CROSS REFERENCE TO RELATED APPLICATION 
     This application 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 which are hereby incorporated by reference. 
    
    
     FIELD OF THE INVENTION 
     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 
     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. 
     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. 
     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). 
     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. 
     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. 
     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 
     The present invention is directed to compounds of the formula (I): 
                        
 
wherein
 
     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; 
     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; 
     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 ; 
     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; 
     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 ; 
     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; 
     provided that A is not -1,3-cyclopentyl-1-ene-alkyl; 
     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; 
     Y is selected from the group consisting of —O—, —NH—, —S— and —SO 2 —; 
     n is an integer from 0 to 5; 
     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; 
     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; 
     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     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;
 
     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. 
     In a preferred embodiment of the present invention are those compounds of general formula (I) wherein: 
     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; 
     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; 
     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 ; 
     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; 
     provided that A is not -1,3-cyclopentyl-1-ene-alkyl; 
     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; 
     Y is —O—; 
     n is an integer from 0 to 3; 
     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; 
     R 5  is selected from the group consisting of hydrogen and lower alkyl; 
     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. 
     In a preferred embodiment are compounds of the general formula (I) wherein: 
     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; 
     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; 
     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 ; 
     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; 
     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; 
     Y is —O—; 
     n is an integer from 0 to 3; 
     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: 
                        
 
where p and t are integers from 1-6;
 
     R 5  is selected from hydrogen and lower alkyl; 
     and the pharmaceutically acceptable salts esters and pro-drug forms thereof. 
     In a more preferred embodiment of the present invention are compounds of the general formula (I) wherein 
     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; 
     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-trimethyl-cyclopentyl, cyclopentylethyl, (1-carboxymethyl-cyclopentyl)-methyl, 2-furyl, 2-pyridyl-(2-ethyl), 1-pyrrolidinyl-(2-ethyl), 2-theinylmethyl and 2-thienylethyl; 
     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 ; 
     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-; 
     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; 
     Y is selected from the group consisting of -3-O— and -4-O—; 
     n is an integer selected from 0, 2 or 3; 
     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; 
     R 5  is selected from the group consisting of hydrogen, 2-methyl and 6-methyl; 
     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. 
     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. 
     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. 
     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. 
     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. 
     In a class of the invention are compounds of the formula (I) wherein 
     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; 
     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; 
     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; 
     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-; 
     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; 
     Y is selected from the group consisting of -3-O— and −4-O—; 
     n is an integer selected from 2 or 3; 
     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; 
     R 5  is selected from the group consisting of hydrogen, 2-methyl and 6-methyl; 
     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. 
     In another class of the invention are compounds of the formula (I) wherein 
     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; 
     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; 
     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; 
     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-; 
     R 3  is selected from the group consisting of phenylamino, 4-fluorophenyl, 3-fluorobenzyl and 4-fluorobenzyl; 
     Y is -3-O—; 
     n is 2; 
     R 4  is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl and di(methyl)amino; 
     R 5  is selected from the group consisting of hydrogen, 2-methyl and 6-methyl; 
     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. 
     Particularly preferred are compounds of the formula (I) wherein 
     R 1  is selected from the group consisting of benzyl, 3-nitrobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl and 3-trifluoromethylbenzyl; 
     R 2  is selected from the group consisting of t-butyl, 2-(phenyl)ethyl, trichloromethyl, 2-(2-pyridyl)ethyl and 2-(2-thienyl)ethyl; 
     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; 
     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-; 
     R 3  is selected from the group consisting of phenylamino, 4-fluorophenyl, 3-fluorobenzyl and 4-fluorobenzyl; 
     Y is -3-O—; 
     n is 2; 
     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; 
     and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. 
     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. 
     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. 
     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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 R 3   
                 Y 
                 n 
                 R 4   
                 R 5   
               
               
                   
               
               
                 129 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 159 
                 benzyl 
                 3-(phenyl)propyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 162 
                 3-chlorobenzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 169 
                 benzyl 
                 2-(phenyl)ethyl 
                 3-fluorobenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 170 
                 benzyl 
                 2-(phenyl)ethyl 
                 2-fluorobenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 171 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-methoxybenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 172 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-trifluoromethylbenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 173 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-chlorobenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 175 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O— 
                 0 
                 H 
                 H 
               
