AU2003248247A1 - Aminoalcohol derivatives - Google Patents

Description

WO2004/002939 PCT/JP2003/008061 1 DESCRIPTION AMINOALCOHOL DERIVATIVES 5 FIELD OF THE INVENTION This invention relates to new aminoalcohol derivatives and salts thereof which are beta-3 (13) adrenergic receptor agonists and useful as a medicament. 10 BACKGROUND OF THE INVENTION International Publications No. WO 90/06299, published June 14, 1990, describes derivatives of phenylethanolamines as having an effect on the metabolism, preferably reduction of the blood sugar level and body fat, and International 15 Publication No. WO 02/32897, published April 25, 2002, describes derivatives of alpha-aryl ethanolamines useful as P3 adrenergic receptor agonists. DISCLOSURE OF THE INVENTION 20 This invention relates to new aminoalcohol derivatives which are P3 adrenergic receptor agonists and salts thereof. More particularly, it relates to new aminoalcohol derivatives and salts thereof which have gut sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary 25 incontinence, anti-pollakiuria activities, anti-diabetes and anti-obesity, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by 30 smooth muscle contractions in a human being or an animal. One object of this invention is to provide new and useful aminoalcohol derivatives and salts thereof which have gut sympathomimetic, anti-ulcerous, lipolytic, anti-urinary incontinence, anti-pollakiuria activities, anti-diabetes and 35 anti-obesity.

WO 2004/002939 PCT/JP2003/008061 2 Another object of this invention is to provide processes for the preparation of said aminoalcohol derivatives and salts thereof. A further object of this invention is to provide a 5 pharmaceutical composition comprising, as an active ingredient, said aminoacohol derivatives and salts thereof. Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in a human being or an animal, using said 10 aminoalcohol derivatives and salts thereof. The object aminoalcohol derivatives of this invention are new and can be represented by compound of the following formula [I]: 15 OH

R

2

R

1 N CH 2 iR5 A X Y-Z 20 wherein is or 25 is ,4; , or N -CH- -C X is bond, -CH 2 -, I ' I , -0-, -OCH 2 -, -CH 2 0-, -S OH 0

-N

or I (in which R 7 is hydrogen or lower alkyl), R,7 30 Y is bond, -O-(CH2)n - (in which n is 1, 2, 3 or 4),

-(CH

2 )m - (in which m is 1, 2, 3 or 4), , -0 - or -0 , 35 Z is cyano, tetrazolyl, (benzylsulfonyl)carbamoyl, WO 2004/002939 PCT/JP2003/008061 3 benzoylsulfamoyl, formyl, carboxy or protected carboxy,

R

1 is hydrogen, lower alkyl or halogen,

R

2 is hydrogen or an amino protective group,

R

3 is hydrogen or lower alkyl, 5 R 4 is hydrogen or lower alkyl,

R

5 and R 8 are each independently hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, hydroxy(lower)alkoxy, mono(or di or tri)halo(lower)alkoxy, lower alkoxy(lower)alkoxy, lower 10 alkenyloxy, cyclo(lower)alkyloxy, cyclo(lower)alkyl(lower)alkoxy, benzyloxy, phenoxy, lower alkylthio, cyclo(lower)alkylthio, lower alkylsulfonyl, cyclo(lower)alkylsulfonyl, amino, mono(or di)(lower)alkylamino, mono(or di or 15 tri)halo(lower)alkyl, cyano, piperidinyl or phenyl,

R

6 is hydrogen, lower alkyl or halogen,

R

9 is hydrogen or lower alkyl, and i is 1 or 2, provided that -CH- -C 20 (1) when X is bond, -CH 2 -, I or II OH 0 is , and 25 -is, then R 5 is not hydrogen, or (2) when i is 1, N SN 30 then is not or 30 or a salt thereof. According to this invention, the object compounds can be prepared by processes which are illustrated in the 35 following schemes.

WO 2004/002939 PCT/JP2003/008061 4 Process 1

R

2 OH 5 HT I ( R6 R 1 CH-CH + R3 R i X9 Y-Z [TI] [III] or a salt thereof 10 OH R 2 15 A (CH 2 )i X , 5 15R 9 ;3 R 4 x 8I a3~ ~~ "R x Y-zi 15 [I] or a salt thereof Process 2 20 OH Rp, 2 R 1 N (CH 2 ) i X R 5 ) R 9 RS 3R 4 B X Y-Z 25 I] or a salt thereof elimination reaction OH H of the amino protective

R

1 N (CH) 30 group N 4 2 i R 5 30 R3 p 4 B [Ib] or a salt thereof 35 WO 2004/002939 PCT/JP2003/008061 5 Process 3 OH R 2 Ni AN (CH;)j B R 5 5 RR 9 R RH 4 OH + (HO) 2B Y-Z [IV] [V] or a salt thereof or a salt thereof 10 OH R 2 R A]

(CH

2 ) i

R

5

R

9 p30 Y-Z [Ic] s15 or a salt thereof Process 4 OH R 2 20 N C H 6 R 5 AB -B 2R3 4 OH + X1 Y-Z Re [IV] [VI] or a salt thereof or a salt thereof 25 OH R2 3 1

N<(CH

2 ) i O R 5

R

9 R3 R 4 B O Y-Z or a salt thereof 35 WO 2004/002939 PCT/JP2003/008061 6 Process 5 OH R 2 A N (CH 2 ) R6 R 5 R R 3

R

4 X2 + (HO) 2 B y-Z [VII] [V] or a salt thereof or a salt thereof OH R 2 10 R 1 N (CH 2 )i RR A RR3 R 4

R

5 /B Y-Z [Id] 8 or a salt thereof 15 Process 6 OH R 2 a N (CH2)i

C

6 20 9 R "

R

4 [Ie] or a salt thereof OH R2 25 deesterification R 1 N (C 2 )R5 25 reaction

R

9 ,3 R 4 SR3 R4 X Y-COOH [If] or a salt thereof 30 elimination reaction OHH of the amino OH H protective group R1 N (CH2)R R 5 Qa R9 R3 R4 X - Y-COOH [Ig] 35 or a salt thereof WO2004/002939 PCT/JP2003/008061 7 wherein F , , X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 ,

R

8 , R 9 and i are each as defined above, Ra is an amino protective group, 5 R1 0 is lower alkyl, and

X

1 and X 2 are each a leaving group. As to the starting compounds [II], [III], [Ia], [IV], [V], [VI] and [VII], some of them are novel and can be 10 prepared by the procedures described in the Preparations and Examples mentioned below or a conventional manner. In the above and subsequent description of the present specification, suitable examples of the various definition 15 to be included within the scope of the invention are explained in detail in the following. The term "lower" is intended to mean a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise 20 indicated. Suitable "lower alkyl" and "lower alkyl" moiety in the terms of "mono(or di)(lower)alkylamino" and "mono(or di or tri)halo(lower)alkyl" may include straight or branched one 25 having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylpentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl and the like. 30 Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like, in which preferable one is methoxy or ethoxy. 35 Suitable "cyclo(lower)alkyl" moiety in the term of WO 2004/002939 PCT/JP2003/008061 8 "cyclo(lower)alkyloxy" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, in which preferable one is cyclohexyl. 5 Suitable "halogen" may be fluoro, chloro, bromo and iodo, in which preferable one is chloro. Suitable "mono(or di or tri)halo(lower)alkyl" may include chloromethyl, dichloromethyl, trichloromethyl, 10 bromomethyl, dibromomethyl, tribromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 or 2-chloroethyl, 1 or 2 bromoethyl, 1 or 2-fluoroethyl, 1,1-difluoroethyl, 2,2 difluoroethyl and the like. 15 Suitable "protected carboxy" may include esterified carboxy such as lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.], halo(lower)alkoxycarbonyl [e.g. (chloromethoxy)carbonyl, 20 (2,2,2-trichloroethoxy)carbonyl, (2,2,2-trifluoroethoxy) carbonyl, (2-chloropropoxy)carbonyl, (1-fluoro-4 bromobutoxy)carbonyl, (4-chloropentyloxy)carbonyl, (6 chlorohexyloxy)carbonyl, etc.], higher alkoxycarbonyl [e.g. heptyloxycarbonyl, 25 octyloxycarbonyl, 2-ethylhexyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, 3,7-dimethyloctyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl, 3-methyl-10 ethyldodecyloxycarbonyl, hexadecyloxycarbonyl, 30 heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl, icosyloxycarbonyl, etc.], aryloxycarbonyl [e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc.], aryl(lower)alkoxycarbonyl which may have one or more 35 (preferably 1 to 3) suitable substituent(s) such as WO2004/002939 PCT/JP2003/008061 9 phenyl(lower)alkoxycarbonyl which may have nitro or lower alkoxy [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, p nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc.], and the like, 5 in which preferable one is lower alkoxycarbonyl and more preferable one is methoxycarbonyl, ethoxycarbonyl or tert butoxycarbonyl. Suitable "leaving group" may include hydroxy, reactive 10 group derived from hydroxy and the like. Suitable "reactive group derived from hydroxy" may include acid residue and the like. Suitable "acid residue" may include halogen (e.g. fluoro, chloro, bromo, iodo), acyloxy (e.g. acetoxy, 15 tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, etc.) and the like. Suitable example of "amino protective group" moiety may be common amino protective group such as substituted or 20 unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], 25 substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, ar(lower)alkyl [e.g. trityl, benzyl, etc.], and the like, in which preferable one is tert-butoxycarbonyl. 30 Suitable salts of the object aminoalcohol derivative [I] are pharmaceutically acceptable salts and include conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. 35 formate, acetate, trifluoroacetate, oxalate, maleate, WO2004/002939 PCT/JP2003/008061 10 fumarate, tartrate, citrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc., an alkali metal salt [e.g. sodium salt, potassium salt, etc.] or the like. 5 The Processes 1 to 6 for preparing the object compounds of the present invention are explained in detail in the following. Process 1 10 The object compound [I) or a salt thereof can be prepared by reacting a compound [II] with a compound [III] or a salt thereof. Suitable salt of the compound [III] may be the same as those exemplified for the compound [I]. 15 The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, 20 potassium bicarbonate, etc.], tri(lower)alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline or the like. The reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, 25 dioxane, or any other organic solvent which does not adversely influence the reaction. The reaction temperature is not critical, and the reaction can be carried out under cooling to heating. 30 Process 2 The object compound [Ib] or a salt thereof can be prepared by subjecting a compound [Ia] or a salt thereof to elimination reaction of the amino protective group. Suitable salts of the compounds [Ia] and [Ib] may be 35 the same as those exemplified for the compound [I].

WO2004/002939 PCT/JP2003/008061 11 This reaction can be carried out in a similar manner to that of Example 11 mentioned below. Process 3 5 The object compound [Ic] or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with a compound [V] or a salt thereof. Suitable salts of the compounds [Ic], [IV] and [V] may be the same as those exemplified for the compound [I]. 10 This reaction can be carried out in a similar manner to that of Example 15 mentioned below. Process 4 The object compound [Ic] or a salt thereof can be 15 prepared by reacting a compound [TV] or a salt thereof with a compound [VII or a salt thereof. Suitable salts of the compound [Ic], [IV] and [VI] may be the same as those exemplified for the compound [I]. This reaction can be carried out in a similar manner to 20 that of Example 9 mentioned below. Process 5 The object compound [Id] or a salt thereof can be prepared by reacting a compound [VII] or a salt thereof with 25 a compound [V] or a salt thereof. Suitable salts of the compounds [Id], [VII] and [V] may be the same as those exemplified for the compound [I]. This reaction can be carried out in a similar manner to that of Example 7 mentioned below. 30 Process 6 The object compound [Ig] or a salt thereof can be prepared by subjecting a compound [Ie] or a salt thereof to deesterification reaction followed by subjecting a compound 35 [If] or a salt thereof to elimination reaction of the amino WO2004/002939 PCT/JP2003/008061 12 protective group. Suitable salts of the compound [Ig], [Ie] and [If] may be the same as those exemplified for the compound [I]. These reactions can be carried out in a similar manner 5 to that of Example 18 mentioned below. The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, 10 reprecipitation, or the like, and converted to the desired salt in conventional manners, if necessary. It is to be noted that the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture 15 thereof are included within the scope of this invention. It is further to be noted that isomerization or rearrangement of the object compound [I] may occur due to the effect of the light, acid base or the like, and the compound obtained as the result of said isomerization or 20 rearrangement if also included within the scope of the present invention. It is also to be noted that the solvating form of the compound [I] (e.g. hydrate, etc.) and any form of the crystal of the compound [I] are included within the scope of 25 the present invention. The object compound [I] or a salt thereof possesses gut sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence and anti-pollakiuria activities, 30 and are useful for the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animals, and more parcitularly for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, 35 gastritis, gastric ulcer, duodenal ulcer, enteritis, WO2004/002939 PCT/JP2003/008061 13 cholecystopathy, cholantitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer causes by non steroidal anti-inflammatory drags, or the like; for the 5 treatment and/or prevention of dysuria or overactive bladder disorder such as pollakiuria, urinary incontinence, urge incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis, prostatic 10 hypertrophy or the like; for the treatment and/or prevention of pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma, melancholia, depression or the like; for the treatment and/or prevention of diseases as the result of insulin 15 resistance (e.g. hypertension, hyperinsulinemia, etc.); for the treatment and/or prevention of neurogenetic inflammation; and for reducing a wasting condition, and the like. Additionally, P3 adrenergic receptor agonists are known 20 to lower triglyceride and cholesterol levels and to raise high density lipoprotein levels in mammals (US Patent No. 5,451,677). Accordingly, the object compound [I] in useful in the treatment and/or prevention of conditions such as hyper-triglyceridaemia, hypercholesterolaemia and in 25 lowering high density lipoprotein levels as well as in the treatment of atherosclerotic and cardiovascular diseases and relates conditions. Moreover, the object compound [I] is useful for 30 inhibiting uterine contractions, preventing premature labor, and treating and preventing dysmenorrhea. In order to show the usefulness of the compound [I] for the prophylactic and therapeutic treatment of above 35 mentioned disease in human being or animals, a WO2004/002939 PCT/JP2003/008061 14 representative compound of the compound [I] was tested on the following pharmaceutical test. Test 5 Effect on the increase in intravesical pressure induced by carbachol in anesthetized dog Test compound (1) 4'-[(2R)-2-[[(2R)-2-Phenyl-2-hydroxyethyl]amino] 10 propyl]-3-methoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride, (2) 4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-2,3-dimethyl-1,1'-biphenyl-4-carboxylic acid hydrochloride, 15 (3) 4'-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]ethyl] 2-methyl-l,1'-biphenyl-4-carboxylic acid dihydrochloride, (4) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] propyl]-3-methoxy-l,1'-biphenyl-4-carboxylic acid 20 dihydrochloride. Test Method Female Beagle dogs weighing 8.0-15.0 kg were fasted for 24 hours and maintained under halothane anesthesia. A 12F 25 Foley catheter was lubricated with water soluble jelly, inserted into the urethral orifice and advanced approximately 10 cm until the balloon tip was placed well inside the bladder. The balloon was then inflated with 5 ml of room air and catheter slowly withdrawn just part the 30 first resistance that is felt at the bladder neck. Urine was completely drained out through the catheter, and 30 ml of biological saline was infused. The catheter was connected to pressure transducer, and intravesical pressure (IVP) was continuously recorded. The test compound was 35 administered intravenously at 30 minutes before the WO 2004/002939 PCT/JP2003/008061 15 administration of carbachol (1.8 pLg/kg). Percent inhibition of IVP increase by test compound was calculated by dividing IVPa (IVP increase induced by carbachol after test compound administration) by IVPb (IVP increase induced by carbachol 5 just before test compound administration). Test Results Treatment Percent inhibition of IVP increase Test Compound (1) 93 (0.032 mg/kg) Test Compound (2) 91 (0.032 mg/kg) Test Compound (3) 86 (0.032 mg/kg) Test Compound (4) 96 (0.032 mg/kg) 10 Preferred embodiments of the object compound [I] are as follows: N A is or , 15is , , or X is bond, -0-, -OCH 2 -, -S- or -N- (in which R 7 is R7 20 hydrogen or lower alkyl (more preferably C1-C4 alkyl, most preferably methyl)), Y is bond, -O-(CH2)n - (in which n is 1, 2, 3 or 4), -(CH 2 )m (in which m is 1, 2, 3 or 4), 25 , -0 , -o or -o , WO2004/002939 PCT/JP2003/008061 16 Z is carboxy or lower alkoxycarbonyl (more preferably Cl-C 4 alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl),

R

1 is hydrogen or halogen (more preferably chloro), 5 R 2 is hydrogen,

R

3 is hydrogen or lower alkyl (more preferably C 1

-C

4 alkyl, most preferably methyl),

R

4 is hydrogen,

R

5 is halogen (more preferably chloro), hydroxy, lower alkyl 10 (more preferably C 1

-C

6 , most preferably methyl), lower alkoxy (more prefefably C 1

-C

6 alkoxy, most preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy or pentyloxy), hydroxy(lower)alkoxy (more preferably hydroxy(C 1

-C

4 )alkyl, most preferably 2-hydroxyethoxy), 15 mono(or di or tri)halo(lower)alkoxy (more preferably mono(or di or tri)halo(Cl-C 4 )alkoxy, most preferably 2 fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropoxy or 3,3,3-trifluoropropoxy), lower alkoxy(lower)alkoxy (more preferably C 1

-C

4 20 alkoxy(C 1

-C

4 )alkoxy, most preferably 2-methoxyethoxy), lower alkenyloxy (mpre preferably C 2

-C

4 alkenyl, most preferably allyloxy), cyclo(lower)alkyloxy (more preferably cyclo(C 3

-C

6 )alkyloxy, most preferably cyclohexyloxy), phenoxy or phenyl, 25 R 6 is hydrogen,

R

8 is hydrgen or lower alkyl (more preferably C 1

-C

4 alkyl, most preferably methyl),

R

9 is hydrogen or lower alkyl (more preferably C1-C 4 alkyl, most preferably methyl), and 30 i is 1 or 2. More preferred embodiments of the object compound [I] are as follows: 35 WO 2004/002939 PCT/JP2003/008061 17 is or 5 is , or X is bond, -0-, -OCH 2 -, -S- or -N- (in which R 7 is I R7 hydrogen or lower alkyl (more preferably C 1

-C

4 alkyl, 10 most preferably methyl)), Y is bond, -O-(CH2)n- (in which n is 1 or 2) or -(CH2)m - (in which m is 1 or 2), Z is carboxy or lower alkoxycarbonyl (more preferably

C

1

-C

4 alkoxycarbonyl, most preferably methoxycarbonyl, 15 ethoxycarbonyl or tert-butoxycarbonyl),

R

1 is hydrogen or halogen (more preferably chloro),

R

2 is hydrogen,

R

3 is hydrogen or lower alkyl (more preferably C 1

-C

4 alkyl, most preferably methyl), 20 R 4 is hydrogen,

R

5 is hydrogen, halogen (more preferably chloro), hydroxy, lower alkyl (more preferably C 1

-C

6 , most preferably methyl), or lower alkoxy (more preferaly C 1

-C

6 alkoxy, most preferably methoxy), 25 R 6 is hydrogen,

R

8 is hydrogen or lower alkyl (more preferably C 1

-C

4 alkyl, most preferably methyl), and i is 1. 30 Further more preferred embodiments of the compound [I] are as follows: is or 35 WO 2004/002939 PCT/JP2003/008061 18 is X is bond, 5 Y is bond, Z is carboxy or lower alkoxycarbonyl (more preferably C 1

-C

4 alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl),

R

1 is hydrogen or halogen (more preferably chloro), 10 R 2 is hydrogen,

R

3 is hydrogen or lower alkyl (more preferably C 1

-C

4 alkyl, most preferably methyl),

R

4 is hydrogen,

R

5 is hydrogen (more preferably chloro), hydroxy, lower 15 alkyl (more preferably C1-C4 alkyl, most preferably methyl) or lower alkoxy (more preferably C 1

-C

4 alkoxy, most preferably methoxy or ethoxy),

R

6 is hydrogen,

R

8 is hydrogen or lower alkyl (more preferably CI-C4 alkyl, 20 most preferably methyl),

R

9 is hydrogen or lower alkyl (more preferably Cl-C4 alkyl, most preferably methyl), and i is 1. 25 The following Preparations and Examples are given for the purpose of illustrating this invention. Preparation 1 A solution of N-benzyl-2-(4-bromophenyl)ethanamine 30 (13.5 g) in ethanol (270 ml) was added (2R)-2-(3 chlorophenyl)oxirane (8.63 g) and the solution was refluxed for 48 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was chromatographed on silica gel (eluent: hexane/ethyl acetate 35 = 9/1) to give (lR)-2-[benzyl[2-(4-bromophenyl)ethyl]amino]- WO 2004/002939 PCT/JP2003/008061 19 1-(3-chlorophenyl)ethanol (18.6 g) as a colorless oil. NMR (CDC1 3 , 5): 2.58 (1H, dd, J=10, 13Hz), 2.68-2.89 (5H, m), 3.56 (1H, d, J=13Hz), 3.92 (1H, d, J=13Hz), 4.59 (1H, dd, J=3.4, 10Hz), 6.97 (2H, d, 5 J=8.3Hz), 7.21-7.40 (12H, m) (+)ESI-MS (m/z): 444 and 446 (MH + ) Preparation 2 To a solution of (1R)-2-[benzyl[2-(4 10 bromophenyl)ethyl]amino]-1-(3-chlorophenyl)ethanol (18.5 g) in N,N-dimethylformamide (40 ml) were successively added imidazole (3.96 g) and tert-butyldimethylsilyl chloride (7.52 g) and the solution was stirred at room temperature for 14 hours. The reaction mixture was quenched by the 15 addition of water (100 ml) and extracted with ethyl acetate (100 ml x 1). The extract was washed with water (100 ml x 2), brine (100 ml x 1), and dried over magnesium sulfate. Filtration followed by evaporation gave a colorless oil, which was chromatographed on silica gel (eluent: 20 hexane/ethyl acetate) to give (2R)-N-benzyl-N-[2-(4 bromophenyl)ethyl] -2-[[tert-butyl(dimethyl)silyl] oxy]-2-(3 chlorophenyl)ethanamine (21.0 g) as a colorless oil. NMR (CDC1 3 , a): 0.15 (6H, s), 1.01 (9H, s), 2.72-2.82 (5H, m), 2.92 (1H, dd, J=5.9, 13Hz), 3.75 (IH, d, 25 J=13.7Hz), 3.86 (1H, d, J=13.7Hz), 4.71 (1H, t like, J=6.2Hz), 7.01 (2H, d, J=8.3Hz), 7.26-7.47 (9H, m), 7.48 (2H, d, J=8.3Hz) (+)ESI-MS (m/z): 558 and 560 (MH + ) 30 Preparation 3 To a solution of tert-butyl [2-(4 bromophenyl)ethyl] [(2R)-2-(3-chlorophenyl)-2 hydroxyethyl]carbamate (500 mg) in 1,2-dimethoxyethane (6 ml) was added 5-formyl-2-thiopheneboronic acid (206 mg), 35 tetrakis(triphenylphosphine)palladium (63 mg) and aqueous WO 2004/002939 PCT/JP2003/008061 20 solution of sodium carbonate (2M, 1.0 ml), and the mixture was stirred at 80 0 C for 7 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium 5 sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give tert-butyl [(2R)-2-(3 chlorophenyl)-2-hydrxyethyl] [2-[4-(5-formyl-2 thienyl)phenyl]ethyl]carbamate (187 mg). 10 (+)ESI-MS (m/z): 508 (M+Na) + Preparation 4 To a suspension of tert-butyl [(2R)-2-(3-chlorophenyl) 2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (710 mg), 15 4-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid (457 mg), triethylamine (1.26 ml) and powdered 4Amolecular sieves (700 mg) in dichloromethane (18 ml) was added copper(II) acetate (330 mg), and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. The 20 resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert-butyl [2-[4-[4-[[tert-butyl(dimethyl) silyl]oxy]phenoxy]phenyl]ethyl] [(2R)-2-(3-chlorophenyl)-2 25 hydroxyethyl]carbamate (600 mg). (-)ESI-MS (m/z): 569 (M-H) Preparation 5 The following compounds were obtained according to a 30 similar manner to that of Preparation 4. (1) tert-Butyl [2-[4-[[4-[[tert-butyl(dimethyl)silyl]oxy] phenyl]amino]phenyl]ethyl] [(2R)-2-(3-chlorophenyl)-2 hydroxyethyl] carbamate 35 (+)ESI-MS (m/z) .597 (M+H)

