WO1999021846A1

WO1999021846A1 - Cyclopentene derivatives useful as antagonists of the motilin receptor

Info

Publication number: WO1999021846A1
Application number: PCT/US1998/022765
Authority: WO
Inventors: Robert H. Chen; Min Xiang; John B. Moore, Jr.; Mary Pat Beavers
Original assignee: Ortho-Mcneil Pharmaceutical Inc.
Priority date: 1997-10-28
Filing date: 1998-10-27
Publication date: 1999-05-06
Also published as: BR9813169A; ATE267186T1; UA58563C2; ZA989784B; CA2307661A1; HRP20000241A2; MY129173A; NZ504040A; KR20010031569A; EE200000254A; PL340282A1; CN1278255A; NO20002036D0; EE04493B1; HK1028399A1; DE69824031T2; EA003252B1; AU1202499A; AU738370B2; PL194805B1

Abstract

The compounds of formula (I) are useful in treating gastrointestinal disorders associated with antagonizing the motilin receptor disorders. The compounds compete with erythromycin and motilin for the motilin receptor. In addition the compounds are antagonists of the contractile smooth muscle response to those ligands.

Description

CYCLOPENTENE DERIVATIVES USEFUL AS ANTAGONISTS OF THE MOTILIN RECEPTOR

CROSS REFERENCE TO RELATED APPLICATION This application claims the priority of provisional application Serial

Number 60/063,669, filed October 28, 1997

FIELD OF THE INVENTION This invention relates to a series of novel cyclopentene derivatives, pharmaceutical compositions containing them and intermediates used in their manufacture The compounds of the invention are useful as non-peptidyl antagonists of the motilin receptor In addition, the compounds display efficacy and potency which are comparable to known motilin and erythromycin antagonists

BACKGROUND In mammals, the digestion of nutrients and the elimination of waste is controlled by the gastrointestinal system This system is, to say the least, complicated There are a number of natural peptides, gands, enzymes, and receptors which play a vital role in this system 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 ammo acids which is produced in the gastrointestinal system of 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 ammo 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 agonsits are not always welcome physiological events. The increased gut motility induced by motilin has been implicated in diseases such as Irritable Bowel Syndrome and esophageal reflux. Therefore researchers have been searching for motilin antagonists.

One such antagonist is OHM-11526. This is a peptide derived from porcine motilin which competes with both motilin and erythromycin for the motilin receptor in a number of species, including rabbits and humans. In addition, this peptide is an antagonist of the contractile smooth muscle response to both erythromycin and motilin in an in vitro rabbit model. Depoortere, I. et al., European Journal of Pharmacology, 286, 241-47, (1995). Although this substance is potent in that model (IC ₅₀ 1.0 nm) it is a peptide and as such offers little hope as an oral drug since it is susceptible to the enzymes of the digestive tract. Zen Itoh, Motilin, xvi (1990). Therefore it is desirable to find other agents which are not peptides as potential 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 erythomycin 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 Formula I

wherein

Ri is hydrogen, Cι.₅aikyl, substituted d.₅alkyl (where the alkyl substituents are one or more halogens), aminoCι.₅alkyl, Cι.₅alkylaminoCι-₅alkyl; di-Cι.₅alkylaminoCι-₅aikyl, R_aR_bN-Cι.₅alkyl (where the R_a and R_b are independently selected from hydrogen and Cι.₅alkyl, or are taken together to form a morpholine, piperazine, piperidine, or N-substituted piperidine where the N- substitutent is

Cι.₅alkyl or phenylCι-₅alkyl), Cι-₅alkylcarbonyl, Cι-₅alkoxycarbonyl, aminocarbonyl, Cι-₉alkylaminocarbonyl, cycloC₃.₉alkylaminocarbonyl, pyridinylcarbonyl, substituted pyridinylcarbonyl (where the pyridinyl substituents are selected from the group consisting of one or more halogens and C_halky), thiophenecarbonyi, substituted thiophenecarbonyl (where the thiophene substituents are selected from the group consisting of one or more halogens and Cι-₅alkyl), phenyl, phenylCι.₅alkyl, phenoxycarbonyl, phenylcarbonyl, diphenylmethylcarbonyl, phenylaminocarbonyl, phenylthiocarbonyl, phenylaminothiocarbonyl, substituted phenyl, substituted phenylCι-₅alkyl, substituted phenoxycarbonyl, substituted phenylcarbonyl, substituted phenylammocarbonyl, substituted diphenylmethylcarbonyl, substituted phenylthiocarbonyl, and substituted phenylaminothiocarbonyl (where the phenyl substituents are selected from the group consisting of one or more of halogen, Cι-₅alkyl, tπhalomethyl, Cι.₅alkoxy, ammo, nitπle, nitro, Ci-salkylamino, dι-Cι.₅alkylamιno, if there are more than one substitutents they may be taken together with the phenyl ring to form a fused bicyclic 7-10 membered heterocyc c ring having one to two heteroatoms selected from oxygen, sulfur or nitrogen or the substituents may be taken together to form a fused bicyclic 7-10 membered aromatic ring, R₂ is hydrogen, Cι.₅alkyl, Cι_-5alkoxy, phenyl, substituted phenyl (where the phenyl substituents are selected from one or more of the group consisting of halogen and Cι.₅alkyl), phenyiCι.₅alkyl, substituted phenylCi ₅alkyl (where the phenyl substituents are selected from one or more of the group consisting of halogen, Cι-₅alkyl, Ci.salkoxy, halo and dι-Cι.₅alkylamιno) R₃ is hydrogen, Ci ₅alkylcarbonyl, substituted Cι.₅alkylcarbonyl (where the alkyl substituents are selected from one or more halogens), phenylcarbonyl, and substituted phenylcarbonyl (where the phenyl substituents are selected from one or more of the group consisting of halogen, Cι.₅alkyl, Cι.₅alkoxy, am o, Cι.₅alkylamιno, and di-Ci-salkylamino)

R₄ is hydrogen, Ci-salkylcarbonyl, substituted Cι-₅alkylcarbonyl (where the alkyl substituents are selected from one or more halogens), phenylcarbonyl, and substituted phenylcarbonyl (where the phenyl substituents are selected from one or more of the group consisting of halogen, Ci salkyl, Ci ₅alkoxy, am o, Ci ₅alkylamιno, and dι-Cι.₅alkylamιno)

where

X is oxygen, CH_2l sulfur, or NR_C where

Re is hydrogen, Cι-₅alkyl, morpholιnoCι-₅alkyl, pιperιdιnylCι-₅alkyl, N-phenylmethylpipeπdinyl or piperazinylCi-₅alkyl, with the proviso that if q and t are 0, then X is hydroxy, thiol, or am o, A is Cι.₅alkoxycarbonyl, phenylcarbonyl, or R₇R₈N- where R₇ is independently selected from hydrogen, Ci.salkyl, cycloC₃-₉alkyl, or R₇ is taken together with R₈ to form a 5 or 6 membered heterocychc ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur and N-oxides thereof, R₈ is independently selected from hydrogen, Cι-₅alkyl, cycloC_{3 9}alkyl or taken together with R₇ to form a 5 or 6 membered heterocychc ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, and N-oxides thereof, R₆ is hydrogen, halogen, Cι.₅alkoxy, Ci-salkylamino, or dι-Cι-₅alkylamιno or pharmaceutically acceptable salts thereof The compounds of formula I are useful in treating gastrointestinal disorders associated with the motilin receptor The compounds compete with erythromycin and motilin for the motilin receptor In addition, the compounds are antagonists of the contractile smooth muscle response to those hgands The present invention also comprises pharmaceutical compositions containing one or more of the compounds of formula I as well as methods for the treatment of disorders related to the gastrointestinal system which are associated with the motilin receptor Such diseases include Irritable Bowel

5 Syndrome, esophageal reflux, and the gastrointestinal side effects of erythromycin

DETAILED DESCRIPTION OF THE INVENTION

The terms used in describing the invention are commonly used and known to those skilled in the art However, the terms that could have other meanings are defined "Independently" means that when there are more than one substituent, the substituents may be different The term "alkyl" refers to straight, cyclic and branched-cham alkyl groups and "alkoxy" refers O-alkyl where alkyl is as defined supra The symbol "Ph" refers to phenyl, the term "fused bicyclic aromatic" includes fused aromatic rings such as naphthyl and the like The term "fused bicyclic heterocycle" includes benzodioxoles and

Since the compounds of the invention have a chiral center, some of the compounds are isolated as enantiomers In those cases the determination of absolute stereochemistry is pending

When compounds contain a basic moiety, acid addition salts may be prepared and may be chosen from hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuπc, nitric, phosphoric, acetic, propionic, glycohc, lactic, pyruvic, oxalic, malonic, succ ic, maleic, fumaπc, malic, tartaπc, citric, benzoic, cinnamic, mandehc, methanesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, 2-phenoxybenzoιc, 2-acetoxybenzoιc, or saccharin, and the like Such salts can are made by reacting the free base of compounds of formula I with the acid and isolating the salt

The compounds of the invention may be prepared by the following schemes, where some schemes produce more than one embodiment of the invention In those cases, the choice of scheme is a matter of discretion which is within the capabilities of those skilled in the art A synthesis of the compounds of the invention is depicted in Scheme

1 Essentially this scheme assembles two halves of the molecule and couples them For one half, 3-ethoxy-2-cyclohexen-1 -one, 1_a, is the starting material. 1_a is treated with a Grignard reagent, 1_b, such as 4-fluorobenzyl magnesium bromide at room temperature under an inert atmosphere, using ether as a solvent to give the α,β-unsaturated ketone derivative 1_c. Treatment of 1_c with a reducing agent such as LAH at 0 °C to room temperature over 16 h gives the alcohol, 1_d. This alcohol is treated with a strong base such as NaH and trichloroacetonitrile from 0 °C to room temperature for 16 h to give the amide 1_e. This six membered ring amide is sequentially treated with ozone at -78 °C, dimethylsulfide, and a catalytic amount of acid such as toluene sulfonic acid. Once addition is complete, the mixture is allowed to warm to room temperature over 24-64 h to give the five membered ring aldehyde 1_f, as a racemic mixture.

