AU2006202092A1 - Aminoalcohol derivatives - Google Patents

Description

Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

Name of Applicant: Actual Inventors: Address for Service: Invention Title: Astellas Pharma Inc.

of 3-11, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo, 103- 8411,Japan Hattori Kouji Washizuka Kenichi Toda Susumu Sakurai Minoru Ito Shinji Tanabe Daisuke Araki Takanobu DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne 3000, Victoria, Australia "Aminoalcohol derivatives" Details of Associated Provisional Application No: 2005903307 22 June 2005 The following statement is a full description of this invention, including the best method of performing it known to us:

DESCRIPTION

AMINOALCOHOL DERIVATIVES TECHN~ICAL FIELD This invention relates to new amiLnoalcohol derivatives and salts thereof which are beta-3 (03) adrenergic receptor agonists: and useful as a medicament.

BACKGROUND OF THE INVENTION International.Publlcation 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, International Publication No.:WO 02/32897, published April 25, 2002, describes derivatives. of alpha-aryl ethanolamines useful as P3~ adrenergic receptor agonists, and International Publication.No. WO:2004/002939, published January 8, 2004, describes .aminoalcohol derivatives. useful as P33 adrenergic receptor agonists.

DISCLOSURE OF INVENTION This invention relates to new aminoalcohol derivatives which are 133 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-overactive bladder, anti-urinary incontinence, anti-pollakiuria activities, anti-diabetes and anti-obesity, to processes for the preparation thereof, to a phazmaceutical composition comprising the same and to a method of using the samne therapeutically In the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions In a humnan being or an animal.

One object of this ivention :Ss to provide new e.nd useful aminoalcohol derivatives and salts thereof which have gut sympathomimetic, anti-ulcerous, lipolytic, antioveractive bladder, anti-urinary incontinence, antipollakiuria activities, anti-diabetes and anti-obesity.

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 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 aminoalcohol derivatives and salts thereof.

The.object aminoalcohol derivatives of this invention are .new and can be represented by compound of the following formula OH

R

3 R7 A T, N X-D-E

R

2

R

4

R

5

R

wherein A is or D is r E is or- X is bond, -CH2-, or -NH-c R1 is hydrogen, halogen, hydroxy, amino or (lower alkanoyl)amino,

R

2

R

4 and R5 are each independently hydrogen or optionally substituted lower alkyl,

R

3 is hydrogen or an amino protective group,

R

6 is hydrogen, carboxy, lower alkoxycarbonyl or (lower alkylsulfonyl)carbamoyl, and

R

7 is -Y-R 8 in which Y is bond, or and R8 is hydrogen, lower alkyl, cyclo(lower)alkyl, carboxy(lower)alkyl or (lower alkoxycarbonyl)(lower)alkyl.

provided that when A is D is and E is then(1].. X is bond, R 1 is hydroxy, R 2 is methyl, R 4 and

R

5 are each hydrogen., R 3 is hydrogen R 6 is (methylsulfonyl)carbamoyl, and

R

7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; [2I.X is -CH 2 or R 1 is halogen, R 2

R

4 and

R

5 are each hydrogen, R is hydrogen, R 6 is carboxy, and R7is -Y-R 8 in which Y is and R 8 is isobutyl or cyclohexyl; or X is -CH 2 or R 1 is para-chloro, R 2 is hydrogen or methyl, R 4 and R5 are each hydrogen,

R

3 is hydrogen, R 6 is carboxy, and

R

7 is -Y-R 8 in which Y is and R is propyl, wen! D Is 0 then X is bond, R1 is amino, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and RIs -Y-R 8 in which Y is bond, or and R 8 Is ethyl, isopropyl, isobutyl or cyclopentyl; [23 X is bond, 1 is amino, R 2

R

4 and R 5 are each hydrogen, R3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and RIs -Y-R 8 In which Y Is or arnd RB is ethyl or isopropyl; [31 X is bond, RI is chioro or (lower alkanoyl)amino, R 2

R

4 and R 5 are each hydrogen,

R

3 is hydrogen, R 6 is (methylsulfonyl )carbamoyl. and Ris- -Y-Ra, in which Y is and R 8 is cyclohexy.; X is bond, R 1 is hydrogen, R 2

R

4 and R 5 'are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R1 7 is -Y-R 8 in which Y is and R 8 is cyclo Clower) alkyl: X is bond, RI is hydrogen, R 2

R

4 and R 5 are each-hydrogen, R 3 is hydrogen, R 6 Is carboxy, and

K

7 is -Y-R 8 (substituted at 2' or 6' position in 4-biphenyl of in which Y Is bond or and R 8 Is isopropyl, butyl or cyclohexyl; [61 X is -Cl! 2

R

1 is amino, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and :i -Y-R8, in which Y is and R8 is cyclo(lower)alkyl: E71 X is -CH~ 2 or is amino, R 2

R

4 and RS are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and

R

7 i:s -Y-RS, in, whi ch Y Is bond or and R 8 is isobutyl or cyclohexyl; or X is -NHl-, Rl is hydrogen, R 2

R

4 and R 5 axe each hydrogen, R 3 is hydrogen, R 6 is carboxy.

and

R

7 is -Y-R 8 in which Y is and R 8 is lower alkcyl, when Ais Di \s ,and E IsO1 then X is bond, Rl Is halogen, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen. R 6 is carboxy or (lower alkysulfonyl) carbamoyl, and

R

7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen, or (4).when-A'is >j D is V and E is then X is. bond,-Rl is hydrogen, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy or (lower alkysulfonyl)carbamfoyl, and

R

7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen, or prodrug thereof. or a pharmaceutically acceptable salt thereof.