+

WO2004/002939 PCT/JP2003/008061 21 (2) tert-Butyl [ 2

-[

4 -[[4-[[tert-butyl(dimethyl)silyl]oxy] phenyl] (methyl)amino]phenyl]ethyl] [(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]carbamate 5 (+)ESI-MS (m/z): 611 (M+H) + Preparation 6 To a solution of tert-butyl [2-(4-aminophenyl) ethyl] [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate 10 (1.75 g) and formaldehyde (37% w/w solution in water, 390 ptl) in 1,2-dichloroethane (20 ml) was added sodium triacetoxyborohydride (1.23 g), and the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. The resulting mixture was poured into a mixture of iN sodium 15 hydroxide and chloroform, and the mixture was stirred for 20 minutes. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert 20 butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4 (methylamino)phenyl]ethyl]carbamate (550 mg). (+)ESI-MS (m/z): 405 (M+H) + Preparation 7 25 To a suspension of 2

-[

4 -[(4-methoxyphenyl)thio]phenyl] ethanamine (6.3 g) in methanol (45 ml) and tetrahydrofuran (10 ml) was added ethyl trifluoroacetate (2.89 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure. The residue 30 was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give 2,2,2-trifluoro-N-[2 [4-[(4-methoxyphenyl)thio]phenyl]ethyl]acetamide (3.95 g). (+)ESI-MS (m/z): 378 (M+Na) + 35 Preparation 8 WO 2004/002939 PCT/JP2003/008061 22 Under nitrogen at 40C, to a solution of 2,2,2 trifluoro-N-[2-[4- [ (4-methoxyphenyl)thio]phenyl]ethyl] acetamide (1.5 g) in dichloromethane (15 ml) was added IM boron tribromide in dichloromethane (10.5 ml), and the 5 mixture was stirred at room temperature for 15 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane and saturated aqueous sodium bicarbonate. After separation, the organic layer was dried over magnesium sulfate and evaporated under 10 reduced pressure to give 2,2,2-trifluoro-N-[2-[4-[(4 hydroxyphenyl)thio]phenyl]ethyl]acetamide (1.42 g). (+)ESI-MS (m/z): 364 (M+Na) + Preparation 9 15 To a solution of 2,2,2-trifluoro-N-[2-[4-[(4 hydroxyphenyl)thio]phenyl]ethyl]acetamide (480 mg) in methanol (5.0 ml) was added lN sodium hydroxide solution (2.8 ml). The mixture was refluxed for 12 hours. The mixture was evaporated under reduced pressure. The residue 20 was dissolved in a mixture of dichloromethane (40 ml), IN hydrochloric acid solution (2.0 ml) and water (15 ml). After separation, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 4-[[4 (2-aminoethyl)phenyl]thio]phenol (300 mg). 25 (-)ESI-MS (m/z): 244 (M-H) Preparation 10 4-[[4-(2-Aminoethyl)phenyl]thio]phenol (295 mg) and

(

2 R)-2-(3-chlorophenyl)oxirane (186 mg) in ethanol (3.5 ml) 30 was refluxed for 6 hours. The mixture was evaporated. The residue was purified by column chromatography on silica gel (chloroform/methanol = 100/3) to give 4-[[4-[2-[[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino] ethyl]phenyl] thio]phenol (155 mg). 35 (+)ESI-MS (m/z): 400 (M+H)

+

WO 2004/002939 PCT/JP2003/008061 23 The object compound above was protected at the imino group in a conventional manner to give tert-butyl [(2R)-2 (3-chlorophenyl)-2-hydroxyethyl][2-[4-[(4-hydroxyphenyl) 5 thio]phenyl]ethyl]carbamate (200 mg). (+)ESI-MS (m/z): 500 (M+H) + Preparation 11 The following compounds were obtained according to a 10 similar manner to that of Preparation 10. (1) (1R)-2-[[2-(4-Bromophenyl)ethyl]amino]-l1-(3 chlorophenyl)ethanol (+)ESI-MS (m/z): 354 (M+H) + 15 (2) tert-Butyl [2-(4-bromophenyl)ethyl] [(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]carbamate (+)ESI-MS (m/z): 454 (M+H) + 20 Example 1 To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2 hydroxyethyl][2-[4-(5-formyl-2-thienyl)phenyl]ethyl] carbamate (180 mg) in acetonitrile (2 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1 ml) was added 30% 25 hydrogen peroxide solution (30 pl) and 80% sodium chlorite (67 mg) below 10oC. The reaction mixture was stirred at 50C0 for 3 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 5-[4 30 [2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl]amino]ethyl]phenyl]-2-thiophenecarboxylic acid (160 mg). (-)ESI-MS (m/z): 500 (M-H) 35 Example 2 WO 2004/002939 PCT/JP2003/008061 24 The following compounds were obtained according to a similar manner to that of Example 4. (1) 5-[4-[2-[ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] 5 amino]ethyl]phenyl] -2-thiophenecarboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 3.00-3.25 (6H, m), 4.95-4.99 (1H, m), 6.34 (1H, br), 7.33-7.47 (6H, m), 7.55 (IH, d, J=3.9Hz), 7.70-7.81 (3H, m), 9.05 (IH, br) 10 (-)ESI-MS (m/z): 400 (M-HC1-H) (2) [4-[[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethyl]phenyl] amino]phenoxy]acetic acid hydrochloride 15 NMR (DMSO-d 6 , S): 2.84-3.30 (6H, m), 4.39 (1H, br), 4.59 (2H, s), 4.97-5.03 (1H, m), 6.37 (1H, br), 6.80-7.07 (8H, m), 7.34-7.48 (4H, m), 8.85 (1H, br), 9.11 (1H, br) (-)ESI-MS (m/z): 439 (M-HC1-H) 20 (3) [4-[[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyll amino]ethyl]phenyl] (methyl)amino]phenoxy]acetic acid hydrochloride NMR (DMSO-d 6 , 5): 2.85-3.23 (6H, m), 3.17 (3H, s), 25 3.89-4.15 (1H, br), 4.65 (2H, s), 4.98-5.02 (1H, m), 6.68-7.08 (8H, m), 7.34-7.46 (4H, m), 8.86 (1H, br), 9.14 (1H, br) (-)ESI-MS (m/z): 453 (M-HCl-H) 30 (4) [4-[[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino] ethyl]phenyl]thio]phenoxy]acetic acid hydrochloride NMR (DMSO-d 6 , 5): 2.94-3.33 (6H, m), 4.70 (2H, s), 4.97-5.01 (IH, m), 6.34 (IH, br), 6.96 (2H, d, 35 J=8.7Hz), 7.02-7.23 (4H, m), 7.33-7.45 (6H, m), WO2004/002939 PCT/JP2003/008061 25 8.97-9.18 (IH, br) (-)ESI-MS (m/z): 456 (M-HC1-H) Example 3 5 To a solution of tert-butyl [2-[4-[4-[[tert butyl(dimethyl)silyl]oxy]phenoxy]phenyl]ethyl] [(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]carbamate (370 mg) in tetrahydrofuran (4.0 ml) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (1.2 ml), and the mixture was 10 stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a phenol product. To a solution of the product and 15 potassium carbonate (94 mg) in N,N-dimethylformamide (4.0 ml) was added tert-butyl bromoacetate (133 mg), and the mixture was stirred at room temperature for 5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, 20 dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert butyl [4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]lamino]ethyl]phenoxy]phenoxy] 25 acetate (360 mg). (-)ESI-MS (m/z): 597 (M-H) Example 4 A solution of tert-butyl [4-[4-[2-[(tert 30 butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] amino]ethyl]phenoxy]phenoxy]acetate (305 mg) and 4N hydrochloride in 1,4-dioxane (5.0 ml) was stirred at room temperature for 24 hours. The resulting solid was collected by filtration and dried to give [4-[4-[2-[[(2R)-2-(3 35 chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]phenoxy]- WO 2004/002939 PCT/JP2003/008061 26 acetic acid hydrochloride (220 mg) as a white solid. NMR (DMSO-d 6 , 6) : 2.95-3.33 (6H, m), 4.65 (2H, s), 4.99-5.04 (1H, m), 6.35 (1H, br),' 6.83-7.00 (6H, m), 7.23 (9H, d, J=8.5Hz), 7.39-7.47 (4H, m), 5 8.98-9.12 (1H, br) (+)ESI-MS (m/z): 442 (M-HC1+H) + Example 5 To a suspension of tert-butyl [(2R)-2-(3-chlorophenyl) 10 2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (550 mg), (4-methoxycarbonylphenyl)boronic acid (300 mg), O triethylamine (1.0 ml) and powdered 4Amolecular sieves (600 mg) in dichloromethane (8 ml) was added copper(II) acetate (255 mg), and the mixture was stirred at room temperature 15 for 18 hours under ambient atmosphere. The resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 20 chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]benzoate (185 mg). (+)ESI-MS (m/z): 526 (M+H) + Example 6 25 To a solution of methyl 4-[4-[2-[(tert butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl]amino]ethyl]phenoxy]benzoate (183 mg) in ethanol (1.2 ml) was added 1N aqueous sodium hydroxide solution (0.6 ml), and the mixture was stirred at 40 0 C for 3 30 hours. The solvent was removed by evaporation, and the aqueous solution was acidified with 1N aqueous hydrochloride solution and extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated under reduced 35 pressure to give a benzoic acid product. To a solution of WO 2004/002939 PCT/JP2003/008061 27 the product in tetrahydrofuran (2.0 ml) was added 4N hydrochloride in 1,4-dioxane (1.0 ml), and the mixture was stirred at room temperature for 12 hours. The resulting solid was collected by filtration and dried to give 4-[4-[2 5 [[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl] phenoxy]benzoic acid hydrochloride (127 mg). hNMR (DMSO-d 6 , 5): 3.00-3.28 (6H, m), 4.99-5.04 (1H, m), 6.35 (IH, br), 6.97-7.12 (4H, m), 7.32-7.48 (6H, m), 7.90-7.98 (2H, m), 9.03-9.35 (1H, br) 10 (-)ESI-MS (m/z): 410 (M-HCl-H) Example 7 To a solution of tert-butyl [2-(4-bromophenyl)ethyl] [(2R)-2-( 3 -chlorophenyl)-2-hydroxyethyl]carbamate (400 mg) 15 in 1,2-dimethoxyethane (6 ml) was added (4-methoxycarbonyl 2-methylphenyl)boronic acid (171 mg), tetrakis(triphenylphosphine)palladium (55 mg) and aqueous solution of sodium carbonate (2M, 0.92 ml), and the mixture was stirred at 800C for 2 hours under nitrogen. The mixture 20 was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4'-[2-[(tert 25 butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] amino]ethyl]-2-methyl-l,l'-biphenyl-4-carboxylate (320 mg). (+)ESI-MS (m/z): 524 (M+H) + Example 8 30 The following compounds were obtained according to a similar manner to that of Example 6. (1) 5-Chloro-6-[4-[2-[[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl]amino]ethyl]phenoxy]nicotinic acid 35 hydrochloride WO 2004/002939 PCT/JP2003/008061 28 NMR (DMSO-d 6 , 5): 3.04-3.32 (6H, m), 5.03-5.07 (1H, m), 5.14 (1H, br), 7.18 (2H, d, J=8.5Hz), 7.33-7.48 (6H, m), 8.38 (1H, d, J=2.0Hz), 8.54 (1H, d, J=2.0Hz), 9.00 (1H, br), 9.35 (1H, br) 5 (-)ESI-MS (m/z): 445 (M-HC1-H) (2) 4'-[2-[[( 2

R)-

2 -(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]- 2 -methyl-1,1'-biphenyl-4-carboxylic acid hydrochloride 10 NMR (DMSO-d 6 , 5): 2.28 (1H, s), 3.01-3.27 (6H, m), 5.00-5.04 (1H, m), 6.36 (1H, br), 7.28-7.48 (9H, m), 7.79-7.90 (2H, m), 9.02 (IH, br) (-)ESI-MS (m/z): 408 (M-HC1-H) 15 Example 9 To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2 hydroxyethyl] [2-(4-hydroxyphenyl)ethyl]carbamate (600 mg) and potassium carbonate (254 mg) in dimethylsulfoxide (6.0 ml) was added methyl 5, 6 -dichloro-3-pyridinecarboxylate (347 20 mg), and the mixture was stirred at room temperature for 12 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column 25 chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl) -2-hydroxyethyl] amino]ethyl]phenoxy] -5 chloronicotinate (770 mg). (+)ESI-MS (m/z) : 561 (M+H) + 30 Example 10 Under nitrogen at 5 0 C, to a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4 hydroxyphenyl)ethyl]carbamate (1.5 g), ethyl [3 35 (hydroxymethyl)phenoxy]acetate (885 mg) and triphenyl WO 2004/002939 PCT/JP2003/008061 29 phosphine (1.1 g) in tetrahydrofuran (30 ml) was added diethyl azodicarboxylate (0.66 ml). The mixture was stirred at room temperature for 12 hours and evaporated under reduced pressure. The residue was purified by column 5 chromatography on silica gel (hexane/ethyl acetate = 2/1) to give ethyl [3-[[4-[2-[(tert-butoxycarbonyl) [ (2R)-2-(3 chlorophenyl) -2-hydroxyethyl] amino]ethyl]phenoxy]methyl] phenoxy]acetate (1.04 g). (+)ESI-MS (m/z): 585 (M+H) + 10 Example 11 To a solution of ethyl [3-[[4-[2-[(tert butoxycarbonyl)[(2R)-2-( 3 -chlorophenyl)-2-hydroxyethyl] amino]ethyl]phenoxy]methyl]phenoxy]acetate (1.0 g) in 15 tetrahydrofuran (5.0 ml) was added 4N hydrochloride in dioxane (4.3 ml). The mixture was stirred at room temperature for 8 hours and evaporated under reduced pressure. The residue was diluted with ethyl acetate and saturated sodium bicarbonate solution. The organic layer 20 was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol/chloroform = 1/20) to give ethyl [3-[[4-[2-[[(2R) 2-(3-chlorophenyl)-2-hydroxyethyl] amino] ethyl]phenoxy] 25 methyl]lphenoxy]lacetate (632 mg). (+)ESI-MS (m/z): 484 (M+H) + The object compound above was hydrolyzed in a conventional manner to give sodium [3-[[4-[2-[[(2R)-2-(3 30 chlorophenyl)-2-hydroxyethyl] amino]ethyl]phenoxy]methyl] phenoxy]acetate (492 mg). NMR (DMSO-d 6 , 6): 2.56-2.73 (6H, m), 4.09 (2H, s), 4.58-4.64 (1H, m), 4.98 (2H, s), 6.72-6.77 (1H, m), 6.85-6.91 (4H, m), 7.08 (2H, d, J=8.5Hz), 7.17 35 7.26 (4H, m), 7.38 (IH, s) WO 2004/002939 PCT/JP2003/008061 30 (-)ESI-MS (m/z) : 454 (M-Na-H) Example 12 The following compounds were obtained according to a 5 similar manner to that of Example 3. (1) tert-Butyl [ 4

-[[

4 -[2-[(tert-butoxycarbonyl) [ (2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino] ethyl]phenyl] amino] phenoxy] acetate 10 (+)ESI-MS (m/z): 597 (M+H) + (2) tert-Butyl [4-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]ethyl]phenyl] (methyl)amino]phenoxy] acetate 15 (+)ESI-MS (m/z): 611 (M+H) + Example 13 To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2 hydroxyethyl][2-[4- [ (4-hydroxyphenyl)thio]phenyl]ethyl] 20 carbamate (195 mg) and potassium carbonate (59 mg) in N,N dimethylformamide (3 ml) was added tert-butyl bromoacetate (84 mg), and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with 25 water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give tert-butyl [4-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino] ethyl]phenyl] thio] 30 phenoxy]acetate (168 mg). (+)ESI-MS (m/z): 636 (M+Na) + Preparation 12 To a solution of 4 -bromo-2-fluorobenzoate (1.5 g) in 35 N,N-dimethylformamide (30 ml) was added bis(pinacolato)- WO 2004/002939 PCT/JP2003/008061 31 diboron (1.8 g), 1,1'-bis(diphenylphosphino)ferrocene palladium(II)dichloridedichloromethane complex (1:1) (263 mg) and potassium acetate (1.9 g), and the mixture was stirred at 1000C for 18 hours under nitrogen. The mixture 5 was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 5/1) to give methyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2 10 dioxaborolan-2-yl)benzoate (350 mg). (+)ESI-MS (m/z): 303 (M+Na) + Preparation 13 To a solution of methyl 4-bromo-2-methoxybenzoate (2.0 15 g) in 1,4-dioxane (40 ml) was added bis(pinacolato)diboron (2.07 g), dichlorobis(triphenylphosphine)palladium(II) (286 mg) and potassium acetate (2.4 g), and the mixture was stirred at 950C for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer 20 was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give methyl 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2 dioxaborolan-2-yl)benzoate (2.0 g). 25 (+)ESI-MS (m/z): 293 (M+H) + Preparation 14 To a suspension of methyl 2-methoxy-4-(4,4,5,5 tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (2.0 g) in 30 acetone (70 ml) and water (70 ml) was added ammonium acetate (1.11 g) and sodium periodate (3.08 g), and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated and the residue was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, 35 dried over magnesium sulfate and evaporated under reduced WO 2004/002939 PCT/JP2003/008061 32 pressure to give [3-methoxy-4-(methoxycarbonyl)phenyl] boronic acid (1.4 g). (+)ESI-MS (m/z): 209 (M-H) 5 Preparation 15 The following compounds were obtained according to a similar manner to that of Preparation 14. (1) [3-Fluoro-4-(methoxycarbonyl)phenyl]boronic acid 10 (+)ESI-MS (m/z): 197 (M-H) (2) [2-Chloro-4-(methoxycarbonyl)phenyl]boronic acid (+)ESI-MS (m/z): 213 (M-H) 15 (3) [4-(Ethoxycarbonyl)-2-methoxyphenyl]boronic acid (+)ESI-MS (m/z): 223 (M-H) Preparation 16 To a solution of ethyl 3-methoxy-4-[[(trifluoromethyl) 20 sulfonyl]oxy]benzoate (1.52 g) in 1,4-dioxane (35 ml) was added bis(pinacolato)diboron (1.18 g), 1,l'-bis(diphenyl phosphino)ferrocene-palladium(II)dichloridedichloromethane complex (1:1) (309 mg) and potassium acetate (1.36 g), and the mixture was stirred at 1000C for 10 hours under nitrogen. 25 The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 5/1) to give ethyl 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2 30 dioxaborolan-2-yl)benzoate (700 mg). (+)ESI-MS (m/z): 293 (M+H) + Preparation 17 The following compound was obtained according to a 35 similar manner to that of Preparation 16.

WO 2004/002939 PCT/JP2003/008061 33 Methyl 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)benzoate (+)ESI-MS (m/z): 297 (M+H) + 5 Preparation 18 To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2 hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (5.0 g) and 2,6-lutidine (2.97 ml) in dichloromethane (75 ml) was added 10 trifluoromethanesulfonic anhydride (2.36 ml) dropwise at -70 0 C under nitrogen and the mixture was stirred at -70 0 C for 30 minutes. The mixture was allowed to warm to room temperature and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. 15 The organic layer was separated, washed with saturated sodium biscarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give 4-[2-[(tert 20 butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] amino]ethyl]phenyl trifluoromethanesulfonate (6.6 g). (+)ESI-MS (m/z): 546 (M+Na) + Preparation 19 25 To a solution of methyl 4-bromo-2-methylbenzoate (6.9 g) in 1,4-dioxane (150 ml) was added bis(pinacolato)diboron (8.03 g), dichlorobis(triphenylphosphine)palladium(II) (1.69 g) and potassium acetate (8.87 g), and the mixture was stirred at 95 0 C for 2 hours under nitrogen. The mixture was 30 diluted with ethyl acetate and water. The organic layer was separated, washed with IN hydrochloric acid and brine, dried over magnesium sulfate and evaporated. To a suspension of the crude product (11 g) in acetone (200 ml) and water (200 ml) was added ammonium acetate (5.1 g) and sodium periodate 35 (14.1 g), and the mixture was stirred at room temperature WO 2004/002939 PCT/JP2003/008061 34 for 6 hours. The solvent was evaporated, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The 5 resultant solid was triturated with diisopropyl ether to give [3-methyl-4-(methoxycarbonyl)phenyl]boronic acid (2.65 g). (+)ESI-MS (m/z): 193 (M-H) 10 Preparation 20 To a solution of 4-hydroxy-2,3-dimethylbenzaldehyde (1.9 g) and pyridine (5.12 ml) in dichloromethane (40 ml) was added trifluoromethanesulfonic anhydride (2.34 ml) under nitrogen and the mixture was stirred at room temperature for 15 30 minutes and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 4 20 formyl-2,3-dimethylphenyl trifluoromethanesulfonate (2.7 g). (+)ESI-MS (m/z): 281 (M-H) Preparation 21 To a solution of 4-formyl-2,3-dimethylphenyl 25 trifluoromethanesulfonate (2.5 g) in 1,4-dioxane (50 ml) was added bis(pinacolato)diboron (2.47 g), l,l'-bis(diphenyl phosphino)ferrocene-palladium(II)dichloridedichloromethane complex (1:1) (1.09 g) and potassium acetate (2.61 g), and the mixture was stirred at 90 0 C for 5 hours under nitrogen. 30 The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with IN hydrochloric acid and brine, dried over magnesium sulfate and evaporated. To a suspension of the crude product in acetone (80 ml) and water (80 ml) was added ammonium acetate (1.4 g) and sodium 35 periodate (3.95 g), and the mixture was stirred at room WO2004/002939 PCT/JP2003/008061 35 temperature for 6 hours. The solvent was evaporated, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. 5 The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1/1) to give (4-formyl-2,3 dimethylphenyl)boronic acid (560 mg). (+)ESI-MS (m/z): 177 (M-H) 10 Preparation 22 To a solution of N-benzyl-N-[2-(4-bromophenyl)ethyl] carbamate (1.3 g) in 1,2-dimethoxyethane (20 ml) was added [4-(methoxycarbonyl)-2-methylphenyl]boronic acid (792 mg), tetrakis(triphenylphosphine)palladium (360 mg) and aqueous 15 solution of sodium carbonate (2M, 4.1 ml), and the mixture was stirred at 80 0 C for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue 20 was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give methyl 4'-[2 [[(benzyloxy)carbonyl]amino]ethyl]-2-methyl-l,1'-biphenyl-4 carboxylate (660 mg). (+)ESI-MS (m/z): 426 (M+Na) + 25 Preparation 23 To a solution of 2