To assemble the other half, an aromatic alcohol 1_g, such as 3- hydroxyaniline is treated with a mild base, such as K₂CO₃, in a suitable solvent such as EtOH at 60 °C over 4-6 h. This mixture is subsequently treated with a halide derivative 1_h, such as 3-chloropropylmorpholine at room temperature to give the amine 1_i. This amine is treated with the aldehyde If and NaCNBH₃ in MeOH at room temperature over 30 min to give a compound of the invention, 1j as a racemic mixture.

If pure enantiomers are desired, they may be obtained in any of three stages of the synthesis. The alcohol 1_d, the aldehyde 1_f, and the product 1j may all be separated via HPLC using chiral columns or methods known of those skilled in the art. With respect to all three compounds, they may be further manipulated to give other compounds of the invention without sacrificing their enantiomeric purity. This scheme may be used to produce other compounds of the invention. For example, to produce compounds where X is sulfur, simply replace reagent 1_h with an aromatic thiol, such as 3-aminothiophenol and carry out the remaining steps of the Scheme. Scheme 1

To produce other substitutions at R₃ or R₄ some of the products of Scheme 1 may be used. For example, to produce a compound where R₃ is hydrogen and R₄ is CH₃C(O)-, the six-membered ring intermediate 1_e, is treated with a base, such as barium hydroxide, at reflux in EtoH to give the free amine 2a. The amine is subsequently treated with an acid anhydride, such as trifluoroacetic anhydride to give 2b. This intermediate may be carried through the remaining steps of Scheme 1 to produce the desired compound.

Scheme 2

The products of Scheme 1 may be used to produce other compounds of the invention. For example, to produce compounds of type 3a, treat compound 1j with a phenyl isocyanate at room temperature over 24 h. To produce compounds of type 3b, 1j may be treated at room temperature with acid chloride derivatives such as benzoyi chloride. In order to produce thiols 3c, compounds of type 1j may be treated with isothiocyanates, such as phenylisothiocyanate at room temperature. As discussed earlier, if pure enantiomers are desired, they may be obtained by chromatography of the reactant, K or the products. Scheme 3

Yet another scheme (Scheme 4) makes use of the intermediate of Scheme 1 Treatment of the aldehyde, 1j, with a nitroaniline derivative 4a, and NaCNBH₃ at room temperature gives the coupled intermediate 4b. This intermediate may be acylated with benzoyi chloride and a mild base such as triethylamine to give the N-acyl intermediate 4c. 4c may be treated with a reducing agent such as Pd/C to give the aniline compound 4d. This compound may be coupled with a halogen derivative 4e, such as 3-chloropropylpiperidine, using DBU and an alcoholic solvent at reflux over 4 h to give a mixture of mono and di amine products.

Scheme 4

To prepare compounds of the invention where n is 1-3, products of Scheme 1 are used in Scheme 5. Intermediate If is treated with 3-(m- hydroxyphenyl)propylamine, an aromatic amino alcohol derivative 5a, and NaCNBH₃ at room temperature over 16 h to give the amine 5b. Treatment of 5b with a thiocyanate derivative 5c, and a mild base at room temperature gives the substituted thioamide 5d. This compound may be treated with a halide reagent, 5e, and a base such as DBU in an alcoholic solvent at reflux to give the O-substituted compound of the invention.

Scheme 5

The compounds of the invention were tested for their ability to compete with radiolabeled motilin (porcine) for the motilin receptors located on the colon of mature rabbits. The colon from mature New Zealand rabbits was removed, dissected free from the mucosa and serosa layers, and diced into small pieces. The muscle tissues were homogenized in 10 volumes of buffer (50 mM Tris-CI, 10 mM MgCI₂, 0.1 mg/mL bactracin, and 0.25 mM Peflabloc, pH 7.5) in a Polytron (29,000 rpm, 4 x 15 seconds). The homogenate was centrifuged at 1000 xg for 15 min. and the supernatant discarded. The pellet was washed twice before being suspended in homogenizing buffer. This crude homogenate is then passed first through a 19 gauge needle then a 23 gauge needle to further suspend the material and stored as -80 °C. In a total volume of 0.50 mL, the binding assay contains the following components added sequentially, buffer (50 mM Tris-CI, 10 mM MgCI_2, 1 mM EDTA, 15 mg/mL BSA, 5 μg/mL leupeptin, aprotinin, and pepstatin, and 0.1 mg/mL, bactracin), I¹²⁵ motilin (Amersham, ca 50,000-70,000 cpm, 25-40 pM), the test compound (the initial concentration was 2 mM/100% DMSO, which diluted with H₂O to a final concentration of 10 μM) and membrane protein (100-300 μg). After 30 min, at 30 °C, the material was cooled on ice and centrifuged at 13,000 xg for 1 minute. The pellet was washed with 1 mL 0.9% saline and centrifuged at 13,000 xg for 15 seconds. The pellet was washed again with cold saline and the supernatant was removed. The pellet was counted in the gamma counter to determine the percentage of unbound motilin and thereby the percent inhibition of the test compound. IC _50s were determined for some compounds by standard techniques.

Table A

RWJ/Cod R, n R< R IC™ / % Inhib on

8 phemlNH-C(O) 0 3-0(CH₂)₂morpho n- 1 -yl H 20 nM **

9 p enylNH-C(O) 0 3-0(CH₂)_:moφholιn-l-yl H >300 nM ***

69 H 0 4-OH H H% @ 10 μM

50 (CH₂)₂NEt₂ 0 3-OH H 81% @ 10 μM

51 (CH_:)₂NEt2 0 3-0(CH₂)₂NEt₂ H 0 6% @ 10 μM

52 (CH-)-NEt₂ 0 3-0(CH₂)₂pipcndin-l-yl H 0 6

53 (CH₂)₂NEt₂ 0 3-0(CH_:)₂moφho n- 1 -yl H 0 3

54 (CH2)_:NEt₂ 0 3-0(CH₂)₃pιpeπdιn-l-yl H 0 9

55 (CH₂)₂NEt2 0 3-0(CH₂)₂pyrrohdin-l-yl H 0 9

70 (CH₂)₂NEt₂ 0 2-0(CH₂)₂moφho n-l-yl H 80% @ 10 μM

71 (CH₂)₂NEt₂ 0 4-0(CH₂)₂NMe₂ H 85% @ 10 μM

57 (CH₂)₂- 1 3-0(CH₂)₂moφholιn-l -> 1 H 0 7 mo hohn-1-yl

72 (CH_:)₂NEt₂ 0 2-0(CH₂)₂moφholιn-l-yl H 0 9

73 (CH₂)₂NEt₂ 0 2-OH H 84% @ 10 μM

74 (CH₂) NEt2 0 4-OH H 81% 10 μM

75 H 0 3-NH₂ H 41% @ 10 μM

76 (CH₂)₂NEt₂ 2 4-OH H 84% @ 10 μM

77 1-benzylpιp- 1 3-0(CH₂)₂NEt₂ H 0 8 eπdιn-4-yI

58 H 0 3-S(CH_:)2NEt₂ H 61% @ 10 μM

78 CH,C(0) 0 3-0(CH₂)₂moφholιn-l-yl H 1 03

10 phenvlC(O) 0 3-0(CH₂)₂moφholιn- 1 -yl H 0 3

6 H 0 3-0(CH₂)₂moφholιn-l-yl H 37% @ 10 μM

46 phenylC(O) 0 3-OCH₂C0₂Et H 51 % @ 10 μM

79 phenvlC(O) 0 3-S(CH₂)₂NEt₂ H 98% (0⁾ 10 μM phcnylNH-C(O) 0 3-S(CH₂)₂ιnoφholin-l-yi H 83% ®. 10 μM

