HK1058669A

HK1058669A - Alpha-aryl ethanolamines and their use as beta-3 adrenergic receptor agonists

Info

Publication number: HK1058669A
Application number: HK04101417.9A
Authority: HK
Inventors: R‧F‧戴; J‧A‧拉方丹
Original assignee: 辉瑞产品公司
Priority date: 2000-10-20
Filing date: 2001-10-04
Publication date: 2004-05-28

Description

Alpha-arylethanolamines and their use as beta-3 adrenergic receptor agonists

Technical Field

The invention relates to compounds of the formula (I) which are beta₃Adrenergic receptor agonists, and thus have utility as hypoglycemic and anti-obesity agents.

The invention also relates to intermediates useful in the preparation of compounds of formula (I); a combination of a compound of formula (I) and an anti-obesity agent; pharmaceutical compositions comprising said compounds and combinations; treatment of beta in mammals using said compounds, combinations and pharmaceutical compositions₃A method of treating an adrenergic receptor-mediated disease, condition or disorder. The compounds and combinations of the present invention also have application in increasing lean meat content in edible animals, i.e., ungulates such as cattle, swine and the like and poultry.

The compounds and combinations of the present invention are also useful in the treatment of disorders of intestinal motility, depression, prostate disorders, dyslipidemia, and inflammatory diseases of the airways.

Background

Diabetes mellitus is a disease characterized by metabolic defects in the production and utilization of carbohydrates, resulting in the failure to maintain proper blood glucose levels. The consequences of these defects are in particular an increase in blood glucose or hyperglycemia. Research on the treatment of diabetes has focused on attempting to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral medications, and dietary therapies.

Diabetes is divided into two main types. Type 1 diabetes, or Insulin Dependent Diabetes Mellitus (IDDM), is the result of an absolute deficiency of insulin, a hormone that regulates carbohydrate utilization. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often occurs in normal or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most type 2 diabetes is also obesity.

The compounds of the present invention are effective in lowering blood glucose levels when orally administered to a mammal suffering from hyperglycemia or obesity.

Obesity is a major health threat leading to death and development of type 2 diabetes, hypertension and dyslipidemia. In the united states, over 50% of adults are overweight, and almost 25% of the population are considered obese. In the united states, the incidence of obesity increases at an accumulative rate of 3% per year. Although the vast majority of obesity occurs in the united states and europe, the incidence of obesity is also increasing in japan. Furthermore, obesity is a devastating disease that can also severely undermine an individual's mental well-being and confidence, which can ultimately affect an individual's ability to socialize with others. Unfortunately, the exact cause of obesity is complex and poorly understood, and social compliance and speculation about obesity often only exacerbates the psychological impact of the disease. Due to the impact of obesity on general society, great efforts have been made to treat obesity, however, success in the long-term treatment and/or prevention of obesity remains insignificant.

The compounds, pharmaceutical compositions and combinations of the present invention may also reduce body weight or reduce the increase in body weight when administered to a mammal. The compounds of the invention are able to exert an effect on weight gain due to the activation of beta which stimulates the metabolism of adipose tissue₃Caused by adrenergic receptors.

The beta-adrenergic receptors are divided into beta₁、β₂And beta₃A receptor-specific subtype. Beta-receptor agonists promote activation of adenylate cyclase. Beta is a₁Activation of the receptor may cause an increase in heart rate, whereas beta₂Activation of the receptors can cause smooth muscle relaxation, resulting in a drop in blood pressure and the onset of skeletal muscle tremors. Known as beta₃Activation of the receptor stimulates lipolysis (e.g., breakdown of adipose tissue triglycerides into glycerol and fatty acids) and metabolic rate (energy expenditure), thereby promoting the reduction of adipose tissue. Thus, can stimulate beta₃The compounds of the receptor can be used as anti-obesity agents, and can also be used to increase lean muscle mass in food animals. In addition, as beta₃Compounds that are receptor agonists have hypoglycemic activity, but the mechanism of this action is not known.

Until recently β was not discovered₃Adrenergic receptors are predominantly present in adipose tissue. However, now β is known₃Receptors are present in different tissues such as the intestine (j.clin.invest.,91344(1993)) and in the brain (eur.j. (pharm.,219193 (1992)). Has proved to stimulate beta₃Receptors can cause smooth muscle relaxation in the colon, trachea and bronchi. See for example Life Sciences,44，1411(1989)，Br.J.Pharm.，112，55(1994)，Br.J.Pharmacol.， 110,1311(1993). Furthermore, it has been found that the stimulus β₃The receptor can cause relaxation of the guinea pig ileum which is histamine-contracted. See, e.g., j.pharm.exp.thr.,260，1，192(1992)。

β₃the receptor is also expressed in the human prostate (j.clin.invest.,91,344(1993)). Due to stimulationβ₃Receptor induction has been shown to express beta₃Relaxation of smooth muscle of the recipient, i.e., intestinal smooth muscle, one skilled in the art would also expect relaxation of smooth muscle of the prostate. Thus, β₃Agonists may be used to treat or prevent prostate disorders.

Commonly assigned U.S. patent 5,977,124 discloses certain beta-peptides having utility in the treatment of, inter alia, hypoglycemia and obesity₃An adrenergic receptor agonist.

U.S. patent 5,776,983 discloses that some can be used as beta₃Catecholamines as agonists.

U.S. patent 5,030,640 discloses certain α -heterocyclic ethanolaminoalkyl indoles useful as growth promoters, bronchodilators, antidepressants and antiobesity agents.

U.S. patent 5,019,578 discloses certain α -heterocyclic ethanolamines that can be used as growth promoters.

U.S. patent 4,478,849 discloses pharmaceutical compositions comprising certain ethanolamine derivatives and methods of using such compositions for the treatment of obesity and/or hyperglycemia.

U.S. patent 4,358,455 discloses certain hets-CHOH-CH₂-NH-aralkyl, which is useful for the treatment of glaucoma and cardiovascular diseases.

European patent application publication 0516349, published on 2.12.1992, discloses certain 2-hydroxyphenylethylamines having anti-obesity, hyperglycemic and related effects.

U.S. patent 5,153,210 discloses certain formulae R⁰-X-CH(OH)-CH₂-N(R¹)-C(R²)(R³)-(CH₂)_n-Y-A-R⁴-R⁵Heterocyclic compounds of formula (I) which are useful as antiobesity and antihyperglycemic agents.

PCT International patent application publication WO99/65877, published on 23.12.1999, discloses heterocyclic compounds having the formulaThe compounds are useful in the treatment of diseases susceptible to amelioration by administration of atypical beta-adrenoreceptor agonists.

Summary of The Invention

The present invention provides beta of formula (I)₃(ii) an agonist of an adrenergic receptor, wherein,stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, wherein Ar, R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈X and Y are as defined below.

In another aspect, the present invention provides intermediates useful in the preparation of compounds of formula (I); compounds of formula (I), stereoisomers and prodrugs thereof, and combinations of pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs with anti-obesity agents; pharmaceutical compositions containing compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, or pharmaceutical compositions containing compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, and anti-obesity agents; and treating beta in mammals₃A method of treating a disease, condition or disorder mediated by an adrenergic receptor, the method comprising administering to the mammal an effective amount of a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutical composition thereof; or a compound of formula (I), a combination of a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug and an anti-obesity agent, or a pharmaceutical composition thereof.

Detailed description of the inventionthe present invention provides beta of formula (I)₃Adrenergic(ii) a receptor agonist which is a peptide agonist,stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, wherein: ar is pyridyl, oxazolyl, thiazolyl, or phenyl; r is hydrogen, hydroxy, oxo, halogen, -CF₃、-(C₁-C₆) Alkyl, - (C)₁-C₆) Alkoxy, - (C)₃-C₈) Cycloalkyl, -NR₉R₁₀、-NR₉SO₂R₁₀、-NR₉COR₁₀or-SO₂R₉；R₁Is hydrogen, - (C)₁-C₆) Alkyl, halogen, - (C)₁-C₆) Alkoxy or hydroxy; r₂、R₃、R₄Independently is hydrogen or- (C)₁-C₆) An alkyl group; r₅Is a 5 or 6 membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen; r₆And R₇Independently hydrogen, halogen, cyano, oxo, - (C)₁-C₆) Acyl radical, -CO₂R₉、-NR₉R₁₀Hydroxy, - (C)₁-C₆) Alkoxy, -CONR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀or-SO₂R₉；-(C₁-C₆) Alkyl, said group being optionally substituted with: - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; - (C)₃-C₈) Cycloalkyl, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; aryl, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₇) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; or a heterocycle, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; r₈Is hydrogen, - (C)₁-C₄) Alkyl or halogen; and R₉And R₁₀Independently of each other hydrogen, - (C)₁-C₆) Alkyl, alkylalkoxy, - (C)₃-C₈) Cycloalkyl, - (C)₁-C₆) Haloalkyl, - (C)₁-C₆) Alkoxy, aryl or heterocyclic; x is a bond or oxygen, and Y is a bond, - (C)₁-C₆) Alkyl, -OCH₂-、-CH₂O-or oxygen; with the following conditions: (i) when Ar is phenyl, R is-NR₉SO₂R₁₀、-SO₂NR₉R₁₀or-SO₂R₉(ii) a And (ii) when Ar is phenyl, -NR₉SO₂R₁₀And R is₆And R₇When both are hydrogen, R₅Is not an imidazolyl group.

In the (R) -stereoconfiguration, represented hereinafter by formula (I'), wherein Ar, R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈X and Y are as defined above, a compound of formula (I) and their useStereoisomers and prodrugs, and pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs are particularly preferred.

A first generally preferred subgroup of compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs include those compounds defined as follows: wherein Ar is pyridyl; r, R₁、R₂、R₃、R₄And R₈Is hydrogen; x is oxygen; y is a bond; and R is₅Is a 5 or 6 membered heterocyclic ring selected from: dihydropyridazinonyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidinyl, thiadiazolyl, thiazolinyl, thiazolyl, triazinyl, and triazolyl.

Of the first generally preferred subgroup of compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, the following compounds are particularly preferred: (R) -2- {2- [4- (4-benzofuran-2-yl-thiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-benzyloxymethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-butyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-tert-butyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-cyclopentyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2, 5-dimethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- (2- {4- [2- (2-ethyl-pyridin-4-yl) -thiazol-4-yl ] -phenoxy } -ethylamino) -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-ethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (4-ethyl-thiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-ethyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-hydroxymethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -6- {4- [2- (2-hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy ] -phenyl } -4, 5-dihydropyridazin-3-one; (R) -2- [2- (4-imidazol-1-yl-phenoxy) -ethylamino ] -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-isopropyl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-isopropyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-isopropyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methoxymethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- {4- [2- (4-methoxy-phenyl) -thiazol-4-yl ] -phenoxy } -ethylamino) -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methyl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (5-methyl- [1, 3, 4] oxadiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (5-methyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- (2- {4- [2- (2-methyl-propane-2-sulfonylmethyl) -thiazol-4-yl ] -phenoxy } -ethylamino) -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (1-methyl-1H-pyrazol-3-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (4-methyl-thiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (5-methyl-4H- [1, 2, 4] triazol-3-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2 '-methyl- [2, 4' ] bithiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- [2- (4-oxazol-4-yl-phenoxy) -ethylamino ] -1-pyridin-3-yl-ethanol; (R) -2- [2- (4-oxazol-5-yl-phenoxy) -ethylamino ] -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-phenyl-1H-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-phenyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (4-phenyl-thiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-propyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (1H-pyrazol-3-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-3-yl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-4-yl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-3-yl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-4-yl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- [2- (4-thiazol-2-yl-phenoxy) -ethylamino ] -ethanol; (R) -1-pyridin-3-yl-2- [2- (4-thiazol-4-yl-phenoxy) -ethylamino ] -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-thiophen-2-yl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-thiophen-2-yl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (4-p-tolyl-thiazol-2-yl) -phenoxy ] -ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-p-tolyl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-trifluoromethyl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- (2- {4- [2- (4-trifluoromethyl-phenyl) -thiazol-4-yl ] -phenoxy } ethylamino) -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (4-trifluoromethyl-thiazol-2-yl) -phenoxy ] -ethylamino } ethanol; and (R) -1-pyridin-3-yl-2- {2- [4- (2-trifluoromethyl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol.

Among the first generally preferred subgroup of compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, the following compounds are particularly preferred: (R) -2- {2- [4- (ethyl-thiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methoxymethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- [2- (4-oxazol-4-yl-phenoxy) -ethylamino ] -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (1H-pyrazol-3-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol; (R) -1-pyridin-3-yl-2- [2- (4-thiazol-2-yl-phenoxy) -ethylamino ] -ethanol; (R) -1-pyridin-3-yl-2- [2- (4-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol; and (R) -1-pyridin-3-yl-2- {2- [4- (4-trifluoromethyl-thiazol-2-yl) -phenoxy ] -ethylamino } -ethanol.

A second generally preferred subgroup of compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs include those compounds defined as follows: wherein Ar is phenyl; r is-NR₉SO₂R₁₀；R₁Is hydrogen, hydroxy or halogen; r₂、R₃、R₄And R₈Is hydrogen; x is oxygen and Y is a bond; and R is₅Is a 5 or 6 membered heterocyclic ring selected from: dihydropyridazinonyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidinyl, thiadiazolyl, thiazolinyl, thiazolyl, triazinyl, and triazolyl.

Of the second generally preferred subgroup of compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, the following compounds are particularly preferred: (R) -N- [ 2-chloro-5- (2- {2- [4- (2-ethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-hydroxy-ethyl) -phenyl ] -methanesulfonamide; (R) -N- [ 2-chloro-5- (2- {2- [4- (2-ethyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-hydroxy-ethyl) -phenyl ] -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-isopropyl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-isopropyl-oxazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-methyl-1H-imidazol-4-yl) -phenoxy ] ethylamino } -ethyl) -phenyl ] -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] ethylamino } -ethyl) -phenyl ] -methanesulfonamide; (R) -N- (2-chloro-5- { 1-hydroxy-2- [2- (4-oxazol-4-yl-phenoxy) -ethylamino ] -ethyl } -phenyl) -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-phenyl-1H-imidazol-4-yl) -phenoxy ] ethylamino } -ethyl) -phenyl ] -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-pyridin-3-yl-1H-imidazol-4-yl) phenoxy) -ethylamino } -ethyl) -phenyl ] -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-pyridin-4-yl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide; (R) -N- (2-chloro-5- { 1-hydroxy-2- [2- (4-thiazol-4-yl-phenoxy) -ethylamino ] -ethyl } -phenyl) -methanesulfonamide; and (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-trifluoromethyl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide.

Among the second generally preferred subgroup of compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, the following compounds are particularly preferred: (R) -N- [ 2-chloro-5- (2- {4- (2-ethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-hydroxyethyl) -phenyl ] -methanesulfonamide; (R) -N- [ 2-chloro-5- (2- {4- (2-ethyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-hydroxyethyl) -phenyl ] -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- (4- (2-methyl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide (R) -N- (2-chloro-5- { 1-hydroxy-2- [2- (4-thiazol-4-yl-phenoxy) -ethylamino ] -ethyl } -phenyl) -methanesulfonamide (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl } -ethyl) -methanesulfonamide H-methanesulfonamide; and (R) -N- (2-chloro-5- { 1-hydroxy-2- [2- (4-oxazol-4-yl-phenoxy) -ethylamino ] -ethyl } phenyl) -sulfonamide.

The present invention also provides certain amine intermediates useful in the preparation of compounds of formula (I), including compounds of the formula and acid addition salts thereof,wherein: r₅Is a 5 or 6 membered heterocyclic ring selected from: isothiazolyl, isooxaOxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazolyl, pyridazinyl, thiadiazolyl, thiazolinyl, thiazolyl, and triazinyl; r₆And R₇Independently hydrogen, halogen, cyano, oxo, - (C)₁-C₆) Acyl radical, -CO₂R₉、-NR₉R₁₀Hydroxy, - (C)₁-C₆) Alkoxy, -CONR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀or-SO₂R₉；-(C₁-C₆) Alkyl, said group being optionally substituted with: - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; - (C)₃-C₈) Cycloalkyl, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; aryl, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₇) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; or a heterocycle, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; r₈Is hydrogen, - (C)₁-C₄) Alkyl or halogen; and Y is a bond or-CH₂-。

Generally preferred amine intermediates of the above formula include compounds selected from the group consisting of: 2- [4- (4-benzofuran-2-yl-thiazol-2-yl) -phenoxy ] -ethylamine; 2- [4- (2-benzyloxymethyl-oxazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (2-tert-butyl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (2-butyl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (2-cyclopentyl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (2, 5-dimethyl-oxazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (2-ethyl-oxazol-4-yl) -phenoxy ] -ethylamine; 2- {4- [2- (2-ethyl-pyridin-4-yl) -thiazol-4-yl ] -phenoxy } -ethylamine; 2- [4- (4-ethyl-thiazol-2-yl) -phenoxy ] -ethylamine; 2- [4- (4-ethyl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (2-hydroxymethyl-oxazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (2-isopropyl-oxazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (2-isopropyl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (2-methoxymethyl-oxazol-4-yl) -phenoxy ] -ethylamine; 2- {4- [2- (4-methoxy-phenyl) -thiazol-4-yl ] -phenoxy } -ethylamine; 2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (5-methyl-oxazol-4-yl) -phenoxy ] -ethylamine; 2- (3-methyl-4-oxazol-4-yl) -phenoxy ] -ethylamine; 2- {4- [2- (2-methyl-propane-2-sulfonylmethyl) -thiazol-4-yl ] -phenoxy } -ethylamine; 2- [4- (1-methyl-1H-pyrazol-3-yl) -phenoxy ] -ethylamine; 2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (4-methyl-thiazol-2-yl) -phenoxy ] -ethylamine; 2- [4- (2 '-methyl- [2, 4' ] bithiazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (5-methyl- [1, 3, 4] oxadiazol-2-yl) -phenoxy ] -ethylamine; 2- (4- [1, 3, 5] oxadiazol-2-yl-phenoxy) -ethylamine; 2- (4-oxazol-2-yl-phenoxy) -ethylamine; 2- (4-oxazol-4-yl-phenoxy) -ethylamine; 2- (4-oxazol-5-yl-phenoxy) -ethylamine; 2- [4- (2-phenethyl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (5-phenyl- [1, 3, 4] oxadiazol-2-ylmethyl) -phenoxy ] -ethylamine; 2- [4- (4-phenyl-thiazol-2-yl) -phenoxy ] -ethylamine; 2- [4- (2-phenyl-thiazol-4-yl) -phenyl ] -ethylamine; 2- [4- (2-propyl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- (4-pyrazol-1-yl-phenoxy) -ethylamine; 2- [4- (1H-pyrazol-3-yl) -phenoxy ] -ethylamine; 2- [4- (2-pyridin-3-yl-thiazol-4-yl) -phenoxy ] -ethylamine; 2-4- (2-pyridin-4-yl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- (4- [1, 2, 3] thiazol-5-yl-phenoxy) -ethylamine; 2- (4-thiazol-2-yl-phenoxy) -ethylamine; 2- (4-thiazol-4-yl-phenoxy) -ethylamine; 2- [4- (2-thiophen-2-ylthiazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (2-p-tolyl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- [4- (4-p-tolyl-thiazol-2-yl) -phenoxy ] -ethylamine; 2- [4- (2-trifluoromethyl-thiazol-4-yl) -phenoxy ] -ethylamine; 2- {4- [2- (4-trifluoromethyl-phenyl) -thiazol-4-yl ] -phenoxy } -ethylamine; 2- [4- (4-trifluoromethyl-thiazol-2-yl) -phenoxy ] -ethylamine; and 2- [4- (5-trifluoromethyl-2H-pyrazol-3-yl) -phenoxy ] -ethylamine; and acid addition salts thereof.