,

2

,

2 -trifluoro-N-[3-(4-iodophenyl) propyllacetamide (2.5 g) in 1,2-dimethoxyethane (15 ml) was added [ 4 -(methoxycarbonyl)phenyl]boronic acid (1.51 g), 30 tetrakis(triphenylphosphine)palladium (809 mg) and aqueous solution of sodium carbonate (2M, 7 ml), and the mixture was stirred at 75°C for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium 35 sulfate and evaporated. The residue was purified by column WO2004/002939 PCT/JP2003/008061 36 chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4'-[3-[(trifluoroacetyl)amino]propyl]-l,l' biphenyl-4-carboxylate (920 mg). MS (m/z): 366 (M+H) 5 Preparation 24 The following compound was obtained according to a similar manner to that of Preparation 23. 10 Ethyl 4'-[2-[[(benzyloxy)carbonyl]amino]ethyl]-2 methoxy-l,1'-biphenyl-4-carboxylate MS (m/z): 434 (M+H) Preparation 25 15 A mixture of methyl 4'-[3-[(trifluoroacetyl)amino] propyl]-l,l'-biphenyl-4-carboxylate (920 mg), 4N hydrochloride in ethanol (2 ml) and ethanol (2 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The residue was diluted with ethyl acetate and saturated 20 aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (chloroform:methanol = 100:1) to give ethyl 4'-(3-aminopropyl)-1,1'-biphenyl-4-carboxylate 25 (200 mg) as a colorless foam. MS (m/z) : 284 (M+H) Preparation 26 To a solution of ethyl (1R)-l-(6-chloro-3-pyridyl)-2 30 [[ 3 -(4-iodophenyl)propyl]amino]ethanol (2.0 g) in tetrahydrofuran (3.5 ml) was added di-tert-butyl dicarbonate (53 mg), and the mixture was stirred at room temperature for 2 hours. The mixture was evaporated. The residue was purified by column chromatography on silica gel 35 (hexane/ethyl acetate = 2/1) to give tert-butyl [(2R)-2-(6- WO 2004/002939 PCT/JP2003/008061 37 chloro-3-pyridyl)-2-hydroxyethyl] [3-(4-iodophenyl)propyl] carbamate (2.62 g). MS (m/z): 517 (M+H) 5 Preparation 27 To a solution of 2,2,2-trifluoro-N-[(1R)-2-(4 iodophenyl)-l-methylethyl]acetamide in dioxane (10 ml) was added 1N sodium hydroxide (12 ml) and the mixture was stirred for 1 hour at room temperature. The mixture was 10 diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to give [(1R)-2-(4-iodophenyl)-l methylethyl]amine (2.34 g) as a yellow oil. MS (m/z): 262 (M+H) 15 Preparation 28 A solution of [(1R)-2-(4-iodophenyl)-1-methylethyl] amine (1.0 g) and 2-chloro-5-[(2R)-2-oxiranyl]pyridine (298 mg) in ethanol (10 ml) was refluxed for 18 hours. The 20 mixture was evaporated in vacuo. To the residue was added di-tert-butyl dicarbonate (418 mg) and tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 2 hours and then evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 25 1/1) to give tert-butyl [(2R)-2-(6-chloro-3-pyridyl)-2 hydroxyethyl] [ (1R)-2-(4-iodophenyl)-l-methylethyl]carbamate (700 rag). MS (m/z'): 517 (M+H) 30 Preparation 29 The following compound was obtained according to a similar manner to that of Preparation 28. tert-Butyl [(2R)-2-(6-chloro-3-pyridyl)-2 35 hydroxyethyl] [2-(4-hydroxyphenyl)ethyl]carbamate WO 2004/002939 PCT/JP2003/008061 38 MS (m/z): 393 (M+H) Preparation 30 Under nitrogen at -60 0 C, to a solution of tert-butyl 5 [2-(4-hydroxyphenyl)ethl][(2R)-2-hydroxy-2-(3-pyridyl) ethyl]carbamate (570 mg) and 2,6-lutidine (0.22 ml) in dichloromethane (10 ml) was added trifluoromethanesulfonic anhydride (0.28 ml), and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was poured 10 into aqueous ammonia and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 15 The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1:1) to give 4-[2-[(tert butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino] ethyl]phenyl trifluoromethanesulfonate (640 mg) as a colorless foam. 20 MS (m/z): 491 (M+H) Preparation 31 The following compound was obtained according to a similar manner to that of Preparation 30. 25 4-[2-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3 chlorophenyl)ethyl]amino]propyl]phenyl trifluoromethanesulfonate MS (m/z): 538 (M+H) 30 Preparation 32 To a solution of 2,2,2-trifluoro-N-[(iR)-l-methyl-2 phenylethyl]acetamide (3.75 g) in acetic acid (32 ml) water (6.5 ml) - sulfuric acid (0.97 ml) were added iodine 35 (1.65 g) and periodic acid dihydrate (740 mg) at room WO 2004/002939 PCT/JP2003/008061 39 temperature, and the mixture was heated to 60 - 80 0 C for 5 hours. After being allowed to cool to room temperature, the mixture was partitioned between hexane/ethyl acetate and water. The organic layer was separated, washed successively 5 with water, sodium sulfite solution, water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was recrystallized from diisopropyl ether (44 ml) to give 2,2,2-trifluoro-N-[(1R)-2 (4-iodophenyl)-l-methylethyl]acetamide (2.15 g) as a 10 colorless needle. NMR (CDCl 3 , 5): 1.21 (3H, d, J=7Hz), 2.74 (1H, dd, J=14, 7Hz), 2.85 (1H, dd, J=14, 6Hz), 4.26 (IH, m), 6.04 (1H, br s), 6.92 (2H, d, J=8Hz)., 7.65 (2H, d, J=S8Hz) 15 (+)ESI-MS (m/z): 380 (M+Na) + Preparation 33 The following compound was obtained according to a similar manner to that of Preparation 32. 20 2,2,2-Trifluoro-N-[3-(4-iodophenyl)propyl]acetamide NMR (CDCl 3 , 5): 1.90 (2H, quintet, J=7Hz), 2.62 (2H, t, J=7Hz), 3.38 (2H, q, J=7Hz), 6.26 (1H, br s), 6.93 (2H, d, J=8Hz), 7.62 (2H, d, J=8Hz) 25 (+)ESI-MS (m/z): 380 (M+Na) + Preparation 34 To a mixture of 3-(4-hydroxyphenyl)propanoic acid (15.0 g), (IR)-2-amino-l-(3-chlorophenyl)ethanol hydrochloride 30 (18.8 g), and l-hydroxybenzotriazole (14.6 g) in N,N dimethylformamide (100 ml) was added 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.0 g), and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate 35 and water. The organic layer was separated, washed WO2004/002939 PCT/JP2003/008061 40 successively with sodium bicarbonate solution and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give 5 N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-3-(4 hydroxyphenyl)propanamide (11.61 g) as a white amorphous powder. MS (m/z): 320 (M+H) 10 Preparation 35 To a solution of N-[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl]-3-(4-hydroxyphenyl)propanamide (11.61 g) in tetrahydrofuran (70 ml) was added borane-methyl sulfide complex (10M, 11.9 ml) at 0 0 C, and the mixture was heated to 15 80'C for 1 hour. After being allowed to cool to room temperature, the mixture was added 2N hydrochloric acid (20 ml) at 00C. The mixture was heated to 80 0 C for 1 hour. After being allowed to cool to room temperature, the mixture was added lN sodium hydroxide (40 ml) and di-tert-butyl 20 dicarbonate (8.72 g) and stirred for 1 hour at room temperature. The mixture was partitioned between hexane/ethyl acetate and water. The organic layer was separated, washed successively with water, sodium sulfite solution, water and brine, dried over magnesium sulfate, and 25 filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give tert-butyl [(2R)-2-(3-chlorophenyl)-2 hydroxyethyl][3-(4-hydroxyphenyl)propyl]carbamate (11.36 g) as a white powder. 30 MS (m/z) : 406 (M+H) Preparation 36 A mixture of methyl 4'-[2-[[(benzyloxy)carbonyl] amino]ethyl]-2-methyl-1,1'-biphenyl-4-carboxylate (650 mg), 35 ammonium formate (500 mg) and palladium on carbon powder WO 2004/002939 PCT/JP2003/008061 41 (400 mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 2 hours. The reaction mixture was filtrated and poured into water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and 5 evaporated to give methyl 4'-(2-aminoethyl)-2-methyl-1,l' biphenyl-4-carboxylate (380 mg). (+)ESI-MS (m/z): 270 (M+H) + Preparation 37 10 The following compounds were obtained according to a similar manner to that of Preparation 36. (1) Ethyl 4'-(2-aminoethyl)-2-methoxy-l, l'-biphenyl-4 carboxylate 15 MS (m/z): 300 (M+H) (2) tert-Butyl [2-(4-hydroxyphenyl)ethyl] [(2R)-2-hydroxy-2 (3-pyridyl) ethyl] carbamtate MS (m/z): 359 (M+H) 20 Preparation 38 The following compound was obtained according to a similar manner to that of Example 14. 25 tert-Butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2 (4'-formyl-2',3'-dimethyl-l,1'-biphenyl-4-yl)ethyl]carbamate (+)ESI-MS (m/z): 530 (M+Na)+ Example 14 30 To a solution of tert-butyl [2-(4-bromophenyl)ethyl] [(2R)-2-( 3 -chlorophenyl)-2-hydroxyethyl]carbamate (365 mg) in 1,2-dimethoxyethane (6 ml) was added [4-(ethoxycarbonyl) 2-methoxyphenyl]boronic acid (216 mg), tetrakis(triphenylphosphine)palladium (46 mg) and aqueous 35 solution of sodium carbonate (2M, 0.85 ml), and the mixture WO 2004/002939 PCT/JP2003/008061 42 was stirred at 80 0 C for 4 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue 5 was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give ethyl 4'-[2-[(tert butoxycarbonyl) [( 2 R)-2-(3-chlorophenyl)-2-hydroxyethyl] amino]lethyl]-2-methoxy-1,1'-biphenyl-4-carboxylate (222 mg). MS (m/z): 554 (M+H) + 10 Example 15 The following compounds were obtained according to a similar manner to that of Example 14. 15 (1) 4'- [ (2R)-2- [ [(2R)-2-(3-Chlorophenyl)-2 hydroxyethyl] amino]propyl] -3-methoxy-1,1' -biphenyl-4 carboxylic acid hydrochloride NMR (DMSO-d 6 , 8): 1.14 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m), 3.92 (3H, s), 5.0-5.3 (1H, m), 6.3-6.4 (IH, m), 20 7.2-7.8 (10H, m), 8.13 (1H, br s), 8.85 (1H, br s), 9.42 (1H, br s) MS (m/z): 440 (M+H) (2) 4'-[ (2R)-2-[ [( 2

R)-

2 -(3-Chlorophenyl)-2-hydroxyethyl] 25 amino]propyl]-2-methoxy-l,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , ) : 1.17 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m), 3.83 (3H, s), 5.0-5.2 (1H, m), 6.3-6.4 (1H, m), 7.2-7.8 (10H, m), 8.11 (1H, br s), 8.86 (1H, br s), 30 9.37 (1H, br s) MS (m/z): 440 (M+H) (3) 4'-[ (2R)-2-[ [( 2

R)-

2

-(

3 -Chlorophenyl)-2-hydroxyethyl] amino]propyl]-2-methyl-1,1'-biphenyl-4-carboxylic acid 35 hydrochloride WO 2004/002939 PCT/JP2003/008061 43 MAR (DMSO-d 6 , 5): 1.17 (3H, d, J=6.4Hz), 2.28 (3H, s), 2.8-3.8 (5H, m), 5.0-5.3 (1H, M), 6.3-6.4 (1H, m), 7.2-7.6 (8H, m), 7.7-7.9 (2H, m), 8.11 (1H, br s), 8.86 (1H, br s), 9.39 (1H, br s) 5 MS (m/z): 424 (M+H) (4) 4'-[(2R)-2-[[(2S)-2-(3-Chlorophenyl)-2-hydroxyethyll amino]propyl]-3-methoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride 10 MR (DMSO-d 6 , 5): 1.16 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m), 3.91 (3H, s), 5.0-5.3 (1H, nm), 6.3-6.4 (1H, m), 7.2-7.8 (11H, m), 8.77 (1H, br s), 9.13 (1H, br s) MS (m/z): 440 (M+H) 15 (5) 4'-[(2R)-2-[[(2R)-2-Phenyl-2-hydroxyethyl]amino] propyl]-3-methoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.15 (3H, d, J=6.4Hz), 2.8-3.8 (5H, 20 m), 3.92 (3H, s), 5.0-5.2 (1H, m), 6.3-6.4 (IH, mn), 7.2-7.6 (9H, m), 7.7-7.9 (3H, m), 8.81 (1H, br s), 9.31 (1H, br s) MS (m/z): 406 (M+H) 25 (6) 4'-[(2R)-2-[ [(2R)-2-Phenyl-2-hydroxyethyl]amino] propyl]-2-methyl-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.17 (3H, d, J=6.4Hz), 2.28 (3H, s), 2.8-3.8 (5H, m), 5.0-5.2 (IH, m), 6.3-6.4 (1H, m), 30 7.2-7.6 (9H, m), 7.7-7.9 (3H, m), 8.81 (1H, br s), 9.24 (1H, br s) MS (m/z) : 390 (M+H) (7) 4'-[(2R)-2-[[(2S)-2-Phenyl-2-hydroxyethylamino] 35 propyl] -2-methyl-1, 1' -biphenyl-4-carboxylic acid WO 2004/002939 PCT/JP2003/008061 44 hydrochloride NMR (DMSO-d 6 , ) : 1.19 (3H, d, J=6.4Hz), 2.27 (3H, s), 2.8-3.8 (5H, m), 5.0-5.2 (1H, m), 6.2-6.3 (1H, m), 7.2-7.6 (9H, min), 7.7-7.9 (3H, m), 8.80 (1I, br s), 5 9.35 (IH, br s) MS (m/z): 390 (M+H) (8) 4'-[(2R)-2- l(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]propyl] -3-isopropyloxy-1,1'-biphenyl-4-carboxylic 10 acid hydrochloride NMR (DMSO-d 6 , a): 1.14 (3H, d, J=6.4Hz), 1.30 (6H, d, J=5.8Hz), 2.8-3.8 (5H, m), 4.6-4.9 (1H, m), 5.0 5.3 (IH, m), 6.2-6.4 (IH, m), 7.2-7.8 (11H, m), 8.82 (1H, br s), 9.,24 (1H, br s) 15 MS (m/z): 468 (M+H) (9) 4'-[ (2R)-2-[[ (2R)-2-Phenyl-2-hydroxyethyl]amino] propyl]-3-isopropyloxy-1,1'-biphenyl-4-carboxylic acid hydrochloride 20 NMR (DMSO-d 6 , a): 1.12 (3H, d, J=6.4Hz), 1.30 (6H, d, J=5.8Hz), 2.8-3.8 (5H, m), 4.6-4.9 (1H, m), 5.0 5.3 (IH, m), 6.2-6.4 (1H, m), 7.2-7.8 (12H, m), 8.82 (IH, br s) MS (m/z): 434 (M+H) 25 (10) 4'-[(2R)-2-[ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]propyl] -3-cyclohexyloxy-1,1'-biphenyl-4 carboxylic acid hydrochloride NMR (DMSO-d 6 , 8): 1.14 (3H, d, J=6.4Hz), 1.2-2.0 (10H, 30 m), 2.8-3.8 (5H, m), 4.65 (1H, m), 5.0-5.2 (IH, m), 6.3-6.4 (1H, m), 7.2-7.9 (11H, m), 8.79 (1H, br s), 9.10 (1H, br s) MS (m/z): 508 (M+H) 35 (11) 4'-L(2R)-2-[[(2R)-2-Phenyl-2-hydroxyethyllamino]- WO 2004/002939 PCT/JP2003/008061 45 propyll]-3-cyclohexyloxy-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 6): 1.14 (3H, d, J=6.4Hz), 1.2-2.0 (10H, m), 2.8-3.8 (5H, m), 4.65 (1H, m), 4.9-5.1 (1H, m), 5 6.23 (IH, m), 7.1-7.9 (12H, inm) MS (m/z): 474 (M+H) (12) Methyl 4'-[2-[ (tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]ethyl] -3-methoxy 10 1,1'-biphenyl-4-carboxylate (+)ESI-MS (m/z): 562 (M+Na) + (13) Methyl 4'-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]ethyl]-2-chloro 15 1,1'-biphenyl-4-carboxylate (+)ESI-MS (m/z): 544 (M+H) + Example 16 To a solution of 4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 20 chlorophenyl)-2-hydroxyethyl] amino]ethyl]phenyl trifluoromethanesulfonate (300 mg) in 1,2-dimethoxyethane (5 ml) was added [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (125 mg), tetrakis(triphenylphosphine)palladium (53 mg) and aqueous solution of sodium carbonate (2M, 0.6 ml), and 25 the mixture was stirred at 80 0 C for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica 30 gel (hexane/ethyl acetate = 3/1) to give methyl 4'-[2 [(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl] amino]ethyl]-3-fluoro-l, 1'-biphenyl-4 carboxylate (230 mg). (+)ESI-MS (m/z): 528 (M+H) + 35 WO2004/002939 PCT/JP2003/008061 46 Example 17 The following compound was obtained according to a similar manner to that of Example 16. 5 Methyl 4'-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-methyl-1,1' biphenyl-4-carboxylate (+)ESI-MS (m/z): 546 (M+Na) + 10 Example 18 To a solution of ethyl 4'-[2-[(tert-butoxycarbonyl) [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2 methoxy-l,l'-biphenyl-4-carboxylate (220 mg) in ethanol (2.0 ml) was added 1N aqueous sodium hydroxide solution (1.2 ml), 15 and the mixture was stirred at 40 0 C for 3 hours. The solvent was removed by evaporation, and the aqueous solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with water and brine, dried over magnesium sulfate 20 and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in tetrahydrofuran (1.5 ml) was added 4N hydrochloride in dioxane (1.0 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to 25 give 4'-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino] ethyl]-2-methoxy-l,1'-biphenyl-4-carboxylic acid hydrochloride (83 mg). NMR (DMSO-d 6 , 6): 3.02-3.27 (6H, m), 3.82 (3H, s), 4.98-5.02 (1H, m), 6.35 (IH, br), 7.30-7.64 (11H, 30 m), 9.05 (1H, br) (-)ESI-MS (m/z): 424 (M-HC1-H) Example 19 The following compounds were obtained according to a 35 similar manner to that of Example 18.

WO 2004/002939 PCT/JP2003/008061 47 (1) 4'-[2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-3-methoxy-1, 1'-biphenyl-4-carboxylic acid hydrochloride 5 NMR (DMSO-d 6 , 6): 3.01-3.34 (6H, m), 3.92 (3H, s), 5.02-5.06 (IH, m), 6.37 (1H, br), 7.26-7.48 (9H, m), 7.74 (2H, d, J=7.9Hz), 9.25 (1H, br) (-)ESI-MS (m/z): 424 (M-HC1-H) 10 (2) 2-Chloro-4'-[2-[[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl] amino ] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 6): 3.01-3.34 (6H, m), 4.99-5.03 (1H, m), 6.36 (1H, br), 7.37-7.55 (9H, nm), 7.93-8.03 (2H, 15 m), 9.10 (1H, br) (-)ESI-MS (m/z): 424 (M-HCI-H) (3) 4'-[2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-3-fluoro-1,1'-biphenyl-4-carboxylic acid 20 hydrochloride NMR (DMSO-d 6 , 6): 3.01-3.33 (6H, m), 4.98-5.03 (1H, m), 6.34 (1H, br), 7.35-7.47 (6H, nm), 7.61-7.98 (SH, m), 9.10 (IH, br) (-)ESI-MS (m/z): 412 (M-HC1-H) 25 (4) 4'-[2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl] -3-methyl-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 2.60 (3H, s), 3.01-3.34 (6H, m), 30 4.98-5.02 (IH, m), 6.34 (1H, br), 7.36-7.60 (8H, m), 7.72 (2H, d, J=8.0Hz), 7.91 (IH, d, J=8.0Hz), 9.25 (1H, br) (-)ESI-MS (m/z) : 408 (M-HC1-H) 35 Example 20 WO 2004/002939 PCT/JP2003/008061 48 To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2 hydroxyethyl][2-(4'-formyl-2',3'-dimethyl-l,l'-biphenyl-4 yl)ethyl]carbamate in acetonitrile (2.5 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1.3 ml) was added 30% 5 hydrogen peroxide solution (60 4l).and 80% sodium chlorite (128 mg) below 10 0 C. The reaction mixture was stirred at 40 0 C for 1.5 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a 10 benzoic acid product. To a solution of the product in tetrahydrofuran (1.0 ml) was added 4N hydrochloride in dioxane (1.18 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4'-[2-[[(2R)-2-(3 15 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2,3-dimethyl-l,1' biphenyl-4-carboxylic acid hydrochloride (140 mg). NMR (DMSO-d 6 , 6): 2.14 (3H, s), 2.45 (3H, s), 3.00-3.34 (6H, m), 4.99-5.03 (1H, m), 6.34 (IH, br), 7.07 (IH, d, J=8.0Hz), 7.05-7.59 (9H, m), 9.25 (IH, br) 20 (-)ESI-MS (m/z): 422 (M-HC1-H) Example 21 A solution of ethyl 4'-(3-aminopropyl)-1,1'-biphenyl-4 carboxylate (200 mg), and 2-chloro-5-[(2R)-2-oxiranyl] 25 pyridine (71.5 mg) in ethanol (10 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 100:1) to give ethyl 4'-[3-[[(2R)-2 (6-chloro-3-pyridyl)-2-hydroxyethyl]aminolpropyl-l,1 ' 30 biphenyl-4-caroxylate (96 mg) as a colorless foam. MS (m/z): 439 (M+H) Example 22 The following compounds were obtained according to a 35 similar manner to that of Example 21.

WO 2004/002939 PCT/JP2003/008061 49 (1) Methyl 4'-[2-[[(2R)-2-(6-chloro-3-pyridyl)-2 hydroxyethyl]amino]ethyl]-2-methyl-1,1'-biphenyl-4 carboxylate 5 (+)ESI-MS (m/z): 425 (M+H) + (2) Ethyl 4'-[2-[[(2R)-2-(6-chloro-3-pyridyl)-2 hydroxyethyl]amino]ethyl]-2-methoxy-l,1'-biphenyl-4 carboxylate 10 MS (m/z): 454 (M + ) Example 23 To a solution of ethyl 4 '-[3-[[(2R)-2-(6-chloro-3 pyridyl)-2-hydroxyethyl]amino]propyl]-1,1'-biphenyl-4 15 carboxylate (96 mg) in tetrahydrofuran (3.5 ml) was added di-tert-butyl dicarbonate (53 mg), and the mixture was stirred at room temperature for 30 minutes and then evaporated. To the residue were added iN sodium hydroxide solution (0.5 ml) and methanol (0.5 ml), and was stirred for 20 2 hours at room temperature. The residue was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel 25 (hexane/ethyl acetate = 1/1) to give 4 '-[3-[(tert butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl] amino]propyl]-1,1'-biphenyl-4-carboxylic acid (100 mg) as a colorless foam. MS (m/z): 512 (M+H) 30 Example 24 The following compounds were obtained according to a similar manner to that of Example 23. 35 (1) 4'-[2-[(tert-Butoxycarbonyl) [(2R)-2-(6-chloro-3- WO 2004/002939 PCT/JP2003/008061 50 pyridyl)-2-hydroxyethyl] amino] ethyl] -2-methyl-i, 1' biphenyl-4-carboxylic acid (+)ESI-MS (m/z): 509 (M-H) 5 (2) 4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-(6-chloro-3 pyridyl)-2-hydroxyethyl] amino] ethyl] -2-methoxy-1, 1' biphenyl-4-carboxylic acid MS (m/z): 527 (M+H) 10 Example 25 4'-[3-[(tert-Butoxycarbonyl)[(2R)-2-(6-chloro-3 pyridyl) -2-hydroxyethyl] amino]propyl] -1,1' -biphenyl-4 carboxylic acid (100 mg), ammonium formate (50 mg) and palladium on carbon powder (30 mg) in methanol (5 ml) and 15 water (1.0 ml) was refluxed for 30 minutes. The reaction mixture was filtrated and poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. A mixture of the residue was chromatographed (chloroform 20 methanol) over silica gel to give 4'-[3-[(tert butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino] propyl]-l,l'-biphenyl-4-carboxylic acid (90 mg) as a colorless foam. MS (m/z): 477 (M+H) 25 Example 26 The following compounds were obtained according to a similar manner to that of Example 25. 30 (1) 4'-[2-[ (tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3 pyridyl)ethyl]amino] ethyl] -2-methyl-1, 1' -biphenyl-4 carboxylic acid (+)ESI-MS (m/z): 475 (M-H) 35 (2) 4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3- WO 2004/002939 PCT/JP2003/008061 51 pyridyl)ethyl] aminol] ethyl] -2-methoxy-1,1' -biphenyl-4 carboxylic acid MS (m/z): 493 (M+H) 5 (3) 4'-[3-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3 pyridyl)ethyl]amino]propyll]-2-methoxy-1, 1' -biphenyl-4 carboxylic acid MS (m/z): 507 (M+H) 10 (4) 4'-L (2R)-2-[ (tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3 pyridyl)ethyllamino]propyl]-1,1'-biphenyl-4-carboxylic acid MS (m/z): 477 (M+H) 15 Example 27 A solution of tert-butyl 4'-[3-[(tert-butoxycarbonyl)

