and R 4  is 4-morpholinyl.  
         [0065]     In a class of the invention are compounds of the formula (I) wherein  
         [0066]     R 1  is selected from the group consisting of benzyl, 2-(phenyl)ethyl, 3-nitrobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 3,5-dichlorobenzyl, 3-trifluoromethylbenzyl and 2-pyridyl-methyl;  
         [0067]     R 2  is selected from the group consisting of t-butyl, 2-(phenyl)ethyl, trichloromethyl, 3-carboxybenzyl, 3-methoxybenzyl, 2-(4-methoxyphenyl)ethyl, 2-(4-chlorophenyl)ethyl, diphenylmethyl, 2-(2-pyridyl)ethyl, 2-(1-pyrrolidinyl)ethyl and 2-(2-thienyl)ethyl;  
         [0068]     X 1 , X 2 , X 3  and X 4  are independently absent or CO; such that one of X 1  or X 2  and one of X 3  or X 4  is CO;  
         [0069]     A is selected from the group consisting of 1,2-ethyl, 1,3-propyl, 2-methyl-1,3-propyl, 1,1,-dimethyl-(1,3-propyl), 2-cyclopentyl-1,3-n-propyl, 1S,3R-cyclopentyl-methyl, 1,3-cyclohexyl-methyl, 1S,3R-cyclohexyl-methyl- and 1R,3S-cyclohexyl-methyl-;  
         [0070]     R 3  is selected from the group consisting of phenylamino, 4-fluorophenyl, 3-fluorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl and 4-trifluoromethylbenzyl;  
         [0071]     Y is selected from the group consisting of -3-O— and -4-O—;  
         [0072]     n is an integer selected from 2 or 3;  
         [0073]     R 4  is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, di(methyl)amino and di(ethyl)amino;  
         [0074]     R 5  is selected from the group consisting of hydrogen, 2-methyl and 6-methyl;  
         [0075]     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
         [0076]     In another class of the invention are compounds of the formula (I) wherein  
         [0077]     R 1  is selected from the group consisting of benzyl, 2-(phenyl)ethyl, 3-nitrobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 3,5-dichlorobenzyl and 3-trifluoromethylbenzyl;  
         [0078]     R 2  is selected from the group consisting of t-butyl, 2-(phenyl)ethyl, trichloromethyl, 3-carboxybenzyl, 3-methoxybenzyl, 2-(2-pyridyl)ethyl and 2-(2-thienyl)ethyl;  
         [0079]     X 1 , X 2 , X 3  and X 4  are independently absent or CO; such that one of X 1  or X 2  and one of X 3  or X 4  is CO;  
         [0080]     A is selected from the group consisting of 1,3-propyl, 1S,3R-cyclopentyl-methyl, 1,3-cyclohexyl-methyl-, 1S,3R-cyclohexyl-methyl- and 1R,3S-cyclohexyl-methyl-;  
         [0081]     R 3  is selected from the group consisting of phenylamino, 4-fluorophenyl, 3-fluorobenzyl and 4-fluorobenzyl;  
         [0082]     Y is -3-O—;  
         [0083]     n is 2;  
         [0084]     R 4  is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl and di(methyl)amino;  
         [0085]     R 5  is selected from the group consisting of hydrogen, 2-methyl and 6-methyl;  
         [0086]     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
         [0087]     Particularly preferred are compounds of the formula (I) wherein  
         [0088]     R 1  is selected from the group consisting of benzyl, 3-nitrobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl and 3-trifluoromethylbenzyl;  
         [0089]     R 2  is selected from the group consisting of t-butyl, 2-(phenyl)ethyl, trichloromethyl, 2-(2-pyridyl)ethyl and 2-(2-thienyl)ethyl;  
         [0090]     X 1 , X 2 , X 3  and X 4  are independently absent or CO; such that one of X 1  or X 2  and one of X 3  or X 4  is CO;  
         [0091]     A is selected from the group consisting of 1,3-propyl, 1S,3R-cyclopentyl-methyl, 1,3-cyclohexyl-methyl-, 1S,3R-cyclohexyl-methyl- and 1R,3S-cyclohexyl-methyl-;  
         [0092]     R 3  is selected from the group consisting of phenylamino, 4-fluorophenyl, 3-fluorobenzyl and 4-fluorobenzyl;  
         [0093]     Y is -3-O—;  
         [0094]     n is 2;  
         [0095]     R 4  is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl and 1-piperidinyl; 
        R 5  is selected from the group consisting of hydrogen and 2-methyl;        
 
         [0097]     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
         [0098]     In still another particularly preferred embodiment of the present invention are compounds of the formula (I) wherein R 1  is 3-chlorobenzyl, R 2  is trichloromethyl, X 1  is CO, X 2  is absent, X 3  is absent, X 4  is CO, A is 1S,3R-cyclohexyl-methyl-, R 3  is 4-fluorophenyl, Y is -3-O—, n is 2, R 4  is 1-piperidinyl, R 5  is hydrogen and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
         [0099]     In still another particularly preferred embodiment of the present invention are compounds of the formula (I) wherein R 1  is 3-chlorobenzyl, R 2  is trichloromethyl, X 1  is CO, X 2  is absent, X 3  is absent, X 4  is CO, A is 1R,3S-cyclohexyl-methyl-, R 3  is 4-fluorophenyl, Y is -3-O—, n is 2, R 4  is 1-piperidinyl, R 5  is hydrogen and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
         [0100]     Listed in Tables 1-16 are specific compounds of the present invention.  
                                 TABLE 1                                                                                  ID #   R 1     R 2     R 3                 128   benzyl   2-(phenyl)ethyl   4-fluorobenzyl       163   3-chlorobenzyl   2-(phenyl)ethyl   4-fluorobenzyl       164   benzyl   2-(phenyl)ethyl   3-fluorobenzyl       165   benzyl   2-(phenyl)ethyl   2-fluorobenzyl       166   benzyl   2-(phenyl)ethyl   4-methoxybenzyl       167   benzyl   2-(phenyl)ethyl   4-trifluoromethylbenzyl       168   benzyl   2-(phenyl)ethyl   4-chlorobenzyl                  
 
         [0101]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 R 3   
                 Y 
                 n 
                 R 4   
                 R 5   
               
               
                   
               
               
                 129 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluoro 
                 3-O 
                 2 
                 4- 
                 H 
               
               
                   
                   
                   
                 benzyl 
                   
                   
                 morpholinyl 
               
               
                 159 
                 benzyl 
                 3- 
                 4-fluoro 
                 3-O 
                 2 
                 4- 
                 H 
               
               
                   
                   
                 (phenyl)propyl 
                 benzyl 
                   
                   
                 morpholinyl 
               
               
                 162 
                 3-chloro 
                 2-(phenyl)ethyl 
                 4-fluoro 
                 3-O 
                 2 
                 4- 
                 H 
               
               
                   
                 benzyl 
                   
                 benzyl 
                   
                   
                 morpholinyl 
               
               
                 169 
                 benzyl 
                 2-(phenyl) 
                 3-fluoro 
                 3-O 
                 2 
                 4- 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 morpholinyl 
               
               
                 170 
                 benzyl 
                 2-(phenyl) 
                 2-fluoro 
                 3-O 
                 2 
                 4- 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 morpholinyl 
               
               
                 171 
                 benzyl 
                 2-(phenyl) 
                 4-methoxy 
                 3-O 
                 2 
                 4- 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 morpholinyl 
               
               
                 172 
                 benzyl 
                 2-(phenyl) 
                 4-trifluoro 
                 3-O 
                 2 
                 4- 
                 H 
               
               
                   
                   
                 ethyl 
                 methyl benzyl 
                   
                   
                 morpholinyl 
               
               
                 173 
                 benzyl 
                 2-(phenyl) 
                 4-chloro 
                 3-O 
                 2 
                 4- 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 morpholinyl 
               
               
                 175 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3- 
                 0 
                 H 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                 O— 
               
               
                 176 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 2-oxo- 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 pyrrolidin-1-yl 
               
               
                 177 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 dimethyl amino 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 ethyloxy ethyl 
               
               
                 178 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 diethyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 amino 
               
               
                 179 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 1-piperazinyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
               
               
                 180 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
               
               
                 181 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 dimethyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 amino 
               
               
                 182 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 1-piperidinyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
               
               
                 187 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 3 
                 dimethyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 amino 
               
               
                 188 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 3 
                 1-piperidinyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
               
               
                 191 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 4-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
               
               
                 192 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 4-O 
                 2 
                 4- 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 morpholinyl 
               
               
                 193 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 4-O 
                 3 
                 1-piperidinyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
               
               
                 194 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 4-O 
                 2 
                 dimethyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 amino 
               
               
                 195 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 4-O 
                 2 
                 diethyl 
                 H 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 amino 
               
               
                 196 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 2- 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                   
                 methyl 
               
               
                 197 
                 3-nitro 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                   
                 benzyl 
                 ethyl 
                 benzyl 
               
               
                 198 
                 3-chloro 
                 3-methoxy 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                   
                 benzyl 
                 benzyl 
                 benzyl 
               
               
                 199 
                 3,5- 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                   
                 dichloro benzyl 
                 ethyl 
                 benzyl 
               
               
                 200 
                 3-trifluoro 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                   
                 methyl benzyl 
                 ethyl 
                 benzyl 
               
               
                 201 
                 3-chloro 
                 2-(2- 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                   
                 benzyl 
                 pyridyl)ethyl 
                 benzyl 
               
               
                 202 
                 3-chloro 
                 2-(4-chloro 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                   
                 benzyl 
                 phenyl) ethyl 
                 benzyl 
               
               
                 203 
                 3-chloro 
                 2-(1- 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                   
                 benzyl 
                 pyrrolidinyl)ethyl 
                 benzyl 
               
               
                 204 
                 3-chloro 
                 2-(2-thienyl) 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                   
                 benzyl 
                 ethyl 
                 benzyl 
               
               
                 205 
                 3-nitro 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 4- 
                 H 
               
               
                   
                 benzyl 
                 ethyl 
                 benzyl 
                   
                   
                 morpholinyl 
               
               
                 206 
                 3-chloro 
                 3-methoxy 
                 4-fluoro 
                 3-O 
                 2 
                 4- 
                 H 
               
               
                   
                 benzyl 
                 benzyl 
                 benzyl 
                   
                   
                 morpholinyl 
               
               
                 207 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 6- 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                   
                 methyl 
               
               
                 215 
                 2-(phenyl) 
                 3-carboxy 
                 4-fluoro 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 2- 
               
               
                   
                 ethyl 
                 benzyl 
                 benzyl 
                   
                   
                   
                 methyl 
               
               
                 234 
                 benzyl 
                 2-(phenyl) 
                 4-fluoro 
                 3-O 
                 2 
                 4- 
                 2- 
               
               
                   
                   
                 ethyl 
                 benzyl 
                   
                   
                 morpholinyl 
                 methyl 
               
               
                   
               
             
          
         
       
     
         [0102]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 A 
                 R 3   
               
               
                   
               
               
                 154 
                 benzyl 
                 2-(phenyl)ethyl 
                 2-cyclopentyl-1,3-n- 
                 4-fluorobenzyl 
               
               
                   
                   
                   
                 propyl 
               
               
                 155 
                 benzyl 
                 2-(phenyl)ethyl 
                 cis-1,2-cyclohex-4- 
                 4-fluorobenzyl 
               
               
                   
                   
                   
                 enyl 
               
               
                 156 
                 benzyl 
                 2-(phenyl)ethyl 
                 1,2-cylopentenyl 
                 H 
               
               
                 160 
                 benzyl 
                 2-(phenyl)ethyl 
                 1,3-n-butyl 
                 4-fluorobenzyl 
               
               
                 189 
                 benzyl 
                 2-(phenyl)ethyl 
                 2-methyl-(1,3-propyl) 
                 4-fluorobenzyl 
               
               
                 190 
                 benzyl 
                 2-(phenyl)ethyl 
                 1,1-dimethyl-(1,3- 
                 4-fluorobenzyl 
               
               
                   
                   
                   
                 propyl) 
               
               
                   
               
             
          
         
       
     
         [0103]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 X 4   
                 R 3   
               
               
                   
               
             
          
           
               
                 5 
                 benzyl 
                 2-(phenyl)ethyl 
                 CO 
                 phenylamino 
               
               
                 6 
                 benzyl 
                 2-(phenyl)ethyl 
                 CO 
                 4-methylphenyl 
               
               
                 7 
                 benzyl 
                 2-(phenyl)ethyl 
                 CO 
                 4-fluorophenyl 
               
               
                 12 
                 benzyl 
                 ethyl 
                 SO 2   
                 4-methylphenyl 
               
               
                 13 
                 benzyl 
                 ethyl 
                 CO 
                 4-methylphenyl 
               
               
                 14 
                 benzyl 
                 ethyl 
                 CO 
                 4-fluorophenyl 
               
               
                 19 
                 benzyl 
                 methyl 
                 CO 
                 phenylamino 
               
               
                 20 
                 benzyl 
                 methyl 
                 SO 2   
                 4-methylphenyl 
               
               
                 21 
                 benzyl 
                 methyl 
                 CO 
                 4-methylphenyl 
               
               
                 22 
                 benzyl 
                 methyl 
                 CO 
                 4-fluorophenyl 
               
               
                 26 
                 benzyl 
                 benzyl 
                 CO 
                 phenylamino 
               
               
                 27 
                 benzyl 
                 benzyl 
                 SO 2   
                 4-methylphenyl 
               
               
                 28 
                 benzyl 
                 benzyl 
                 CO 
                 4-methylphenyl 
               
               
                 29 
                 benzyl 
                 benzyl 
                 CO 
                 4-fluorophenyl 
               
               
                 34 
                 4-methylbenzyl 
                 ethyl 
                 CO 
                 phenylamino 
               
               
                 35 
                 4-methylbenzyl 
                 ethyl 
                 SO 2   
                 4-methylphenyl 
               
               
                 36 
                 4-methylbenzyl 
                 ethyl 
                 CO 
                 4-methylphenyl 
               
               
                 37 
                 4-methylbenzyl 
                 ethyl 
                 CO 
                 4-fluorophenyl 
               
               
                   
               
             
          
         
       
     
         [0104]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 X 4   
                 R 3   
               
               
                   
               
             
          
           
               
                 1 
                 benzyl 
                 2-(phenyl)ethyl 
                 CO 
                 phenylamino 
               
               
                 2 
                 benzyl 
                 2-(phenyl)ethyl 
                 SO 2   
                 4-methylphenyl 
               
               
                 3 
                 benzyl 
                 2-(phenyl)ethyl 
                 CO 
                 4-methylphenyl 
               
               
                 4 
                 benzyl 
                 2-(phenyl)ethyl 
                 CO 
                 4-fluorophenyl 
               
               
                 8 
                 benzyl 
                 ethyl 
                 CO 
                 phenylamino 
               
               
                 9 
                 benzyl 
                 ethyl 
                 SO 2   
                 4-methylphenyl 
               
               
                 10 
                 benzyl 
                 ethyl 
                 CO 
                 4-methylphenyl 
               
               
                 11 
                 benzyl 
                 ethyl 
                 CO 
                 4-fluorophenyl 
               
               
                 15 
                 benzyl 
                 methyl 
                 CO 
                 phenylamino 
               
               
                 16 
                 benzyl 
                 methyl 
                 SO 2   
                 4-methylphenyl 
               
               
                 17 
                 benzyl 
                 methyl 
                 CO 
                 4-methylphenyl 
               
               
                 18 
                 benzyl 
                 methyl 
                 CO 
                 4-fluorophenyl 
               
