# Patent

## Title
Substituted diamine derivatives useful as motilin antagonists

## Abstract

The present invention relates to novel substituted diamine derivatives for the formula




    
    
        wherein R1, R2, R3, R4, X1, X2, X3, X4, 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.

## Background
CROSS REFERENCE TO RELATED APPLICATION
This is a divisional application of and claims priority to application Ser. No. 10/291,133, filed Nov. 8, 2002, which is a divisional application of U.S. application Ser. No. 09/829,767, filed Apr. 10, 2001, now issued as U.S. Pat. No. 6,511,980, which claims priority from U.S. provisional application Ser. No. 60/202,131, filed May 5, 2000, the contents of 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'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 (IC50 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
R1 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;
R2 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;
X1, X2, X3 and X4 are independently absent or selected from the group consisting of CO and SO2; provided that at least one of X1 or X2 and at least one of X3 or X4 is CO or SO2;
alternatively R1, R2 and X1 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 R7;
where R7 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;
R3 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 —SO2—;
n is an integer from 0 to 5;
R4 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;
R5 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, R4 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, R4 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, R4 is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl and di(methyl)amino. Most preferably, R4 is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl and 1-piperidinyl;

Preferably R5 is selected from the group consisting of hydrogen and lower alkyl. More preferably R5 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:
R1 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;
R2 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;
X1, X2, X3 and X4 are independently absent or selected from the group consisting of CO and SO2; such that at least one of X1 or X2 and at least one of X3 or X4 is CO or SO2;
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;
R3 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;
R4 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;
R5 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:
R1 is selected from the group consisting of hydrogen, phenyl (C1–C6) alkyl-, naphthyl(C1-6)alkyl and heterocyclyl(C1–C6)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;
R2 is selected from the group consisting of (C1–C6)branched or unbranched alkyl, phenyl, phenyl(C1–C6)alkyl-, tri-halomethyl, phenylamino-, biphenyl, diphenyl(C1–C6)alkyl-, C5-8cycloalkyl, C5-8cycloalkyl-alkyl, heterocyclyl and heterocyclyl(C1–C6)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(C1-4)alkyl, hydroxy, phenyl, diphenylmethyl, trihalomethyl and trihaloalkylacetyl;
X1, X2, X3 and X4 are independently absent or selected from the group consisting of CO and SO2; such that at least one of X1 or X2 and at least one of X3 or X4 is CO or SO2;
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;
R3 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 -0-;
n is an integer from 0 to 3;
R4 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;
R5 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
R1 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;
R2 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;
X1, X2, X3 and X4 are independently absent or selected from the group consisting of CO and SO2; such that one of X1 or X2 and one of X3 or X4 is CO or SO2;
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,3-R-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-;
R3 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;
R4 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;
R5 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 R1, R2 and X1 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 R1, R2 and X1 are taken together (with the amine nitrogen) to form 1-phenyl-1,2,3,4-tetrahydroisquinolinyl, X2 is C(O), A is 1,3-propyl, X3 is C(O), R3 is 4-fluorobenzyl, Y is 3-O—, n is 2 and R4 is 4-morpholinyl.
In another preferred embodiment R1, R2 and X1 are taken together (with the amine nitrogen) to form 4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl, X2 is C(O), A is 1,3-n-propyl, X3 is absent, R3 is 4-fluorophenyl, X4 is C(O), Y is 3-O—, n is 2 and R4 is 4-morpholinyl.
In still another preferred embodiment, R1, R2 and X1 are taken together (with the amine nitrogen) to form 2-[1-benzyl-6-methoxy-1,2,3,4-tetrahydro]-naphthyl, X2 is C(O), A is 1,3-n-propyl, X3 is absent, R3 is 4-fluorophenyl, X4 is C(O), Y is 3-O—, n is 2 and R4 is 4-morpholinyl.
In a class of the invention are compounds of the formula (I) wherein
R1 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;
R2 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;
X1, X2, X3 and X4 are independently absent or CO; such that one of X1 or X2 and one of X3 or X4 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-;
R3 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;
R4 is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, di(methyl)amino and di(ethyl)amino;
R5 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

    
    
        R1 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;
    
    


R2 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;
X1, X2, X3 and X4 are independently absent or CO; such that one of X1 or X2 and one of X3 or X4 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-;
R3 is selected from the group consisting of phenylamino, 4-fluorophenyl, 3-fluorobenzyl and 4-fluorobenzyl;
Y is -3-O—;
n is 2;
R4 is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl and di(methyl)amino;
R5 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
R1 is selected from the group consisting of benzyl, 3-nitrobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl and 3-trifluoromethylbenzyl;
R2 is selected from the group consisting of t-butyl, 2-(phenyl)ethyl, trichloromethyl, 2-(2-pyridyl)ethyl and 2-(2-thienyl)ethyl;
X1, X2, X3 and X4 are independently absent or CO; such that one of X1 or X2 and one of X3 or X4 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-;
R3 is selected from the group consisting of phenylamino, 4-fluorophenyl, 3-fluorobenzyl and 4-fluorobenzyl;
Y is -3-O—;
n is 2;
R4 is selected from the group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl and 1-piperidinyl;
R5 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 R1 is 3-chlorobenzyl, R2 is trichloromethyl, X1 is CO, X2 is absent, X3 is absent, X4 is CO, A is 1S,3R-cyclohexyl-methyl-, R3 is 4-fluorophenyl, Y is −3-O—, n is 2, R4 is 1-piperidinyl, R5 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 R1 is 3-chlorobenzyl, R2 is trichloromethyl, X1 is CO, X2 is absent, X3 is absent, X4 is CO, A is 1R,3S-cyclohexyl-methyl-, R3 is 4-fluorophenyl, Y is −3-O—, n is 2, R4 is 1-piperidinyl, R5 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#
R1
R2
R3