According to this invention, the object compounds can be prepared byt processes which are illustrated in the following schemes.

Process I 0 1 3 R' RC or a salt thereoforasttheo om a salt thereof )H

R

3

RI

R

7 'X D

R

[I]

or a salt thereof Process 2 I Ial or a salt thereof elimination reaction of the armno protective group Process 3 11b] or a salt thereof (H)3 E cr a. salt thereof E IV) or a salt thereof

[I]

or a salt thereof Process 4 'X-D-Xl+

IV]

or a salt thereof [ViI or a salt thereof

MI

or a salt thereof Process 7 'X D E C O O

RO

or a salt thereof deesterification IFl7 reactionN A 2 R4 F5

COOH

or a salt thereof elimination reaction OH H of the amino R7 protective gro up 81J A'R

T

XD

R

2

R

4

A

5

\COOH

or a salt thereof wherein A, D. B, X, R 1

R

2

R

3

R

4

R

5 R6 and R7are each as defined above,

X

3 a is an amino protective group,

R

9 is lower alky and X, is a leaving group.

As to the starting compounds [IIXI, [IV], and some of them are novel and can be 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 to be included within the scope of the :..vetlom axre P-T .L&aied ixi deta.i L z the folowipnq The term "lower" is inteaded to mean a group having 1 to Preferably I to carbon atom(s), u-nless otherwise indicated.

Suitable 'lower alkyl' and "lower alkyl' moiety in the terms of *(oe alkylsulfonyl )carbamoyl", "carboxy( lower) aikylo and "(lower alkoxycarbonyl)(lower)alkylo may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tert-butyl, pentyl, 1-methylpentyl, tert-pentyl. neopentyl, hexy., isohexyl and the like, in which more preferable one is Cl-C 4 alkyl, and the most preferable one is methyl,* ethyl,. propy.. isopropyl., butyl or isobutyl.

Suitable "lower alkoxym moiety in the terms of "lower alkoxycarbolyl"'and "(lower alkoxycarbonyl) (lower) alkyl" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, iLsobutoxy., tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the: like,-in which preferable one is C 1

-C

4 alicoxy. and the most preferable one is methoxy or ethoxy.

Suitable.'lower alkanoyl" moiety in the term of "(lower alkanoyl) amino Omay include formyl, acetyl, proparioyl, butanbyl, 2-methylpropanoyl, pentanoyl, 2,2dimethyipropanoyl, hexanoyl and the like, in which preferable one is C 1

-C

4 alkanoyl, and the most preferable one Is acetyl.

Suitable-'cyclo(lower)alkylo may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, in-which more preferable one is cYclO(C 3

-C

6 )alkyl, and 30 *.the -most preferable one is cyclopentyi or cyclohexyl.

.Suitable "halogen' m~ay iaclude Cluerro, chloro, brOETLO amd iodo, in which the preferable one is cbhloro.

Suitable examnple of "amino protective grou.p" Moiety may be conmmon amino protective group such as substituted or unsubstituted lower alicanoyl formyl, acetyl, propiorxyl, trifluoroacetyl, phthaloyl, lower alkoxycarbonyl tert-butoxycartbolyl, tertamyloxycarbonyl, etc.), substituted or unsubstituted aralkyloxycarbolyl benzyloxycarbolyl, pnitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl benzenesulfonyl, tosyl, etc.), nitrophenylsulfeflyl, ax (lower) alkyl trityl. benzyl, etc.] and the like., in which the preferable one is benzyl or tert -but oxycarbonyl.

The term "optionally substituted" refers to unsubstituted or substituted by one or'more suitable substituent(s)".

Suitable "optionally substituted-'lower alkyl' may include lower alkyl which is optionally substituted by suitable slbstituent(s) such as lower alkoxy, hydroxy,.

cyclo(lower)alkcyl and the like.

Suitable "leaving group" may Include hydroxy, reactive 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 acetoxy, tosyloxy, mesyloxy-, triflucromethaflesulfonYloxy, etc.) and the like.

Suitable'salts of the o~bject amInaalcohol derivative Ell are pharnacutically acceptable salts and includa convs~ntloal non-toxlc salts such as arn. inorganic acid addition salt hydrochloride.. hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt g., formate, acetate,. tr fluoroacetate., oxclate, maleate, fumarate, tartrate, citrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc., an alkali metal S salt sodium salt, potassium salt, etc.] and the like.

CI 5 The Processes 1 to 5 for preparing the object compounds 0 of the present invention are explained in detail'in the D following.

Process 1 CLO The object compound or a salt thereof can be prepared by reacting a compound [II] or a salt thereof with a compound [III] or a salt thereof.

Suitable salts of the compounds [III and [III] may be the same as those exemplified for the compound [Il.

The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate sodium bicarbonate, potassium bicarbonate, etc.], tri(lower)alkylamine trimethylamine,: triethylamine, etc.], picoline or the like.

The reaction is usually carried out in a conventional solvent, such as an alcohol methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, 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.

Process 2 The object compound [Ib or a salt thereof can be prepared by subjecting a compound [la] or a salt thereof to elimination reaction of the amino protective group.

Suitable salts of the compounds [la] and E[b] may be the same as those exemplified for the compound This reaction can be carried out in a similar manner to that of Example 27 or 82 mentioned below.

Process 3 The object compound or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with Nq a compound IV] or a salt thereof.

Suitable salts of the compounds [IV] and may be the CL 0 same as those exemplified for the compound This reaction can be carried out in a similar manner to that of Example 16 mentioned below.

Process 4 The object compound or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with a compound [VI] or a salt thereof.