               
                 176 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 2-oxo-pyrrolidin-1-yl 
                 H 
               
               
                 177 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 dimethylamino 
                 H 
               
               
                   
                   
                   
                   
                   
                   
                 ethyloxyethyl 
               
               
                 178 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 diethylamino 
                 H 
               
               
                 179 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-piperazinyl 
                 H 
               
               
                 180 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                 181 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 dimethylamino 
                 H 
               
               
                 182 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-piperidinyl 
                 H 
               
               
                 187 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 3 
                 dimethylamino 
                 H 
               
               
                 188 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 3 
                 1-piperidinyl 
                 H 
               
               
                 191 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 4-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                 192 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 4-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 193 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 4-O 
                 3 
                 1-piperidinyl 
                 H 
               
               
                 194 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 4-O 
                 2 
                 dimethylamino 
                 H 
               
               
                 195 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 4-O 
                 2 
                 diethylamino 
                 H 
               
               
                 196 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 2-methyl 
               
               
                 197 
                 3-nitrobenzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                 198 
                 3-chlorobenzyl 
                 3-methoxybenzyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                 199 
                 3,5-dichlorobenzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                 200 
                 3-trifluoromethylbenzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                 201 
                 3-chlorobenzyl 
                 2-(2-pyridyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                 202 
                 3-chlorobenzyl 
                 2-(4-chlorophenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                 203 
                 3-chlorobenzyl 
                 2-(1-pyrrolidinyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                 204 
                 3-chlorobenzyl 
                 2-(2-thienyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 H 
               
               
                 205 
                 3-nitrobenzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 206 
                 3-chlorobenzyl 
                 3-methoxybenzyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 H 
               
               
                 207 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 6-methyl 
               
               
                 215 
                 2-(phenyl)ethyl 
                 3-carboxybenzyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 1-pyrrolidinyl 
                 2-methyl 
               
               
                 234 
                 benzyl 
                 2-(phenyl)ethyl 
                 4-fluorobenzyl 
                 3-O 
                 2 
                 4-morpholinyl 
                 2-methyl 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 A 
                 R 3   
               
               
                   
               
               
                 154 
                 ben- 
                 2-(phe- 
                 2-cyclopentenyl-1,3-n-propyl 
                 4-fluorobenzyl 
               
               
                   
                 zyl 
                 nyl)ethyl 
               
               
                 155 
                 ben- 
                 2-(phe- 
                 cis-1,2-cyclohex-4-enyl 
                 4-fluorobenzyl 
               
               
                   
                 zyl 
                 nyl)ethyl 
               
               
                 156 
                 ben- 
                 2-(phe- 
                 1,2-cylopentenyl 
                 H 
               
               
                   
                 zyl 
                 nyl)ethyl 
               
               
                 160 
                 ben- 
                 2-(phe- 
                 1,3-n-butyl 
                 4-fluorobenzyl 
               
               
                   
                 zyl 
                 nyl)ethyl 
               
               
                 189 
                 ben- 
                 2-(phe- 
                 2-methyl-(1,3-propyl) 
                 4-fluorobenzyl 
               
               
                   
                 zyl 
                 nyl)ethyl 
               
               
                 190 
                 ben- 
                 2-(phe- 
                 1,1-dimethyl-(1,3-propyl) 
                 4-fluorobenzyl 
               
               
                   
                 zyl 
                 nyl)ethyl 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 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-methyl- 
                 ethyl 
                 CO 
                 phenylamino 
               
               
                   
                 benzyl 
               
               
                 31 
                 4-methyl- 
                 ethyl 
                 SO 2   
                 4-methylphenyl 
               
               
                   
                 benzyl 
               
               
                 32 
                 4-methyl- 
                 ethyl 
                 CO 
                 4-methylphenyl 
               
               
                   
                 benzyl 
               
               
                 33 
                 4-methyl- 
                 ethyl 
                 CO 
                 4-fluorophenyl 
               
               
                   
                 benzyl 
               
               
                 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)ethyl 
                 CO 
                 4-fluorophenyl 
               