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
R1
R2
R3
Y
n
R4
R5





129
benzyl
2-(phenyl)
4-fluoro
3-O
2
4-
H




ethyl
benzyl


morpho-








linyl


159
benzyl
3-
4-fluoro
3-O
2
4-
H




(phenyl)
benzyl


morpho-




propyl



linyl


162
3-
2-(phenyl)
4-fluoro
3-O
2
4-
H



chloro
ethyl
benzyl


morpho-



benzyl




linyl


169
benzyl
2-(phenyl)
3-fluoro
3-O
2
4-
H




ethyl
benzyl


morpho-








linyl


170
benzyl
2-(phenyl)
2-fluoro
3-O
2
4-
H




ethyl
benzyl


morpho-








linyl


171
benzyl
2-(phenyl)
4-methoxy
3-O
2
4-
H




ethyl
benzyl


morpho-








linyl


172
benzyl
2-(phenyl)
4-trifluoro
3-O
2
4-
H




ethyl
methyl


morpho-








linyl





benzyl


173
benzyl
2-(phenyl)
4-chloro
3-O
2
4-
H




ethyl
benzyl


morpho-








linyl


175
benzyl
2-(phenyl)
4-fluoro
3-O-
0
H
H




ethyl
benzyl


176
benzyl
2-(phenyl)
4-fluoro
3-O
2
2-oxo-
H




ethyl
benzyl


pyrro-








lidin-1-








yl


177
benzyl
2-(phenyl)
4-fluoro
3-O
2
dimethyl
H




ethyl
benzyl


amino








ethyloxy








ethyl


178
benzyl
2-(phenyl)
4-fluoro
3-O
2
diethyl
H




ethyl
benzyl


amino


179
benzyl
2-(phenyl)
4-fluoro
3-O
2
1-piper-
H




ethyl
benzyl


azinyl


180
benzyl
2-(phenyl)
4-fluoro
3-O
2
1-pyrro-
H




ethyl
benzyl


lidinyl


181
benzyl
2-(phenyl)
4-fluoro
3-O
2
dimethyl
H




ethyl
benzyl


amino


182
benzyl
2-(phenyl)
4-fluoro
3-O
2
1-piperi-
H




ethyl
benzyl


dinyl


187
benzyl
2-(phenyl)
4-fluoro
3-O
3
dimethyl
H




ethyl
benzyl


amino


188
benzyl
2-(phenyl)
4-fluoro
3-O
3
1-piperi-
H




ethyl
benzyl


dinyl


191
benzyl
2-(phenyl)
4-fluoro
4-O
2
1-pyrro-
H




ethyl
benzyl


lidinyl


192
benzyl
2-(phenyl)
4-fluoro
4-O
2
4-
H




ethyl
benzyl


morpho-








linyl


193
benzyl
2-(phenyl)
4-fluoro
4-O
3
1-piperi-
H




ethyl
benzyl


dinyl


194
benzyl
2-(phenyl)
4-fluoro
4-O
2
dimethyl
H




ethyl
benzyl


amino


195
benzyl
2-(phenyl)
4-fluoro
4-O
2
diethyl
H




ethyl
benzyl


amino


196
benzyl
2-(phenyl)
4-fluoro
3-O
2
1-pyrro-
2-




ethyl
benzyl


lidinyl
methyl


197
3-nitro
2-(phenyl)
4-fluoro
3-O
2
1-pyrro-
H



benzyl
ethyl
benzyl


lidinyl


198
3-chloro
3-methoxy
4-fluoro
3-O
2
1-pyrro-
H



benzyl
benzyl
benzyl


lidinyl


199
3,5-
2-(phenyl)
4-fluoro
3-O
2
1-pyrro-
H



dichloro
ethyl
benzyl


lidinyl



benzyl


200
3-
2-(phenyl)
4-fluoro
3-O
2
1-pyrro-
H



trifluoro
ethyl
benzyl


lidinyl



methyl



benzyl


201
3-chloro
2-(2-
4-fluoro
3-O
2
1-pyrro-
H



benzyl
pyridyl)
benzyl


lidinyl




ethyl


202
3-chloro
2-(4-
4-fluoro
3-O
2
1-pyrro-
H



benzyl
chloro
benzyl


lidinyl




phenyl)




ethyl


203
3-chloro
2-(1-
4-fluoro
3-O
2
1-pyrro-
H



benzyl
pyrro-
benzyl


lidinyl




lidinyl)




ethyl


204
3-chloro
2-(2-
4-fluoro
3-O
2
1-pyrro-
H



benzyl
thienyl)
benzyl


lidinyl




ethyl


205
3-nitro
2-(phenyl)
4-fluoro
3-O
2
4-
H



benzyl
ethyl
benzyl


morpho-








linyl


206
3-chloro
3-methoxy
4-fluoro
3-O
2
4-
H



benzyl
benzyl
benzyl


morpho-








linyl


207
benzyl
2-(phenyl)
4-fluoro
3-O
2
1-pyrro-
6-




ethyl
benzyl


lidinyl
methyl


215
2-
3-carboxy
4-fluoro
3-O
2
1-pyrro-
2-



(phenyl)
benzyl
benzyl


lidinyl
methyl



ethyl


234
benzyl
2-(phenyl)
4-fluoro
3-O
2
4-
2-




ethyl
benzyl


morpho-
methyl








linyl
















TABLE 3













 











ID
R1
R2
A
R3





154
benzyl
2-(phenyl)ethyl
2-cyclopentyl-1,3-n-
4-fluorobenzyl





propyl


155
benzyl
2-(phenyl)ethyl
cis-1,2-cyclohex-4-
4-fluorobenzyl





enyl


156
benzyl
2-(phenyl)ethyl
1,2-cylopentenyl
H


160
benzyl
2-(phenyl)ethyl
1,3-n-butyl
4-fluorobenzyl


189
benzyl
2-(phenyl)ethyl
2-methyl-(1,3-propyl)
4-fluorobenzyl


190
benzyl
2-(phenyl)ethyl
1,1-dimethyl-(1,3-
4-fluorobenzyl





propyl)
















TABLE 4













 











ID
R1
R2
X4
R3





 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
SO2
4-methylphenyl


13
benzyl
ethyl
CO
4-methylphenyl


14
benzyl
ethyl
CO
4-fluorophenyl


19
benzyl
methyl
CO
phenylamino


20
benzyl
methyl
SO2
4-methylphenyl


21
benzyl
methyl
CO
4-methylphenyl


22
benzyl
methyl
CO
4-fluorophenyl


26
benzyl
benzyl
CO
phenylamino


27
benzyl
benzyl
SO2
4-methylphenyl


28
benzyl
benzyl
CO
4-methylphenyl


29
benzyl
benzyl
CO
4-fluorophenyl


34
4-methylbenzyl
ethyl
CO
phenylamino


35
4-methylbenzyl
ethyl
SO2
4-methylphenyl


36
4-methylbenzyl
ethyl
CO
4-methylphenyl


37
4-methylbenzyl
ethyl
CO
4-fluorophenyl
















TABLE 5













 











ID
R1
R2
X4
R3





 1
benzyl
2-(phenyl)ethyl
CO
phenylamino


 2
benzyl
2-(phenyl)ethyl
SO2
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
SO2
4-methylphenyl


 10
benzyl
ethyl
CO
4-methylphenyl


 11
benzyl
ethyl
CO
4-fluorophenyl


 15
benzyl
methyl
CO
phenylamino


 16
benzyl
methyl
SO2
4-methylphenyl


 17
benzyl
methyl
CO
4-methylphenyl


 18
benzyl
methyl
CO
4-fluorophenyl


 23
benzyl
benzyl
CO
phenylamino


 24
benzyl
benzyl
SO2
4-methylphenyl


 25
benzyl
benzyl
CO
4-methylphenyl


 30
4-methylbenzyl
ethyl
CO
phenylamino


 31
4-methylbenzyl
ethyl
SO2
4-methylphenyl


 32
4-methylbenzyl
ethyl
CO
4-methylphenyl


 33
4-methylbenzyl
ethyl
CO
4-fluorophenyl


143
H
diphenylmethyl
CO
4-fluorophenyl


144
benzyl
3-(phenyl)propyl
CO
4-fluorophenyl


145
benzyl
2,2-dimethylpropyl
CO
4-fluorophenyl


146
benzyl
2-(4-methoxyphenyl)
CO
4-fluorophenyl




ethyl


147
3-chlorobenzyl
2-(4-methoxyphenyl)
CO
4-fluorophenyl




ethyl
















TABLE 6













 