Compounds and intermediates of the invention may be named according to IUPAC (International Union for pure and Applied chemistry) or CAS (chemical abstracts) naming systems.

The number of carbon atoms of different hydrocarbon-containing groups can be represented by a prefix indicating the minimum and maximum number of carbon atoms in the group, i.e., the prefix (C)_a-C_b) Means that the group has the integer "a" - "b" and includes "a" and "b" carbon atoms. Thus, for example, (C)₁-C₃) Alkyl means alkyl having 1 to 3 and including 1 and 3 carbon atoms, or methyl, ethyl, propyl, isopropyl and all isomeric forms thereof as well as straight or branched chain forms.

The term "alkyl" refers to a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, and hexyl.

The term "alkoxy" refers to an alkyl group bonded to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, propoxy, and isobutoxy.

The term "halogen" refers to a group derived from chlorine, fluorine, bromine or iodine.

The term "cycloalkyl" refers to cyclic hydrocarbons. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may also have one or more double or triple bonds or a combination of double and triple bonds, but are not aromatic groups. Examples of the cycloalkyl group having a double bond or a triple bond include cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclobutadienyl and the like. It is also noted that cycloalkyl includes polycyclic compounds such as bicyclic or tricyclic compounds.

The term "acyl" refers to a group derived from an organic acid (-COOH) by removal of a hydroxyl (-OH) group.

The term "aryl" refers to a cyclic aromatic hydrocarbon. Examples of aryl groups include phenyl, naphthyl, biphenyl. The aryl group may be substituted or unsubstituted.

The term "heteroatom" includes oxygen, nitrogen, sulfur and phosphorus.

At R₅、R₆、R₇、R₉And R₁₀The term "heterocycle" as used in the definition of (1) refers to a cyclic aromatic or non-aromatic hydrocarbon group in which 1 to 4 carbon atoms are replaced by heteroatoms. If a heterocyclyl contains more than one heteroatom, the individual heteroatoms may be the same or different. Representative examples of 5-and 6-membered aromatic or heteroaromatic heterocyclic groups include chromenyl, dihydropyridazinonyl, furyl, imidazolidinyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuryl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinonyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinolizinyl, quinolinyl, quinoxalinylLinyl, thiazolyl, thiazolinyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl and xanthenyl. It is understood that a heterocyclyl group may be bonded to another group in more than one way. All bonding means are included if no particular bonding means is specified. For example, the term "pyridyl" includes 2-pyridyl, 3-pyridyl or 4-pyridyl, and the term "thienyl" includes 2-thienyl or 3-thienyl.

Specific representative examples of 5-to 6-membered aromatic or nonaromatic heterocycles are 1, 4-dioxanyl, 3H-1, 2, 3-dioxanyl, 1, 2, 4-dioxanyl, 1, 3, 2-dioxanyl, 1, 3, 4-dioxanyl, 1, 2-dioxanyl, 1, 3-dioxolanyl, 1, 4-dithiinyl, 1, 2-dithiopentenyl, 1, 3-dithiopentenyl, 2-imidazolinyl, 2H-imidazolyl, o-isoxazolyl, p-isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1H-oxadiazolyl, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 4H-1, 2-oxazinyl, 2H-1, 3-oxazinyl, 6H-1, 2-oxazinyl, 1, 4-oxazinyl, 2H-1, 2-oxazinyl, 4H-1, 4-oxazinyl, 1, 2, 5-oxathiazinyl, 1, 2, 6-oxathiazinyl, 1, 4, 2-oxadiazinyl, 5H-1, 2, 5-oxathiazolyl, 3H-1, 2-oxathiolanyl, 1, 3-oxathiolanyl, 2H-pyranyl, 4H-pyranyl, 2-pyrazolinyl, 2-pyrrolinyl, 3-pyrrolinyl 1, 3, 4-thiazolyl, 1, 2, 3-triazinyl, 1, 2, 4-triazinyl, 1, 3, 5-triazinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl and 1, 3, 5-trithianyl.

It should also be noted that a heterocyclyl group may contain more than one ring. For example, naphthyl is a representative example of a fused bicyclic ring system. The invention also includes cyclic groups having a bridge atom or cyclic groups having a spiro orientation. For example, the term "spirocycloalkyl" refers to a cycloalkyl ring having a spiro linkage (a linkage formed through a single atom that is the only common unit of the ring). Furthermore, it is to be understood that all suitable isomers of the cyclic groups are included within the scope of the present invention unless otherwise indicated.

Examples of bicyclic rings consisting of two fused rings which are independently partially saturated, fully saturated or fully unsaturated 5-and/or 6-membered rings optionally having 1 to 4 heteroatoms are benxotolactonyl (anthracenyl), benzimidazolyl, benzofuranyl, 2H-1-benzopyranyl, benzothiazolyl, benzo [ b ] thienyl, benzo [ c ] thienyl, 2H-1, 3-benzoxazinyl, 2H-1, 4-benzoxazinyl, 1H-2, 3-benzoxazinyl, 4H-3, 1-benzoxazinyl, 2H-1, 2-benzoxazinyl, 4H-1, 4-benzoxazinyl, cinnolinyl, cyclopenta [ b ] pyridyl, decahydronaphthyl, indazolyl, indenyl, indolinyl, Indolizinyl, indolyl, 1H-indolizinyl, isobenzofuranyl, isoindolyl, isoquinolinyl, naphthyl, naphthyridinyl, phthalazinyl, 1, 8-pteridinyl, purinyl, pyrano [3, 4-b ] pyrrolyl, pyrido [3, 2-b ] -pyridinyl, pyrido [3, 4-b ] -pyridinyl, pyrido [4, 3-b ] -pyridinyl, quinazolinyl, quinolinyl, quinoxalinyl and tetrahydronaphthyl.

The term "substituted" means that a hydrogen atom on a molecule has been replaced with a different atom or molecule. The atoms or molecules replacing the hydrogen atoms are referred to as substituents ".

The phrase "therapeutically effective amount" refers to an amount of a compound of formula (I), a stereoisomer, or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, that reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder.

The term "mammal" refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans. Preferred mammals include humans, including both males and females.

The phrase "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith.

The term "treatment" includes both prophylactic, i.e. prophylactic, and palliative treatment.

In another aspect of the invention, the compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, may be used in combination with anti-obesity agents.

The anti-obesity agent is preferably selected from the group consisting of an apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, an MCR-4 agonist, a cholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor (e.g. sibutramine), a sympathomimetic, a serotonergic (e.g. fenfluramine or dextrofenfluramine), a dopamine agonist (e.g. bromocriptine), a melanocyte stimulating hormone receptor analogue, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, leptin (OB protein), a leptin analogue, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor (e.g. tetrahydrolipstatin, orlistat), an anorectic agent (e.g. bombesin agonist), a neuropeptide-Y antagonist, thyromimetic, dehydroepiandrosterone or an analogue thereof, a glucocorticoid receptor agonist or antagonist, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (e.g., axokinine), and human agouti-related protein (AGRP). Other anti-obesity agents, including the preferred anti-obesity agents hereinafter, are well known to those skilled in the art or will be apparent in light of the present disclosure.

Particularly preferred anti-obesity agents include compounds selected from the group consisting of: orlistat, sibutramine, fenfluramine, dextrofenfluramine, bromocriptine, phentermine, ephedrine, leptin, phenylpropanolamine, and pseudoephedrine.

Representative anti-obesity agents for use in the combinations, pharmaceutical compositions and methods of the invention may be prepared by methods known to those skilled in the art, for example phentermine may be prepared according to the methods described in U.S. patent 2,408,345; sibutramine can be prepared according to the method disclosed in patent 4,929,629; fenfluramine and dextrofenfluramine can be prepared according to the method described in U.S. patent 3,198,834; bromocriptine can be prepared according to the methods described in U.S. patents 3,752,814 and 3,752,888; orlistat can be prepared according to the methods described in U.S. patents 5,274,143, 5,420,305, 5,540,917 and 5,643,874.

The invention also provides methods of treating beta in a mammal in need thereof₃A method of treating a disease, condition or disorder mediated by adrenergic receptors, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug; a combination of a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug, and an anti-obesity agent; a pharmaceutical composition comprising an effective amount of a compound of formula (I), a stereoisomer or a prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug, and a pharmaceutically acceptable excipient, carrier or diluent; or a pharmaceutical composition comprising an effective amount of a compound of formula (I), a stereoisomer or a prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug, together with a pharmaceutically acceptable excipient, carrier or diluent, and an anti-obesity agent.

β₃The adrenergic receptor-mediated disease, condition, or disorder is preferably selected from the group consisting of obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenitis, crohn's disease, proctitis, asthma, bowel movement disorders, ulcers, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, and inflammatory diseases of the airways.

The present invention also provides a method of increasing lean meat content in an edible animal, comprising administering to the edible animal a lean meat increasing amount of a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug; a pharmaceutical composition comprising a lean meat enhancing amount of a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug, and a pharmaceutically acceptable excipient, carrier or diluent; or a pharmaceutical composition comprising a lean meat enhancing amount of a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug, together with a pharmaceutically acceptable excipient, carrier or diluent, and an anti-obesity agent.

The compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs can be administered to a patient at dosage levels of about 0.01 to about 1,000 mg/day. For a normal adult human weighing about 70kg, a dosage of about 0.01 to about 300mg is generally sufficient. However, depending on the age and weight of the subject being treated, the route of administration to be used, the particular anti-obesity agent being administered, etc., some variation in the general dosage range may be required. The determination of dosage ranges and optimal dosages for a particular patient is well within the ability of those skilled in the art using the present disclosure. It is also noted that the compounds of the present invention may be employed in sustained release, controlled release, and delayed release formulations, which are also well known to those skilled in the art.

The dosage of an anti-obesity agent will also generally depend on a variety of factors, including the health of the individual being treated, the degree of treatment desired, the nature and kind of concurrent treatment, and the frequency of treatment, if any, and the nature of the effect desired. The dosage range of the anti-obesity agent is generally from about 0.001 to about 100mg/kg of individual body weight per day, preferably from about 0.1 to about 10mg/kg of individual body weight per day. However, depending on the age and weight of the subject being treated, the route of administration to be used, the particular anti-obesity agent being administered, etc., some variation in the general dosage range may be required. The determination of dosage ranges and optimal dosages for a particular patient is well within the ability of those skilled in the art using the present disclosure.

According to the methods of the present invention, a compound of formula (I), a stereoisomer or a prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or the prodrug; or a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of a stereoisomer or prodrug thereof, is administered to a subject in need of treatment therewith along with an anti-obesity agent, preferably in the form of a pharmaceutical composition. In the combination therapeutic aspect of the present invention, the compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug, and the anti-obesity agent may be administered separately or in a pharmaceutical composition containing them. Such administration is generally preferably oral administration. However, if the individual being treated is unable to swallow, or oral administration is damaging or undesirable, parenteral or transdermal administration is suitable.

According to the methods of the present invention, when a compound of formula (I), a stereoisomer or a prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or the prodrug; or a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of a stereoisomer or prodrug thereof, is administered with an anti-obesity agent, such administration may be sequential or simultaneous, with methods of simultaneous administration generally being preferred. For sequential administration, the compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug and the anti-obesity agent may be administered in any order. Such administration is generally preferably oral administration. Such administration is particularly preferably oral and simultaneous. When the compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug and the anti-obesity agent are administered sequentially, each administration may be by the same or different methods.

According to the methods of the present invention, a compound of formula (I), a stereoisomer or a prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or the prodrug; or a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of a stereoisomer or prodrug thereof, and an anti-obesity agent are preferably administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent. Accordingly, a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug; or a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug and the anti-obesity agent may be administered separately or together in any conventional oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, topical (e.g., powders, ointments, or drops), or buccal or nasal dosage form.

Compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size (for dispersions) and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like, can be used to prevent contamination of the composition by microorganisms. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents capable of delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is mixed with: at least one inert conventional pharmaceutical excipient (or carrier) such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders such as starches, lactose, sucrose, mannitol, and silicic acid; (b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some complex silicates and sodium carbonate; (e) solution retarders such as paraffin; (f) absorption promoters such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin and bentonite; and/or (i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. For capsules and tablets, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft or hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Solid dosage forms such as tablets, dragees, capsules and granules can be prepared with coatings and shells such as enteric coatings as well as other coatings well known in the art. They may also comprise opacifying agents and may also be of a composition that releases the active compound in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate with one or more of the abovementioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame seed oil, glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

In addition to such inert diluents, the compositions of the present invention may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances and the like.

Compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by: the compounds of the present invention are mixed with a suitable non-irritating excipient or carrier such as coconut oil which is solid at ordinary room temperature, but liquid at body temperature and therefore melts in the rectum or vaginal cavity, thereby releasing the active ingredients.

For topical administration of compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs; and compounds of formula (I), stereoisomers and prodrugs thereof, and the dosage forms of the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs with anti-obesity agents may include ointments, powders, sprays, and inhalants. The active agent is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants which may be required. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also included within the scope of the present invention.

Exemplary formulations, dosages, and the like for non-human animals are described below. Compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs; and compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs and anti-obesity agents may be administered orally or non-orally, e.g. by injection.

A compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug; or a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug, and an anti-obesity agent are administered in an effective, usually daily effective dose, which when administered orally to an animal is usually about 0.01 to about 1,000mg/kg body weight, preferably about 0.01 to about 300mg/kg body weight.

Conveniently, the compounds of the invention may be added to drinking water to supplement the daily water intake with a therapeutic dose of the compound. The compounds can be metered directly into the drinking water, preferably in the form of a liquid, water-soluble concentrate (e.g. an aqueous solution of a water-soluble salt).

For convenience, the compounds may also be added to the feed as such or as an animal feed additive, also known as a premix or concentrate. For incorporation into feed, premixes or concentrates of the compounds in a carrier are more often employed. Suitable carriers are, as desired, liquids or solids, such as water, various meals such as alfalfa meal, soybean meal, cottonseed meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and mineral mixtures such as those commonly used in poultry feed. Particularly effective carriers are the respective animal feed itself; that is, a small portion of such feed. The carrier facilitates uniform distribution of the compound in the final feed mixed with the premix. It is important that the compound is thoroughly mixed into the premix and subsequently the feed. In this regard, the compounds can be dispersed or dissolved in a suitable oil carrier such as soybean oil, corn oil, cottonseed oil, and the like, or a volatile organic solvent, and then mixed with the carrier. It will be appreciated that the proportion of the compound in the concentrate may vary within wide limits, as the amount of active compound in the final feed may be adjusted by mixing the premix with the feed in appropriate proportions to achieve the desired level of compound.

A feed producer may mix the high potency concentrate with a protein carrier such as soybean oil meal and other meals described above to obtain a concentrated additive suitable for direct feeding to an animal. In such cases, the animal is allowed to ingest the usual diet. Alternatively, such concentrated additives may be added directly to the feed to produce a nutritionally balanced final feed containing therapeutically effective levels of the compounds of the invention. The mixture is thoroughly mixed by standard operations, for example in a double shell mixer, to ensure homogeneity.

If the additive is used as a top coat for a feed, it also helps to ensure that the compound is evenly distributed along the coated feed.

Drinking water and feed for effectively increasing lean meat deposition and improving the ratio of lean meat to fat are generally prepared by devitalizing the inventionThe compound is mixed with sufficient animal feed to provide a concentration of about 10 in the feed or water^-3500 ppm.

Preferred medicated pig, cattle, sheep and goat feed typically contain 1-400 grams of active ingredient per ton of feed, with an optimum amount for these animals ranging from about 50-300 grams per ton of feed.

Preferred poultry and pet feeds generally contain from about 1 to 400 grams, preferably from 10 to 400 grams, of active ingredient per ton of feed.

For parenteral administration to an animal, the compounds of the invention may be prepared in the form of a paste or pill and administered as an implant, usually under the skin of the animal's head or ear where enhanced lean meat deposition and improved lean meat to fat ratio are sought.

Parenteral administration generally comprises injecting a compound of the invention in an amount sufficient to provide the animal with 0.01 to 20mg/kg body weight/day of the active ingredient. For poultry, pigs, cattle, sheep, goats and pets, the preferred dosage is 0.05-10mg/kg body weight/day of active ingredient.

Pastes may be prepared by dispersing the active compound in a pharmaceutically acceptable oil, for example peanut oil, sesame oil, corn oil and the like.

Pellets containing an effective amount of a compound, pharmaceutical composition or combination of the present invention can be prepared by mixing the compound of the present invention with diluents such as carbowax, carnuba wax and the like, and a lubricant such as magnesium stearate or calcium stearate can be added to improve the pelletizing process.

It will of course be appreciated that more than one pill may be administered to an animal to achieve the desired dosage level which increases lean meat deposition and improves the lean meat to fat ratio. In addition, it has been found that the implant can also be administered periodically during treatment of the animal to maintain appropriate levels of the drug in the animal.

The present invention has several advantageous features in veterinary terms. For pet owners or veterinarians who wish to add lean meat and/or subtract unwanted fat from the pet, the present invention provides a means to accomplish this. For poultry and pig breeders, animals can be made thin using the compounds of the present invention, which leads to higher sales prices in the meat industry.

The term pharmaceutically acceptable salt, ester, amide or prodrug refers to carboxylic acid salts, amino acid salts, esters, amides and prodrugs of compounds which are within the scope of this invention, are suitable for use in patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, effective for their intended use, and include zwitterionic forms, if possible.

The term "salts" refers to both inorganic and organic salts of the compounds of formula (I) or stereoisomers or prodrugs thereof. These salts can be prepared in situ during the final isolation and purification of the compounds, and the patient can be prepared by separately reacting a compound of formula (I) or a stereoisomer or prodrug thereof with a suitable organic or inorganic acid, and isolating the salt formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, benzenesulfonate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate, and the like. These salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, e.g., Berge et al, j.pharm.sci., 66, 1-19 (1977).

The term "prodrug" refers to a compound that is converted in vivo to yield a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer. The transformation can be carried out by a variety of mechanisms, for example by hydrolysis in blood. For a discussion of prodrug applications see t.higuchi and w.stella, "Pro-drugs as Novel Delivery Systems," vol.14of the a.c.s.symposium Series, and Bioreversible Carriers in drug Delivery, ed.edward b.roche, American Pharmaceutical association and permamon Press, 1987.