               
                 23 
                 benzyl 
                 benzyl 
                 CO 
                 phenylamino 
               
               
                 24 
                 benzyl 
                 benzyl 
                 SO 2   
                 4-methylphenyl 
               
               
                 25 
                 benzyl 
                 benzyl 
                 CO 
                 4-methylphenyl 
               
               
                 30 
                 4-methylbenzyl 
                 ethyl 
                 CO 
                 phenylamino 
               
               
                 31 
                 4-methylbenzyl 
                 ethyl 
                 SO 2   
                 4-methylphenyl 
               
               
                 32 
                 4-methylbenzyl 
                 ethyl 
                 CO 
                 4-methylphenyl 
               
               
                 33 
                 4-methylbenzyl 
                 ethyl 
                 CO 
                 4-fluorophenyl 
               
               
                 143 
                 H 
                 diphenylmethyl 
                 CO 
                 4-fluorophenyl 
               
               
                 144 
                 benzyl 
                 3-(phenyl)propyl 
                 CO 
                 4-fluorophenyl 
               
               
                 145 
                 benzyl 
                 2,2-dimethylpropyl 
                 CO 
                 4-fluorophenyl 
               
               
                 146 
                 benzyl 
                 2-(4-methoxyphenyl) 
                 CO 
                 4-fluorophenyl 
               
               
                   
                   
                 ethyl 
               
               
                 147 
                 3-chlorobenzyl 
                 2-(4-methoxyphenyl) 
                 CO 
                 4-fluorophenyl 
               
               
                   
                   
                 ethyl 
               
               
                   
               
             
          
         
       
     
         [0105]    
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 Stereo #   
                 R 3   
                 R 4   
               
               
                   
               
               
                 232 
                 3-chlorobenzyl 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 N-methyl-N- 
               
               
                   
                   
                   
                 racemate 
                   
                 benzyl-amino 
               
               
                 233 
                 3-chlorobenzyl 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 di(ethyl)amino 
               
               
                   
                   
                   
                 racemate 
               
               
                 235 
                 3-chlorobenzyl 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 2-(1-methyl) 
               
               
                   
                   
                   
                 acemate 
                   
                 pyrrolidinyl 
               
               
                 236 
                 3-chlorobenzyl 
                 trichloro 
                 cis 
                 4-fluorophenyl 
                 2-(1-methyl) 
               
               
                   
                   
                 methyl 
                 racemate 
                   
                 pyrrolidinyl 
               
               
                 237 
                 3-chlorobenzyl 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                   
                   
                   
                 racemate 
               
               
                 238 
                 3-chlorobenzyl 
                 trichloro 
                 cis 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                   
                   
                 methyl 
                 racemate 
               
               
                     239 a   
                 3-chlorobenzyl 
                 trichloro 
                 1S, 3R 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                   
                   
                 methyl 
               
               
                     240 b   
                 3-chlorobenzyl 
                 trichloro 
                 1R, 3S 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                   
                   
                 methyl 
               
               
                 264 
                 hydrogen 
                 3-carboxy- 
                 cis 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                   
                   
                 n-propyl 
                 racemate 
               
               
                 265 
                 hydrogen 
                 3-carboxy- 
                 cis 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                   
                   
                 1,2,2-trimethyl- 
                 racemate 
               
               
                   
                   
                 cyclopentyl 
               
               
                 266 
                 hydrogen 
                 3-methyl- 
                 cis 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                   
                   
                 3-carboxy-n-butyl 
                 racemate 
               
               
                 267 
                 hydrogen 
                 (1-carboxy methyl- 
                 cis 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                   
                   
                 cyclopentyl)-methyl 
                 racemate 
               
               
                 268 
                 hydrogen 
                 3-carboxy- 
                 cis 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                   
                   
                 2,2-dimethyl-n-propyl 
                 racemate 
               
               
                   
               
               
                     # The term “cis racemate” denotes a mixture of four possible diastereomers, with the two cis diastereomers predominately present.    
               
             
          
         
       
     
         [0106]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 X 1   
                 R 2   
                 R 3   
               
               
                   
               
             
          
           
               
                 40 
                 benzyl 
                 CO 
                 phenylamino 
                 phenylamino 
               
               
                 41 
                 benzyl 
                 CO 
                 3-methoxyphenyl 
                 phenylamino 
               
               
                 42 
                 benzyl 
                 CO 
                 t-butyl 
                 phenylamino 
               
               
                 43 
                 benzyl 
                 CO 
                 2-(phenyl)ethyl 
                 phenylamino 
               
               
                 44 
                 benzyl 
                 CO 
                 2-naphthyl 
                 phenylamino 
               
               
                 45 
                 benzyl 
                 CO 
                 3-nitrophenyl 
                 phenylamino 
               
               
                 46 
                 benzyl 
                 CO 
                 diphenylmethyl 
                 phenylamino 
               
               
                 47 
                 3-chlorobenzyl 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                 48 
                 benzyl 
                 CO 
                 2-furyl 
                 phenylamino 
               
               
                 49 
                 3-chlorobenzyl 
                 CO 
                 3,5-di-trifluoro 
                 phenylamino 
               
               
                   
                   
                   
                 methylphenyl 
               
               
                 50 
                 3-chlorobenzyl 
                 CO 
                 4-biphenyl 
                 phenylamino 
               
               
                 51 
                 3-chlorobenzyl 
                 CO 
                 3-methoxy 
                 phenylamino 
               
               
                   
                   
                   
                 phenyl 
               
               
                 52 
                 3-chlorobenzyl 
                 CO 
                 t-butyl 
                 phenylamino 
               
               
                 53 
                 3-chlorobenzyl 
                 CO 
                 2-(phenyl)ethyl 
                 phenylamino 
               
               
                 54 
                 3-chlorobenzyl 
                 CO 
                 2-naphthyl 
                 phenylamino 
               
               
                 55 
                 3-chlorobenzyl 
                 CO 
                 3-nitrophenyl 
                 phenylamino 
               
               
                 56 
                 3-chlorobenzyl 
                 CO 
                 diphenyl methyl 
                 phenylamino 
               
               
                 57 
                 benzyl 
                 SO 2   
                 2-naphthyl 
                 phenylamino 
               
               
                 58 
                 3-fluorobenzyl 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                 59 
                 3,4-dichloro 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                   
                 benzyl 
               
               
                 60 
                 3,5-dichloro 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                   
                 benzyl 
               
               
                 61 
                 3-methoxybenzyl 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                 62 
                 3-trifluoromethyl 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                   
                 benzyl 
               
               
                 63 
                 4-chlorobenzyl 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                 64 
                 1-naphthyl-methyl 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                 65 
                 3-nitrobenzyl 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                 66 
                 2,3-dichloro 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                   
                 benzyl 
               
               
                 67 
                 benzyl 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                 68 
                 2-pyridyl-methyl 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                 69 
                 H 
                 CO 
                 phenynamino 
                 phenylamino 
               
               
                 70 
                 H 
                 CO 
                 2-furyl 
                 phenylamino 
               
               
                 71 
                 H 
                 SO 2   
                 2-naphthyl 
                 phenylamino 
               
               
                 72 
                 H 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                 73 
                 H 
                 CO 
                 trifluoromethyl 
                 phenylamino 
               
               
                 74 
                 H 
                 CO 
                 3,5-di-trifluoro 
                 phenylamino 
               
               
                   
                   
                   
                 methylphenyl 
               
               
                 75 
                 H 
                 CO 
                 4-biphenyl 
                 phenylamino 
               
               
                 76 
                 H 
                 CO 
                 3-methoxyphenyl 
                 phenylamino 
               
               
                 77 
                 H 
                 CO 
                 t-butyl 
                 phenylamino 
               
               
                 78 
                 H 
                 CO 
                 2-(phenyl)ethyl 
                 phenylamino 
               
               
                 79 
                 H 
                 CO 
                 2-naphthyl 
                 phenylamino 
               
               
                 80 
                 H 
                 CO 
                 3-nitrophenyl 
                 phenylamino 
               
               
                 81 
                 H 
                 CO 
                 diphenylmethyl 
                 phenylamino 
               
               
                 82 
                 benzyl 
                 CO 
                 3,5-di(trifluoro 
                 phenylamino 
               
               
                   
                   
                   
                 methyl)phenyl 
               
               
                 83 
                 benzyl 
                 CO 
                 4-biphenyl 
                 phenylamino 
               
               
                 86 
                 3-chlorobenzyl 
                 CO 
                 3-hydroxyphenyl 
                 phenylamino 
               
               
                 90 
                 2-pyridyl-methyl 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 91 
                 H 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 92 
                 2,3-dichloro 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                   
                 benzyl 
               
               
                 93 
                 3-nitrobenzyl 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 94 
                 1-naphthyl-methyl 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 95 
                 4-chlorobenzyl 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 96 
                 3-trifluoromethyl 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                   
                 benzyl 
               
               
                 97 
                 3-methoxybenzyl 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 98 
                 3,5-dichloro 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                   
                 benzyl 
               
               
                 99 
                 3,4-dichloro 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                   
                 benzyl 
               
               
                 100 
                 3-fluorobenzyl 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 101 
                 3-chlorobenzyl 
                 CO 
                 diphenylmethyl 
                 4-fluorophenyl 
               
               
                 102 
                 3-chlorobenzyl 
                 CO 
                 3-nitrophenyl 
                 4-fluorophenyl 
               
               
                 103 
                 3-chlorobenzyl 
                 CO 
                 2-naphthyl 
                 4-fluorophenyl 
               
               
                 104 
                 3-chlorobenzyl 
                 CO 
                 2-(phenyl)ethyl 
                 4-fluorophenyl 
               
               
                 105 
                 3-chlorobenzyl 
                 CO 
                 t-butyl 
                 4-fluorophenyl 
               
               
                 106 
                 3-chlorobenzyl 
                 CO 
                 3-methoxyphenyl 
                 4-fluorophenyl 
               
               
                 107 
                 3-chlorobenzyl 
                 CO 
                 3,5-di-trifluoro 
                 4-fluorophenyl 
               
               
                   
                   
                   
                 methylphenyl 
               
               
                 108 
                 3-chlorobenzyl 
                 CO 
                 trifluoromethyl 
                 4-fluorophenyl 
               
               
                 109 
                 3-chlorobenzyl 
                 CO 
                 4-biphenyl 
                 4-fluorophenyl 
               
               
                 110 
                 3-chlorobenzyl 
                 CO 
                 3,3,3-trifluoro 
                 4-fluorophenyl 
               
               
                   
                   
                   
                 propan-2-onyl 
               
               
                 111 
                 3-chlorobenzyl 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 112 
                 benzyl 
                 CO 
                 diphenylmethyl 
                 4-fluorophenyl 
               
               
                 113 
                 benzyl 
                 CO 
                 3-nitrophenyl 
                 4-fluorophenyl 
               
               
                 114 
                 benzyl 
                 CO 
                 2-naphthyl 
                 4-fluorophenyl 
               
               
                 115 
                 benzyl 
                 CO 
                 2-(phenyl)ethyl 
                 4-fluorophenyl 
               
               
                 116 
                 benzyl 
                 CO 
                 t-butyl 
                 4-fluorophenyl 
               
               
                 117 
                 benzyl 
                 CO 
                 3-methoxyphenyl 
                 4-fluorophenyl 
               
               
                 118 
                 benzyl 
                 CO 
                 4-biphenyl 
                 4-fluorophenyl 
               
               
                 119 
                 benzyl 
                 CO 
                 3,5-ditrifluoro 
                 4-fluorophenyl 
               
               
                   
                   
                   
                 methylphenyl 
               
               
                 120 
                 benzyl 
                 CO 
                 trifluoromethyl 
                 4-fluorophenyl 
               
               
                 121 
                 benzyl 
                 CO 
                 3,3,3-trifluoro 
                 4-fluorophenyl 
               
               
                   
                   
                   
                 propan-2-onyl 
               
               
                 122 
                 benzyl 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 123 
                 benzyl 
                 SO 2   
                 2-naphthyl 
                 4-fluorophenyl 
               
               
                 124 
                 benzyl 
                 CO 
                 2-furyl 
                 4-fluorophenyl 
               
               
                 125 
                 benzyl 
                 CO 
                 phenylamino 
                 4-fluorophenyl 
               
               
                 241 
                 3-chlorobenzyl 
                 CO 
                 3-methoxybenzyl 
                 4-fluorophenyl 
               
               
                 242 
                 3-chlorobenzyl 
                 CO 
                 2- 
                 4-fluorophenyl 
               
               
                   
                   
                   
                 cyclopentylethyl 
               
               
                 243 
                 3-chlorobenzyl 
                 CO 
                 4-methoxybenzyl 
                 4-fluorophenyl 
               
               
                 244 
                 3-chlorobenzyl 
                 CO 
                 Benzyl 
                 4-fluorophenyl 
               
               
                 245 
                 3-chlorobenzyl 
                 CO 
                 3,4- 
                 4-fluorophenyl 
               
               
                   
                   
                   
                 dimethoxybenzyl 
               
               
                 246 
                 3-chlorobenzyl 
                 CO 
                 t-butylmethyl 
                 4-fluorophenyl 
               
               
                 247 
                 3-chlorobenzyl 
                 CO 
                 1(1-phenyl) 
                 4-fluorophenyl 
               
               
                   
                   
                   
                 propyl 
               
               
                 248 
                 3-chlorobenzyl 
                 CO 
                 2-thienylmethyl 
                 4-fluorophenyl 
               
               
                 249 
                 3-chlorobenzyl 
                 CO 
                 4-fluorobenzyl 
                 4-fluorophenyl 
               
               
                   
               
             
          
         
       
     
         [0107]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                   
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 ID 
                 R 1   
                 R 2   
                 R 3   
               
               
                   
                   
               
               
                   
                 158 
                 H 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                   
                 161 
                 3-chlorobenzyl 
                 t-butyl 
                 4-fluorophenyl 
               
               
                   
                 157 
                 benzyl 
                 trifluoromethyl 
                 4-fluorophenyl 
               
               
                   
                   
               
             
          
         
       
     
         [0108]    
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 Stereo #   
                 R 3   
                 R 5   
               
               
                   
               
               
                 208 
                 3-nitrobenzyl 
                 trichloromethyl 
                 1S, 3R 
                 4-fluorophenyl 
                 CH 3   
               
               
                 209 
                 3-chlorobenzyl 
                 trichloromethyl 
                 1S, 3R 
                 4-fluorophenyl 
                 CH 3   
               
               
                 210 
                 benzyl 
                 trichloromethyl 
                 1S, 3R 
                 4-fluorophenyl 
                 CH 3   
               
               
                 223 
                 3-chlorobenzyl 
                 trichloromethyl 
                 cis 
                 phenylamino 
                 H 
               
               
                   
                   
                   
                 race- 
               
               
                   
                   
                   
                 mate 
               
               
                 224 
                 benzyl 
                 trichloromethyl 
                 cis 
                 phenylamino 
                 H 
               
               
                   
                   
                   
                 race- 
               
               
                   
                   
                   
                 mate 
               
               
                 225 
                 benzyl 
                 t-butyl 
                 cis 
                 phenylamino 
                 H 
               
               
                   
                   
                   
                 race- 
               
               
                   
                   
                   
                 mate 
               
               
                 226 
                 3-chlorobenzyl 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                   
                   
                 race- 
               
               
                   
                   
                   
                 mate 
               
               
                 227 
                 3,4- 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                 dichlorobenzyl 
                   
                 race- 
               
               
                   
                   
                   
                 mate 
               
               
                 228 
                 3,4- 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                 difluorobenzyl 
                   
                 race- 
               
               
                   
                   
                   
                 mate 
               
               
                 229 
                 benzyl 
                 t-butyl 
                 1S, 3R 
                 4-fluorophenyl 
                 H 
               
               
                 230 
                 benzyl 
                 t-butyl 
                 1R, 3S 
                 4-fluorophenyl 
                 H 
               
               
                 211 
                 3-nitrobenzyl 
                 trichloromethyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                   
                   
                 race- 
               
               
                   
                   
                   
                 mate 
               
               
                 212 
                 3-chlorobenzyl 
                 trichloromethyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                   
                   
                 race- 
               
               
                   
                   
                   
                 mate 
               
               
                 213 
                 benzyl 
                 trichloromethyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                   
                   
                 race- 
               
               
                   
                   
                   
                 mate 
               
               
                 214 
                 benzyl 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                   
                   
                 race- 
               
               
                   
                   
                   
                 mate 
               
               
                   
               
               
                     # The term “cis racemate” denotes a mixture of four possible diastereomers, with the two cis diastereomers predominately present.    
               