4-F-phenyl-C(0) 0 3-S(CH₂)₂moφholin-l-yl H 79% ®. 10 μM

H 2 3-0(CH₂)₂moφholin-l-yl H 81% ®. 10 μM phcnylC(O) 0 3-S(CH₂)₂moφholin-l-yl H 80 % ®, 10 μM phenyΙC(O) 1 3-0(CH₂)₂NEt₂ H 100% 10 μM

4-CH₃0-phcnylC(0) 0 3-S(CH₂)₂moφholin-l-yl H 59 % @ 10 μM

(CH₂)₂- 2 3-0-C(0)phenyl H 9 % @ 2.0 μM moφholin-1-yl phcnylC(O) 0 4-S(CH₂)₂N(CH₃)₂ H 49% ® 2.0 μM

H 0 3-0(CH₂)₂moφholin-l-yl 4-OCH₃ 27% @ lOμM

H 0 3-OH 4-OCH, 32%®. lOμ M benzyl 1 3-0(CH₂)₂moφholin-l-yl H 94% ®, 10 μM

4-CH,0-phcnylNH-C(0) 0 3-0(CH₂)₂moφhoIin-l-yl H 26% l®. 5.0 μM

3-CH,0-phcnyl-C(0) 0 3-0(CH₂)-moφholin-l-yl H 65% ®, 0.5 μM phenylC(O) 1 1-benzylpip- H 77% ® 10 μM eridin-4-amino

(CH₂)₂NEt2 2 3-0(CH₂)₂itιoφholin-l-yl H 95% ®. 10 μM phenylC(O) 1 3-0(CH₂)₂moφhoIin-l-yl H 70 % @ 10 μM

4-F-phcnyl-C(0) 0 3-0(CH₂)_:moφholin-l-yl H 52 nM

4-CH₃0-phcnyl-C(0) 0 3-0(CH₂)₂moφholin-l-yl H 90 nM phenylNH-C(O) 0 3-0(CH₂)₂moφholin-l-yl H 45 nM benzyl 0 3-0(CH₂)₂moφholin-l-yI 4-OCH₃ 62%®.10μM

H 0 3-0(CH₂)₂moφholin-l-yl 4-OCH₃ 48% ®, lOμM phcnylC(O) 0 3-0(CH₂)₂moφholin-l-yl 4-OCH₃ 74% ®. lOμM

(CH.fc- 2 3-0-C(0)phcnyl 4-OCH, 22%®.2.0μM moφholin-1-yl phenylC(O) 2 3-0(CH₂)₂moφholin-l-yl H 82% 10 μM

4-(CH₃)₂N-phenylC(0) 2 3-0(CH₂)₂moφholin-l-yl H 62% ®, 1.0 μM

3,4-dichlorophcnylC(0) 0 3-0(CH₂)₂moφholin-l-yl H 260 nM

4-F-phenylC(0) 0 3-(CH₂)₃moφholin-l-yl H 17 % @ 1.0 μM

3,5-di-CF₃-phenylC(0) 0 3-0(CH_:)₂moφholin-l-yl H 28 % ®, 1.0 μM 100 2.3.4,5,6-pentafluoro- 0 3-0(CH₂)_:moφholιn- 1-yl H 1000 nM -phenylC(O)

19 phenyl-NHC(O) 0 3-(CH₂)₃moφholιn- 1 -yl H 59 % ® 1 0 μM

61 4-Br-phenylC(0) 0 3-0(CH₂)₂moφholιn- l-yl H 64% ® 0 05 μM

101 3-Br-phenylC(0) 0 3-0(CH₂)₂moφhohn- l-yl H 54% ® 0 1 μM

102 4-Cl-phenylC(0) 0 3-0(CH₂)₂moφhohn- l-yl H 61% ® 0 1 μM

103 3-CF₃-phenylC(0) 0 3 -0(CH₂)₃mo hol l n- l-yl H 52 % ® 0 1 μM

104 4-CF₃-phenylC(0) 0 3-0(CH₂)₂moφholιn- l-yl H 29 % @ 0 1 μM

105 4-I-phenylC(0) 0 3-0(CH₂)₂moφho n- -yl H 59 % @ 0 1 μM

106 3,5-dι-F₂-phenylC(0) 0 3-0(CH₂)₂mo hohn- -yl H 78 % @ 0 1 μM 2 3,4-dι-F₂-phenvlC(0) 0 3 -0(CH₂)₂moφhohn- -yl H 50 nM

1407 4-(phenyl)phenylC(0) 0 3-0(CH₂)₂moφholιn- -yl H 58% ® 1 0 μM

108 thιophcn-2-yl-C(0) 0 3-0(CH₂)₂moφholιn- -yl H 84% ® 1 0 μM

11 phenylNH-C(S) 0 3-0(CH₂)₂moφholιn- -yl H 45 % ® 0 1 μM

109 4-NC-phenylC(0) 0 3-0(CH-)₂moφhohn- -yl H 98 nM

110 4-t-butyl-phcnylC(0) 0 3-0(CH₂)₂moφholιn- -yl H 19 % ® 1 O μM

111 pyπdιn-4-yl-C(0) 0 3-0(CH₂)₂moφhohn- -yl H 51% ® l O μM 3 3-F-phenyl-NHC(0) 0 3-0(CH₂)₂moφholιn- -yl H 37 nM

112 3-Br-phenyl-NHC(0) 0 3-0(CH₂)₂moφho n- -yl H 51% ® 1 O μM 8 4-Br-phenyI-C(0) 0 3-0(CH₂)₂moφhohn-] -yl 6-C1 59% ® 1 0 μM

113 3-F-phenyl-C(0) 0 3-0(CH₂)₂moφholιn-l -yl 6-C1 59% ® 1 0 μM

114 3,4-dιF-phcn>l-C(0) 0 3-0(CH )₂moφhohn- 1 -yl 6-C1 52% ® 100 μM

115 2-Br-thιophen- 0 3-0(CH₂)₂mo hohn-1 -yi H 65% ® 1 0 μM l-yl-C(O)-

116 4-N0₂-phenvlC(0) 0 3-0(CH₂)₂moφholιn-l -yi H 69% ® 0 1 μM

117 dι-phenvl-CH-C(O) 0 3-0(CH₂)₂moφholιn-] -yl H 42% ® 1 0 μM

118 phenyl-OC(O) 0 3-0(CH₂)₂mo holιn- 1 -yl H 51% ® 1 O μM

119 cyclohcxyl-NHC(O) 0 3-0(CH₂)₂moφhohn-I -yi H 56% ® 1 0 μM

Table B

CDd. R, n R, ICsn / % Inhibition

120 4-F-phcnyl-NH-C(0) 0 3-Cl-benzyl 10 nM

121 4-F-phcnyl-C(0) 0 3-Cl-benzyl 30 nM

65 4-F-phenyl-C(0) 0 4-McO-benzyl 56 nM

66 phcnyl-C(O) 0 4-McO-benzyl 56 nM

122 1.3-benzodιo\ol-5-yl-C(0) 0 benzyl 77% @ 1.0 μM

123 phenyl-NH-C(O) 0 (CH₃)₂CH- 51% ® 1.0 μM

124 naphlhy-l -yl-C(O) 0 bcnzyl 40% ® 0.1 μM

125 4-F-phenyl-C(0) 0 4-F-bcnzyl 43% ® 0.04 μM

126 3-F-phenyl-C(0) 0 4-F-benzyl 44% @ 0.04 μM

67 phcnyl-NHC(O) 0 4-F-bcnzyl 34% ® 0.25 μM

127 phcnyl-NHC(O) 0 phenyl 33% @ 0.1 μM

128 4-F-phcnyl-C(0) 0 phenyl 43% ® 0.1 μM

68 phcnyl-NHC(O) 0 3-Cl-benzyl 70% ® 0.1 μM

129 4-Br-phcnyl-C(0) 0 3-Cl-bcnzyl 70% ® 0.1 μM

130 3.4-dι-F-phenyl-C(0) 0 3-Cl-bcnzyl 78% ® 0.1 μM

Inhibition

131 H benzyl CF₃C(0) 3-0(CH₂)_:moφholin-l-yl 25 % ® 10 μM

132 phenyl-C(O) benzyl CF₃C(0) 3-0(CH₂)₂moφholin-l-yl 0.73 nM 15 phenyl-NH-C(O) benzyl CH₃C(0) 3-0(CH₂)₂ιnoφholin-l-yl 40 % ® 1 0 μM 133 4-F-phenyl-C(0) benzyl CH₃C(0) 3-0(CH₂)₂moφholin-l-yl 51 % ®. 1.0 μM

