BACKGROUND OF THE INVENTION Chronic renal disease is the progressive loss of renal function due to irreversible and progressive glomerular, tubular or interstitial disease. Currently, over 200,000 people in the U. S. have end-stage renal disease with the majority on dialysis. There are an estimated 675,000 people with pre-dialysis chronic renal failure and a further 3 million at risk. Current therapy includes treatment of underlying disease, control of hypertension, protein restriction and use of angiotensin converting enzyme (ACE) inhibitor, all of which have limited efficacy.

The ACE inhibitor, captopril, is the only approved drug for chronic renal failure and its effects are modest. Data from clinical trials on angiotensin II receptor antagonists indicate some degree of effect, however, it is unclear whether they will provide a dramatic improvement over the ACE inhibitors.

Carcinoma of the prostate is the most common malignant disease of men in the U. S., and the second most common cause of cancer-related death in men of all ages. Current therapy for prostate cancer involves radical prostatectomy, radiation therapy, and either surgical (orchiectomy) or medical (leuprolide) castration.

Surgical or medical castration have had variable success, and cytotoxic chemotherapy is generally not effective. Anti-androgenic therapy has significant side effects, and relapse can occur as a result of the development of hormone- insensitive cells.

Gastrin releasing peptide ("GRP") is a 27 amino acid peptide which is normally produced in neuroendocrine cells of the gastrointestinal tract, lung and central nervous system. It acts by binding to a specific G-protein-coupled seven transmembrane spanning receptor and has diverse physiological effects, including

stimulation of cell proliferation, hormone section, gastric motility, immune cell activation, and modulation of neurotransmission. Blockade of GRP for 4 weeks by systemic administration of a GRP antibody, however, failed to reveal any adverse behavioral, clinical or pathological effects. Although the role of GRP in pathophysiology has not been fully explored, there are indications that it may have a significant effect on cell growth. It has been established that GRP receptors are present in the kidney, and that GRP stimulates mesangial cell proliferation and the expression of extracellular matrix. In addition, a peptide receptor antagonist to GRP attenuates these effects.

GRP is recognized as an autocrine factor in some cancer cells (Dietrich, 1994; Cuttitta et al., 1985). Furthermore, the effects of GRP on cell proliferation and differentiation have been explored in a number of organ systems. In the lung, GRP stimulates lipid surfactant secretion by pneumocytes, indicating a role for GRP in development (Asokananthan and Cake, 1996). In addition, GRP stimulates proliferation of lung (Cuttitta et al., 1985), breast (Nelson et al., 1, 991) and prostate (Bologna et al., 1989) carcinoma cells in vitro. Several lung and prostate cancer cells which proliferate in response to GRP in vitro are inhibited by treatment with GRP antibodies (Maruno and Said, 1993; Shimoda, 1992) and peptide receptor antagonists (Moody et al., 1995). In addition, the growth of prostate and breast cancer cell xenografts in a nude mouse host are inhibited by treatment of the mice with peptide antagonists (Pinski et al., 1993a, b; Shirahige et al., 1994) or GRP antibodies (Shimoda, 1992).

The amino acid structure of GRP, neuromedin B (NMB), and bombesin are depicted below. GRP and NMB are mammalian peptides which have homology to the amphibian peptide, bombesin. Conserved amino acids are indicated by solid vertical lines.

Peptide sequence of GRP-like peptides 1 10 13 GRP (27) Val-Pro-Leu-Pro-Ala-Gly-Gly-Gly-Thr-Val-Leu-Thr-Lys 14 17 27 L Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala-V71-G ; y-Hif-Leu-Met-NH2 bombesin pGlu-Gin-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 neuromedin B (NMB) Gly-Asn-Leu-Trp-Ala-Thr-Gly-His-Phe-Met-NH2 pGlu denotes pyroglutamate; NH2 denotes amidated carboxy-terminal residue To date, two mammalian receptor subtypes have been cloned, and they are named GRP (BB2) and NMB (BB 1) receptors. While bombesin binds to both receptors with equal affinity, GRP receptor binds GRP with high affinity, whereas NMB receptor binds neuromedin B with high affinity.

Recently, a third type of mammalian bombesin receptor [BRS3 (BB3)] has been identified and cloned (Pathi et al., 1993; Gorbulev et al., 1992) which shares 51 % and 47% amino acid sequence homology to the GRP and NMB receptor, respectively. While GRP and NMB demonstrate a widespread tissue distribution (Battey et al., 1991; Vigna et al., 1987), BRS3 is present in pregnant uterus (Gorbulev et al., 1992), a few brain regions (Gorbulev et al., 1992), human lung (Pathi et al., 1993), breast and epidermal cancer lines (Gorbulev et al., 1994).

BRS3-deficient mice generated by target disruption were obese, and developed diabetes and hypertension (Ohki-Hamazaki et al., 1997). Although the natural ligand for this receptor is not known, the synthetic analogue of bombesin, [D- Phe6, ß-Alal 1, Phel3, Nlel4 Bn (6-14), has been identified as a high affinity agonist for this receptor (Mantey et al., 1997). In addition, this agonist stimulated inositol phosphate accumulation (ECo = 25-30 nM) and tyrosine phosphorylation of pl25FAK (ECso = 0.2-0.7 nM) in hBRS3-transfected BALB 3T3 cells and NCI- HI299 cell lines (Ryan et al., 1998). The natural ligand as well as the involvement of this receptor in renal and prostate diseases are yet to be identified.

It is believed that selective inhibition of GRP receptor in kidney and prostate will have therapeutic utility in chronic renal diseases and prostate as well as other

cancers. Potent nonselective (GRP/NMB) antagonists will have additional therapeutic utility in treating lung cancer.

Based on the foregoing, there is a need to identify a potent nonpeptide GRP receptor antagonist for the treatment of chronic renal disease and prostate cancer.

SUMMARY OF THE INVENTION The present invention involves compounds represented by Formula (I) hereinbelow, pharmaceutical compositions comprising such compounds and methods of antagonizing the GRP receptor using these compounds. The present invention further provides novel methods for the synthesis of the present compounds and novel intermediates involves therein.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of Formula (I), hereinbelow: Formula (I) or a pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of C2-C12 alkyl, heteroalkyl and arylalkyl; R 1 is selected from the group consisting of hydrogen, OH, halogen, CN, N02, CF3, CF2H, Cl-Clo alkoxy and NR4R5; R2 is aryl which may be unsubstituted or substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, CF3, CF2H, halogen, CO2R6, COR6, O (CH2) nCO2R6, C1-C6 alkoxy, CN, N02, OH, and NR4R5; aryl may be further substituted by a substituent selected from the group consisting of pyrrolyl, thiazolyl, oxadiazolyl, all of which may be unsubstituted or substituted by R6;

R3 is selected from the group consisting of hydrogen, C2-C6 aminoalkyl and C-)-C6 hydroxyalkyl; R4 and Rs are independently selected from the group consisting of hydrogen, C2- C 12 alkyl, heteroalkyl and arylalkyl; R6 is selected from the group consisting of hydrogen, and Cl-C6 alkyl; X is selected from the group consisting of NCN, O, S and NH; m is an interger from 1 to 4; and n is an integer from 1 to5.