               
                 147 
                 3-chloro- 
                 2-(4-methoxyphenyl)ethyl 
                 CO 
                 4-fluorophenyl 
               
               
                   
                 benzyl 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 Stereo #   
                 R 3   
                 R 4   
               
               
                   
               
               
                 232 
                 3-chlorobenzyl 
                 t-butyl 
                 cis racemate 
                 4-fluorophenyl 
                 N-methyl-N-benzyl-amino 
               
               
                 233 
                 3-chlorobenzyl 
                 t-butyl 
                 cis racemate 
                 4-fluorophenyl 
                 di(ethyl)amino 
               
               
                 235 
                 3-chlorobenzyl 
                 t-butyl 
                 cis racemate 
                 4-fluorophenyl 
                 2-(1-methyl)pyrrolidinyl 
               
               
                 236 
                 3-chlorobenzyl 
                 trichloromethyl 
                 cis racemate 
                 4-fluorophenyl 
                 2-(1-methyl)pyrrolidinyl 
               
               
                 237 
                 3-chlorobenzyl 
                 t-butyl 
                 cis racemate 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                 238 
                 3-chlorobenzyl 
                 trichloromethyl 
                 cis racemate 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                 239 a   
                 3-chlorobenzyl 
                 trichloromethyl 
                 1S, 3R 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                 240 b   
                 3-chlorobenzyl 
                 trichloromethyl 
                 1R, 3S 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                 264 
                 hydrogen 
                 3-carboxy-n-propyl 
                 cis racemate 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                 265 
                 hydrogen 
                 3-carboxy-1,2,2-trimethylcyclopentyl 
                 cis racemate 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                 266 
                 hydrogen 
                 3-methyl-3-carboxy-n-butyl 
                 cis racemate 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                 267 
                 hydrogen 
                 (1-carboxymethyl-cyclopentyl)-methyl 
                 cis racemate 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                 268 
                 hydrogen 
                 3-carboxy-2,2-dimethyl-n-propyl 
                 cis racemate 
                 4-fluorophenyl 
                 1-piperidinyl 
               
               
                   
               
               
                   # The term “cis racemate” denotes a mixture of four possible diastereomers, with the two cis diastereomers predominately present.  
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 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-tri- 
                 phenylamino 
               
               
                   
                   
                   
                 fluoromethylphenyl 
               
               
                 50 
                 3-chlorobenzyl 
                 CO 
                 4-biphenyl 
                 phenylamino 
               
               
                 51 
                 3-chlorobenzyl 
                 CO 
                 3-methoxyphenyl 
                 phenylamino 
               
               
                 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-trifluoro- 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                   
                 methylbenzyl 
               
               
                 63 
                 4-chlorobenzyl 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                 64 
                 1-naphthyl- 
                 CO 
                 trichloromethyl 
                 phenylamino 
               
               
                   
                 methyl 
               
               
                 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- 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                   
                 methyl 
               
               
                 95 
                 4-chlorobenzyl 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                 96 
                 3-trifluoro- 
                 CO 
                 trichloromethyl 
                 4-fluorophenyl 
               
               
                   
                 methylbenzyl 
               
               
                 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-tri- 
                 4-fluorophenyl 
               
               
                   
                   
                   
                 fluoropropan-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-cyclopentylethyl 
                 4-fluorophenyl 
               
               
                 243 
                 3-chlorobenzyl 
                 CO 
                 4-methoxybenzyl 
                 4-fluorophenyl 
               
               
                 244 
                 3-chlorobenzyl 
                 CO 
                 Benzyl 
                 4-fluorophenyl 
               
               
                 245 
                 3-chlorobenzyl 
                 CO 
                 3,4-dimethoxybenzyl 
                 4-fluorophenyl 
               
               
                 246 
                 3-chlorobenzyl 
                 CO 
                 t-butylmethyl 
                 4-fluorophenyl 
               
               
                 247 
                 3-chlorobenzyl 
                 CO 
                 1(1-phenyl)propyl 
                 4-fluorophenyl 
               