For example, if a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer, contains a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing a hydrogen atom on the carboxylic acid group with: (C)₁-C₈) Alkyl, (C)₂-C₁₂) Alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having 4 to 10 carbon atoms, 3-benzofuranone, 4-crotonolactone, gamma-butyrolactone-4-yl, di-N, N- (C)₁-C₂) Alkylamino radical (C)₂-C₃) Alkyl (e.g.. beta. -dimethylaminoethyl), carbamoyl- (C)₁-C₂) Alkyl, N-di (C)₁-C₂) Alkylcarbamoyl- (C)₁-C₂) Alkyl and piperidino (C)₂-C₃) Alkyl, pyrrolidin-1-yl (C)₂-C₃) Alkyl or morpholino (C)₂-C₃) An alkyl group.

Similarly, if a compound of formula (I) or a stereoisomer thereof comprises an alcohol functional group, a prodrug may be formed by replacing the hydrogen atom on the alcohol group with a group such as: (C)₁-C₆) Alkanoyloxymethyl, 1- ((C)₁-C₆) Alkanoyloxy) ethyl, 1-methyl-1- ((C)₁-C₆) Alkanoyloxy) ethyl group, (C)₁-C₆) Alkoxycarbonyloxymethyl, N- (C)₁-C₆) Alkoxycarbonylaminomethyl, succinyl, and,(C₁-C₆) Alkanoyl, alpha-amino (C)₁-C₄) Alkanoyl, arylacyl and alpha-aminoacyl or alpha-aminoacyl-alpha-aminoacyl wherein each alpha-aminoacyl is independently selected from the group consisting of a natural L-amino acid, P (O) (OH)₂、-P(O)(O(C₁-C₆) Alkyl radical)₂Or a glycosyl group (a group formed by removing the hydroxyl group of a hemiacetal form of a carbohydrate).

If a compound of formula (I) or a stereoisomer thereof contains an amine functional group, a prodrug may be formed by replacing a hydrogen atom on the amine group with a group such as: r-carbonyl, RO-carbonyl, NRR '-carbonyl, wherein R and R' are each independently (C)₁-C₁₀) Alkyl, (C)₃-C₇) Cycloalkyl, benzyl, or R-carbonyl is a natural alpha-aminoacyl or a natural alpha-aminoacyl-natural alpha-aminoacyl, -C (OH) C (O) OY, wherein Y is H, (C)₁-C₆) Alkyl or benzyl, -C (OY)₀)Y₁Wherein Y is₀Is (C)₁-C₄) Alkyl, and Y₁Is (C)₁-C₆) Alkyl, carboxyl (C)₁-C₆) Alkyl, amino (C)₁-C₄) Alkyl or mono-N-or di-N, N- (C)₁-C₆) Alkylaminoalkyl, -C (Y)₂)Y₃Wherein Y is₂Is H or methyl, and Y₃Is mono-N-or di-N, N- (C)₁-C₆) Alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

The compounds of formula (I) may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of formula (I) and mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention includes all geometric and positional isomers. For example, if the compound of formula (I) contains a double bond, both the cis and trans forms and mixtures thereof are included within the scope of the present invention.

Mixtures of diastereomers may be separated into their individual diastereomers on the basis of differences in their physicochemical properties by methods well known to those skilled in the art, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by: the enantiomeric mixture is converted into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., an alcohol), the diastereomers are separated, and the individual diastereomers are converted (e.g., hydrolyzed) to the corresponding pure enantiomers. Furthermore, certain compounds of formula (I) may be sterically hindered isomers (e.g. substituted biaryls) and are part of the present invention.

The compounds of formula (I) may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, and the present invention includes solvated as well as unsolvated forms.

The compounds of formula (I) may also exist in different tautomeric forms, and all such forms are within the scope of the invention. For example, all tautomeric forms of the imidazole moiety are included within the invention. Dihydro, e.g., all keto-enol or imine-enamine forms of the compounds are included in the invention.

The invention disclosed herein includes compounds of formula (I) that can be synthesized in vitro using laboratory techniques, e.g., techniques well known in the art of synthetic organic chemistry, or synthesized using in vivo techniques, e.g., by metabolism, fermentation, digestion, etc. The compounds of formula (I) may be synthesized using a combination of in vitro and in vivo techniques.

The invention also includes isotopically-labelled compounds of formula (I), which are identical to those recited in the present invention, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of formula (I) containing the aforementioned isotopes and/or other isotopes of other atoms, stereoisomers thereofThe structures and prodrugs, as well as pharmaceutically acceptable salts of the compounds, stereoisomers, or prodrugs, are included within the scope of the invention.

Some isotopically labelled compounds of formula (I), e.g. incorporating radioactive isotopes such as³H and¹⁴c are useful in compound and/or substrate tissue distribution assays. Tritium, i.e.³H and carbon 14, i.e.¹⁴The C isotope is particularly preferred because of its ease of preparation and detection. In addition, with heavier isotopes such as deuterium, i.e.²H substitution may result in some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Isotopically labelled compounds of formula (I) can generally be prepared by: isotopically-labeled reagents are substituted for non-isotopically-labeled reagents in accordance with procedures analogous to those disclosed in the reaction schemes and/or in the examples below.

The compounds of formula (I) may be prepared by methods including, or analogous to, methods known in the chemical arts. The process for preparing the compounds of formula (I) as defined above is illustrated by the exemplary synthetic routes set forth in reaction schemes I-III below. In addition, reaction schemes IV-VI illustrate exemplary synthetic routes for intermediates used in the preparation of compounds of formula (I). Unless otherwise indicated, the general groups have the meanings indicated above.

In the synthetic route shown in scheme 1, an appropriately substituted oxirane derivative (III) is fused with an appropriately substituted amine (II) to produce a compound of formula (I).

Amine derivatives (II) can be conveniently prepared according to the procedures described in general reaction schemes IV, V and VI below, however, other methods of preparing such amine derivatives are known to those skilled in the art by utilizing the teachings of the present disclosure.

The ethylene oxide derivative (III) can be produced according to known methods including the methods disclosed in, for example, u.s. patents 5,541,197, 5,561,142, 5,705,515 and 6,037,362, which are specific toThe disclosure of the patent is hereby incorporated by reference. Such ethylene oxide derivatives may also be obtained from commercial sources, if applicable. Reaction scheme I

The condensation of ethylene oxide (III) with amine (II) is most conveniently carried out in a polar aprotic solvent, for example an alcohol such as methanol or ethanol, at elevated temperature. Alternatively, a co-solvent may also be used, for example a polar aprotic co-solvent such as dimethyl sulfoxide is added to the protic solvent. The isolation and purification of the compound of formula (I) thus formed can then be carried out according to known methods. Examples of such condensation and purification are disclosed below in the general preparation designated as method a.

Alternatively, as shown in reaction scheme II, the compounds of formula (I) can also be prepared by condensing an appropriately substituted protected alcohol (IV) with an amine (II). The protected alcohol (IV) contains a suitable leaving group susceptible to displacement by nucleophilic attack of the nitrogen atom of the amine (II). Suitable leaving groups that may be employed in the protected alcohol (IV) may include, for example, mesylate, tosylate and napsylate, or chloride such as chloride, bromide or iodide. The protected alcohol derivatives (IV) can be prepared according to known methods, including, for example, the method disclosed in commonly assigned U.S. patent 6,008,361, the disclosure of which is incorporated herein by reference. However, methods of making such protected alcohols are known or will be apparent to those skilled in the art in light of the present disclosure. See, e.g., T.W.Greene, Protective group in Organic Synthesis, John Wiley & Sons, New York (1991) and references cited therein.

Reaction scheme II

The condensation of the protected alcohol (IV) with the amine (II) is generally carried out in the presence of a suitable sterically hindered base such as N, N-diisopropylethylamine (Hunig's base) in a polar aprotic solvent such as dimethylsulfoxide at elevated temperatures. The protected aminoalcohol (V) thus formed may then be deprotected according to well known methods, for example, when (V) is a silylated derivative, deprotection is preferably by treatment with tetrabutylammonium fluoride. Examples of such condensation and deprotection are disclosed below in the general preparation designated as method B.

Alternatively, as shown in reaction scheme III, the compounds of formula (I) may also be prepared by dehalogenation of a compound of formula (Ia) wherein Ar represents an appropriately substituted 6-chloropyridine derivative.

Reaction scheme III

The dehalogenation of the above 6-chloropyridine derivative (Ia) can be carried out according to known methods. Most conveniently, such dehalogenation is carried out using a metal catalyst, preferably palladium on carbon, in a polar solvent such as methanol. The reaction is preferably carried out at room temperature for several hours, i.e. overnight. One method of carrying out such dehalogenation reactions is well known to those skilled in the art. Examples of such dehalogenation reactions are disclosed below in the general preparation designated as method C.

With respect to reaction schemes I and II, the above-described amine derivatives of formula (II) can be prepared according to the exemplary synthetic sequence described in reaction schemes IV, V, and VI below. However, it is to be understood that such examples are provided for illustration only and are not to be construed as limiting the invention in any way, however, other methods of making such amine derivatives are known or will be apparent to those skilled in the art in light of the present disclosure. Reaction scheme IV

The general reaction scheme IV above describes a convenient exemplary synthetic route for the preparation of amine derivatives (II) from which appropriately substituted anisole derivatives (VI) are from which heterocycles can be constructedRadical R₅The synthesis platform of (1). Such anisole derivatives are well known to those skilled in the art and may be obtained according to known methods or commercially available. Anisole derivatives (VI) can be functionalized to produce heteroaryl derivatives (VII) as shown in reaction schemes IVa-IVc below. While general reaction scheme IV and the synthetic reaction schemes shown below in connection therewith describe the use of anisole derivatives (VI), it is to be understood that it is also possible to replace anisole derivatives with appropriately substituted phenol derivatives, wherein such phenols are chemically compatible with functional groups that may be present or used in subsequent synthetic steps. The resulting heteroaryl derivative (VII) may then be demethylated, for example, with methanesulfonic acid or boron tribromide, to form the appropriately substituted phenol derivative (VIII). The resulting phenol derivative (VIII) is then coupled with a protected amino alcohol to form the amine-protected derivative (IX). An example of such a coupling reaction is provided in example 1 below. The ability to select the appropriate amine protecting group to form the amine-protected alcohol (IX) is within the ability of one skilled in the art. For example, general amine protecting groups are described in the literature, e.g., t.w. greene, supra and incorporated herein by reference. The coupling reaction of the phenol derivative (VIII) with the amine-protected derivative (IX) can be carried out according to methods well known to those skilled in the art, however, such a coupling reaction is preferably carried out by the so-called Mitsunobu reaction. The reaction is generally carried out in the presence of a dehydrating agent such as a stoichiometric amount of a diazocarboxylic compound such as 1, 1' - (azodicarbonyl) -bipiperidine (ADDP) and a phosphine such as triphenylphosphine, with stirring at room temperature (or, if desired, at elevated temperature). The reaction can be carried out in any reaction-inert solvent, for example tetrahydrofuran, dimethylformamide or a hydrocarbon or halogenated hydrocarbon solvent. The amine-protected derivative (IX) formed may then be deprotected in a conventional manner, for example by treatment with methanesulfonic acid or a variety of other deprotecting agents under conditions well known to those skilled in the art, including hydrogenolysis in the presence of a suitable metal catalyst, for example palladium on charcoal, in an inert solvent. Hydrogenolysis reactions are generally carried out at room temperature to about 90 ℃. An example of such a deprotection reaction is provided in example 2 below。

The following specific reaction schemes, designated reaction schemes IVa-IVe, illustrate the synthesis of synthetic precursors of different amine derivatives (II) as shown in reaction schemes I, II and IV, wherein heterocyclyl R₅As follows. As noted above, it is to be understood that these examples are for purposes of illustration only and are not limiting.

Reaction scheme IVa

Anisole derivatives (VIIa) functionalized with thiazoles, oxazoles and imidazoles can be prepared according to the exemplary route shown in reaction scheme IVa, starting with appropriately substituted thioamide, amide or amidine derivatives (VIa). Such thioamide, amide or amidine derivatives are well known to those skilled in the art and are commercially available or can be obtained by known methods of preparation. The thioamide, amide or amidine derivative (VIa) is cyclized with the appropriate α -bromoketone to form the desired derivative (VIIa). Such α -bromoketones are well known to those skilled in the art and are commercially available or made by those skilled in the art according to known methods.

Reaction scheme IVb

Alternatively, regioisomeric thiazole, oxazole and imidazole derivatives (VIIb) can be synthesized according to the exemplary synthetic route shown in reaction scheme IVb. In reaction scheme IVb, the appropriately substituted anisole derivatives (VIb) are α -halogenated, preferably α -brominated, according to conventional methods, e.g. (VIb) with tetrabutylammonium tribromide (TBABBr)₃) Or dibromobarbituric acid (DBBA). The resulting α -bromoketone (VIb') is then reacted with a suitable thioamide, amide or amidine derivative to form a thiazole, oxazole or imidazole derivative (VIIb). Such condensation may be carried out without solvent or, preferably, in the presence of a polar solvent, for example an alcohol or a halogenated hydrocarbon such as chloroform.

Reaction scheme IVc

The intermediate isoxazole or pyrazole derivative (VIIc) can be synthesized according to the exemplary route described in reaction scheme IVc. In reaction scheme IVc, an acylated anisole derivative (VIc) is reacted with appropriately substituted esters and crown ethers such as 18-crown-6 in the presence of an organic base such as potassium tert-butoxide in an aprotic solvent such as tetrahydrofuran at elevated temperatures. The diketo derivative (VIc ') is then cyclized with an appropriately substituted hydrazine derivative or hydroxylamine in a polar solvent such as ethanol at elevated temperature to form the pyrazole derivative (VIIc) and its regioisomer (VIIc').

Reaction scheme IVd

The intermediate isoxazole or pyrazole derivative (VIId) can be synthesized according to the exemplary route shown in reaction scheme IVd. In reaction scheme IVd, an appropriately substituted diketo derivative (IVd) is reacted with an appropriately substituted hydrazine derivative or hydroxylamine to obtain a phenol derivative (VIId). The intermediate diketo derivatives (VId) may be obtained from commercial sources or may be prepared according to known methods. The condensation reaction is preferably carried out in a polar solvent such as ethanol at elevated temperature. An example of the preparation of the compound of formula (VIId) is provided in example 35 below.

Reaction scheme IVe

Intermediate imidazole derivatives (VIIe) or pyrazole derivatives (VIIe') can be prepared as shown in the exemplary reaction scheme (IVe) above. The appropriately substituted boronic acid derivative (VIe) is reacted with an appropriately substituted imidazole or pyrazole derivative in the presence of a suitable catalyst, preferably copper (II) acetate, in a halogenated hydrocarbon solvent, preferably dichloromethane, to form the imidazole derivative (VIIe) or pyrazole derivative (VIIe'), respectively, as shown in reaction scheme (IVe). Boronic acid derivatives (VIe) and appropriately substituted imidazole or pyrazole derivatives are commercially available or can be prepared by known methods. An example of the preparation of the compound of formula (VIIe') is provided in example 30 below.

Reaction scheme V

Reaction scheme V above describes another exemplary process for the preparation of amines of formula (II) starting from an appropriately substituted fluorobenzene derivative (X). Such fluorobenzene derivative (X) is commercially available or can be produced by a known method. Will be as from which a heterocyclyl R may be constructed₅The fluorobenzene derivative (X) of the synthesis platform of (a) is reacted with an appropriately functionalized aminoalcohol to obtain the amine (II). The reaction between the amino alcohol and the fluorobenzene derivative (XI) is generally carried out in a polar aprotic solvent, preferably dimethyl sulfoxide, in the presence of an organic or inorganic base, preferably potassium tert-butoxide, at elevated temperature. Representative syntheses of amines (II) shown in reaction scheme V are described in examples 28 and 29, below.

Reaction scheme Va

Reaction scheme Va above describes a reaction scheme in which R₅A convenient, generally applicable synthesis of heterocyclic amine precursors of formula (XI) represented by amine V, which represents the reaction scheme for pyridazin-3-one groups. In this reaction scheme, fluorobenzene starting material (Xa) is condensed with hydrazine hydrate in a polar protic solvent such as ethanol at elevated temperature to form the amine precursor (XIa). An exemplary synthesis of precursor (XIa) shown in reaction scheme Va is described in example 28 below.

Reaction scheme VI

Reaction scheme VI shows another synthesis for the preparation of amine intermediate (II) starting from protected amine (XII). Functionalization of protected amines (XII) which can be prepared by known methods to form amines (IX) for subsequent preparation of R comprising substituted heterocyclic groups₅The amine (IX) of (4). The following schemes VIa-VId illustrate representative preparations of such heterocyclic groups. In general, the protected amine starting material (XII) wherein X is a bond is prepared by derivatizing a commercially available phenalkylamine starting material. An example of such derivatization is disclosed in example 11 below. When X represents oxygen, such an amine derivative (XII) is generally obtained by Mitsunobu coupling of an appropriately substituted commercially available phenol with an ethanolamine derivative. An example of such a coupling reaction is provided in example 20 below.

Reaction scheme VIa

In reaction scheme VIa, the amine protected derivative (XIIa) is acylated under standard Friedel-Crafts reaction conditions to form the acyl derivative (XIIa'). Such acylation is well known to those skilled in the art and is generally carried out by treating (XIIa) with the appropriately substituted acid chloride in the presence of a lewis acid, i.e. aluminum (III) chloride, in a reaction inert solvent such as dichloromethane or similar halogenated hydrocarbon solvent at or below room temperature. The acylated derivative (XIIa) thus obtained is then subjected to alpha-halogenation (in which the alpha position is relative to the keto group of the acyl group) to form the alpha-haloketone (XIIa'). Such α -halo, preferably α -bromo, is according to conventional methods, preferably by reacting (XIIa) with tetrabutylammonium tribromide (TBABBr)₃) Or dibromobarbituric acid (DBBA). An example of such an α -bromination reaction is provided in example 21 below. The resulting preferred α -bromoketone (XIIa ") is then condensed with a suitable thioamide, amide or amidine derivative to form a protected thiazole, oxazole or imidazole derivative (IXa), respectively. Although the condensation reaction can be carried out without a solvent, i.e., without using a solventHowever, for product purity and ease of work-up and purification after the reaction, the condensation reaction is generally preferably carried out in a reaction-inert solvent including, for example, ethanol, chloroform or the like. An example of such a condensation reaction is provided in example 22 below. The resulting protected amine derivative (IXa) can then be deprotected as described in reaction scheme IV above. An example of such a deprotection reaction is provided in example 23 below.

Reaction scheme VIb

The protected triazole derivative (IXb) shown in reaction scheme VIb can be prepared by: the amine protected amide derivative (XIIb) is reacted with an appropriately substituted dimethylaminoaldehyde dimethanol without the use of solvents at elevated temperatures, followed by treatment with hydrazine hydrate in glacial acetic acid at elevated temperatures. The resulting protected amine derivative (IXb) is then deprotected according to the procedures shown and described in reaction scheme IV.