Preferably, aryl substituents of R are selected from the group consisting of Cl-C2 alkoxy, C 1-C4 alkyl, CF3, Cl, and F.

Preferably, R l is hydogen or C 1-C2 alkoxy.

Preferably, R2 is phenyl.

Preferably, R3 is hydrogen.

Preferably, X is NCN.

As used herein,"alkyl"refers to an optionally substituted hydrocarbon group joined together by single carbon-carbon bonds. The alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Preferably, the group is saturated linear or cyclic.

As used herein,"aryl"may be phenyl, naphthyl, pyridyl, indolyl, thienyl, pyrimidyl.

Preferred compounds useful in the present invention include: (R)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-methoxyphenyl) but- 3-ynyl] guanidine (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyl guanidine, (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl thiourea, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (benzyl) guanidine,

(+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (N, N-dimethylaminopropyl) guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (piperidin-1-ylethyl) guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (3-hydroxypropyl) guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-hydroxyethyl) guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-aminoethyl) guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (3-aminopropyl) guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (4-aminobutyl) guanidine, (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl urea, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-chlorophenyl) but-3- ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-chlorophenyl) but-3- ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (2-t-butylphenyl) but-3- ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3- carboxymethylphenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4- methoxycarbonylmethoxyphenyl) but-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- 3- (5-methyl- 1,3,4 thiadiazol-2-yl) phenyl but-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4- carboxymethoxyphenyl) but-3-ynyl guanidine,

(+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-fluoro-3- chlorophenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-chloro-3- fluorophenyl)but-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3,4- difluorophenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-methoxyphenyl) but- 3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4- trifluoromethoxyphenyl) but-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- 3- (5-methyl- 1,3,4 oxadiazol-2-yl) phenyl] but-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3- trifluoromethylphenyl) but-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-N- pyrrolylphenyl) but-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (naphthalen-2-yl) but-3- ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-methoxyphenyl) but- 3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-acetylphenyl) but-3- ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-methoxyphenyl) but- 3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-carboxyphenyl) but- 3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-hydroxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-ethyloxy-4-metoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-butyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine,

(+/-)-N-cyano-N'- 2- (3- (4- (ethylcarbonylmethyl) thiazolyl-2-aminocarbonyl- methyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclobutylmethoxy-4-methoxyphenyl)-4-phenylbut-3- ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3- (4-ethyoxycarbonylbutyloxy)-4-methoxyphenyl)-4- phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclohexylcarbonylmethyloxy)-4-methoxyphenyl-4- phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3- (cyclohexylethoxy)-4-methoxyphenyl)-4-phenylbut-3- ynyl guanidine, and (+/-)-N-cyano-N'- 2- (3- (2-ethylhexyloxy)-4-methoxyphenyl)-4-phenylbut-3- ynyl guanidine.

More preferred compounds useful in the present invention include: (R)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-methoxyphenyl) but- 3-ynyl guanidine (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyl] guanidine, (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynylJthiour ea, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-hydroxyethyl) guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-aminoethyl) guanidine, (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl urea, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-chlorophenyl) but-3- ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-chlorophenyl) but-3- ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4- methoxycarbonylmethoxyphenyl) but-3-ynyl] guanidine,

(+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-fluoro-3- chlorophenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-chloro-3- fluorophenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3,4- difluorophenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-methoxyphenyl) but- 3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4- trifluoromethoxyphenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3- trifluoromethylphenyl) but-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-methoxyphenyl) but- 3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-acetylphenyl) but-3- ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-methoxyphenyl) but- 3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-hydroxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-ethyloxy-4-metoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-butyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3- (4- (ethylcarbonylmethyl) thiazolyl-2-aminocarbonyl- methyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclobutylmethoxy-4-methoxyphenyl)-4-phenylbut-3- ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclohexylcarbonylmethyloxy)-4-methoxyphenyl-4- phenylbut-3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3- (cyclohexylethoxy)-4-methoxyphenyl)-4-phenylbut-3- ynyl] guanidine, and

(+/-)-N-cyano-N'- 2- (3- (2-ethylhexyloxy)-4-methoxyphenyl)-4-phenylbut-3- ynyl guanidine.

The most preferred compounds useful in the present invention include: (R)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-methoxyphenyl) but- 3-ynyl guanidine (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-chlorophenyl) but-3- ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-chlorophenyl) but-3- ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-fluoro-3- chlorophenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-chloro-3- fluorophenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3,4- difluorophenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-methoxyphenyl) but- 3-ynyl guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4- trifluoromethoxyphenyl) but-3-ynyl] guanidine, (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3- trifluoromethylphenyl) but-3-ynyl guanidine, and (+/-)-N-cyano-N'- 2- (3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine.

The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.

The present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof. Pharmaceutically acceptable salts are non- toxic salts in the amounts and concentrations at which they are administered.

Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, fumarate. maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.

The present compounds are prepared using the following novel process: which can be prepared by a process comprising: treating a hydroxy aryl aldehyde of Formula (2) with a halide such as cyclopentyl bromide in the presence of a base such as potassium carbonate in a suitable solvent such as N, N-dimethylformamide at 90°C to afford a cyclopentyl aryl ether of Formula (3).

Knoevenagel reaction of an aryl aldehyde of Formula (3) with Meldrum's acid (4) in the presence of an ammonium salt such as piperidinium acetate in an appropriate solvent such as refluxing benzene provides a Meldrum's acid adduct of Formula (5).

Addition of trimethylsilylacetylide or phenylacetylide resulting from treatment of trimethylsilylacetylene or phenylacetylene with n-BuLi in THF to a Meldrum's acid adduct of Formula (5) affords a 1,4-addition product of Formula (6).

Hydrolysis of the isopropylidine group of a compound of Formula (6) with, e. g., aqueous hydrochloric acid in dioxane followed by decarboxylation in a suitable solvent such as N, N-dimethylacetami. de under heat (when R = trimethylsilyl, the resulting compound is further treated with aqueous base such as aqueous NaOH in methanol) provides a mono-acid of Formula (7).

Upon treatment of an acid chloride derived from an acid of Formula (7) with sodium azide in a solvent such as toluene, the resulting intermediate is then treated with aqueous hydrochloride in dioxane to afford a Curtius rearrangement product of Formula (8).

Reaction of an amine of Formula (8) with dimethylcyanodithioiminocarbonate in a suitable solvent such as pyridine under heat provides a compound of Formula (9).

Alternatively, reaction of an amine of Formula (8) with an isocyanate (10) or isothiocyanate (11) R3NCO (10) or R-NCS provides an urea or thiourea of Formula (I).

Alternatively, treatment of an amine of Formula (8) with di-Boc-thiourea in a solvent such as N, N-dimethylformamide in presence of 2-chloro-1- methylpyridinium iodide and an amine such as triethylamine gave a protected guanidine of Formula (12)

Treatment of a compound of Formula (12) with trifluoroacetic acid in a solvent such as dichloromethane affords a guanidine of Formula (I).

Treatment of a compound of Formula (9) with cyanodithioiminocarbonate provides a compound of Formula (13).

A compound of Formula (13) is treated with a base such as sodium hydride followed by addition of di-t-butyl dicarbonate to afford a compound of Formula (14).