               
                 248 
                 3-chlorobenzyl 
                 CO 
                 2-thienylmethyl 
                 4-fluorophenyl 
               
               
                 249 
                 3-chlorobenzyl 
                 CO 
                 4-fluorobenzyl 
                 4-fluorophenyl 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
           
               
                 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 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                 ID 
                 R 1   
                 R 2   
                 Stereo #   
                 R 3   
                 R 5   
               
               
                   
               
               
                 208 
                 3-nitrobenzyl 
                 tri- 
                 1S, 3R 
                 4-fluorophenyl 
                 CH 3   
               
               
                   
                   
                 chloromethyl 
               
               
                 209 
                 3-chlorobenzyl 
                 tri- 
                 1S, 3R 
                 4-fluorophenyl 
                 CH 3   
               
               
                   
                   
                 chloromethyl 
               
               
                 210 
                 benzyl 
                 tri- 
                 1S, 3R 
                 4-fluorophenyl 
                 CH 3   
               
               
                   
                   
                 chloromethyl 
               
               
                 223 
                 3-chlorobenzyl 
                 tri- 
                 cis 
                 phenylamino 
                 H 
               
               
                   
                   
                 chloromethyl 
                 racemate 
               
               
                 224 
                 benzyl 
                 tri- 
                 cis 
                 phenylamino 
                 H 
               
               
                   
                   
                 chloromethyl 
                 racemate 
               
               
                 225 
                 benzyl 
                 t-butyl 
                 cis 
                 phenylamino 
                 H 
               
               
                   
                   
                   
                 racemate 
               
               
                 226 
                 3-chlorobenzyl 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                   
                   
                 racemate 
               
               
                 227 
                 3,4-dichloro- 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                 benzyl 
                   
                 racemate 
               
               
                 228 
                 3,4-difluoro- 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                 benzyl 
                   
                 racemate 
               
               
                 229 
                 benzyl 
                 t-butyl 
                 1S, 3R 
                 4-fluorophenyl 
                 H 
               
               
                 230 
                 benzyl 
                 t-butyl 
                 1R, 3S 
                 4-fluorophenyl 
                 H 
               
               
                 211 
                 3-nitrobenzyl 
                 tri- 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                   
                 chloromethyl 
                 racemate 
               
               
                 212 
                 3-chlorobenzyl 
                 tri- 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                   
                 chloromethyl 
                 racemate 
               
               
                 213 
                 benzyl 
                 tri- 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                   
                 chloromethyl 
                 racemate 
               
               
                 214 
                 benzyl 
                 t-butyl 
                 cis 
                 4-fluorophenyl 
                 H 
               
               
                   
                   
                   
                 racemate 
               
               
                   
               
               
                   # The term “cis racemate” denotes a mixture of four possible diastereomers, with the two cis diastereomers predominately present.  
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
           
               
                 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 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
           
               
                   
                 R 1 , R 2  and X 1  Taken 
                   
                   
                   
                   
               
               
                 ID 
                 Together (with the 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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 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 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
             
               
               
             
           
               
                 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 
               
               
                   
               
             
          
         
       
     
     Particularly preferred intermediates in the preparation of compounds of formula (I) are listed in Table 17 below. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 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 
               
               
                   
               
             
          
         
       
     
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     The term “heteroatom” shall include oxygen, sulfur and nitrogen. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     The term “tri-halomethyl” refers to trichloromethyl, trifluoromethyl, tribromomethyl and triiodomethyl. 
     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 
                        
 
     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. 
     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%. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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   EDCl=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       

     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. 
                        
 
     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). 
                        
 
     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). 
     Schemes 1-8 below depict synthesis routes for producing compounds of the formula (I). 
     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). 
                        
 
     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). 
     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). 
     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. 
     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. 
     The acid-amide compound of formula (VIII) is activated using a known coupling agent, such as EDCl 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). 
     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). 
     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). 
     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). 
     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. 
                        
 
     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). 
     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). 
     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). 
     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. 
     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). 
     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). 
                        
 
     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. 
     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). 
     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. 
     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. 
                        
 
     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). 
     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). 
     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). 
     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). 
     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-. 
                        