ID
R1
R2
Stereo#
R3
R4





232
3-chloro-
t-butyl
cis
4-fluorophenyl
N-methyl-



benzyl

racemate

benzyl-







amino


233
3-chloro-
t-butyl
cis
4-fluorophenyl
di(ethyl)-



benzyl

racemate

amino


235
3-chloro-
t-butyl
cis
4-fluorophenyl
2-



benzyl

racemate

(1-methyl)







pyrro-







lidinyl


236
3-chloro-
trichloro
cis
4-fluorophenyl
2-



benzyl
methyl
racemate

(1-methyl)







pyrro-







lidinyl


237
3-chloro-
t-butyl
cis
4-fluorophenyl
1-piper-



benzyl

racemate

idinyl


238
3-chloro-
trichloro
cis
4-fluorophenyl
1-piper-



benzyl
methyl
racemate

idinyl


239a
3-chloro-
trichloro
1S, 3R
4-fluorophenyl
1-piper-



benzyl
methyl


idinyl


240b
3-chloro-
trichloro
1R, 3S
4-fluorophenyl
1-piper-



benzyl
methyl


idinyl


264
hydrogen
3-carboxy-
cis
4-fluorophenyl
1-piper-




n-propyl
racemate

idinyl


265
hydrogen
3-carboxy-
cis
4-fluorophenyl
1-piperi-




1,2,2-
racemate

dinyl




trimethylcy




clopentyl


266
hydrogen
3-methyl-
cis
4-fluorophenyl
1-piper-




3-carboxy-
racemate

idinyl




n-butyl


267
hydrogen
(1-carboxy
cis
4-fluorophenyl
1-piper-




methyl-
racemate

idinyl




cyclopentyl)-




methyl


268
hydrogen
3-carboxy-
cis
4-fluorophenyl
1-pipe-




2,2-
racemate

ridinyl




dimethyl-n-




propyl





#The term “cis racemate” denotes a mixture of four possible diastereomers, with the two cis diastereomers predominately present.













TABLE 7













 