Reaction of a compound of Formula (14) with ammonia or an amine of Formula (15) R-NH2 (15) followed by deprotection with an acid such as trifluoroacetic acid gave a cyanoguanidine of Formula (16).

Alternatively, an amine of Formula (8) can be reacted with diphenyl cyanocarbonimidate to form a compound of Formula (17).

Treatment of a compound of Formula (17) with ammonia or an amine (15) in a suitable solvent such as isopropyl alcohol also provides a compound of Formula (16).

Palladium-catalyzed coupling of a compound of Formula (14), where R2 = H, with aryl iodide in the presence of copper iodide and a suitable base such as triethylamine in a solvent such as N, N-dimethylformamide affords a compound of Formula (I), wherein R represents cyclopentyl, R2 represents aryl, and X represents NCN.

Treatment of a compound of Formula (18) with a Lewis acid such as tribromoborane in a suitable solvent such as dichloromethane at low temperature affords a phenol of Formula (19).

Alkylation of a phenol of Formula (16) with a halide of Formula (20) R-X (20) in presence of a base such as potassium carbonate in a suitable solvent such as N, N- dimethylformamide provides a compound of Formula (I), wherein R3 represents H.

Alternatively, Mitsunobu reaction of a phenol of Formula (19) with an alcohol of Formula (21) R-OH (21) in presence of activating agents such as tri-n-butylphosphine and diethyl azodicarboxylate in an appropriate solvent such as tetrahydrofuran affords a compound of Formula (I).

Esterification of an acid of Formula (7) in methanol in presence of catalytic amount of concentrated hydrochloric acid afforded a methyl ester of Formula (22).

Resolution of a methyl ester of Formula (22) with chiral HPLC column provided two enantiomers of Formula (23) and Formula (24), respectively.

Basic hydrolysis of a methyl ester of Formula (23) or Formula (24) followed by acidic work up afforded the corresponding enantiomer pure acid of Formula (25) or Formula (26).

Conversion of an acid of Formula (25) or Formula (26) to a compound of Formula (I) can be achieved following the procedure described above.

With appropriate manipulation and protection of any chemical functionality, synthesis of the remaining compounds of Formula (I) is accomplished by methods analogous to those above and those described in the Experimental section hereinafter.

Novel intermediates represented by the present invention include: In order to use a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

The present ligands can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.

Alternatively, injection (parenteral administration) may be used, e. g., intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection, the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in

solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.

Systemic administration can also be by transmucosal or transdermal means.

For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation.

Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.

For topical administration, the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.

The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound ICo, ECo, the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.

Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered.

Preferably the composition is in unit dosage form. For oral application, for example, a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose.

Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. The daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula (I). A topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).

The active ingredient may be administered from 1 to 6 times per day. preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.

As used herein,"treatment"of a disease includes, but is not limited to prevention, retardation and prophylaxis of the disease.

As used herein,"diseases"treatable using the present compounds include, but are not limited to: prostate cancer, small-cell and non-small-cell lung carcinomas, breast cancer, gastric-carcinoma, glioblastoma, colon cancer, thyroid cancer, and pituitary tumor.

Composition of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.

Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.

A typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.

Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.

No unacceptable toxological effects are expected when compounds of the present invention are administered in accordance with the present invention.

The biological activity of the compounds of Formula (I) are demonstrated by the tests indicated hereinbelow.

Membrane preparation: Human embryonic kidney (HEK 293) cells transfected with rhGRP receptor clone were washed two times with DPBS and scraped in the same buffer. After pelleting by centrifugation, the cells were frozen in liquid nitrogen and thawed on ice. The cell pellet was resuspended in 20 mM Tris HCI, pH 7.5,5 mM EDTA, 0.5 mM phenylmethylsulfonyl fluoride, 5 ug/mL leupeptin, and 0.1 U/mL aprotinin, and the suspension was homogenized 20 times using a glass dounce homogenizer and centrifuged at 800 x g for 10 min to remove unbroken cells and nuclei. The supernatant was centrifuged at 40,000 x g for 30 min and the pellet was resuspended in 50 mM Tris HCI, pH 7.5 and 10 mM MgCl2.

Bindingstudies: Binding of 125g-bombesin to the membrane preparation was performed in 50 uL assay volume containing 50 mM Tris HCI, pH 7.5,10 mM MgCl2, and 0.05% bovine serum albumin. Saturation binding experiments were performed with increasing concentrations of 125I-bombesin and 1-2 ug of the membrane protein in the absence (total binding) and presence (non-specific binding) 1 uM unlabelled

GRP. Incubations were carried out at 30 °C for 30 min and terminated by rapid vacuum filtration through GF/C filters, and the filters were counted using a gamma counter with 75% efficiency.

Inositol phosphates measurement: HEK293 cells transfected with rhGRP receptors grown in T-150 flasks were labeled with 3H-myoinositol (1 uCi/mL) for 24 hr in inositol-free DMEM without serum. Before the experiment, the radioactive medium was removed and the cells were washed once with DPBS++ (DPBS containing 5 mM glucose, 0.2% bovine serum albumin and 10 mM MgC12) and incubated in 10-15 mL of DPBS++ containing 10 mM LiCI for 10 min at 37 °C. At the end of incubation, cells (2xi5) were pipetted into 12x75 glass tubes which contained indicated concentrations of antagonists or agonists or antagonists plus agonists and the reaction continued for 20 min. The reaction was stopped by adding 50 uL of 100% trichloroacetic acid.

Samples were centrifuged, 0.4 mL of supernatant were withdrawn and neutralized with 10 uL of 1 M Tris base and 2 ml of 5 mM Na tetraborate, containing 0.5 mM EDTA. Total inositol phosphates were separated from free inositol using ion exchange chromatography.

The following examples are illustrative of the present invention but not intended to be limiting in any way.

Example 1 (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynylguanidi ne 1 (a) 6- dione A mixture of 3-cyclopentyloxy-4-methoxybenzaldehyde (12.8 g, 0.058 mol), 6-dione (8.3 g, 0.058 mol), piperidine (1 mL) and HOAc (0.5 mL) in benzene (150 mL) was refluxed for 2h, using a Dean-Stark trap to remove the water that was formed. Hexane (75 mL) was added, the mixture was cooled, and the crystalline product filtered and dried (18.7 g, 93%). mp 116-119°C.

1 (b) (+/-)-2, 2-dimethyl-5-([1-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenyl ] prop- 2-yne)-1,3-dioxane-4,6-dione

A solution of phenylacetylene (2.66 g, 0.026 mol) in THF (50mL) at 0°C was treated slowly with a solution of n-BuLi (0.026 mol) in hexane (16.4 mL).

After the addition, the reaction was stirred for 15 min at 23°C, and then cooled to- 78°C. A solution of the compound of Example 1 (a) (8.0 g, 0.022 mol) in THF (125 mL) was added over 5 min, and stirring was continued at-78°C for 30 min. The reaction was quenched with water (500 mL) and 3N HCI (20 mL), and extracted with ether. The extracts were washed with water, dried (CaS04), and the solvent evaporated. The residue was recrystallized from a mixture of CH2Cl2 and cyclohexane, and gave the titled compound (8. 31 g, 84%). mp 108-114°C.