Suitable salts of the compounds [IV] and [VI] may be the same as those exemplified for the compound This reaction can be carried out in a similar manner to that of Example 58 mentioned below.

Process The object compound [Ie] or.a salt thereof can be prepared by subjecting a compounds [Ic] or a salt thereof to deesterification reaction followed by subjecting a compound [Id] or a salt thereof to elimination reaction of the amino protective group.

Suitable salts of the compound [Ic] and [Id] may be the same as those exemplified for the compound EI].

These reactions can be carried out in a similar manner 'o that of Example 16 msntioned below.

The compounds obtained by the above processes can be Isolated and purified by a conventLonal method such as pulverization, recrystallization column chromatography, reprecipitation, or the like, and converted to the desired salt in conventional manners, if necessary.

It is to be noted that the compound and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention.

It is further to be noted that isomerization or rearrangement of the object compound may occur due to LO the effect of the light, acid base or the like, and the compound obtained as the result of said isomerization or rearrangement if also included within the scope of the present invention.

It is also to be noted that the solvating form of the compound hydrate, etc.) and any form of the crystal of the compound are included within the scope of the present invention.

The object compound or a salt thereof are useful for the treatment and/or prevention of gastro-intestinal disorders in:human beings or animals, and more particularly for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholantitis, urinary calculus and the like: for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, or the like; for the treatment and/or prevention of overactive bladder such as nervous.pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis, prostatic hypertrophy or the like; for the treatment and/or prevention of mieturiation disorder such as stress incontinence, urge incontinence, mixed incontinence, functional incontinence, overflow incontinence; 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 resistance 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 to lower triglyceride and cholesterol levels and to raise LO high density lipoprotein levels in mammals (US Patent No.

5,451,677). Accordingly, the object compound is useful in the treatment and/or prevention of conditions such as hyper-triglyceridaemia, hypercholesterolaemia and in lowering high density lipoprotein levels as well as in the treatment of atherosclerotic and cardiovascular diseases and relates conditions.

Moreover, the object compound is useful for inhibiting uterine contractions, preventing premature labor, and treating and preventing dysmenorrhea.

Additionally, the object compound may be expected, when used together with an anticholinergic agent for overactive bladder such as propiverine hydrochloride, oxybutinin hydrochloride, flavoxate hydrochloride, tolterodine tartrate or the like, to exert an enhanced antioveractive-bladder effect.

For therapeutic purpose, the compound and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, or liquid excipient suitable for oral, parenteral, external including topical, internal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration. The pharmaceutical preparations may be solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, c- 5 ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying C- 0 agents, buffers and other commonly used additives.

While the dosage of the compound will vary depending upon the age and condition of a patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg,. 500 mg and 1000 mg of the compound may be effective for treating diseases such as overactive bladder, micturiation disorder and the like. In general, amounts between 0.1. mg/body and about 1,000 mg/body may be administered per day.

In order. to show the usefulness of the compound for the prophylactic and therapeutic treatment of abovementioned disease in human being or animals, the pharmacological test data of a representative compound thereof are shown in the following.

Test Effect of 03 adrenergic receptor agonist on contractile responses in isolated dog detrusor smooth muscle Test Compound 2-(Cyclohe1oylo)y)-4'-[2-[ (2R)-2-hydroxY-2-(3pyridyl) ethyl] amino] ethyl) -4 -biphenylcarbo~cylic acid dihydrochloride (the object compound of Example mentioned below) t Test Method SFemale beagle dogs were anesthetized with pentobarbital and exsanguinated. The urinary bladder was collected, and top, trigon and mucosa were removed. Strips of the detrusor c- 5 of about 2 mm width and 8 nunmm length were prepared. Detrusor S strips were suspended in organ baths containing 25 mL of oxygenated Krebs-Henseleit solution at 37°C. The tension of the strips was measured isometrically with a force Sdisplacement transducer coupled to a carrier amplifier.

C .0 Resting was adjusted to 0.5 g. Potassium chloride (20 mM) was added at about 30 minutes intervals. After confirming reproducibility of the contractile response, test compound was cumulatively added after contraction of potassium chloride. Contractile response was expressed as a percentage of the contraction before addition of the test compound. EC50 values were calculated by liner regression analysis.

Test Result Treatment ECS0

O

Test Compound 13 nM Preferred embodiments of the object compound are as follows: A is ,or or f Ej r X is bond, -CH 2 or -NH-, R' is hydrogen, halogen (more pref erably chioro) hydroxy, amino or (lower alicanoyl) amino (more preferably (Cl-C 4 S alkcanoyl) amino, most preferably acetylamino),

RR

4 and R 5 are each Independently hydrogen 'or lower alkcyl (more preferably

C

1

-C

4 alkyl, most preferably methyl), R~3 Is hydrogen, N0 R6is hydrogen, carboxy or (lower allcylsulfonyl)carbamfoyl (more preferably

(C

1

-C

4 alkylsulfoflyl)carbamoyl, most .preferably (methylsulfoflyl)carbZUoyl),.and RIs -Y-R 8 ±nwhIch Y Is bond, or and

R

8 is hydrogen, lower alicyl.(more preferably cl-c 4 alkyl,' most preferably -ethyl, propyl, isopropyl, butyl or isobutyl), cyclo(lower)alkyl (more preferably cyclo-

(C

3

-C

6 )alkyl, most preferably cyclopentyl or cyclohexyl), carboxy( lower) alkyl (more ao preferably carboxy(Cl-C4 )alkyl, most preferably carboxymethyl) or (lower alkoxycarbonyl)- (lower)alkyl (more preferably (Cl-C 4 alkoxycarbonyl) (Cl-C 4 )alkyl, most preferably ethoxycarbonylmethyl) provided that when A is D Is and E i then IlI X is bond, R 1 is hydrocxy, R 2 is methyl, R4# and