[(

2 R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-1,1' biphenyl-4-carboxylic acid (90 mg) and 4N hydrochloride in dioxane (5.0 ml) was stirred at room temperature for 24 20 hours. The resultant solid was collected by filtration and dried to give 4'-[3-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl] amino]propyl]-1,1l'-biphenyl-4-carboxylic acid dihydrochloride (80 mg) as a white solid. NMR (DMSO-d 6 , 5): 2.90-3.90 (8H, m), 5.10-5.20 (1H, m), 25 7.35 (1H, d, J=8Hz), 7.65-7.85 (6H, m), 8.05 (IH, d, J=8Hz), 8.25 (1H, d, J=8Hz), 8.70-8.85 (2H, inm) MS (m/z) : 377 (M+H) Example 28 30 The following compounds were obtained according to a similar manner to that of Example 27. (1) 4'-[2-[ [ (2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] ethyl] 2-methyl-1,1'-biphenyl-4-carboxylic acid 35 dihydrochloride WO 2004/002939 PCT/JP2003/008061 52 NMR (DMSO-d 6 , 5): 3.10-3.80 (6H, m), 3.90 (3H, s), 5.10-5.20 (1H, m), 7.40-7.70 (7H, m), 7.8-7.90 (1H, m), 8.25 (1H, d, J=8Hz), 8.70-8.85 (2H, m) (-)ESI-MS (m/z): 375 (M-2HC1-H) 5 (2) 4'-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino]ethyl] 2-methoxy-1,1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 5): 3.10-3.80 (6H, m), 3.90 (3H, s), 10 5.10-5.20 (IH, m), 7.40-7.70 (7H, m), 7.80-7.90 (1H, m), 8.25 (1H, d, J=8Hz), 8.70-8.85 (2H, m) MS (m/z): 393 (M+H) (3) 4'-[3-[ [(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] 15 propyl]-2-methoxy-1,1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 6) ; 2.90-3.90 (8H, m), 3.95 (3H, s), 5.10-5.20 (1H, m), 7.35 (1H, d, J=8Hz), 7.65-7.85 (6H, m), 8.05 (1H, d, J=8Hz), 8.25 (1H, d, J=8Hz), 20 8.70-8.85 (2H, m) MS (m/z): 407 (M+H) (4) 2-Chloro-4'-[2-[ [(2R)-2-hydroxy-2-(3-pyridyl)ethyl] amino]ethyl]-1,1'-biphenyl-4-carboxylic acid 25 dihydrochloride NMR (DMSO-d 6 , 5): 3.10-3.80 (6H, m), 5.10-5.20 (i1, m), 7.40-7.70 (7H, m), 7.90-8.10 (2H, m), 8.70-8.85 (2H, m) MS (m/z): 397 (M+H) 30 (5) 4'-[(2R)-2-[ [(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] propyl]-1,1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 5): 1.70 (3H, d, J=6Hz), 3.30-3.90 (6H, m), 5.10-5.20 (1H, m), 7.40-7.70 (7H, m), 7.80 35 7.90 (1H, m), 8.25 (1H, d, J=8Hz), 8.70-8.85 (2H, WO 2004/002939 PCT/JP2003/008061 53 m) MS (m/z): 377 (M+H) (6) 4'-[3-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] 5 propyl]-2-methyl-1,l'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 6): 2.00-2.15 (2H, m), 2.30 (3H, s), 2.60-3.30 (6H, m), 5.00-5.10 (IH, m), 7.20-7.60 (9H, m), 7.75-7.90 (2H, m) 10 MS (m/z): 424 (M+H) Example 29 The following compounds were obtained according to a similar manner to that of Example 23. 15 (1) Ethyl 4'-[3-[(tert-butoxycarbonyl) [ (2R)-2-(6-chloro-3 pyridyl)-2-hydroxyethyl] amino]propyl] -2-methoxy-1, 1' biphenyl-4-carboxylate MS (m/z): 569 (M+H) 20 (2) Methyl 4'-[2-[(tert-butoxycarbonyl) [ (2R)-2-hydroxy-2 (3-pyridyl)ethyll]amino]lethyl]-2-chloro-1, 1'-biphenyl-4 carboxylate MS (mr/z): 512 (M+H) 25 (3) Methy 4'-[(2R)-2-[ (tert-butoxycarbonyl)[(2R)-2-(6 chloro-3-pyridyl) -2-hydroxyethyl] aminol]propyl] -1,1' biphenyl-4-carboxylate MS (m/z): 524 (M+H) 30 (4) Methyl 4'-[3-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyll]amino]propyll]-2-methyl 1,1'-biphenyl-4-carboxylate MS (m/z): 538 (M+H) 35 WO 2004/002939 PCT/JP2003/008061 54 (5) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]aminol propyl] -3-methoxy-1,1' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 5): 1.14 (3H, d, J=6.4Hz), 2.8-3.8 (5H, 5 m), 3.92 (3H, s), 5.1-5.3 (IH, m), 7.2-7.5 (4H, m), 7.7-7.9 (4H, m), 8.2-8.4 (1H, m), 8.8-9.0 (2H, m), 9.36 (1H, br s) MS (m/z): 407 (M+H) 10 (6) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] propyl] -2-methoxy-1, 1' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 5): 1.14 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m), 3.83 (3H, s), 5.1-5.3 (1H, m), 7.2-7.8 (7H, m), 15 7.8-8.0 (1H, m), 8.2-8.5 (1H, m), 8.7-9.0 (2H, m), 9.02 (1R, br s), 9.36 (1H, br s) MS (m/z) : 407 (M+H) (7) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] 20 propyl]-2-methyl-1,1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 6): 1.19 (3H, d, J=6.4Hz), 2.48 (3H, s), 2.8-3.8 (5H, m), 5.1-5.3 (1H, m), 7.2-7.5 (5H, m), 7.8-8.0 (3H, m), 8.37 (1H, d, J=8.2Hz), 8.78 (IH, 25 d, J=4.6Hz), 8.87 (1H, s), 9.04 (IH, br s), 9.35 (IH, br s) MS (m/z) : 391 (M+H) (8) 4'-[(2R)-2-[ [(2R)-2-Hydroxy-2-(3-pyridyl)ethyllamino] 30 propyl]-3-methyl-1,1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 6): 1.19 (3H, d, J=6.4Hz), 2.60 (3H, s), 2.8-3.8 (5H, m), 5.1-5.3 (1H, m), 7.2-8.0 (8H, m), 8.37 (1H, d, J=8.2Hz), 8.79 (1H, d, J=4.6Hz), 8.87 35 (1H, s), 9.05 (1H, br s), 9.35 (1H, br s) WO 2004/002939 PCT/JP2003/008061 55 MS (r/z): 391 (M+H) (9) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] propyl]-3-isopropyloxy-1,1'-biphenyl-4-carboxylic acid 5 dihydrochloride NMR (DMSO-d 6 , 5): 1.19 (3H, d, J=6.4Hz), 1.31 (6H, d, J=6.0Hz), 2.8-3.8 (5H, m),,4.6-4.9 (1H,1m), 5.1 5.3 (1H, m), 7.2-7.5 (4H, m), 7.6-8.0 (4H, m), 8.37 (1H, d, J=8.2Hz), 8.80 (IH, d, J=4.6Hz), 8.88 10 (1H, s), 9.02 (IH, br s), 9.35 (IH, br s) MS (m/z) : 435 (M+H) (10) 4'-[(2R)-2-[[(2S)-2-Hydroxy-2-(3-pyridyl)ethylamino] propyl]-1,1'-biphenyl-4-carboxylic acid dihydrochloride 15 NMR (DMSO-d 6 , 5): 1.19 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m), 5.1-5.3 (1H, m), 7.2-8.1 (8H, m), 8.57 (1H, d, J=7.8Hz), 8.81 (IH, d, J=4.6Hz), 8.90 (1H, s), 9.10 (1H, br s), 9.56 (1H, br s) MS (m/z): 357 (M-H) 20 (11) 4'-[(2R)-2-[[(2S)-2-Hydroxy-2-(6-chloro-3-pyridyl) ethyl]amino]propyl]-1,1'-biphenyl-4-carboxylic acid dihydrochloride NIMR (DMSO-d 6 , 5): 1.17 (3H, d, J=6.4Hz), 2.8-3.8 (5H, 25 m), 5.1-5.3 (1H, m), 7.39 (2H, d, J=8.0Hz), 7.58 (1H, d, J=8.0Hz), 7.6-8.2 (7H, m), 8.48 (1H, d, J=2.4Hz), 8.86 (IH, br s), 9.22 (1H, br s) MS (m/z): 409 (M-H) 30 (12) 4 '-[(2R)-2-[[(2R)-2-Hydroxy-2-(6-chloro-3-pyridyl) ethyllamino]propyl]-1,1'-biphenyl-4-carboxylic acid dihydrochloride MR (DMSO-d 6 , 8): 1.16 (3H, d, J=6.4Hz), 2.8-3.8 (5H, mn), 5.1-5.3 (IH, m), 7.38 (2H, d, J=8.0Hz), 7.58 35 (IH, d, J=8.0Hz), 7.6-8.2 (7H, m), 8.49 (1H, d, WO 2004/002939 PCT/JP2003/008061 56 J=2.4Hz), 8.86 (1H, br s), 9.45 (IH, br s) MS (m/z): 409 (M-H) (13) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] 5 propyl]-3-cyclohexyloxy-1,1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 5): 1.15 (3H, d, J=6.4Hz), 1.2-2.0 (10H, m), 2.7-3.8 (SH, m), 4.65 (1H, m), 5.31 (1H, m), 7.2-7.5 (5H, m), 7.6-7.8 (2H, m), 7.9-8.0 (1H, m), 10 8.45 (IH, m), 8.82 (1H, d, J=2.6Hz), 8.90 (1H, s), 9.07 (1H, br s), 9.43 (1H, br s) MS (m/z) : 475 (M+H) Example 30 15 To a solution of ethyl 4'-[3-[(tert-butoxycarbonyl) [(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]lamino]propyl-2 methoxy-1,1'-biphenyl-4-carboxylate in ethanol (5.0 ml) was added 1N sodium hydroxide (1.0 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was 20 diluted with ethyl acetate and IN hydrochloric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1/1) to give 4'-[3-[(tert-butoxycarbonyl)[(2R)-2-(6 25 chloro-3-pyridyl)-2-hydroxyethyl] amino]propyl] -2-methoxy 1,l'-biphenyl-4-carboxylic acid (100 rmg). MS (m/z) : 541 (M+H) Example 31 30 The following compounds were obtained according to a similar manner to that of Example 30. (1) 4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3 pyridyl)ethyl] amino]ethyl]-2-chloro-l, 1'-biphenyl-4 35 carboxylic acid WO 2004/002939 PCT/JP2003/008061 57 MS (m/z): 497 (M+H) (2) 4'-[(2R)-2-[(tert-Butoxycarbonyl)[(2R)-2-(6-chloro-3 pyridyl) -2-hydroxyethyl ] amino] propyl] -1,1'-biphenyl-4 5 carboxylic acid MS (m/z): 511 (M+H) (3) 4'-[3- [(tert-Butoxycarbonyl) [ (2R)-2-(3-chlorophenyl)-2 hydroxyethyl] amino]propyl]-1,1'-biphenyl-4-carboxylic 10 acid MS (m/z): 524 (M+H) Preparation 39 The following compound was obtained according to a 15 similar manner to that of Preparation 34. N-L (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] -3-(3 hydroxyphenyl)propanamide MS (m/z): 320 (M+H) 20 Preparation 40 The following compound was obtained according to a similar manner to that of Preparation 35. 25 tert-Butyl N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] N-[3-(3-hydroxyphenyl)propyl] carbamate MS (m/z): 405 (M+H) Preparation 41 30 The following compounds were obtained according to a similar manner to that of Preparation 30. (1) tert-Butyl N-[ ( 2 R)-2-(3-chlorophenyl)-2-hydroxyethyl] N-[3-[3-[[(trifluoromethyl)sulfonyl]oxy]phenyl]propyl] 35 carbamate WO 2004/002939 PCT/JP2003/008061 58 MS (m/z): 537 (M+H) (2) 4-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(5-chloro-3 pyridyl)-2-hydroxyethyl] amino] ethyl]phenyl 5 trifluoromethanesulfonate MS (m/z): 525 (M+H) (3) Methyl 4-f [ (trifluoromethyl)sulfonyl]oxy]-1-naphthoate MS (m/z): 358 (M+Na) 10 (4) Methyl [4-[[(trifluoromethyl)sulfonyl]oxy]phenyl] acetate NMR (DMSO-d 6 , 5): 3.63(3H, s), 3.90(2H, s), 7.46(4H, s) 15 (5) Methyl [3-[[(trifluoromethyl)sulfonyl]oxy]phenyl] acetate NMR (DMSO-d 6 , 5): 3.63(3H, s), 3,83(2H, s), 7.30 7.60(4H, m) 20 (6) 5-Hydroxy-l-naphthyl trifluoromethanesulfonate NMR (DMSO-d 6 , 5): 6.80(2H, d, J=8Hz), 7.20(2H, t, J=8Hz), 7.50(2H, d, J=8Hz) (7) Ethyl 5-[[(trifluoromethyl)sulfonyl]oxy]--naphthoate 25 (8) 4-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-hydroxy-2 phenylethyl] amino] ethyl]lphenyl trifluoromethane sulfonate MS (m/z) : 490 (M+H) 30 (9) Methyl 4-(benzyloxy)-2-[[(trifluoromethyl)sulfonyl] oxy]benzoate MS (m/z): 413 (M+Na) 35 (10) Methyl 5-[[(trifluoromethyl)sulfonyl]oxy]-1,l'- WO 2004/002939 PCT/JP2003/008061 59 biphenyl-2-carboxylate MS (m/z): 383 (M+Na) Preparation 42 5 The following compounds were obtained according to a similar manner to that of Preparation 21. (1) 4-[2-[[(2R)-2-(5,6-Dichloro-3-pyridyl)-2 hydroxyethyl]amino]ethyl]phenol 10 MS (m/z): 327 (M+H) (2) 4-[2-[[ (2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]phenol MS (m/z): 258 (M+H) 15 Preparation 43 To a solution of 4-[2-[[(2R)-2-(5,6-dichloro-3 pyridyl)-2-hydroxyethyl]amino]ethyl]phenol (850 mg) in acetic acid (15 ml) and water (1.0 ml) were added tetramethylammonium bromide (5.2 mg) and zinc dust (509 mg), 20 and the mixture was stirred at 500C for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel 25 (hexane/ethyl acetate = 2/1) to give 4-[2-[[(2R)-2-(5 chloro-3-pyridyl)-2-hydroxyethyllamino]ethyl]phenol (500 mg) as a colorless oil. MS (m/z): 292 (M+H) 30 Preparation 44 The following compounds were obtained according to a similar manner to that of Preparation 26. (1) tert-Butyl N-[(2R)-2-(5-chloro-3-pyridyl)-2 35 hydroxyethyl]-N-[2-(4-hydroxyphenyl)ethyl]carbamate WO 2004/002939 PCT/JP2003/008061 60 MS (m/z): 393 (M+H) (2) tert-Butyl N- [ (2R)-2-hydroxy-2-phenylethyl-N-[2-(4 hydroxyphenyl)ethyl] carbamate 5 MS (m/z): 358 (M+H) Preparation 45 To a solution of benzamide (1.42 g) in tetrahydrofuran (50 ml) were added sodium hydride (611 mg) and 4 10 bromobenzenesulfonyl chloride (3.0 g), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column 15 chromatography on silica gel (hexane/ethyl acetate = 2/1) to give N-benzoyl-4-bromobenzenesulfonamide (2.1 g) as a colorless powder. NMR (CDC1 3 , 5): 7.20-8.10(8H, m) 20 Preparation 46 The following compounds were obtained according to a similar manner to that of Preparation 12. (1) 2-Phenoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 25 yl)benzaldehyde MS (m/z): 325 (M+H) (2) N-Benzoyl-4-( 4 ,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 yl)benzenesulfonamide 30 MS (m/z): 386 (M-H) (3) Methyl 2 -isobutyl-4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)benzoate MS (m/z): 319 (M+H) 35 WO 2004/002939 PCT/JP2003/008061 61 (4) Methyl 2-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)benzoate MS (m/z): 327 (M+Na) 5 (5) Methyl 2 -propyl-4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)benzoate MS (m/z): 327 (M+Na) (6) Benzyl (iR)-1l-methyl-2-[4-(4,4,5,5-tetramethyl-l,3,2 10 dioxaborolan-2-yl)phenyl]ethylcarbamate MS (m/z): 396 (M+H) Preparation 47 The following compound was obtained according to a 15 similar manner to that of Example 1. 4-Methoxy-l-naphthoic acid NMR (DMSO-d 6 , 5): 7.00(lH, d, J=6Hz), 7.50-7.70(2H, m), 8.20-8.30(2H, m), 9.00(IH, d, J=8Hz) 20 Preparation 48 Under nitrogen, 4-methoxy-1-naphthoic acid (4.33 g) in dichloromethane (45 ml) was added boron tribromide (IM in dichloromethane, 63 ml) dropwise at 09C, and the mixture was 25 stirred at the same temperature for 2 hours. The resulting mixture was poured into ice-cold water and the precipitate was collected by filtration. The filter cake was added to the mixture of water and ethyl acetate, and then adjusted to pH 9 with lN sodium hydroxide. After separation, the 30 organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford 4-hydroxy-l-naphthoic acid (2.19 g) as a colorless powder. MS (m/z): 187 (M-H) 35 Preparation 49 WO 2004/002939 PCT/JP2003/008061 62 To a solution of 4-hydroxy-l1-naphthoic acid (2.18 g) in methanol (15 ml) was added sulfuric acid (1.0 ml), and the mixture was stirred at 70 0 C for 3 hours. The solution was diluted with water and ethyl acetate. The organic layer was 5 separated and washed with brine. The extract was dried over magnesium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate and hexane to give methyl 4-hydroxy-l-naphthoate (1.64 g) as a white solid. 10 MS (m/z): 239 (M+Na) Preparation 50 The following compounds were obtained according to a similar manner to that of Preparation 16. 15 (1) Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 1-naphthoate MS (m/z): 313 (M+H) 20 (2) Methyl [ 4 -(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 yl)phenyl] acetate NMR (DMSO-d 6 , 5): 1.66(12H, s), 3.60(3H, s), 3.70(2H, s), 7.20(2H, d, J=8Hz), 7.60(2H, d, J=8Hz) 25 (3) Methyl [3-( 4

,

4 ,5,5-tetramethyl-1l,3,2-dioxaborolan-2 yl)phenyl] acetate NMR (DMSO-d 6 , 5): 3.60(3H, s), 3.82(2H, s),7.20-7.60(6H, m) 30 (4) Methyl 5-( 4

,

4 ,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) 1, 1'-biphenyl-2-carboxylate MS (m/z) : 361 (M+Na) Preparation 51 35 To a solution of 4-bromo-2-fluorobenzaldehyde (5.0 g) WO 2004/002939 PCT/JP2003/008061 63 in dimethylsulfoxide (40 ml) were added phenol (2.78 g) and potassium carbonate (4.08 g), and the mixture was stirred at 100 C for 3 hours. The solution was diluted with water and ethyl acetate. The organic layer was separated and washed 5 with brine. The extract was dried over magnesium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate and hexane to give 4-bromo-2-phenoxy-l benzaldehyde (7.3 g) as a white solid. 10 NMR (CDC1 3 , 6): 6.90-7.60(7H, m), 7.80(lH, d,J=8Hz), 10.48(lH, s) Preparation 52 The following compounds were obtained according to a 15 similar manner to that of Preparation 14. (1) 4-(2-Methoxy-2-oxoethyl)phenylboronic acid MS (m/z): 193 (M-H) 20 (2) 3-(2-Methoxy-2-oxoethyl)phenylboronic acid MS (m/z): 194 (M+H) (3) 4-[(2R)-2-[ [ (Benzyloxy)carbonyl]amino]lpropyl] phenylboronic acid 25 MS (m/z): 312 (M-H) (4) 4-[2-[N-Benzyl-N-(tert-butoxycarbonyl)amino] ethyl] phenylboronic acid (-)ESI-MS m/z: 354 (M-H) 30 Preparation 53 The following compounds were obtained according to a similar manner to,that of Preparation 23. 35 (1) Methyl [4'-[(2R)-2-[[(benzyloxy)carbonyl]amino]propyl]- WO 2004/002939 PCT/JP2003/008061 64 1,1'-biphenyl-4-yl] acetate MS (m/z): 418 (M+H) (2) Ethyl 5-[4-[(2R)-2-[[(benzyloxy)carbonyl]amino]propyl] 5 phenyl] -l-naphthoate MS (m/z): 490 (M+Na) (3) Methyl 5-(benzyloxy)-1,1'-biphenyl-2-carboxylate MS (m/z): 341 (M+Na) 10 Preparation 54 The following compounds were obtained according to a similar manner to that of Preparation 36. 15 (1) Methyl [4'-[(2R)-2-aminopropyl]-l,l'-biphenyl-4 yl] acetate MS (m/z): 284 (M+H) (2) Ethyl 5-[4-[(2R)-2-aminopropyl]phenyl]-l-naphthoate 20 MS (m/z): 356 (M+Na) (3) Methyl 5-hydroxy-1,1'-biphenyl-2-carboxylate MS (m/z): 251 (M+Na) 25 Preparation 55 To a mixture of 5-hydroxy-l-naphthyl trifluoromethane sulfonate (8.0 g) in N,N-dimethylformamide (35 ml) and ethanol (5.0 ml) were added 1,3-bis(diphenylphosphino) propane (621 mg), palladium acetate(II) (3.7 mg) and 30 triethylamine (1.35 g), and the mixture was stirred at 1000C for 1 hour under carbon-monoxide. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column 35 chromatography on silica gel (hexane/ethyl acetate = 5/1) to WO 2004/002939 PCT/JP2003/008061 65 give ethyl 5-hydroxy-1-naphthoate (1.7 g) as a colorless oil. MS (m/z): 239 (M+Na) Preparation 56 5 To a solution of 4-bromo-2-fluorobenzoic acid (2.0 g) in tetrahydrofran (15 ml) was added 2M isobutylmagnesium bromide in diethyl ether (13.5 ml) dropwise on ice-cooling, and the mixture was stirred at 0aC for 1 hour. The mixture was diluted with ethyl acetate and water. The organic layer 10 was separated, washed with brine, dried over magnesium sulfate and evaporated. To the solution of the residue in N,N-dimethylformamide (20 ml) was added methyliodide (1.14 g) and potassium carbonate (1.89 g), and the mixture was stirred at 20 0 C for 3 hours. The mixture was diluted with 15 ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4-bromo-2-isobutylbenzoate (1.5 g) as a 20 colorless oil. NMR (DMSO-d 6 , 5): 0.80(6H, d, J=8Hz), 1.80-2.00(IH, m), 2.80(2H, d, J=8Hz), 3.80(3H, s), 7.40-7.80(3H, m) Preparation 57 25 The following compounds were obtained according to a similar manner to that of Preparation 56. (1) Methyl 4-bromo-2-isopropylbenzoate NMR (DMSO-d 6 , 5): 1.20(6H, d, J=7Hz), 3.50-3.60(lH, m), 30 3.83(lH, s), 7.50-7.70(3H, m) MS (m/z) : 516 (M+H) (2) Methyl 4-bromo-2-propylbenzoate NMR (DMSO-d 6 , 5): 0.85(3H, t, J=7Hz), 1.40-1.70(2H, m), 35 2.80-3.00(2H, m), 3.82(3H, s), 7.60-7.70(3H, m) WO2004/002939 PCT/JP2003/008061 66 Preparation 58 The following compound was obtained according to a similar manner to that of Preparation 28. 5 tert-Butyl N-((2R)-2-hydroxy-2-phenylethyl)-N-[(1R)-2 (4-iodophenyl)-1l-methylethyl]carbamate MS (m/z): 482 (M+H) 10 Preparation 59 The following compounds were obtained according to a similar manner to that of Preparation 13. (1) tert-Butyl N-benzyl-N-[2-[4-(4,4,5,5-tetramethyl-1,3,2 15 dioxaborolan-2-yl)phenyl] ethyl] carbamate (+)ESI-MS m/z: 460 (M+Na)+ (2) 2-(l-Piperidinyl)-4-(4,4,5,5-tetramethyl-l,3,2 dioxaborolan-2-yl)benzaldehyde 20 (+)ESI-MS m/z: 581 (M+Na) + Preparation 60 To a solution of 2-(3-methoxyphenyl)ethanamine (5.6 g) in dichloromethane (50 ml) was added IM boron tribromide in 25 dichloromethane (75 ml). The mixture was stirred at 20°C for 16 hours and evaporated in vacuo. To the residue, saturated sodium bicarbonate (50 ml) and tetrahydrofuran (150 ml) were added. The pH value of the mixture was kept between 7 to 8 with 1N aqueous sodium hydroxide solution. 30 To the mixture, a solution of di-tert-butyl dicarbonate (8.08 g) in tetrahydrofuran (10 ml) was added, stirred at 20 0 C for 1 hour. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to give 35 tert-butyl 2-(3-hydroxyphenyl)ethylcarbamate (8.2 g).