Reaction scheme VIc

The oxadiazole derivative (IXc), shown in reaction scheme VIc, can be synthesized by: the appropriately substituted hydrazide (XIIc) is reacted with the acid chloride under standard conditions, i.e. in the presence of a base, preferably an organic base such as triethylamine, in a reaction inert solvent such as dichloromethane. If desired, the resulting diacylhydrazine intermediate can be treated with a cyclizing agent such as trifluoromethanesulfonic anhydride to effect ring closure. The protected amine derivative (IXc) thus produced can then be deprotected according to the procedures shown and described in reaction scheme IV. An exemplary synthetic route is provided below in examples 24-27, wherein preparation of a protected amine derivative (IXc) and subsequent deprotection thereof is illustrated, wherein Y represents-CH₂-。

Reaction scheme VId

Protected thiazole, oxazole or imidazole derivatives (IXd) shown in reaction scheme VId can be prepared using nitrile (XIId) as the starting material. The nitrile (XIId) is generally obtained by the Mitsunobu coupling reaction described above between commercially available phenol and ethanolamine derivatives. Reduction of nitrile (XIId) with, for example, a metal hydride such as diisobutylaluminum hydride (DIBAL-H) in a reaction-inert hydrocarbon solvent such as toluene or hexane or a halogenated hydrocarbon solvent such as dichloromethane affords aldehyde (XIId'). The resulting aldehyde (XIId') is then halogenated to form an α -haloaldehyde (XIId "). Such alpha-halogenation reactions are preferably made as described in reaction scheme VIa. The preferred α -bromoaldehyde (XIIa ") is then condensed with a suitable thioamide, amide or amidine derivative to form the protected thiazole, oxazole or imidazole derivative (IXd), preferably also according to the method disclosed in reaction scheme VIa above. The resulting protected amine derivative (IXd) can then be deprotected according to the method shown and described in reaction scheme IV.

Conventional isolation and purification methods and/or techniques known to those skilled in the art can be used to isolate the compounds of formula (I) and the various intermediates associated therewith. Such techniques are well known to those skilled in the art and may include, for example, all types of chromatography (HPLC, column chromatography using common adsorbents such as silica gel and thin layer chromatography), recrystallization, and differential (i.e., liquid-liquid) extraction techniques.

Experimental chemical synthesis

Embodiments of the present invention are illustrated by the following examples. It is to be understood, however, that embodiments of this invention are not limited to the specific details of these examples, as other variations thereof will be apparent to those skilled in the art, or may be apparent in light of the present disclosure.

Example 1

{2- [ -4- (4-methyl-oxazol-2-yl) -phenoxy]-ethyl } -carbamic acid benzyl ester

Reacting [2- (4-carbamoyl-phenoxy) -ethyl]Benzyl carbamate (322mg, 1.02mmol) and 1-bromo-2, 2-dimethoxypropane (3.8g, 20.4mmol) were combined in a round-bottomed flask and heated at about 130 ℃ for about 30 minutes. The reaction mixture was then cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (1: 1 hexane/ethyl acetate) to afford the desired oxazole product (167mg, 47% yield). LRMS ([ M + H)]⁺)＝353.1。

Example 2

2- [4- (4-methyl-oxazol-2-yl) -phenoxy]-ethylamine

The title compound of example 1 {2- [4- (4-methyl-oxazol-2-yl) -phenoxy [ ] -]Benzyl-ethyl } -carbamate (166mg, 0.47mmol) was dissolved in methanol (5ml), and 10% Pd/C (50mg) and 1, 4-cyclohexadiene (192mg, 2.4mmol) were added to the resulting solution. The mixture was stirred for about 16 hours, then filtered through celite, washing the filter pad with methanol. Concentrating the filtrate under vacuum to dryness, filtering¹The resulting product (92mg, 90% yield) was used without further purification as determined by H NMR as a pure compound. LRMS ([ M + H)]⁺)＝219.2。

Example 3

4-Hydroxythiobenzamide

In a round-bottomed flask, 4-hydroxybenzonitrile (5.00g, 41.9mmol), diethyl thiophosphoric acid (7.02g, 41.9mmol) and water (8ml) were put under stirringHeated at about 80 ℃ for about 30 minutes. Then 10ml of water are added to the suspension and the solution is heated for about 1 hour. The mixture was stirred at room temperature for about 16 hours and extracted with water and 1: 1 diethyl ether/ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was purified by column chromatography (silica gel; hexane to ethyl acetate). The product was isolated as a yellow solid (5.54g, 87% yield).¹H NMR(CD₃OD)：δ6.74(d，2H，J＝9.1Hz)，7.83(d，2H，J＝8.7Hz)。

Example 4

4- (4-phenyl-thiazol-2-yl) -phenol

In a round-bottom flask, 2-bromoacetophenone (520mg, 2.61mmol) and 4-hydroxythiobenzamide (400mg, 2.61mmol) were dissolved in ethanol (10ml), and the resulting solution was heated to reflux. After about 1 hour, the reaction was cooled to about 35 ℃ and stirred for about 12 hours. The reaction mixture was then concentrated in vacuo to an oil, and the residue was redissolved in ethyl acetate and dichloromethane and extracted with saturated aqueous sodium bicarbonate. The combined extracts were then extracted with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. The crude product was purified by column chromatography (silica gel; dichloromethane to 2% methanol/dichloromethane). The title product was isolated as a white solid (516mg, 78% yield). LRMS ([ M + H)]⁺)＝254.1。

Example 5

{2- [4- (4-phenyl-thiazol-2-yl) -phenoxy ] -2]-ethyl } -carbamic acid benzyl ester

4- (4-phenyl-thiazol-2-yl) -phenol (516mg, 2.03mmol) was dissolved in toluene (6.8ml) and triphenylphosphine (786mg, 3.00mmol) and benzyl N- (2-hydroxyethyl) -carbamate (585mg, 3) were added.00 mmol). The solution was cooled to about 0 ℃ and 1, 1- (azodicarbonyl) -bipiperidine (757mg, 3.00mmol) was added. The mixture was stirred at about 0 ℃ for about 10 minutes and then warmed to room temperature. To the viscous solution were added 6.8ml of toluene and 6.8ml of tetrahydrofuran. The reaction mixture was stirred for about 48 hours, then the solid was filtered off and washed with a minimum volume of 1: 1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuo to a semi-solid and then purified by column chromatography (silica; dichloromethane to 2% methanol/dichloromethane) to yield 396mg of pure product (45% yield). LRMS ([ M + H)]⁺)＝430.9。

Example 6

2- [4- (4-phenyl-thiazol-2-yl) -phenoxy]-ethylamine

Reacting {2- [4- (4-phenyl-thiazol-2-yl) -phenoxy)]Benzyl-ethyl } -carbamate (396mg, 0.92mmol) was dissolved in dichloromethane (4.6ml) and methanesulfonic acid (0.895ml, 13.8mmol) was added dropwise to give a homogeneous yellow solution. The reaction was stirred for about 16 hours, diluted with dichloromethane and adjusted to basic pH (12-13) with 1M sodium hydroxide. The mixture was then extracted with dichloromethane and the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel; dichloromethane to 2% methanol/dichloromethane) to give the product (213mg) in 78% yield. LRMS ([ M + H)]⁺)＝297.2。

Example 7

{2- [4- (2-methyl-1H-imidazol-4-yl) -phenoxy ] -n-butyl methyl-phenoxy]-ethyl } -carbamic acid benzyl ester

Acetamidine hydrochloride (112mg, 1.18mmol) and [2- (4-bromoacetylphenoxy) -ethyl]-benzyl carbamate (160mg, 0.39mmol) and sodium ethoxide (80.3mg, 1.18mmol) were combined in a round bottom flask, dissolved in ethanol and heated at about 80 ℃ for about 2 hours. Cooling the reaction mixture to room temperature and filteringThe mixture was homogeneous. The filtrate was then concentrated in vacuo to an oil and purified by column chromatography (silica; 5% methanol/dichloromethane to 10% methanol/dichloromethane) to yield 92mg (64% yield) of the desired product. LRMS ([ M + H)]⁺)＝352.2。

Example 8

2- [4- (2-methyl-1H-imidazol-4-yl) -phenoxy ] -n-butyl ether]-ethylamine

In a nitrogen purged Parr flask, {2- [4- (2-methyl-1H-imidazol-4-yl) -phenoxy]Benzyl-ethyl } -carbamate (78mg, 0.22mmol) was dissolved in methanol (15ml) and 10% Pd/C (20mg) was added in one portion. The mixture was then hydrogenated at about 45psi for about 4 hours. The reaction mixture was filtered through a pad of celite, and the filter pad was washed with methanol. The filtrate was concentrated in vacuo and the resulting product (49mg, 100% yield) was used without further purification. LRMS ([ M + H)]⁺)＝218.2。

Example 9

N- [2- (4-acetyl-phenyl) -ethyl]-acetamide

In a 500ml flame-dried flask, N-phenethylacetamide (6.53g, 40.0mmol) was dissolved in dichloromethane (65ml) and acetyl chloride (7.22g, 92.0mmol) was added in one portion. The resulting solution was cooled to about 0 ℃ and aluminum chloride (18.1g, 136mmol) was added in portions over about 30 minutes. The solution was stirred at about 0 ℃ for about 5 minutes, the ice bath was removed, and the mixture was heated to reflux for about 30 minutes. After cooling to room temperature, the reaction mixture was poured onto ice water, stirred for about 10 minutes and then extracted with dichloromethane (2 × 100 ml). The combined organic extracts were washed successively with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting white solid (7.52g, 92% yield) was confirmed by NMR to be about 90% pure and used without further purification. LRMS ([ M + H)]⁺)＝206.2。

Example 10

N- [2- (4-Bromoacetylphenyl) -ethyl]-acetamide

In a round-bottom flask, N- [2- (4-acetyl-phenyl) -ethyl ] -acetamide (7.23g, 35.2mmol) was dissolved in dichloromethane (120ml) and methanol (60 ml). Tetrabutylammonium tribromide (17.0g, 35.2mmol) is added to the solution in one portion, and the mixture is stirred at room temperature overnight. The volatiles were then removed in vacuo to give an oil which was suspended in 100ml of dichloromethane and extracted with 125ml of saturated aqueous sodium bicarbonate. The resulting aqueous extract was extracted with more dichloromethane (3X 100ml) and the combined organic extracts were washed with water, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; dichloromethane to 7% methanol/dichloromethane) and the resulting material was washed with 110ml water to yield 8.27g (83% yield) of pure product as a white solid. LRMS ([ M-1] -) -283.0, 284.9. Example 11

N- {2- [4- (2-phenyl-thiazol-4-yl) -phenyl]-ethyl } -acetamide

In a round-bottomed flask, thiobenzamide (357mg, 2.60mmol) and N- [2- (4-bromoacetyl-phenyl) -ethyl]-acetamides (740mg, 2.60mmol) were combined in ethanol (30ml) and heated at about 80 ℃ for about 3 hours. The reaction mixture was then concentrated in vacuo to afford an off-white solid. The product obtained (838mg, yield 100%) was confirmed by NMR to be pure compound and was used directly in the next step without further purification. LRMS ([ M + H)]⁺)＝323.2。

Example 12

2- [4- (2-phenyl-thiazol-4-yl) -phenyl]-ethylamine

In a round-bottom flask, N- {2- [4- (2-phenyl-thiazol-4-yl) -phenyl ] -was placed]-Ethyl } acetamide (838mg, 2.60mmol) was added to 5.0ml of concentrated hydrochloric acid and the resulting solution was heated at about 120 ℃ for about 16 hours. The solution was then cooled to about 0 ℃, adjusted to pH12 with 5M sodium hydroxide, and extracted with 4 parts dichloromethane. The combined organic extracts were then washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel; dichloromethane to 20% methanol/dichloromethane) to give the product (617mg, 85% yield). LRMS ([ M + H)]⁺)＝281.2。

Example 13

N- (1, 1-dimethyl-2-phenylethyl) -2, 2, 2-trifluoroacetamide

In a 500ml flame dried flask, tert-butylamine hydrochloride (5.0g, 26.9mmol) and pyridine (7.0ml, 86.2mmol) were dissolved in dichloromethane (100 ml). The resulting solution was cooled to about 0 deg.C and trifluoroacetic anhydride (7.6ml, 53.9mmol) was added dropwise over about 4 minutes. The solution was stirred at about 0 ℃ for about 5 minutes, and then the ice bath was removed. After stirring at room temperature for about 90 minutes, the reaction mixture was cooled to about 0 ℃ and 100ml of saturated aqueous ammonium chloride solution was added. Then, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with 100ml of dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting white solid (6.35g, 96% yield) was used without further purification. LRMS ([ M-1]]^-)＝244.2。

Example 14

N- [2- (4-acetyl-phenyl) -1, 1-dimethyl-ethyl]-2, 2, 2-trifluoroacetamide

To a flame dried 250ml flask were added N- (1, 1-dimethyl-2-phenyl-ethyl) -2, 2, 2-trifluoroacetamide (5.93g, 24.2mmol), acetyl chloride (4.00g, 5.2mmol)5.6mmol) and dichloromethane. The resulting solution was cooled to about 0 ℃ and aluminum (III) chloride (11.0g, 82.2mmol) was added portionwise over about 30 minutes. During the addition, the solution changed from colorless to green-brown. After the addition was complete, the solution was heated to reflux for about 30 minutes, then cooled to room temperature and poured into 300ml of ice water. After stirring for about 10 minutes, the mixture was diluted with 125ml of dichloromethane and the layers were separated. The aqueous layer was extracted with 125ml of dichloromethane. The combined organic extracts were then washed successively with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil (6.9g, 99% yield) was confirmed by NMR to be about 85% pure and used in the subsequent reaction without further purification. LRMS ([ M + 1]]⁺)＝288.2。

Example 15

N- [2- (bromoacetylphenyl) -1, 1-dimethylethyl]-2, 2, 2-trifluoroacetamide

In a round-bottom flask, N- (1, 1-dimethyl-2-phenyl-ethyl) -2, 2, 2-trifluoroacetamide (6.90g, 21.0mmol) was dissolved in dichloromethane (66ml) and methanol (33 ml). Tetrabutylammonium tribromide (10.6g, 22.0mmol) is added to the solution in one portion, and the mixture is stirred at room temperature overnight. The volatiles were then removed in vacuo to give an oil, which was resuspended in 100ml of dichloromethane and extracted with 125ml of saturated aqueous sodium bicarbonate. The aqueous extract was extracted with more dichloromethane (3X 10ml) and the combined organic extracts were washed with water, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude oil was purified by column chromatography (silica gel; 60% dichloromethane/hexane to 10% ethyl acetate/dichloromethane) and the resulting product (5.18g) was recrystallized from hexane to yield 3.14g (41% yield) of pure product as a fluffy white solid.

Example 16N- {1, 1-dimethyl-2- [4- (2-methyl-thiazol-4-yl) -phenyl ]]-ethyl } -2, 2, 2-trifluoroacetamide

In a round-bottom flask, N- [2- (bromoacetyl-phenyl) -1, 1-dimethyl-ethyl]-2, 2, 2-trifluoroacetamide (388mg, 1.06mmol) and thioacetamide (80mg, 1.06mmol) are dissolved in ethanol (10ml) and the mixture is heated at about 80 ℃ for 2.5 hours. The reaction mixture was concentrated in vacuo to an oil and used without further purification in the subsequent reaction. LRMS ([ M + 1]]⁺)＝343.2。

Example 17

1, 1-dimethyl-2- [4- (2-methyl-thiazol-4-yl) -phenyl]-ethylamine

In a round bottom flask, N- {1, 1-dimethyl-2- [4- (2-methyl-thiazol-4-yl) phenyl]-Ethyl } -2, 2, 2-trifluoroacetamide (. about.362 mg, 1.06mmol) is suspended in 7.5ml of 2: 1 (v: v) methanol/tetrahydrofuran and 5M sodium hydroxide (3.2ml, 15 equivalents) is added dropwise. The solution changed from colorless to golden brown and was then stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo to remove volatiles and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was removed and washed 2 times with ethyl acetate. The combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the product (242mg, 93% yield over two steps), which was used without further purification. LRMS ([ M + 1]]⁺)＝247.3。

Example 18{2- [4- (5-methyl-4H- [1, 2, 4]]Triazol-3-ylmethyl) -phenoxy]-Ethyl } -carbamic acid tert-butyl ester

Reacting [2- (4-carbamoylmethyl-phenoxy) -ethyl]Tert-butyl carbamate (605mg, 2.05mmol) and N, N-dimethylacetamide ketal dimethanol (5ml) were combined and heated at about 120 ℃ for about 90 minutes. The orange solution was allowed to cool to room temperature and concentrated in vacuo. The resulting oil was then dissolved in acetic acid (6ml) and hydrazine hydrate (0.20ml, 4.10mmol) was added to the solution. Mixing the mixture at about 9Heated at 0 ℃ for about 90 minutes, then poured into water and adjusted to pH7 by the addition of 5M sodium hydroxide. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; chloroform to 4% methanol/chloroform) to yield 403mg (59% yield) of the desired product. LRMS ([ M + H)]⁺) 333.2. Example 19

2- [4- (5-methyl-4H- [1, 2, 4]]Triazol-3-ylmethyl) -phenoxy]-ethylamine

To {2- [4- (5-methyl-4H- [1, 2, 4) }]Triazol-3-ylmethyl) -phenoxy]To a solution of tert-butyl-ethyl } -carbamate (380mg, 1.14mmol) in dichloromethane (10ml) was added trifluoroacetic acid (1.7 ml). The resulting mixture was stirred for about 30 minutes and then concentrated in vacuo. The resulting oily residue was dissolved in ethyl acetate and adjusted to pH10 with aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 120mg (45% yield) of the amine product. LRMS ([ M + H)]⁺)＝233.1。

Example 20

[2- (4-acetyl-phenoxy) -ethyl]-carbamic acid benzyl ester

In a round bottom flask equipped with a mechanical stirrer, 4-hydroxyacetophenone (5.00g, 36.7mmol) was dissolved in toluene (122ml) and triphenylphosphine (14.4g, 55.1mmol) and benzyl N- (2-hydroxyethyl) carbamate (10.8g, 55.1mmol) were added. The reaction mixture was cooled to 0 ℃ and 1, 1' - (azodicarbonyl) bipiperidine (13.9g, 55.1mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature. After stirring for 10 minutes, 122ml of toluene and 122ml of tetrahydrofuran were added to the thick solution. The reaction mixture was stirred for a further 24 hours, thenThe solid was filtered off. The filtrate was concentrated in vacuo and the resulting solid was purified by column chromatography (silica; hexane to 2: 1 hexane/ethyl acetate) to afford 9.68g (84% yield) of the desired product as a white solid. LRMS ([ M-1]]^-)＝312.2。

Example 21

[2- (4-Bromoacetylphenoxy) -ethyl]-carbamic acid benzyl ester

Reacting [2- (4-acetyl-phenoxy) -ethyl]-benzyl carbamate (10.2g, 32.5mmol) was dissolved in dichloromethane (100ml) and methanol (50ml) and tetrabutylammonium tribromide (15.7g, 32.5mmol) was added in one portion. The reaction mixture was stirred for about 16 hours and then treated with water. The aqueous phase was extracted with ethyl acetate and then saturated aqueous sodium bicarbonate and saturated Na₂S₂O₃And (6) washing. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica; hexane to 2: 1 hexane/ethyl acetate) to give a colorless oil which solidified on standing (11.5g, 90% yield).