1 (c) (+/-)-3- (3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylpropionic acid A solution of the compound of Example 1 (b) (4.2 g, 9.4 mmol) in dioxane (70 mL), water (3mL) and 3N HCI (5 mL) was heated at 100°C for 90 min. The reaction was cooled, diluted with water (200 mL), and extracted with ether. The extracts were washed with water, dried (CaS04), and the solvent evaporated. The residue was dissolved in dimethylacetamide (10 mL), and the solution was heated at 135°C for 30 min. The reaction was cooled, diluted with water (200 mL) and extracted with ether. The extracts were washed well with water, dried (CaS04), and the solvent evaporated. The residue was recrystallized from a mixture of CH2Cl2 and hexane, and gave the titled compound (2.8 g, 82%). mp 86-88°C.

1 (d) (+/-)-4-amino-3- (3-cyclopentyloxy-4-methoxyphenyl)-l-phenyl-l-butyne hydrochloride A solution of the compound from Example l (c) (1.2 g, 3.3 mmol) in Me2CO (40 mL) was cooled to OoC and treated with Et3N (0.5 mL, 3.3mmol) and then ethyl chloroformate (0.35 mL, 3,63 mmol) dropwise. A solution of NaN3 (0.47 g, 7.25 mmol) in H20 (2 mL) was added dropwise to the cold solution, and stirring continued for 0.25 h. The reaction was diluted with H20, and extracted with Et20.

The organic phase was washed with water, was dried (Na2SO4), and was filtered.

The ether extract was slowly added to refluxing toluene (100 mL), and the solution was heated at 1 lOoC for 0.5 h, and was evaporated. The residue was dissolved in a mixture of dioxane (5 mL), water (3 mL), and conc. HCI (3 mL), was refluxed for

0.2 h, was cooled and the solid was filtered. Recrystallization from a mixture of isopropanol and ether gave the titled compound as the HCI salt, 1.03 g (84%). mp 212-215°C. l (f) (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N', N"-bis- (t-butoxycarbonyl) guanidine The compound from Example l (d) (0.1 g, 0.3 mmol) was partitioned between 10% NaOH and EtOAc. The organic phase was dried (K2CO3) and was evaporated. The residue was dissolved in DMF (0.2 mL) and di-boc-thiourea (0.1 g, 0.36 mmol), prepared according the procedure described by Iwanowicz et. al., Synthetic Communications, 23 (10), 1993,1443-5, was added. 2-Chloro-l-methyl pyridinium iodide (0.09 g, 0.36 mmol) and triethylamine (0.09 mL, 0.66 mmol) were added and the mixture was stirred 18 h. The reaction mixture was diluted with water and was extracted with CH2Cl2. The organic extract was dried (Na2SO4) and was evaporated. Purification by flash chromatography (silica gel, 0.15 EtOAc/hexanes) provided the title compound as a white solid, 0.13 g (75%). mp 63- 660C. l (g) (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine A solution of the compound from Example 1 (f) (0.12 g, 0.2 mmol) in CH2Cl2 (4 mL) was treated with TFA (4 mL). The solution was stirred for 4 h and solid NaHCO3 was added to pH 7. The mixture was diluted with water, was extracted with CH2Cl2. The organic extract was dried (Na2SO4) and was evaporated to provide the title compound as a brown solid, 0.04 g (50%). Anal.

(C23H27N302.0.9TFA) calcd: C, 62.04; H, 5.86; N, 8.75 found: C, 62.11; H, 6.18; N, 8.39.

Example 2 (+/-)-N-cyano-N'-2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyl guanidine 2 (a) (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl- S-methylisothiourea A mixture of the compound from Example l (d) (0.22 g, 0.6mmol) and cyanodithioiminocarbonate (0.18 g, 1.3 mmol) were placed in pyridine (2.5 mL) and

refluxed for 4 h under an argon atmosphere. The mixture was evaporated, was partitioned between 10% aqueous HC1 and CH2Cl2. The organic layer was separated and was dried (Na,) S04) and was evaporated. The residue was purified by flash chromatography (silica gel, 50% hexanes/EtOAc) to provide the title compound as a white solid, 0.18 g (69%). mp 122-123oC.

2 (b) (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl- N'- (t-butoxycarbonyl)-S-methylisothiourea A 60% NaH/mineral oil suspension (0.03 g, 0.6 mmol) was washed with hexanes under an argon atmosphere and was suspended in THF (1 mL). A solution of the compound from Example 4 (a) (0.18 g, 0.4 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at RT for 1 h and di-t-butyl dicarbonate (0.18 g, 0.8 mmol) was added to the mixture. After 18 h at room temperature, the mixture was diluted with water and was extracted with CH2C12. The organic extract was dried (Na2SO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 20% EtOAc/hexanes) to give the title compound as a white solid, 0.2 g (95%). mp 49-5 loC.

2 (c) (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl- N'- (t-butoxycarbonyl) guanidine To the compound from Example 2 (b) (0.2 g, 0.38 mmol) at-4OoC was condensed ammonia (5 mL). The solution was stirred for 8 h and the ammonia was evaporated at room temperature. The residue was diluted with ether and filtered to provide the title compound as a white solid, 0.14 g (71%). mp 150-151oC.

2 (d) (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyl guanidine To a solution of the compound from Example from 2 (c) (0.13 g, 0.26 mmol) in CH2C12 (2 ml) at OoC under an argon atmosphere was added TFA (2 mL). The mixture was stirred for 0.4 h and neutralized with solid NaHCO3. The mixture was diluted with CH2Cl2 and was washed with 10% aqueous NaOH. The organic extract was dried (Na2SO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 3% MeOH/CH2Cl2) to provide the title compound as a white solid, 0.06 g (57%). mp 87-89oC.

Example 3 (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl thiourea 3 (a) (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N'- benzoylthiourea To a suspension of the compound from Example l (d) (0.5 g, 1.3 mmol) in CHC13 (10 mL) at OoC was added triethylamine (0.14 g, 1.4 mmol) and benzoylisothiocyanate (0.2 g, 1.3 mmol). The mixture was stirred at room temperature for 0.5 h, was diluted with water and was extracted with CHC13. The organic extract was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 20% EtOAc/hexanes) and triturated (EtOAc/hexanes) to provide 0.5 g (75%) of the title compound as a white solid: mp 118-119 OC.

3 (b) (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl thiourea To a solution of the compound from Example 3 (a) (0.25 g, 0.5 mmol) in 4: 1 MeOH/H2O (5 mL) was added K2CO3 (0. 19 g, 1.5 mmol) and the mixture was stirred for 5 h. The mixture was partitioned between water and 10% MeOH/CH2CI2.

The organic extract was dried (Na2SO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 50% EtOAc/hexanes) to provide the title compound as yellow solid, (0.14 g, 68%). mp 69-71OC.

Example 4 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (benzyl) guanidine 4 (a) (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl- N'-(t-butoxycarbonyl)-N"-(benzyl)(t-butoxycarbonyl)-N"-(benz yl) guanidine A mixture of the compound from Example 2 (b) (0.05 g, 0.09 mmol) and benzyl amine (0.01 g, 0.09 mmol) was stirred in DMF (0.2 mL) for 4 days. The mixture diluted with water and extracted with CH2Cl2. The organic extract was dried (MgS04) and was evaporated. The residue was purified by flash chromatography (silica gel, 20% EtOAc/hexanes) to provide the title compound as a white gum, (0.034 g, 64%). MS (ES) m/e 593 [M+H] +.