WO 2004/002939 PCT/JP2003/008061 67 (+)ESI-MS m/z: 260 (M+Na) + Preparation 61 To a solution of tert-butyl 2-(3-hydroxyphenyl) 5 ethylcarbamate (730 mg) and potassium carbonate (893 mg) in N,N-dimethylformamide (10 ml) was added methyl 4-bromo-(3 bromomethyl)benzoate (1.52 g), and the mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic 10 layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4-bromo-3 [[3-[2- [ (tert-butoxycarbonyl)amino]ethyl]phenoxy]methyl] 15 benzoate (970 mg). (+)ESI-MS m/z: 464 (M+H) + Preparation 62 To a solution of methyl 4-bromo-3-[[3-[2-[(tert 20 butoxycarbonyl)amino]ethyl]phenoxy]methyl]benzoate (410 mg) in N,N-dimethylacetamide (4.0 ml) was added dichlorobis(triphenylphosphine)palladium(TTII) (124 mg) and sodium acetate (362 mg), and the mixture was stirred at 130C for 1.5 hours under nitrogen. The mixture was cooled 25 to room temperature, diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give methyl 3-[2-[(tert 30 butoxycarbonyl)amino]ethyl]-6H-benzo[c]chromene-8 carboxylate (190 mg). (+)ESI-MS m/z: 406 (M+Na) + Preparation 63 35 The following compounds were obtained according to a WO 2004/002939 PCT/JP2003/008061 68 similar manner to that of Example 7. (1) Ethyl 6-[4-[2-[N-benzyl-N-(tert-butoxycarbonyl)amino] ethyl] phenyl]nicotinate 5 (+)ESI-MS m/z: 461 (M+H) + (2) Methyl 4'-[2-[N-benzyl-N-(tert-butoxycarbonyl)amino] ethyl]-2,6-dimethyl-l, 1 '-biphenyl-4-carboxylate (+)ESI-MS m/z: 474 (M+H) + 10 Preparation 64 The following compounds were obtained according to a similar manner to that of Example 27. 15 (1) Methyl 3-(2-aminoethyl)-6H-benzo[c]chromene-8 carboxylate (+)ESI-MS m/z: 284 (M+H) + (2) Ethyl 6-[4-[2-(benzylamino)ethyl]phenyl]nicotinate 20 hydrochloride (+)ESI-MS m/z: 361 (M+H) + Preparation 65 The following compounds were obtained according to a 25 similar manner to that of Preparation 16. (1) 3-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyll] amino]ethyl] phenyl trifluoromethanesulfonate 30 (+)ESI-MS m/z: 546 (M+Na) + (2) 4-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino] ethyl] -2 methoxyphenyl trifluoromethanesulfonate 35 (+)ESI-MS m/z: 576 (M+Na)

+

WO2004/002939 PCT/JP2003/008061 69 (3) 4-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2 chlorophenyl trifluoromethanesulfonate 5 (+)ESI-MS m/z: 581 (M+Na) + Preparation 66 The following compound was obtained according to a similar manner to that of Example 5. 10 Methyl 4'-[2-(benzylamino)ethyl]-2,6-dimethyl-l,l' biphenyl-4-carboxylate (+)ESI-MS m/z: 374 (M+H) + 15 Preparation 67 To a mixture of 3-chloro-4-hydroxyphenylacetic acid (2.96 g), (lR)-2-amino-l-(3-chlorophenyl)ethanol hydrochloride (3.0 g), and l-hydroxybenzotriazole (2.14 g) in N,N-dimethylformamide (20 ml) was added 1-(3 20 dimethylaminopropyl)-3-ethylcarbodiimide (2.46 g), and the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed successively with sodium bicarbonate solution and brine, dried over magnesium 25 sulfate and evaporated under reduced pressure to give an amide product. To a tetrahydrofuran (30 ml) solution of the product, 2M borane-dimethyl sulfide complex in tetrahydrofuran (23 ml) was added at room temperature, and the mixture was refluxed for 30 minutes. To the mixture, 6N 30 hydrochloride acid (29.5 ml) was added dropwise below 10C, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, 3N aqueous sodium hydroxide solution (58 ml) below 100C was added and di-tert-butyl dicarbonate (3.46 g) was added portionally at room 35 temperature. The pH value was kept between 7 to 8 by using WO2004/002939 PCT/JP2003/008061 70 IN aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed brine, dried over magnesium 5 sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert-butyl N-[2-(3 chloro-4-hydroxyphenyl)ethyl]-N-[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl]carbamate (7.0 g). 10 (+)ESI-MS m/z: 448 (M+Na) + Preparation 68 The following compound was obtained according to a similar manner to that of Preparation 67. 15 tert-Butyl N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]carbamate (+)ESI-MS m/z: 444 (M+Na) + 20 Preparation 69 A mixture of 4-bromo-2-fluorobenzaldehyde (3.0 g), piperidine (2.93 ml) and potassium carbonate (5.11 g) in N,N-dimethylformamide (30 ml) was stirred at 100 0 C for 12 hours. The mixture was cooled to room temperature. The 25 mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, saturated aqueous ammonium chloride solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography 30 on silica gel (hexane/ethyl acetate = 9/1) to give 4-bromo 2-(l-piperidinyl)benzaldehyde (3.5 g). (+)ESI-MS m/z: 268 (M+H) + Preparation 70 35 The following compound was obtained according to a WO 2004/002939 PCT/JP2003/008061 71 similar manner to that of Example 23. tert-Butyl N-benzyl-N-[2-(4-bromophenyl)ethyl] carbamate (+)ESI-MS m/z: 390 (M+H) + 5 Example 32 The following compounds were obtained according to a similar manner to that of Example 7. 10 (1) 4'-[ (2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]propyl]-3-propoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.05(3H, t, J=7.4Hz), 1.35(3H, d, J=6.2Hz), 1.6-1.9(2H, m), 2.8-3.8(5H, m), 4.11(2H, 15 t, J=7.4Hz), 5.0-5.3(IH, m), 6.3-6.4(1H, m), 7.2 7.8(11H, m), 8.55(1H, br s), 9.19(1H, br s) MS m/z: 468 (M+H) (2) 4'-[2-[ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] 20 ethyl]-3-hydroxy-l,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 2.8-3.0(6H, m), 4.8-5.0(lH, m), 6.33(1H, m), 7.0-7.9(11H, m) MS m/z: 411 (M+H) 25 (3) 3-Hydroxy-4'-[(2R)-2-[ [(2R)-2-hydroxy-2-phenylethyl] amino]propyl]-1,1 1 -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.12(3H, d, J=6.4Hz), 2.6-3.2(5H, m), 30 4.9-5.1(1H, m), 6.23(1H, m), 7.2-7.9(11H, m), 8.77(IH, br s), 9.03(IH, br s) MS m/z: 392 (M+H) (4) 3-Ethoxy-4'-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyll 35 amino]propyl]-1,1'-biphenyl-4-carboxylic acid WO 2004/002939 PCT/JP2003/008061 72 hydrochloride NMR (DMSO-d 6 , 5): 1.15(3H, d, J=6.4Hz), 1.36(3H, t, J=7.0Hz), 2.6-3.2(5H, m), 4.21(2H, q, J=7.0Hz), 4.9-5.1(1H, m), 6.23(1H, m), 7.2-7.7(11H, m) 5 MS m/z: 418 (M-H) (5) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]lamino] propyl]-3-propoxy-l,1'-biphenyl-4-carboxylic acid hydrochloride 10 NMR (DMSO-d 6 , 5): 1.03(3H, t, J=7.4Hz), 1.12(3H, d, J=6.4Hz), 1.74(2H, m), 2.6-3.2(5H, m), 4.11(2H, q, J=7.0Hz), 4.9-5.1(IH, m), 6.23(1H, m), 7.2-7.7(11H, m) MS m/z: 434 (M+H) 15 (6) 3-Butoxy-4'-[(2R)-2-[ [(2R)-2-hydroxy-2-phenylethyl] amino]propyl]-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 0.94(3H, t, J=7.4Hz), 1.12(3H, d, 20 J=6.4Hz), 1.3-1.8(4H, m), 2.6-3.2(5H, m), 4.15(2H, q, J=7.0Hz), 4.9-5.1(1H, m), 6.23(1H, m), 7.2 7.7(11H, m) MS m/z: 448 (M+H) 25 (7) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino] propyl]-3-(pentyloxy)-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 0.89(3H, t, J=7.4Hz), 1.13(3H, d, J=6.4Hz), 1.2-1.8(6H, m), 2.6-3.2(5H, m), 4.14(2H, 30 q, J=7.0Hz), 4.9-5.1(1H, m), 6.23(1H, m), 7.2 7.7(11H, _m) MS m/z: 462 (M+H) (8) 3-(Heptyloxy)-4'-[ (2R)-2-[[(2RP)-2-hydroxy-2 35 phenylethyl]amino]propyl] -1,1 ' -biphenyl-4-carboxylic WO 2004/002939 PCT/JP2003/008061 73 acid hydrochloride NMR (DMSO-d 6 , 6): 0.86(3H, t, J=7.4Hz), 1.16(3H, d, J=6.4Hz), 1.1-1.8(10H, m), 2.6-3.2(5H, m), 4.14(2H, q, J=7.0Hz), 4.9-5.1(1H, m), 6.23(1H, m), 7.2 5 7.7(11H, m) MS min/z: 490 (M+H) (9) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]aminol propyl]-3-isobutoxy-1,1'-biphenyl-4-carboxylic acid 10 hydrochloride NMR (DMSO-d 6 , 5): 1.03(6H, t, J=6.2Hz), 1.16(3H, d, J=6.4Hz), 1.8-2.2(1H, m), 2.6-3.2(5H, m), 3.93(2H, d, J=6.2Hz), 4.9-5.1(IH, m), 6.23(IH, m), 7.2 7.7(11H, m) 15 MS m/z: 448 (M+H) (10) 3- (Allyloxy)-4'- [ (2R)-2-[ [ (2R)-2-hydroxy-2 phenylethyl] amino] propyl]-1,1' -biphenyl-4-carboxylic acid hydrochloride 20 NMR (DMSO-d 6 , 6): 1.16(3H, d, J=6.4Hz), 2.6-3.2(5H, m), 4.77(2H, m), 4.9-5.1(1H, m), 5.27(1H, dd, J=1.8, 10.6Hz), 5.40(1H, dd, J=1.8, 17.2Hz), 5.9-6.2(IH, m), 6.23(1H, m), 7.2-7.7(11H, m) MS m/z: 432 (M+H) 25 (11) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino] propyl]l-3-[ (2-methyl-2-propenyl)oxy]-1,1'-biphenyl-4 carboxylic acid hydrochloride NMR (DMSO-d 6 , 6): 1.16(3H, d, J=6.4Hz), 1.69(3H, s), 30 2.6-3.2(5H, m), 4.77(2H, m), 4.65(2H, s), 4.9 5.1(1H, m), 4.9-5.2(2H, mi), 6.23(1H, m), 7.2 7.7(11H, m) MS m/z: 446 (M+H) 35 (12) 3-(2-Fluoroethoxy)-4'-[(2R)-2-[[ (2R)-2-hydroxy-2- WO 2004/002939 PCT/JP2003/008061 74 phenylethyl] amino]propyl] -1,1 '-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 6): 1.16(3H, d, J=6.4Hz), 2.6-3.2(5H, m), 4.3-4.8(4H, m), 4.9-5.1(1H, m), 6.23(1H, min), 7.2 5 7.7(11H, m) MS m/z: 438 (M+H) (13) 3-(2,2-Difluoroethoxy)-4'-[(2R)-2- [ [(2R)-2-hydroxy-2 phenylethyl]amino]propyl]-1,1'-biphenyl-4-carboxylic 10 acid hydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6.4Hz), 2.6-3.2(5H, m), 4.3-4.7(2H, m), 4.9-5.1(1H, m), 6.0-6.5(2H, m), 7.2-7.7(11H, m) MS m/z: 456 (M+H) 15 (14) 4'- (2R)-2-[ [ (2R)-2-Hydroxy-2-phenylethyl]amino] propyl]-3-(2,2,2-trifluoroethoxy)-1, 1 '-biphenyl-4 carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6.4Hz), 2.6-3.2(5H, m), 20 4.7-5.1(3H, m), 6.24(1H, m), 7.2-7.7(11H, m) MS m/z: 472 (M-H) (15) 3-(2-Hydroxyethoxy)-4'-[(2R)-2-[[(2R)-2-hydroxy-2 phenylethyl]amino]propyl]-1,1'-biphenyl-4-carboxylic 25 acid hydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6.4Hz), 2.6-3.2(5H, m), 3.8(2H, m), 4.15(2H, m), 4.9-5.1(1H, m), 6.24(1H, m), 7.2-7.7(11H, m) MS m/z: 434 (M-H) 30 (16) 4'-[(2R)-2-[ [(2R)-2-Hydroxy-2-phenylethyl] amino] propyl]-3-(2-methoxyethoxy)-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.12(3H, d, J=6.4Hz), 2.6-3.2(5H, m), 35 3.33(3H, s), 3.70(2H, m), 4.29(2H, m), 4.9-5.1(IH, WO 2004/002939 PCT/JP2003/008061 75 m), 6.22(1H, m), 7.2-7.7(11H, m) MS m/z: 450 (M+H) (17) 3-(3-Fluoropropoxy)-4'-[(2R)-2-[[(2R)-2-hydroxy-2 5 phenylethyllamino]propyl]-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6.4Hz), 2.0-2.4(2H, m), 2.6-3.2(5H, m), 4.25(2H, t, J=6.0Hz), 4.56(IH, t, J=5.8Hz), 4.83(1H, t, J=6.0Hz), 4.9-5.1(1H, m), 10 6.24(1H, m), 7.2-7.7(11H, m) MS m/z: 452 (M+H) (18) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino] propyl]-3-(3,3,3-trifluoropropoxy)-1,1 '-biphenyl-4 15 carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6.4Hz), 2.6-3.2(7H, m), 4.39(2H, t, J=6.0Hz), 4.9-5.1(1H, m), 6.24(1H, m), 7.2-7.7(11H, m) MS m/z: 488 (M+H) 20 (19) 3-(Cyclopropyloxy)-4'-[(2R)-2-[[(2R)-2-hydroxy-2 phenylethyl]amino]propyl]-1, 1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6.4Hz), 2.6-3.2(5H, m), 25 4.9-5.1(2H, m), 6.24(1H, m), 7.2-7.7(11H, m) MS m/z: 432 (M+H) (20) 3-(Cyclobutyloxy)-4'-[(2R)-2-[[(2R)-2-hydroxy-2 phenylethyl]amino]propyl] -1,1' -biphenyl-4-carboxylic 30 acid hydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6.4Hz), 1.2-2.4(6H, m), 2.6-3.2(5H, m), 4.9-5.1(2H, m), 6.24(1H, m), 7.2 7.7(11H, m) MS m/z: 446 (M+H) 35 WO 2004/002939 PCT/JP2003/008061 76 (21) 3-(Cyclopentyloxy)-4'-[ (2R)-2-[[(2R)-2-hydroxy-2 phenylethyl] amino]propyl] -1,1 '-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6.4Hz), 1.2-2.0(8H, m), 5 2.6-3.2(5H, m), 4.9-5.1(2H, m), 6.24(IH, m), 7.2 7.7(11H, m) MS m/z: 460 (M+H) (22) 3-(Cyclopropylmethoxy)-4'-[(2R)-2-[ [ (2R)-2-hydroxy-2 10 phenylethyl] amino]propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 0.2-0.7(2H, m), 0.9-1.3(6H, m), 2.6 3.2(5H, m), 4.03(2H, d, J=6.6Hz), 4.9-5.1(1H, m), 6.24(1H, m), 7.2-7.7(11H, m) 15 MS m/z: 446 (M+H) (23) 3-(Cyclohexylmethoxy)-4'-[(2R)-2- [ (2R)-2-hydroxy-2 phenylethyl] amino]propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride 20 NMR (DMSO-d 6 , 5): 1.0-1.9(14H, m), 2.6-3.2(5H, m), 3.93(2H, d, J=6.6Hz), 4.9-5.1(1H, m), 6.24(lH, m), 7.2-7.7(11H, m) MS m/z: 488 (M+H) 25 (24) 4 '-[2-[(2R)-2-Phenyl-2-hydroxyethyl]amino]ethyl]-l,1' biphenyl-4-nitrile MS m/z: 457 (M+H) (25) 4'-[ (2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino] 30 propyl]-3-phenoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6.4Hz), 2.6-3.2(5H, m), 4.9-5.1(1H, m), 6.24(1H, m), 6.8-7.9(16H, m) MS m/z: 468 (M+H) 35 WO 2004/002939 PCT/JP2003/008061 77 (26) 4'-[2-[ [(2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3 methoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 2.8-3.3(6H, m), 4.9-5.1(1H, m), 6.22(1H, m), 7.2-7.8(12H, m) 5 MS m/z: 392(M+H) (27) 3-Ethoxy-4'-[2-[ [ (2R)-2-hydroxy-2-phenylethyl]amino] ethyl]-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.35(3H, t, J=6.8Hz), 2.8-3.3(6H, m), 10 4.20(2H, q, J=6.8Hz), 4.9-5.1(1H, m), 6.22(IH, m), 7.2-7.8(12H, m) MS m/z: 406 (M+H) (28) 4'-[2-[ [(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]- 3 15 propoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.01(3H, t, J=6.8Hz), 1.6-1.9(2H, m), 2.9-3.4(6H, m), 4.11(2H, q, J=6.8Hz), 4.9-5.1(1H, m), 6.22(1H, m), 7.2-7.8(12H, m) MS m/z: 420 (M+H) 20 (29) 4'-[2-[ [ (2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]- 3 isopropoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.31(6H, t, J=6.8Hz), 2.9-3.4(6H, m), 25 4.7-4.9(1H, m), 4.9-5.1(1H, m), 6.22(IH, m), 7.2 7.8(12H, m) MS m/z: 420 (M+H) (30) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3 30 isobutoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.02(6H, t, J=6.8Hz), 1.9-2.1(1K, m), 2.9-3.4(6H, m), 3.92(2H, d, J=6.8Hz), 4.9-5.1(I1H, m), 6.22(1H, m), 7.2-7.8(12H, m) MS m/z: 434 (M+H) 35 WO 2004/002939 PCT/JP2003/008061 78 (31) 3- (Allyloxy) -4 '-[2-[ [ (2R)-2-hydroxy-2-phenylethyl] amino]ethyl]-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 2.9-3.4(6H, m), 3.92(2H, d, J=6.8Hz), 5 4.72(2H, m), 5.2-5.7(2H, m), 4.9-5.1(1H, ia), 6.0 6.2(1H, m), 6.22(1H, m), 7.2-7.8(12H, m) MS m/z: 418 (M+H) (32) 3-(2-Fluoroethoxy)-4'-[2-[[(2R)-2-hydroxy- 2 10 phenylethyll]amino]ethyl]-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 2.9-3.4(6H, m), 4.3-4.7(3H, m), 4.8 4.9(1H, m), 4.9-5.1(1H, m), 6.22(IH, m), 7.2 7.8(12H, m) 15 MS m/z: 424 (M+H) (33) 3-(3-Fluoropropoxy)-4'-[2-[[(2R)-2-hydroxy-2 phenylethyll]amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride 20 NMR (DMSO-d6, 5): 1.9-2.3(2H, m), 2.9-3.4(6H, mn), 4.25(2H, t, J=6.0Hz), 4.56(1H, t, J=5.9Hz), 4.80(1H, t, J=5.8Hz), 4.9-5.1(1H, mi), 6.22(1H, m), 7.2-7.8(12H, m) MS m/z: 438 (M+H) 25 (34) 3-(Cyclopropyloxy)-4'-[2-[[(2R)-2-hydroxy-2 phenylethyl]amino] ethyl] -1,1 '-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 2.9-3.4(6H, m), 4.9-5.1(1H, m), 30 6.22(1H, m), 7.2-7.8(12H, im) MS m/z: 392 (M+H) (35) 3-(Cyclohexyloxy)-4'-[2-[ [(2R)-2-hydroxy-2 phenylethyl]amino]ethyl]-1,1'-biphenyl-4-carboxylic 35 acid hydrochloride WO 2004/002939 PCT/JP2003/008061 79 NMR (DMSO-d 6 , 5): 1.2-2.0(10H, m), 2.9-3.4(6H, m), 4.64(1H, m), 4.9-5.1(1H, min), 6.22(IHK, m), 7.2 7.8(12H, m) MS m/z: 460 (M+H) 5 (36) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl] -3 phenoxy-1, 1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 2.9-3.4(6H, m), 4.9-5.1(1H, m), 6.22(1H, m), 6.9-8.0(17H, im) 10 MS m/z: 454 (M+H) (37) 3-(Benzyloxy)- 4

'-[

2 -[[(2R)-2-hydroxy-2 phenylethyll]amino]ethyl] -1,1'-biphenyl-4-carboxylic acid hydrochloride 15 NMR (DMSO-d 6 , 5): 2.9-3.4(6H, m), 4.9-5.1(1H, m), 5.33(2H, nm), 6.22(1H, m), 7.2-7.8(17H, m) MS m/z: 468 (M+H) (38) 4'-[2-[ [ (2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3 20