             
          
         
       
     
         [0109]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                 Cyclohexyl Relative Conformation is CIS 
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 R 3   
               
               
                   
               
               
                 174 
                 2-pyridylmethyl 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 183 
                 benzyl 
                 benzyl 
                 phenylamino 
               
               
                 184 
                 3-chlorobenzyl 
                 3-methoxyphenyl 
                 phenylamino 
               
               
                 185 
                 3-chlorobenzyl 
                 2-furyl 
                 phenylamino 
               
               
                 186 
                 3-nitrobenzyl 
                 3-methoxyphenyl 
                 phenylamino 
               
               
                   
               
             
          
         
       
     
         [0110]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 Stereo 
                 R 3   
               
               
                   
               
               
                 216 
                 benzyl 
                 t-butyl 
                 1S, 3R 
                 4-fluorophenyl 
               
               
                 217 
                 3-chlorobenzyl 
                 t-butyl 
                 1S, 3R 
                 4-fluorophenyl 
               
               
                 218 
                 benzyl 
                 trichloromethyl 
                 1S, 3R 
                 4-fluorophenyl 
               
               
                 219 
                 3-nitrobenzyl 
                 trichloromethyl 
                 1S, 3R 
                 4-fluorophenyl 
               
               
                 220 
                 3,4-difluorobenzyl 
                 t-butyl 
                 1S, 3R 
                 4-fluorophenyl 
               
               
                 231 
                 benzyl 
                 trichloromethyl 
                 1R, 3S 
                 4-fluorophenyl 
               
               
                   
               
             
          
         
       
     
         [0111]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 X 1   
                 R 2   
               
               
                   
               
               
                 130 
                 H 
                 CO 
                 2-(phenyl)ethyl 
               
               
                 131 
                 H 
                 CO 
                 trichloromethyl 
               
               
                 132 
                 H 
                 CO 
                 4-biphenyl 
               
               
                 133 
                 H 
                 CO 
                 diphenylmethyl 
               
               
                 134 
                 H 
                 CO 
                 3-methoxybenzyl 
               
               
                 135 
                 H 
                 SO 2   
                 4-biphenyl 
               
               
                 151 
                 benzyl 
                 CO 
                 trichloromethyl 
               
               
                 152 
                 benzyl 
                 CO 
                 2-(phenyl)ethyl 
               
               
                   
               
             
          
         
       
     
         [0112]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
               
               
                   
               
               
                 136 
                 benzyl 
                 2-(phenyl)ethyl 
               
               
                 137 
                 H 
                 diphenylmethyl 
               
               
                 138 
                 H 
                 2-(phenyl)ethyl 
               
               
                 139 
                 benzyl 
                 3-(phenyl)propyl 
               
               
                 140 
                 benzyl 
                 2,2-dimethylpropyl 
               
               
                 141 
                 3-chlorobenzyl 
                 2,2-dimethylpropyl 
               
               
                   
               
             
          
         
       
     
         [0113]    
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                   
                 R 1,  R 2  and X 1  Taken 
                   
                   
                   
                   
               
               
                   
                 Together with the 
               
               
                 ID 
                 amine nitrogen) 
                 A 
                 X 3   
                 X 4   
                 R 3   
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
               
               
                 142 
                 1-phenyl-1,2,3,4- 
                 1,3-phenyl- 
                 absent 
                 CO 
                 4-fluoro 
               
               
                   
                 tetrahydroisoquinolin-2-yl 
                 methyl 
                   
                   
                 phenyl 
               
               
                 148 
                 1-phenyl-1,2,3,4- 
                 1,3-n-propyl 
                 absent 
                 CO 
                 4-fluoro 
               
               
                   
                 tetrahydroisoquinolin-2-yl 
                   
                   
                   
                 phenyl 
               
               
                 149 
                 4-[(4- 
                 1,3-n-propyl 
                 absent 
                 CO 
                 4-fluoro 
               
               
                   
                 chlorophenyl)phenylmethyl]- 
                   
                   
                   
                 phenyl 
               
               
                   
                 piperazin-1-yl 
               
               
                 150 
                 2-[1-benzyl-6-methoxy- 
                 1,3-n-propyl 
                 absent 
                 CO 
                 4-fluoro 
               
               
                   
                 1,2,3,4-tetrahydro]-naphthyl 
                   
                   
                   
                 phenyl 
               
               
                 153 
                 1-phenyl-1,2,3,4- 
                 1,3-n-propyl 
                 CO 
                 absent 
                 4-fluoro 
               
               
                   
                 tetrahydroisoquinolinyl 
                   
                   
                   
                 benzyl 
               
               
                   
               
             
          
         
       
     
         [0114]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 15 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 A 
                 R 3   
                 R 4   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
               
               
                 39 
                 3-chloro 
                 trichloro 
                 methyl-1,3- 
                 phenyl 
                 4-morpholinyl 
               
               
                   
                 benzyl 
                 methyl 
                 cyclopentyl 
                 amino 
               
               
                 221 
                 benzyl 
                 t-butyl 
                 1,4-cyclopentyl- 
                 4-fluoro 
                 1-pyrrolidinyl 
               
               
                   
                   
                   
                 2-ene-methyl 
                 phenyl 
               
               
                   
               
             
          
         
       
     
         [0115]    
       
         
               
             
               
               
             
           
               
                 TABLE 16 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 R 1 , R 2  and X 1  Taken Together 
               
               
                 ID 
                 (with the amine nitrogen) 
               
               
                   
               
               
                 250 
                 5-t-butyl-isoindole-1,3-dione 
               
               
                 251 
                 5-fluoro-isoindole-1,3-dione 
               
               
                 252 
                 benzo[e]isoindole-1,3-dione 
               
               
                 253 
                 5-methyl-isoindole-1,3-dione 
               
               
                 254 
                 8-aza-spiro[4.5]decane-7,9-dione 
               
               
                 255 
                 5,6-dichloro-isoindole-1,3-dione 
               
               
                 256 
                 5-methyl-isoindole-1,3-dione 
               
               
                 257 
                 isoindole-1,3-dione 
               
               
                 258 
                 4,4-dimethyl-piperidine-2,6-dione 
               
               
                 259 
                 5-bromo-isoindole-1,3-dione 
               
               
                 260 
                 5-acetyloxy-isoindole-1,3-dione 
               
               
                 261 
                 8-fluoro-benzo[e]isoindole-1,3-dione 
               
               
                 262 
                 3-aza-bicyclo[3.1.0]hexane-2,4-dione 
               
               
                 263 
                 4,7-dichloro-isoindole-1,3-dione 
               
               
                   
               
             
          
         
       
     
         [0116]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 17 
               
             
             
               
                   
               
               
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 ID # 
                 R 1   
                 R 2   
                 R 3   
                 R 4   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
               
               
                 84 
                 benzyl 
                 H 
                 phenylamino 
                 4-morpholino 
               
               
                 85 
                 3-chlorobenzyl 
                 H 
                 phenylamino 
                 4-morpholino 
               
               
                 87 
                 3,5-dichlorobenzyl 
                 H 
                 phenylamino 
                 4-morpholino 
               
               
                 88 
                 1-naphthylmethyl 
                 H 
                 phenylamino 
                 4-morpholino 
               
               
                 89 
                 4-(1-hydroxy)-pyridyl 
                 H 
                 phenylamino 
                 4-morpholino 
               
               
                 222 
                 benzyl 
                 benzyl 
                 4-fluorophenyl 
                 1-pyrrolidinyl 
               
               
                   
               
             
          
         
       
     
         [0117]     Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. Illustrating the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. A further illustration of the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.  
         [0118]     Included in the invention is the use of any of the compounds described above for the preparation of a medicament for treating a disorder mediated by the motilin receptor, in a subject in need thereof.  
         [0119]     Also included in the invention is the use of any of the compounds described above for the preparation of a medicament for treating a condition selected from gastrointestinal reflux disorders, eating disorders leading to obesity and irritable bowel syndrome in a subject in need thereof.  
         [0120]     Exemplifying the invention are methods of treating a disorder mediated by the motilin receptor, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.  
         [0121]     An example of the invention is a method for treating a condition selected from gastrointestinal reflux disorders, eating disorders leading to obesity and irritable bowel syndrome in a subject in need thereof, comprising administering to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.  
         [0122]     Another example of the invention is the use of any of the compounds described above in the preparation of a medicament for: (a) treating gastrointestinal reflux disorders, (b) treating irritable bowel syndrome, (c) treating eating disorders leading to obesity, in a subject in need thereof.  
         [0123]     Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.  
         [0124]     The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.  
         [0125]     The term “alkyl”, unless otherwise specified, refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. The expression “lower alkyl” refers to straight or branched chain unsubstituted alkyl groups of 1 to 6 carbon atoms. For example, alkyl radicals include, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-pentyl, 2-methylpropyl, 2-methylbutyl, 3,3-dimethylpropyl, neo-pentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Similarly, the term “alkenyl”, unless otherwise specified, refers to straight or branched chain alkene groups of 2 to 10 carbon atoms. The term “lower alkenyl” refers to straight or branched chain alkene groups of 2 to 6 carbon atoms.  
         [0126]     The term “substituted alkyl”, unless otherwise specified, refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyoxy, heterocyclyloxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the amino substituents are independently selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO 2 NH 2 ), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH 2 ) substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.  
         [0127]     The term “cycloalkyl”, unless otherwise specified, refers to saturated unsubstituted cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 8 carbon atoms per ring. For example, cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Similarly, the term “cycloalkenyl” refers to partially unsaturated, unsubstituted cyclic hydrocarbon groups of 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Suitable examples of cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclooctyl, cyclodecyl, cyclododecyl, adamantyl, and the like.  
         [0128]     The term “alkoxy”, unless otherwise specified, refers to oxygen ether radical of the above described straight or branched chain alkyl groups. The expression “lower alkoxy” refers to unsubstituted alkoxy groups of 1 to 6 carbon atoms. Suitable examples of alkoxy groups include methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.  
         [0129]     The term “aryl”, unless otherwise specified, refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl, each of which may be optionally substituted.  
         [0130]     The term “aralkyl”, unless otherwise specified, refers to an aryl group bonded directly through an alkyl group, such as benzyl, 2-(phenyl)ethyl, 3-(phenyl)propyl, naphthyl-methyl and the like.  
         [0131]     The term “substituted aryl” refers to an aryl group substituted by, for example, one to five substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like.  
         [0132]     The term “diarylalkyl”, unless otherwise specified, refers to an alkyl group substituted with two independently selected aryl groups. Suitable examples include diphenylmethyl, 1,1-diphenylethyl, and the like.  
         [0133]     The term “heteroatom” shall include oxygen, sulfur and nitrogen.  
         [0134]     The terms “heterocyclyl”, “heterocyclic” and “heterocyclo”, unless otherwise specified, refer to a saturated, unsaturated, partially unsaturated, aromatic, partially aromatic or non-aromatic cyclic group. Such a group, for example, can be a 4 to 7 membered monocyclic or a 7 to 11 bicyclic ring system which contains at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and where the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.  
         [0135]     Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropryanyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, triazolyl, tetrazolyl and the like.  
         [0136]     Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like.  
         [0137]     The term “monocyclic or fused bicyclic or tricyclic secondary amine ring structure” shall mean any 4 to 8 monocyclic or 7 to 11 fused bicyclic or 13 to 14 tricyclic ring structure; wherein the ring structure is saturated, partially unsaturated or benzo-fuzed; wherein the ring structure contains at least one nitrogen atom through which the ring structure is bound directly to the other portions of the compound; and wherein the ring structure may optionally containing one to three additional heteroatoms selected from nitrogen, oxygen or sulfur.  
         [0138]     Suitable examples include 1,2,3,4-tetrahydroisoquinolinyl, 1-piperazinyl, 1,2,3,4-tetrahydronaphthyl, isoindolyl, benzo[e]isoindolyl, 8-aza-spiro[4.5]decane, 3-aza-bicyclo[3.1.o]hexane, and the like.  
         [0139]     The monocylic, bicyclic or tricyclic secondary amine ring structure may optionally be substituted with one to five substituents independently selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido nitro, cyano, oxo, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy, aryl, aralkyl, heterocyclyl, and the like.  
         [0140]     The term “tri-halomethyl” refers to trichloromethyl, trifluoromethyl, tribromomethyl and triiodomethyl.  
         [0141]     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 “phenyl(alkyl)amido(alkyl)” substituent refers to a group of the formula  
                         
 
         [0142]     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.  
         [0143]     As used herein, the term “cis racemate” indicates a mixture of four possible diastereomers, more particularly, two cis diastereomers and two trans diastereomers, with the two cis diastereomers present in a amount equal to greater than about 75%, preferably in an amount greater than about 90%, more preferably in an amount greater than about 95%.  
         [0144]     When a particular group is “substituted” (e.g., aryl, heteroaryl, heterocyclyl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents. Where the group has a plurality of moieties, such as “alkylamino” or “heterocyclyl-alkyl” the substitution may be on any or all of the moieties independently, e.g. in the case of “alkylamino” the substitution may be on the alkyl or amino moiety, or both.  
         [0145]     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.  
         [0146]     Suitable protecting groups as referred to within this specification include the standard hydroxy and amino protecting groups, as applicable. The terms “hydroxy protecting group” and “amino protecting group” as used herein mean any of the known protecting groups used in the art of organic synthesis, for example as described in Protective Groups in Organic Synthesis, 2 nd  Ed., T. W. Greene and P. G. M. Wuts, John Wiley &amp; Sons, New York, 1991, hereby incorporated by reference.  
         [0147]     Examples of hydroxy-protecting groups P, include, but are not limited to, methyl, benzyl, tetrahydropyranyl, tri(C 1 -C 6 )alkylsilyl such as t-butyldimethylsilyl, t-butyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl and O-phenoxyacetyl ethers. The hydroxy-protecting group selected is preferably one that is easily removable in the reaction process.  
         [0148]     Examples of suitable amino protecting groups include, but are not limited to, acetyl(Ac), benzoyl(Bz), trifluoroacetyl(Tfa), toluenesulfonyl(Tos), benzyl (Bn), triphenylmethyl(Trt), o-nitrophenyl-sulfenyl(Nps), benzyloxycarbonyl(Cbz or Z), t-butoxycarbonyl(Boc), allyloxycarbonyl(alloc), 9-fluorenylmethyloxycarbonyl(Fmoc), 2-bromo-benzyloxycarbonyl (2-Br-Z), 2-chloro-benzyloxycarbonyl (2-Cl-Z), t-butyl-dimethylsilyloxycarbonyl, [2-(3,5-dimethoxyphenyl)-propyl-2-oxycarbonyl] (Ddz), 2,2,2-trichloroethyloxycarbonyl (Troc), biphenylylisopropyloxycarbonyl(Bpoc), and o-nitrobenzyloxycarbonyl.  
         [0149]     Throughout this specification, certain abbreviations are employed having the following meanings, unless specifically indicated otherwise. 
        AcOH=Acetic Acid     ADDP=1,1′-(azodicarbonyl)dipiperidine     BSA=Bovine Serum Albumin     DCM=Dichloromethane     DEAD=Diethyl azodicarboxylate     DIEA=Diisopropylethylamine     DMAP=Di(methyl)aminopyridine     DMF=N,N-dimethylformamide     DMSO=Dimethylsulfoxide     EA=Ethyl acetate     EDCI=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide     EDTA=Ethylenediamine tetraacetic acid     EGTA=Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid     Et 2 O=Diethyl ether     EtOAc=Ethyl acetate     EtOH=Ethanol     Et 3 N=Triethylamine     HEPES=N-(2-hydroxyethyl)piperazine-N-ethanesulfonic acid     LAH=Lithium Aluminum Hydride     MeOH=Methanol     MeI=Methyl Iodide     Oms=Mesylate     Otos=Tosylate     Phe=Phenyl     Pt=Protecting Group     PyBOP=Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate     TBAF=Tetrabutylammonium fluoride     TEA=Triethylamine     TFA=Trifluoroacetic Acid     THF=Tetrahydrofuran     Tris-HCl=Tris[hydroxymethyl]aminomethyl hydrochloride        
 
         [0181]     The synthesis of substituted N-benzyl-m-anisidines, compounds of formula (II), intermediates used in the synthetic route for select compounds of the invention, are known in the art.  
                         