ID
R1
X1
R2
R3





40
benzyl
CO
phenylamino
phenylamino


41
benzyl
CO
3-methoxyphenyl
phenylamino


42
benzyl
CO
t-butyl
phenylamino


43
benzyl
CO
2-(phenyl)ethyl
phenylamino


44
benzyl
CO
2-naphthyl
phenylamino


45
benzyl
CO
3-nitrophenyl
phenylamino


46
benzyl
CO
diphenylmethyl
phenylamino


47
3-chlorobenzyl
CO
trichloromethyl
phenylamino


48
benzyl
CO
2-furyl
phenylamino


49
3-chlorobenzyl
CO
3,5-di-trifluoro
phenylamino





methylphenyl


50
3-chlorobenzyl
CO
4-biphenyl
phenylamino


51
3-chlorobenzyl
CO
3-methoxy
phenylamino





phenyl


52
3-chlorobenzyl
CO
t-butyl
phenylamino


53
3-chlorobenzyl
CO
2-(phenyl)ethyl
phenylamino


54
3-chlorobenzyl
CO
2-naphthyl
phenylamino


55
3-chlorobenzyl
CO
3-nitrophenyl
phenylamino


56
3-chlorobenzyl
CO
diphenyl methyl
phenylamino


57
benzyl
SO2
2-naphthyl
phenylamino


58
3-fluorobenzyl
CO
trichloromethyl
phenylamino


59
3,4-dichloro
CO
trichloromethyl
phenylamino



benzyl


60
3,5-dichloro
CO
trichloromethyl
phenylamino



benzyl


61
3-methoxybenzyl
CO
trichloromethyl
phenylamino


62
3-trifluoromethyl
CO
trichloromethyl
phenylamino



benzyl


63
4-chlorobenzyl
CO
trichloromethyl
phenylamino


64
1-naphthyl-methyl
CO
trichloromethyl
phenylamino


65
3-nitrobenzyl
CO
trichloromethyl
phenylamino


66
2,3-dichloro
CO
trichloromethyl
phenylamino



benzyl


67
benzyl
CO
trichloromethyl
phenylamino


68
2-pyridyl-methyl
CO
trichloromethyl
phenylamino


69
H
CO
phenynamino
phenylamino


70
H
CO
2-furyl
phenylamino


71
H
SO2
2-naphthyl
phenylamino


72
H
CO
trichloromethyl
phenylamino


73
H
CO
trifluoromethyl
phenylamino


74
H
CO
3,5-di-trifluoro
phenylamino





methylphenyl


75
H
CO
4-biphenyl
phenylamino


76
H
CO
3-methoxyphenyl
phenylamino


77
H
CO
t-butyl
phenylamino


78
H
CO
2-(phenyl)ethyl
phenylamino


79
H
CO
2-naphthyl
phenylamino


80
H
CO
3-nitrophenyl
phenylamino


81
H
CO
diphenylmethyl
phenylamino


82
benzyl
CO
3,5-di(trifluoro
phenylamino





methyl)phenyl


83
benzyl
CO
4-biphenyl
phenylamino


86
3-chlorobenzyl
CO
3-hydroxyphenyl
phenylamino


90
2-pyridyl-methyl
CO
trichloromethyl
4-fluorophenyl


91
H
CO
trichloromethyl
4-fluorophenyl


92
2,3-dichloro
CO
trichloromethyl
4-fluorophenyl



benzyl


93
3-nitrobenzyl
CO
trichloromethyl
4-fluorophenyl


94
1-naphthyl-methyl
CO
trichloromethyl
4-fluorophenyl


95
4-chlorobenzyl
CO
trichloromethyl
4-fluorophenyl


96
3-trifluoromethyl
CO
trichloromethyl
4-fluorophenyl



benzyl


97
3-methoxybenzyl
CO
trichloromethyl
4-fluorophenyl


98
3,5-dichloro
CO
trichloromethyl
4-fluorophenyl



benzyl


99
3,4-dichloro
CO
trichloromethyl
4-fluorophenyl



benzyl


100 
3-fluorobenzyl
CO
trichloromethyl
4-fluorophenyl


101 
3-chlorobenzyl
CO
diphenylmethyl
4-fluorophenyl


102 
3-chlorobenzyl
CO
3-nitrophenyl
4-fluorophenyl


103 
3-chlorobenzyl
CO
2-naphthyl
4-fluorophenyl


104 
3-chlorobenzyl
CO
2-(phenyl)ethyl
4-fluorophenyl


105 
3-chlorobenzyl
CO
t-butyl
4-fluorophenyl


106 
3-chlorobenzyl
CO
3-methoxyphenyl
4-fluorophenyl


107 
3-chlorobenzyl
CO
3,5-di-trifluoro
4-fluorophenyl





methylphenyl


108 
3-chlorobenzyl
CO
trifluoromethyl
4-fluorophenyl


109 
3-chlorobenzyl
CO
4-biphenyl
4-fluorophenyl


110 
3-chlorobenzyl
CO
3,3,3-trifluoro
4-fluorophenyl





propan-2-onyl


111 
3-chlorobenzyl
CO
trichloromethyl
4-fluorophenyl


112 
benzyl
CO
diphenylmethyl
4-fluorophenyl


113 
benzyl
CO
3-nitrophenyl
4-fluorophenyl


114 
benzyl
CO
2-naphthyl
4-fluorophenyl


115 
benzyl
CO
2-(phenyl)ethyl
4-fluorophenyl


116 
benzyl
CO
t-butyl
4-fluorophenyl


117 
benzyl
CO
3-methoxyphenyl
4-fluorophenyl


118 
benzyl
CO
4-biphenyl
4-fluorophenyl


119 
benzyl
CO
3,5-ditrifluoro
4-fluorophenyl





methylphenyl


120 
benzyl
CO
trifluoromethyl
4-fluorophenyl


121 
benzyl
CO
3,3,3-trifluoro
4-fluorophenyl





propan-2-onyl


122 
benzyl
CO
trichloromethyl
4-fluorophenyl


123 
benzyl
SO2
2-naphthyl
4-fluorophenyl


124 
benzyl
CO
2-furyl
4-fluorophenyl


125 
benzyl
CO
phenylamino
4-fluorophenyl


241 
3-chlorobenzyl
CO
3-methoxybenzyl
4-fluorophenyl


242 
3-chlorobenzyl
CO
2-
4-fluorophenyl





cyclopentylethyl


243 
3-chlorobenzyl
CO
4-methoxybenzyl
4-fluorophenyl


244 
3-chlorobenzyl
CO
Benzyl
4-fluorophenyl


245 
3-chlorobenzyl
CO
3,4-
4-fluorophenyl





dimethoxybenzyl


246 
3-chlorobenzyl
CO
t-butylmethyl
4-fluorophenyl


247 
3-chlorobenzyl
CO
1(1-phenyl)
4-fluorophenyl





propyl


248 
3-chlorobenzyl
CO
2-thienylmethyl
4-fluorophenyl


249 
3-chlorobenzyl
CO
4-fluorobenzyl
4-fluorophenyl
















TABLE 8













 












ID
R1
R2
R3







158
H
trichloromethyl
4-fluorophenyl



161
3-chlorobenzyl
t-butyl
4-fluorophenyl



157
benzyl
trifluoromethyl
4-fluorophenyl

















TABLE 9













 












ID
R1
R2
Stereo#
R3
R5





208
3-nitro-
trichloromethyl
1S, 3R
4-fluorophenyl
CH3



benzyl


209
3-chloro-
trichloromethyl
1S, 3R
4-fluorophenyl
CH3



benzyl


210
benzyl
trichloromethyl
1S, 3R
4-fluorophenyl
CH3


223
3-chloro-
trichloromethyl
cis
phenylamino
H



benzyl

racemate


224
benzyl
trichloromethyl
cis
phenylamino
H





racemate


225
benzyl
t-butyl
cis
phenylamino
H





racemate


226
3-chloro-
t-butyl
cis
4-fluorophenyl
H



benzyl

racemate


227
3,4-di-
t-butyl
cis
4-fluorophenyl
H



chlorobenzyl

racemate


228
3,4-di-
t-butyl
cis
4-fluorophenyl
H



fluorobenzyl

racemate


229
benzyl
t-butyl
1S, 3R
4-fluorophenyl
H


230
benzyl
t-butyl
1R, 3S
4-fluorophenyl
H


211
3-nitro-
trichloromethyl
cis
4-fluorophenyl
H



benzyl

racemate


212
3-chloro-
trichloromethyl
cis
4-fluorophenyl
H



benzyl

racemate


213
benzyl
trichloromethyl
cis
4-fluorophenyl
H





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
R1
R2
R3





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
R1
R2
Stereo
R3





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
R1
X
R2





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
SO2
4-biphenyl


151
benzyl
CO
trichloromethyl


152
benzyl
CO
2-(phenyl)ethyl
















TABLE 13













 









ID
R1
R2





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













 













R1 R2 and X Taken







Together (with the amine


ID
nitrogen)
A
X3
X4
R3





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



tetrahydroisoguinolinyl



benzyl
















TABLE 15













 












ID
R1
R2
A
R3
R4















39
3-chloro
trichloro
methyl-1,3-
phenyl
4-morpho-



benzyl
methyl
cyclopentyl
amino
linyl


221
benzyl
t-butyl
1,4-cyclopentyl-
4-fluoro
1-pyrro-





2-ene-methyl
phenyl
lidinyl
















TABLE 16













 









R1, R2 and X 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 #
R1
R2
R3
R4














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. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2) 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, 2nd Ed., T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, 1991, hereby incorporated by reference.
Examples of hydroxy-protecting groups P, include, but are not limited to, methyl, benzyl, tetrahydropyranyl, tri(C1–C6)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



Et2O
=
Diethyl ether



EtOAc
=
Ethyl acetate



EtOH
=
Ethanol



Et3N
=
Triethylamine



HEPES
=
N-(2-hydroxyethyl)piperazine-N-





ethanesulfonic acid



LAH
=
Lithium Aluminum Hydride



MeOH
=
Methanol



Mel
=
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 X2 and X3 are each carbonyl, X1 and X4 are each absent and R3 is —CH2—R6, 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 R1X1R2N 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 R3A 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 EDCI and the like, and coupled with a suitably substituted amine of formula (IX), in an organic base such as TEA, DIEA, and the like, in the presence of an organic solvent such as THF, DMF, DCM and the like, to produce the corresponding diamide of formula (X).
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 X2 and X3 are each carbonyl, X1 and X4 are each absent and R3 is —CH2—R6 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 R3A 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 X2 and X3 are each carbonyl, X1 and X4 are each absent and R3 is —CH2—R6, 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 R1X1R2N 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 X1 and X3 are each absent, X2 is carbonyl, and X4 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 R3A 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 X1 and X4 are each carbonyl or sulfonyl and X2 and X3 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 A1 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 R3A 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 R1A 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 R2A 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 R1A 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 R2A 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 —CH2—RIA group, wherein R1A is as previously defined.
Compounds of formula (I), particularly those wherein X1 and X3 are each absent, X2 is carbonyl and X4 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 R3A 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 X1 and X4 are each carbonyl or sulfonyl and X2 and X3 are each absent may be prepared according to the process outlined in Scheme 8