134 phenyl-NH-C(O) benzyl CF₃C(0) 3-0(CH₂)_: oφholin-l-yl 69 % ®, 1.0 μM

135 (CH₂)₂NEt₂ (CH₃)CH CC1₃C(0) 3-0(CH₂)₂N(CH₃)₂ 1.6 nM

Table D

Cpd. R, ICso / % Inhibition

136 phcnyl-NH-C(O) 57% ®, 1.0 μM

137 4-Br-phcnyl-C(0) 50% ®. 1.0 μM Select compounds of the invention were evaluated for their ability to inhibit motilin and erythromycin induced contractions in the rabbit duodenum smooth muscle. Rabbits were fasted 24-48 h and euthanized . The venral midline incision was made approximately 7.5 cm above the umbilicus upto the xyphoid process, exposing the upper peritoneal cavity. The first 8 cm. of the duodenum starting at the pyloric valve was quickly removed and placed in Krebs solution containing NaCl, (120 m), KCI (4.7 mM), MgSO₄ ^*7 H₂O (1.2 mM), CaCI₂*2 H₂O (2.4 mM), KH₂PO₄ (1 mM), D-glucose (10 mM), and NaHCO₃ (24 mM). The lumen was flushed with Krebs and excess tissue was removed. The tissue was cut lengthwise, splayed open with the longitudinal muscle layer facing up, and the longitudinal muscle layer was released away from the circular muscle and cut into 3x30 mm strips. A pre-tied 4-0 silk ligature with a loop was placed at the middle of the strip and the strip was folded over the loop so the strip was half its original length. The tissues were mounted in a 10 mL tissue bath (Radnotti Glass Technology, Inc., Monrovia, CA.) containing Krebs solution gassed with 95% O₂ 5% CO₂ at 37 °C. The tissues were attached to a force displacement transducer (FT03, Grass

Instruments, Quincy, MA.) and resting tension was slowly increased to 1 g.

The tissues were allowed to equilibrate for 60-90 min with 2-3 wash cycles. The tissues were equilibrated with two initial contractions induced by a concentration of acetylcho ne (1 x 10^"4 M) that produced a maximal contraction (0.1 mM), with the highest taken as 100% maximal contraction of that tissue. Base line and response levels are expressed as grams tension developed and as a percent of the response to acetylchohne. The test compounds were dissolved in DMSO (2 mM/100% DMSO) and applied to the prepared strips 5-15 minutes prior to the addition of porcine motilin. After addition, the tension is constantly monitored over 5 min and the maximum tension is recorded The percent contraction was measured at four ascending concentrations and where appropriate IC_50s were determined.

Table A

8 phenylNH-C(O) 0 3-0(CH₂)₂moφholιn-l-yi H 280 nM **

9 phenylNH-C(O) 0 3-0(CH₂)₂moφholιn-l-yl H 890 nM ***

50 (CH₂)-NEt- 0 3-OH H 98% ® 20 μM

51 (CH_:)_NEt2 0 3-0(CH₂)₂NEt₂ H 74% ® 5 μM

52 (CH₂)₂NEt_: 0 3-0(CH₂):pιpeπdιn-l-yl H 70% ® 10 μM

53 (CH₂)_:NEt₂ 0 3-0(CH₂)₂moφholm-l-yl H 3.93 mM

54 (CH₂)₂NEt₂ 0 3-0(CH₂)₃pιpeπdιn-l-yl H 24% ® 5 μM

55 (CH_:)_:NEl₂ 0 3-0(CH₂)₂pyrrolidιn-l-yl H 43% ® 2 μM

56 H 0 4-S(CH₂)₂NMe₂ H 24% ® 2 μM

57 (CH₂)₂- 1 3-0(CH₂)₂moφholin-l-yl H 1 06 moφholιn-1-yl

58 H 0 4-S(CH₂)2NEt₂ H 44% ® 2.0 μM

10 phenylC(O) 0 3-0(CH₂)₂moφholιn-l -yl H 393 nM

59 4-F-phenyl-C(0) 0 3-0(CH₂)₂moφholιn-l-yl H 54% ® 3 0 μM

60 4-CH,0-phcnyl-C(0) 0 3-0(CH₂)₂moφhohn-l-yl H 49% ® 10 μM 7 phenvlNH-C(O) 0

H 287 nM

61 4-Br-phenyIC(0) 0 3-0(CH₂)₂ oφholιn-l-yl H 63% ® 1.0 μM 62 3,4-di-F₂-phenylC(0) 0 3-0(CH₂)₂moφholin-l-yl H 65% ®. 1.0 μM

63 3-F-phenyl-NHC(0) 0 3-0(CH₂)₂moφholin-l-yl H 63.8% ®, 1.0 μM

c, ^cl

Table B

Cod. R, n Rs ICsn / % Inhibition

65 4-F-phenyl-C(0) 0 4-MeO-benzyl 72% ®. 1.0 μM

66 phenyl-C(O) 0 4-McO-benzyl 58% ®. 1.0 μM

67 phenyl-NHC(O) 0 4-F-benzyl 25.7% ®. 1.0 μM

68 phenyl-NHC(O) 0 3-Cl-benzyl 51% ®. 1.0 μM

Although the claimed compounds are useful as modulators of the motilin receptor, some compounds are more active than others. These compounds are particularly preferred.

The particularly preferred compounds are those where: Ri is phenylaminocarbonyl, phenylcarbonyl, substituted phenylaminocarbonyl, substituted phenylcarbonyl, and hydrogen; R₂ is phenylCι.₅alkyl; R₃ is hydrogen; R₄ is trifluoromethylacetyl; R₅ is O-(CH₂)₂-morpholin-1-yl; R₆ is hydrogen; n is 0; and m is 1. 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, glycois, 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 1-2tιmes 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 EXAMPLES Example 1

Cpd.1 A solution of 3-ethoxy-2-cyclohexen-1 -one (125 g, 0.89 mol) in ether (500 mL) was added at room temperature to a solution of 2M benzyl magnesium chloride (800 mL) under N₂ and stirred for 6h. The resulting mixture was poured into a solution of 30% H₂SO and stirred for 5 h. The resulting organic layer was separated, and the aqueous layer was extracted with several portions of ether. The combined organic layer was dried (MgSO₄), and concentrated in vacuo to give compound 1 (161 g) as a colorless oil. NMR(CDCI3): 3.45 (s, 2H, benzylic protons), 5.83 (bs, 1 H, olefinic proton), 7.22 (m, 5H, aromatic protons).

Example 2

Cpd. 2 A solution of compound 1 (161 g, 0.87 mol) in ether (700 mL) was slowly added to a suspension of LAH (33 g, 0.87 mol) and ether (100 mL) at 0 C under N₂.. The resulting mixture was stirred overnight at ambient temperature and cooled to O °C. Saturated K₂CO₃ solution was added to quench the excess LAH, the mixture was filtered through Celite and washed with several portions of ether. The combined organic layers were dried (MgSO₄) and concentrated in vacuo to give compound 2 (150 g) as a colorless oil.

NMR(CDCI3): 3.23 (s, 2H, benzylic protons), 4.20 (bs, 1 H, CHOH),5.52 (bs, 1 H, olefinic proton), 7.22 (m, 5H, aromatic protons). Example 3

Cpd. 3 A solution of compound 2 (132 g, 0.7 mol) in ether (500 mL) was added to a suspension of hexane washed 60% NaH (27 g, 0 7 mol) in ether (500 mL) at 0 C under N₂and stirred for 1 h Trichloroacetonitπle (1 15 g, 0.8 mol) was slowly added and the resulting mixture was allowed to warm to ambient temperature and stirred overnight The solvent was removed in vacuo, hexane (1 L) was added and the mixture was cooled to 0 C. Methanol (150 mL) was added and the resulting solid was filtered through Celite The organic solvent was removed in vacuo to give a crude intermediate (215 g). This intermediate was dissolved in xylene (1 L) and heated to reflux for 3 h under N₂. The solvent was removed in vacuo, ether (3 L) and the solid precipitate was filtered to give compound 3 (106 g) as a white crystal: mp 105-06 °C; NMR(CDCI3) 3 20 (Abq, J = 8 Hz, 2H), 5.92 (m, 2H, olefinic protons), 6.28 (bs, 1 H, NH), 7 22 (m, 5H, aromatic protons).

Example 4

Cpd. 4a Cpd. 4b

A solution of compound 3 (35 g, mmol) in methyiene chloride (500 mL) was treated with ozone at -78 °C until the solution turned blue. The excess of ozone was removed with a stream of N₂, dimethyl sulfide (5 mL) was added and the mixture was allowed to warm to room temperature. TsOH-H₂O (3.0 g) was added and the resulting mixture was stirred for 48 h. The solvent was removed in vacuo and residue was dissolved in methyiene chloride and treated with hexane. The resulting mixture was stirred for 2 h and the resulting solid was filtered. This solid was washed with hexane and dried in vacuum oven overnight to give compound 4 (21.8 g) as a racemic mixture: mp 162 °C. NMR(CDCI3): 3.20 (Abq, J = 8 Hz, 2H), 6.85 (bs, 1 H, NH), 7.05 (s, 1 H, olefinic proton), 7.22 (m, 5H, aromatic protons). 9.91 (s, 1 H, CHO). Compound 4 was separated into the pure enantiomers 4a, and 4b by using a chiral column.