 
         [0182]     Routes for synthesis of substituted N-benzyl-m-anisidines include alkylation (Hoerlein; Chem. Ber.; 87; 1954; 463, 467, 468), reductive amination (Nussbaumer, P.; et. al.; J Med. Chem.; 37; 24; 1994; 4079-4084) and reduction of the corresponding N-benzoyl-m-anisidine (Pratt; McGovern; J. Org. Chem.; 29; 1964; 1540, 1542). Additionally, N-benzyl-N-phenyl-malonamic acid methyl ester, a compound of formula (III) below, is a known compound, a variant of one of the intermediates elucidated in the synthesis that follows (Wee, A.; Tetrahedron, 50; 3; 1994; 609-626).  
                         
 
         [0183]     Routes to the synthesis of 4-phenyl-1,2,3,4-tetrahydroisoquinolines are also known in the literature (Maryanoff, B., et. al., J. Org. Chem., 46, 1981, 355 360; Schwan, T. et. al., J. Heterocycl. Chem., 1974, 11, 807; and references therein).  
         [0184]     Schemes 1-8 below depict synthesis routes for producing compounds of the formula (I).  
         [0185]     Compounds of formula (I) wherein X 2  and X 3  are each carbonyl, X 1  and X 4  are each absent and R 3  is —CH 2 —R 6 , may be produced according to the process outlined in Scheme 1. The process of Scheme 1 is particularly preferred for preparation of compounds of formula (I) wherein A is incorporated into the molecule via reaction with a suitably selected unsymmetrically substituted anhydride; wherein A is a substituted alkyl; and wherein it is desired to have the substituent closer to the R 1 X 1 R 2 N portion of the compound of formula (I).  
                         
 
         [0186]     More specifically, a protected aniline derivative of formula (IV), wherein Pt represents a protecting group, a known compound or compound prepared by known methods, is reacted with a suitably substituted aldehyde of the formula (V), wherein R 3A  is selected from hydrogen, aryl, heterocyclyl, aralkyl, diarylalkyl, heterocyclo-alkyl, tri-halomethyl, alkylamino, dialkylamino, alkylaminoalkyl, arylamino, diarylamino or lower alkyl; in the presence of a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, and the like, under dehydrating conditions, for example, in an acid alcohol solution such as acidic methanol or in a solution of titanium tetraisopropoxide in DCM, to produce the corresponding secondary aniline derivative of formula (VI).  
         [0187]     The secondary aniline derivative of formula (VI) is coupled with a suitably selected, protected dicarboxylic acid of formula (VII), wherein Pt′ is a protecting group or with an anhydride of the desired substituent A, to produce the corresponding acid-amide of formula (VIII).  
         [0188]     When the secondary aniline derivative of formula (VI) is coupled with a cyclic anhydride of the desired substituent A, such as glutaric anhydride and the like, the anhydride ring is subjected to ring opening, preferably at a temperature between about room temperature and about 110° C., in an organic solvent such as chloroform, toluene, and the like.  
         [0189]     When the secondary aniline derivative of formula (VI) is coupled with a protected dicarboxylic acid of formula (VII), the protecting group is then removed by hydrolysis, using an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, in an alcohol or in an organic solvent/water mixture such as methanol, ethanol, THF/water, preferably lithium hydroxide in THF/water.  
         [0190]     The acid-amide compound of formula (VIII) is activated using a known coupling agent, such as EDCI and the like, and coupled with a suitably substituted amine of formula (IX), in an organic base such as TEA, DIEA, and the like, in the presence of an organic solvent such as THF, DMF, DCM and the like, to produce the corresponding diamide of formula (X).  
         [0191]     Alternatively, the acid-amine compound of formula (VIII) may be converted to the corresponding acid chloride with a reagent such thionyl chloride, oxalyl chloride, and the like, and then coupled to the substituted amine of formula (IX) to produce the diamide of formula (X).  
         [0192]     The compound of formula (X) is deprotected by known methods [for example, when the protecting group is methyl ether, the methyl group is removed with boron tribromide in dichloromethane at −78° C.; when the protecting group is t-butyldimethylsilylether, the silyl group is removed with tetrabutylammonium fluoride in THF] to produce the corresponding compound of formula (XI).  
         [0193]     The compound of formula (XI) is reacted with a suitably substituted compound of formula (XII), wherein W represents a leaving group such as halogen, OMS, OTos, and the like, in the presence of a base such as sodium hydride, potassium carbonate, and the like, in an organic solvent such as DMF, THF, and the like, to produce the corresponding compound of formula (Ia). Alternatively, when W is OH, the compound of formula (XI) may be reacted directly, under Mitsunobu conditions, to a suitably substituted compound of formula (XII).  
         [0194]     Compounds of formula (I) wherein X 2  and X 3  are each carbonyl, X 1  and X 4  are each absent and R 3  is —CH 2 —R 6  may alternatively be prepared according to the process outlined in Scheme 2.  
                         
 
         [0195]     Accordingly, a suitably substituted nitrobenzene of formula (XIII), a compound prepared by known methods, is reacted with a suitably substituted compound of formula (XII), wherein W represents a leaving group such as halogen, OMS, OTos, and the like, in the presence of a base such as sodium hydride, triethylamine, and the like, in an organic solvent such as DMF, THF, and the like, to produce the corresponding compound of formula (XIV).  
         [0196]     The nitro group on the compound of formula (XIV) is reduced by known methods, for example by hydrogenation over palladium on carbon in ethyl acetate, to produce the corresponding compound of formula (XV).  
         [0197]     The compound of formula (XV) is reacted with a suitably substituted aldehyde of formula (V), wherein R 3A  is as previously defined, in the presence of a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, and the like, under dehydrating conditions, for example, in an acid alcohol solution such as acidic methanol or in a solution of titanium tetraisopropoxide in DCM, to produce the corresponding compound of formula (XVI).  
         [0198]     The compound of formula (XVI) is reacted with a suitably selected anhydride of the desired A substituent, optionally in an organic solvent such as THF, DMF, DCM, and the like, to produce the corresponding compound of formula (XVII). When reacting with a cyclic anhydride of the desired substituent A, such as glutaric anhydride and the like, the anhydride ring is subjected to ring opening, preferably at a temperature between about room temperature and about 110° C., in an organic solvent such as chloroform, toluene, and the like.  
         [0199]     The compound of formula (XVII) is coupled with a suitably substituted amine of formula (IX), in the presence of a coupling agent, such as PyBOP, and the like, in an organic solvent such as THF, DMF, DCM, and the like, to produce the corresponding compound of formula (Ib).  
         [0200]     Compounds of formula (I) wherein X 2  and X 3  are each carbonyl, X 1  and X 4  are each absent and R 3  is —CH 2 —R 6 , may alternatively be prepared according to the process outlined in Scheme 3. This process is particularly preferred for preparation of compounds of formula (I) wherein A is incorporated into the molecule via reaction with a suitably selected, unsymmetrically substituted anhydride; wherein A is a substituted alkyl; and wherein it is desired to have the substituent distal to the R 1 X 1 R 2 N portion of the compound of formula (I).  
                         
 
         [0201]     More specifically, a suitably substituted amine of formula (IX) is reacted with a suitably selected anhydride of the desired A substituent, in an organic solvent such as THF, DMF, DCM, and the like, to produce the corresponding compound of formula (XVIII). When the compound of formula (IX) is coupled with a cyclic anhydride of the desired A substituent, such as glutaric anhydride and the like, the anhydride ring is subjected to ring opening, preferably at a temperature between about room temperature and about 110° C., in an organic solvent such as chloroform, toluene, and the like.  
         [0202]     The compound of formula (XVIII) is coupled with a suitably substituted compound of formula (XVI), prepared as in Scheme 2 above, in an organic solvent such as THF, DMF, DCM and the like, after conversion of the compound of formula (XVIII) to the corresponding acid chloride using a reagent such as thionyl chloride, oxalyl chloride, and the like, to produce the corresponding compound of formula (Ib).  
         [0203]     Alternatively, the compound of formula (XVIII) may be coupled directly with a suitably substituted compound of formula (XVI), optionally in the presence of a coupling agent such as PyBrop, and the like, in an organic solvent such as THF, DMF, DCM, and the like.  
         [0204]     Compounds of formula (I) wherein X 1  and X 3  are each absent, X 2  is carbonyl, and X 4  is carbonyl or sulfonyl, may be prepared according to the process outlined in Scheme 4.  
                         
 
         [0205]     More specifically, an anhydride of the desired substituent A is reacted with a suitably substituted compound of formula (XIV), prepared as outlined in scheme 2, in an organic solvent such as THF, DMF, DCM and the like, to produce the corresponding compound of formula (XIX).  
         [0206]     The compound of formula (XIX) is coupled with a suitably substituted amine of formula (IX), in the presence of a coupling agent, such as PyBOP, and the like, in an organic solvent such as THF, DMF, DCM and the like, to produce the corresponding compound of formula (XX).  
         [0207]     The compound of formula (XX) is selectively reduced, by known methods, for example, by reacting with sodium cyanoborohydride in AcOH (Tetrahedron Letters, 10, 763-66, 1976), to produce the corresponding compound of formula (XXI).  
         [0208]     The compound of formula (XXI) is reacted with an appropriately selected and suitably substituted isocyanate of formula (XXII), wherein R 3A  is a previously defined, or a sulfonyl chloride of formula (XXIII) or a carbonyl chloride of formula (XXIV), in an organic solvent such as THF, DMF, DCM and the like, to produce the corresponding compound of formula (Ic).  
         [0209]     Compounds of formula (I) wherein X 1  and X 4  are each carbonyl or sulfonyl and X 2  and X 3  are each absent, may be prepared according to the process outlined in Scheme 5. This process is particularly preferred for the preparation of compounds of formula (I) wherein A is -cyclohexyl-methyl-, -cyclopentyl-methyl and -cyclopentenyl-methyl-.  
                         
                         
 
         [0210]     Accordingly, a trityl-protected compound of formula (XXV), wherein A 1  is cycloalkyl, cycloalkenyl, alkyl-cycloalkyl, aryl or alkyl-aryl, a known compound or compound prepared by known methods, [for example by the method disclosed in K. Barlos, D. Theodoropoulos, and D. Papaioannou in J. Org. Chem. 1982, 47, 1324-1326], is coupled to a suitably substituted compound of formula (XIV), prepared according to Scheme 2 above, using a coupling agent such as PyBOP, and the like, to produce the corresponding compound of formula (XXVI).  
         [0211]     The compound of formula (XXVI) is subjected to reduction of the carbonyl group using known reducing agents, for example borane dimethylsulfide at reflux, lithium aluminum hydride in THF, and the like, to produce the corresponding compound of formula (XXVII).  
         [0212]     The compound of formula (XXVII) is reacted with an appropriately selected and suitably substituted isocyanate of formula (XXII), wherein R 3A  is as previously defined, sulfonyl chloride of formula (XXIII) or carbonyl chloride of formula (XXIV), in an organic solvent such as DCM, toluene, chloroform, and the like, to produce the corresponding compound of formula (XXVIII).  
         [0213]     The compound of formula (XXVIII) is deprotected by removal of the trityl protecting group, using a solution of trifluoroacetic acid in dichloromethane, to produce the corresponding compound of formula (XXIX).  
         [0214]     The compound of formula (XXIX) is reacted with a suitably substituted aldehyde of formula (XXX), wherein R 1A  is selected from the group consisting of hydrogen, aryl, aralkyl, heterocyclyl, diarylalkyl, heterocyclyl-alkyl, and lower alkyl; wherein the alkyl, aryl, heterocyclyl or amino group may be substituted with one or more substituents independently selected from halogen, hydroxy, nitro, carboxy, cyano, amino, dialkylamino, lower alkoxy, lower alkyl, tri-halomethyl, alkylamino, carboxy or alkoxycarbonyl; by known methods, [for example by reductive amination or by the method of R. Mattson, et. al., in J. Org. Chem. 1990, 55, 2552-2554 using stepwise addition of titanium tetraisopropoxide neat or in a dichloromethane, followed by addition of methanol and sodiumcyanoborohydride], to produce the corresponding compound of formula (XXXI).  
         [0215]     The compound of formula (XXXI) is reacted with an appropriately selected and suitably substituted isocyanate of formula (XXXII), wherein R 2A  is selected from aryl, aralkyl, heterocyclyl, heterocyclyl-alkyl, diarylalkyl, tri-halomethyl, arylamino or lower alkyl, or a sulfonyl chloride of formula (XXXIII) or a carbonyl chloride of formula (XXXIV), or an anhydride of formula (XXXXVII) in an organic solvent such as DCM, toluene, and the like, to produce the corresponding compound of formula (Id). When the compound of formula (XXXI) is reacted with a sulfonyl chloride of formula (XXXIII) or a carbonyl chloride of formula (XXXIV), the reaction is carried out with further addition of an organic base such as TEA, DIPEA, and the like.  
         [0216]     Compounds of formula (I) wherein A is a substituted alkyl may alternatively be prepared according to the process outlined in Scheme 6.  
                         