Accordingly, wherein A1 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 R3A 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 R1A 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 R2A 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 R1, X1 and R2 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 R1, R2 and X1 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 R2′—C(O)—C(O)—R2′′, wherein R2′ and R2′′ are different), the R2 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 R2′ and R2′′ 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-I-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved by enzymatic resolution or by using a chiral HPLC column.
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 CH2Cl2—CH3CN (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 Et2O 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 MgSO4 and evaporated down to give a white foam, 67.4 g, 85% yield.
MS 384 (M−)
1H NMR (CDCl3) 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 H2(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 MgSO4, 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% Et3N to yield a pale yellow oil.
MS 237 (MH+)
1H NMR (CDCl3) 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 H2(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 MgSO4, 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+)
1H NMR (CDCl3) 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+)
1H NMR (CDCl3) 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 >10 with 2M NaOH. The aqueous layer was extracted with ether (3×20 ml), dried over MgSO4 and concentrated in vacuo. The product was eluted through a silica gel pad (75% ethyl acetate/hexane/1% Et3N) to yield the product as a pale yellow oil.
MS 207 (MH+)
1H NMR (CDCl3) 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=8.2 Hz, 2H), 6.22–6.39 (m, 3H), 7.05 (virtual t, J=9.1 Hz, 1H).
EXAMPLE 4
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-cis-3-(triphenylmethylamino)cyclohexylcarboxamide
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% Et3N/hexane, then 60% EtOAc/2% Et3N/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)cyclohexyl methyl-carboxamide (2.1 g, 3.7 mmol) in THF (10 ml) under nitrogen at ambient temperature. The reaction was refluxed for 8 h, cooled to room temperature and quenched with a saturated solution of Rochelle'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 MgSO4. 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 MgSO4 and evaporated onto silica gel in vacuo. The product was purified by chromatography on a silica gel column, preconditioned with Et3N, using 50% EtOAc/2% Et3N/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)cyclohexyl methyl]-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 (MgSO4) 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 MgSO4 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 NaHCO3, extracted with DCM (3×10 ml), dried over MgSO4 and evaporated onto silica gel. The product was purified by flash chromatography (50% EtOAc/1% Et3N/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% Et3N/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 MgSO4 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 NaHCO3, extracted into DCM (3×15 ml), dried over MgSO4 and evaporated onto silica gel. The product was purified by chromatography (50% EtOAc/2% Et3N/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+)
1H NMR (CDCl3) 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>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+)
1H NMR (CDCl3) 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 (<3 h). Chromatography on silica gel with 1% MeOH in ethyl acetate provided the title compound.
MS 638 (MH+); HPLC (RT 4.32 min.)
1H NMR (CDCl3) (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-methyl phenyl]-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 MgSO4. The crude material was purified by flash chromatography on silica gel using 80% ethyl acetate/2% Et3N/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-methyl phenyl]-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% CH3CN/water/0.1% TFA to 60% CH3CN/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 NaHCO3 and extracted with ether. The ether layers were combined, washed with water and dried over MgSO4. The title product was isolated by flash chromatography (15% EA/hexane) as a clear oil (3.75 g, 58%).
MS 332 (MH+)
1H NMR (CDCl3) 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 MgSO4. 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+)
1H NMR (CDCl3) (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 MgSO4 and evaporated down to an oil. The title product was isolated by semi-prep HPLC (C-18 column, 30% CH3CN/water/0.1% TFA to 60% CH3CN/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 MgSO4, 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+);
1H NMR (CD3OD) (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 Et3N (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 MgSO4. 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>10. The aqueous layer was extracted with EtOAc and the organic layers combined and dried over MgSO4.
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




EDCI-MeI (0.33 g, 1.1 mmol) was added to N-(4-fluorophenylmethyl)-4-(2-(3-aminophenoxy)ethyl)morpholine (0.27 g, 0.83 mmol) (Prepared in Example 19), and Fmoc-L-Phe-OH (0.39 g, 1.0 mmol) in CHCl3 (15 mL). After 8 h, the reaction was diluted with a saturated solution of NaHCO3, extracted with DCM and dried over MgSO4. The desired product was isolated by flash chromatography (50–100% EA/hexane) to yield a white solid.
MH+ 700.
EXAMPLE 31




(#152)
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 NaBH3CN (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 MgSO4 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 CHCl3 (5 mL), that contained Et3N (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 Et3N (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 MgSO4 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 EDCI-MeI (29 mg, 0.10 mmol). After 16 h, the reaction mixture was washed 2× with water and evaporated down to yield a brown residue. The title compound was isolated by semi-prep HPLC (reverse phase, C-18) as the TFA salt.
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 NaBH3CN (925 mg, 14.5 mmol) in portions. After 12 h, the solvent was evaporated off and the residue partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted With ethyl acetate, the combined organic layers were dried over MgSO4 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-cyanocyclopentyl-4-(2-(3-amino-phenoxy)ethyl)morpholine (1.88 g, 5.95 mmol) partially dissolved in THF (25 ml) at room temperature. After 15 h, crude material was placed on a silica gel column and eluted with ethyl acetate to give 680 mg of a yellow oil.
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'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 MgSO4. 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 MgSO4, 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% Et3N/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 MgSO4 and evaporated to dryness.
The crude product and Et3N (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% Et3N/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 MgSO4.
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 (Cl 8 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 MgCl2, 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 MgCl2, 1 mM EDTA, 15 mg/ml BSA, 5 mg/ml of pepstatin, leupeptin, aprotinin, and 0.15 mg/ml bacitracin), I125 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. IC50 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 MgCl2, 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 MgCl2, 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 MgCl2, 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. IC50 values were determined from Kaleidograph curves.
125I-Motilin Binding to Human Antral Stomach Membranes and the Human Cloned Receptor:
















Human Antrum IC50 (nM)
1.0 ± 0.1



Human Cloned Receptor IC50 (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% CO2) Tyrodes buffer (NaCl 136.9 mM, KCl 2.7 mM, CaCl2 1.8 mM, MgCl2 1.04 mM, NaH2PO4 0.42 mM, NaHCO3 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% O2— 5% CO2. The tissues were adjusted to 1.0 g resting tension and maintained at that tension throughout the equilibration period. An Ml2 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 (Carbamoylcholine Chloride-Sigma). After maximal contraction was attained, the tissues were washed 3 times with Tyrodes. The tissues were allowed a 20 minute resting/equilibration period, during which time they were washed once and readjusted to 1 g resting tension. The tissues were challenged a second time with 3 μM Carbachol, and this contraction was considered as maximal, or 100% contraction. The tissues were washed 3 times, equilibrated for 10 minutes, washed again and readjusted to 1 g resting tension. Vehicle or test compound in 30% DMSO-50 mM HEPES was added directly to the bath and the tissues were incubated for 20 minutes. Test compounds and vehicle were run in duplicate. The tissues were then challenged with 3 nM Porcine Motilin (Bachem) and when maximum contraction was attained another 3 μM aliquot of Carbachol was added to see if the test compound inhibited this contraction.
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. IC50 values were determined by graphing results with Kaleidograph graphing program.
Tables 18 and 19 below list molecular weight, % Inhibition and IC50 values measured for select compounds of the present invention.











TABLE 18









Rabbit Colon
Human Antrum
Tissues














Mol. Wt.*
% Inh

% Inh
IC50
IC50














ID
Cal'd
(MH+)
@1 mM
IC50 (μM)
@1 μM
(μM)
(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


>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


>.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
>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


>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'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 ion, with examples provided for the purpose of illustration, it will be stood that the practice of the invention encompasses all of the usual ions, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

## Claims

1. A compound having the formula



wherein R1, R2 and X1 are taken together (with the amine nitrogen), A, X3, X4 and R3 are selected in concert from the group consisting of















R1, R2 and






X1 Taken Together


(with the amine nitrogen)
A
X3
X4
R3







1-phenyl-1,2,3,4-
1,3-phenyl-
absent
CO
4-fluorophenyl


tetrahydroisoquinolin-
methyl


2-yl


1-phenyl-1,2,3,4-
1,3-n-propyl
absent
CO
4-fluorophenyl


tetrahydroisoquinolin-


2-yl


4-[(4-
1,3-n-propyl
absent
CO
4-fluorophenyl


chlorophenyl)phenyl-


methyl]-piperazin-1-yl


2-[1-benzyl-6-methoxy-
1,3-n-propyl
absent
CO
4-fluorophenyl


1,2,3,4-tetrahydro]-


naphthyl


1-phenyl-1,2,3,4-
1,3-n-propyl
CO
ab-
4-fluorobenzyl


tetrahydroisoquinolinyl


sent









and pharmaceutically acceptable salts, esters and pro-drug forms thereof.