Cpd. 5 A mixture of 3-hydroxyaniline (20.1 g, 190 mmol) K₂CO₃ (38 g) and EtOH (300 mL) was stirred at 60 °C for 6 h under N₂. The mixture was cooled to room temperature and 2-chloroethylmorpholine (16 g, mmol) was added. The resulting mixture was heated to reflux for 7 h, cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using 3 MeOH/ ethyl acetate to give compound 5 as a brown oil (22.5 g).

Cpd. 6

Cpd. 6a

Cpd. 6b NaCNBH₄ (1.0.g) was added in three portions to a solution of compound 4 (7.3 g, 21.0 mmol), compound 5 (6.2 g, 279 mmol) acetic acid (5.5 mL) in methanol (300 mL) at room temperature under N₂. and stirred for 30 min. Most of methanol was removed in vacuo and the residue was diluted with methyiene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel using ethyl acetate: hexane 9:1 to give compound 6 (10.3 g) as a light brown oil. NMR(CDCI3): 3.20 (Abq, J = 8 Hz, 2H), 5.63 (s, 1 H, olefinic proton), 6.61 (bs, 1 H, NH). This racemic mixture was separated by HPLC using a chiral column (CHIRALCEL®OD™) and isopropanol and hexane (1 :1 ) as an eluent into 6a and 6b. The oxalate salt of racemic 6, mp 90-92 °C. MS ( MH⁺= 552)

Example 7 3-Benzyl-3-trιchloroacetyiamιπo-1 -(Λ/-phenylamιnocarbonyl)-Λ/-[(3- (2-morphohnoethoxy)phenyl)amιno]methylcyclopentene

Cpd 7

To a solution of compound 6 (10 1 g) and tnethylamine (0 1 mL) in methyiene chloride (300 mL) was added phenyl isocyanate (7 8 g, mmol) at room temperature under N₂ dropwise The resulting mixture was stirred for 24 h and most of solvent was removed in vacuo The oily residue was purified by column chromatography on silica gel using ethyl acetate hexane 95 5 as an eluent to give an oil (12 5 g) NMR(CDCI3) 3 17 (Abq, J = 8 Hz, 2H), 3 73 (m, 4H,CH2NCH2) 4 08 (t, 2H OCH2-) 5 92 (m, 2H, olefinic protons), 6 28 (bs, 1 H, NH), 7 22 (m, 5H, aromatic protons) Treatment of the oil with 1 N HCI in ether gives compound 7, the title compound (12 2) as a solid mp 70-73(dec ) MS 657(MH⁺)

Example 8 3-Benzyl-3-trιchloroacetylamιno-1 -(Λ/-pheπylamιnocarbonyl)-Λ/-[(3- (2-morphohnoethoxy)phenyl)amιno]methylcyclopentene

^HN-coccι₃

Cpd 8

To a solution of compound 6b (15 mg) and tnethylamine (1 drop) in methyiene chloride (5 mL) was added phenyl isocyanate (16 mg) at room temperature under N₂ dropwise The resulting mixture was stirred for 24 h and most of solvent was removed in vacuo The oily residue was purified by preparative TLC on silica gel using ethyl acetate hexane 95:5 as an eluent to give an oil. Treatment the oil with oxalic acid (or HCI) in ether gives compound 8, the title compound (15 mg) as a solid: mp 92-94 °C. MS ( MH⁺= 671 )

Example 9

3-Benzyl-3-trichloroacetylamino-1-(Λ/-phenylaminocarbonyl)-Λ/-[(3-

(2-morpholinoethoxy)phenyl)amino]methylcyclopentene

Cpd. 9 To a solution of compound 6a (14 mg) and tnethylamine (1 drop) in methyiene chloride (5 mL) was added phenyl isocyanate (14 mg) at room temperature under N₂ dropwise . The resulting mixture was stirred for 24 h and most of solvent was removed in vacuo. The oily residue was purified by preparative TLC on silica gel using ethyl acetate hexane 95:5 as an eluent to give an oil. Treatment the oil with oxalic acid in ether gives compound 9, the title compound (14 mg) as a solid.

Example 10

3-Benzyl-3-trichloroacetylamino-1-(Λ/-phenylcarbonyl)-Λ/-[(3-

(2-morpholinoethoxy)phenyl)amino]methylcyclopentene

Cpd. 10 Benzoyi chloride (31 mg) was added to a solution of compound 6 (55 mg) and tnethylamine (0.3 mL) in methyiene chloride (30 mL) at room temperature under N₂ and stirred for 2 hours. Most of solvent was removed in vacuo and the oily residue was purified by column chromatography on silica gel using ethyl acetate as an eluent to give a light brown oil (53 mg). This oil was treated with oxalic acid in ether to give the title compound as an off-white powder (47 mg): mp 79-81 °C. MS ( MH⁺= 656)

Example 1 1

3-Benzyl-3-trichloroacetylamino-1 -(Λ/-phenyiaminosulfonyl)-Λ/-[(3-

(2-morpholinoethoxy)phenyl)amino]methylcyclopentene

Cpd. 1 1 Phenyl isothiocyanate (15 mg) was added dropwise to a solution of compound 6 (30 mg) and triethylamine (1 drop) in methyiene chloride (5 mL) at room temperature under N₂. The resulting mixture was stirred for 24 h and most of solvent was removed in vacuo. The oily residue was purified by prep TLC on silica gel using ethyl acetate hexane 95:5 as an eluent to give an oil. Treatment the oil with 1 N HCI in ether gives compound 1 1 , the title compound (33 mg), as a solid: mp 105-108 °C. MS ( MH⁺= 687)

Example 1 1

Cpd. 11 A mixture of compound 3 (3.5 g), barium hydroxide (4 g) and EtOH (100 mL) was heated at reflux overnight. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1 % triethylamine/ethyl acetate as an eluent to give compound 11 as a pale yellow oil (1.1 g). NMR; 2.72 (Abq, J = 8 Hz, 2H, benzilic protons), 5.54 (bd, J = 9 Hz, 1 H, olefinic proton at 2 position), 5.63(dt, 1 H, the other olefinic proton), 7.23 (m, 5H, aromatic protons).

Example 12

Cpd. 12 A mixture of compound 9 ( should be 11 ) (350 mg) tnethylamine (200 mg), acetic anhydride (200 mg) and methyiene chloride (50 mL) was stirred at room temperature under N₂ for 3h. The mixture was diluted with methyiene chloride (50 mL) and poured into ice cold 1 N NaOH (50 mL). The organic layer was separated, dried and the solvent was removed in vacuo to give compound 12 (376 mg) as a pale yellow oil. NMR(CDCI3): 1.94 (s, 3H, acetyl), 3.10 (Abq, J = 8 Hz, 2H), 5.92 (m, 2H, olefinic protons), 6.28 (bs, 1 H, NH), 7.22 (m, 5H, aromatic protons).

Example 13

A solution of compound 12 (376 mg) in methyiene chloride (100 mL) was treated with ozone at -78 °C until the solution turned blue. The excess of ozone was removed with a stream of N₂, dimethyl sulfide (0.5 g) was added and the mixture was allowed to warm to room temperature. TsOH-H₂O (100 mg) was added and the resulting mixture was stirred for 4 days. The mixture was poured into ice cold 1 N NaOH (50 mL) and the resulting organic layer was separated and purified by column chromatography on silica gel using ethyl acetate and hexane (1 :5) as an eluent to give compound 13 (273 mg) as an oil. NMR(CDCI3): 1.96 (s, 3H, acetyl), 3.20 (Abq, J = 8 Hz, 2H), 6.85 (bs, 1 H, NH), 7.03 (s, 1 H, olefinic proton), 7.22 (m, 5H, aromatic protons). 9.85 (s, 1 H, CHO).

Cpd. 14

NaCNBH (150 mg) was added in three portions to a solution of compound 13 (273 mg), compound 5 (297 mg) acetic acid (0.5 mL) in methanol (50 mL) at room temperature under N₂. and stirred for 30 min. Most of methanol was removed in vacuo and the residue was diluted with methyiene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel using ethyl acetate:MeOH:triethylamine (100:1 :0.5) to give compound 14 (303 mg) as a light brown oil NMR; 1.88 (s, 3H. acetyl) 3.13 (Abq, J = 8 Hz, 2H, benzilic protons), 4.10 (t, J = 6Hz, 2H, phenoxymethylene protons), 5.62 (bs, 1 H, olefinic proton),

Example 15 3-Benzyl-3-acetylamino-1-(Λ/-phenylaminocarbonyl)-/V-[(3- (2-morpholinoethoxy)phenyl)amino]methylcyclopentene

Cpd. 15

To a solution of compound 14 (25 mg) and tnethylamine (1 drop) in methyiene chloride (5 mL) was added phenyl isocyanate (14 mg) at room temperature under N₂. The resulting mixture was stirred for 24 h and most of solvent was removed in vacuo. The oily residue was purified by prep TLC on silica gel using ethyl acetate hexane 95:5 as an eluent to give an oil. Treatment the oil with oxalic acid in ether gives compound 15, the title compound (33 mg) as a solid: mp 85-89 °C. MS ( MH⁺= 569)