Example 22

{2- [4- (2-methyl-oxazol-4-yl) -phenoxy]-ethyl } -carbamic acid benzyl ester

Acetamide (2.95g, 50.0mmol) and [2- (4-bromoacetylphenoxy) -ethyl]-benzyl carbamate (1.20g, 3.06mmol) was combined in a round bottom flask and heated at about 130 ℃ for about 90 minutes. The reaction mixture was then cooled to room temperature and the resulting orange solid was partitioned between ethyl acetate and water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid crude product was purified by column chromatography (silica gel; dichloromethane to 10% ethyl acetate/dichloromethane) to afford 621mg (58% yield) of product as a white solid. L isRMS([M+H⁺])＝353.3。

Example 23

2- [4- (2-methyl-oxazol-4-yl) -phenoxy]-ethylamine

Will contain {2- [4- (2-methyl-oxazol-4-yl) -phenoxy group]A round-bottomed flask of benzyl-ethyl } -carbamate (788mg, 2.07mmol) was purged with nitrogen and 10% Pd/C (200mg, 20 wt%), ethyl acetate (15ml) and methanol (5ml) were added. 1, 4-cyclohexadiene (0.90ml, 9.60mmol) was then added to the mixture, and the solution was stirred at room temperature for about 1 hour. The reaction mixture was then filtered through a pad of celite, washing the filter cake with methanol. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica; dichloromethane to 20% methanol/dichloromethane) to afford 456mg (89% yield) of the desired product. LRMS ([ M + H)]⁺)＝247.2。

Example 24 Iminodicarbonate, [2- [4- [2- [ [ (1, 1-dimethylethoxy) carbonyl ] carbonyl]Methylamino radical]-2-oxoethyl group]Phenoxy radical]Ethyl radical]-, bis (1, 1-dimethylethyl) ester

In a round-bottomed flask, 2- [4- (2-amino-ethoxy) -phenyl ] -N-methyl-acetamide (7.78g, 37.3mmol) was dissolved in dimethyl sulfoxide (30ml), and di-tert-butyl dicarbonate (12.2g, 55.9mmol) was added in one portion at room temperature. After the reaction was stirred for about 90 minutes, dimethylaminopyridine (4.56g, 37.3mmol) and a further 8.14g (37.3mmol) of di-tert-butyl dicarbonate were added. After a total of about 4 hours, an additional portion of dimethylaminopyridine (12.2g, 55.9mmol) was added and the reaction stirred overnight. The mixture was then diluted with ether (150ml) and poured into water (150 ml). The aqueous phase was extracted 2 times with ether and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel; 5% ethyl acetate/hexane 35% ethyl acetate/hexane) to afford the desired product (11.5g, 22.6 mmol).

Example 25

Phenylacetic acid, 4- [2- (bis [ (1, 1-dimethylethoxy) carbonyl]Amino group]Ethoxy radical]-, hydrazides

To a round bottom flask containing iminodicarbonic acid, [2- [4- [2- [ [ (1, 1-dimethylethoxy) carbonyl ] methylamino ] -2-oxoethyl ] phenoxy ] ethyl ] -, bis (1, 1-dimethylethyl) ester (3.10g, 6.09mmol) in methanol (30ml) was added hydrazine monohydrate (1.03ml, 21.3mmol) dropwise. The resulting solution was stirred at room temperature overnight and then concentrated in vacuo to an oil. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate and extracted with dichloromethane. The crude product was purified by column chromatography (silica gel; dichloromethane to 5% methanol/dichloromethane) to yield 1.63g (65% yield) of the desired product as an oil which solidified on standing.

Example 26 Phenylacetic acid, 4- [2- (bis [ (1, 1-dimethylethoxy) carbonyl ] carbonyl]Amino group]Ethoxy radical]-2-benzoylhydrazide

To phenylacetic acid, 4- [2- (bis [ (1, 1-dimethylethoxy) carbonyl]Amino group]Ethoxy radical]To a solution of hydrazide (760mg, 1.86mmol) in dichloromethane (20ml) were added benzoyl chloride (0.258ml, 2.22mmol) and triethylamine (0.310ml, 2.22 mmol). The resulting solution was stirred for about 24 hours, quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product as a solid. The resulting crude product was purified by column chromatography (silica gel; hexane to 50% ethyl acetate/hexane) to obtain 451mg (47% yield) of the product as a white solid. LRMS ([ M-H)]^-)＝512.1。

Example 27

2- [4- (5-phenyl- [1, 3, 4]]Oxadiazol-2-ylmethyl) -phenoxy]-ethylamine

To phenylacetic acid, 4- [2- (bis [ (1, 1-dimethylethoxy) carbonyl]Amino group]Ethoxy radical]Pyridine (0.150ml, 1.86mmol) was added to a solution of-2-benzoylhydrazide (435mg, 0.847 mmol) in dichloromethane (12 ml). The mixture was cooled to about-10 ℃ and trifluoromethanesulfonic anhydride (0.299ml, 1.78mmol) was added dropwise. After the addition was complete, the cooling bath was removed and the reaction mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted 3 times with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel; dichloromethane to 20% methanol/dichloromethane) to yield 60mg (25% yield) of the product amine. LRMS ([ M + H)]⁺)＝296.1。

Example 28

6- (4-fluoro-phenyl) -4, 5-dihydro-2H-pyridazin-3-ones

In a round-bottom flask, 4- (4-fluoro-phenyl) -4-oxobutanoic acid (4.90g, 25.0mmol) and hydrazine hydrate (1.70ml, 35.0mmol) were dissolved in ethanol (50ml), and the reaction mixture was heated at about 80 ℃ for about 90 minutes. The mixture was cooled to room temperature and then concentrated in vacuo. The resulting solid was suspended in ethanol (10ml) and stirred for 10 min, then the mixture was filtered to give the pure product (4.14g, 21.5mmol, 86% yield). LRMS ([ M + H)]⁺)＝193.2；m.p.191-193℃。

Example 29

6- [4- (2-amino-ethoxy) -phenyl]-4, 5-dihydro-2H-pyridazin-3-ones

In a flame-dried round-bottom flask, ethanolamine (1.7ml, 28.1mmol) was dissolved in dimethyl sulfoxide (9.5ml), and potassium tert-butoxide (95%, 3.3g, 28.1mmol) was added to the solution.The mixture was stirred at about 65 ℃ for about 10 minutes, then 6- (4-fluorophenyl) -4, 5-dihydro-2H-pyridazin-3-one (3.6g, 18.7mmol) was added. The dark solution was heated at about 80 ℃ for about 12 hours and then cooled to room temperature. Water was added and the resulting tan solid was filtered off. The solid crude product was then purified by column chromatography (silica gel; 5% methanol/dichloromethane to 15% methanol/dichloromethane) to afford the product as a white solid (1.5g, 34% yield). LRMS ([ M + H)]⁺)＝234.2。

Example 30

1- (4-methoxy-phenyl) -1H-pyrazole

Copper (II) acetate (960mg, 5.28mmol) was added to a flame dried flask containing pyrazole (240mg, 3.52mmol), 4-methoxyphenylboronic acid (1.07g, 7.04mmol), 4  molecular sieve (1.35 activated powder) and pyridine (570. mu.l, 7.04mmol) in dichloromethane. The reaction was stirred at room temperature for about 2 days, then filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography (silica; isocratic elution with 8% ethyl acetate/hexane) to give 381mg (2.18mmol, 62% yield) of the title compound. LRMS ([ M + H)]⁺)＝175.2。

Example 31

4-pyrazol-1-yl-phenols

The title compound of example 30, 1- (4-methoxy-phenyl) -1H-pyrazole (400mg, 2.30mmol) was dissolved in dichloromethane (8ml) and the solution was cooled to-78 ℃. To the solution was added dropwise boron tribromide (1.0M dichloromethane solution, 5.05ml) over about 5 minutes to obtain a brown solution. The reaction mixture was stirred for 30 minutes, the cooling bath was removed and the mixture was stirred at room temperature for an additional 3 hours. The mixture was poured into water and the resulting mixture was adjusted to about pH 8. The mixture was extracted with dichloromethane (3X 25ml) and the combined organic phase wasThe organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (25% ethyl acetate/hexanes) to afford 183mg (50% yield) of the desired product as an oil. LRMS ([ M + H)]⁺) 161.1. Example 32

2- (4-pyrazol-1-yl-phenoxy) -ethylamine

To a round bottom flask was added 4-pyrazol-1-yl-phenol (175mg, 1.09mmol), followed by 3.6ml of toluene, triphenylphosphine (430mg, 1.64mmol) and benzyl N- (2-hydroxyethyl) carbamate (320mg, 1.64 mmol). The solution was cooled to 0 ℃ and 1, 1' - (azodicarbonyl) -bipiperidine (414mg, 1.64mmol) was added. The mixture was stirred at about 0 ℃ for about 10 minutes and then warmed to room temperature. To the viscous solution were added 3.6ml of toluene and 3.6ml of tetrahydrofuran. The reaction mixture was stirred for about 48 hours, and the solid precipitate was filtered off and washed with a minimum volume of 1: 1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuo to afford the intermediate [2- (4-pyrazol-1-yl-phenoxy) -ethyl ] carbamic acid benzyl ester as an oil, which was used directly in the next step.

The crude benzyl ester (1.23g) was dissolved in methanol (5ml), and 10% Pd/C (350mg) and ammonium formate (315mg, 5.0mmol) were added to the resulting mixture. The mixture was stirred for about 16 hours and then filtered through celite. The filtrate was concentrated to dryness in vacuo, and the residue was suspended in water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (15% methanol/dichloromethane) to yield 130mg (57% yield in two steps) of the desired product.

Example 33

2- [4- (5-trifluoromethyl-1H-pyrazol-3-yl) -phenoxy ] -benzene]-ethylamine

In flame-dried round bottomIn a flask, ethanolamine (836mg, 13.7mmol) was dissolved in dimethyl sulfoxide (2.7ml), and potassium tert-butoxide (95%, 1.54g, 13.7mmol) was added to the solution. The mixture was stirred at about 65 ℃ for about 10 minutes, then 5- (4-fluoro-phenyl) -3-trifluoromethyl-1H-pyrazole (630mg, 2.74mmol) was added. The dark solution was heated at about 85 ℃ for about 18 hours and then cooled to room temperature. Water was added and the resulting tan solid was collected by filtration. The crude product was purified by column chromatography (5% methanol/dichloromethane to 20% methanol/dichloromethane) to afford the product as a white solid (255mg, 25% yield). LRMS ([ M + H)]⁺)＝272.2。

Example 34

4-[1，2，3]Thiazol-4-yl-phenols

Reacting 4- (4-methoxy-phenyl) - [1, 2, 3]]Thiazole (1.06g, 5.50mmol) was dissolved in dichloromethane (20ml) and the solution was cooled to about-78 ℃. To the solution was added dropwise boron tribromide (1.0M dichloromethane solution, 12.1ml) to obtain a brown solution. The reaction mixture was stirred for about 15 minutes, the cooling bath was removed, and the mixture was stirred at room temperature for an additional 12 hours. The mixture was poured into water and the resulting mixture was adjusted to about pH 6. The mixture was extracted with dichloromethane (3 × 100ml), the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 924mg (94% yield) of the desired product as a tan solid. LRMS ([ M + H)]⁺)＝179.1。

Example 35

2-(4-[1，2，3]Thiazol-4-yl-phenoxy) -ethylamine

To a round bottom flask was added 4- [1, 2, 3] thiazol-4-yl-phenol (875mg, 4.90mmol) and 16ml of toluene, triphenylphosphine (1.93g, 7.36mmol) and benzyl N- (2-hydroxyethyl) carbamate (1.44g, 7.36 mmol). The solution was cooled to 0 ℃ and 1, 1' - (azodicarbonyl) -bipiperidine (1.86g, 7.36mmol) was added. The mixture was stirred at about 0 ℃ for about 10 minutes and then allowed to warm to room temperature. To the viscous solution were added 16ml of toluene and 16ml of tetrahydrofuran. The reaction mixture was stirred for about 48 hours, and the solid precipitate was filtered off and washed with a minimum volume of 1: 1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography (50% hexane/ethyl acetate) to give [2- (4- [1, 2, 3] thiazol-4-phenoxy) -ethyl ] -carbamic acid benzyl ester (3.0g, 57% yield).

The benzyl ester was dissolved in dichloromethane (7ml), and methanesulfonic acid (1.35ml, 20.9mmol) was added to the solution. The resulting solution was heated at about 35 ℃ for about 2 hours and diluted with dichloromethane and water. The pH was adjusted to about 12 with 5N sodium hydroxide and the mixture was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (20% methanol/dichloromethane) to yield 168mg (59% yield) of the desired amine product. LRMS ([ M + H)]⁺)＝222.2。

Example 36

4- (4-methoxy-phenyl) -isoxazoles

To a round bottom flask were added potassium carbonate (1.45g, 10.5mmot) and ethanol (14 ml). To the mixture was added hydroxylamine hydrochloride (730mg, 10.5mmol) and 2- (4-methoxyphenyl) -malonic anhydride (1.25g, 7.00 mmol). The reaction mixture was heated at about 80 ℃ for about 3 hours. The reaction mixture was then concentrated in vacuo to about one-quarter volume and partitioned between water and ethyl acetate. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to a dark oil. The crude product was purified by column chromatography (10% ethyl acetate/hexane) to afford 1.06g (86% yield) of the desired product. LRMS ([ M-H)]^-)＝174.1。

Example 37

4-isoxazol-4-yl-phenols

To a round bottom flask was added D, L-methionine (1.30g, 8.73mmol), 4- (4-methoxy-phenyl) -isoxazole (1.02g, 5.82mmol) and methanesulfonic acid (24 ml). The resulting solution was heated to about 70 ℃ for about 18 hours, then allowed to cool to room temperature and poured onto ice water. The mixture was adjusted to about pH4 and the heterogeneous mixture was filtered. The solid was washed with water and then dried to give the title compound as an off-white solid (640mg, 68% yield). LRMS ([ M-H)]^-)＝160.0。

Example 38

[2- (4-isoxazol-4-yl-phenoxy) -ethyl]-carbamic acid benzyl ester

To a round bottom flask was added 4-isoxazol-4-yl-phenol (570mg, 3.54mmol) and 12ml toluene, triphenylphosphine (1.39g, 5.30mmol) and benzyl N- (2-hydroxyethyl) carbamate (1.04g, 5.30 mmol). The solution was cooled to 0 ℃ and 1, 1' - (azodicarbonyl) -bipiperidine (1.34g, 5.30mmol) was added. The mixture was stirred at about 0 ℃ for about 10 minutes and then allowed to warm to room temperature. To the viscous solution were added 12ml of toluene and 12ml of tetrahydrofuran. The reaction mixture was stirred for about 24 hours, and the solid precipitate was filtered off and washed with a minimum volume of 1: 1 toluene/tetrahydrofuran. The filtrate was concentrated to give the crude product, which was purified by column chromatography (30% ethyl acetate/hexanes) to afford the desired product as a white solid (1.06g, 88% yield).

Example 39

2- (4-isoxazol-4-yl-phenoxy) -ethylamine

Reacting [2- (4-isoxazol-4-yl-phenoxy) -ethylBase of]Benzyl carbamate (1.00g, 2.81mmol) was dissolved in dichloromethane (14ml) and methanesulfonic acid (2.73ml, 42.2mmol) was added. The resulting solution was heated at about 35 ℃ for about 2 hours and diluted with dichloromethane and water. The pH was adjusted to about 12 with 5N sodium hydroxide and the mixture was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (20% methanol/dichloromethane) to yield 202mg (53% yield) of the desired amine. LRMS ([ M + H)]⁺)＝205.3。

The compounds of formula (I) may be prepared according to 3 general preparative methods described in reaction schemes I, II and III, using suitable synthetic precursors, including the precursors disclosed in examples 1-38 above or analogs thereof, hereinafter referred to as method a, method B and method C, respectively. Process A (reaction scheme I) (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (4-phenyl-thiazol-2-yl) -phenoxy ] -2]-ethylamino } ethanol

In a round bottom flask, (R) -2-chloro-5-oxirane-pyridine (u.s. patent 5,541,197) (73.0mg, 0.477mmol) and the title compound of example 4 (2- [4- (4-phenyl-thiazol-2-yl) -phenoxy)]-ethylamine) (212mg, 0.716mmol) was dissolved in 5ml ethanol and the mixture was heated at about 80 ℃ for about 16 hours. The solution was then concentrated in vacuo to an oil which was purified by column chromatography (dichloromethane to 2% dichloromethane/methanol) to yield 107mg (0.236mmol, 50%) of the title compound as a white solid. LRMS ([ M + H)]⁺)＝452.2。