 
         [0217]     More specifically, a suitably substituted compound of formula (XVI), prepared as described in Scheme 2 above, is coupled with an appropriately selected, Fmoc protected compound of formula (XXXV), in an organic solvent such as DCM, DMF, and the like, to produce the corresponding compound of formula (XXXVI).  
         [0218]     The compound of formula (XXXVI) is deprotected by removal of the Fmoc protecting group by known methods [for example by treating with piperidine in DM F], to produce the corresponding compound of formula (XXXVII).  
         [0219]     The compound of formula (XXXVII) is reacted with a suitably substituted aldehyde of formula (XXX), wherein R 1A  is as previously defined, in the presence of a reducing agent such as sodium cyanoborohydride, and the like, under dehydrating conditions, for example in an acid alcohol solution such as acidic methanol or in a solution of titanium tetraisopropoxide in DCM, followed by addition of methanol and sodium cyanoborohydride, to produce the corresponding compound of formula (XXXVIII).  
         [0220]     The compound of formula (XXXVIII) is coupled with an appropriately selected and suitably substituted isocyanate of formula (XXXII), wherein R 2A  is as previously defined, sulfonyl chloride of formula (XXXIII) or carbonyl chloride of formula (XXXIV), in an organic solvent such as DCM, and the like, in the presence of an organic base such as TEA, DIEA, and the like, to produce the corresponding compound of formula (Ie).  
         [0221]     Optionally, the compound of formula (XXXVIII) may be further reacted with a second equivalent of the compound of formula (XXX) to yield a derivative of the compound of formula (XXXVIII), wherein the leftmost amine nitrogen is di-substituted with the —CH 2 —R 1A  group, wherein R 1A  is as previously defined.  
         [0222]     Compounds of formula (I), particularly those wherein X 1  and X 3  are each absent, X 2  is carbonyl and X 4  is carbonyl or sulfonyl may be prepared according to the process outlined in Scheme 7. This process is particularly preferred for preparation of compounds of formula (I) wherein A is contains a non-hydrogen substituent alpha to the right-hand most amine nitrogen.  
                         
 
         [0223]     Accordingly, a suitably substituted compound of formula (XV), prepared as in Scheme 2 above, is alkylated with an appropriately selected compound of formula (XXXIX), ins an organic solvent such as DCM, chloroform, and the like, to produce the corresponding compound of formula (XXXX).  
         [0224]     The compound of formula (XXXX) is coupled with an appropriately selected and suitably substituted isocyanate of formula (XXII), wherein R 3A  is as previously defined, sulfonyl chloride of formula (XXIII) or carbonyl chloride of formula (XXIV), in an organic solvent such as DCM, and the like, to produce the corresponding compound of formula (XXXXI). When the compound of formula (XXXX) is reacted with a sulfonyl chloride of formula (XXXI II) or a carbonyl chloride of formula (XXXIV), the reaction is run in the presence of an organic base such as TEA, DIEA, and the like.  
         [0225]     The compound of formula (XXXXI) is subjected to hydrolysis of the methyl ester, in the presence of an inorganic base such as sodium hydroxide, and the like, to produce the corresponding compound of formula (XXXXII).  
         [0226]     The compound of formula (XXXXII) is coupled with a suitably substituted amine of formula (IX), in the presence of a coupling agent such as PyBOP, and the like, in an organic solvent such as DCM, and the like, to produce the corresponding compound of formula (If).  
         [0227]     Compounds of formula (I), particularly those wherein X 1  and X 4  are each carbonyl or sulfonyl and X 2  and X 3  are each absent may be prepared according to the process outlined in Scheme 8 
                         
 
         [0228]     Accordingly, wherein A 1  is an oxo and cyano substituted cycloalkyl, an oxo and cyano substituted cycloalkenyl, an oxo and cyano substituted cycloalkyl-alkyl, an oxo-alkyl and cyano substituted aryl or an oxo-alkyl and cyano-alkyl substituted aryl-alkyl, a known compound or compound prepared by known methods, is reacted with a compound of formula (XV), prepared as outlined in Scheme 2, in the presence of a reducing agent such as sodium cyanoborohydride, and the like, under dehydrating conditions, for example in an acid alcohol solution such as acidic methanol, to produce the corresponding compound of formula (XXXXIII).  
         [0229]     The compound of formula (XXXXIII) is reacted with an appropriately selected and suitably substituted isocyanate of formula (XXII), wherein R 3A  is as previously defined, sulfonyl chloride of formula (XXIII) or carbonyl chloride of formula (XXIV), in an organic solvent such as DCM, and the like, to produce the corresponding compound of formula (XXXXIV). When the compound of formula (XXXXIII) is reacted with a sulfonyl chloride of formula (XXIII) or a carbonyl chloride of formula (XXIV), the reaction is run in the presence of an organic base such as TEA, DIEA, and the like.  
         [0230]     The cyano functional group on the compound of formula (XXXXIV) is reduced by known methods, for example by treatment with lithium aluminum hydride, in an organic solvent such as THF, and the like, to produce the corresponding compound of formula (XXXXV).  
         [0231]     The compound of formula (XXXXV) is reacted with a suitably substituted aldehyde of formula (XXX), wherein R 1A  is as previously defined, in the presence of a reducing agent such as sodium cyanoborohydride, and the like, under dehydrating conditions, for example in an acid alcohol solution such as acidic methanol or in a solution of titanium tetraisopropoxide in DCM, followed by addition of methanol and sodium cyanoborohydride, to produce the corresponding compound of formula (XXXXVI).  
         [0232]     The compound of formula (XXXXVI) is reacted with an appropriately selected and suitably substituted isocyanate of formula (XXXII), wherein R 2A  is as previously defined, sulfonyl chloride of formula (XXXI II), or carbonyl chloride of formula (XXXIV), in an organic solvent such as DCM, and the like, to produce the corresponding compound of formula (Ig). When the compound of formula (XXXXVI) is reacted with a sulfonyl chloride of formula (XXXIII) or a carbonyl chloride of formula (XXXIV), the reaction is run in the presence of an organic base such as TEA, DIEA, and the like.  
         [0233]     Compounds of formula (I) wherein R 1 , X 1  and R 2  are taken together (with the amine nitrogen) to form an oxo substituted heterocyclyl group, may be prepared according to the process outlined in Scheme 9.  
                         
 
         [0234]     More particularly, the compound of formula (XXIX), prepared as in Scheme 5, is reacted with a suitably substituted symmetric or asymmetric anhydride, a compound of formula (XXXXVII), preferably a symmetric anhydride, in an organic solvent such as toluene, DCM, and the like, to yield the corresponding compound of formula (XXXXVIII).  
         [0235]     The compound of formula (XXXXVIII) is heated at an elevated temperature in the range of about 40-180° C., or treated with addition of an anhydride such as acetic anhydride, trifluoroacetic anhydride, and the like, in an organic solvent such as methylene chloride, toluene, 1,2-dichlorobenzene, and the like, to yield the corresponding compound of formula (Ih), wherein  
                         
 
 represents the group wherein R 1 , R 2  and X 1  are taken together (with the amine nitrogen) to form a cyclic oxo substituted heterocyclyl. 
 
         [0236]     Wherein the compound of formula (XXXXVII) is an asymmetric anhydride, (a compound of the formula R 2 ′-C(O)—C(O)—R 2 ″, wherein R 2 ′ and R 2 ″ are different), the R 2  group which is coupled onto the compound of formula (XXIX) may be readily determined by one skilled in the art, based on the relative reactivities of the carbonyl groups adjacent to the R 2 ′ and R 2 ″ groups.  
         [0237]     It is generally preferred that the respective product of each process step be separated from other components of the reaction mixture and subjected to purification before its use as a starting material in a subsequent step. Separation techniques typically include evaporation, extraction, precipitation and filtration. Purification techniques typically include column chromatography (Still, W. C. et. al.,  J. Org. Chem.  1978, 43, 2921), thin-layer chromatography, HPLC, acid-base extraction, crystallization and distillation.  
         [0238]     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.  
         [0239]     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-I-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 by enzymatic resolution or by using a chiral HPLC column.  
         [0240]     To prepare the pharmaceutical compositions of this invention, one or more compounds or salts thereof, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will preferably contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, from about 5 to about 500 mg of the active ingredient, although other unit dosages may be employed.  
         [0241]     In therapeutic use for treating disorders of the gastrointestinal system in mammals, the compounds of this invention may be administered in an amount of from about 0.5 to 100 mg/kg 1-2 times per day orally. In addition the compounds may be administered via injection at 0.1-10 mg/kg per day. Determination of optimum dosages for a particular situation is within the capabilities of formulators.  
         [0242]     In order to illustrate the invention, the following examples are included. These examples do not limit the invention. They are meant to illustrate and suggest a method of practicing the invention. Although there are other methods of practicing this invention, those methods are deemed to be within the scope of this invention.  
       EXAMPLE 1  
     N-trityl-cis-3-aminocyclohexanecarboxylic acid  
       [0243]     Adapting the method of K. Barlos, D. Papaioannou and D. Theodoropoulos,  JOC,  1982, 47, 1324-1326, cis-3-aminocyclohexanecarboxylic acid was protected as the N-trityl derivative.  
         [0244]     TMSCI (26.1 ml, 0.205 mmol) was added to a suspension of cis-3-aminocyclohexanecarboxylic acid (29.4 g, 0.205 mmol) suspended in a 5:1 solution of CH 2 Cl 2 -CH 3 CN (500 ml) at room temperature. The mixture was heated at reflux for 2 hours and then allowed to cool to ambient temperature. TEA (57.2 ml, 0.410 mmol) was added dropwise to the mixture, followed immediately by portionwise addition of triphenylmethyl chloride (57.2 g, 0.205 mmol). After stirring for 18 h, MeOH was added to the mixture to give a homogeneous solution. The mixture was evaporated down to dryness and the resultant residue partitioned between Et 2 O and 10% citric acid (1:1, 800 ml total). The ether layer was collected and combined with an ether extraction (150 ml) of the citric acid layer. The combined ether fractions were then extracted with 2 M NaOH (3×250 ml) and water (1×100 ml). The aqueous layers were washed with ether (2×150 ml). After cooling to 0° C., the aqueous layer was acidified to pH 7 with concentrated HCl and extracted with ethyl acetate (3×200 ml). The combined extracts were dried over MgSO 4  and evaporated down to give a white foam, 67.4 g, 85% yield.  
         [0245]     MS 384 (M − )  
         [0246]      1 H NMR (CDCl 3 ) δ 0.44-0.95 (br m, 3H), 0.97-1.22 (br m, 2H), 1.30-1.48 (br m, 1H), 1.53-1.79 (br m, 2H), 1.8-2.04 (br m, 1H), 2.10-2.29 (br m, 1H), 6.95-7.24 (m, 9H), 7.36-7.59 (m, 6H).  
       EXAMPLE 2  
     1-(2-(3-nitrophenoxy)ethyl)pyrrolidine  
       [0247]     Following the procedure disclosed in GB 924961; 1959; Chem. Abstr.; 59; 9883b; 1963.  
         [0248]     3-nitrophenol (3.29 g, 23.7 mmol) in DMF (20 ml) was added dropwise to 60% NaH (2.65 g, 66.2 mmol) in 30 ml DMF at 0° C., under nitrogen. The reaction was stirred until H 2 (g) evolution ceased. 1-(2-chloroethyl)pyrrolidine hydrochloride (5.63 g, 33.1 mmol) was then added portionwise. The mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with 2N NaOH (50 ml) and the desired product extracted into ether (3×50 ml). The combined ether layers were washed (2×50 ml) with water, dried over MgSO 4 , and evaporated to dryness in vacuo. The residue was purified through a silica gel plug using 10% ethyl acetate/hexane to remove the impurities and then the desired product was eluted off with 40% ethyl acetate/hexane containing 2% Et 3 N to yield a pale yellow oil.  
         [0249]     MS 237 (MH + )  
         [0250]      1 H NMR (CDCl 3 ) δ1.78-1.88 (m, 4H), 2.55-2.66 (m, 4H), 2.94 (t, J=5.8 Hz, 2H), 4.18 (t, J=5.8 Hz, 2H), 7.23-7.28 (m, 1H), 7.42 (virtual t, J=8.2 Hz, 1H), 7.75-7.76 (m, 1H), 7.80-7.83 (m, 1H).  
       EXAMPLE 2B  
     2-(2-(3-aminophenoxy)ethyl)-1-methylpyrrolidine  
       [0251]     3-aminophenol (0.74 g, 6.8 mmol) in DMF (10 ml) was added dropwise to 95% NaH (0.49 g, 20.4 mmol) in 10 ml DMF at 0° C., under nitrogen. The reaction was stirred until H 2 (g) evolution ceased. 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (1.25 g, 6.8 mmol) was then added portionwise. The mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with 1N NaOH (50 ml) and the desired product extracted into ether (3×50 ml). The combined ether layers were washed (2×50 ml) with water, dried over MgSO 4 , and evaporated to dryness in vacuo. The residue was purified on silica gel by flash chromatography using 2% TEA in ethyl acetate to give an oil.  
         [0252]     MS 221 (MH + )  
         [0253]      1 H NMR (CDCl 3 ) δ1.46-2.31 (m, 8H), 2.34 (s, 3H), 3.08 (ddd, J=8.3, 7.6, 2.4 Hz, 1H), 3.64 (br s, 2H), 3.89-4.08 (m, 2H), 6.20-6.36 (m, 3H), 7.04 (t, J=8.0 Hz, 1H).  
       EXAMPLE 2C  
     1-(2-(3-aminophenoxy)ethyl)piperidine  
       [0254]     Following the procedure as described in Example 2B, 19.9 g (0.182 mol) of 3-aminophenol was converted into the title compound as a light yellow oil.  
         [0255]     MS 221 (MH + )  
         [0256]      1 H NMR (CDCl 3 ) δ1.38-1.50 (m, 2H), 1.52-1.66 (m, 4H), 2.43-2.56 (m, 4H), 2.75 (t, J=6.1 Hz, 2H), 3.65 (s br, 2H) 4.07 (t, J=6.1 Hz, 2H), 6.22-6.35 (m, 3H), 7.04 (t, J=7.9 Hz, 1H).  
       EXAMPLE 3  
     1-(2-(3-aminophenoxy)ethyl)pyrrolidine  
       [0257]     A mixture of 1-(2-(3-nitrophenoxy)ethyl)pyrrolidine (3.49 g, 14.8 mmol), 10% palladium on carbon (400 mg) and ethyl acetate (20 ml) was reduced under 50 psi hydrogen for 10 h. The reaction mixture was filtered through Celite 545 and the product extracted into 1M HCl (3×20 ml). The acidic layer was washed with ether (2×20 ml) and then the pH adjusted to &gt;10 with 2M NaOH. The aqueous layer was extracted with ether (3×20 ml), dried over MgSO 4  and concentrated in vacuo. The product was eluted through a silica gel pad (75% ethyl acetate/hexane/1% Et 3 N) to yield the product as a pale yellow oil.  
         [0258]     MS 207 (MH + )  
         [0259]      1 H NMR (CDCl 3 ) δ1.72-1.80 (m, 2H), 2.54-2.71 (m, 2H), 2.88 (t, J=8.2 Hz, 2H), 3.48-3.79 (br s, 2H), 4.07 (t, J=8.2 Hz, 2H), 6.22-6.39 (m, 3H), 7.05 (virtual t, J=9.1 Hz, 1H).  
       EXAMPLE 4  
     N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-cis-3-(triphenylmethylamino)cyclohexylcarboxamide  
       [0260]     Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBop) (4.8 g, 9.3 mmol) was added to a mixture of N-trityl-cis-3-aminocyclohexanecarboxylic acid (3.3 g, 8.4 mmol), 1-(2-(3-aminophenoxy)ethyl)pyrrolidine (1.4 g, 7.0 mmol), DIEA (1.6 ml, 9.3 mmol) and dichloromethane (30 ml). After stirring overnight, the crude mixture was evaporated onto silica gel and purified by flash chromatography (20% EtOAc/2% Et 3 N/hexane, then 60% EtOAc/2% Et 3 N/hexane). The title compound was isolated as a white foam upon evaporation.  
         [0261]     Yield: 3.2 g, 78%  
         [0262]     MS 596 (MNa + ), 574 (MH + ), 332 (MH + -trt), 243 (trt + ).  
       EXAMPLE 5  
     N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-cis-3-(triphenylmethylamino)cyclohexylmethylamine  
       [0263]     LAH (220 mg, 5.8 mmol) was added to N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-cis-(3-(triphenylmethyl)amino)cyclohexylmethyl-carboxamide (2.1 g, 3.7 mmol) in THF (10 ml) under nitrogen at ambient temperature. The reaction was refluxed for 8 h, cooled to room temperature and quenched with a saturated solution of Rochelle&#39;s salt (potassium sodium tartrate). The precipitate was filtered away through Celite 545 leaving the crude product as an oil upon evaporation. The residue was dissolved in EtOAc (20 ml), washed with water (2×20 ml) and dried over MgSO 4 . Evaporation of the solvent yielded the product as a white foam.  
         [0264]     MS 582 (MNa + ), 560 (MH + ), 318 (MH + -trt), 243 (trt + ).  
       EXAMPLE 6  
     N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-[cis-3-(triphenylmethylamino)cyclohexylmethyl]-4-fluorophenylcarboxamide  
       [0265]     4-fluorobenzoyl chloride (0.34 ml, 2.9 mmol) in dichloromethane (5 ml) was added dropwise to a solution of N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-cis-3-(triphenylmethylamino)cyclohexylmethylamine (1.4 g, 2.6 mmol), triethylamine (0.40 ml, 2.9 mmol) and dichloromethane (10 ml). After 3 h the reaction was quenched with 2M NaOH (3 ml) and extracted with DCM (3×20 ml). The organic layers were combined, dried over MgSO 4  and evaporated onto silica gel in vacuo. The product was purified by chromatography on a silica gel column, preconditioned with Et 3 N, using 50% EtOAc/2% Et 3 N/hexane. The product was isolated as a white foam.  
         [0266]     MS 682 (MH + ), 440 (MH + -trt), 243 (trt + ).  
       EXAMPLE 7  
     N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-[cis-(3-aminocyclohexyl)methyl]-4-fluorophenylcarboxamide  
       [0267]     10% TFA/1% triethylsilane/DCM (35 ml) was added to N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-[cis-3-(triphenylmethylamino)cyclohexylmethyl]-4-fluorophenylcarboxamide (1.75 g, 2.57 mmol). Upon completion, after 3 h, the desired product was extracted into 1 M HCl (3×20 ml). The extracts were washed with DCM (2×20 ml) and the aqueous layer (cooled to 0 C) made basic with NaOH. Extraction of the aqueous layer with EtOAc (3×20 ml) yielded, upon drying (MgSO 4 ) and evaporation, the product as a pale yellow oil.  
         [0268]     MS 462 (MNa + ), 440 (MH + ).  
       EXAMPLE 8 
       [0269]    
       