                         
 
     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). 
     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). 
     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). 
     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). 
     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). 
     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. 
     Compounds of formula (I) wherein A is a substituted alkyl may alternatively be prepared according to the process outlined in Scheme 6. 
                        
 
     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). 
     The compound of formula (XXXVI) is deprotected by removal of the Fmoc protecting group by known methods [for example by treating with piperidine in DMF], to produce the corresponding compound of formula (XXXVII). 
     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). 
     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). 
     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. 
     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. 
                        
 
     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). 
     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 (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. 
     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). 
     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). 
     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 
                        
 
     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). 
     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. 
     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). 
     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). 
     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 (XXXIII), 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. 
     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. 
                        
 
     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). 
     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.
 
     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. 
     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. 
     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. 
     Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved by enzymatic resolution or by using a chiral HPLC column. 
     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. 
     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. 
     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 
     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. 
     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. 
     MS 384 (M − ) 
       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 
     Following the procedure disclosed in GB 924961; 1959; Chem. Abstr.; 59; 9883b; 1963. 
     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. 
     MS 237 (MH + ) 
       1 H NMR (CDCl 3 ) δ 1.78-1.88 (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 
     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. 
     MS 221 (MH + ) 
       1 H NMR (CDCl 3 ) δ 1.46-2.31 (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 
     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. 
     MS 221 (MH + ) 
       1 H NMR (CDCl 3 ) δ 1.38-1.50 (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 
     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. 
     MS 207 (MH + ) 
       1 H NMR (CDCl 3 ) δ 1.72-1.80 (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=8.2Hz, 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 
     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. 
     Yield: 3.2 g, 78% 
     MS 596 (MNa + ), 574 (MH + ), 332 (MH + -trt), 243 (trt + ). 
     EXAMPLE 5 
     N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-cis-3-(triphenylmethylamino)cyclohexylmethylamine 
     LAH (220 mg, 5.8 mmol) was added to N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-cis-(3-(triphenylmethyl)amino)cyclohexylmethylcarboxamide (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. 
     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 
     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. 
     MS 682 (MH + ), 440 (MH + -trt), 243 (trt + ). 
     EXAMPLE 7 
     N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-[cis-(3-aminocyclohexyl)methyl]-4-fluorophenylcarboxamide 
     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. 
     MS 462 (MNa + ), 440 (MH + ). 
     EXAMPLE 8 
     
       
                 
         
             
             
         
      
     
     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. 
     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. 
     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 
     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. 
     MS 679 (MH + ), 437 (MH + -trt), 243 (trt + ). 
     EXAMPLE 10 
     
       
                 
         
             
             
         
      
     
     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. 
     MS 437 (MH + ). 
     EXAMPLE 11 
     N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-[(cis-3-(3-nitrobenzyl)aminocyclohexylmethyl]-4-fluorophenylcarboxamide 
     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 
     
       
                 
         
             
             
         
      
     
     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. 
     MS 736 (MH + ); HPLC (RT 4.11 min.). 
     EXAMPLE 13 
     N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-{(cis3-(benzylamino)cyclohexyl)methyl}-N′-phenylurea 
     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. 
     MS 543 (MH + ). 
     EXAMPLE 14 
     
       
                 
         
             
             
         
      
     
     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. 
     MS 662 (MH + ); HPLC (RT 4.38 min.). 
     EXAMPLE 15 
     
       
                 
         
             
             
         
      
     
     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. 
     MS 733 (MH + ); HPLC (RT 4.97 min.). 
     EXAMPLE 16 
     
       
                 
         
             
             
         
      
     
     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. 
     MS 599 (MH + ); HPLC (RT 3.59 min.). 
     EXAMPLE 17 
     1-(2-(3-amino-2-methylphenoxy)ethyl)pyrrolidine 
     By the method of examples 2 and 3, 1-(2-chloroethyl)pyrrolidine hydrochloride and 2-methyl-3-nitrophenol were converted into the title compound. 
     MS 221 (MH + ) 
       1 H NMR (CDCl 3 ) δ 1.75-1.86 (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 
     By the method of examples 2 and 3, 4-(2-chloroethyl)morpholine hydrochloride and 3-nitrophenol were converted into the title compound. 
     MS 223 (MH + ) 
     EXAMPLE 19 
     N-(4-fluorophenylmethyl)-4-(2-(3-aminophenoxy)ethyl)morpholine 
     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. 
     MS 331 (MH + ) 
       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 
     