4 (b) (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl- N"- (benzyl) guanidine To a solution of the compound from Example 4 (a) (0.03 g, 0.05 mmol) in CH2C12 (1 mL) was added TFA (0.5 mL). The mixture was stirred for 0.4 h and neutralized with solid NaHCO3. The mixture was diluted with CH2Cl2 and was washed with 10% aqueous NaOH. The organic extract was dried (MgS04) and was evaporated. The residue was purified by flash chromatography (silica gel, 2% MeOH/CH2Cl2) to provide the title compound as a yellow foam, 0.019 g (74%).

MS (ES) m/e 493 [M+H] +.

Example 5 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (4-methoxyphenyl) guanidine Following the procedures of Example 4 except substituting 4-methoxyaniline for benzylamine, the titled compound was prepared (70%). MS (ES) m/e 509 [M+H]+.

Example6 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (3-pyridylmethyl) guanidine Following the procedures of Example 4 except substituting 3- aminomethylpyridine for benzylamine, the titled compound was prepared (34%).

MS (ES) m/e 494 [M+H] +.

Example 7 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl- N" 2- (indol-3-yl) ethyl] guanidine Following the procedures of Example 4 except substituting tryptamine for benzylamine, the titled compound was prepared (64%). MS (ES) m/e 546 [M+H] +.

Example 8 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (morpholin-4-yl) guanidine

Following the procedures of Example 4 except substituting 4- aminomorpholine for benzylamine, the titled compound was prepared (72%).

MS (ES) m/e 488 [M+H] +.

Example 9 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (1-benzylpiperidin-4-yl) guanidine Following the procedures of Example 4 except substituting 1-benzyl-4- aminopiperidine for benzylamine, the titled compound was prepared (71 %). MS (ES) m/e 576 [M+H] +.

Example 10 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl- N", N"- (ethylether) guanidine Following the procedures of Example 4 except substituting morpholine for benzylamine, the titled compound was prepared (35%). MS (ES) m/e 473 [M+H] +.

Example 11 (+/-)-N-cyano-N'-2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phen ylbut-3-ynyl-N"- (4-pyridylmethyl) guanidine Following the procedures of Example 4 except substituting 4- aminomethylpyridine for benzylamine, the titled compound was prepared (56%).

MS (ES) m/e 494 [M+H] +.

Example12 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (imidazol-1-ylpropyl) guanidine Following the procedures of Example 6 except substituting 1- aminopropylimidazole for benzylamine, the titled compound was prepared (74%).

MS (ES) m/e 511 [M+H] +.

Example13 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (thiophen-2-ylethyl) guanidine

Following the procedures of Example 6 except substituting 2- aminoethylthiophene for benzylamine, the titled compound was prepared (61%).

MS (ES) m/e 513 [M+H] +.

Example 14 (+/-)-N-cyano-N'-2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phen ylbut-3-ynyl-N"- (cyclohexyl)guanidine Following the procedures of Example 6 except substituting cyclohexylamine for benzylamine, the titled compound was prepared (48%). MS (ES) m/e 485 [M+H] +.

Example 15 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-methoxyethyl) guanidine Following the procedures of Example 6 except substituting 2- methoxyethylamine for benzylamine, the titled compound was prepared (32%).

MS (ES) m/e461 [M+H] +.

Example 16 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-pyridylmethyl) guanidine Following the procedures of Example 6 except substituting 2- aminomethylpyridine for benzylamine, the titled compound was prepared (70%).

MS (ES) m/e 494 [M+H] +.

Example 17 (+/-)-N-cyano-N'-2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (4-methoxyphenylmethyl) guanidine Following the procedures of Example 6 except substituting 4- methoxybenzylamine for benzylamine, the titled compound was prepared (68%).

MS (ES) m/e 523 [M+H] +.

Example18 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (morpholin-4-ylethyl) guanidine

Following the procedures of Example 6 except substituting 4- aminoethylmorpholine for benzylamine, the titled compound was prepared (86%).

MS (ES) m/e 516 M+H +.

Example19 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (4-t-butylphenyl) guanidine Following the procedures of Example 6 except substituting 4-t-butylaniline for benzylamine, the titled compound was prepared (54%). MS (ES) m/e 535 [M+H] +.

Example20 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (N, N-dimethylaminopropyl) guanidine Following the procedures of Example 6 except substituting N, N- dimethylpropylenediamine for benzylamine, the titled compound was prepared (68%). MS (ES) m/e 488 [M+H] +.

Example 21 (+/-)-N-cyano-N'-2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (phenethyl) guanidine Following the procedures of Example 6 except substituting phenethylamine for benzylamine, the titled compound was prepared (80%). MS (ES) m/e 507 M+H +.

Example22 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (acetophenon-2-yl) guanidine Following the procedures of Example 6 except substituting 2- aminoacetophenone for benzylamine, the titled compound was prepared (26%).

MS (ES) m/e 521 [M+H] +.

Example 23 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (piperidin-1-ylethyl) guanidine

Following the procedures of Example 6 except substituting 1- aminoethylpiperidine for benzylamine, the titled compound was prepared (76%).

MS (ES) m/e 514 [M+H] +.

Example 24 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (indan-2-yl) guanidine Following the procedures of Example 6 except substituting 2-aminoindane for benzylamine, the titled compound was prepared (64%). MS (ES) m/e 519 [M+H] +.

Example 25 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-cyanoethyl) guanidine Following the procedures of Example 6 except substituting 3- aminopropionitrile for benzylamine, the titled compound was prepared (66%).

MS (ES) m/e 456 [M+H] +.

Example 26 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (3-hydroxypropyl) guanidine Following the procedures of Example 6 except substituting 3-amino-1- propanol for benzylamine, the titled compound was prepared (48%). MS (ES) m/e 461 [M+H] +.

Example 27 (+/-)-N-cyano-N'-2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phen ylbut-3-ynyl-N"- (1-methylpyrrol-2-ylethyl) guanidine Following the procedures of Example 6 except substituting 2-aminoethyl-1- methylpyrrole for benzylamine, the titled compound was prepared (31 %). MS (ES) m/e 510 [M+H] +.

Example28 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (6-hydroxyhexyl) guanidine

Following the procedures of Example 6 except substituting 6-amino-1- hexanol for benzylamine, the titled compound was prepared (60%). MS (ES) m/e 503 [M+H] +.

Example29 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (octyl)guanidine Following the procedures of Example 6 except substituting 1-octylamine for benzylamine, the titled compound was prepared (78%). MS (ES) m/e 515 [M+H] +.

Example30 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (4-amidosulfonylphenylmethyl) guanidine Following the procedures of Example 6 except substituting 4- aminomethylbenzenesulfonamide for benzylamine, the titled compound was prepared (31%). MS (ES) m/e 572 [M+H] +.

Example 31 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-ethoxycarbonylethyl) guanidine Following the procedures of Example 6 except substituting P-alanine ethyl ester for benzylamine, the titled compound was prepared (60%). MS (ES) m/e 503 [M+H] +.

Example 32 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (4-methylsulfonylphenylmethyl) guanidine Following the procedures of Example 6 except substituting methyl-p- toluenesulfonate for benzylamine, the titled compound was prepared (46%). MS (ES) m/e 571 [M+H] +.