                 
         
             
             
         
       
     
         [0270]     To a stirred solution of N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-amino-cyclohexyl)methyl-4-fluorophenylcarboxamide (1.0 g, 2.3 mmol) and benzaldehyde (0.26 ml, 2.5 mmol) in toluene (4 ml) was added titanium(IV) isopropoxide (0.82 ml, 2.8 mmol) under nitrogen. After 18 h, EtOH (0.8 ml) was added followed by portionwise addition of sodium triacetoxyborohydride (0.63 g, 2.8 mmol). After an additional 4 h of stirring, the reaction was quenched with 2M NaOH. The precipitate was filtered off through Celite 545, then dried over MgSO 4  and evaporated in vacuo to yield crude N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(benzylamino)cyclohexyl)methyl-4-fluorophenylcarboxamide.  
         [0271]     The crude residue (1.2 g) was taken up in DCM (4 ml), followed by addition of trimethylacetyl chloride (0.31 ml, 2.5 mmol). The reaction was complete in less than 2 h. The reaction was neutralized with a saturated solution of NaHCO 3 , extracted with DCM (3×10 ml), dried over MgSO 4  and evaporated onto silica gel. The product was purified by flash chromatography (50% EtOAc/1% Et 3 N/hexane) to yield a white foam (690 mg). Addition of 1M HCl (1.2 ml, 1.2 mmol) in ether to the free base in ether (5 ml) yielded the product.  
         [0272]     MS 614 (MH + ); HPLC (RT 4.11 min.)  
       EXAMPLE 9  
     N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(triphenylmethylamino)cyclohexyl)methyl-N′-phenylurea  
       [0273]     Phenylisocyanate (0.31 ml, 2.9 mmol) was added dropwise to a solution of N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(triphenylmethylamino)-cyclohexyl)methylamine (1.4 g, 2.6 mmol) in dichloromethane (5 ml). After stirring for 18 h, the reaction mixture was evaporated onto silica gel. The title product was isolated by chromatography (50% EtOAc/hexane, then 60% EtOAc/2% Et 3 N/hexane) as a white foam.  
         [0274]     MS 679 (MH + ), 437 (MH + -trt), 243 (trt + ).  
       EXAMPLE 10 
       [0275]    
       
                 
         
             
             
         
       
     
         [0276]     By the method of example 7 and 8, N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(triphenylmethyl)aminocyclohexyl)methyl-N′-phenylurea, benzaldehyde and trimethylaacetyl chloride were reacted to yield the title compound.  
         [0277]     MS 437 (MH + ).  
       EXAMPLE 11  
     N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-[(cis-3-(3-nitrobenzyl)aminocyclohexylmethyl]-4-fluorophenylcarboxamide  
       [0278]     To a stirred solution of N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis-3-aminocyclohexyl)methyl-4-fluorophenylcarboxamide (5.3 g, 12 mmol) and 3-nitrobenzaldehyde (2.0 g, 13 mmol) in DCM (30 ml) was added titanium(IV) isopropoxide (4.6 ml, 16 mmol) under nitrogen. After 3 h, EtOH (20 ml) was added followed by portionwise addition of sodium cyanoborohydride (1.0 g, 16 mmol). The reaction was stirred overnight, then quenched with 2M NaOH. The resulting precipitate was filtered off through Celite 545, the filtrate was dried over MgSO 4  and evaporated in vacuo to yield crude product. MS 591 (MH + ).  
       EXAMPLE 12 
       [0279]    
       
                 
         
             
             
         
       
     
         [0280]     Trichloroacetyl chloride (0.93 ml, 8.3 mmol) was added to crude N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-[(cis-3-(3-nitrobenzyl)aminocyclohexylmethyl]4-fluorophenylcarboxamide (4.9 g, 8.3 mmol) taken up in DCM (20 ml). The reaction was complete in less than 2 h. The reaction was neutralized with a saturated solution of NaHCO 3 , extracted into DCM (3×15 ml), dried over MgSO 4  and evaporated onto silica gel. The product was purified by chromatography (50% EtOAc/2% Et 3 N/hexane) to yield the title compound as a white foam.  
         [0281]     MS 736 (MH + ); HPLC (RT 4.11 min.).  
       EXAMPLE 13  
     N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-{(cis3-(benzylamino)cyclohexyl)methyl}-N′-phenylurea  
       [0282]     By the method of example 11, N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis -3-aminocyclohexyl)methyl-N′-phenylurea and benzaldehyde were converted into the title compound.  
         [0283]     MS 543 (MH + ).  
       EXAMPLE 14 
       [0284]    
       
                 
         
             
             
         
       
     
         [0285]     By the method of example 9, N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-{(cis-3-(benzylamino)cyclohexyl)methyl}-N′-phenylurea and phenylisocyanate were converted into the title compound.  
         [0286]     MS 662 (MH + ); HPLC (RT 4.38 min.).  
       EXAMPLE 15 
       [0287]    
       
                 
         
             
             
         
       
     
         [0288]     By the method of example 12, N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-{(cis-3-(benzylamino)cyclohexyl)methyl}-N′-phenylurea and 2-naphthalenesulfonyl chloride were converted into the title compound.  
         [0289]     MS 733 (MH + ); HPLC (RT 4.97 min.).  
       EXAMPLE 16 
       [0290]    
       
                 
         
             
             
         
       
     
         [0291]     By the method of example 12, N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-cis -3-(aminocyclohexyl)methyl}-N′-phenylurea and trichloroacetyl chloride were converted into the title compound.  
         [0292]     MS 599 (MH + ); HPLC (RT 3.59 min.).  
       EXAMPLE 17  
     1-(2-(3-amino-2-methylphenoxy)ethyl)pyrrolidine  
       [0293]     By the method of examples 2 and 3,1-(2-chloroethyl)pyrrolidine hydrochloride and 2-methyl-3-nitrophenol were converted into the title compound.  
         [0294]     MS 221 (MH + )  
         [0295]      1 H NMR (CDCl 3 ) δ1.75-1.86 (m, 4H), 2.05 (s, 3H), 2.62-2.67 (m, 4H), 2.92 (t, J=6.0 Hz, 2H), 3.60 (br s, 2H), 4.09 (t, J=6.0 Hz, 2H), 6.33 (virtual d, J=8.1 Hz, 2H), 6.95 (virtual t, J=9.1 Hz, 1H).  
       EXAMPLE 18  
     4-(2-(3-aminophenoxy)ethyl)morpholine  
       [0296]     By the method of examples 2 and 3,4-(2-chloroethyl)morpholine hydrochloride and 3-nitrophenol were converted into the title compound.  
         [0297]     MS 223 (MH + )  
       EXAMPLE 19  
     N-(4-fluorophenylmethyl)-4-(2-(3-aminophenoxy)ethyl)morpholine  
       [0298]     4-fluorobenzaldehyde (1.3 ml, 12 mmol) was added to a stirred solution of 4-(2-(3-aminophenoxy)ethyl)morpholine (2.2 g, 10 mmol) in 2% AcOH/MeOH (40 ml). After 1 h, sodium cyanoborohydride (0.50 g, 12 mmol) was added portionwise to the mixture. After an additional 2 h, 2M NaOH (20 ml) was added and the mixture evaporated to give a tan residue. The residue was partitioned between 1N HCl and ether. The acid layer was washed 2×40 ml with ether and then adjusted to a pH&gt;10 with NaOH. The product was extracted into ethyl acetate (3×50 ml), dried over magnesium sulfate and evaporated down to yield the title compound as a brown oil.  
         [0299]     MS 331 (MH + )  
         [0300]      1 H NMR (CDCl 3 ) δ 2.50-2.65 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 3.68-3.82 (m, 4H), 4.01-4.16 (m, 3H), 4.29 (d, J=5.3 Hz, 2H), 6.18 (s, 1H), 6.22-6.33 (m, 2H), 6.97-7.13 (m, 3H), 7.29-7.40 (m, 2H).  
       EXAMPLE 20 
       [0301]    
       
                 
         
             
             
         
       
     
         [0302]     N-(4-fluorophenylmethyl)-4-(2-(3-amino-phenoxy)ethyl)morpholine (260 mg, 0.79 mmol) and glutaric anhydride (95 mg, 0.79 mmol) were combined and refluxed in chloroform (3 ml) overnight. To the organic solution at ambient temperature was added, N-benzylphenethylamine (170 mg, 0.79 mmol), DIEA (0.28 ml, 1.6 mmol) and PyBOP (420 mg, 0.80 mmol). The sample was concentrated down upon completion (&lt;3 h). Chromatography on silica gel with 1% MeOH in ethyl acetate provided the title compound.  
         [0303]     MS 638 (MH + ); HPLC (RT 4.32 min.)  
         [0304]      1 H NMR (CDCl 3 ) (approximately 1:1 mixture of rotomers) δ 1.85-2.01 (m, 2H), 2.08-2.22 (m, 2H), 2.26-2.43 (m, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.9-3.13 (m, 2H), 3.32-3.74 (m, 6H), 3.88-4.05 (m, 4H), 4.24-4.42 (m, 3H), 4.54 (s, 1H), 4.75-4.88 (m, 2H), 6.45 (s, 1H), 6.59 (t, J=6.2 Hz, 1H), 6.78-7.00 (m, 3H), 7.03-7.39 (m, 13H).  
       EXAMPLE 21  
     N-(3-nitrophenyl)methyl)phenethylamine  
       [0305]     Sodium cyanoborohydride (0.18 g, 2.7 mmol) was added to a preformed imine of phenethylamine (0.28 g, 2.3 mmol) and 3-nitrobenzaldehyde (0.38 g, 2.5 mmol) in 2% AcOH-MeOH. The reaction was quenched after 4 h with a saturated solution of sodium bicarbonate and the solvent removed in vacuo. The resultant residue was partitioned between water and dichloromethane (20 ml total). The aqueous layer extracted with DCM (3×20 ml), the organic extracts were combined and dried over sodium sulfate. The crude material was used without further purification.  
         [0306]     MS 257 (MH + ).  
       EXAMPLE 22  
     N-(4-fluorophenyl)methyl)-N-[3-(2-(1-pyrrolidino)ethyloxy)-2-methylphenyl]-N′-(2-phenethyl)-1,5-pentyldiamide  
       [0307]     A solution of N-(4-fluorophenylmethyl)-1-(2-(3-amino-2-methylphenoxy)-ethyl)pyrrolidine (4.85 g, 14.8 mmol) and glutaric anhydride (2.02 g, 17.7 mmol) in toluene (30 ml) was heated to reflux. After 12 h the reaction was concentrated in vacuo. PyBop (430 mg, 0.81 mmol) was added to the solution of crude N-(4-fluorophenylmethyl)-N-3-(2-(1-pyrrolidino)ethyloxy)-2-methylphenylcarboxamidopentyric acid (330 mg, 0.74 mmol) and phenethylamine (90 mg, 0.74 mmol) in DMF (2 ml). The reaction mixture was stirred overnight, diluted with 2 M NaOH and then extracted with ether (3×20 ml). The combined extracts were washed with a brine solution and dried over MgSO 4 . The crude material was purified by flash chromatography on silica gel using 80% ethyl acetate/2% Et 3 N/hexane as eluent to yield the title compound as a brown oil. MS 546 (MH + ).  
       EXAMPLE 23 
       [0308]    
       
                 
         
             
             
         
       