2. A compound having the formula



wherein R1, R2 and X1 are taken together (with the amine nitrogen) and are selected from the group consisting of 5-t-butyl-isoindole-1,3-dione, 5-fluoro-isoindole-1,3-dione, benzo[e]isoindole-1,3-dione, 5-methyl-isoindole-1,3-dione, 8-aza-spiro[4.5]decane-7,9-dione, 5,6-dichloro-isoindole-1,3-dione, 5-methyl-isoindole-1,3-dione, isoindole-1,3-dione, 4,4-dimethyl-piperidine-2,6-dione, 5-bromo-isoindole-1,3-dione, 5-acetyloxy-isoindole-1,3-dione, 8-fluoro-benzo[e]isoindole-1,3-dione, 3-aza-bicyclo[3.1.0]hexane-2,4-dione, 4,7-dichloro-isoindole-1,3-dione, and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

3. A compound having the formula




wherein R1, R2 and R3 are selected in concert from the group consisting of















R1
R2
R3









benzyl
2-(phenyl)ethyl
4-fluorobenzyl



3-chlorobenzyl
2-(phenyl)ethyl
4-fluorobenzyl



benzyl
2-(phenyl)ethyl
3-fluorobenzyl



benzyl
2-(phenyl)ethyl
2-fluorobenzyl



benzyl
2-(phenyl)ethyl
4-methoxybenzyl



benzyl
2-(phenyl)ethyl
4-trifluoromethylbenzyl.

4. A compound having the formula




wherein R1, R2, R3, Y, n, R4 and R5 are selected in concert from the group consisting of
















R1
R2
R3
Y
n
R4
R5





















Benzyl
2-(phenyl)ethyl
4-fluorobenzyl
3-O
2
4-morpholinyl
H


Benzyl
3-
4-fluorobenzyl
3-O
2
4-morpholinyl
H



(phenyl)propyl


3-chlorobenzyl
2-(phenyl)ethyl
4-fluorobenzyl
3-O
2
4-morpholinyl
H


Benzyl
2-(phenyl) ethyl
3-fluorobenzyl
3-O
2
4-morpholinyl
H


Benzyl
2-(phenyl) ethyl
2-fluorobenzyl
3-O
2
4-morpholinyl
H


Benzyl
2-(phenyl) ethyl
4-methoxybenzyl
3-O
2
4-morpholinyl
H


Benzyl
2-(phenyl) ethyl
4-trifluoromethyl
3-O
2
4-morpholinyl
H




benzyl


Benzyl
2-(phenyl) ethyl
4-chlorobenzyl
3-O
2
4-morpholinyl
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O—
0
H
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
2-oxo-
H







pyrrolidin-1-yl


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
dimethyl amino
H







ethyloxy ethyl


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
diethyl amino
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
1-piperazinyl
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
dimethyl amino
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
1-piperidinyl
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
3
dimethyl amino
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
3
1-piperidinyl
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
4-O
2
1-pyrrolidinyl
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
4-O
2
4-morpholinyl
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
4-O
3
1-piperidinyl
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
4-O
2
dimethyl amino
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
4-O
2
diethyl amino
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
2-methyl


3-nitrobenzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
H


3-chlorobenzyl
3-methoxybenzyl
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
H


3,5-dichlorobenzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
H


3-trifluoromethylbenzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
H


3-chlorobenzyl
2-(2-
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
H



pyridyl)ethyl


3-chlorobenzyl
2-(4-chlorophenyl)
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
H



ethyl


3-chlorobenzyl
2-(1-
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
H



pyrrolidinyl)ethyl


3-chlorobenzyl
2-(2-thienyl)
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
H



ethyl


3-nitrobenzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
4-morpholinyl
H


3-chlorobenzyl
3-methoxybenzyl
4-fluorobenzyl
3-O
2
4-morpholinyl
H


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
6-methyl


2-(phenyl)
3-carboxybenzyl
4-fluorobenzyl
3-O
2
1-pyrrolidinyl
2-methyl


ethyl


Benzyl
2-(phenyl) ethyl
4-fluorobenzyl
3-O
2
4-morpholinyl
2-methyl.

5. A compound having the formula




wherein R1, R2 and R3 are selected in concert from the group consisting of













R1
R2
A
R3







Benzyl
2-(phenyl)ethyl
2-cyclopentyl-1,3-n-propyl
4-fluorobenzyl


Benzyl
2-(phenyl)ethyl
cis-1,2-cyclohex-4-enyl
4-fluorobenzyl


Benzyl
2-(phenyl)ethyl
1,2-cylopentenyl
H


Benzyl
2-(phenyl)ethyl
1,3-n-butyl
4-fluorobenzyl


Benzyl
2-(phenyl)ethyl
2-methyl-(1,3-propyl)
4-fluorobenzyl


Benzyl
2-(phenyl)ethyl
1,1-dimethyl-(1,3-propyl)
4-fluorobenzyl.

6. A compound having the formula




wherein R1, R2, X4 and R3 are selected in concert from the group consisting of
















R1
R2
X4
R3









benzyl
2-(phenyl)ethyl
CO
phenylamino



benzyl
2-(phenyl)ethyl
CO
4-methylphenyl



benzyl
2-(phenyl)ethyl
CO
4-fluorophenyl



benzyl
ethyl
SO2
4-methylphenyl



benzyl
ethyl
CO
4-methylphenyl



benzyl
ethyl
CO
4-fluorophenyl



benzyl
methyl
CO
phenylamino



benzyl
methyl
SO2
4-methylphenyl



benzyl
methyl
CO
4-methylphenyl



benzyl
methyl
CO
4-fluorophenyl



benzyl
benzyl
CO
phenylamino



benzyl
benzyl
SO2
4-methylphenyl



benzyl
benzyl
CO
4-methylphenyl



benzyl
benzyl
CO
4-fluorophenyl



4-methylbenzyl
ethyl
CO
phenylamino



4-methylbenzyl
ethyl
SO2
4-methylphenyl



4-methylbenzyl
ethyl
CO
4-methylphenyl



4-methylbenzyl
ethyl
CO
4-fluorophenyl.

7. A compound having the formula




wherein R1, R2, X4 and R3 are selected in concert from the group consisting of













R1
R2
X4
R3







benzyl
2-(phenyl)ethyl
CO
phenylamino


benzyl
2-(phenyl)ethyl
SO2
4-methylphenyl


benzyl
2-(phenyl)ethyl
CO
4-methylphenyl


benzyl
2-(phenyl)ethyl
CO
4-fluorophenyl


benzyl
ethyl
CO
phenylamino


benzyl
ethyl
SO2
4-methylphenyl


benzyl
ethyl
CO
4-methylphenyl


benzyl
ethyl
CO
4-fluorophenyl


benzyl
methyl
CO
phenylamino


benzyl
methyl
SO2
4-methylphenyl


benzyl
methyl
CO
4-methylphenyl


benzyl
methyl
CO
4-fluorophenyl


benzyl
benzyl
CO
phenylamino


benzyl
benzyl
SO2
4-methylphenyl


benzyl
benzyl
CO
4-methylphenyl


4-methylbenzyl
ethyl
CO
phenylamino


4-methylbenzyl
ethyl
SO2
4-methylphenyl


4-methylbenzyl
ethyl
CO
4-methylphenyl


4-methylbenzyl
ethyl
CO
4-fluorophenyl


H
diphenylmethyl
CO
4-fluorophenyl


benzyl
3-(phenyl)propyl
CO
4-fluorophenyl


benzyl
2,2-dimethylpropyl
CO
4-fluorophenyl


benzyl
2-(4-methoxyphenyl) ethyl
CO
4-fluorophenyl


3-chlorobenzyl
2-(4-methoxyphenyl) ethyl
CO
4-fluorophenyl.