Example 33 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2,4-dimethoxyphenylmethyl) guanidine

Following the procedures of Example 6 except substituting 2.4- dimethoxybenzylamine for benzylamine, the titled compound was prepared (64%).

MS (ES) m/e 553 [M+H] +.

Example 34 (+/-)-N-cyano-N'-2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phen ylbut-3-ynyl-N"- 3-(2-pyrrolidinon-1-yl) propyl guanidine Following the procedures of Example 6 except substituting 1- (3- aminopropyl)-2-pyrrolidinone for benzylamine, the titled compound was prepared (55%). MS (ES) m/e 528 [M+H] +.

Example 35 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2,2,2-trifluoroethyl) guanidine Following the procedures of Example 6 except substituting 2,2,2- trifluoroethylamine for benzylamine, the titled compound was prepared (58%).

MS (ES) m/e 485 [M+H] +.

Example36 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (cyclopropylmethyl)guanidine Following the procedures of Example 6 except substituting cyclopropylmethylamine for benzylamine, the titled compound was prepared (50%).

MS (ES) m/e 457 [M+H] +.

Example37 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-hydroxyethyl) guanidine Following the procedures of Example 4 except substituting ethanolamine for benzylamine, the titled compound was prepared (71%). MS (ES) m/e 447 [M+H] +.

Example38 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (benzimidazol-2-ylmethyl) guanidine

Following the procedures of Example 4 except substituting 2- aminomethylbenzimidazole for benzylamine, the titled compound was prepared (79%). MS (ES) m/e 533 [M+H] +.

Example 39 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-aminoethyl) guanidine Following the procedures of Example 4 except substituting N-boc- ethylenediamine for benzylamine, the titled compound was prepared (36%). MS (ES) m/e 446 [M+H] +.

Example 40 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (3-aminopropyl) guanidine Following the procedures of Example 4 except substituting N-boc- propylenediamine for benzylamine, the titled compound was prepared (32%).

MS (ES) m/e 460 [M+H] +.

Example 41 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (4-aminobutyl) guanidine Following the procedures of Example 4 except substituting N-boc- butylenediamine for benzylamine, the titled compound was prepared (36%). MS (ES) m/e 474 [M+H] +.

Example 42 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl-N"- (2-carboxyethyl) guanidine A solution of the compound from Example 31 (0.025 g, 0.05 mmol) in 5: 5: 2 THF/MeOH/H20 (2 ml) was treated with KOH (0.01 g, 0.15 mmol) and stirred 5 h.

The mixture was acidified with 3 N aqueous HCl and extracted with CH2C12. The organic extract was dried (MgS04) and was evaporated. The residue was purified by flash chromatography (silica gel, 10% MeOH/CHC13) to provide the titled compound as a tan foam, 0.007g (30%). MS (ES) m/e 475 [M+H] +.

Example 43 (+/-)-N- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl urea A mixture of the compound from Example 1 (d) (0.05 g, 0.13 mmol) and potassium cyanate (0.022 g, 0.16mmol) in 2: 1 H2O/AcOH (1 mL) was stirred for 8 days. The mixture was diluted with water and was extracted with CH2Cl2. The organic extract was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography (silica gel, 66% EtOAc/hexanes, then 75% EtOAc/CH2Cl2) to provide the titled compound as a pale-yellow solid, 0.02 g (40%). mp 68-70 °C.

Example 44 (+/-)-3- (3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylpropionic acid 44 (a) (+/-)-2, 2-dimethyl-5-([1-(3-cyclopentyloxy-4-methyoxyphenyl)-3- trimethylsilyl prop-2-yne)-1,3-dioxane-4,6-dione Following the procedure of Example 1 (b), except substituting trimethylsilylacetylene for phenylacetylene, the titled compound was prepared (63%). mp 105-107°C.

44 (b) (+/-)-3- (3-Cyclopentyloxy-4-methoxyphenyl)-3- trimethylsilylethynylpropionic acid Following the procedure of Example 1 (c), except substituting (+/-)-2,2- dimethyl-5- ( 1- (3-cyclopentyloxy-4-methoxyphenyl)-3-trimethylsilyl prop-2-yne)- 1,3-dioxane-4,6-dione for (+/-)-2,2-dimethyl-5- ( [ 1- (3-cyclopentyloxy-4- methoxyphenyl)-3-phenyl prop-2-yne)-1,3-dioxane-4,6-dione the titled compound was prepared (78%). 1H NMR (400MHz, CDC13)? 6.98 (d, 1H), 6.88 (d of d, 1H), 6.80 (d, 1H), 4.80 (m, 1H), 4.12 (t, 1H), 3.82 (s, 3H), 2.86 (d of d, 1H), 2.74 (d of d, 1H), 1.78-2.00 (m, 6H), 1.62 (m, 2H).

44 (c) (+/-)-3- (3-Cyclopentyloxy-4-methoxyphenyl)-3-ethynylpropionic acid The compound from Example 44 (b) (12.5 g, 37.6 mmol) was dissolved in a mixture of MeOH (75 mL) and H20 (40 mL) and treated with 10% aqueous NaOH (90 mL). The reaction was stirred 1 h at room temperature, was diluted with H20 (200 mL) and was treated with activated carbon. The mixture was filtered and the filtrate was acidified, and extracted with ether. The extracts were washed with H20,

dried (MgSO4), and the solvent evaporated. The residue was crystallized from 1: 1 hexanes/CH2Cl2 (200 ml) providing the titled compound (6.5 g, 60%). mp 128- 131°C.

Example 45 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-chlorophenyl) but-3- ynyl]-guanidine 45 (a) (+/-)-4-amino-3- (3-cyclopentyloxy-4-methoxyphenyl)-1-butyne A solution of the compound from Example 44 (c) (8.5 g, 29 mmol) in Me2CO (300 mL) was cooled to 0°C and treated with Et3N (4.5 mL, 32 mmol) and then isobutyl chloroformate (4.2 mL, 32 mmol) dropwise. A solution of NaN3 (4.2 g, 64 mmol) in H20 (25 mL) was added dropwise to the cold solution, and stirring continued for 0.25 h. The reaction was diluted with H20, and extracted with Et20.

The organic phase was washed with water, was dried (Na2SO4), and was filtered.

The ether extract was slowly added to refluxing toluene (500 mL), and the solution was heated at 110°C for 0.5 h, and was evaporated. The residue was dissolved in a mixture of dioxane (50 mL), water (30 mL), and conc. HCl (30 mL), was refluxed for 0.2 h and was cooled and was evaporated. The residue was treated with 10% aqueous NaOH to pH 9 and was extracted with CH2C12. The organic extract was washed with brine, was dried (K2CO3) and was evaporated to provide the titled compound as a brown oil, 7.5 g (87%). MS (ES) m/e 260 [M+H] +.

45 (b) (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-but-3-ynyl-O- (phenyl) isourea To a solution of the compound from Example 45 (a) (7.6 g, 29 mmol) in isopropanol (200 mL) was added diphenyl cyanocarbonimidate (8.1 g, 34 mmol).

The mixture was stirred 18 h and was filtered to provide the titled compound as a white solid, 10.7 g (95%). mp 170-172°C.