     
         [0309]     60% sodium hydride (˜3 mg, 0.07 mmol) was added to N-(4-fluorophenyl)methyl)-N-[3-(2-(1-pyrrolidino)ethyloxy)-2-methylphenyl]-N′-(2-phenethyl)-1,5-pentyldiamide (30 mg, 0.06 mmol) in DMF (1 ml). After 10 min, methyl-3-(bromomethyl)benzoate (16 mg, 0.07 mmol) was added to the stirred solution. The reaction was quenched with sodium bicarbonate after 18 h and then extracted (3×15 ml) into ether. The title product was isolated by semi-prep HPLC (C-18 column, 30% CH 3 CN/water/0.1% TFA to 60% CH 3 CN/water/0.1% TFA). Note: the methyl ester was hydrolyzed under the acidic mobile phase conditions.  
         [0310]     MS 680 (MH + ); HPLC (RT 3.53 min.)  
       EXAMPLE 24  
       [0311]     N-(3-tert-butyldimethylsiloxyphenyl)-4-fluorobenzylamine  
         [0312]     By the method of example 19, 4-fluorobenzaldehyde (4.41 g, 35.5 mmol) and 3-aminophenol (3.60 g, 32.3 mmol) were reacted to yield a clear oil (6.75 g) upon silica gel purification (15% ethyl acetate/hexane).  
         [0313]     MS 218 (MH + ).  
         [0314]     The resultant N-3-hydroxyphenyl-4-fluorobenzylamine (4.25 g, 19.6 mmol) and imidazole (1.33 g, 19.6 mmol) were combined in DMF (20 ml) and treated with tetrabutyldimethylsilyl chloride (3.05 g, 19.6 mmol). After 5 h, the reaction was diluted with saturated NaHCO 3  and extracted with ether. The ether layers were combined, washed with water and dried over MgSO 4 . The title product was isolated by flash chromatography (15% EA/hexane) as a clear oil (3.75 g, 58%).  
         [0315]     MS 332 (MH + )  
         [0316]      1 H NMR (CDCl 3 ) δ 0.12 (s, 6H), 0.81 (s, 9H), 3.84 (br s, 1H), 4.12 (s, 2H), 5.96 (t, J=2.2 Hz, 1H), 6.10 (td, J=8.0, 2.2 Hz, 2H), 6.84-6.91 (m, 3H), 7.16-7.21 (m, 2H).  
       EXAMPLE 25  
     N-((4-fluorophenyl)methyl)-N-(3-hydroxyphenyl)-N′-(2-phenethyl)-N′-benzyl-1,5-pentyldiamide (#175)  
       [0317]     N-(4-fluorophenyl)methyl)-N-(3-tert-butyldimethylsiloxyphenyl)-N′-(2-phenethyl)-N′-benzyl-1,5-pentyldiamide (4.2 g, 6.6 mmol), prepared by method of example 20, in THF (10 ml) was treated with 1 M TBAF (7.3 ml, 7.3 mmol). The reaction, complete in less than 15 h, was quenched with 0.1 M HCl. The aqueous layer was extracted with ethyl acetate (3×30 ml) and the organic layers dried over MgSO 4 . The crude material was purified by flash chromatography using 50% ethyl acetate/hexane as eluent. The title compound was recovered as a clear oil.  
         [0318]     MS 525 (MH + )  
         [0319]      1 H NMR (CDCl 3 ) (approximately 1:1 mixture of rotomers) δ 1.84-2.02 (m, 2H), 2.08-2.21 (m, 2H), 2.25 (t, J=7.3 Hz, 1H), 2.34 (t, J=7.3 Hz, 1H), 2.72-2.86 (m, 2H), 3.38-3.59 (m, 2H), 4.37 (s, 1H), 4.55 (s, 1H), 4.76 (s, 1H), 4.78 (s, 1H), 6.40 (t, J=7.7 Hz, 1H), 6.52 (m, 1H), 6.77-6.93 (m, 3H), 7.03-7.39 (m, 13H), 8.41 (s, 1H).  
       EXAMPLE 26 
       [0320]    
       
                 
         
             
             
         
       
     
         [0321]     To N-(4-fluorophenyl)methyl)-N-(3-hydroxyphenyl)-N′-(2-phenethyl)-N′-benzyl-1,5-pentyldiamide (75 mg, 0.14 mmol) in THF (1 ml) was added 1-(2-hydroxyethyl)piperazine (22 mg, 0.17 mmol), tri-n-butylphosphine (0.14 ml, 0.57 mmol), and ADDP (86 mg, 0.34 mmol). After 18 h the reaction was diluted with a solution of saturated sodium bicarbonate and then extracted into ethyl acetate (3×15 ml). The combined organic layers were dried over MgSO 4  and evaporated down to an oil. The title product was isolated by semi-prep HPLC (C-18 column, 30% CH 3 CN/water/0.1% TFA to 60% CH 3 CN/water/0.1% TFA).  
         [0322]     MS 637 (MH + ); HPLC (RT 3.34 min.).  
       EXAMPLE 27  
     N-[3-(2-(4-morpholino)ethoxy)phenyl]-N′-(2-phenethyl)-N′-benzyl-1,4-butyldiamide  
       [0323]     Applying the procedure used in Example 20, with substitution of 4-(2-(3-aminophenoxyethyl)morpholine and succinic anhydride for N-(4-fluorophenylmethyl)-4-(2-(3-aminophenoxy)ethyl)morpholine and glutaric anhydride respectively, yielded the title compound as a white solid.  
         [0324]     MS 516 (MH + )  
       EXAMPLE 28 
       [0325]    
       
                 
         
             
             
         
       
     
         [0326]     N-[3-(2-(4-morpholino)ethoxy)phenyl]-N′-(2-phenethyl)-N′-benzyl-1,4-butyldiamide (0.39 g, 0.75 mmol) was dissolved in a solution of sodium borohydride (0.14 g, 3.8 mmol) in THF (4 mL). Acetic acid (0.22 ml, 3.75 mmol) was slowly added to the reaction mixture at 0° C. After 18 h, the reaction was quenched with 1N HCl, neutralized with saturated sodium bicarbonate and the THF layer collected. The organic layer was dried over MgSO 4 , filtered and then treated with phenyl isocyanate (0.080 ml, 0.75 mmol) to yield crude solid product. The crude material was purified by flash chromatography using 50% ethyl acetate/hexane as eluent. The title compound was recovered as a clear oil.  
         [0327]     MS 621 (MH + );  
         [0328]      1 H NMR (CD 3 OD) (approximately 1:1 mixture of rotomers) δ 1.72-1.97 (m, 2H), 2.25 (t, J=6.8 Hz, 1H), 2.45 (t, J=6.8 Hz, 1H), 2.73-2.94 (m, 2H), 3.18-3.42 (m, 2H), 3.48-3.91 (m, 10H), 3.97-4.15 (m, 2H), 4.40 (t, J=4.9 Hz, 2H), 4.49 (s, 1H), 4.63 (s, 1H), 6.89-7.06 (m, 4H), 7.09-7.48 (m, 15H).  
       EXAMPLE 29  
     2,2-dimethylpropylbenzylamine  
       [0000]     Step A: N-3-chlorobenzyltrimethylacetamide  
         [0329]     3-chlorobenzylamine (3.54 g, 25 mmol) was added dropwise to trimethylacetyl chloride (2.65 ml, 21.5 mmol) and Et 3 N (3.5 ml, 25 mmol) in DCM (25 ml). After two hours, the reaction mixture was washed with 1N HCl and the organic layer collected and dried over MgSO 4 . N-3-chlorobenzyltrimethylacetamide was precipitated from DCM/hexane as a white solid, 3.95 g,  
         [0330]     MS 192 (MH + ).  
         [0000]     Step B:  
         [0331]     N-benzyltrimethylacetamide (2.35 g, 12.3 mmol) in THF (10 ml) was refluxed with 1M borane-tetrahydrofuran (13.5 ml) for 15 hours. The reaction was quenched with 1N HCl, washed with ether, and the aqueous layer adjusted to a pH&gt;10. The aqueous layer was extracted with EtOAc and the organic layers combined and dried over MgSO 4 .  
         [0332]     The title compound may be alternatively be prepared according to the procedure described in Overman, Larry E.; Burk, Robert M.; TELEAY;  Tetrahedron Lett.;  25; 16; 1984; 1635-1638  
       EXAMPLE 30 
       [0333]    
       
                 
         
             
             
         
       
     
         [0334]     EDCI-MeI (0.33 g, 1.1 mmol) was added to N-(4-fluorophenylmethyl)-4-(2-(3-aminophenoxy)ethyl)morpholine (0.27 g, 0.83 mmol) (Prepared in Example 19), and Fmoc-L-Phe-OH (0.39 g, 1.0 mmol) in CHCl 3  (15 mL). After 8 h, the reaction was diluted with a saturated solution of NaHCO 3 , extracted with DCM and dried over MgSO 4 . The desired product was isolated by flash chromatography (50-100% EA/hexane) to yield a white solid.  
         [0335]     MH+700.  
       EXAMPLE 31 
       [0336]    
       
                 
         
             
             
         
       
     
       #152  
       [0337]     The product prepared in Example 29, (31 mg, 0.044 mmol) was dissolved in DCM (1 mL) and deprotected with piperidine (7.4 μl, 0.082 mmol) to yield a white solid upon evaporation.  
         [0338]     MH+478.  
         [0339]     The crude product was then dissolved along with benzaldehyde (16 μl, 0.16 mmol) in 2% AcOH/MeOH (1 ml). To this solution was added NaBH 3 CN (20 mg, 0.32 mmol) in two portions. After 1 h, the solvent was evaporated and the residue partitioned between 1N HCl and ether. The aqueous layer was washed with ether, adjusted to pH ˜10 with 2N NaOH and extracted with DCM. The organic layer was dried over MgSO 4  and evaporated down. Hydrocinnamoyl chloride (12 μl, 0.08 mmol) was then added to the residue dissolved in DCM (2 ml) and DIEA (16 μl, 0.09 mmol). The title compound was isolated by semi-prep HPLC as the TFA salt.  
         [0340]     MH+700; HPLC (RT 5.16 mins).  
       EXAMPLE 32 
       [0341]    
       
                 
         
             
             
         
       
     
         [0342]     4-(2-(3-amino-phenoxy)ethyl)morpholine (389 mg, 1.75 mmol) and methyl 3-bromomethylbenzoate (482 mg, 2.1 mmol) were reacted in CHCl 3  (5 mL), that contained Et 3 N (293 μl, 2.1 mmol). The reaction was refluxed for 16 h, until completion, as evidenced by disappearance of the starting aniline derivative on TLC (Rf 0.5 for product, ethyl acetate eluent)).  
         [0343]     MS (MH + ) 371  
         [0344]     The reaction mixture was cooled and then treated with Et 3 N (293 μl, 2.1 mmol) and 4-fluorobenzoyl chloride (207 μl, 1.75 mmol). Upon completion, the reaction mixture was quenched with 1N NaOH and extracted 3 times with DCM. The organic layer was dried over MgSO 4  and evaporated down onto silica gel.  
         [0345]     The title compound was isolated by flash chromatography (gradient from 80% EA/hexane to 100% EA) to yield a white solid.  
         [0346]     MS (MH + ) 493  
       EXAMPLE 33 
       [0347]    
       
                 
         
             
             
         
       
     
         [0348]     The compound prepared in Example 31 (375 mg, 0.82 mmol) was refluxed in a mixture of 10% NaOH/EtOH (30 ml). After 2 h, the EtOH was evaporated under vacuum. The residue was diluted with 2N NaOH and washed with ether. The aqueous layer was then acidified to pH 1 with concentrated HCl and extracted with DCM. The organic layer was dried over MgSO4 and evaporated down. The residue was dissolved in DCM (10 mL) and partitioned into ten aliquots. One aliquot was treated with phenethylamine (12 mg, 0.10 mmol) and EDCI-MeI (29 mg, 0.10 mmol). After 16 h, the reaction mixture was washed 2× with water and evaporated down to yield a brown residue. The title compound was isolated by semi-prep HPLC (reverse phase, C-18) as the TFA salt.  
         [0349]     MH+582; HPLC (RT 3.41 mins).  
       EXAMPLE 34  
     N-3-cyanocyclopentyl-4-(2-(3-amino-phenoxy)ethyl)morpholine  
       [0350]     4-(2-(3-aminophenoxy)ethyl)morpholine (2.15 g, 9.67 mmol) and 3-cyanocyclopentanone (1.06 g, 9.67 mmol) (prepared according to the process decsribed by Della, E.; Knill, A.;  Aust. J. Chem.;  47; 10; 1994; 1833-1842) were combined in 1% AcOH/MeOH (50 ml). To this solution was added NaBH 3 CN (925 mg, 14.5 mmol) in portions. After 12 h, the solvent was evaporated off and the residue partitioned between saturated NaHCO 3  and ethyl acetate. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over MgSO 4  and evaporated down. The title compound was purified by flash chromatography with ethyl acetate as the eluent, 2.1 g  
         [0351]     MS (MH + ) 316.  
       EXAMPLE 35 
       [0352]    
       
                 
         
             
             
         
       
     
         [0353]     Phenylisocyanate (0.65 ml, 5.9 mmol) was added to N-3-cyanocyclopentyl-4-(2-(3-amino-phenoxy)ethyl)morpholine (1.88 g, 5.95 mmol) partially dissolved in THF (25 ml) at room temperature. After 15 h, crude material was placed on a silica gel column and eluted with ethyl acetate to give 680 mg of a yellow oil.  
         [0354]     MS (MH + ) 435.  
       EXAMPLE 36 
       [0355]    
       
                 
         
             
             
         
       
     
         [0356]     The product prepared in Example 34 (0.65 g, 1.5 mmol) dissolved in THF (10 ml) was added to 1M LAH (4.5 ml) at −78° C. and allowed to warm to room temperature. After 15 h, the reaction was quenched with a saturated solution of Rochelle&#39;s salt (potassium sodium tartrate). The precipitate was filtered away through Celite 545 to yield the crude product as an oil upon evaporation. The residue was dissolved in EtOAc, washed with water and dried over MgSO 4 . Evaporation of the solvent yielded the product as an oil.  
         [0357]     (MH + ) 439  
       EXAMPLE 37 
       [0358]    
       
                 
         
             
             
         
       
     
         [0359]     Sodium cyanoborohydride (34 mg, 0.54 mmol) was added to the product prepared in Example 35 (78 mg, 0.18 mmol) and 3-chlorobenzaldehyde (40 μl, 0.36 mmol) in 1% AcOH/MeOH (2 ml). After 6 hours the reaction was acidified with 1N HCl, then neutralized with 2N NaOH and extracted into dichloromethane.  
         [0360]     (MH + ) 563.  
         [0361]     The organic layer was dried over MgSO 4 , cooled to 0° C. and then treated with trichloroacetyl chloride (20 μl, 0.18 mmol). The final product was isolated by flash chromatography (ethyl acetate).  
         [0362]     (MH + ) 707  
       EXAMPLE 38 
       [0363]    
       
                 
         
             
             
         
       
     
         [0364]     N-trityl-cis-3-aminocyclohexanecarboxylic acid (13.1 g, 34 mmol) was added to a solution of PyBop (17.7 g, 34 mmol) and DIEA (11.8 ml, 68 mmol) in DCM (70 mL) and stirred for 10 minutes. 1-(2-(3-aminophenoxy)ethyl)piperidine (6.8 g, 30.9 mmol) in DCM (30 mL) was added to the reaction mixture over the course of 20 mins. The coupled product was purified by flash chromatography (25% ethyl acetate/1% Et 3 N/hexane) and evaporated down to yield a white foam.  
         [0365]     The foam was dissolved in THF (100 mL), treated with LAH (1.3 g, 34 mmol) and refluxed for 7 hrs. Upon cooling, the reaction mixture was alternately quenched with NaOH and water to yield a granular solid. The heterogenous reaction mixture was then filtered through Celite 545. The reduced product was extracted into ether from water. The combined organic layers were dried over MgSO 4  and evaporated to dryness.  
         [0366]     The crude product and Et 3 N (4.7 ml, 34 mmol) were dissolved in DCM (100 mL). 4-fluorobenzoyl chloride (4.0 ml, 34 mmol) of was added dropwise to this solution. After 2 hours the reaction mixture was evaporated onto silica gel and then purified by flash chromatography (20% ethyl acetate/1% Et 3 N/hexane) to yield the title compound.  
       EXAMPLE 39 
       [0367]    
       
                 
         
             
             
         
       
     
         [0368]     The compound prepared as in Example 38, was dissolved in 20% TFA/1% TES/DCM and stirred for 1 hr. The reaction mixture was evaporated down to dryness. The crude material was partitioned between ether and 1N HCl. The aqueous solution was washed twice with ether, cooled to 0° C. and the pH adjusted to 12 with NaOH. The deprotected amine was extracted into DCM and dried over MgSO 4 .  
         [0369]     Following the procedure as described in Example 8, the deprotected amine, 3-chlorobenzaldehyde and trichloroacetyl chloride were reacted to yield the title compound. The enantiomers were separated using a Chiralpak AD HPLC column.  
       EXAMPLE 40 
       [0370]    
       
                 
         
             
             
         
       