(

2 ,2,2-trifluoroethoxy)-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 2.9-3.4(6H, m), 4.3-5.1(2H, m), 6.22(IH, m), 7.2-7.8(12H, m) MS m/z: 460(M+H) 25 (39) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]- 2 methyl-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 2.28(3H, s), 2.9-3.4(6H, m), 4.9 5.1(1H, m), 5.33(2H, m), 6.22(IH, m), 7.2-7.8(12H, 30 m) MS m/z: 476 (M+H) (40) 4'-[2-[[(2R)-2-(3-Fluorophenyl)-2-hydroxyethyl] amino]ethyl]-3-propoxy-1, 1' -biphenyl-4-carboxylic acid 35 hydrochloride WO 2004/002939 PCT/JP2003/008061 80 NMR (DMSO-d 6 , 5): 1.01(3H, t, J=7.4Hz), 1.5-1.9(2H, min), 2.9-3.4(6H, m), 4.11(2H, q, J=7.4Hz), 4.9-5.1(1H, m), 6.22(1H, m), 7.1-7.8(11H, m) MS m/z: 438 (M+H) 5 (41) 4'-[ (2R)-2-[[(2R)-2-(3-Fluorophenyl)-2-hydroxyethyl] aminol]propyl]-3-propoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 0.99(3H, t, J=7.4Hz), 1.10(3H, d, 10 J=6.8Hz), 1.5-1.9(2H, m), 2.7-3.4(5H, m), 4.03(2H, q, J=7.4Hz), 4.9-5.1(1H, m), 6.22(1H, m), 7.1 7.8(11H, m) MS m/z: 450 (M-H) 15 (42) 4'-[2-[[(2R)-2-(3-Fluorophenyl)-2-hydroxyethyl]amino] ethyl]-3-isopropoxy-l,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.31(6H, d, J=6.0Hz), 2.9-3.4(6H, m), 4.81(1H, m), 4.9-5.1(1H, m), 6.22(1H, m), 7.1 20 7.8(11H, m) MS m/z: 438 (M+H) (43) 4'-[(2R)-2-[[(2R)-2-(3-fluorophenyl)-2-hydroxyethyl] amino] propyl]-3-isopropoxy-1,1'-biphenyl-4-carboxylic 25 acid hydrochloride NMR (DMSO-d 6 , 5): 1.10(3H, d, J=6.8Hz), 1.31(6H, d, J=6.0Hz), 2.7-3.4(5H, m), 4.82(IH, m), 4.9-5.1(1H, m), 6.22(1H, m), 7.1-7.8(11H, m) MS m/z: 450 (M-H) 30 (44) 3-(Cyclohexyloxy)-4'7-[( 2 R)-2-[[(2R)-2-(3-fluorophenyl) 2-hydroxyethyll]amino]propyl] -1, 1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6.8Hz), 1.2-2.0(10H, m), 35 2.7-3.4(5H, m), 4.65(IH, m), 4.9-5.1(1H, m), WO 2004/002939 PCT/JP2003/008061 81 6. 22 (lH, in), 7 1- 7 .8(11H, m) MS m/z: 490 (N-H) (45) 4'-[2-E I(2R,)-2- (4-~Chrophenyl)-2--hydroxyethyllaiinoV 5 ethyl]-3-propoxy-1,1Thiphenl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 6): 1.01(3H, t, J=7.4Hz), 1.5-1.9(2H, mn), 2.9-3.4(6H, m1), 4.10(2H, q, J=7.4Hz), 4.9-5.1(1H, in), 6.28(1H, mn), 7.1-7.8(11H, in) 10 MS in/z: 438 (M+H) (46) 4'-[2-[ Ii(2R)-2-(4-ChlorophenyV2-hydroxyethy1]ainino] ethyl]-3-isopropoxy1,1'-biphefyl-4carboxylic acid hydrochloride 15 NMR (DMSO-d 6 , 6): 1.29(6H, d, J=6.OHz), 2.9-3.4(6H, mn), 4.84(1H, mn), 4.9-5.1(1H, mn), 6.30(lH, mn), 7.1 7.8(11H, mn) MS in/z: 454 (N-IH) 20 (47) 4'-[ (2R)-2-[ I(2R)-2- (4-Chlorophenyl)-2-hydroxyethyl] aininoipropyl] -3-propoxy-l, 1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.00 (3H, t, J=7. 4Hz) , 1.12 (3H, d, J=6.8Hz), 1.5-1.9(2H, mn), 2.7-3.4(5H, mn), 4.03(2H, 25 q, J=7.4Hz), 4.9-5.l(lH, in), 6.32(lH, rn), 7.1 7.8(11H, mn) MS in/z: 468 (M--) (48) 4'-1 (2R)-2-[ [(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl] 30 aminolpropyl]-3-isopropoxyl1,1I-biphenl- 4 -carboxylic acid hydrochloride NMYR (DMSO-d 5 , 5): 1.09(3H, d, J=6.8Hz), 1.29(6H, d, J=6.0Hz), 2.7-3.4(5H, in), 4.82(1K, in), 4.9-5.1(1K, mn), 6.32(lH, mn), 7.1-7.8(11H, mn) 35 MS rn/z: 468 (N-H) WO 2004/002939 PCT/JP2003/008061 82 (49) 3-Ethoxy-4'-[ (2R)-2-[ [ (2R)-2-hydroxy-2-(3-pyridyl) ethyl]amino]propyl]-1,1'-biphenyl-4-carboxylic acid dihydrochloride 5 NMR (DMSO-d 6 , 5): 1.19(3H, d, J=6.8Hz), 1.36(3H, t, J=7.0Hz), 2.7-3.4(5H, m), .4.23(2H, q, J=7.0Hz), 5.1-5.3(1H, m), 6.32(1H, m), 7.2-7.9(8H, m), 8.25(IH, d, J=8Hz), 8.7-8.9(2H, m), 8.94(IH, m), 9.20(1H, m) 10 MS m/z: 421 (M+H) (50) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl] amino]propyl]-3-propoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride 15 NMR (DMSO-d6, 5): 1.01(3H, t, J=7.4Hz), 1.19(3H, d, J=6.8Hz), 1.5-1.9(2H, m), 2.7-3.4(5H, m), 4.04(2H, q, J=7.4Hz), 5.1-5.3(1H, m), 6.32(IH, m), 7.2 7.9(8H, m), 8.25(1H, d, J=8Hz), 8.7-8.9(2H, m), 8.94(1H, m), 9.20(1H, m) 20 MS m/z: 435 (M+H) (51) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl] amino] propyl] -3-isobutoxy-1, 1' -biphenyl-4-carboxylic acid dihydrochloride 25 NMR (DMSO-d 6 , 5): 1.01(6H, t, J=6.8Hz), 1.17(3H, d, J=6.8Hz), 1.9-2.1(1H, m), 2.7-3.4(5H, m), 3.93(2H, d, J=6.4Hz), 5.2-5.4(1H, m), 7.2-7.9(8H, m), 8.4(1H, d, J=8Hz), 8.7-8.9(2H, m), 9.09(1H, m), 9.42 (1H, m) 30 MS m/z: 449 (M+H) (52) N-[[4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl] amino]propyl]-1,1'-biphenyl-4-yl]carbonyl]-1 phenylmethanesulfonamide dihydrochloride 35 MS m/z: 528 (M-H) WO 2004/002939 PCT/JP2003/008061 83 (53) 4'-[(2R)-2-[[(2R)-2-(6-Chloro-3-pyridyl)-2 hydroxyethyll]amino]propyl]-3-propoxy-1,1'-biphenyl-4 carboxylic acid dihydrochloride 5 NMR (DMSO-d 6 , 6): 1.01(3H, t, J=7.4Hz), 1.12(3H, d, J=6.8Hz), 1.7-1.9(2H, m), 2.7-3.4(5H, m), 4.11(2H, q, J=7.4Hz), 4.9-5.3(1H, m), 7.2-7.8(10H, m), 8.56(IH, s) MS m/z: 469 (M+H) 10 (54) 4'-[2- [ (2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] ethyl] -3-isopropoxy-1, 1' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 5): 1.29(6H, d, J=6.0Hz), 2.9-3.4(6H, m), 15 4.84(IH, m), 4.9-5.1(1H, m), 7.2-7.5(4H, m), 7.6 7.9(4H, m), 8.2-8.5(IH, m), 8.7-8.9(2H, m), 9.0 9.4(2H, m) MS nm/z: 421 (M+H) 20 (55) 4'-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] ethyl]-3-propoxy-l,1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 5): 1.01(3H, t, J=7.4Hz), 1.5-1.9(2H, m), 3.0-3.4(6H, m), 4.11(2H, q, J=7.4Hz), 5.0-5.3(1H, 25 m), 7.2-7.5(4H, m), 7.6-7.9(4H, m), 8.3-8.5(1H, m), 8.7-8.9(2H, m), 9.0-9.4(2H, m) MS m/z: 421 (M+H) (56) 3-(Cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy-2-(3 30 pyridyl)ethyl]amino]ethyl]-1, 1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 5): 1.0-2.0(10H, m), 2.9-3.4(6H, m), 4.65(IH, m), 5.0-5.3(1H, m), 7.2-7.5(4H, m), 7.6 8.0(4H, m), 8.4-8.6(1H, m), 8.7-8.9(2H, m), 9.0 35 9.4(2H, m) WO 2004/002939 PCT/JP2003/008061 84 MS m/z: 461 (M-H) (57) 4'-[2-[[(2R)-2-(6-Chloro-3-pyridyl)-2-hydroxyethyll amino]ethyl]-3-propoxy-l,1'-biphenyl-4-carboxylic acid 5 dihydrochloride NMR (DMSO-d 6 , 5): 1.01(3H, t, J=7.4Hz), 1.6-1.9(2H, m), 3.0-3.4(6:H, m), 4.11(2H, q, J=7.4Hz), 5.0-5.3(1H, m),r 7.1-7.9(9H, m), 8.46(1H, s) MS m/z: 453 (M-H) 10 (58) 3-Butyl-4'-[(2R)-2-[[(2R)-2-hydroxy-2-phenylethyl] amino]propyl]-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 0.90(3H, t, J=7.4Hz), 1.0-1.8(9H, m), 15 2.8-3.8(5H, m), 5.0-5.3(1H, m), 6.3-6.4(1H, m), 7.2-7.8 (11H, m) MS m/z: 432(M+H) (59) 3-(3-Butenyl)-4'-[(2R)-2-[[(2R)-2-hydroxy-2 20 phenylethyl] amino]lpropyl]-1,1'-biphenyl-4-carboxylic acid hydrochloride MS m/z: 430 (M+H) (60) 4'-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]- 2 25 methylpropyl] -3-isopropoxy-1,1' -biphenyl-4-carboxylic acid hydrochloride MS m/z: 482 (M+H) (61) 4'-[3-[[(2R)-2-Hydroxy-2-phenylethyl]amino]propyl]-3 30 isopropoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride MS m/z: 434 (M+H) (62) 4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] 35 ethyl]-3-isopropoxy-1,l'-biphenyl-4-carboxylic acid WO 2004/002939 PCT/JP2003/008061 85 hydrochloride NMR (DMSO-d 6 , 5): 1.31 (6H, d, J=6.0Hz), 2.8-3.0 (6H, m), 4.79 (1H, q, J=6.0Hz), 4.8-5.0 (1H, m), 6.33 (1H, m), 7.0-7.9 (11H, m) 5 MS m/z: 454 (M+H) (63) Ethyl 4'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1' biphenyl-3-carboxylate 10 (+)ESI-MS m/z: 524 (M+H) + (64) Methyl 3'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1' biphenyl-4-carboxylate 15 (+)ESI-MS m/z: 510 (M+H) + (65) Methyl 4'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2-fluoro 1,1'-biphenyl-4-carboxylate 20 (+)ESI-MS m/z: 550 (M+Na) + (66) Methyl 4'-[2- [N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]ethyl]-3-chloro 1,1'-biphenyl-4-carboxylate 25 (+)ESI-MS m/z: 566 (M+Na) + (67) Methyl 4'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]ethyl] -2'-methoxy 1, 1 '-biphenyl-4-carboxylate 30 (+)ESI-MS m/z: 540 (M+H) + (68) Methyl 4'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino] ethyl] -2'-chloro 1,1'-biphenyl-4-carboxylate 35 (+)ESI-MS m/z: 544 (M+H)

+

WO 2004/002939 PCT/JP2003/008061 86 (69) tert-Butyl N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] N-[2-[4 '-formyl-3'- (1-piperidinyl)-1,1'-biphenyl-4 yl] ethyl] carbamate 5 (+)ESI-MS m/z: 563 (M+H) + (70) Methyl 4'-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]propyl] -1, 1' biphenyl-4-carboxylate 10 MS (m/z): 524 (M+H) (71) Ethyl 4'-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]propyl]-1,1' biphenyl-3-carboxylate 15 MS (m/z): 538 (M+H) (72) Methyl 4'-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl) -2-hydroxyethyl] amino]propyl] -3-fluoro 1,1'-biphenyl-4-carboxylate 20 MS (m/z): 542 (M+H) (73) Methyl 4'-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]propyl] -3-methoxy 1,1'-biphenyl-4-carboxylate 25 MS (m/z): 554 (M+H) (74) Methyl 4'-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]propyl] -3-chloro 1,1'-biphenyl-4-carboxylate 30 MS (m/z): 558 (M+H) (75) Methyl 4'-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyll]amino]propyl] -3-methyl 1,1'-biphenyl-4-carboxylate 35 MS (m/z): 538 (M+H) WO 2004/002939 PCT/JP2003/008061 87 (76) Methyl 3'-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl) -2-hydroxyethyl] amino]propyll]-1,1' biphenyl-4-carboxylate 5 MS (m/z): 523 (M+H) (77) Ethyl 3'-[3-[N-(tert-butoxycarbonyl)-N-[(2R)-2-( 3 chlorophenyl)-2-hydroxyethyl] amino]jpropyl]-1,1' biphenyl-3-carboxylate 10 MS (m/z): 538 (M+H) (78) Methyl 4'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(5 chloro-3-pyridyl)-2-hydroxyethyl] amino] ethyl] -1,1' biphenyl-4-carboxylate 15 MS (m/z): 511 (M+H) (79) tert-Butyl N-[(2R)-2-(6-chloro-3-pyridyl)-2 hydroxyethyl] -N-[ (lR)-2-(4'-formyl-3'-phenoxy-l,1' biphenyl-4-yl) -1-methylethyl] carbamate 20 MS (m/z): 587 (M+H) (80) tert-Butyl N-[2-(4'-formyl-3'-phenoxy-1,1'-biphenyl-4 yl)ethyl]-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl] carbamate 25 MS (m/z): 539 (M+H) (81) Methyl [4'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]ethyl] -1, 1' biphenyl-4-yll] acetate 30 MS (m/z): 524 (M+H) (82) Methyl [4'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino]ethyl] -1,1 ' biphenyl-3-yl] acetate 35 MS (m/z): 524 (M+H) WO 2004/002939 PCT/JP2003/008061 88 (83) Methyl 4-[4-[(2R)-2-[N-(tert-butoxycarbonyl)-N-[(2R)-2 (6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyll] phenyl] -1-naphthoate 5 MS (m/z): 575 (M+H) (84) tert-Butyl N-[ (lR)-2-[4'-[(benzoylamino)sulfonyl]-1,1' biphenyl-4-yl]-l-methylethyl]-N-[(2R)-2-(6-chloro-3 pyridyl) -2-hydroxyethyl ]carbamate 10 MS (m/z): 650 (M+H) (85) tert-Butyl N-[2-[4'-formyl-3'-(l-piperidinyl)-l,l' biphenyl-4-yl] ethyl]-N-[(2R)-2-hydroxy-2-phenylethyl] carbamate 15 MS (m/z): 529 (M+H) (86) 4'-[2-[[ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl] -3-(2-methoxyethoxy)-1,1' -biphenyl-4-carboxylic acid hydrochloride 20 MS (m/z): 470 (M+H) (87) 3-(2-Ethoxyethoxy)-4'-[2-[[(2R)-(3-chlorophenyl)-2 hydroxyethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride 25 MS (m/z): 484 (M+H) (88) 4'-[2- [ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-3-propyl-1,1'-biphenyl-4-carboxylic acid hydrochloride 30 MS (m/z): 438 (M+H) (89) 4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl] -3-propoxy-1, 1' -biphenyl-4-carboxylic acid hydrochloride 35 MS (m/z): 454 (M+H) WO 2004/002939 PCT/JP2003/008061 89 (90) 4'-[2-[ [ (2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-(2 methoxyethoxy)-1,1' -biphenyl-4-carboxylic acid hydrochloride 5 NMR (DMSO-d 6 , o): 2.8-3.0 (6H, m), 3.32 (3H, s), 3.70 (2H, m), 4.29 (2H, m), 4.8-5.0 (1H, m), 6.33 (1H, m), 7.0-7.9 (12H, m) MS m/z: 436 (M+H) 10 (91) 3-(2-Ethoxyethoxy)-4'-[2-[[(2R)-2-hydroxy-2 phenylethyl]amino]ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride MS m/z: 450 (M+H) 15 (92) 3-[2-(Dimethylamino)ethoxy]-4'-[2-[[(2R)-2-hydroxy-2 phenylethyl] amino] ethyl] -1,1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 5): 1.12 (3H, d, J=6.5Hz), 2.8-3.6 (7H, m), 2.88 (6H, s), 4.58 (2H, m), 4.8-5.0 (1H, m), 20 6.33 (1H, m), 7.0-7.9 (12H, m) MS m/z: 462 (M+H) (93) 4'-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1 methylethyl] amino] ethyll -3-isopropoxy-1, 1' -biphenyl-4 25 carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 0.98 (3H, d, J=6.6Hz), 1.31 (6H, d, J=6.0Hz), 2.8-3.5 (5H, m), 4.79 (1H, q, J=6.0Hz), 5.0-5.2 (IH, m), 6.0 (IH, m), 6.7-7.9 (11H, rm) MS m/z: 450 (M+H) 30 Example 33 To the mixture of 4'-[2-[[(2R)-2-phenyl-2 hydroxyethyl]amino]ethyl]-1,1'-biphenyl-4-nitrile (100 mg) in DMF (N,N-dimethylformamide) (10 ml) were added sodium 35 azide (30 mg) and ammonium chloride (30 mg), and stirred at WO 2004/002939 PCT/JP2003/008061 90 120 0 C for 12 hours. The resulting mixture was poured into a mixture of ethyl acetate and water, and the organic layer was washed with brine. After the solvent was evaporated under pressure, the residue was purified by column 5 chromatography on silica gel to give the corresponding tetrazole. The obtained tetrazole was diluted with 6N hydrogen chloride in 1,4-dioxane (10 ml) and the mixture was allowed to keep at the room temperature for 4 hours. The mixture was evaporated under reduced pressure and the 10 obtained solid was washed with ether to give (1R)-2-[[(1R)-l-methyl-2-[4'-(1H-tetrazol-5-yl)-1,1' biphenyl-4-yl]ethyl]amino]-1-phenylethanol hydrochloride (25 mg). NMR (DMSO-d 6 , 6): 1.14(3H, d, J=6.4Hz), 2.6-3.2(5H, m), 15 3.93(2H, d,,J=6.6Hz), 4.9-5.1(1H, m), 6.24(lH, m), 7.2-7.5(7H, m), 7.77(2H, d, J=8.0Hz), 7.94(2H, d, J=8.0Hz), 8.15(2H, d, J=8.0Hz) MS m/z: 400 (M+H) 20 Example 34 The following compounds were obtained according to a similar manner to that of Example 30. (1) 4'-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 25 chlorophenyl) -2-hydroxyethyl]amino]propyl] -1,1' biphenyl-4-carboxylic acid MS (m/z) : 510 (M+H) (2) 4'-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 30 chlorophenyl) -2-hydroxyethyl] amino]propyl] -1,1' biphenyl-3-carboxylic acid MS (m/z): 510 (M+H) (3) 4'-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 35 chlorophenyl)-2-hydroxyethyl]amino]propyl] -3-fluoro- WO 2004/002939 PCT/JP2003/008061 91 1,1'-biphenyl-4-carboxylic acid MS (m/z): 528 (M+H) (4) 4'-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 5 chlorophenyl)-2-hydroxyethyl] amino]propyl] -3-methoxy 1,1'-biphenyl-4-carboxylic acid MS (m/z): 540 (M+H) (5) 4'-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 10 chlorophenyl)-2-hydroxyethyl] amino]propyl]-3-chloro 1,1'-biphenyl-4-carboxylic acid MS (m/z): 544 (M+H) (6) 4'-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 15 chlorophenyl)-2-hydroxyethyl] amino]propyll]-3-methyl 1,1'-biphenyl-4-carboxylic acid MS (m/z): 524 (M+H) (7) 3'-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 20 chlorophenyl)-2-hydroxyethyl] amino]propyl] -1,1 ' biphenyl-4-carboxylic acid MS (m/z): 523 (M+H) (8) 3'-[3-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 25 chlorophenyl)-2-hydroxyethyll] amino]propyl] -1,1' biphenyl-3-carboxylic acid MS (m/z): 510 (M+H) (9) [4'-[(2R)-2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(3 30 chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,1' biphenyl-4-yl]acetic acid MS (m/z): 524 (M+H) (10) 4'-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(5-chloro-3 35 pyridyl)-2-hydroxyethyll]aminc]ethyl]-1,1'-biphenyl-4- WO 2004/002939 PCT/JP2003/008061 92 carboxylic acid MS (m/z): 497 (M+H) (11) [41-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-( 3 5 chlorophenyl)-2-hydroxyethyl] amino]ethyl]-1,1

'