Example 16 Preparation of Compound 16

Cpd. 16 A solution 1 N BHs/THF (20 mL) was added to a solution of 3-(3- aminophenyl)propionic acid (1.5 g) in THF (15 mL) at 0 °C under N₂. After addition the mixture was allowed to warm up to room temperature and was stirred overnight. 2N NaOH was carefully added, the resulting mixture was stirred for 4 h and most of the solvent was removed in vacuo. The residue was extracted with methyiene chloride (200 mL) and the organic layer was dried and concentrated in vacuo to give compound 16 as a light yellow oil (1.1 g). NMR(CDCI3);3.71 ( t, J = 6Hz, 2H, CH2OH), 6.72-7.13 ( m, 4H, aromatic protons). Example 17 Preparation of Compound 17

Cpd. 17 NaCNBH₄ (30 mg) was added in three portions to a solution of compound 4 (150 mg), compound 16 (100 mg) and acetic acid (10 drops) in methanol (25 mL) at room temperature under N₂. and stirred for 30 min. Most of methanol was removed in vacuo and the residue was diluted with methyiene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel using ethyl acetate: hexane (1 :1 ) to give compound 15 (201 mg) as a pale yellow oil. NMR(CDCI3); 3.16 (Abq, J = 8 Hz, 2H, benzilic protons), 3.72 (t. J = 6 Hz, 2H, CH2OH), 3.82 (s, 2H, CH2N), 5.62 (s, 1 H, olefinic proton), 6.50-7.25 ( m, 9H, aromatic protons).

Example 18

Cpd. 18 Mesyl chloride (46 mg) was added to a solution of compound 17 (2.01 mg) and triethylamine (0.2 mL)in methyiene chloride (50 mL) at -5 °C under N . This mixture was stirred for 5 min and MeOH (2 drops) was added and the resulting mixture was allowed to warm to room temperature and poured into 1 N NaOH (10 mL). The organic layer was separated, dried and the solvent was removed in vacuo to give a thick brown oil. This oil was dissolved in THF (10 mL) and morphohne (50 mg) and the resulting mixture was heated at reflux for 16 h

The mixture was cooled to room temperature and the solvent was removed m vacuo The residue was purified by column chromatography on silica gel using ethyl acetate tnethylamine (100 0 5) to give compound 18 (85 mg) as a pale yellow oil NMR(CDCI3), 3 18 (Abq, J = 8 Hz, 2H, benzihc protons), 3 82 (s, 2H, CH2N), 5 62 (s, 1 H, olefinic proton), 6 50-7 25 ( m, 9H, aromatic protons)

Example 19

3-Benzyl-3-trιchloroacetylamιno-1-(Λ/-phenylamιnocarbonyl)-Λ -[(3- (3-morphohnopropyl)phenyl)amιno]methylcyclopentene

Cpd 19 To a solution of compound 18 (32 mg) and tnethylamine (1 drop) in methyiene chloride (5 mL) was added phenyl isocyanate (25 mg) at room temperature under N₂ dropwise The resulting mixture was stirred for 24 h and most of solvent was removed in vacuo The oily residue was purified by preparative TLC on silica gel using ethyl acetate hexane 95 5 as an eluent to give an oil (41 mg) Treatment of the oil with oxalic acid in ether gives compound 19, the title compound (40 mg) as a solid mp 85-88 °C MS ( MH⁺= 669)

Example 20

Cpd. 20 A mixture of 3-aminothiophenol (1.25 g, 10.0 mmol), 2-chloroethylmorpholine (2.3 g, 12.0 mmol) and K₂CO₃ (1.8 g) in THF (150 mL) was heated to reflux for 8 h. The resulting mixture was filtered and partitioned between H₂O and ethyl actetate. The aqueous layer was washed with several portions of ethyl actetate and the combined organic extracts were dried Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 10% MeOH/ethyl acetate as an eluent to give compound 20 as an oil (600 mg). NMR(CDCI3); 2.60 (t, J = 6 Hz, 2H, CH2N), 3.02 (t, J = 6Hz, 2H, CH2S), 6.44-7.06 ( m, 4H, aromatic protons).

Example 21

Cpd. 21

NaCNBH₄ (300 mg) was added in three portions to a solution of compound 4 (800 mg), compound 20 (600 mg), and acetic acid (2.0 mL) in methanol (100 mL) at room temperature under N₂. The reaction mixture was stirred for 30 min, most of methanol was removed in vacuo. The residue was diluted with methyiene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel using ethyl acetate: MeOH:t ethylamine (100:2:0.1 ) to give compound 21 (735 mg) as a pale yellow oil. NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzihc protons), 3.82 (s, 2H, CH2N), 5.62 (s, 1 H, olefinic proton), 6.50-7.25 ( m, 9H, aromatic protons). MS ( MH⁺= 568) Example 22 3-Benzyl-3-trichloroacetylamino-1 -(Λ/-phenylaminocarbonyl)-Λ/-[(3- (2-morpholinoethyl)phenyl)thio]methylcyclopentene

Cpd. 22 To a solution of compound 18 (53 mg) and tnethylamine (1 drop) in methyiene chloride (30 mL) was added phenyl isocyanate (38 mg) at room temperature under N₂ dropwise . The resulting mixture was stirred for 24 h and most of solvent was removed in vacuo. The oily residue was purified by column chromatography on silica gel using ethyl acetate:triethylamine (100:0.2) as an eluent to give an oil (55 mg). Treatment the oil with oxalic acid in ether gives compound 19, the title compound (57 mg) as a white solid: mp 88-92 °C. MS ( MH⁺= 687)

Example 23

Cpd. 23

NaCNBH₄ (589 mg) was added in three portions to a solution of compound 4

(2.0 g), 3-nitroaniline (1.59 g, 1 1 .5 mmol) acetic acid ( 2 mL) in methanol (100 mL) at room temperature under N₂. and stirred overnight. Most of methanol was removed in vacuo and the residue was diluted with methyiene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel using ethyl acetate: hexane 1 :1 to give compound 23 (2.0 g) as a pale yellow oil. NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), 3.85 (d, J = 6Hz, 2H, CH2N), 5.62 (s, 1 H, olefinic proton), 6.80-7.44 ( m, 9H, aromatic protons).

Cpd. 24 Benzoyi chloride (125 mg, 0.89 mmol) was added to a solution of compound 23 (350 mg, 0.748 mmol) and tnethylamine (1.3 mg) in methyiene chloride (30 mL) at room temperature under N₂ and this mixture was stirred for 2 h. Most of solvent was removed in vacuo and the oily residue was purified by column chromatography on silica gel using ethyl acetate: hexane (1 :4) as an eluent to give compound 24 as a light brown oil (350 mg). NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), 4.65 (d, J = 8Hz, 2H, CH2N), 5.62 (s, 1 H, olefinic proton), 6.08-8.01 ( m, 14H, aromatic protons).

Cpd. 25

A mixture of compound 24 (350 mg, 0.61 mmol), 10% Pd/C (5 mg) and acetic acid (2 drops) in EtOH (20 mL) was hydrogenated at 50 psi at room temperature for 8 h. The resulting mixture was filtered through Celite and concentrated in vacuo. The residue was treated with methyiene chloride (300 mL) washed with H₂O, dried and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate as an eluent to give compound 25 (200 mg) as an oil. NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), 4.58 (d, J = 8Hz, 2H, CH2N), 5.62 (s, 1 H, olefinic proton), 6.28-7.41 ( m, 14H, aromatic protons).

Example 26

Cpd. 23a

Cpd. 23b A solution of compound 25 (160 mg, 0.3 mmol), chloroethylmorpholine (82 mg, 0.44 mmol), and DBU (101 mg) in 2-propanol (25 mL) was heated to reflux for 2 days. The solvent was removed in vacuo and the residue was treated with 0.5 N NaOH (100 mL) and extracted with several portions of ethyl acetate. The organic layer was dried concentrated in vacuo. The residue was purified by column chromotography on silica gel. The bis-alkylated compound (84 mg) was eluted with ethyl acetate:MeOH 95:5. This compound was treated with oxalic acid and ether to give compound 23a (70 mg) as a solid, mp 86-92 °C. MS ( MH⁺= 655) Continued elution with methyiene chloride:MeOH:triethylamine 85:10:5) to give the mono-alkylated product 23b, which was converted to the oxalate salt with oxalic acid and ether (40 mg). mp 88-96 °C. MS ( MH⁺= 768)

Example 27

Cpd. 27 NaCNBH (146 mg) was added in three portions to a solution of 4- chlorobenzaldehyde (308 mg, 2.2 mmol), 3-aminophenol (200 mg, 1.83 mmol) acetic acid (1.0 mL) in methanol (100 mL) at room temperature under N₂. and stirred for 30 min. Most of methanol was removed in vacuo and the residue was diluted with methyiene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel using ethyl acetate to give compound 27 (230 mg) as a pale yellow oil. NMR(CDCI3); 4.26 (s, 2H, benzylic protons), 6.10-7.24 ( m, 8H, aromatic protons). MS ( MH⁺= 234)

Compound 28

Cpd. 28

NaCNBH₄ (60 mg) was added in three portions to a solution of compound 4 (259 mg), compound 27 (230 mg,) and acetic acid (1.0 mL) in methanol (50 mL) at room temperature under N₂. and stirred for 16 h. Most of methanol was removed in vacuo and the residue was diluted with methyiene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel to give compound 28 (100 mg) as an oil. NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), 4.00 (d, J = 8Hz, 2H, CH2N), 4.42(s, 2H, 4-chlorobenzyl protons), 5.42 (s, 1 H, olefinic proton), 6.21-7.25 ( m, 13H, aromatic protons).