45 (c) (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-but-3-ynyl- guanidine To a suspension of the compound from Example 45 (b) (1.5 g, 3.7 mmol) in isopropanol (50 mL) in a pressure vessel at-78°C was condensed ammonia (15

mL). The vessel was sealed and was warmed to room temperature. After 36 h. the reaction mixture was cooled to-78°C, the reaction vessel was opened and the mixture was warmed to RT and was evaporated. The residue was dissolved in EtOAc, was washed with 10% aqueous NaOH, was dried (MgS04) and was evaporated to provide the titled compound as a white foam, 1.2 g (100%). MS (ES) m/e 327 [M+H] +.

45 (d) (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3- chlorophenyl) but-3-ynyl] guanidine A mixture of the compound from Example 45 (c) (0.06 g, 0.18 mmol), 3- chloro-1-iodobenzene (0.05 g, 0.2 mmol), Cul (0.004 g, 9 u. mol) and tertrakis (triphenylphosphine) palladium (0) (0.01 g, 9"mol) in triethylamine (5 mL) was refluxed under an argon atmosphere for 3 h. The mixture was cooled and was evaporated. The residue was purified by flash chromatography (silica gel, 3% MeOH/CH2CI2) to provide the titled compound as a tan solid, 0.05 g (61%).

MS (ES) m/e 437 [M+H] +.

Example46 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-chlorophenyl) but-3- ynyl guanidine Following the procedure of Example 45 (d), except substituting 4-chloro-1- iodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (40%).

MS (ES) m/e 437 [M+H] +.

Example 47 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (2-t-butylphenyl) but-3- ynyl guanidine Following the procedure of Example 45 (d), except substituting 4-iodo-1-t- butylbenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (14%).

MS (ES) m/e 459 [M+H] +.

Example 48 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3- carboxymethylphenyl) but-3-ynyl guanidine

Following the procedure of Example 45 (d), except substituting methyl 3- iodobenzoate for 3-chloro-1-iodobenzene, the titled compound was prepared (34%).

MS (ES) m/e 461 M+H +.

Example 49 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (2- carboxymethylphenyl) but-3-ynyl] guanidine Following the procedure of Example 45 (d), except substituting methyl 2- iodobenzoate for 3-chloro-1-iodobenzene, the titled compound was prepared (15%).

MS (ES) m/e461 [M+H] +.

Example50 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4- methoxycarbonylmethoxyphenyl) but-3-ynyl] guanidine Following the procedure of Example 45 (d), except substituting methyl 4- iodophenoxyacetate for 3-chloro-1-iodobenzene, the titled compound was prepared (44%). MS (ES) m/e 491 [M+H] +.

Example 51 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (2-carboxyphenyl) but- 3-ynyl guanidine A solution of the compound from Example 49 (0.035 g, 0.08 mmol) in 5: 5: 2 THF/MeOH/H20 (2 mL) was treated with NaOH (0.01 g, 0.24 mmol) and stirred 5 h. The mixture was acidified with 3 N aqueous HCI and filtered to provide the titled compound as a tan solid, 0.016g (50%). mp 173-177 °C.

Example52 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- 3- (5-methyl- [1,3,4] thiadiazol-2-yl) phenyl but-3-ynyl guanidine Following the procedure of Example 45 (d), except substituting 3- (5-methyl- 1,3,4 thiadiazol-2-yl)-1-iodobenzene) for 3-chloro-1-iodobenzene, the titled compound was prepared (18%). MS (ES) m/e 501 [M+H] +.

Example 53 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4- carboxymethoxyphenyl) but-3-ynyl-guanidine A solution of the compound from Example 50 (0.05 g, 0.1 mmol) in 5: 5: 2 THF/MeOH/H20 (2 mL) was treated with NaOH (0.012 g, 0.3 mmol) and stirred 5 h. The mixture was acidified with 3 N aqueous HCI, was extracted with CH2Cl2 was dried (MgSO4) to provide the titled compound as a tan foam, 0.033g (67%). MS (ES) m/e 477 [M+H] +.

Example54 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-fluoro-3- chlorophenyl) but-3-ynyl] guanidine Following the procedure of Example 45 (d), except substituting 3-chloro-4- fluoroiodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (17%). MS (ES) m/e 455 [M+H] +.

Example 55 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-chloro-3- fluorophenyl) but-3-ynyl] guanidine Following the procedure of Example 45 (d), except substituting 4-chloro-3- fluoroiodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (3%). MS (ES) m/e 455 [M+H] +.

Example56 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3,4- difluorophenyl) but-3-ynyl guanidine Following the procedure of Example 45 (d), except substituting 3,4- difluoroiodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (1%). MS (ES) m/e 439 [M+H] +.

Example 57 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-methoxyphenyl) but- 3-ynyl] guanidine

Following the procedure of Example 45 (d), except substituting 3- methoxyiodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (23%). MS (ES) m/e 433 [M+H] +.

Example 58 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4- trifluoromethoxyphenyl) but-3-ynyl guanidine Following the procedure of Example 45 (d), except substituting 4- (trifluoromethoxy) iodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (26%). MS (ES) m/e 487 [M+H] +.

Example 59 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- 3- (5-methyl- 1,3,4 oxadiazol-2-yl) phenyl] but-3-ynyl guanidine Following the procedure of Example 45 (d), except substituting 3- (5-methyl- 1,3,4 oxadiazol-2-yl)-1-iodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (9%). MS (ES) m/e 485 [M+H] +.

Example 60 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3- trifluoromethylphenyl) but-3-ynyl] guanidine Following the procedure of Example 45 (d), except substituting 3- (trifluoromethyl) iodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (14%). MS (ES) m/e 471 M+H +.

Example 61 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-N- pyrrolylphenyl) but-3-ynyl] guanidine Following the procedure of Example 45 (d), except substituting 1- (4- iodophenyl) pyrrole for 3-chloro-1-iodobenzene, the titled compound was prepared (21%). MS (ES) m/e 468 [M+H] +.

Example 62 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (naphthalen-2-yl) but-3- ynyl] guanidine

Following the procedure of Example 45 (d), except substituting 2- iodonaphthalene for 3-chloro-l-iodobenzene, the titled compound was prepared (7%). MS (ES) m/e 453 [M+H] +.

Example 63 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-methoxyphenyl) but- 3-ynyl] guanidine Following the procedure of Example 45 (d), except substituting 4- methoxyiodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (8%). MS (ES) m/e 433 [M+H] +.

Example 64 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-acetylphenyl) but-3- ynyl] guanidine Following the procedure of Example 45 (d), except substituting 3'- iodoacetophenone for 3-chloro-1-iodobenzene, the titled compound was prepared (9%). MS (ES) m/e 445 [M+H] +.

Example 65 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (4-methoxyphenyl) but- 3-ynyl] guanidine Following the procedure of Example 45 (d), except substituting 3- fluoroiodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (8%). MS (ES) m/e 421 [M+H] +.

Example 66 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-carboxyphenyl) but- 3-ynyl guanidine A solution of the compound from Example 48 (0.045 g, 0.1 mmol) in 5: 5: 2 THF/MeOH/H2O (2 mL was treated with NaOH (0.013 g, 0.3 mmol) and stirred 5 h.