RB

5 are each hydrogen, R3 is hydrogen, R 6 is (methylsuufoiy1 arbwnoyl, and

R

7 is -yR8 !a y~c Y~ is -0,adei cyclohexyl; X is -CH2- or RI is halogen (more preferably chiaro), R 2 R4 and RSare each hydrogen. R 3 is hydrogen, R 6 is carboxy, and

R

7 is -Y-R 8 in which Y is and R 8 is isobutyl or cyclohexyl: or X is -CH 2 or

R

1 is para-chloro,

R

2 is c- 5 hydrogen or methyl, R 4 and R 5 are each hydrogen,

R

3 is hydrogen, R 6 is carboxy, and

R

7 is'-Y-R 8 in which Y is and R 8 is \c propyl, 0 when A i i, D is and E is then X is bond, R 1 is amino, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and

R

7 is -Y-R 8 in which Y is bond, or and R 8 is ethyl, isopropyl, isobutyl or cyclopentyl; X is bond, R 1 is amino, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R? is -Y-R 8 in which Y is or and R 8 is ethyl or isopropyl: X is bond, R1 is chloro or (lower alkanoyl)amino (more preferably (CI-C 4 alkanoyl)amino, most preferably acetylamino).

R

2

R

4 and R 5 are each hydrogen, R 3 is hydrogen,

R

6 is (methylsulfonyl)carbamoyl, and

R

7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; X is bond, R 1 is hydrogen, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is caxboxy, and R7 is -Y-RS, in -which Y is and R 8 is cyclo(lower)alkyl (more preferably cyclo(C 3 -C6)alkyl, most preferably wb cyclohexyl); X is bond, R 1 is hydrogen, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and c- 5 R 7 is -Y-R 8 (substituted at 2' or 6' position in 4-biphenyl of in which Y is bond or and R 8 is isopropyl, butyl or cyclohexyl: X is -CH 2

R

1 is amino, R 2

R

4 and R 5 are each C 10 hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and

R

7 is -Y-R 8 in which Y is and R 8 is cyclo(lower)alkyl (more preferably cyclo(C 3

-C

6 )alkyl, most preferably cyclohexyl); 17] X is -CH 2 or R 1 is amino, R2, R 4 and R are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and

R

7 is -Y-R 8 in which Y is bond or and R 8 is isobutyl or cyclohexyl; or X is NH-, R 1 is hydrogen, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and

R

7 is -Y-R 8 in which Y is and R 8 is lower alkyl (more preferably C 1

-C

4 alkyl, most preferably isobutyl), when A is D is and E is then X is bond, R 1 is halogen (more preferably chloro),

R

2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy or (loweralkysulfonyl )carbmoyi (more preferably (C 1

-C

4 alkylsulfonyl)carbamoyl), and

R

7 is -Y-R 8 in which Y is bond, and R 8 .is hydrogen, or when A is K) Dis Cj and Z isToo then X is bond, R 1 is hydrogen, R 2

R

4 and R 5 are each N- 5 hydrogen, R 3 is hydrogen, R 6 is carboxy or (lower alkysulfonyl)carbamoyl (more preferably (C 1

-C

4 alkylsulfony1)carbamoyl), and

R

7 is -Y-R 8 In which Y Is bond, and R8is hydrogen.

More preferred-embodiments of the object compound [I] are as follows: A is for79 D is E is or X is bond, -CH 2 or -NH-,

R

1 Is hydrogen, chioro, hydroxy or amino, R23 R 4 and .Rs are'.each independently hydrogen or -methyl,

R

3 Is hydrogen, R6 Is hydrogen, *carboxy or (lower alicylsulf onyl) carbaxnoyl (more preferably (Cl-C 4 allylsulfonyl)carbamoyl, most preferably (methylsulfonyl) carbaxnoyl), and

R

7 i:s -Y-R 8 ,..inw hich Y is bond, or and 1is hydrogen, lower alkyl (more preferably Ck-C 4 alkyl, most preferably ethyl, propyla isopropyl, butyl or Isobutyl) or cyclo(lovlar)alkyl (more preferably cyclO(C 3

-C

6 )alkyl, most preferably cyclopentyl or cyclohaxyl), provIded that when A is Dn isi and E is -K\7 I/ f L b then X is bond, R 1 is hydroxy, R 2 is methyl, R 4 and

R

5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl) carbamoyl, and Ris -Y-R 8 in which Y Is and R8is cyclohexyl; X is -CH 2 or R 1 Is chioro, R 2

R

4 and R are each hydrogen, R 3 is hydrogen, R 6 is carboxy. and

R

7 .is -Y-R 8 in which Y is and R 8 is isobutyl or cyclohexyl; or is -CH 2 or RI is para-chioro, R 2 is hydrogen or methyl, R 4 and R 5 are each hydrogen,

R

3 is hydrogen, R 6 is carboxy, and R7 is -Y-R 8 in whiLch.Y is -0-,.and R8is propyl, when A is DI and E is then-[1] X is bond,'Rl is amino,* RZ, R 4 andRS are each hydrogen, R 3 Is hydrogen,.R 6 Is carboxy. and R7is- -y-RS. in which Y is bond,. or and R8Is ethyl, isopropyl, isobut yl or cyclopentyl; is bond, R 1 is amino,.R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl) carbamoyl, and i ,R 7 :is yR 8 in which Y is or and R 8 ie ethyl or isopropyl; X LS bond, RI is Chio0ro, R2 R and R5 are aa hydxogen, R1 Is hydrogen, R 6 Is (methylsulifonyl) carbamoyl, and R7 is -y-RS, in which Y is and R 8 is cyclohexyl: X is bond, R 1 is hydrogen, R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and Ci 5