8. A compound having the formula




wherein R1, R2, R3, R4 and the stereo-configuration at the cyclohexyl group are selected in concert from the group consisting of














R1
R2
Stereo
R3
R4







3-chlorobenzyl
t-butyl
cis Racemate
4-fluorophenyl
N-methyl-






N-benzyl-amino


3-chlorobenzyl
t-butyl
cis Racemate
4-fluorophenyl
di(ethyl)amino


3-chlorobenzyl
t-butyl
cis Racemate
4-fluorophenyl
2-(1-methyl)






pyrrolidinyl


3-chlorobenzyl
trichloromethyl
cis Racemate
4-fluorophenyl
2-(1-methyl)






pyrrolidinyl


3-chlorobenzyl
t-butyl
cis Racemate
4-fluorophenyl
1-piperidinyl


3-chlorobenzyl
trichloromethyl
cis Racemate
4-fluorophenyl
1-piperidinyl


3-chlorobenzyl
trichloromethyl
1S, 3R
4-fluorophenyl
1-piperidinyl


3-chlorobenzyl
trichloromethyl
1R, 3S
4-fluorophenyl
1-piperidinyl


hydrogen
3-carboxy-n-
cis Racemate
4-fluorophenyl
1-piperidinyl



propyl


hydrogen
3-carboxy-
cis Racemate
4-fluorophenyl
1-piperidinyl



1,2,2-



trimethylcyclopentyl


hydrogen
3-methyl-3-
cis Racemate
4-fluorophenyl
1-piperidinyl



carboxy-n-



butyl


hydrogen
1-(3-carboxy
cis Racemate
4-fluorophenyl
1-piperidinyl



methyl-



cyclopentyl)-



methyl


hydrogen
3-carboxy-
cis Racemate
4-fluorophenyl
1-piperidinyl



2,2-dimethyl-



n-propyl.