The following compounds were prepared in analogy to the procedure used for the preparation of the title compound of method a, using the appropriate starting materials: (R) -2- {2- [4- (4-benzofuran-2-yl-thiazol-2-yl) -phenoxy ] -phenoxy]-ethylamino } -1- (6-chloropyridin-3-yl) -ethanol; (R) -2- {2- [4- (4-Biphenyl-4-Yl-Thiazol-2-Yl) -Phenoxy]-ethylamino } -1- (6-chloro-pyridin-3-yl) -ethanol; (R) -2- {2- [4- (2-butyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1- (6-chloro-pyridin-3-yl) -ethanol; (R) -2- {2- [4- (2-tert-butyl-thiazol-4-yl)-phenoxy group]-ethylamino } -1- (6-chloro-pyridin-3-yl) -ethanol; (R) -N- [ 2-chloro-5- (2- {1, 1-dimethyl-2- [4- (2-methyl-thiazol-4-yl) -phenyl ] -methyl-ethyl } -propionic acid methyl ester]-ethylamino } -1-hydroxy-ethyl) -phenyl]-a methanesulfonamide; (R) -N- [ 2-chloro-5- (2- {1, 1-dimethyl-2- [4- (2-phenyl-thiazol-4-yl) -phenyl ] -methyl } -propionic acid]-ethylamino } -1-hydroxy-ethyl) -phenyl]-a methanesulfonamide; (R) -N- (2-chloro-5- (2- {2- [4- (2-ethyl-oxazol-4-yl) -phenoxy]-ethylamino } -1-hydroxy-ethyl) -phenyl]-a methanesulfonamide; (R) -N- [ 2-chloro-5- (2- {2- [4- (2-ethyl-thiazol-4-yl) -phenoxy ] -N- [ 2-chloro-5- (2-ethyl-thiazol-4-yl) -phenoxy ] -N-methyl-phenoxy]-ethylamino } -1-hydroxy-ethyl) -phenyl]-a methanesulfonamide; (R) -N- [ 2-chloro-5- (2- {2- [4- (2-ethyl-thiazol-4-yl) -phenyl ] -methyl } -propionic acid methyl ester]-1, 1-dimethylethylamino } -1-hydroxy-ethyl) -phenyl]-a methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-isopropyl-1H-imidazol-4-yl) -phenoxy ] -N- [ 4-methyl-ethyl-phenyl ] -methyl-ethyl-phenyl]Ethylamino } -ethyl) -phenyl]-a methanesulfonamide; (R) -N- (2-chloro-5- { 1-hydroxy-2- {2- [4- (2-isopropyl-oxazol-4-yl) -phenoxy ] -N-methyl-ethyl-phenoxy]Ethylamino } -ethyl) -phenyl]-a methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-methyl-1H-imidazol-4-yl) -phenoxy ] -N- [ 4-methyl-1H-methyl-phenoxy ] -ethyl acetate]-ethylamino } -ethyl) -phenyl]-a methanesulfonamide; (R) -N- (2-chloro-5- (1-hydroxy-2- {2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -N-methyl-2-methyl-ethyl-phenoxy-4-methyl-ethyl]-ethylamino } -ethyl) -phenyl]-a methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -2]-ethylamino } -ethyl) -phenyl]-a methanesulfonamide; (R) -N- (2-chloro-5- { 1-hydroxy-2- [2- (4-oxazol-4-yl-phenoxy) -ethylamino]-ethyl } phenyl) -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2-4- (2-phenyl-1H-imidazol-4-yl) -phenoxy ] -N- [ 2-chloro-4- (1-hydroxy-2-hydroxy-phenyl-1H-imidazol-4-yl) -phenoxy ] -N-methyl-phenoxy]-ethylamino } -ethyl) -phenyl]-a methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-pyridin-3-yl-1H-imidazol-4-yl) phenoxy ] methyl ethyl ester]-ethylamino } -ethyl) -phenyl]-a methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-pyridin-4-yl-1H-imidazol-4-yl) phenoxy ] methyl ethyl ester]-ethylamino } -ethyl) -phenyl]-a methanesulfonamide; (R) -N- (2-chloro-5- { 1-hydroxy-2- [2- (4-thiazol-4-yl-phenoxy) -ethylamino ] -ethyl]-ethyl } -phenyl) -methanesulfonamide; (R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-trifluoromethyl-1H-imidazol-4-yl) phenoxy ] N]-ethylamino } -ethyl) -phenyl]-a methanesulfonamide; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-cyclopentyl-thiazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {1,1-dimethyl-2- [4- (2-methyl-thiazol-4-yl) -phenyl]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- [1, 1-dimethyl-2- (4-oxazol-4-yl-phenoxy) ethylamino]-ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2, 5-dimethyl-oxazol-4-yl) -phenoxy } -ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- [1, 1-dimethyl-2- (4-oxazol-5-yl-phenoxy) ethylamino]-ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {1, 1-dimethyl-2- [4- (2-phenyl-thiazol-4-yl) -phenyl]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-ethyl-oxazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- (2- {4- [2- (2-ethyl-pyridin-4-yl) -thiazol-4-yl]Phenoxy } -ethylamino) -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [3- (2-ethyl-thiazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (4-ethyl-thiazol-2-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-ethyl-thiazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-ethyl-thiazol-4-yl) -phenyl]-ethylamino } ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-ethyl-thiazol-4-yl) -phenyl]-1, 1-dimethylethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-isopropyl-1H-imidazol-4-yl) -phenoxy]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-isopropyl-oxazol-4-yl) -phenoxy]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-isopropyl-thiazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- (2- {4- [2- (4-methoxy-phenyl) -thiazol-4-yl]-phenoxy } -ethylamino) -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2 '-methyl- [2, 4']Bithiazol-4-yl) -phenoxy]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-methyl-1H-imidazol-4-yl) -phenoxy]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (5-methyl-oxazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- (2- {4- [2- (2-methyl-propane-2-sulfonylmethyl) thiazol-4-yl]-phenoxy } -ethylamino) -ethanol(ii) a (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (4-methyl-thiazol-2-yl) -phenoxy ] -2]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [3- (2-methyl-thiazol-4-yl) -phenoxy ] -2]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-methyl-thiazol-4-yl) -phenyl ] -methyl-ethyl } -propionic acid methyl ester]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (5-methyl-1H- [1, 2, 4)]Triazol-3-ylmethyl) phenoxy]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- [2- (4-oxazol-4-yl-phenoxy) -ethylamino]-ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- [2- (4-oxazol-5-yl-phenoxy) -ethylamino]-ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-phenethyl-thiazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-phenyl-1H-imidazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (5-phenyl- [1, 3, 4)]Oxadiazol-2-ylmethyl) -phenoxy]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (4-phenyl-thiazol-2-yl) -phenoxy ] -2]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [3- (2-phenyl-thiazol-4-yl) -phenoxy ] -phenoxy]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-phenyl-thiazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-phenyl-thiazol-4-yl) -phenyl ] -amide]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-propyl-thiazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (1H-pyrazol-3-yl) -phenoxy ] -phenoxy]-ethylamino } ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-pyridin-3-yl-1H-imidazol-4-yl) -phenoxy]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-pyridin-4-yl-1H-imidazol-4-yl) -phenoxy]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [3- (2-pyridin-3-yl-thiazol-4-yl) -phenoxy ] -2]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [3- (2-pyridin-4-yl-thiazol-4-yl) -phenoxy ] -2]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-pyridin-3-yl-thiazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-pyridin-4-yl-thiazole-4-yl) -phenoxy]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-pyridin-3-yl-thiazol-4-yl) -phenyl]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- [2- (4-thiazol-2-yl-phenoxy) -ethylamino]-ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- [2- (4-thiazol-4-yl-phenoxy) -ethylamino]-ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-thiophen-2-yl-1H-imidazol-4-yl) -phenoxy]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-thiophen-2-yl-thiazol-4-yl) -phenoxy ] -2]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-p-tolyl-thiazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (4-p-tolyl-thiazol-2-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-trifluoromethyl-1H-imidazol-4-yl) -phenoxy]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- (2- {3- [2- (4-trifluoromethyl-phenyl) -thiazol-4-yl]Phenoxy } -ethylamino) -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- (2- {4- [2- (4-trifluoromethyl-phenyl) -thiazol-4-yl]-phenoxy } -ethylamino) -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-trifluoromethyl-thiazol-4-yl) -phenyl]-ethylamino } -ethanol; (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (2-trifluoromethyl-thiazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; and (R) -1- (6-chloro-pyridin-3-yl) -2- {2- [4- (4-trifluoromethyl-thiazol-2-yl) -phenoxy ] -n]Ethylamino } -ethanol. Process B (reaction scheme II) (R) -N- [5- (1- (tert-butyl-dimethyl-silanyloxy) -2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -N- [5- (tert-butyl-dimethyl-silanyloxy) -2- [4- (2-methyl-thiazol-4-yl) -phenoxy ]]Ethylamino } -ethyl) -pyridin-2-yl]-acetamide

In a round bottom flask, 2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -was added]-ethylamine (175mg, 0.747mmol) and toluene-4-sulfonic acid 2- (6-acetylamino-pyridin-3-yl) -2- (tert-butyl-dimethyl-silanyloxy) -ethyl ester (231mg, 0.498mmol) were dissolved in dimethyl sulfoxide (0.50mL) and charged to diisopropylethylamine (0.105mL, 0.600mmol) in one portion. The resulting mixture was heated at about 80 ℃ for about 16 hours and then partitioned between ether and water. The aqueous phase was extracted 4 times with ether,the combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting white solid (dichloromethane to 10% methanol/dichloromethane) was purified by column chromatography to obtain 117mg (45%) of a white solid. LRMS ([ M + 1]]⁺): 527.1. (R) -N- [5- (1-hydroxy-2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -ethyl) pyridin-2-yl]-acetamide

To (R) -N- [5- (1- (tert-butyl-dimethyl-silanyloxy) -2- {2- [4- (2-methylthiazol-4-yl) -phenoxy ] -N-butyl-benzyl at room temperature]-ethylamino } -ethyl) -pyridin-2-yl]To a solution of acetamide (115mg, 0.218mmol) in tetrahydrofuran (1.5mL) was added tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 0.65mL, 0.65 mmol). The resulting solution was stirred for about 2.5 hours, then the reaction mixture was partitioned between ethyl acetate and water. The pH of the mixture was adjusted to about 10-11 and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (dichloromethane to 20% methanol/dichloromethane) to yield 75mg (83%) of the desired product. LRMS ([ M + 1]]⁺): 413.2. (R) -1- (6-amino-pyridin-3-yl) -2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -n]-ethylamino } ethanol

In a round bottom flask, (R) -N- [5- (1-hydroxy-2- {2- [4- (2-methyl-thiazol-4-yl) phenoxy ] was placed in a flask]-ethylamino } -ethyl) -pyridin-2-yl]-acetamide (74mg, 0.18mmol) was dissolved in 1.0mL ethanol and 1.0mL 2M sodium hydroxide was added to the solution. The reaction mixture was then heated at about 80 ℃ for about 20 minutes, then diluted with water and adjusted to about pH 11. The aqueous phase is extracted with 4 parts of dichloromethane and the combined organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (dichloromethane to 20% methanol/dichloromethane) to yield 49mg (74%) of the desired product. LRMS ([ M + 1]]⁺): 371.2. method C (reaction scheme III)2- {2- [4- (4)-phenyl-thiazol-2-yl) -phenoxy]-ethylamino group]-1-pyridin-3-yl-ethanol

In a nitrogen purged round bottom flask, 1- (6-chloro-pyridin-3-yl) -2- {2- (4-phenyl-thiazol-2-yl) -phenoxy]-Ethylamino } -ethanol (107mg, 236mmol) was dissolved in a mixture of methanol (2.3ml), THF (0.5ml) and ethyl acetate (0.5 ml). Palladium on carbon (10%, 107mg, 100 wt%) and ammonium formate (149mg, 2.36mmol) were then added in this order. The reaction mixture was stirred overnight, filtered through celite, and the filter cake was washed with ethyl acetate. The filtrate was concentrated to a white solid and purified by column chromatography (dichloromethane to 4% methanol/dichloromethane) to give a light yellow solid (44mg, 44%). LRMS ([ M + H)]⁺)＝418.3。

Following a procedure analogous to that used for the title compound of preparation C, using the appropriate starting materials, the following compounds were prepared: (R) -1- (6-amino-pyridin-3-yl) -2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-3-yl-1H-imidazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-4-yl-1H-imidazol-4-yl) -phenoxy ] -n]Ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [3- (2-pyridin-3-yl-thiazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [3- (2-pyridin-4-yl-thiazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-3-ylthiazol-4-yl) -phenoxy ] -n]-ethylamino } ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-3-yl-thiazol-4-yl) -phenyl]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-4-yl-thiazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- [2- (4- [1, 2, 3)]Thiadiazol-5-ylphenoxy) -ethylamino]-ethanol; (R) -1-pyridin-3-yl-2- [2- (4-thiazol-2-yl-phenoxy) -ethylamino]-ethanol; (R) -1-pyridin-3-yl-2- [2- (4-thiazol-4-yl-phenoxy) -ethylamino]-ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-thiophen-2-yl-1H-imidazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-Thien-2-yl-thiazol-4-yl) -phenoxy]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (4-p-tolyl-thiazol-2-yl) -phenoxy ] -c]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-p-tolyl-thiazol-4-yl) -phenoxy ] -c]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (4H- [1, 2, 4)]Thiazol-3-yl) -phenoxy]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-trifluoromethyl-1H-imidazol-4-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- (2- {3- [2- (4-trifluoromethyl-phenyl) -thiazol-4-yl]-phenoxy } ethylamino) -ethanol; (R) -1-pyridin-3-yl-2- (2- {4- [2- (4-trifluoromethyl-phenyl) -thiazol-4-yl]-phenoxy } -ethylamino) -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (5-trifluoromethyl-2H-pyrazol-3-yl) -phenoxy ] -phenoxy]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (4-trifluoromethyl-thiazol-2-yl) -phenoxy ] -n]-ethylamino } -ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-trifluoromethyl-thiazol-4-yl) -phenoxy ] -n]-ethylamino } ethanol; (R) -1-pyridin-3-yl-2- {2- [4- (2-trifluoromethyl-thiazol-4-yl) -phenyl]-ethylamino } -ethanol; (R) -2- {2- [4- (4-benzofuran-2-yl-thiazol-2-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-benzyloxymethyl-oxazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-butyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-tert-butyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl ethanol; (R) -2- {2- [4- (2-cyclopentyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {1, 1-dimethyl-2- [4- (2-methyl-thiazol-4-yl) -phenyl]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2, 5-dimethyl-oxazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- [1, 1-dimethyl-2- (4-oxazol-4-yl-phenoxy) -ethylamino]-1-pyridin-3-yl-ethanol; (R) -2- [1, 1-dimethyl-2- (4-oxazol-5-yl-phenoxy) -ethylamino]-1-pyridin-3-yl-ethanol; (R) -2- {1, 1-dimethyl-2- [4- (2-phenyl-thiazol-4-yl) -phenyl]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-ethyl-oxazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- (2- {4- [2- (2-Ethyl-pyridin-4-yl) -thiazol-4-yl]-phenoxy } -ethylamino) -1-pyridin-3-yl-ethanol; (R) -2- {2- [3- (2-Ethyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (4-Ethyl-thiazol-2-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-Ethyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-Ethyl-thiazol-4-yl) -phenyl]-1, 1-dimethyl-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-Ethyl-thiazol-4-yl) -phenyl]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-hydroxymethyl-oxazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -6- {4- [2- (2-hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy]-phenyl } -4, 5-dihydro-pyridazin-3-one; (R) -2- {2- [4- (2-isopropyl-1H-imidazol-4-yl) -phenoxy ] -n-propyl } -propionic acid methyl ester]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-isopropyl-oxazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- (4- (2-isopropyl-thiazol-4-yl) -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methoxymethyl-oxazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- (2- {4- [2- (4-methoxy-phenyl) -thiazol-4-yl]-phenoxy } -ethylamino) -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methyl-1H-imidazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2 '-methyl- [2, 4']Bithiazol-4-yl) -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- [2- (3-methyl-4-oxazol-4-yl-phenoxy) -ethylamino]-1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (5-methyl-oxazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- (2- {4- [2- (2-methyl-propane-2-sulfonylmethyl) -thiazol-4-yl]-phenoxy } ethylamino) -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (1-methyl-1H-pyrazol-3-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (5-methyl-1H- [1, 2, 4)]Triazol-3-ylmethyl) -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (4-methyl-thiazol-2-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [3- (2-methyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-methyl-thiazol-4-yl) -phenyl ] -amide]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (5-methyl-4H- [1, 2, 4)]Triazol-3-yl) -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- [2- (4- [1, 3, 4)]Oxadiazol-2-yl-phenoxy) -ethylamino]-1-pyridin-3-yl-ethanol; (R) -2- [2- (4-oxazol-2-yl-phenoxy) -ethylamino]-1-pyridin-3-ylethanol; (R) -2- [2- (4-oxazol-4-yl-phenoxy) -ethylamino]-1-pyridin-3-yl-ethanol; (R) -2- [2- (4-oxazol-5-yl-phenoxy) -ethylamino]-1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-phenethyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-phenyl-1H-imidazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl ethanol; (R) -2- {2- [3- (2-phenyl) -thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-phenyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-phenyl-thiazol-4-yl) -phenyl ] -amide]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (4-phenyl-thiazol-2-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (5-phenyl- [1, 3, 4)]Oxadiazol-2-ylmethyl) -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- {2- [4- (2-propyl-thiazol-4-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol; (R) -2- [2- (4-pyrazol-3-yl-phenoxy) -ethylamino]-1-pyridin-3-yl-ethanol; and (R) -2- {2- [4- (1H-pyrazol-3-yl) -phenoxy ] -phenoxy]-ethylamino } -1-pyridin-3-yl-ethanol.Salt formation

The hydrochloride salt of the compound of formula (I) can be prepared according to the following examples.

The compound (R) -2- {2- [4- (4-phenyl-thiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol (40mg, 0.095mmol) was dissolved in about 3ml of dichloromethane, and 1.0M HCl in ether (0.28ml, 0.28mmol) was added dropwise to the solution. The resulting cloudy suspension was concentrated in vacuo to yield 47mg of a white solid. Biological assay

The utility of the compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, in the practice of the present invention can be demonstrated by activity in at least one of the assay protocols described below.

Measurement 1For beta is₃Receptor rather than p₁And beta₂Selectivity for adrenergic receptors

Beta in vitro₃Receptor agonist activity and binding to beta₃Receptor rather than p₁And beta₂The selectivity of adrenergic receptors can be determined by measuring the accumulation of cyclic adenosine monophosphate (cAMP) in chinese hamster ovary cells.

According to the method described in American Type Culture Catalog of Cell Lines and hybrids, seven Edition, 1992, p.36, ATCC CCL 61 CHO-K1, human beta will be used₁、β₂Or beta₃cDNA specific transfection of adrenergic receptors Chinese hamster ovary cells were grown to confluence in Ham's F12 medium (Gibco BRL, Life Technologies, Inc., Grand Island, NY) containing 10% fetal bovine serum, 500mg/ml geneticin, 100U/ml penicillin, 100mg/ml streptomycin, and 250ng/ml amphotericin. Compounds were prepared as 25mM stock solutions in DMSO (0.1% DMSO final concentration), diluted in Ham's F12 medium, and diluted at 10%^-10To 10^-5The concentration of M is added together with 10-5M isobutylmethylxanthine to inhibit phosphodiesterase activity. The medium was then incubated with the cells at 37 ℃ for 60 minutes. At the end of the culture, the medium was aspirated and the cells were lysed in 0.01N HCl. The cellular content of cAMP was then determined by Radioimmunoassay (RIA) using a kit from New England Nuclear (Burlington, MA). Cell content in cAMP and beta₁、β₂Or beta₃There is a direct correlation between the agonistic effects of the adrenergic receptors. Use 10^-5The non-selective, all β -adrenergic agonist of M, isoproterenol, served as a positive control.

Measurement 2

Many G protein-coupled receptors (GPCRs) exhibit at least two states of agonist affinity. High affinity agonists that bind GPCRs require binding or coupling of the receptor to the GDP-bound heterotrimeric G protein complex. The low affinity agonist binding site is indicative of the uncoupled receptor state. The high affinity agonist binding site can be converted to a low affinity site by the addition of GTP or an analogue thereof. In the absence of agonist, G protein exhibits high affinity for GDP. In the presence of agonists, G proteins exhibit high affinity for GTP. Thus, when agonist and GTP are added to a receptor/G protein complex, GTP replaces GDP and decouples the receptor from the G protein. The two affinity states for an agonist can be detected in a radioligand competitive binding assay. For many agonists of GPCRs, a two-point fit is generally observed and can be calculated using commercially available software. High affinity sites (K)_iH) Corresponding to the G protein coupled state and for beta₃Adrenergic receptors, and functional ED for stimulation of cAMP accumulation₅₀Are well correlated.