The mixture was acidified with 3 N aqueous HCI, was extracted with CH2CI2 was dried (MgS04) to provide the titled compound as a yellow foam, 0.036g (83%).

MS (ES) m/e 477 [M+H] +.

Example67 (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl -0- (phenyl) isourea (+/-)-4-Amino-3- (3-cyclopentyloxy-4-methoxyphenyl)-1-phenyl-1-butyne hydrochloride (10.0 g, 26.9 mmol), isopropanol (600 mL), triethylamine (4.0 g, 40.3 mmol) and diphenylcyanocarbonimidate (8.0 g, 33.6 mmol) were combined and stirred at 25 °C for 1 hour. The precipitate material was filtered and washed with isopropanol to afford 6.2 g (48%) of white crystalline: mp 159-161°C.

(+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl -0- (phenyl) isourea (6.2 g 12.93 mmol), isopropanol (400 mL) and anhydrous ammonia were combined in a sealed tube and stirred overnight at 25°C. Most of the isopropanol was evaporated in vacuo, water was added, the mixture was extracted with ethyl acetate (3 x 100 mL) and the combined extracts was concentrated to afford 5.0 g (96.0%) of white solid: mp 68-69°C; MS ES+ m/z 403.4 (MH+).

Example 68 (+/-)-N-cyano-N'- 2- (3-hydroxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine To a solution of (+/-)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)- 4-phenylbut-3-ynyl guanidine (3.6 g 8.94 mmol) in methylene chloride (160 mL) was cooled to-78 °C and borontribromide (4.5 g 17.9 mmol) was added slowlly and the resulting mixture was stirred for 15 min. The reaction was quenched with sodium methoxide solution in methanol, and the mixture was poured into water and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried (Na2SO4) and concentrated to afford 1.0 g white solid: mp 90-92 °C; MS ES+ m/z 335.4 (MH+).

Example 69 (+/-)-N-cyano-N'- 2- (3-decyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine To a solution of (+/-)-N-cyano-N'- 2- (3-hydroxy-4-methoxyphenyl)-4- phenylbut-3-ynyl guanidine (70 mg 0.21 mmol) in dimethylformamide (50 mL) was added 1-iododecane (62 mg 0.23 mmol) and potassium carbonate (32 mg 0.23 mmol), respectively, and the resulting mixture was stirred at 25 °C for 18 h. The mixture was poured into water and extracted with ethyl acetate. The organic phase was separated, washed with brine and dried (Na2SO4). The residue was concentrated and chromatographed over silica gel (100% ethyl acetate) to afford the title compound (30 mg) as an off-white solid: mp 56-58°C; MS ES+ m/z 475.5 (MH+).

Following compounds were prepared according to the procedure for Example 69 using the appropriate halide reagents.

Example70 (+/-)-N-cyano-N'- 2- (3-ethyloxy-4-metoxyphenyl)-4-phenylbut-3-ynyl guanidine: MS ES+ m/z 363 (MH+).

Example 71 (+/-)-N-cyano-N'- 2- (3-butyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine: MS ES+ m/z 391 (MH+).

Example72 (+/-)-N-cyano-N'- 2- (3- (4- (ethylcarbonylmethyl) thiazolyl-2-aminocarbonyl- methyloxy-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine: MS ES+ m/z 561 (MH+).

Example 73 (+/-)-N-cyano-N'- 2- 4- (6, 7-dimethoxycumoarin)-3-methoxy-4-methoxy phenyl-4- phenylbut-3-ynyl guanidine: MS ES+ m/z 553 (MH+).

Example74 (+/-)-N-cyano-N'- 2- (3-cyclobutylmethoxy-4-methoxyphenyl)-4-phenylbut-3- ynyl] guanidine: MS ES+ m/z 403 (MH+).

Example 75 (+/-)-N-cyano-N'- 2- (3- (4-ethyoxycarbonylbutyloxy)-4-methoxyphenyl)-4- phenylbut-3-ynyl guanidine: MS ES+ m/z 463 (MH+).

Example76 (+/-)-N-cyano-N'- 2- (3- (4-chlorophenylthiazolylmethoxy-3-methyloxy)-4- methoxyphenyl)-4-phenylbut-3-ynyl guanidine: MS ES+ m/z 543 (MH+).

Example 77 (+/-)-N-cyano-N'-2- (3-cyclohexylcarbonylmethyloxy)-4-methoxyphenyl-4- phenylbut-3-ynyl] guanidine: MS ES+ m/z 475 (MH+).

Example 78 (+/-)-N-cyano-N'-2- (3- (2-methylthiazole-4-ylmethoxy-4-methoxyphenyl)-4- phenylbut-3-ynyl guanidine: MS ES+ m/z 446 (MH+).

Example 79 (+/-)-N-cyano-N'-2- (3- (cyclohexylethoxy)-4-methoxyphenyl)-4-phenylbut-3-ynyl guanidine: MS ES+ m/z 445 (MH+).

Example 80 (+/-)-N-cyano-N'- 2- (3-diethyldicarbonylpropoxy)-4-methoxyphenyl)-4-phenylbut- 3-ynyl guanidine: MS ES+ m/z 535 (MH+).

Example 81 (+/-)-N-cyano-N'- 2- (3-geranyloxy-4-methoxyphenyl)-4-phenylbut-3- ynyl] guanidine: MS ES+ m/z 471 (MH+).

Example82 (+/-)-N-cyano-N'- 2- (3-tetrahydrofuryl-2-methoxy-4-methoxyphenyl)-4-phenylbut- 3-ynyl guanidine: MS ES+ m/z 419 (MH+).

Example 83 (+/-)-N-cyano-N'-2- (3- (2-ethylhexyloxy)-4-methoxyphenyl)-4-phenylbut-3- ynyl] guanidine: MS ES+ m/z 447 (MH+).

Example84 (+/-)-N-cyano-N'- 2- (3- (4- (2, 6-dichlorobenzylsulphonylbenzyloxy)-4- methoxyphenyl)-4-phenylbut-3-ynyl] guanidine: MS ES+ m/z 648 (MH+).

Example 85 (R)-N-cyano-N'- 2- (3-cyclopentyloxy-4-methoxyphenyl)-4- (3-methoxyphenyl) but- 3-ynyl] guanidine Following the procedure of Example 45 (d) using enantiomer pure acetylene derived from an acid of Formula (24), except substituting 3-methoxyiodobenzene for 3-chloro-1-iodobenzene, the titled compound was prepared (81%). MS (ES) m/e 433 [M+H] +.

Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerus excipients.

Examples of such formulations are given below: Example 86 Inhalant Formulation A compound of Formula (I), (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.

Example 87 Tablet Formulation Tablets/Ingredients Per Tablet 40 mg 1. of Form. (1) 20 mg 20 mg 20 mg (Cpd 3 Form. (I) Procedure for tablet formulation: Ingredients 1,2,3 and 4 are blended in a suitable mixer/blender. Sufficient water is added portion-wise to the blend with careful mixing after each addition until

the mass is of a consistency to permit its conversion to wet granules. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. The wet granules are then dried in an oven at 140°F (60°C) until dry. The dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press.

Example 88 Parenteral Formulation A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections (to 100 mL).

The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

All publications, including but not limited to patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference as though fully set forth.