biphenyl-4-yl]acetic acid MS (m/z): 510 (M+H) (12) 4-[4-[N-(2R)-2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-(6 10 chloro-3-pyridyl)-2-hydroxyethyl]amino]lpropyl]phenyl] 1-naphthoic acid MS (m/z): 561 (M+H) Example 35 15 The following compounds were obtained according to a similar manner to that of Example 27. (1) 4'-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] propyl]-1,1'-biphenyl-4-carboxylic acid hydrochloride 20 NMR (DMSO-d 6 , 5): 1.70-2.10(2H, m), 2.60-3.40(6H, m), 4.90-5.10(1H, m), 7.40-7.60(6H, m), 7.70-7.90(4H, m), 8.10(IH, d, J=8Hz) MS (m/z): 410 (M+H) 25 (2) 4'-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]propyl]-1,1'-biphenyl-3-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.80-2.10(2H, m), 2.60-3.40(6H, m), 4.90-5.10(1H, m), 7.30-7.60(9H, m), 7.80-7.90(1H, 30 m), 8.10(1H, s) MS (m/z): 410 (M+H) (3) 4'-[3-[ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] propyl]-3-fluoro-l,1'-biphenyl-4-carboxylic acid 35 hydrochloride WO 2004/002939 PCT/JP2003/008061 93 NMR (DMSO-d 6 , 5): 1.80-2.10(2H, m), 2.60-3.40(6H, m), 4.90-5.10(1H, m), 7.30-7.80(10H, m), 8.00(1H, t, J=8Hz) MS (m/z): 428 (M+H) 5 (4) 4'-[3-[ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] propyl]-3-methoxy-l,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.80-2.10(2H, m), 2.60-3.40(6H, m), 10 4.00(3H, s), 4.90-5.10(1H, m), 7.30-7.50(8H, m), 7.70-7.80(3H, m) MS (m/z): 440 (M+H) (5) 3-Chloro-4'-[3-[[(2R)-2-(3-chlorophenyl)-2 15 hydroxyethyl] amino]propyl]-1,1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.80-2.10(2H, m), 2.60-3.40(6H, m), 4.90-5.10(1H, m), 7.30-7.60(6H, m), 7.70-7.90(5H, m) 20 MS (m/z): 444 (M+H) (6) 4'-[3-[ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] propyl]-3-methyl-l,1'-biphenyl-4-carboxylic acid hydrochloride 25 NMR (DMSO-d 6 , 5): 1.80-2.10(2H, m), 2.60(3H, s), 2.60 3.40(6H, m), 4.90-5.10(1H, m),7.30-7.60(10H, m), 7.90(1H, s) MS (m/z): 424 (M+H) 30 (7) 3'-[3-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] propyl]-l,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.80-2.10(2H, m), 2.60-3.40(6H, m), 4.90-5.10(1H, m), 7.30-7.60(8H, m), 7.80(2H, d, J=8Hz), 8.10(2H, d, J=8Hz) 35 MS (m/z): 410 (M+H) WO 2004/002939 PCT/JP2003/008061 94 (8) 3'-[3-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyllamino] propyl]-1,1'-biphenyl-3-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.80-2.10(2H, m), 2.60-3.40(6H, m), 5 4.90-5.10(1H, m), 7.30-7.60(9H, m), 7.80-7.90(2H, m), 8.20(1H, s) MS (m/z): 410 (M+H) (9) [4'-[ (2R)-2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] 10 amino]propyl]-1,1'-biphenyl-4-yl]acetic acid hydrochloride MR (DMSO-d 6 , 5): 1.05(3H, d, J=6Hz), 2.80-3.60(7H, m), 5.00-5.15(1H, m), 7.20-7.70(12H, m) MS (m/z): 424 (M+H) 15 (10) 4'-[2-[ [(2R)-2-(5-Chloro-3-pyridyl)-2-hydroxyethyl] amino]ethyl]-1,1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 5): 3.10-3.40(6H, ma), 5.00-5.10(IH, m), 20 7.40-8.10(9H, m), 7.70-7.80(2H, m) MS (m/z) : 397 (M+H) (11) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl] amino]propyl] -3-phenoxy-1, 1'-biphenyl-4-carboxylic acid 25 dihydrochloride NMR (DMSO-d 6 , 5): 1.13(3H, d, J=6Hz), 2.70-2.80(1H, m), 2.80-3.60(4H, m), 5.30-5.40(1IH, m),6.90-7.60(7H, m), 7.90-8.00(2H, m), 8.50-8.60(lH, m), 8.80 8.90(2H, m) 30 MS (m/z): 469 (M+H) (12) 4'-[2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl)ethyl]lamino] ethyl] -3-phenoxy-1, 1 '-biphenyl-4-carboxylic acid dihydrochloride 35 NMR (DMSO-d 6 , 5): 3.00-3.50(6H, m), 5.20-5.30(1H, m), WO 2004/002939 PCT/JP2003/008061 95 7.00-7.70(7H, m), 7.90-8.00(2H, m), 8.40-8.50(IH, m), 8.80-8.90(2H, m) MS (m/z): 455 (M+H) 5 (13) [ 4 '-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-1,1'-biphenyl-4-yl]acetic acid hydrochloride NMR (DMSO-d 6 , 6): 2.90-3.40(6H, m), 3.62(2H, s), 4.90 5.10(1H, m), 7.30-7.70(12H, m) MS (m/z): 410 (M+H) 10 (14) N-Benzoyl-4'-[(2R)-2-[ [ (2R)-2-hydroxy-2-(3-pyridyl) ethyllamino]lpropyl]-1,1'-biphenyl-4-sulfonamide dihydrochloride NMR (DMSO-d 6 , 6): 1.01(3H, d, J=6Hz), 2.60-3.60(5H, m), 15 5.00-5.15(1H, m), 7.20-8.10(13H, m), 8.30-8.40(1H, m), 8.70-8.80(2H, m) MS (m/z): 516 (M+H) (15) 4'-[2- [ (2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3-(1 20 piperidinyl)-1,1'-biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-d 6 , 6): 1.50-1.80(6H, d, m), 3.00-3.40(10H, m), 5.00-5.10(IH, m), 7.20-7.50(7H, m), 7.70 7.80(3H, m), 8.10-8.20(2H, m) 25 MS (m/z) : 445 (M+H) Example 36 The following compounds were obtained according to a similar manner to that of Example 21. 30 (1) Methyl 4'-[2-[ [(2R)-2-(6-chloro-3-pyridyl)-2 hydroxyethyl] amino]ethyl] -1,1 '-biphenyl-4-carboxylate MS (m/z) : 410 (M+H) 35 (2) Methyl [4'-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2- WO 2004/002939 PCT/JP2003/008061 96 hydroxyethyll]amino]propyl]-1,1 '-biphenyl-4-yl]acetate MS (m/z): 438 (M+H) (3) Ethyl 5-[4-[(2R)-2-[[ (2R)-2-(6-chloro-3-pyridyl)- 2 5 hydroxyethyl] amino] propyl] phenyl] -1-naphthoate MS (m/z): 489 (M+H) (4) Methyl 4'-[2-[[(2R)-2-(4-chlorophenyl)- 2 hydroxyethyl] amino]ethyl]-1,1 '-biphenyl-4-carboxylate 10 MS (m/z): 410 (M+H) (5) Ethyl 6-[4-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl]amino] ethyl]phenyl] nicotinate (+)ESI-MS m/z: 515 (M+H) 15 (6) Methyl 4'-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)- 2 hydroxyethyl] amino]ethyl]-2,6-dimethyl-1, 1 '-biphenyl-4 carboxylate (+)ESI-MS m/z: 528(M+H)+ 20 Example 37 Under nitrogen to a solution of methyl 4'-[2-[[(2R)-2 (6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1' biphenyl-4-carboxylate (110 mg) in tetrahydrofran (10 ml) 25 was added lM methylzinc chloride in tetrahydrofran (0.8 ml) and tetrakis(triphenylphosphine)palladium (15.5 mg) at room temperature. The mixture was stirred at 80 0 C for 24 hours, and then poured into an aqueous solution (60 ml) of ethylenediaminetetraacetic acid (1 g). The resulting 30 mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel 35 (chloroform:methanol = 100:1) to give methyl 4'-[2-[[(2R)-2- WO 2004/002939 PCT/JP2003/008061 97 hydroxy-2- (6-methyl-3-pyridyl) ethyl] amino] ethyl]-1, 1' biphenyl-4-carboxylate (41 mg) as a colorless oil. MS (m/z) : 391 (M+H) 5 Example 38 The following compounds were obtained by alkaline hydrolysis of each ester thereof in a conventional manner. (1) Sodium 4'-[2-[[(2R)-2-hydroxy-2-(6-methyl- 3 10 pyridyl)ethyl]amino]ethyl]-1,1 '-biphenyl-4-carboxylate NMR (DMSO-d 6 , 6): 2.50(3H, s), 2.60-2.90(6H, m), 4.60 4.70(lH, m), 7.10-7.40(3H, m), 7.50-7.70(5H, m), 7.90(1H, d, J=8Hz), 8.40(1H, s) 15 (2) Sodium 4'-[2-[[(2R)-2-(6-chloro-3-pyridyl)-2 hydroxyethyll]amino] ethyl] -1,1' -biphenyl-4-carboxylate NMR (DMSO-d 6 , 6): 2.80-3.80(6H, m), 4.90(1H, t, J=6Hz), 7.10-7.90(8H, m), 7.98(2H, d, J=8Hz), 8.30(1H, d, J=2Hz) 20 MS (m/z): 397 (M+H) (3) Sodium 4'-[2-[[(2R)-2-(4-chlorophenyl)-2 hydroxyethyl] amino]ethyl]-1,1' -biphenyl-4-carboxylate NMR (DMSO-d 6 , 5): 2.70-3.50(6H, m), 4.50-4.60(1H, m), 25 7.10-7.60(8HI, m), 7.94(2H, d, J=8Hz) MS (m/z) : 396 (M+H) Example 39 The following compounds were obtained according to a 30 similar manner to that of Preparation 29. (1) Methyl [4'-[(2R)-2-[N-(tert-butoxycarbonyl)-N-[(2R)-2 (3-chlorophenyl)-2-hydroxyethyl] amino] propyl] -1,1' biphenyl-4-yl] acetate 35 MS (m/z): 538 (M+H) WO 2004/002939 PCT/JP2003/008061 98 (2) Ethyl 5-[4-[(2R)-2-[N-(tert-butoxycarbonyl)-N-[(2R)-2 (6-chloro-3-pyridyl) -2-hydroxyethyl]aminol]propyl] phenyl] -1-naphthoate 5 MS (m/z): 589 (M+H) Example 40 The following compounds were obtained according to a similar manner to that of Example 18. 10 (1) [4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-l,1'-biphenyl-3-yl]acetic acid hydrochloride NMR (DMSO-d 6 , 5): 2.80-3.40(6H, m), 3.65(2H, s), 4.90 5.10(1H, m), 7.20-7.70(12H, m) 15 MS (m/z): 408 (M-H) (2) 4'-[2- [ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-1,1'-biphenyl-3-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 3.01-3.29(6H, m), 4.97-5.02(IH, min), 20 6.34(1H, br), 6.90(1H, m), 7.71-7.48(9H, m), 7.89 7.95(2H, m),8.18(1H, d, J=1.5Hz), 8.96(lH,br) (-)ESI-MS m/z: 394 (M-HC1-H) (3) 3-[2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] 25 ethyl]-6H-benzo[c]chromene-8-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 3.00-3.28(6H, m), 4.96-5.01(1H, m), 5.20(2H, s), 6.34(1H, br), 6.94-7.03(2H, m), 7.34 7.47(4H, m), 7.86-7.94(4H, m), 8.94(1H, br) 30 (-)ESI-MS m/z: 422 (M-HCI-H) (4) 2-[2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-6H-benzo(c]chromene-8-carboxylic acid hydrochloride 35 NMR (DMSO-d 6 , 5): 3.00-3.26(6H, m), 5.03-5.07(lH, m), WO 2004/002939 PCT/JP2003/008061 99 5.19(2H, s), 6.38(1H, br), 6.99(1H, d, J=8.2Hz), 7.20-7.25(2H, m), 7.35-7.48(4H, m), 7.85-7.98(4H, m), 9.10(1H, br) (-)ESI-MS m/z: 422 (M-HC1-H) 5 (5) 6-[4-[2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethyl]phenyl]nicotinic acid hydrochloride NMR (DMSO-d 6 , 5): 3.08-3.24(6H, m), 5.00-5.07(1H, br), 7.34-7.47(6H, m), 8.09-8.17 (3H, m), 8.31-8.38(IH, 10 m), 8.98(IH, br), 9.12-9.16(1H, m), 9.30(1H, br) (-)ESI-MS m/z: 395 (M-HC1-H) (6) 3'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-1,1'-biphenyl-4-carboxylic acid hydrochloride 15 NMR (DMSO-d 6 , 5): 3.01-3.28(6H, m), 4.97-5.02(1H, m), 6.34(1H, br), 7.34-7.48(6H, m), 7.62-7.65(2H, m), 7.78-7.83(2H, m), 8.01-8.05(2H, m), 8.96(1H, br) (-)ESI-MS m/z: 394 (M-HC1-H) 20 (7) 4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-2-fluoro-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 3.01-3.28(6H, m), 5.02-5.05(1H, m), 6.38(1H, br), 7.37-7.87(11H, m), 9.10(1H, br) 25 (-)ESI-MS m/z: 412 (M-HCl-H) (8) 4'-[2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-2,6-dimethyl-1,1'-biphenyl-4-carboxylic acid hydrochloride 30 NMR (DMSO-d 6 , 5): 2.00(6H, m), 3.06-3.11(6H, m),4.98 5.04(1H, m), 6.36-6.85(1H, br), 7.11-7.15(2H, m),7.35-7.49(6H, m), 7.70-7.72(2H, m), 9.06(1H, br) (-)ESI-MS m/z: 422 (M-HC1-H) 35 WO 2004/002939 PCT/JP2003/008061 100 (9) 3-Chloro-4'-[2-[[(2R)-2-(3-chlorophenyl)- 2 hydroxyethyl] amino]ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 3.01-3.28(6H, m), 5.00-5.04(lH, m), 5 6.36(1H, br), 7.35-7.47(6H, nm), 7.70-7.91(5H, m), 9.07(1H, br) (-)ESI-MS m/z: 428 (M-HC1-H) (10) 4'-[2-[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] 10 ethyl]-2'-methoxy-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 3.03-3.27(6H, m), 3.80(3H, s), 5.03 5.07(1H, m), 6.38(1:H, br), 6.96(1H, d, J=7.9Hz), 7.06(1H, s), 7.29-7.48(5H, m), 7.58(1H, d, 15 J=8.3Hz), 7.96(1H, d, J=8.3Hz), 9.13-9.18(1H, br) (-)ESI-MS m/z: 424 (M-HC1-H) (11) 2'-Chloro-4'-[2-[[(2R)-2-(3-chlorophenyl)- 2 hydroxyethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic 20 acid hydrochloride NMR (DMSO-d 6 , 5): 3.00-3.27(6H, m), 5.01-5.07(1H, m), 6.37-6.39(1H, br), 6.96(1H, d, J=7.9Hz), 7.34 7.57(9H, m), 8.04(2H, d, J=8.3Hz), 9.04 9.30(1H,br) 25 (-)ESI-MS m/z: 428 (M-HCl-H) (12) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]- 3 (isopropylthio)-1,1'-biphenyl-4-carboxylic acid hydrochloride 30 NMR (DMSO-d 6 , 5): 1.31 (6H, d, J=6.5Hz), 2.99-3.33 (6H, m), 3.69-3.82 (IH, m), 4.96-5.00 (1H, m), 6.22 (11H, m), 7.30-7.92 (12H, m) (-)ESI-MS m/z: 434 (M-HCl-H) 35 (13) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3- WO 2004/002939 PCT/JP2003/008061 101 (isopropylsulfonyl)-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 6): 1.25 (6H, d, J=6.8Hz), 2.99-3.33 (6H, m), 3.94-4.08 (1H, m), 4.96-5.00 (1H, m), 6.22 (IH, 5 m), 7.27-8.12 (12H, m) (-)ESI-MS m/z: 466 (M-HC1-H) Example 41 The following compounds were obtained according to a 10 similar manner to that of Example 14 followed by a similar manner to that of Example 18. (1) 4'-[2-[ [(2R)-2-Hydroxy-2-phenylethyl]lamino]ethyl]-3 isobutyl-1,1'-biphenyl-4-carboxylic acid hydrochloride 15 NMR (DMSO-d 6 , 5): 0.89(6H, d, J=8Hz), 1.80-2.00(1IH, m), 2.90-3.40(8H, m), 4.90-5.10(IH, m), 7.30-7.80(12H, m) MS (m/z) : 418 (M+H) 20 (2) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-phenylethyllamino] propyl]-3-isobutyl-l,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 6): 0.89(7H, d, J=6Hz), 1.21(3H, d, J=6Hz), 1.80-1.90(1H, m), 2.70-3.60(7H, m), 5.00 25 5.10(1H, m), 7.20-7.80(12H, m) MS (m/z) : 432 (M+H) (3) 4'-[2-[ [(2R)-2-Hydroxy-2-phenylethyl] amino] ethyl]-3 isopropyl-1,1'-biphenyl-4-carboxylic acid hydrochloride 30 NMR (DMSO-d 6 , 5): 1.20(3H, d, J=7Hz), 2.90-3.40(6H, m), 3.80-3.90(1H, m), 4.90-5.00(1H, m), 7.20-7.80(12H, m) MS (m/z): 404 (M+H) 35 (4) 4'-[2-[ [(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-3- WO 2004/002939 PCT/JP2003/008061 102 phenyl-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 2.90-3.40(6H, m), 4.95-5.10(1H, m), 7.30-7.80(17H, m) MS (m/z): 438 (M+H) 5 (5) 4'-[2-[ [(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]- 3 propyl-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 0.90-1.05(3H, m), 1.50-1.70(2H, m), 2.80-3.40(8H, m), 4.90-5.05(lH, m), 7.20-7.80(12H, 10 m) MS (m/z): 404 (M+H) (6) 4'-[ (2R)-2-[[(2R)-2-Hydroxy-2-phenylethyl]amino] propyl]-3-propyl-1,1'-biphenyl-4-carboxylic acid 15 hydrochloride NMR (DMSO-d 6 , 5): 0.80-1.70(BH, m), 2.70-3.20(7H, m), 5.00-5.15(1H, m), 7.10-7.90(12H, m) MS (m/z) : 418 (M+H) 20 (7) 4'-[(2R)-2- [ (2R)-2-Hydroxy-2-phenylethyl]amino] propyl]-3-isopropyl-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 5): 1.05-1.10(9H, m), 2.05-2.15(1H, m), 2.80-3.60(5H, m), 5.00-5.15(1H, m), 7.20-7.80(121H, 25 m) MS (m/z): 418 (M+H) (8) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl] amino]propyll]-3-phenyl-1, 1' -biphenyl-4-carboxylic acid 30 dihydrochloride NMR (DMSO-d 6 , 5): 1.15(3H, d, J=6Hz), 2.80-2.90(IH, m), 3.20-3.60(4H, m), 5.10-5.20(1H, m), 7.30-7.90(13H, m), 8.30-8.40(1H, m), 8.70-8.90(2H, m) MS (m/z): 453 (M+H) 35 WO 2004/002939 PCT/JP2003/008061 103 (9) 4'-[2-[ [ (2R)-2-Hydroxy-2-phenylethyll]amino]ethyl]-3 phenyl-1,1'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d 6 , 6): 3.00-3.60(6H, m), 5.20-5.30(lH, m), 7.20-7.90(13H, m), 8.30-8.40(IH, m), 8.70-8.80(2H, 5 m) MS (m/z) : 439 (M+H) Example 42 The following compounds were obtained by conversion of 10 an amino protective group from each corresponding amino protective group of benzyl in a conventional manner. (1) Ethyl 6-[4-[2-[N-(tert-butoxycarbonyl)-N-[ (2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino] ethyl]phenyl] 15 nicotinate (+)ESI-MS m/z: 547 (M+Na) + (2) Methyl 4'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino] ethyl]-2,6-dimethyl 20 1, 1'-biphenyl-4-carboxylate (+)ESI-MS m/z: 560 (M+Na) + Example 43 The following compound was obtained according to a 25 similar manner to that of Example 55. tert-Butyl N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] N-[2-(3'-hydroxy-l, 1' -biphenyl-4-yl)ethyl]carbamate (+)ESI-MS m/z: 468 (M+H) + 30 Example 44 The following compound was obtained by a replacement reaction of the object compound of Example 43 with tert butyl 2-bromoacetate in a conventional manner. 35 WO 2004/002939 PCT/JP2003/008061 104 tert-Butyl [[4'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2 (3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1'-biphenyl 3-yl]oxy]acetate (+)ESI-MS m/z: 582 (M+H) + 5 Example 45 The following compound was obtained by elimination of two amino protective groups of the object compound of Example 44 in a conventional manner. 10 [[4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethyl]-l,1'-biphenyl-3-yl]oxy]acetic acid hydrochloride NIMR (DMSO-d 6 , 6): 3.00-3.27(6H,m), 4.76(2H,s), 5.01 15 5.05(1H,m), 6.36(1H,br), 6.90(lH,m), 7.15 7.48(9H,m), 7.64(2H,d,J=8.0Hz), 9.09-9.21(lH,br) (-)ESI-MS m/z: 424 (M-HC1-H) Example 46 20 The following compound was obtained according to a similar manner to that of Preparation 61. Methyl 4-bromo-3-[[4-[2-[N-(tert-butoxycarbonyl)-N [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl] 25 phenoxy]methyl]benzoate (+)ESI-MS m/z: 617, 619 (M+H) + Example 47 The following compound was obtained according to a 30 similar manner to that of Example 20. tert-Butyl N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] N-[2-[4'-formyl-3'-(l-piperidinyl)-1,1'-biphenyl-4 yl]ethyl]carbamate 35 NMR (DMSO-d 6 , 6): 1.71-2.00(6H, m), 3.09-3.20(6H,m), WO 2004/002939 PCT/JP2003/008061 105 3.47-3.59(4H, br), 5.06-5.10(1H, m), 7.28-7.48(6H, m), 7.82-7.89(3H, m), 8.12-8.21(2H, m) (-)ESI-MS m/z: 474 (M-HC1-H) 5 Example 48 The following compound was obtained according to a similar manner to that of Preparation 28. Methyl 3-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 10 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-6H benzo[c]chromene-8-carboxylate (+)ESI-MS m/z: 538 (M+H) + Example 49 15 The following compound was obtained according to a similar manner to that of Preparation 62. Methyl 2-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-6H 20 benzo[c]chromene-8-carboxylate (+)ESI-MS m/z: 560 (M+Na) + Example 50 The following compounds were obtained according to a 25 similar manner to that of Example 1. (1) 4'-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-hydroxy-2-(3 pyridyl)ethyl]lamino]ethyl]-3-phenoxy-l,1'-biphenyl-4 carboxylic acid 30 MS (m/z): 555 (M+H) (2) 4'-[2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-hydroxy-2 phenylethyl]amino]ethyl]-3-(1-piperidinyl)-1,1' biphenyl-4-carboxylic acid 35 MS (m/z): 545 (M+H) WO 2004/002939 PCT/JP2003/008061 106 Example 51 The following compound was obtained according to a similar manner to that of Example 1 followed by a similar 5 manner to that of Example 25. 4'-[(2R)-2-[N-(tert-Butoxycarbonyl)-N-[(2R)-2-hydroxy 2-(3-pyridyl)ethyl]lamino]propyl]-3-phenoxy-l,1'-biphenyl-4 carboxylic acid 10 MS (m/z): 569 (M+H) Example 52 The following compound was obtained according to a similar manner to that of Example 25 followed by a similar 15 manner to that of Example 18. 5-[4-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl] amino]propyl]phenyl]-l-naphthoic acid dihydrochloride MS (m/z): 426 (M+H) 20 Example 53 The following compound was obtained according to a similar manner to that of Example 25 followed by a similar manner to that of Example 27. 25 4-[4-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl] amino]propyl]phenyl]-l-naphthoic acid dihydrochloride MS (m/z): 427 (M+H) 30 Example 54 The following compound was obtained according to a similar manner to that of Example 25. tert-Butyl N-[(lR)-2-[4'-[(benzoylamino)sulfonyl]-l,l' 35 biphenyl-4-yl]-l-methylethyl]-N-[(2R)-2-hydroxy-2-(3- WO 2004/002939 PCT/JP2003/008061 107 pyridyl)ethyl]carbamate MS (m/z): 616 (M+H) Example 55 5 The following compound was obtained according to a similar manner to that of Example 7. Methyl 4'-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2 hydroxy-2-pyenylethyl]amino]ethyl]-3-(isopropylthio)-1,1' 10 biphenyl-4-carboxylate (+)ESI-MS (m/z): 572 (M+Na) Example 56 To a solution of methyl 4'-[2-[N-(tert-butoxycarbonyl) 15 N-[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]- 3 (isopropylthio)-l,l'-biphenyl-4-carboxylate (338 mg) in chloroform (8 ml) and N,N-dimethylformamide (4 ml) was added m-chloroperbenzoic acid (594 mg) at room temperature and the mixture was stirred at the same temperature for 1 hour. To 20 the mixture was added water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4'-[2-[N-(tert 25 butoxycarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]amino] ethyl]-3-(isopropylsulfonyl)-1,1'-biphenyl-4-carboxylate (340 mg). (+)ESI-MS m/z: 604 (M+Na) + 30 Preparation 71 To a solution of (2R)-N-benzyl-N-[2-(4-bromophenyl) ethyl]-2-[[tert-butyl(dimethyl)silyl] oxy] -2-(3 chlorophenyl)ethanamine (2.1 g) in tetrahydrofuran (25 ml) was added a solution of butyllithium in hexane (1.59M, 2.83 35 ml) dropwise at -70'C under nitrogen and the mixture was WO 2004/002939 PCT/JP2003/008061 108 stirred at -70 0 C for 30 minutes. To the reaction mixture was added 4-[[tert-butyl(dimethyl)silyl]oxy]benzaldehy.de (977 mg) at -70'C, and the mixture was stirred at -70 0 C for 1 hour. The mixture was allowed to warm to room temperature 5 and partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium biscarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel 10 (hexane/ethyl acetate = 10/1) to give [4-[2-[N-benzyl-N [(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl) ethyl]amino]ethyl]phenyl][4-[[tert-butyl(dimethyl)silyl] oxy]phenyl]methanol (1.1 g). (+)ESI-MS m/z: 716 (M+H) + 15 Preparation 72 To a solution of (iR)-2-[[2-(4-bromophenyl)ethyl] amino]-l-(3-chlorophenyl)ethanol (5.1 g) and imidazole (2.9 g) in N,N-dimethylformamide (30 ml) was added tert 20 butyl(dimethyl)silyl chloride (5.85 g) and the mixture was stirred at 40 0 C for 24 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, 5% acetic acid solution, saturated sodium biscarbonate solution and brine, dried over 25 magnesium sulfate and evaporated under reduced pressure to give a crude product. To a solution of the product in tetrahydrofuran (80 ml) and triethylamine (2.0 ml) was added di-tert-butyl dicarbonate (3.14 g), and the mixture was stirred at room temperature for 3 hours. The mixture was 30 partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 20/1) to give tert-butyl N-[2 35 (4-bromophenyl)ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)- WO 2004/002939 PCT/JP2003/008061 109 silyl]oxy]-2-(3-chlorophenyl)ethyl]carbamate (5.0 g). (+)ESI-MS m/z: 568 (M+H) + Preparation 73 5 To a solution of tert-butyl N-[2-(4-bromophenyl) ethyl]-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy] -2-(3 chlorophenyl)ethyl]carbamate (880 mg) in tetrahydrofuran (13 ml) was added a solution of butyllithium in hexane (1.59M, 1.07 ml) dropwise at -70 0 C under nitrogen and the mixture 10 was stirred at -70 0 C for 30 minutes. To the reaction mixture was added 4-[[tert-butyl(dimethyl)silyl]oxy]-N methoxy-N-methylbenzamide (480 mg) at -70 0 C, and the mixture was stirred at -70'C for 1 hour. The mixture was allowed to warm to room temperature and partitioned between ethyl 15 acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 10/1) to give tert-butyl N-[2 20 [4-[4-[[tert-butyl(dimethyl)silyl]oxy]benzoyl]phenyl] ethyl] N-[(2R)-2-[[tert-butyl(dimethyl)silyl] oxy]-2-(3 chlorophenyl)ethyl]carbamate (710 mg). (+)ESI-MS m/z: 746 (M+Na) + 25 Preparation 74 Di-tert-butyl dicarbonate (2.18 g) was added to a solution of 2-(4-bromophenyl)ethanamine (2.0 g) in tetrahydrofuran (5 ml) under ice water cooling over 10 minutes and the mixture was stirred at room temperature for 30 further 1 hour. The reaction mixture was evaporated in vacuo to give tert-butyl 2-(4-bromophenyl)ethylcarbamate (2.98 g) as a colorless foam. NMR (CDC1 3 , 5): 1.43 (9H, s), 2.75 (2H, t, J=8Hz), 3.36 (2H, t, J=8Hz), 7.00-7.10 (2H, m), 7.30-7.50 (2H, 35 inm) WO 2004/002939 PCT/JP2003/008061 110 Preparation 75 The following compound was obtained according to a similar manner to that of Preparation 3. 5 Methyl 4'-[2-[(tert-butoxycarbonyl)amino]ethyl]-l,l' biphenyl-4-carboxylate MS m/z: 356 (M+H) 10 Preparation 76 The following compound was obtained according to a similar manner to that of Example 4. Methyl 4'-(2-aminoethyl)-l,l'-biphenyl-4-carboxylate 15 hydrochloride NMR (DMSO-d 6 , 5): 2.80-3.10 (4H, m), 3.88 (3H, s), 7.40 (2H, d, J=8Hz), 7.60-8.10 (6H, m) Preparation 77 20 To a solution of methyl 4'-(2-aminoethyl)-l,l' biphenyl-4-carboxylate hydrochloride (420 mg) and benzaldehyde (153 mg) in dichloromethane (5 ml) was stirred for 3 hours, and the mixture was evaporated in vacuo. To the residue in methanol (10 ml) was added sodium borohydride 25 (65 mg) on ice cooling, and stirred at the same temperature for 1 hour. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The 30 residue was chromatographed (hexane - ethyl acetate) over silica gel to afford methyl 4'-[2-(benzylamino)ethyl]-l,l' biphenyl-4-carboxylate (460 mg) as a colorless powder. MS m/z: 346 (M+H) 35 Preparation 78 WO 2004/002939 PCT/JP2003/008061 111 Under nitrogen at 4 0 C, to a solution of 2,2,2 trifluoro-N-[2-[4-[(4-methoxyphenyl)thio]phenyl]ethyl] acetamide (1.5 g) in dichloromethane (15 ml) was added IM boron tribromide in dichloromethane (10.5 ml), and the 5 mixture was stirred at room temperature for 15 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane and saturated aqueous sodium bicarbonate. After separation, the organic layer was dried over magnesium sulfate and evaporated under 10 reduced pressure to give 2,2,2-trifluoro-N-[2-[4-[(4 hydroxyphenyl)thio]phenyl]ethyl]acetamide (1.42 g). (+)ESI-MS m/z: 364 (M+Na)+ Preparation 79 15 To a solution of 2,2,2-trifluoro-N-[2-[4-[(4 hydroxyphenyl)thio]phenyl]ethyl]acetamide (480 mg) in methanol (5.0 ml) was added lN sodium hydroxide solution (2.8 ml). The mixture was refluxed for 12 hours. The mixture was evaporated under reduced pressure. The residue 20 was dissolved in a mixture of dichloromethane (40 ml), IN hydrochloric acid solution (2.0 ml) and water (15 ml). After separation, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 4-[[4 (2-aminoethyl)phenyl]thio]phenol (300 mg). 25 (-)ESI-MS m/z: 244 (M-H) Preparation 80 To a solution of (aS,PR)-4-hydroxynorephedrine (500 mg) and 4-bromophenylethyl bromide (500 mg) in N,N 30 dimethylformamide (5 ml) was added N,N-diiospropylethylamine (0.5 ml), and the mixture was stirred for 6 hours at 80 0 C. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residual 35 oil was diluted in tetrahydrofuran (10 ml). To the solution WO 2004/002939 PCT/JP2003/008061 112 was added di-tert-butyl dicarbonate (1 g) at room temperature, and the mixture was stirred at the same temperature for 12 hours. The resulting mixture was evaporated under pressure and the residue was purified by 5 column chromatography on silica gel to give 4-[2-[N [(IS,2R)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]-N (tert-butyloxycarbonyl)amino]ethyl]phenyl bromide (520 mg). MS m/z: 550 (M+H) 10 Example 57 To a solution of (2R)-N-benzyl-N-[2-(4-bromophenyl) ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3 chlorophenyl)ethanamine (850 mg) in 1,2-dimethoxyethane (9 ml) was added 4-[[tert-butyl(dimethyl)silyl]oxy] 15 phenylboronic acid (498 mg), tetrakis(triphenylphosphine) palladium (88 mg) and aqueous solution of sodium carbonate (2M, 1.6 ml), and the mixture was stirred at 75 0 C for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed 20 with brine, dried over magnesium sulfate and evaporated. To a solution of the residue in tetrahydrofuran (10 ml) was added IM tetrabutylammonium fluoride in tetrahydrofuran (3.6 ml), and the mixture was stirred at room temperature for 8 hours under nitrogen. The mixture was partitioned between 25 ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give 4'-[2-[N-benzyl-N 30 [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]lamino]ethyl]-1,1' biphenyl-4-ol (540 mg). (+)ESI-MS m/z: 458 (M+H) + Example 58 35 A mixture of 4'-[2-[N-benzyl-N-[(2R)-2-(3- WO 2004/002939 PCT/JP2003/008061 113 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1'-biphenyl-4-ol (420-mg) in 4N hydrogen chloride in ethyl acetate (1.0 ml) was stirred for 5 minutes. The solvent was removed by evaporation. A suspension of the residue in ethanol (1.5 5 ml) and chlorobenzene (3.5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 10 mg) under hydrogen atmosphere for 1 hour. The catalyst was filtered off, and the filtrate was evaporated. The residue was diluted with chloroform (40 ml) and methanol (5 ml). The organic layer 10 was washed with saturated sodium biscarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. To the residue was added tetrahydrofuran (3 ml) and di-tert-butyl dicarbonate (220 mg), and the mixture was stirred at room temperature for 12 hours. The 15 mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert 20 butyl (2R)-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-(4' hydroxy-1,l'-biphenyl-4-yl)ethyl]carbamate (245 mg). (+)ESI-MS m/z: 490 (M+Na) + Example 59 25 To a solution of tert-butyl (2R)-N-[2-(3-chlorophenyl) 2-hydroxyethyl]-N-[2-(4' -hydroxy-1, 1' -biphenyl-4 yl)ethyl]carbamate (240 mg) and potassium carbonate (78 mg) in N,N-dimethylformamide (4 ml) was added tert-butyl bromoacetate (110 mg), and the mixture was stirred at room 30 temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel 35 (hexane/ethyl acetate = 3/1) to give tert-butyl [[4'-[2-[N- WO 2004/002939 PCT/JP2003/008061 114 (tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl] amino] ethyl]-1,1' -biphenyl-4-yl] oxy] acetate (245 mg). (+)ESI-MS m/z: 582 (M+H) + 5 Example 60 The following compounds were obtained according to a similar manner to that of Example 4. 10 (1) [[4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethyl]-1,1'-biphenyl-4-yl]oxy]acetic acid hydrochloride NMR (DMSO-d 6 , 5): 3.02-3.35 (6H, m), 4.72 (2H, s), 5.00-5.05 (IH, m), 6.37 (IH, br), 6.99 (2H, d, 15 J=8.7Hz), 7.30-7.61 (10H, m), 9.04 (1H, br), 13.03 (1H, br) (-)ESI-MS m/z: 424 (M-HCl-H) (2) [4-[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyll 20 amino]ethyl]benzoyl]phenoxy]acetic acid hydrochloride NMR (DMSO-d 6 , 5): 3.01-3.32 (6H, m), 4.81 (2H, s), 4.96-5.00 (1H, m), 6.35 (IH, br), 7.07 (2H, d, J=8.8Hz), 7.35-7.47 (6H, m), 7.66-7.75 (4H, m), 8.99 (1H, br) 25 (-)ESI-MS m/z: 452 (M-HC1-H) Example 61 To a solution of tert-butyl N-[2-(4-bromophenyl)ethyl] N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (435 mg) 30 in 1,2-dimethoxyethane (6 ml) were added 4-methoxycarbonyl phenyl boronic acid (224 mg), tetrakis(triphenylphosphine) palladium (55 mg) and aqueous solution of sodium carbonate (2M, 1.0 ml), and the mixture was stirred at 800C for 2 hours under nitrogen. The mixture was diluted with ethyl 35 acetate and water. The organic layer was separated, washed WO 2004/002939 PCT/JP2003/008061 115 with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give methyl 4'-[2-[N-(tert-butoxycarbonyl)-N-[ (2R)-2-(3 5 chlorophenyl)-2-hydroxyethyll] amino] ethyl] -1,1' -biphenyl-4 carboxylate (400 mg). (+)ESI-MS m/z: 510 (M+H) + Example 62 10 The following compound was obtained according to a similar manner to that of Example 6. 4'-[2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino] ethyl]-1,1'-biphenyl-4-carboxylic acid hydrochloride 15 NMR (DMSO-d 6 , 6); 3.01-3.27 (6H, m), 5.01-5.06 (1H, m), 6.36 (1H, br), 7.34-7.48 (6H, m), 7.70-7.81 (6H, m), 8.02 (2H, d, J=8.4Hz), 9.11 (1H, br) (-)ESI-MS m/z: 394 (M-HC1-H) 20 Example 63 To a solution of [4-[2-[N-benzyl-N-[(2R)-2-[[tert butyl(dimethyl)silyl] oxy]-2-(3-chlorophenyl)ethyl] amino] ethyl]phenyl][4-[[tert-butyl(dimethyl)silyl]loxy]phenyl] methanol (1.1 g) in tetrahydrofuran (15 ml) was added IM 25 tetrabutylammonium fluoride in tetrahydrofuran (5.0 ml) at O'C, and the mixture was stirred at room temperature for 24 hours under nitrogen. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate 30 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give 4-[[4-[2-[N-benzyl-N [(2R)-2- (3-chlorophenyl)-2-hydroxyethyl] amino] ethyl] phenyl] (hydroxy)methyl]phenol (550 mg). 35 (+)ESI-MS m/z: 486 (M-H)- WO 2004/002939 PCT/JP2003/008061 116 Example 64 A mixture of 4-[[4-[2-[N-benzyl-N-[(2R)-2-(3 chlorophenyl)-2-hydroxyethyll]amino] ethyl]phenyl](hydroxy) 5 methyl]phenol (545 mg) in 4N hydrogen chloride in 1,4 dioxane (1.0 ml) was stirred for 5 minutes. The solvent was removed by evaporation. A suspension of the residue in ethanol (2.2 ml) and chlorobenzene (5.2 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 55 mg) under 10 hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was evaporated. The residue was diluted with ethyl acetate and saturated sodium biscarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under 15 reduced pressure to give 4-[4-[2-[[(2R)-2-(3-chlorophenyl) 2-hydroxyethyl]amino]ethyl]benzyl]phenol (395 mg). (+)ESI-MS m/z: 382 (M+H) + Example 65 20 To a solution of 4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl]amino]ethyl]benzyl]phenol (390 mg) in tetrahydrofuran (3.5 ml) and water (3.5 ml) was added di tert-butyl dicarbonate (223 mg), and the mixture was stirred at room temperature for 30 minutes. The mixture was 25 partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give tert butyl (2R)-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-[4-(4 hydroxybenzyl)phenyl]ethyl]carbamate (480 mg). 30 (+)ESI-MS m/z: 482 (M+H) + Example 66 The following compounds were obtained according to a similar manner to that of Example 57. 35 WO 2004/002939 PCT/JP2003/008061 117 (1) tert-Butyl [4-[4-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2 (3-chlorophenyl) -2-hydroxyethyl] amino]ethyl]benzyll] phenoxy] acetate (+)ESI-MS m/z: 598 (M+H) + 5 (2) tert-Butyl [4-[4-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2 (3-chlorophenyl)-2-hydroxyethyl] amino] ethyl]benzoyl] phenoxy] acetate (+)ESI-MS m/z: 610 (M+H) + 10 Examle 67 A solution of tert-butyl [4-[4-[2-[N-(tert butoxycarbonyl)-N- [ (2R)-2-(3-chlorophenyl)-2-hydroxyethyl] amino]ethyl]benzyl]phenoxy]acetate (240 mg) and 4N 15 hydrochloride in 1,4-dioxane (3.0 ml) was stirred at room temperature for 24 hours. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol/acetic acid/chloroform = 10/1/100) to give a product. To a 20 tetrahydrofuran (2.0 ml) solution of the product, 4N hydrogen chloride in 1,4-dioxane (1.0 ml) was added. The mixture was stirred for 5 minutes and evaporated under reduced pressure to give [4-[4-[2-[[(2R)-2-(3-chlorophenyl) 2-hydroxyethyl]amino]ethyl]benzyl]phenoxy]acetic acid 25 hydrochloride (72 mg). NMR (DMSO-d 6 , 5): 2.91-3.24 (6H, m), 3.84 (2H, s), 4.61 (2H, s), 4.94-4.99 (1H, m), 6.32 (1H, br), 6.80 (2H, d, J=8.7Hz), 7.10-7.21 (6H, m), 7.29-7.46 (4H, m), 8.89 (1H, br) 30 (-)ESI-MS m/z: 438 (M-HC1-H) Example 68 The following compound was obtained according to a similar manner to that of Example 61. 35 WO 2004/002939 PCT/JP2003/008061 118 tert-Butyl N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] N-[2- [4-(4-hydroxybenzoyl)phenyll]ethyl] carbamate (+)ESI-MS m/z: 496 (M+H) + 5 Example 69 A solution of methyl 4'-[2-(benzylamino)ethyl]-1,1' biphenyl-4-carboxylate (460 mg), and 2-chloro-5-[(2R)-2 oxiranyl]pyridine (207 mg) in ethanol (10 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The 10 residue was purified by column chromatography on silica gel (chlorofor:methanol = 100:1) to give methyl 4'-[2-[N-benzyl