To determine attenuation¹²⁵I]Cyanopindolol (ICYP) and beta₃The compounds for binding of adrenergic receptors can be determined using the following radioligand binding assays. Radioligand binding assay ICYP beta₃Adrenergic receptor competitive binding assays

[¹²⁵I]The specific activity of ICYP was 2000 Ci/mmol. ICYP undergoes catastrophic degradation upon radiolysis. Thus, the specific activity always remains at 2000Ci/mmol, but the concentration will decrease with time. The final concentration of ICYP was 250 pM. Therefore, a stock solution of 2.5nM (10X) needs to be prepared. [¹²⁵I]CYP is available from New England Nuclear, Boston, MA.Competition agent

Up to 4 compounds can be tested in 13 competitive curves in a 96 well format. An example of a single compound is shown below. [ Compound 1] A1, 2-10B 1, 2-9.3C 1, 2-9D 1, 2-8.3E 1, 2-8F 1, 2-7.3G 1, 2-7H 1, 2-6.3A 3, 4-6B 3, 4-5C 3, 4-4D 1, 3 pindolol E3, 4 Overall

The next compound should start at F3, 4. Two pairs of total and non-specific binding were added to the plate. Wells E3, 4 and G7, 8 are for total cpm binding. Well D3, 4 and H7, 8 relate to 100. mu.M pindolol for the determination of non-specific binding.Adding to each well in sequence: add 20. mu.l buffer to "Whole" wells Add 20. mu.l of 1mM pindolol to pindolol wells Add 20. mu.l of each concentration of compound to all wells add 20. mu.l of 2.5nM ICYP diluted to 15. mu.g/160. mu.l of 160. mu.l membraneOperation of1. The assay was set up for a Packard 96 well Unifilter (Packard; Meriden, CT) with GF/C filters using 96 well microtiter plates. 2. Incubate at room temperature for 90-120 minutes with shaking. 3. Samples were aspirated into the processing head using a Packard cell harvester (Packard; Meriden, CT). Pre-soaked (0.3% PEI) filters were used. 4. Wash 4 times with cold wash buffer. 5. The plates were dried and 25. mu.l Microscint (ICN Manufacturers; Costa Mesa, Calif.) was added to each well. 6. The samples were counted in a Wallac beta plate reader (Wallac; Turku, Finland).Binding buffer50mM Hepes/10mM MgCl₂pH7.4 (prepared from 10X stock solution) 0.2% BSA (fraction V) protease inhibitor (prepared from 100X stock solution) 100. mu.g/ml bacitracin 100. mu.g/ml benzamidine 5. mu.g/ml aprotinin 5. mu.g/ml leupeptinWashing buffer50nM Hepes/10mM MgCl₂pH7.4, ice cold (prepared from 10 Xstock solution)

Measurement 3Oxygen consumption

It is known to the person skilled in the art that during increased energy expenditure, the amount of oxygen consumed by the animal generally increases. In addition, metabolic fuels such as glucose and fatty acids are oxidized to CO₂And H₂O, with the release of heat, a function commonly referred to in the art as thermogenesis. Thus, in animals, including humans and petsOxygen consumption can be measured indirectly for thermogenesis, and one skilled in the art can use indirect calorimetry in animals such as humans to measure such energy consumption.

The ability of the compounds of formula (I), stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs to produce a thermogenic response can be demonstrated according to the following assay protocol using male Sprague-Dawley rats (Charles River, Wilmington, Mass.).

Whole animal oxygen consumption can be measured using a loop indirect calorimeter (Oxymax)^TMColumbus instruments, Columbus, OH). The gas sensor was calibrated with nitrogen and gas mixture (0.5% carbon dioxide, 20.5% oxygen, 79% nitrogen; Abco Industrial Supplies, Waterford, CT) before each experiment. Male Sprague-Dawley rats (300-380g body weight) were placed in a sealed chamber (43X 10cm) of a calorimeter, which was placed in an activity monitor. The air flow rate through the chamber was set at 1.6-1.7 liters/min. The calorimeter software calculates the oxygen consumption (ml/kg/hour) from the flow rate through the sealed chamber and the difference in oxygen content at the inlet and outlet sections. The activity monitor had 15 infrared beams, each axis of these beams being spaced one inch from each other; the flow activity was recorded when two consecutive beams were broken (repeated breaks of the same beam were not recorded) and the result was recorded as a count. The baseline oxygen consumption and flow activity were measured every 10 minutes over a period of 2.5-3 hours. At the end of the baseline period, the sealed chamber is opened and the test compound (0.01-20mg/kg, prepared in water, 0.5% methylcellulose or other suitable vehicle) or equivalent amount of vehicle is administered by oral gavage. Oxygen consumption and flow activity were measured every 10 minutes for 2-6 hours after administration. The percentage change in oxygen consumption (value other than the first hour) was calculated by averaging the post-administration values and dividing by the reference oxygen consumption. Oxygen consumption values obtained during the period in which the flow activity exceeded 100 counts were excluded from the calculation. Thus, these values represent the percentage change in the static oxygen consumption.

Measurement 4Hypoglycemic Activity

The compounds of formula (I) may be tested for hypoglycemic activity by determining the dosage when compared to other test compounds and standards according to the following assay protocol.

5-8 week-sized C57 BU6J-ob/ob mice (Jackson Laboratory, Bar Harbor, ME) were housed 5 mice per cage at an ambient temperature of 66 ℃ under standard animal feeding practices. After 1 week of acclimatization, animals were weighed and 25 microliters of blood was collected via ocular bleeding prior to any treatment. Blood samples were immediately diluted 1: 5 in tubes kept on ice with 2% sodium heparin. The blood samples were centrifuged for 2 minutes to remove red blood cells and an automated clinical analyzer (Abbott Spectrum) was used^CCx; abbott Laboratories, Abbott Park, IL) analyzed the glucose concentration in the supernatant. The animals were then regrouped and divided into groups of 5 mice per cage, with the average glucose values for each group being similar. Followed by a test compound (0.01-20mg/kg), a positive control such as englitazone or ciglitazone (50mg/kg p.o.) (U.S. Pat. No. 4,467,902; Sohda et al, chem. pharm. Bull.,324460-4465, (1984)) or vehicle were administered once or twice daily to mice for 5 days. All compounds were administered by oral gavage in a vehicle consisting of 0.5% w/v methylcellulose or with other suitable vehicles. On day 5, the animals were weighed again and blood samples were taken (via ocular route) to determine blood glucose levels as described above. Blood glucose was then calculated by the following formula: blood glucose (mg/dl) sample value x 5 x 1.67 to 8.35 x sample value where 5 is the dilution factor and 1.67 is the plasma hematocrit correction (assuming hematocrit of 40%).

Animals dosed with vehicle maintained a substantially constant high blood glucose level (e.g., 300mg/dl), while the positive control had a reduced blood glucose level (e.g., 130 mg/dl). The hypoglycemic activity of the test compounds is expressed as% blood glucose normalized values. For example, the same blood glucose level as the positive control is expressed as 100%.

Measurement 5β₁And beta₂Receptor selectivity

For beta is₁And beta₂In vivo receptor selectivity can be determined by measuring heart rate, blood pressure and plasma potassium concentration in conscious catheterized rats (male, Sprague-Dawley, 300-400g body weight). For catheter implantation, rats were anesthetized with pentobarbital (50-60mg/kg i.p.) and a PE50 cannula was inserted into the left carotid artery. The catheter was extended subcutaneously, exteriorized on the back of the neck, filled with a solution of polyvinylpyrrolidone in heparinized saline, sealed with a flame, and stoppered. The experiment was performed 7 days after the surgery. On the day of the experiment, the catheter was stoppered and flushed with saline. After at least 30 minutes, baseline values for heart rate and blood pressure were determined by attaching the catheter to a pressure transducer, recording the results on a Grass Model 7 multi-fluctuation recorder (Grass medical instruments, Quincy, Mass.), and obtaining a baseline blood sample (0.5ml) from the arterial catheter. After obtaining the reference value, the test compound was administered by oral gavage, and blood pressure was measured at 15, 30, 45 and 60 minutes (determination of. beta.)₂Activity) and heart rate (determination of. beta.)₁Activity) blood samples (β) for potassium determination were obtained at 30 and 60 minutes₂). Isoproterenol, a non-selective beta agonist, can be tested as a positive control at a dose of 0.001-1mg/kg (injected subcutaneously in saline vehicle). Potassium in plasma was determined by flame spectrophotometry. To determine the change, the baseline value was subtracted from the average of the post-dose values.

Measurement 6Reduction of intestinal peristalsis

The compounds of formula (I) have the effect of reducing intestinal motility and are therefore useful in the adjunctive treatment of various gastrointestinal disorders such as irritable bowel syndrome, gastric ulcers, oesophagitis, gastritis, duodenitis (including that caused by Helicobacter pylori), intestinal ulcers (including inflammatory bowel disease, ulcerative colitis, crohn's disease and proctitis) and gastrointestinal ulcers. Motility without sphincter smooth muscle contraction has been proposedIs formed by beta₃Adrenergic receptor mediated. Obtaining p.beta.₁And beta₂Beta with less activity of the receptor₃Specific agonists will help to pharmacologically control intestinal motility without cardiovascular effects.

The in vivo activity of the compounds of formula (I) for treating or preventing disorders of intestinal motility can be determined according to the following assay protocol. Male Sprague-Dawley origin (CD) rats fasted for 18 hours (175-225g) were administered 0.01-20mg/kg p.o. test compound or vehicle (distilled water). 30 minutes after administration of the test compound, rats were orally administered with a composition containing about 20,000cpm⁵¹A solution of Cr in 0.25ml sodium chromate in 0.9% saline (specific activity 350mCi/mg Cr). After 20 minutes, the rats were sacrificed and then the gastroesophageal, pyloric and ileoceric junctions were ligated and the stomach and small intestine were removed. The small intestine was divided into 10 equal length fragments and the stomach and each length of small intestine were measured using a gamma counter. The proportion of gastric emptying may then be determined by comparing the amount of radioactivity in the intestine relative to the total radioactivity in the intestine plus stomach. Furthermore, the geometric central distribution of the radiolabel was used as a measure of the overall passage ratio through the stomach and intestine. Geometrically centered by centering each segment⁵¹The products of Cr fraction multiplied by the number of segments are summed up: geometric center ═ S ((in each segment)⁵¹Cr fraction) × (number of fragments)). For these calculations, the stomach was considered to be segment 0 and the 10 intestinal segments were numbered 1-10. Thus, geometrically central 0.0 means remaining in the stomach⁵¹The entire load of Cr. Data from both experiments were pooled and statistically evaluated using Dunnett's multiple comparison test.

Alternatively, in group 8, overnight fasted male Sprague-Dawley (CD) rats (175-225g) may be anesthetized with methoxyflurane. A small abdominal incision is then made and the pylorus ligated. Immediately after ligation, the test compound or vehicle (distilled water) was injected into the adjacent duodenum. The dose of test compound should be 0.01-20mg/kg body weight. The incision was then closed and the rats were allowed to recover from anesthesia. After 2 hours of ligation, the rats were sacrificed and gastric juice was collected and clarified by centrifugation. The total volume to weight ratio of the secretions was determined and the acidity was determined by titration with 0.1N sodium hydroxide to ph7.0 using an autotitrator. The data from both experiments were then pooled. With 10mg/kg antisecretory histamine H₂A group of rats treated with the receptor antagonist cimetidine may be used as a positive control. Statistical evaluation can be performed using the Student's t-test.

In vitro activity on the loosely contracted ileum was determined in isolated guinea pig ileum according to the following assay protocol. Freshly isolated guinea pig ileal fragments (approximately 1.5cm in length) were fixed in a tissue bath containing a saline solution of talodex at approximately 30 ℃ and continuously aerated with oxygen: carbon dioxide (95%: 5%). The tissue was then equilibrated at 4.0 grams of tension for 60-90 minutes to obtain a stable baseline. Histamine was added to the tissue bath in a cumulative manner to obtain a concentration of 1nM-10 mM. The maximum tonicity produced after each addition of histamine was recorded on a Grass Physiograph (Grass Medical Instruments, Quincy, Mass.). The tissue was then washed several times with tarder's solution and the baseline tension was readjusted to 4.0 grams, again to obtain a stable baseline. Each tissue was then exposed to a concentration of test compound (1nM-10mM) or vehicle and after 30 minutes of equilibration, the histamine dose-response curve was repeated. Results from multiple experiments were normalized (0-100%) to obtain maximum response in control tissues and plotted as percent maximum tension versus log of histamine concentration in the absence and presence of test compound.

Measurement 7 Protective action against gastric ulcers

Female Sprague-Dawley rats (Charles River, Wilmington, Mass.) weighing 70-120g were not fed food (but not water). They were then allowed to obtain food over a period of 90 minutes. They were then administered orally with a single dose of the test compound (0.01-20mg/kg, in a dosing volume of 1ml/100 g) followed by subcutaneous injection of indomethacin (sigma chemical co., st. louis, MO) (60mg/kg, 1ml/100g body weight). Control rats received subcutaneous indomethacin injection and oral administration of beta₃-adrenergic receptorVehicle for agonist (0.5% solution of methyl cellulose in distilled water). The animals then continue to be able to obtain food, but not water. After 6 hours of indomethacin administration, the rats were sacrificed by cervical dislocation. The stomach was then removed, incised along the maximum curvature, and washed with 0.9% saline. Evaluation of gastric lesions was performed by observers not knowing the dosing regimen. Will be divided into 1mm²The transparent plastic grid of the segment is placed on the sinus, and the macroscopic lesion area is taken as mm²The evaluation was performed as the total area of visible lesions expressed in units. This value was then expressed as a percentage of the total sinus area.

Measurement of 8 Anti-sedative activity

Male CD1 mice weighing 20-25g and Sprague-Dawley rats weighing 200-250g were obtained from Charles River, Wilmington, Mass. The test compound of formula (I) was dissolved in water. The compound was administered to mice in a volume of 10ml/kg and rats in a volume of 2 ml/kg. Control animals received vehicle. Positive test results with respect to the following parameters indicate anti-sedative activity. (1)Antagonism against hypothermia caused by reserpine

Mice were administered reserpine (2.5mg/kg i.p., dissolved in 1% citric acid). Rectal temperature was measured after 3.5 hours. The mice were then divided into different groups to obtain the same mean rectal temperature in each group. Half an hour later (i.e., 4 hours after administration of reserpine), the mice were administered either vehicle or test compound. After 90 minutes (i.e. 5.5 hours after administration of reserpine), the rectal temperature was again determined (Bourin, et al, values of the reserpine test in psychopharmacology, arzneim. forsch.,33，1173，(1983))。(2) antagonism against apomorphine-induced hypothermia

After half an hour of placing the mice in each cage, their rectal temperature was recorded. Animals were grouped to obtain the same average rectal temperature in each group. Apomorphine (16mg/kg s.c.) was administered 30 minutes after the test compound or vehicle was administered. ApomorphineRectal temperature was again measured after 30 minutes of treatment (Puech, et al, antagonism of the low temperature and behavioral response of apomorphine; a simple, rapid and discriminatory test for screening anti-sedatives and psychotropism, psychromermacology,75，84，(1981))。(3) action on learning weakness

The assay was essentially according to Giral, et al, Pupositive 5-HT_1AAgonists reverse the weak behaviour in rats, biol.23The method described in 237 (1988). A foot shock was delivered to male Sprague-Dawley white rats placed in a chamber (20 x 10) with plexiglas walls and a lid. The floor was made of stainless steel grid (1.5cm mesh). A constant current shock is delivered to the grid floor, where the shock is applied as 60 irregular random, non-evasive shocks (15 seconds duration, 0.8mA every 60+15 seconds). Control rats were then placed in the same chamber, but no shock was administered. All pretreatment tests were performed at 11 am from day 1 to day 9. 48 hours (3 days) after the delivery of the non-evasive shock, escape training was initiated in an automated two-way shuttle box (60X 21X 30cm) with plexiglas walls and a floor consisting of stainless steel rods spaced 1.0cm apart to evaluate the escape defect. Each shuttle box was divided into two equally sized compartments by stainless steel partitions with a door providing access to the adjacent compartments through a 7 x 7 space. The shuttle box period was run for 3 consecutive days (days 3, 4 and 5). Animals were individually placed in shuttle boxes, left acclimatized for 5 minutes (only for the first shuttle box period), and then received 30 trials. The interval between trials should be 30 seconds. During the first 3 seconds of each trial, a tight signal was presented which served as a conditioned stimulus. Crossing the gate into the other compartment during this "conditioned stimulus only" period (called avoidance response) spares the rat from the shock. If no avoidance response occurs, a conditioned stimulus plus a sufficient shock (0.8mA) period may be provided. Crossing the door into the other compartment during this conditioned stimulus plus shock is called an escape response. The absence of an escape response was considered escape during the 3 second conditioned stimulus plus shock periodThe detachment failed.

Rats were treated randomly according to one of the following protocols (n-10/group): control samples, no shock received, vehicle only, or experimental animals with non-evasive shocks treated daily with vehicle or test compound. Animals were treated by oral administration for 5 consecutive days, i.e. pre-treatment 6 hours after shock on day 1, twice daily, half dose in the morning (30 minutes before the shuttle box period) and half dose in the afternoon (except on day 5). The mean number of escape failures was statistically analyzed using two-way analysis of variance (individuals × duration) and Dunnett's test, in that order.

Measurement 9 Bronchial relaxation and ciliary movement

The in vitro activity of the compounds of formula (I) for the treatment of inflammatory disorders of the airways, such as asthma and obstructive pulmonary disease, can be determined by measuring the relaxation of the bronchial ring in guinea pigs according to the following assay protocol.

Guinea pig bronchial rings were obtained from either sex of trichromatic guinea pigs (250-350g) anesthetized with urethane (1.25g/kg) and suspended at 37 ℃ in Krebs solution aerated with 95% oxygen: 5% carbon dioxide under an initial tension of 2.0 g. After equilibration for about 1 hour, acetylcholine (10) was used^-3M) contracting the bronchial ring of guinea pigs with theophylline (10)^-3M) relaxed to maximum, then equilibrated for 60 minutes while washing it every 15 minutes with Krebs solution.

The change in tension is measured with a tensiometer and amplifier, etc., and displayed on a recorder. Composition of Krebs solution: (mM): NaCl 118.0, FCl 5.4.4, CaCl₂，2.5，KHPO₄ 1.2，MgSO₄ 1.2，NaHCO₃25.0, and glucose 11.7.

To test the effect of the compounds on static tension, the test compounds (10) were added every 10-20 minutes^-9-10^-6M) until a plateau is reached to obtain a cumulative concentration-response curve. Testing the relaxation of CompoundsAccounts for theophylline (3X 10)^-3M) the percentage of the maximum relaxation induced.

Assay 10 Prostate disease

Male Sprague-Dawley rats (300-. Kept in this buffer at room temperature, adherent adipose and connective tissue were removed. The prostate was then suspended in a 10ml organ bath containing Krebs solution, which was warmed to 37 ℃ and aerated with 95% oxygen and 5% carbon dioxide. The composition of the Krebs solution was 118.4mM NaCl, 4.7mM KCl, 1.2mM MgSO 2 dissolved in deionized distilled water₄，2.5mM CaCl₂11.1mM glucose, 25.0mM NaHCO₃And 1.2mM KH₂PO₄. Tissue was attached to an isometric force displacement transducer and isometric contraction was recorded under a load tension of 0.5 g. Equilibrate for 1 or 2 hours before adding test compound. First, the concentration of the solution is repeatedly increased to 1X 10^-6M phenylephrine causes the next largest contraction until a constant response is obtained. Control and test compound treatment experiments were performed in different preparations. Determination of cumulative phenylephrine or acetylcholine (10)^-9-10^-4M) concentration-response curve of concentration. To test the compounds, the concentration-response curve for phenylephrine or acetylcholine in the presence of the compound is determined.

The in vitro activity of the compounds of formula (I) for the specific potency of the human prostate was determined as described below.