R

7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; X is bond, R 1 is hydrogen, R 2

R

4 and RS are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and

R

7 is -Y-R 8 (substituted at 2' or 6' position in 4-biphenyl of in which Y is bond or and R 8 is isopropyl, butyl or cyclohexyl; X is -CH 2

R

1 is amino, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and

R

7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; X is -CH 2 or R 1 is amino, R 2

R

4 and R are each hydrogen, R 3 is.hydrogen, R 6 is carboxy, and

R

7 is -Y-R 8 in which Y is bond or and R 8 is isobutyl or cyclohexyl; or X is R 1 is hydrogen, R2, R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and

R

7 is -Y-R 8 in which Y is and R 8 is isobutyl, when A Is D is and E isthen X is bond, R 1 is chloro, R, R4 and R 5 are each hydrogen" R3 is hydrogen, R 6 is carboxy, and

R

7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen, or when A is D is and E is then X is bond, R 1 is hydrogen, R 2

R

4 and R5 are each C' 5 hydrogen, R 3 is hydrogen, R 6 is carboxy, and

R

7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen.

IND Further more preferred embodiments of the object compound are as follows: A is D is and E is X is bond, R 1 is hydroxy, R 2 is methyl, R 4 and R are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; Xis -CH 2 or R 1 is chloro, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and

R

7 is: in which Y is and R8 is isobutyl or cyclohexyl; or X is -CH 2 or R 1 is para-chloro,

R

2 is hyd;ogen or methyl, R 4 and R 5 are each hydrogen, R 3 .is hydrogen, R 6 is carboxy, and .R7 is -Y.-R 8 in which Y is and R 8 is propyl, (2)A is >D and E is X is bond, R 1 is amino, R 2

R

4 and RS are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and p7 is in which Y is bond. or and R 8 is ethyl, isopropyl, isobutyl or cyclopentyl; X is bond, R1 is amino, R 2 R and R5 are each hydroghydro g e n, Rydrogen, R 6 is (methylsulfonyl)carbamoyl, and R7 is in which Y is'-O- or and R 8 is ethyl or isopropyl: C 5 X is bond, R 1 is chioro, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and IN

R

7 is -Y-R 8 in which Y is and R 8 is cyclohexy-; X is bond, R 1 is hydrogen, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; X is bond.R is hydrogen, R 2

R

4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 .is carboxy, and

R

7 is -Y-R 8 (substituted at.2'or 6' position in 4biphetyl of in which Y is bond or and:R 8 is isopropyl, butyl or cyclohexyl; is'- -CH 2

R

1 is amino, R 2

R

4 andR 5 are each hydrogen,.R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R7-is -Y-R 8 in which Y is and R 8 is cyclohexyl; is.-C 2:-:or R4 n RI is amino, R 2 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R7 is -y-R.

8 in which Y is bond or and R 8 is isobutyl or cyclohexyl; or :is R 1 is hydrogen, R 2

R

4 and R 5 are each hydrogen, R3 is hydrogen, R 6 is carboxy, and

R

7 .is R 8 in which Y is and R 8 is isobutyl, A Is D is E Is X is bond, R is ohloro, R2 R4 and R 5 are eac-,h hydzogem.

R

3 is hydrogen, R 6 is carboxy, and iR7 s -Y-R8, in which Y is bond, and R 8 is hydrogen, or A is is Eis 2 X is bond, R 1 is hydrogen, R 2 R and R 5 are each hydrogen. R 3 is hydrogen, R 6 is carboxy, and

INDR

7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen.

310 The following Preparations and Examples are given for the purpose of illustrating this invention. The group of carbamoyl" aforementioned may be hereinafter referred as a group of "aminocarbonylo.

Preparation 1 A.mixture of tert-butyl [(2R)-2-[6-(acetylamino)-3-.

pyridyl]-2-[ (tert-butyl(dimethyl)silyl]oxy]ethyl]E2( 4 bromophenyl)ethyl]carbamate (300 mg), [3-ethoxy-4- I[(methylsulfonyl) aminol carbonyliphenyllbbronic acid (174 mg), 11,1 '-bis (diphenyiphosphino) Lerrocene]dichloropalladium ~(II),cmnplex.with dichloromethane 62 mg), l;1'bis(diphenyiphosphino)ferrocene (42.1 mg), N,Ndiethylformamide (6 niL). and 2N sodium carbonate solution.

(1.01 niL). was stirred at 80 0 C for 3 hours. .After cooling to room. temperature the mixture was quenched by the addition of pH 6.86 buffer (30 m14 and extracted with ethyl acetate 10 iL x The extracts were combined and washed'-with pH 6-.86.buffer (20 nL x and brine (20 mL), and dried over magnesium sulfate. Filtration followed by evaporation gave a light brown solid which was cbhomatogiaphed on silica gel (eluent: hexanofethyl acetate) to give'tert-butyl [(2R)-2-C6-Caetylmin)-3-pyryi2P-2- E~ter-butYI~d:Lmethy)slpylSooxlethl(2['-tox-' CE(methylsulfonyl)aminolcarbonylJ-4-biphenylyl]ethyl]carbamate (259 mg) as a white solid.