Example 29

Cpd. 29 A solution of compound 28 (100 mg, 0.18 mmol), chloroethylmorpholine (100 mg, 0.6 mmol), and DBU (115 mg) in 2-propanol (50 mL) was heated to reflux for 2 days. The solvent was removed in vacuo and the residue was treated with 0.5 N NaOH (100 mL) and extracted with several portions of ethyl acetate. The organic layer was dried concentrated in vacuo. The residue was purified by column chromotography on silica gel using ethyl acetate: hexane (1 :1 ) to give an oil (95 mg). Treatment of the oil with oxalic acid and ether gives compound 29, the title compound as a solid:mp 134-136. MS ( MH⁺= 676)

Example 30

NaCNBH₄ (35.3 mg) was added in three portions to a solution of compound 4 (150 mg, 0.43 mmol), 3-hydroxybenzylamine (104.8 mg, 0.87 mmol) acetic acid (1.0 mL) in methanol (50 mL) at room temperature under N₂. and stirred for 16 h. Most of methanol was removed in vacuo and the residue was diluted with methyiene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel to give compound 30 (160 mg) as an oil. NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), 3.38 (s,2H, 3-hydroxybenzyl protons), 3.72 (d, J = 8Hz, 2H, CH2N), 5.62 (s, 1 H, olefinic proton), 6.68-7.25 ( m, 9H, aromatic protons).

Example 31

Cpd. 31

Benzoyi chloride (69 mg, 0.5 mmol) was added to a solution of compound 30 (150 mg, 0.33 mmol) and tnethylamine (1.0 mL) in methyiene chloride (20 mL) at room temperature under N₂ and stirred for 16 h. Most of solvent was removed in vacuo and the oily residue was purified by column chromatography on silica gel using ethyl acetate: hexane 1 :4 as an eluent to give compound 31 as a light brown oil (220 mg). NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), , 5.59 and 5.62, (both s, 1 H total, olefinic proton , two rotamer?), 6.60-8.15 ( m, 14H, aromatic protons).

Example 32

Cpd. 32 A solution of compound 31 (220 mg, 0.4 mmol), chloroethylmorpholine (280 mg, 1.4 mmol), and DBU (120 mg) in 2-propanol (100 mL) was heated to reflux for 16 h. The solvent was removed in vacuo and the residue was treated with 0.5 N NaOH (100 mL) and extracted with several portions of ethyl acetate. The organic layer was dried concentrated in vacuo. The residue was purified by column chromotography on silica gel using ethyl acetate:MeOH (9:1 ) to give an oil (95 mg). Treatement of the oil with oxalic acid and ether gives compound 32, the title compound as a solid:mp 90-95. MS ( MH⁺= 670)

Example 33

Cpd. 33 Benzoyi chloride (280 mg) was added to a solution of compound 24 (300 mg) and triethylamine (2.0 mL) in methyiene chloride (30 mL) at room temperature under N₂ and stirred for 2 hours. Most of solvent was removed in vacuo and the oily residue was purified by column chromatography on silica gel using ethyl acetate: hexane 1 :4 as an eluent. to give compound 33 as a light brown oil (265 mg). NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), 3.35 (s, 2H, allylic methyiene protons) 5.61 (s, 1 H, olefinic proton) 6.60-7.23 ( m, 9H, aromatic protons). MS ( MH⁺= 467)

Example 34 (two -step procedure)

Cpd. 34 A solution of compound 33 (265 mg, 0.46 mmol), chloroethylmorpholine (173 mg, 0.8 mmol), and DBU (107 mg) in 2-propanol (50 mL) was heated to reflux for 16 h. The solvent was removed in vacuo and the residue was treated with 0.5 N NaOH (100 mL) and extracted with several portions of ethyl acetate. The organic layer was dried concentrated in vacuo. The residue was purified by column chromotography on silica gel using ethyl acetate:MeOH (95:5) to give an oil (165 mg). Treatment of the oil with oxalic acid and ether gives compound 34, the title compound as a solid:mρ 126-28 °C. MS ( MH⁺= 684)

Example 35

Compound 35

A solution of 4-chloro-3-nitrophenol (2.0 g, 11.53 mmol), chloroethylmorpholine (2.57 g, 13.8 mmol), and K₂CO₃ (5.0 g) in 2-propanol (200 mL) was heated to reflux for 16 h. The solvent was removed in vacuo and the residue was treated with 0.5 N NaOH (100 mL) and extracted with several portions of ethyl acetate. The organic layer was dried and concentrated in vacuo to give compound 35 as an oil. NMR(CDCI3); 4.18 (t, J = 6 Hz, 2H, phenoxymethylene protons), 7.09-7.44 ( m, 3H, aromatic protons). Example 36

A mixture of compound 35 (500 mg, 1.84 mmol), 10% Pd/C (5 mg) and acetic acid (2 drops) in EtOH (20 mL) was hydrogenated at 55 psi at room temperature for 16 h. The resulting mixture was filtered through Celite and concentrated in vacuo. The residue was treated with methyiene chloride (300 mL) washed with H₂O, dried and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate:MeOH (95:5) as an eluent to give compound 36 (200 mg) as an oil. NMR(CDCI3); 4.06 (t, J = 6 Hz, 2H, phenoxymethylene protons), 6.35-7.10 ( m, 3H, aromatic protons).

Example 37

Cpd. 37

NaCNBH₄ (53 mg) was added in three portions at room temperature under N₂ to a solution of compound 4 (243 mg, 0.7 mmol), compound 36 (200 mg, 0.78 mmol), and acetic acid (2.0 mL) in methanol (75 mL). This mixture was stirred for 16 h and most of methanol was removed in vacuo The residue was diluted with methyiene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel using ethyl acetate:MeOH (95:5) as an eluent to give compound 37 (250 mg) as an oil. NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), 4.08 (t, J = 6Hz, 2H, phenoxymethylene protons), 5.62 (s, 1 H, olefinic proton), 6.22-7.30 ( m, 8H, aromatic protons). Example 38

Example 38 Cpd. 38 4-Bromobenzoyl chloride (25 mg) was added to a solution of compound 37 (45 mg) and tnethylamine (1.0 mL) in methyiene chloride (25 mL) at room temperature under N_2. The reaction mixture was stirred for 16 h and most of solvent was removed in vacuo. The oily residue was purified by preparative TLC using ethyl acetate as an eluent. to give an oil (25 mg). Treatment of the oil with oxalic acid in ether gives compound 38 (20 mg). MS ( MH⁺= 768)

Example 39

Cpd. 39 NaCNBH₄ (204 mg) was added in three portions to a solution of compound 4 (1.04 g, 3.0 mmol), 3-hydroxy-4-methoxyaniline (835 mg, 6.1 mmol), and acetic acid (2.0 mL) in methanol (100 mL) at room temperature under N₂. The reaction mixture was stirred for 6 h and most of methanol was removed Jn vacuo. The residue was diluted with methyiene chloride, washed with 1 N. NaOH and dried. The solvent was removed in vacuo and residue was purified by column chromatography on silica gel using ethyl acetate: hexane (1 :1 ) as an eluent to give compound 39 (1.2 g) as an oil. NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), 4.79 (s, 3H, CH3O), 5.62 (s, 1 H, olefinic proton), 6.12-7.32 ( m, 8H, aromatic protons).

Example 40

Cpd. 40 A solution of compound 39 (500 mg, 1.06 mmol), chloroethylmorpholine (394 mg, 2.12 mmol), and DBU (490 mg) in 2-propanol (100 mL) was heated to reflux for 16 h. The solvent was removed in vacuo and the residue was treated with 0.5 N NaOH (100 mL) and extracted with several portions of ethyl acetate. The organic layer was dried concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate:MeOH:triethylamine (85:10:5) to give an oil. Treatment of the oil with oxalic acid and ether gives compound 40, the title compound as a solid:mp 92-95°C. MS ( MH⁺= 695)

Example 41

Cpd. 41 Benzoyi chloride (43 mg, 0.3 mmol) was added to a solution of compound 40 (120 mg, 0.26 mmol) and tnethylamine (1.0 mL) in methyiene chloride (50 mL) at room temperature under N₂The mixture was stirred for 6 h, poured into 1 N NaOH and extracted with methyiene chloride. The organic extracts were combined, dried, and concentrated in vacuo The oily residue was purified by column chromatography on silica gel using ethyl acetate:hexane (1 :1 ) as an eluent to give compound 41 an oil (100 mg). NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), 3.81 (S, 3H, CH3O), 4.60 (d, J = 8Hz, 2H, CH2N), 5.62 (s, 1 H, olefinic proton), 6.60-7.38 ( m, 13H, aromatic protons).