9. A compound having the formula




wherein R1, X1, R2 and R3 are selected in concert from the group consisting of













R1
X1
R2
R3







benzyl
CO
phenylamino
phenylamino


benzyl
CO
3-methoxyphenyl
phenylamino


benzyl
CO
t-butyl
phenylamino


benzyl
CO
2-(phenyl)ethyl
phenylamino


benzyl
CO
2-naphthyl
phenylamino


benzyl
CO
3-nitrophenyl
phenylamino


benzyl
CO
diphenylmethyl
phenylamino


3-chlorobenzyl
CO
trichloromethyl
phenylamino


benzyl
CO
2-furyl
phenylamino


3-chlorobenzyl
CO
3,5-di-
phenylamino




trifluoromethylphenyl


3-chlorobenzyl
CO
4-biphenyl
phenylamino


3-chlorobenzyl
CO
3-methoxy phenyl
phenylamino


3-chlorobenzyl
CO
t-butyl
phenylamino


3-chlorobenzyl
CO
2-(phenyl)ethyl
phenylamino


3-chlorobenzyl
CO
2-naphthyl
phenylamino


3-chlorobenzyl
CO
3-nitrophenyl
phenylamino


3-chlorobenzyl
CO
diphenyl methyl
phenylamino


benzyl
SO2
2-naphthyl
phenylamino


3-fluorobenzyl
CO
trichloro methyl
phenylamino


3,4-dichloro benzyl
CO
trichloromethyl
phenylamino


3,5-dichloro benzyl
CO
trichloromethyl
phenylamino


3-methoxybenzyl
CO
trichloromethyl
phenylamino


3-trifluoromethyl
CO
trichloromethyl
phenylamino


benzyl


4-chlorobenzyl
CO
trichloromethyl
phenylamino


1-naphthyl-methyl
CO
trichloromethyl
phenylamino


3-nitrobenzyl
CO
trichloromethyl
phenylamino


2,3-dichloro benzyl
CO
trichloromethyl
phenylamino


benzyl
CO
trichloromethyl
phenylamino


2-pyridyl-methyl
CO
trichloromethyl
phenylamino


H
CO
phenynamino
phenylamino


H
CO
2-furyl
phenylamino


H
SO2
2-naphthyl
phenylamino


H
CO
trichloromethyl
phenylamino


H
CO
trifluoromethyl
phenylamino


H
CO
3,5-di-
phenylamino




trifluoromethylphenyl


H
CO
4-biphenyl
phenylamino


H
CO
3-methoxyphenyl
phenylamino


H
CO
t-butyl
phenylamino


H
CO
2-(phenyl)ethyl
phenylamino


H
CO
2-naphthyl
phenylamino


H
CO
3-nitrophenyl
phenylamino


H
CO
diphenylmethyl
phenylamino


benzyl
CO
3,5-di(trifluoromethyl)
phenylamino




phenyl


benzyl
CO
4-biphenyl
phenylamino


3-chlorobenzyl
CO
3-hydroxyphenyl
phenylamino


2-pyridyl-methyl
CO
trichloromethyl
4-fluorophenyl


H
CO
trichloromethyl
4-fluorophenyl


2,3-dichloro benzyl
CO
trichloromethyl
4-fluorophenyl


3-nitrobenzyl
CO
trichloromethyl
4-fluorophenyl


1-naphthyl-methyl
CO
trichloromethyl
4-fluorophenyl


4-chlorobenzyl
CO
trichloromethyl
4-fluorophenyl


3-trifluoromethyl
CO
trichloromethyl
4-fluorophenyl


benzyl


3-methoxybenzyl
CO
trichloromethyl
4-fluorophenyl


3,5-dichloro benzyl
CO
trichloromethyl
4-fluorophenyl


3,4-dichloro benzyl
CO
trichloromethyl
4-fluorophenyl


3-fluorobenzyl
CO
trichloromethyl
4-fluorophenyl


3-chlorobenzyl
CO
diphenylmethyl
4-fluorophenyl


3-chlorobenzyl
CO
3-nitrophenyl
4-fluorophenyl


3-chlorobenzyl
CO
2-naphthyl
4-fluorophenyl


3-chlorobenzyl
CO
2-(phenyl)ethyl
4-fluorophenyl


3-chlorobenzyl
CO
t-butyl
4-fluorophenyl


3-chlorobenzyl
CO
3-methoxyphenyl
4-fluorophenyl


3-chlorobenzyl
CO
3,5-di-
4-fluorophenyl




trifluoromethylphenyl


3-chlorobenzyl
CO
trifluoromethyl
4-fluorophenyl


3-chlorobenzyl
CO
4-biphenyl
4-fluorophenyl


3-chlorobenzyl
CO
3,3,3-trifluoro
4-fluorophenyl




propan-2-only


3-chlorobenzyl
CO
trichloromethyl
4-fluorophenyl


benzyl
CO
diphenylmethyl
4-fluorophenyl


benzyl
CO
3-nitrophenyl
4-fluorophenyl


benzyl
CO
2-naphthyl
4-fluorophenyl


benzyl
CO
2-(phenyl)ethyl
4-fluorophenyl


benzyl
CO
t-butyl
4-fluorophenyl


benzyl
CO
3-methoxyphenyl
4-fluorophenyl


benzyl
CO
4-biphenyl
4-fluorophenyl


benzyl
CO
3,5-ditrifluoromethylphenyl
4-fluorophenyl


benzyl
CO
trifluoromethyl
4-fluorophenyl


benzyl
CO
3,3,3-trifluoro
4-fluorophenyl




propan-2-only


benzyl
CO
trichloromethyl
4-fluorophenyl


benzyl
SO2
2-naphthyl
4-fluorophenyl


benzyl
CO
2-furyl
4-fluorophenyl


benzyl
CO
phenylamino
4-fluorophenyl


3-chlorobenzyl
CO
3-methoxybenzyl
4-fluorophenyl


3-chlorobenzyl
CO
2-cyclopentylethyl
4-fluorophenyl


3-chlorobenzyl
CO
4-methoxybenzyl
4-fluorophenyl


3-chlorobenzyl
CO
Benzyl
4-fluorophenyl


3-chlorobenzyl
CO
3,4-
4-fluorophenyl




dimethoxybenzyl


3-chlorobenzyl
CO
t-butyl-methyl
4-fluorophenyl


3-chlorobenzyl
CO
1(1-phenyl)propyl
4-fluorophenyl


3-chlorobenzyl
CO
2-thienylmethyl
4-fluorophenyl


3-chlorobenzyl
CO
4-fluorobenzyl
4-fluorophenyl.

10. A compound having the formula




wherein R1, R2 and R3 are selected in concert from the group consisting of















R1
R2
R3









H
trichloromethyl
4-fluorophenyl



3-chlorobenzyl
t-butyl
4-fluorophenyl



benzyl
trifluoromethyl
4-fluorophenyl.

11. A compound having the formula




wherein R1, R2, R3, R5, and the stereo-configuration are selected in concert from the group consisting of














R1
R2
Stereo
R3
R5







3-nitrobenzyl
trichloromethyl
1S, 3R
4-fluorophenyl
CH3


3-chlorobenzyl
trichloromethyl
1S, 3R
4-fluorophenyl
CH3


benzyl
trichloromethyl
1S, 3R
4-fluorophenyl
CH3


3-chlorobenzyl
trichloromethyl
cis
phenylamino
H




racemate


benzyl
trichloromethyl
cis racemate
phenylamino
H


benzyl
t-butyl
cis racemate
phenylamino
H




mixture


3-chlorobenzyl
t-butyl
cis racemate
4-fluorophenyl
H




mixture


3,4-dichloro
t-butyl
cis racemate
4-fluorophenyl
H


benzyl

mixture


3,4-difluoro
t-butyl
cis racemate
4-fluorophenyl
H


benzyl

mixture


benzyl
t-butyl
1S, 3R
4-fluorophenyl
H


benzyl
t-butyl
1R, 3S
4-fluorophenyl
H


3-nitrobenzyl
trichloromethyl
cis racemate
4-fluorophenyl
H


3-chlorobenzyl
trichloromethyl
cis racemate
4-fluorophenyl
H


benzyl
trichloromethyl
cis racemate
4-fluorophenyl
H


benzyl
t-butyl
cis racemate
4-fluorophenyl
H.

12. A compound having the formula




wherein the relative conformation at the cyclohexyl group is cis and wherein R1, R2 and R3 are selected in concert from the group consisting of















R1
R2
R3









2-pyridylmethyl
trichloromethyl
4-fluorophenyl



benzyl
benzyl
phenylamino



3-chlorobenzyl
3-methoxyphenyl
phenylamino



3-chlorobenzyl
2-furyl
phenylamino



3-nitrobenzyl
3-methoxyphenyl
phenylamino.

13. A compound having the formula




wherein R1, R2, R3 and the stereo-configuration are selected in concert from the group consisting of













R1
R2
Stereo
R3







benzyl
t-butyl
1S, 3R
4-fluorophenyl


3-chlorobenzyl
t-butyl
1S, 3R
4-fluorophenyl


benzyl
trichloromethyl
1S, 3R
4-fluorophenyl


3-nitrobenzyl
trichloromethyl
1S, 3R
4-fluorophenyl


3,4-difluorobenzyl
t-butyl
1S, 3R
4-fluorophenyl


benzyl
trichloromethyl
1R, 3S
4-fluorophenyl.

14. A compound having the formula




wherein R1, X1, R2 and the stereo-configuration of the benzyl-methyl are selected in concert from the group consisting of















R1
X1
R2









H
CO
2-(phenyl)ethyl



H
CO
trichloromethyl



H
CO
4-biphenyl



H
CO
diphenylmethyl



H
CO
3-methoxybenzyl



H
SO2
4-biphenyl



benzyl
CO
trichloromethyl



benzyl
CO
2-(phenyl)ethyl.

15. A compound having the formula




wherein R1 and R2 are selected in concert from the group consisting of














R1
R2









benzyl
2-(phenyl)ethyl



H
diphenylmethyl



H
2-(phenyl)ethyl



benzyl
3-(phenyl)propyl



benzyl
2,2-dimethylpropyl



3-chlorobenzyl
2,2-dimethylpropyl.

16. A compound having the formula




wherein R1, R2, R3 and R4 are selected in concert from the group consisting of














R1
R2
A
R3
R4







3-chlorobenzyl
trichloromethyl
methyl-1,3-
phenylamino
4-morpholinyl




cyclopentyl


benzyl
t-butyl
1,4-cyclopentyl-2-
4-fluorophenyl
1-pyrrolidinyl




ene-methyl.

17. A compound of formula (XXX):



wherein
R1 is selected from the group consisting of hydrogen, aryl, aralkyl, heterocyclyl, diarylalkyl, heterocyclyl-alkyl, and lower alkyl; wherein the alkyl, aryl, heterocyclyl 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;
X4 is selected from the group consisting of CO and SO2;
A1 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 R7;
where R7 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 group 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 or alkoxycarbonyl;
R3 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, heterocyclyo-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 or alkoxycarbonyl;
Y is selected from the group consisting of —O—, —NH—, —S— and —SO2—;
n is an integer from 0 to 5
R4 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;
R5 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.

18. A compound having the formula



wherein R1, R2, R3 and R4 are selected in concert from the group consisting of














R1
R2
R3
R4







benzyl
H
phenylamino
4-morpholino


3-chlorobenzyl
H
phenylamino
4-morpholino


3,5-dichloro benzyl
H
phenylamino
4-morpholino


1-naphthylmethyl
H
phenylamino
4-morpholino


4-(1-hydroxy)-pyridyl
H
phenylamino
4-morpholino


benzyl
benzyl
4-fluorophenyl
1-pyrrolidinyl









and pharmaceutically acceptable salts, esters and pro-drug forms thereof.