     
         [0371]     N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis-3-aminocyclohexyl)methyl-4-fluorophenylcarboxamide (83 mg, 0.18 mmol) and 3,3-dimethylglutaric anhydride (28 mg, 0.20 mmol) were combined and heated at 90° C. in toluene (2 mL) for two hours. The reaction mixture was concentrated in vacuo and purified by semi-prep HPLC (C18 column, acetonitrile/water/0.1% TFA) to yield the title compound.  
       EXAMPLE 41 
       [0372]    
       
                 
         
             
             
         
       
     
         [0373]     N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis-3-aminocyclohexyl)methyl-4-fluorophenylcarboxamide (83 mg, 0.18 mmol) and phthalic anhydride (30 mg, 0.20 mmol) were dissolved in toluene (2 mL). The reaction was heated at 90° C. for two hours. To the reaction was then added acetic anhydride (0.2 ml, 2.1 mmol) and the reaction refluxed for an additional 15 hours. The reaction mixture was concentrated in vacuo and purified by semi-prep HPLC (C18 column, acetonitrile/water/0.1% TFA) to yield the title compound as a white solid.  
       EXAMPLE 42  
     In Vitro Testing  
       [0000]     Motilin Receptor Binding  
         [0374]     Rabbit colon was removed, dissected free from the mucosa and serosa, and diced into small pieces. The muscle tissue was homogenized in 10 volumes of 50 mM Tris-Cl, 10 mM MgCl 2 , 0.1 mg/ml bacitracin, and 0.25 mM Peflabloc, at pH 7.5 in a Polytron (29000 rpm, 4×15 seconds). The homogenate was centrifuged at 1000×g for 15 minutes and the supernatant discarded. The pellet was washed twice before being suspended in homogenizing buffer. The crude homogenate was resuspended through a 23 gauge needle before storing at −80° C. In a total volume of 0.5 ml, the binding assay contained the following components: buffer (50 mM Tris-Cl, 10 mM MgCl 2 , 1 mM EDTA, 15 mg/ml BSA, 5 mg/ml of pepstatin, leupeptin, aprotinin, and 0.15 mg/ml bacitracin), I 125  radio-labeled porcine motilin (50000-70000 cpm; specific activity 2000 Ci/mmole), test compound, and membrane protein. After 60 minutes at 30° C., the samples were cooled in ice, centrifuged in the cold at 13000×g for 1 minute. The pellet was washed twice with 1 ml of cold saline, the supernatant was aspirated, and the pellet at the bottom of the tube counted in a gamma counter. Non-specific binding was determined by the inclusion of 1 mM of unlabeled motilin. IC 50  values were determined from Kaleidograph curves.  
       EXAMPLE 43  
     In Vitro Testing  
       [0000]     Human Antrum Tissue  
         [0375]     Human antrum tissue from Analytical Biological Services (Wilmington, Del.) was prepared as a motilin receptor preparation in the following manner. The muscle tissue was homogenized in 10 volumes of 50 mM Tris-Cl, 10 mM MgCl 2 , 0.1 mg/ml bacitracin, and 0.25 mM Peflabloc, pH 7.5) in a Polytron (29000 rpm, 4×15 seconds). The homogenate was centrifuged at 1000×g for 15 minutes and the supernatant discarded. The pellet was washed twice before being suspended in homogenizing buffer. The crude homogenate was resuspended through a 23 gauge needle before aliquoting and storing at −80° C. The human cloned receptor was prepared from HEK 293 cells overexpressed with the motilin receptor. Cell pellets were thawed and resuspended in 2-3 volumes of homogenizing buffer (10 mM Tris-Cl, 0.2 mM MgCl 2 , 5 mM KCl, 5 μg/ml aprotinin, leupeptin, and pepstatin A, and 50 μg/ml bacitracin, pH 7.5) and allowed to sit on ice for 15-20 minutes. The suspension was homogenized on ice in a Dounce type homogenizer using 15 strokes. Sucrose and EDTA were added to a final concentration of 0.25M and 1 mM, respectively, and mixed with a few additional strokes. The material was centrifuged at 400×g for 5 minutes, and the supernatant saved. The pellet was re-resuspended twice with 5 ml homogenizing buffer and rehomogenized as before, and the supernatants combined. The supernatant was centrifuged at 100000×g for 1 hour. The pellet is retained and resuspended with 5 ml of homogenizing buffer through a 19 g and 25 g needle. The suspension is aliquoted and stored at −80° C. until used. The binding assay contains the following components (50 mM HEPES, 5 mM MgCl 2 , and 1 mM EGTA, pH 7.0, 15 mg/ml BSA, 10 μg/ml aprotinin, leupeptin, and pepstatin A, 0.25 mg/ml bacitracin, and 10 mM benzamidine), 125I-radiolabelled porcine motilin (50000-70000 cpm; specific activity 2000 Ci/mmol), test compound, and membrane protein. After 60 minutes at 30° C., the samples are placed on ice and centrifuged for 1 minute at 13000×g. The pellet is washed twice with 1 ml cold saline, and after removal of the final supernatant, the pellet at the bottom of the tube is counted in a gamma counter. Non-specific binding is measured by the inclusion of 1 μM unlabelled motilin. IC 50  values were determined from Kaleidograph curves.  
         [0376]     125I-Motilin Binding to Human Antral Stomach Membranes and the Human Cloned Receptor:  
                                                       Human Antrum IC 50  (nM)   1.0 ± 0.1           Human Cloned Receptor IC 50  (nM)   3.55 ± 0.05                      
 
       EXAMPLE 44  
     In Vivo Testing  
       [0000]     Rabbit Tissue Bath Procedure  
         [0377]     One New Zealand White rabbit (Covance) of either sex was euthanized with an IV injection of Sleepaway. The duodenum was quickly excised, the lumen rinsed with saline to clean, and the tissue placed in cold, aerated (95% O 2 -5% CO 2 ) Tyrodes buffer (NaCl 136.9 mM, KCl 2.7 mM, CaCl 2  1.8 mM, MgCl 2 1.04 mM, NaH 2 PO 4  0.42 mM, NaHCO 3  11.9 mM, Glucose 5.55 mM, pH 7.4). The duodenum, being kept moist at all times, was cleaned of any excess mesenteric tissue, and then cut into 3 cm segments starting at the proximal end. Sixteen tissue segments were usually prepared from each duodenum. These segments were tied on both ends with 3-0 silk suture (Ethicon). One end of the tissue was attached to an S-hook on a custom made glass support rod (Crown Glass Co., Somerville) and the rod plus tissue were placed in a 15 ml isolated tissue bath (Radnoti). The other end of the glass rod was attached to a Grass Force Displacement Transducer FT03. The tissue was maintained in room temperature Tyrodes buffer pH 7.4 and continually gassed with 95% O 2 -5% CO 2 . The tissues were adjusted to 1.0 g resting tension and maintained at that tension throughout the equilibration period. An MI2 Tissue Bath Computer was used to record and analyze data.  
         [0378]     The tissues were washed twice during a 30 minute equilibration period and readjusted to 1 g resting tension as necessary. After equilibration the tissues were challenged with 3 μM Carbachol (Carbamoylcholine Chloride-Sigma). After maximal contraction was attained, the tissues were washed 3 times with Tyrodes. The tissues were allowed a 20 minute resting/equilibration period, during which time they were washed once and readjusted to 1 g resting tension. The tissues were challenged a second time with 3 μM Carbachol, and this contraction was considered as maximal, or 100% contraction. The tissues were washed 3 times, equilibrated for 10 minutes, washed again and readjusted to 1 g resting tension. Vehicle or test compound in 30% DMSO-50 mM HEPES was added directly to the bath and the tissues were incubated for 20 minutes. Test compounds and vehicle were run in duplicate. The tissues were then challenged with 3 nM Porcine Motilin (Bachem) and when maximum contraction was attained another 3 μM aliquot of Carbachol was added to see if the test compound inhibited this contraction.  
         [0379]     The percent inhibition by test compound of the motilin induced contraction was calculated by first determining the ratio of the vehicle contractions with Motilin compared to the Carbachol contractions. This Tissue Adjustment Factor (TAF) was used to determine the value for the potential uninhibited contraction with Motilin for each tissue. The percent inhibition was then determined by dividing the actual Motilin contraction in treated tissues by the potential uninhibited contraction and subtracting this number from 1. IC 50  values were determined by graphing results with Kaleidograph graphing program.  
         [0380]     Tables 18 and 19 below list molecular weight, % Inhibition and IC 50  values measured for select compounds of the present invention.  
                                                                                                                                 TABLE 18                                       Rabbit                   Colon   Human Antrum                Mol. Wt.*   % Inh   IC 50     % Inh       Tissues            ID   Cal&#39;d   (MH + )   @1 mM   (μM)   @1 μM   IC 50  (μM)   IC 50  (μM)                    1   621   621   35                       2   656   656   9       3   620   620   35       4   624   624   75   0.69       5   635   635   40       6   634   634   24       7   638   638   42       8   545   545   18       9   580   580   27       10   544   544   29       11   548   548   0       12   594   594   4       13   558   558   21       14   562   562   25       15   531   531   21       16   566   566   21       17   530   530   12       18   534   534   0       19   545   545   5       20   580   580   8       21   544   544   34       22   548   548   23       23   607   607   48       24   642   642   6       25   606   606   23       26   621   621   22       27   656   656   22       28   620   620   13       29   624   624   18       30   559   559   17       31   594   594   39       32   558   558   12       33   562   562   16       34   573   573   7       35   608   608   17       36   572   572   32       37   576   576   11       39   709   707   4       40   662   662   11       41   677   677   58       42   627   627   50       43   675   675   74   0.73       44   697   697   4       45   692   692   67   1.16       46   737   737   32       47   723   721   23       48   637   637   67   0.656       49   817   817   37       50   757   757   32       51   711   711   73   0.65       52   661   661   45       53   709   709   52       54   731   731   42       55   726   726   48       56   771   771   27       57   733   733   15       58   706   705   38       59   757   755   23       60   757   755   65   0.66       61   718   717   55       62   756   755   58       63   723   721   55       64   738   737   32       65   733   732   80   0.035           0.027       66   757   755   39       67   688   687   75   0.957       68   689   688   73   0.66       69   572   572   0       70   547   547   0       71   643   643   43       72   598   597   40       73   549   549   25       74   693   693   29       75   633   633   19       76   587   587   26       77   537   537   19       78   585   585   10       79   607   607   39       80   602   602   34       81   647   647   56       82   783   783   0       83   723   723   3       86   697   697   16       90   692   691   95   0.49           &gt;0.3       91   601   600   36       92   760   758   80       93   736   735   100   0.09           0.0205       94   741   740   28       95   726   724   51       96   759   758   71   1.68           &gt;.03       97   721   720   56       98   760   758   75   0.76       99   760   758   62   0.572       100   709   708   78       101   774   774   59       102   729   729   47       103   734   734   2       104   712   712   30       105   664   664   80   0.39           0.03       106   714   714   69   1.05       107   820   820   29       108   676   676   70   0.815       109   760   760   27       110   718   718   35       111   726   724   72   0.88       112   740   740   70   0.48       113   695   695   51       114   700   700   49       115   678   678   26       116   630   630   61   0.772       117   680   680   17       118   726   726   58       119   786   786   22       120   642   642   69   0.954       121   684   684   37       122   691   690   64   0.84       123   736   736   8       124   640   640   70   0.904       125   665   665   25       128   624   624   75   0.23       129   638   638   90   0.058       130   610   610   8       131   623   622   19       132   658   658   10       133   672   672   6       134   626   626   0       135   694   694   8       136   672   672   43       137   644   644   30       138   582   582   36       139   586   586   13       140   638   638   45       141   672   672   21       142   670   670   17       143   596   596   0       144   638   638   54       145   590   590   35       146   654   654   32       147   688   688   61   0.49       148   622   622   19       149   699   699   27       150   680   680   0       151   713   712   1       152   700   700   0       153   636   636   89   0.081           0.03       154   692   692   62   0.41       155   676   676   34       156   554   554   18       157   642   642   16       158   601   600   37       159   652   652   83   0.275       160   652   652   61   0.96       161   664   664   22       162   672   672   85   0.178           0.021       163   658   658   85   0.174           0.019       164   624   624   84   0.194           0.048       165   624   624   63   0.55       166   636   636   23       167   674   674   42       168   640   640   36       169   638   638   97   0.046           0.24       170   638   638   81   0.163           0.185       171   650   650   63   0.462           0.23       172   688   688   40       173   654   654   84   0.29           0.28       174   692   691   0       175   525   525   0       176   636   636   32       177   640   640   52   &gt;1.0       178   624   624   100   0.07           0.015       179   637   637   85   0.24           0.023       180   622   622   99   0.014           0.011       181   596   596   100   0.093           0.012       182   636   636   94   0.022           0.053       183   661   661   2       184   711   711   6       185   671   671   0       186   722   722   0       187   610   610   100   0.229       188   650   650   100   0.247           0.092       189   652   652   70   0.3       190   666   666   99   0.2           0.067       191   622   622   27       192   638   638   15       193   650   650   7       194   596   596   23       195   624   624   62       196   636   636   100   0.006           0.004       197   667   667   85   0.009           0.0076       198   672   672   100   0.107       199   691   690   91   0.1       200   690   690   92   0.041       201   657   657   93   0.057           0.0168       202   691   690   100   0.33           0.23       203   649   649   98   0.24       204   662   662   89   0.029           0.003       205   683   683   76   0.1       206   688   688   60   0.77       207   636   636   87   0.064       208   734   733   91   0.009           0.048       209   724   722   84   0.059           0.021       210   689   688   90   0.086           0.024       211   720   719   100   0.014           0.072       212   710   708   89   0.058           0.036       213   675   674   84   0.058           0.027       214   614   614   95   0.029           0.024       215   680   680   100   0.084       216   600   600           100       217   634   634           98       218   661   660           98   0.024   0.035       219   706   705           98   0.0076       220   636   636           92   0.042       221   598   598           94       223   707   705   100   0.041       224   672   671   98   0.039       225   611   611   93   0.021       226   648   648           100   0.032   0.009       227   683   682           100   0.025       228   650   650           100   0.025       229   614   614   100   0.01       230   614   614   100   0.072       231   661   660           88   0.13       232   698   698   62       233   650   650   89   0.17       234   652   652   86   0.218       235   662       61       236   724       53       237   662       96   0.168       238   724       98   0.097       239   724           0.073       240   724           &gt;0.70       241   728       14       242   704       36       243   728       35       244   698       42       245   758       40       246   678       73       247   726       41       248   704       86   0.760       249   716       22       250   642       0       251   604       0       252   636       15       253   600       30       254   606       25       255   655       22       256   600       27       257   586       0       258   580       34       259   665       17       260   644       30       261   654       0       262   550       18       263   655       11       264   570       6       265   638       67       266   598       5       267   624       21       268   598       17                 *For compounds containing chlorine, listed Mol. Wt. values are provided for the most abundant isotope.             
 
         [0381]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 19 
               
               
                   
               
               
                   
               
               
                   
                 Cal&#39;d Mol. 
                   
                 % Inh @1 mM 
                 % Inh @1 mM 
               
               
                 ID 
                 Wt. 
                 MW (MH + ) 
                 (Rabbit colon) 
                 (Human antrum) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 38 
                 577.4 
                 576 
                 22 
                   
               
               
                 84 
                 542.7 
                 543 
                 12 
               
               
                 85 
                 577.2 
                 577 
                 28 
               
               
                 87 
                 611.6 
                 611 
                 22 
               
               
                 88 
                 592.8 
                 593 
                 0 
               
               
                 89 
                 561.7 
                 562 
                 3 
               
               
                 222 
                 619.8 
                 620 
                 83 
                 83 
               
               
                   
               
             
          
         
       
     
         [0382]     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.