N-[(

2 R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino] ethyl] l,l'-biphenyl-4-carboxylate (470 mg) as a colorless foam. MS m/z: 501 (M+H) 15 Example 70 Methyl 4'-[2-[N-benzyl-N-[(2R)-2-(6-chloro-3-pyridyl) 2-hydroxyethyl]amino]ethyl]-1,1'-biphenyl-4-carboxylate (470 mg), ammonium formate (296 mg) and palladium on carbon 20 powder (100 mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 30 minutes. The reaction mixture was filtrated and poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. A mixture of the residue 25 was chromatographed (chloroform-methanol) over silica gel to give methyl 4'-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl] amino]ethyl]-1,l'-biphenyl-4-carboxylate (326 mg) as a colorless foam. MS m/z: 377 (M+H) 30 Example 71 At room temperature, to a solution of methyl 4'-[2 [[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-, 1' biphenyl-4-carboxylate (326 mg) in methanol was added IN 35 sodium hydride (0.87 ml), and the mixture was stirred at the WO 2004/002939 PCT/JP2003/008061 119 same temperature for 3 hours. The resulting mixture was evaporated under reduced pressure and dried to give sodium 4-[4-[2- [[(2R)-2-hydroxy-2-(3-pyridyl)ethyl] amino] ethyl]]-l,l'-biphenyl-4-carboxylate (220 mg) as a colorless 5 powder. NMR (DMSO-d 6 , 5): 2.50-2.80 (6H, m), 4.70 (IH, t, J=6Hz), 7.10-7.40 (3H, m), 7.50-7.70 (5H, m), 7.90-8.00 (1H, m), 8.40-8.50 (2H, m) MS m/z: 361 (M-H) 10 Example 72 4-[[4-(2-Aminoethyl)phenyl]thio]phenol (295 mg) and (2R)-2-(3-chlorophenyl)oxirane (186 mg) in ethanol (3.5 ml) was refluxed for 6 hours. The mixture was evaporated. The 15 residue was purified by column chromatography on silica gel (chloroform/methanol = 100/3) to give 4-[[4-[2-[[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl] amino] ethyl] phenyl] thio] phenol (155 mg). (+)ESI-MS m/z: 400 (M+H) + 20 Example 73 To a solution of tert-butyl N-[(2R)-2-(3-chlorophenyl) 2-hydroxyethyl] -N-[2-[4- [ (4-hydroxyphenyl)thio]phenyl] ethyl]carbamate (195 mg) and potassium carbonate (59 mg) in 25 N,N-dimethylformamide (3 ml) was added tert-butyl bromoacetate (84 mg), and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium 30 sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give tert-butyl [4-[[4-[2 [N-(tert-butoxycarbonyl)-N- [ (2R)-2-(3-chlorophenyl)-2 hydroxyethyl] amino] ethyl] phenyl]thio]phenoxy]acetate (168 35 mg).

WO 2004/002939 PCT/JP2003/008061 120 (+)ESI-MS m/z: 636 (M+Na) 5 10 15 20 25 30 35

Claims (11)

1. A compound of the formula [I]: OH R 2 5 R 1 (CH 2 )i X R S R 9 R 3 R 4 X Y-Z wherein NN 10 is or is , or N -CH- -C 15 X is bond, -CH2-, I ' , -0-, -0CH 2 -, -CH 2 0-, -S OH 0 -N or I (in which R 7 is hydrogen or lower alkyl), R 7 Y is bond, -0-(CH 2 )n - (in which n is 1, 2, 3 or 4), -(CH2)m - (in which m is 1, 2, 3 or 4), 20 , -o , -0 or -0 Z is cyano, tetrazolyl, (benzylsulfonyl)carbamoyl, benzoylsulfamoyl, formyl, carboxy or protected 25 carboxy, R 1 is hydrogen, lower alkyl or halogen, R 2 is hydrogen or an amino protective group, R 3 is hydrogen or lower alkyl, R 4 is hydrogen or lower alkyl, 30 R 5 and R 8 are each independently hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, hydroxy(lower)alkoxy, mono(or di or tri)halo(lower)alkoxy, lower alkoxy(lower)alkoxy, lower alkenyloxy, cyclo(lower)alkyloxy, 35 cyclo(lower)alkyl(lower)alkoxy, benzyloxy, phenoxy, WO 2004/002939 PCT/JP2003/008061 122 lower alkylthio, cyclo(lower)alkylthio, lower alkylsulfonyl, cyclo(lower)alkylsulfonyl, amino, mono(or di)(lower)alkylamino, mono(or di or tri)halo(lower)alkyl, cyano, piperidinyl or phenyl, 5 R 6 is hydrogen, lower alkyl or halogen, R 9 is hydrogen or lower alkyl, and i is 1 or 2, provided that -CH- -C (1) when X is bond, -CH 2 -, I or i , OH 0 10 is , and B is 15 then R 5 is not hydrogen, or (2) when i is 1, then 4 is not , or, 20 or a salt thereof.

2. A compound of claim 1, wherein is or 25 N is , , or X is bond, -0-, -OCH 2 -, -S- or -N- (in which R 7 is 30 R7 hydrogen or lower alkyl), Y is bond, -0-(CH2)n - (in which n is 1, 2, 3 or 4), -(CH2) m - (in which m is 1, 2, 3 or 4), 35 , -o or - WO 2004/002939 PCT/JP2003/008061 123 Z is carboxy or lower alkoxycarbonyl, R 1 is hydrogen or halogen, R 2 is hydrogen, R 3 is hydrogen or lower alkyl, 5 R 4 is hydrogen, R5 is halogen, hydroxy, lower alkyl, lower alkoxy, hydroxy(lower)alkoxy, mono(or di or tri)halo(lower)alkoxy, lower alkoxy(lower)alkoxy, lower alkenyloxy, cyclo(lower)alkyloxy, phenoxy or 10 phenyl, R 6 is hydrogen, R 8 is hydrogen or lower alkyl, R 9 is hydrogen or lower alkyl, and i is 1 or 2. 15

3. A compound of claim 2, wherein is or 20 is or -N- 7 X is bond, -0-, -OCH 2 -, -S- or I (in which Ris 25 hydrogen or lower alkyl), Y is bond, -0-(CH 2 )n - (in which n is 1 or 2) or -(CH 2 )m - (in which m is 1 or 2), Z is carboxy or lower alkoxycarbonyl, R 1 is hydrogen or halogen, 30 R 2 is hydrogen, R 3 is hydrogen or lower alkyl, R 4 is hydrogen, R 5 is halogen, hydroxy, lower alkyl or lower alkoxy, R 6 is hydrogen, 35 R 8 is hydrogen or lower alkyl, WO 2004/002939 PCT/JP2003/008061 124 R 9 is hydrogen or lower alkyl, and i is 1.

4. A compound of claim 3, wherein UN A is or 10 is 10 X is bond, Y is bond, Z is carboxy or lower alkoxycarbonyl, R 1 is hydrogen or halogen, 15 R 2 is hydrogen, R 3 is hydrogen or lower alkyl, R 4 is hydrogen, R 5 is halogen, hydroxy, lower alkyl or lower alkoxy, R 6 is hydrogen, 20 R 8 is hydrogen or lower alkyl, R 9 is hydrogen or lower alkyl, and i is 1.

5. A compound of claim 4, which selected from the group 25 consisting of (1) 4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethyl] -2-methyl-1, 1' -biphenyl-4-carboxylic acid, (2) 4'-[(2R)-2-[ [ (2R)-2-Phenyl-2-hydroxyethyl]aminol 30 propyl]-3-methoxy-1, 1' -biphenyl-4-carboxylic acid, (3) 4'-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2 hydroxyethyl]amino]propyl] -3-isopropyloxy-1,1' biphenyl-4-carboxylic acid, (4) 4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] 35 amino]ethyl]-3-methoxy-1,1'-biphenyl-4-carboxylic WO 2004/002939 PCT/JP2003/008061 125 acid, (5) 4'-[2-[ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethyl] -2,3-dimethyl-1,1'-biphenyl-4 carboxylic acid, 5 (6) 4'-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino] ethyl]-2-methyl-l, 1'-biphenyl-4-carboxylic acid, (7) 4'-[(2R)-2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl] amino]propyl]-3-methoxy-1,1' -biphenyl-4-carboxylic acid, 10 (8) 4'-[2-[[(2R)-2-(3-Fluorophenyl)-2-hydroxyethyl] amino]ethyl] -3-propoxy-1, 1' -biphenyl-4-carboxylic acid, (9) 4'-[(2R)-2-[[(2R)-2-(3-Fluorophenyl)-2 hydroxyethyl] amino]propyl]-3-propoxy-l, 1' 15 biphenyl-4-carboxylic acid, (10) 4'-[2-[[(lS,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1 methylethyl] amino] ethyl] -3-isopropoxy-l, 1' biphenyl-4-carboxylic acid, and (11) 4'-[2-[ [(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl] 20 3-isobutyl-l,l'-biphenyl-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.

6. A process for preparing a compound of claim 1, or a salt thereof, 25 which comprises, (i) reacting a compound [II] of the formula: 0 30 R1 CH-CH [II] wherein R1, R and are each as defined in claim 1, with a compound [III] of the formula: 35 WO 2004/002939 PCT/JP2003/008061 126 R2 I R HN (CH 2 )i R6 R 5 R 3 R 4 X[IYZ R 8 wherein , X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and i are each as defined in claim 1, 5 or a salt thereof, to give a compound [I] of the formula: OH R 2 1N k(e L 2 ) R 6 R 5 R 9 i [I] 10 1 10 R X Y- Z wherein , , X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 R 8 , R 9 and i are each as defined in claim 1, 15 or a salt thereof, (ii) subjecting a compound [Ia] of the formula: OH R 2 Ia 20 RN (CH2i X6 R5[ RR 3 RR 4 I[ Ra wherein , , X, Y, Z, R 1 , R 3 , R 4 , R 5 , R 6 , R8, 25 R 9 and i are each as defined in claim 1, and R 2 is an amino protective group, or a salt thereof, to elimination reaction of the amino 30 protective group, to give a compound [Ib] of the WO 2004/002939 PCT/JP2003/008061 127 OH H R1, N (CH2 i R 6 R 5 SR 9 4 B [Ib] '-X Y- Z 5 wherein , , X, Y, Z, R 1 , R 3 , R, R 5 , R 6 , R 8 , R 9 and i are each as defined in claim 1, or a salt thereof, 10 (iii) reacting a compound [IV] of the formula: OH R 2 RI N (C 2 )[IV] 15 RR3 R 4 OH [IV] wherein , R 1 , R 2 , R 3 , R 4 , R 6 , R and i are each as defined in claim 1, or a salt thereof, with a compound [V] of the formula: 20 R B [V] (HO) 2 B Y-Z R 8 wherein B , Y, Z, R 5 and R 8 are each as defined in 25 claim 1, or a salt thereof, to give a compound [Ic] of the formula: OH R 2 30 R1 N R (CH 2 ) i O R 5 [Ic] A R 9 R 3R 4 B'F - [Ic] 0 wherein , , Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , 35 WO 2004/002939 PCT/JP2003/008061 128 R 9 and i are each as defined in claim 1, or a salt thereof, 5 (iv) reacting a compound [IV] of the formula: OH R 2 R1 N(CH 2 ) i R 6 R 9 3 R 4 OH [IV] 10 wherein , R 1 , R 2 , R 3 , R 4 , R 6 , R 9 and i are each as defined in claim 1, or a salt thereof, with a compound [VI] of the formula: 15 R 5 X Y[VI] xl 8Y-z R8 20 wherein , Y, Z, R 5 and R 8 are each as defined in claim 1, and X 1 is a leaving group, or a salt thereof, to give a compound [Ic] of the formula: 25 OH R 2 R1 N (CH 2 )i R 6 R 5 [Ic] SR 9 R3 R 4 [Ic] 0 y-z 8 30 wherein , , Y, Z, R1, R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 and i are each as defined in claim 1, 35 or a salt thereof, WO 2004/002939 PCT/JP2003/008061 129 (v) reacting a compound [VII] of the formula: OH R 2 5 PR1 1 R6 5 N (OH 2 )i R SiX 2 [VII] R 9 p,3 R 4 I 2 wherein , R1, R 2 , R 3 , R 4 , R 6 , R and i are each as 10 defined in claim 1, X 2 is a leaving group, or a salt thereof, with a compound [V] of the formula: R 5 15 (HO) 2 B Y-Z V] R 8 wherein , Y, Z, R 5 and R 8 are each as defined in claim 1, 20 or a salt thereof, to give a compound [Id] of the formula: OH R 2 25 4CH2)i R6 R 5 [Id] ,/ B 25 R 3R Y-Z 8 wherein A , , Y, Z, R1, R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , 30 R 9 and i are each as defined in claim 1, or a salt thereof, and (vi) subjecting a compound [lIe] of the formula: 35 WO 2004/002939 PCT/JP2003/008061 130 OH R 2 a Ri (CH R6 2) i X RCOOR1 [Ie] wherein" , , X, Y, R 1 , .R 3 , R 4 , R 5 , R 6 , R 8 , 10 R 9 and i are each as defined in claim 1, R I0 is lower alkyl, and R 2 is an amino protective group, a or a salt thereof, to deesterification reaction, to give a compound [If] of the formula: 15 OH 2 N (CH 2 ) 1 R R5 A RR 3 R 4 X f'Y OH [If] R3 R4X Y-COOH 20 wherein , X, Y, R 1 , R 3 , R 4 , R 5 , R 6 , R 8 , R and i are each as defined in claim 1, and 25 R 2 is defined above, a or a salt thereof, and then subjecting the compound [If] above to elimination reaction of amino protective group, to give a compound [Ig] of the formula: 30 OH H R N (CH 2 )R R5 R 9 X 3 R 4 IIg] 1H iX Y - C O O H 35 wherein, , X, Y, R, R 3 , R 4 , R 5 , R 6 , R 8 , WO2004/002939 PCT/JP2003/008061 131 or a salt thereof.

7. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a 5 pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers or excipients.

8. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a 10 medicament.

9. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament. 15

10. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as selective P3 adrenergic receptor agonists.

11. A method for the prophylactic and/or the therapeutic 20 treatment of pollakiuria or urinary incontinence which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal. 25 30 35