Prostate tissue samples were obtained from patients with BPH symptoms who underwent prostatectomy. The isolated human prostate tissue was cut into 5-8 strips (each length 3mm wide, 3mm thick, 15mm long). These strips were vertically fixed in an organ bath (mM) containing 20ml of Krebs-Henseleit solution consisting of: NaCl 112, KCl 5.9, MgCl₂ 1.2，CaCl₂ 2，NaHCO₃ 25，NaHPO₄1.2 and 11.5 parts of glucose. The medium is maintained at 37 ℃ and pH7.4 and is enriched with 95% oxygenAnd 5% carbon dioxide. 0.5g of resting tension was applied and isometric responses were recorded with a displacement transducer. The specimens were equilibrated for 90 minutes before the experiment was started.

Determination of dehydroepinephrine or acetylcholine by adding the compounds directly to the bath medium in a cumulative manner (10)^-9-10^-4M) concentration-response curve. To test compounds, prostate bars were incubated in the presence of compound (1 or 10 μ M) for 30 minutes before and after adding phenylephrine or acetylcholine to the medium in a cumulative manner to obtain a concentration-response curve in the presence of compound.

Measurement 11 Effect on triglyceride levels and dyslipidemia

The compounds of formula (I) are capable of lowering triglyceride and cholesterol levels, increasing high density lipoprotein levels and are therefore useful in the treatment of conditions in which such lowering (and increasing) is believed to be beneficial. Thus, the compounds of formula (I) are useful in the treatment of conditions of hypertriglyceridemia, hypercholesterolemia and low HDL (high density lipoprotein) levels, as well as in the treatment of atherosclerotic diseases such as atherosclerosis of the coronary, cerebral and peripheral arteries, cardiovascular diseases and related conditions.

The activity of the compounds of formula (I) on dyslipidemia can be determined according to an hourly assay protocol. C57BL/6J ob/ob mice (male, weight 30-40g, Jackson Lab, Bar Harbor, ME) raised in 5 mice/cage in an environmental control room were dosed 1 or 2 times daily for 3 weeks by oral gavage with test compounds (0.01-20mg/kg, n-15/group) or vehicle (0.5% w/v methylcellulose/distilled water, water or other suitable vehicle). At the end of the experiment, 24 hours after the last compound administration, the mice were sacrificed by decapitation and blood samples were collected. Using a clinical automatic Analyzer (Abbott Spectrum)^CCx; abbott laboratories, Abbott Park, IL) determine plasma concentrations of free fatty acids and triglycerides.

Measurement 12 Reduction of body fat

The body fat reducing activity of the compounds of formula (I) was determined according to the following assay protocol. C57BL/6J ob/ob mice (male, weighing 30-40g, Jackson Lab, Bar Harbor, ME) were housed in 5 mice/cage in an environmentally controlled room and were given access to food (rodent food pellets) and water ad libitum. Test compounds or vehicle (0.5% w/v methylcellulose/distilled water, water or other suitable vehicle) were administered 1 or 2 times daily for 3 weeks (0.01-20mg/kg, n 15/group) by oral gavage. The body weight of each mouse was measured daily and the amount of food intake in each cage was determined by weighing the amount of food remaining in the trough. At the end of the experiment, 24 hours after the last compound administration, the mice were weighed and then sacrificed by cervical dislocation. Epididymal retropatellar fat pads were excised from each mouse and weighed. The ratio of fat to body weight of each mouse was determined using absolute body weight and retropatellar fat pad weight. A decrease in weight of the retropatellar fat pad is an indication of a decrease in total body fat.

Claims

1. A compound of the formula (I),

stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs, wherein:

ar is pyridyl, oxazolyl, thiazolyl, or phenyl;

r is hydrogen, hydroxy, oxo, halogen, -CF₃、-(C₁-C₆) Alkyl, - (C)₁-C₆) Alkoxy, - (C)₃-C₈) Cycloalkyl radicals、-NR₉R₁₀、-NR₉SO₂R₁₀、-NR₉COR₁₀or-SO₂R₉；

R₁Is hydrogen, - (C)₁-C₆) Alkyl, halogen, - (C)₁-C₆) Alkoxy or hydroxy;

R₂、R₃、R₄independently is hydrogen or- (C)₁-C₆) An alkyl group;

R₅is a 5 or 6 membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen;

R₆and R₇Independently hydrogen, halogen, cyano, oxo, - (C)₁-C₆) Acyl radical, -CO₂R₉、-NR₉R₁₀Hydroxy, - (C)₁-C₆) Alkoxy, -CONR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀or-SO₂R₉；-(C₁-C₆) Alkyl, said group being optionally substituted with: - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; - (C)₃-C₈) Cycloalkyl, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; aryl, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₇) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; or a heterocycle, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle;

R₈is hydrogen, - (C)₁-C₄) Alkyl or halogen;

R₉and R₁₀Independently of each other hydrogen, - (C)₁-C₆) Alkyl, alkylalkoxy, - (C)₃-C₈) Cycloalkyl, - (C)₁-C₆) Haloalkyl, - (C)₁-C₆) Alkoxy, aryl or heterocyclic;

x is a bond or oxygen, and

y is a bond, - (C)₁-C₆) Alkyl, -OCH₂-、-CH₂O-or oxygen;

with the following conditions:

(i) when Ar is phenyl, R is-NR₉SO₂R₁₀、-SO₂NR₉R₁₀or-SO₂R₉(ii) a And

(ii) when Ar is phenyl, -NR₉SO₂R₁₀And R is₆And R₇When both are hydrogen, R₅Is not an imidazolyl group.

2. The compound of claim 1, wherein Ar is pyridyl; r, R₁、R₂、R₃、R₄And R₈Is hydrogen; x is oxygen; y is a bond; and R is₅Is a 5 or 6 membered heterocyclic ring selected from: dihydropyridazinonyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinylOxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidonyl, pyrimidinyl, thiadiazolyl, thiazolinyl, thiazolyl, triazinyl and triazolyl.

3. The compound of claim 2, wherein the compound is selected from the group consisting of:

(R) -2- {2- [4- (4-benzofuran-2-yl-thiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-benzyloxymethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-butyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-tert-butyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-cyclopentyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2, 5-dimethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-ylethanol;

(R) -2- (2- {4- [2- (2-ethyl-pyridin-4-yl) -thiazol-4-yl ] -phenoxy } -ethylamino) -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-ethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (4-ethyl-thiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-ethyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-hydroxymethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-ylethanol;

(R) -6- {4- [2- (2-hydroxy-2-pyridin-3-yl-ethylamino) -ethoxy ] -phenyl } -4, 5-dihydropyridazin-3-one;

(R) -2- [2- (4-imidazol-1-yl-phenoxy) -ethylamino ] -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-isopropyl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-isopropyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-isopropyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-methoxymethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- (2- {4- [2- (4-methoxy-phenyl) -thiazol-4-yl ] -phenoxy } -ethylamino) -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-methyl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (5-methyl- [1, 3, 4] oxadiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- (2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (5-methyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- (2- {4- [2- (2-methyl-propane-2-sulfonylmethyl) -thiazol-4-yl ] -phenoxy } -ethylamino) -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (1-methyl-1H-pyrazol-3-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (4-methyl-thiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (5-methyl-4H- [1, 2, 4] triazol-3-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2 '-methyl- [2, 4' ] bithiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- [2- (4-oxazol-4-yl-phenoxy) -ethylamino ] -1-pyridin-3-yl-ethanol;

(R) -2- [2- (4-oxazol-5-yl-phenoxy) -ethylamino ] -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-phenyl-1H-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-phenyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (4-phenyl-thiazol-2-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (2-propyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -2- {2- [4- (1H-pyrazol-3-yl) -phenoxy ] -ethylamino } -1-pyridin-3-yl-ethanol;

(R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-3-yl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethanol;

(R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-4-yl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethanol;

(R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-3-yl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol;

(R) -1-pyridin-3-yl-2- {2- [4- (2-pyridin-4-yl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol;

(R) -1-pyridin-3-yl-2- [2- (4-thiazol-2-yl-phenoxy) -ethylamino ] -ethanol;

(R) -1-pyridin-3-yl-2- [2- (4-thiazol-4-yl-phenoxy) -ethylamino ] -ethanol;

(R) -1-pyridin-3-yl-2- {2- [4- (2-thiophen-2-yl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethanol;

(R) -1-pyridin-3-yl-2- {2- [4- (2-thiophen-2-yl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol;

(R) -1-pyridin-3-yl-2- {2- [4- (4-p-tolyl-thiazol-2-yl) -phenoxy ] -ethylamino } -ethanol;

(R) -1-pyridin-3-yl-2- {2- [4- (2-p-tolyl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol;

(R) -1-pyridin-3-yl-2- {2- [4- (2-trifluoromethyl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethanol;

(R) -1-pyridin-3-yl-2- (2- {4- [2- (4-trifluoromethyl-phenyl) -thiazol-4-yl ] -phenoxy } ethylamino) -ethanol;

(R) -1-pyridin-3-yl-2- {2- [4- (4-trifluoromethyl-thiazol-2-yl) -phenoxy ] -ethylamino } ethanol; and

(R) -1-pyridin-3-yl-2- {2- [4- (2-trifluoromethyl-thiazol-4-yl) -phenoxy ] -ethylamino } -ethanol;

stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs.

4. The compound of claim 1, wherein Ar is phenyl; r is-NR₉SO₂R₁₀；R₁Is hydrogen, hydroxy or halogen; r₂、R₃、R₄And R₈Is hydrogen; x is oxygen and Y is a bond; and R is₅Is a 5 or 6 membered heterocyclic ring selected from: dihydropyridazinonyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidinyl, thiadiazolyl, thiazolinyl, thiazolyl, triazinyl, and triazolyl.

5. The compound of claim 4, wherein the compound is selected from the group consisting of:

(R) -N- [ 2-chloro-5- (2- {2- [4- (2-ethyl-oxazol-4-yl) -phenoxy ] -ethylamino } -1-hydroxy-ethyl) -phenyl ] -methanesulfonamide;

(R) -N- [ 2-chloro-5- (2- {2- [4- (2-ethyl-thiazol-4-yl) -phenoxy ] -ethylamino } -1-hydroxy-ethyl) -phenyl ] -methanesulfonamide;

(R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-isopropyl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide;

(R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-isopropyl-oxazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide;

(R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide;

(R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-methyl-1H-imidazol-4-yl) -phenoxy ] ethylamino } -ethyl) -phenyl ] -methanesulfonamide;

(R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] ethylamino } -ethyl) -phenyl ] -methanesulfonamide;

(R) -N- (2-chloro-5- { 1-hydroxy-2- [2- (4-oxazol-4-yl-phenoxy) -ethylamino ] -ethyl } -phenyl) -methanesulfonamide;

(R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-phenyl-1H-imidazol-4-yl) -phenoxy ] ethylamino } -ethyl) -phenyl ] -methanesulfonamide;

(R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-pyridin-3-yl-1H-imidazol-4-yl) phenoxy) -ethylamino } -ethyl) -phenyl ] -methanesulfonamide;

(R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-pyridin-4-yl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide;

(R) -N- (2-chloro-5- { 1-hydroxy-2- [2- (4-thiazol-4-yl-phenoxy) -ethylamino ] -ethyl } -phenyl) -methanesulfonamide; and

(R) -N- [ 2-chloro-5- (1-hydroxy-2- {2- [4- (2-trifluoromethyl-1H-imidazol-4-yl) -phenoxy ] -ethylamino } -ethyl) -phenyl ] -methanesulfonamide;

6. Treating beta in a mammal in need thereof₃A method of treating a disease, condition or disorder mediated by an adrenergic receptor, the method comprising administering to the mammal a therapeutically effective amount of a compound of claim 1, a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug, wherein the beta is₃The adrenergic receptor-mediated disease, condition, or disorder is selected from the group consisting of obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenitis, crohn's disease, proctitis, asthma, intestinal motility disorders, ulcers, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, and inflammatory diseases of the airways.

7. A method of increasing lean meat content in an edible animal, comprising administering to the edible animal a lean meat increasing amount of a compound of claim 1, a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug.

8. A pharmaceutical composition comprising a compound of claim 1, a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug, and a pharmaceutically acceptable carrier, excipient or diluent.

9. Treating beta in a mammal in need thereof₃A method of treating a disease, condition or disorder mediated by an adrenergic receptor, the method comprising administering to the mammal a therapeutically effective amount of the composition of claim 8, wherein the β is₃The adrenergic receptor-mediated disease, condition, or disorder is selected from the group consisting of obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenitis, crohn's disease, proctitis, asthma, intestinal motility disorders, ulcers, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, and inflammatory diseases of the airways.

10. A method of increasing lean meat content in an edible animal, the method comprising administering to the edible animal a lean meat increasing amount of the pharmaceutical composition of claim 8.

11. A pharmaceutical composition comprising a compound of claim 1, a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug; anti-obesity agents; and a pharmaceutically acceptable carrier, excipient or diluent.

12. The composition of claim 11, wherein the anti-obesity agent is selected from the group consisting of: apo-B/MTP inhibitors, MCR-4 agonists, CCK-A agonists, MCR-4 agonists, monoamine reuptake inhibitors, sympathomimetics, serotonergics, dopamine agonists, melanocyte stimulating hormone receptor analogs, cannabinoid receptor antagonists, melanin concentrating hormone antagonists, leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors, bombesin agonists, neuropeptide-Y antagonists, thyromimetic substances, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, and ciliary neurotrophic factor or AGRP.

13. The composition of claim 12, wherein the anti-obesity agent is selected from the group consisting of: phentermine, ephedrine, leptin, phenylpropanolamine and pseudoephedrine; the monoamine reuptake inhibitor is sibutramine; the serotonergic substance is fenfluramine or dextrofenfluramine; the dopamine agonist is bromocriptine and the lipase inhibitor is orlistat; and the appetite-reducing substance is a bombesin agonist.

14. Treating beta in a mammal in need thereof₃A method of treating a disease, condition or disorder mediated by an adrenergic receptor, the method comprising administering to the mammal a therapeutically effective amount of a composition of claim 11, wherein the β is₃The adrenergic receptor-mediated disease, condition, or disorder is selected from the group consisting of obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenitis, crohn's disease, proctitis, asthma, intestinal motility disorders, ulcers, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, and inflammatory diseases of the airways.

15. A method of increasing lean meat content in an edible animal, the method comprising administering to the edible animal a lean meat increasing amount of the pharmaceutical composition of claim 11.

16. A compound of the formula

Or an acid addition salt thereof, wherein:

R₅is a 5 or 6 membered heterocyclic ring selected from: isothiazolyl group,Isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazolyl, pyridazinyl, thiadiazolyl, thiazolinyl, thiazolyl, and triazinyl;

R₆and R₇Independently hydrogen, halogen, cyano, oxo, - (C)₁-C₆) Acyl radical, -CO₂R₉、-NR₉R₁₀Hydroxy, - (C)₁-C₆) Alkoxy, -CONR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀or-SO₂R₉；-(C₁-C₆) Alkyl, said group being optionally substituted with: - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; - (C)₃-C₈) Cycloalkyl, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; aryl, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₇) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkoxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle; or a heterocycle, said group being optionally substituted with: - (C)₁-C₆) Alkyl, - (C)₃-C₈) Cycloalkyl, halogen, aryl, - (C)₁-C₆) Alkane (I) and its preparation methodOxy, - (C)₁-C₆) Haloalkyl, alkylalkoxy, hydroxy, -NR₉R₁₀、-NR₉SO₂R₁₀、-SO₂NR₉R₁₀、-SO₂R₉Or a heterocycle;

R₈is hydrogen, - (C)₁-C₄) Alkyl or halogen; and is

Y is a bond or-CH₂-。

17. The compound of claim 16, wherein the compound is selected from the group consisting of:

2- [4- (4-benzofuran-2-yl-thiazol-2-yl) -phenoxy ] -ethylamine;

2- [4- (2-benzyloxymethyl-oxazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (2-tert-butyl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (2-butyl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (2-cyclopentyl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (2, 5-dimethyl-oxazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (2-ethyl-oxazol-4-yl) -phenoxy ] -ethylamine;

2- {4- [2- (2-ethyl-pyridin-4-yl) -thiazol-4-yl ] -phenoxy } -ethylamine;

2- [4- (4-ethyl-thiazol-2-yl) -phenoxy ] -ethylamine;

2- [4- (4-ethyl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (2-hydroxymethyl-oxazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (2-isopropyl-oxazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (2-isopropyl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (2-methoxymethyl-oxazol-4-yl) -phenoxy ] -ethylamine;

2- {4- [2- (4-methoxy-phenyl) -thiazol-4-yl ] -phenoxy ] -l-ethylamine;

2- [4- (2-methyl-oxazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (5-methyl-oxazol-4-yl) -phenoxy ] -ethylamine;

2- (3-methyl-4-oxazol-4-yl) -phenoxy ] -ethylamine;

2- {4- [2- (2-methyl-propane-2-sulfonylmethyl) -thiazol-4-yl ] -phenoxy } ethylamine;

2- [4- (1-methyl-1H-pyrazol-3-yl) -phenoxy ] -ethylamine;

2- [4- (2-methyl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (4-methyl-thiazol-2-yl) -phenoxy ] -ethylamine;

2- [4- (2 '-methyl- [2, 4' ] bithiazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (5-methyl- [1, 3, 4] oxadiazol-2-yl) -phenoxy ] -ethylamine;

2- (4- [1, 3, 5] oxadiazol-2-yl-phenoxy) -ethylamine;

2- (4-oxazol-2-yl-phenoxy) -ethylamine;

2- (4-oxazol-4-yl-phenoxy) -ethylamine;

2- (4-oxazol-5-yl-phenoxy) -ethylamine;

2- [4- (2-phenethyl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (5-phenyl- [1, 3, 4] oxadiazol-2-ylmethyl) -phenoxy ] -ethylamine;

2- [4- (4-phenyl-thiazol-2-yl) -phenoxy ] -ethylamine;

2- [4- (2-phenyl-thiazol-4-yl) -phenyl ] -ethylamine;

2- [4- (2-propyl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- (4-pyrazol-1-yl-phenoxy) -ethylamine;

2- [4- (1H-pyrazol-3-yl) -phenoxy ] -ethylamine;

2- [4- (2-pyridin-3-yl-thiazol-4-yl) -phenoxy ] -ethylamine;

2-4- (2-pyridin-4-yl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- (4- [1, 2, 3] thiazol-5-yl-phenoxy) -ethylamine;

2- (4-thiazol-2-yl-phenoxy) -ethylamine;

2- (4-thiazol-4-yl-phenoxy) -ethylamine;

2- [4- (2-thiophen-2-ylthiazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (2-p-tolyl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- [4- (4-p-tolyl-thiazol-2-yl) -phenoxy ] -ethylamine;

2- [4- (2-trifluoromethyl-thiazol-4-yl) -phenoxy ] -ethylamine;

2- {4- [2- (4-trifluoromethyl-phenyl) -thiazol-4-yl ] -phenoxy } -ethylamine;

2- [4- (4-trifluoromethyl-thiazol-2-yl) -phenoxy ] -ethylamine; and

2- [4- (5-trifluoromethyl-2H-pyrazol-3-yl) -phenoxy ] -ethylamine;

or an acid addition salt thereof.