(-)ESI-MS m/z: 753 The following compounds from Preparation 2 to Preparation 11 were obtained in a similar manner Preparation 2 tert-Butyl E(2R)-2-[6-(acetylalifo)-3-pyridYl]-2- [Itert-buty)l(dimethyl)silyl]oxy]Cthyl]( 2 3 (isopropylthio) (methylsulfonyl)aminflcarboll-4biplienylyl] ethyl 3carbamnate (-)ESI-MS m/z: 783 (MH- Preparation 3 [Etett'butyl(dimethy)sily33oxy~ethyl) E3-1 (cyclohexylox,) [(methylsulfonyl)amilcarbonyl] -4biphenylyl Ipropyl] carbamate (-)ESI-MS m/z: 821 (MH- Preparation 4 .tert-Butyl.[(2R)-2-[6-(acetylamiflo)-3-pyridyl]- 2 Etrtbutyl(dimethyl)silyl]oxyJethyl]E2[ 31 (cyclohexyloxy)-4'- ((iethylsulfoflyl) amino I carbonyl] -4biphenyly. Iethyl] carbamate (-)ESI-HS m/z: 807 (MH- PreparatIon Methyl 4'[-[2)2[-aeylmn.)3-yiyl2 [[tert-butyl (dimethyl) silyl Ioxy] ethyl-](tert-butoxycarbolyl) amino] ethyl] -3 -ethoxy- 4-biphenylcarboxylate (+)ESI-MS m/z: 714 (M+Na)+ Preparation 6 Methyl 4'-2[(R--6(ctyaio--yiy32 [Ctert-butyl (adimethyl) silyl] oxy] ethyl) (tert-butoxycarbolyl) amlno Iethyl J-3-(C sopropylthio) -4-biphenvlcarboxylate (+)ESI-MS m~fz- 744 (K44\a)4' Preparation 7 Methyl 4v.C2-EC2R)-2-6(acetylamf)3pyridyl]2dEtertoxy] ethyl) (tert-butoxycarbonyl)amilol ethyl 3-isobutyl- 4-biphenylcarboxylate (+)ESI-MS m/z: 704 (H+H) 4 Preparation 8 Methyl 4'-E2-[[(2R)-2-6-(acetylmino)-3-pyridyl)-2- (Etert-buty1(dimethyl) silyl]oxy) ethyl] (tert-butoxycarbonyl) amino] ethyl] -3 -cyclopentyl- 4-biphenylcarboxylate (+)ESI-MS m/z: 738 (M+Na)+ Preparation 9 Methyl 4'-E3-E[(2R)-2-6-(acetylamino)-3-;pyridylJ- 2 LO [[tert-butyl (dimethyl) silyl ]oxy] ethyl] (tert-butoxycarbonyl) amino] propyl] (cyclohexyloxy) -4 -biphenylcarboxylate (+)ESI-MS m/z: 760 Preparation Methyl 4'-[3-[[(2R)-2-[6-(acetylafinifo)-3-pyridyl]-2 [[tert-butyl(dimethyl) silyl]oxy]ethyl) (tert-butoxycarbonyl) amino] propyl] -3-isopropoxy- 4-biphenylcarboxylate (.)ESI-MS m/z: 720 Preparation 11 Methyl 4'-[2-[[(2R)-2-6-(acetylamfifo)-3-PYridYlP-2-.

t (tert-butyl(dlmethyl) silyl~oxy~ethyl] (tert-butoxycarbonyl) amino] ethoxy] -3-isobutyl-4-biphenylcarboxylate (+)ESI-MS m/z: 742 (M+Na)+ Preparation 12 25 To-a mixture of (2R)-2-[6-(acetylamino)-3-pyridyl]-2- [[tert-butyl(d~methyl) silyl] oxylethy1 4-methylbenzene- .sulfonate (1.00 3-(4-iodopheny.)-1-propalamile (1.12 g), and dimethylsulfoxide (0.5 mL) was added NN-diisopropylethylamine (0.375 niL) and the m~ixture was stirred at 80 0 C for 24 hours. +After cooling to room temperature, the mixture was dilu~ted with ethyl aoetate (20 mL) and water (20 mL) and the two layers ware separated. The organilc layer was washad with water (20 niL r. 2) and brine (20 niL), and dried over magnesium sul~fate, Fltration followed by evaporation gave a brawn paxte 74 g) which was chromatographed on esi:lca gel (eluent; hexane/ethy. acetate) to give the ((tert-butyl(dimethyl)silyl]oxy] 2- C[3- (4-odophenyl) propyl]amino]ethyl]2-pyridyllacetamide (916 mg) as an orange paste.

The following compound was obtained ina similar manner to that of Preparation 12.

IND Preparation 13 jLodophenoxy) ethyl] amino] ethyl] -2-pyriLdyll acetamide (+)ESI-MS m/z: 556 (M4.H)+ Preparation 14 To a-solutiLon of sJlloY--E-4idpenlpoy~mn~ty]2 pyridyljacetamide (916 mg) in tetrahydrofuran (9.2 niL) was added di-tert-butyl dicarbonate (0.418 nIL) and the solution wsstiLrred at, room temperature for 12 hours. -The solvent was removed by evaporation and the residue was on~ sililca gel (eluent: hexane/ethyl acetate) :to give tert-butyl [2)2[-aeyamfO--.i~] C (tert-buty1(dImflthyl)silloxCy1ethyl] 37;(4-iodophenyl) propyllcarbamate (923 mg) as a white foam.

(+)ESI-MS m/z: 654 The following compound was obtained in a similar manner to that of Preparation 14.

Prep2aration tert-Buty. t(2R)-2-[6-Caetylamiflo)3-pyridyl]-Zathyl] carbamate Preparation 16 To a soluti.on of (methylsulfonyl) -4 -biphenylcarboxahide (400 mg) in tetrahydrofuran (1.0 mL) was added tetrabromomethane (762 mg) and triphenyiphosphine (552 mg) at room temperature.