Example 42

Cpd. 41 A solution of compound 41 (100 mg, 0.17 mmol), chloroethylmorpholine (64.7 mg, .35 mmol), and DBU (300 mg) in 2-propanol (50 mL) was heated to reflux for 16 h. The solvent was removed in vacuo and the residue was treated with 0.5 N NaOH (100 mL) and extracted with several portions of ethyl acetate. The organic layer was dried concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate:MeOH (9:1 ) to give an oil. Treatment of the oil with oxalic acid and ether gives compound 42 (81 mg), the title compound as a solid:mp 85-91 °C. MS ( MH⁺= 686)

Example 42

Cpd. 42 NaCNBH₄ (250 mg) was added in three portions to a solution of compound 4 (510 mg, 1.6 mmol), 3-aminophenol (515 mg, 4.9 mmol) acetic acid (1.0 mL) in methanol (200 mL) at room temperature under N_2.. The reaction mixture was stirred for 30 min and most of the methanol was removed in vacuo. The residue was diluted with methyiene chloride, washed with 1 N. NaOH, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate: hexane (1 :2) as an eluent to give compound 42 (385 mg) as a pale yellow oil. NMR(CDCI3); 3.18 (Abq, J = 8 Hz, 2H, benzylic protons), 3.80 (ABq, J = 8Hz, 2H, CH2N), 5.62 (s, 1 H, olefinic proton), 6.21-7.25 ( m, 9H, aromatic protons).

Example 43

Cpd. 43

A mixture of compound 42 (251 mg), K₂CO₃ (1.1 g) ethylbromoacetate (200 mg)

THF (70 mL) was heated to 50 °C for 8 h. The resulting mixture was filtered through Celite and concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate: hexane (1 :3) to give compound 43 a as a pale yellow oil (263 mg). Treatment of the oil with concentrated HCI and MeOH gives compound 43 as a white foam (89 mg): mp 64-66 °C. MS ( MH⁺= 525)

Cpd 45 A solution of compound 43a (59 mg), 1 N NaOH (1 mL) in MeOH (5 mL) was stirred at room temperature under N₂.for 3 h. Most of the MeOH was removed in vacuo and the residue was diluted with H?O (10 mL). This mixture was acidified to pH 4 using 0.1 N HCI and extracted with methyiene chloride. The combined organic extracts were dried and concentrated in vacuo to give compound 45, the title compound as a light brown powder (35 mg): mp 70-73 °C. MS ( MH⁺= 4g7)

Example 46

Cpd 46

Benzoyi chloride (31 mg ) was added to a solution of compound 43a (45 mg) and tnethylamine (0.1 mL) in methyiene chloride (30 mL) at room temperature under N₂ and stirred for 5 h. The resulting mixture was poured into 1 N NaOH and extracted with methyiene chloride. The combined organic extracts were combined, dried and concentrated in vacuo Most of solvent was removed in vacuo and the oily residue was purified by using ethyl acetate: hexane (3:5) as an eluent. to give compound 46 as a pale yellow oil (100 mg). MS ( MH⁺= 629)

Claims

What is claimed is:

1. A compound of the Formula

wherein

Ri is selected from hydrogen, Cι.₅alkyl, substituted Cι-₅alkyl (where the alkyl substituents are one or more halogens), aminoCι.₅alkyl, Cι.₅alkylaminoCι.₅alkyl; di-Cι-salkylaminoCι.₅alkyl, R_aR_bN-Cι.₅alkyl (where the R_a and R_b are independently selected from hydrogen and Cι.₅alkyl, or are taken together to form a morpholine, piperazine, piperidine, or N-substituted piperidine where the N- substitutent is Cι.₅alkyl or phenylCι.₅alkyl), Cι-₅alkylcarbonyl, Cι.₅alkoxycarbonyl, aminocarbonyl, Ci.galkylaminocarbonyl, cycloC₃-₉alkylaminocarbonyl, pyridinylcarbonyl, substituted pyridinylcarbonyl (where the pyridinyl substituents are selected from the group consisting of one or more halogens and Cι.₅alky), thiophenecarbonyl, substituted thiophenecarbonyl (where the thiophene substituents are selected from the group consisting of one or more halogens and Cι-₅alkyl), phenyl, phenylCι-₅alkyl, phenoxycarbonyl, phenylcarbonyl, diphenylmethylcarbonyl, phenylaminocarbonyl, phenylthiocarbonyl, phenylaminothiocarbonyl, substituted phenyl, substituted phenylCι-₅alkyl, substituted phenoxycarbonyl, substituted phenylcarbonyl, substituted phenylaminocarbonyl, substituted diphenylmethylcarbonyl, substituted phenylthiocarbonyl, and substituted phenylaminothiocarbonyl (where the phenyl substituents are selected from the group consisting of one or more of halogen, Cι.₅alkyl, trihalomethyl, Cι.₅alkoxy, amino, nitrile, nitro, Cι.₅alkylamino, di-Cι.₅alkylamino, if there are more than one substitutents they may be taken together with the phenyl ring to form a fused bicyclic 7-10 membered heterocychc ring having one to two heteroatoms selected from oxygen, sulfur or nitrogen or the substituents may be taken together to form a fused bicyclic 7-10 membered aromatic ring; R₂ is selected from hydrogen, Cι-₅alkyl, Cι.₅alkoxy, phenyl, substituted phenyl (where the phenyl substituents are selected from one or more of the group consisting of halogen and Cι-₅al yl), phenylCi-salkyl, substituted phenylCι-₅alkyl (where the phenyl substituents are selected from one or more of the group consisting of halogen, Cι-₅alkyl, Cι-₅alkoxy, halo and di-Cι.₅alkylamino) R₃ is selected from hydrogen, Cι.₅alkylcarbonyl, substituted

Cι-₅alkylcarbonyl (where the alkyl substituents are selected from one or more halogens), phenylcarbonyl, and substituted phenylcarbonyl (where the phenyl substituents are selected from one or more of the group consisting of halogen, Cι-₅alkyl, Cι.₅alkoxy, amino, Cι-₅alkyiamino, and di-Cι_-5alkylamino)

R₄ is selected from hydrogen, Ci-salkylcarbonyl, substituted

Cι-₅alkylcarbonyl (where the alkyl substituents are selected from one or more halogens), phenylcarbonyl, and substituted phenylcarbonyl (where the phenyl substituents are selected from one or more of the group consisting of halogen, Cι.₅alkyl, Cι.₅alkoxy, amino, Cι- alkylamino, and di-Cι.₅alkylamino) n is 0-3; m is 1 -5

. (CH₂)q — (A)t R₅ is where: q is 0-2; t is 0-1 ;

X is oxygen, CH₂, sulfur, or NR_C where

Re is hydrogen, Cι.₅alkyl, morpholinoCι.₅alkyl, piperidinylCι.₅alkyl, N-phenylmethylpipehdinyl or piperazinylCι.₅alkyl, with the proviso that if q and t are 0, then X is hydroxy, thiol, or amino,

A is Ci.₅alkoxycarbonyl, phenylcarbonyl, or R₇R₈N- where R₇ is independently selected from hydrogen, Cι.₅alkyl, cycloCι.₉alkyl, or R₇ is taken together with R₈ to form a

5 or 6 membered heterocychc ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur and N-oxides thereof;

R₈ is independently selected from hydrogen, Cι-₅alkyl, cycloCι.₉alkyl or taken together with R₇ to form a 5 or

6 membered heterocychc ring with one or more heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, and N-oxides thereof;

R₆ is selected from hydrogen, halogen, Cι.₅alkoxy, Ci-salkylamino, or di-Cι-₅alkylamino ; and the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein:

Ri is selected from phenylaminocarbonyl, phenylcarbonyl, substituted phenylaminocarbonyl, substituted phenylcarbonyl, and hydrogen;

R₂ is phenylCι- alkyl;

R₃ is hydrogen;

R₄ is trifluoromethylacetyl;

R₅ is O-(CH₂)₂-morpholin-1 -yi;

Re is hydrogen n is 0; and m is 1 . The compound according to claim 1 of the formula:

4. The compound according to claim 1 of the formula:

5. The compound according to claim 1 of the formula:

The compound according to claim 1 of the formula:

7. The compound according to claim 1 of the formula:

8. A pharmaceutical composition for treating disorders associated with the motilin receptor comprising an effective amount of a compound of claim 1 in association with one or more pharmaceutically acceptable carriers.

9. A method of treating disorders associated with the motilin receptor in humans comprising administering to a human in need of such treatment an effective amount of a compound of claim 1.