       
                 
         
             
             
         
      
     
     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. 
     MS 638 (MH + ); HPLC (RT 4.32 min.) 
       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 
     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. 
     MS 257 (MH + ). 
     EXAMPLE 22 
     N-(4-fluorophenyl)methyl)-N-[3-(2-(1-pyrrolidino)ethyloxy)-2-methylphenyl]-N′-(2-phenethyl)-1,5-pentyldiamide 
     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 
     
       
                 
         
             
             
         
      
     
     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. 
     MS 680 (MH + ); HPLC (RT 3.53 min.) 
     EXAMPLE 24 
     N-(3-tert-butyldimethylsiloxyphenyl)4-fluorobenzylamine 
     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). 
     MS 218 (MH+). 
     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%). 
     MS 332 (MH+) 
       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) 
     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. 
     MS 525 (MH + ) 
       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 
     
       
                 
         
             
             
         
      
     
     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). 
     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 
     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. 
     MS 516 (MH + ) 
     EXAMPLE 28 
     
       
                 
         
             
             
         
      
     
     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. 
     MS 621 (MH + ); 
       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 
     Step A: N-3-chlorobenzyltrimethylacetamide 
     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 1 N 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, 
     MS 192 (MH + ). 
     Step B: 
     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 . 
     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 
     
       
                 
         
             
             
         
      
     
     EDCl-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. 
     MH+700. 
     EXAMPLE 31 
     
       
                 
         
             
             
         
      
     
     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. 
     MH+478. 
     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. 
     MH+700; HPLC (RT 5.16 mins). 
     EXAMPLE 32 
     
       
                 
         
             
             
         
      
     
     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)). 
     MS (MH+) 371 
     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. The title compound was isolated by flash chromatography (gradient from 80% EA/hexane to 100% EA) to yield a white solid. 
     MS (MH+) 493 
     EXAMPLE 33 
     
       
                 
         
             
             
         
      
     
     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 EDCl-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. 
     MH+582; HPLC (RT 3.41 mins). 
     EXAMPLE 34 
     N-3-cyanocyclopentyl-4-(2-(3-amino-phenoxy)ethyl)morpholine 
     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 
     MS (MH+) 316. 
     EXAMPLE 35 
     
       
                 
         
             
             
         
      
     
     Phenylisocyanate (0.65 ml, 5.9 mmol) was added to N-3-cyanocyclopentyl4-(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. 
     MS (MH+) 435. 
     EXAMPLE 36 
     
       
                 
         
             
             
         
      
     
     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. 
     (MH+) 439 
     EXAMPLE 37 
     
       
                 
         
             
             
         
      
     
     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. 
     (MH+) 563. 
     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). 
     (MH+) 707 
     EXAMPLE 38 
     
       
                 
         
             
             
         
      
     
     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. 
     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. 
     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 
     
       
                 
         
             
             
         
      
     
     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 . 
     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 
     
       
                 
         
             
             
         
      
     
     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 
     
       
                 
         
             
             
         
      
     
     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 
     Motilin Receptor Binding 
     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 
     Human Antrum Tissue 
     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. 
     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 
     Rabbit Tissue Bath Procedure 
     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% O2-5% 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. 
     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 (Carbamoyicholine 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. 
     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. 
     Tables 18 and 19 below list molecular weight, % Inhibition and IC 50  values measured for select compounds of the present invention. 
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                   
                 TABLE 18 
               
             
             
               
                   
                   
               
               
                   
                 Mol. Wt. * 
                 Rabbit Colon 
                   
                 Human Antrum 
                 Tissues 
               
             
          
           
               
                 ID 
                 Cal&#39;d 
                 (MH + ) 
                 % Inh @ 1 mM 
                 IC 50  (μM) 
                   
                 % Inh @ 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.  
               
             
          
         
       
     
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 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 
               
               
                   
               
             
          
         
       
     
     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.
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.