After stirring for 30 minutes at room temperature, the reaction mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate-4/1) to give (2-bromoethyl)-3-(cyclohexyloxy)

-N-

(methylsulfolYl)-4 -biphenylcarboxamide (460 mg).

1 H NMR (20014Hz, CDCl 3 1-30-2.40 (10H, rn), 3.24 (2H, t, 3-7.3Hz), 3.42 (3H, 3.62 (2H, t, J-7.3Hz), 4-61-4.71 (111, mn), 7.18 (1.0 d, 3=1.1Hz), 7.26-7.27 (1H, in),.7.34 (2H, d, J-8.3Hz), 7.55 d, J-B.lHz), 8.24 (1H, d, 3=8.1lHz) (+)ESI-MS m/z: 480(M+H)+ -The following compounds from Preparation 17 to+ Preparation 20 were obtained In a similar manner to that of Preparation 1.+ Preparation 17 3- (Cyclohexyloxy) (2-hydroxyethyl)

-N-

(methylsulfolyl) -4-biphenylcrboxamlide 1 H NMR (200MHz, CDCl.

3 1.30-2.25 (9H, rn), 2.95 (2H, t, J=6.5Hz), 3.42.(3H, 3.93 (2H, t, J=6-.5Hz), 4.6-4.71 mn), 7.18 J-1.3Hz), 7.29 (1H, dd, J-1.3, 8.3Hz), 7.36+(2H, d, 7.54 (2H, d, 3=8.2Hz),,8.24 (1H, d., J-8.3Hz) (-)ESI-MS in/z: 416 (M-HF- Preparation 18 Methyl 4' [benzyl( tert-butoxycarbolyl) amino] ethyl] 2- isopropoxy- 4-biphenylcarboxylate to (+)ESI-MS in/z: 526 (M+Na)+ Prepaxation 19 Mthyl4- 2 etyL- 2- (cyclohexyloxy) biphenylcarboxylate (..)ESI-MS m/z: 566 (M+Na)' Pre~aratlon Methyl 4'[-[2)2[-aeyaio--yiyl2 U tert-butyl( dimethyl) silyl Ioxy]I ethyl] (tert -but oxycarborlyl) amino] propyl] -3-isobutyl-4 -biphenylcarboxylate (+)ESI-MS m/z: 719 741 (M+Na) 4 Preparation 21 To a suspension of 2-mn--4boopey~ctmd IND(1.50 g) in tetrahyd-rofuran (15 niL) was added 2.OM dimethy.

sulfide-borane in tetrahydrofuran (6.55 mL) dropwise at 0-5 0 C over 10. minutes. The reaction mi-xture was stirredat 75 0 C for -1.5 hours. After cooling to 0 0 C, to the reaction mixture was addbd.-'12N hydrochloric acid (3.27 niL) slowly.

The mixture -was- stirred at 7 SOC for 30 minutes. After *cooling .to V 0 C, the' pH value was adjusted to 9.8 by addition of 24% aqueous sodium hydroxide solution and the mixture was extracted with ethyl -acetate. The water layer was extracted, with chloroform-methanol and the combined organic layer was washed with water and brine and dried over magnesium. -sulfate., Filtration followed by evaporation under, reduced-pressure-gave N- (4 -bromophenyl) 2-ethanediamine (1.55 g) as a yellow oil.

(.g)ESI-MS m/z; 215, 217 (M+H) 4 Preparat ion 22 -,To +a solution of N-4boohnl.-12ohndaJn (750-mg)-in dimnethyl sulfoxide (5.63 niL) was-added N,Obis(trimethylsly)acetamlide (0.862 niL) and the mixture was stirred at. room temperature for 30 minutes under nitrogen atmosphere. -To the reaction mixture was added [(2R)-2-oxiranyllpyridile. (608 mg) and the mixture was stirred at 900C for 15.5 hours. After cooling to room temperature, the mixture xvas queacohed with water (3.75 miL) and 12N hydrochloriLc acid (0.581 niL) and stirred at room temperature for 20 minutes. The mixture was neutralized with IN aqueous sodium hydroxide solution and extracted with chloroform-methanol washed with water and brine and dried over magnesium sulfate. After filtration, the solvent was removed by evaporation under reduced pressure. To a solution of resulting residue in tetrahydrofuran (7.50 mL) were added water (7.50 mL) and di-tert-butyl dicarbonate (761. mg). The mixture was stirred at room temperature for hours with keeping the pH value between 7.5 and 8.0 by addition of 1N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, washed with water and briLne arnd dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave the crude product -which, was purified by column chromatography on silicA gel -(dlu(ent:: hexane/ethyl acetate=1/3 to 2/1) to give tert-butyl E2-[(4-bromophenyl)amino]ethylJU(2R)-2-(6-chloro- 3-pyridyl)-2-hydroxyethyllcarbauate (7.98 mg) as a paleyellow paste.

(+)ESI-MS m/z: 492, 494 (M+NaV Preparation 23 a: solution of N-(4-bromophenyl) -2-(J4- -chlorophenyl)- 2-hydroxyethyl] amino] acetamide (1.00. g) in terahydrbfuran:.(10.0 mL) was added 2.0m dimethyl sulfiLdeborane..(1:1) in tetrahydrofuran (2.61 mL) dropwise at 0-5 0

C

b6ver. 10.-minutes under nitrogen atmosphere. The reaction miLxture. was stirred at 60*C for 1 hour., To the reaction mixture +was added tetrahydrofuran (10 mL) and the mixture was stirred at+. 60*C for 1 hour. After cooling to 4*C, to the reaction mixture was added 1214 hydrochloric acid (1.74 niL) carefully. +The mixture was stirred at GO0PC for 30 minutes.

Aftar cooling to 4 0 the pH value was adjusted to 10.0 by additIoL of 24ts aqueous sodium hydroxida solution arid the ntixtura vas extracted r.irth ethyl acetate, washed w"ith water anid brine and dried over magnesium sulfate. The solvent was removed by evaporation under reduced pressure. To a solutIon of the resulting residue in tetrahy'drofuriz (10.0 ML) and water (10. 0 niL) was added di-tert-butyl dicarbonate (569 mg) with keeping the pH value between 7.5-8.0 by addition of 1N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 6 hours. The reaction mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate.

Filtration followed by evaporation gave tert-butyl bromophenyl)aminolethylj -2-(4-chlorophenyl)-2hydroxyethyljcarbanate (1.11 g) as a pale yellow paste.

(+)ESI-MS m/z: 469, 471 491, 493 (M+Na) 4 Preparation 24 a To a solution of 2-amino-N-(4-bromopheflyl)acetamide (250 mg) in acetonitirile (1.875 mL) was added.(2R)-2-(,4-.

chlorophenyl) oxirane 169 mg) and the mixture was stirred' at 0 for 19 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent; ckloroform/methanolm 100/0 to.90/.10) to give N-(4-bromophenyl)-2-(((ZR)- 2 4 chloropheniyl) -2-hydroxyethyl] amino] acetazuide (226 nig) -as a+ white solid.

(4.)ESX-M4Sm/z; 383, 385 405, 407 (M44Na)+ Preparation To a-solution of (4-bromophanyl)amrie (5.0 g) in N,14-.

dizuethylformamide (40 mL) were added ((tertbutoxycarbonyll)amiflojacetic acid (5.09 dimethylaminopropyl) ethylcarbodimide hydrochloride (5.57 qc and 1-hydroxybenztriazole hydrate (4.45 The mixture was stirred at room temperature for 3 h~ours~. The reaction m-Lxture was diluted %Aith ethyl acetate and washed wIth O.51 hydrochloric acid, saturated sodium bicarbonate aqueous solution, water and brIne. The organic layer was dried over magnesium sulfate. After flltratiLon, the solvent was removed by evaporation under reduced pressure. To the resulting residue were added ethyl acetate (60 niL) and 4N hydrogen chloride in ethyl acetate (60 mnL). The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried in vacuo.

O The precipitate was dissolved In water and the pH value was O adjusted to 8.0-9.0 by addition of 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, O washed with water and brine. Filtration followed by evaporation under reduced pressure gave 2-amino-N-(4bromophenyl)acetanide (6.05 g) as a white solid.

(+)ESI-MS m/z: 229, 231 Preparation 26 To a solution of methyl 4-bromo-2- (cyclohexylamino)benz~ate (1.45 g) in 1,4-dioxane (15.0 niL) O ere-added bis(pinacolato)diboron (1.30 g), dchlorobis(triphenylphosphine) palladiumi (326 mg) and -poassumacetate .(1.37 g) at room temperature and stiLrred ,a 9 SOO' for, 10, hours The reaction mixture was diluted with :ethyl. acet&te- and ,water and separated the organic layer.

TheT organic. layer: was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography giVe: methyl 2,-(cyclohexylam:nro)-4-(4,4,S,5-tetramethyl- 1,3' 2-dioxaborolan-;2-yl)beflzoate (1.53 To a solution of methyl 2-(cyclohexylamino)-4-(4,4,5,5-tetramfethyl-1, 3 ,2dioxaborojlah-2-_Yl)beflzoate in ethyl acetate (15.3 niL) ard water. (15. 3 mrL) were added ammonium+ acetate (821 mg) -arid 3~sodium periodate.(2.28 g) and stirred at room temparature for S. 5 hours. To the mixture were added more ammonium acetate (32S8mg) and sodium peariodate (911 mg) and stIrred at room tempe)raturs for 2 days. The solid was filtered off and the organic layer was separated. The organic layer was washed with brn, dried over magnesium sulfate and evaporated to give (cyclohexylamino) (methoxycarbonyl) pheniyliboronic acid (1.16 (+)ESI-MS m/z: 278 (M+H)4 Preparation 27 To a solution of 4-azino-3-hydroxybenzoic acid (5.00 g) in methanol (50*mL) was added concentrated sulfuric acid (16.7 mL) and ref luxed for 5 hours. The mixture was poured into saturated sodium bicarbonate aqueous solution and ethyl acetate. The aqueous layer was extracted with ethyl-acetate twiLce. The combined organic layer was washed with brine, dried over,. magnesium sulfate and evaporated to give 4-amino- 3-hydtoxybenzolc acid methyl ester (4.40 g).

(+)ESI-MS m/z !190 (M+Na)+ Preparation 28 .A mixture of 4-amino-3-hydroxybenzoic acid methyl ester (4.40 g):and,:hydrochloric acid aqueous solution (65.8 mL) was ooJed o 0C and. added sodium nitrite' (2..00 g) -aqueous solution. mL) .:dropwiLse. The 'mixture was stirred at the s:amze temperature ,for 1.5 hours and added potassium iodide (8.74.g) and.concentrated sulfuric aciLd (1.40 niL).. -The mixture .was+ stirred. at 40*C and poured into ethyl acetate and watdr.. .The. mixture was poured into ethyl acetate:- and water and-the- organiLc layer was separated. The solution:-was washed. with water, sodium thiosulfate aqueous twice: arnd brine,.+ dried over magnesium sulf ate and. evaporated.

The residue; was purified with silica gel column -chromatography to give .methyl 3-hydroxy-4-Iodobenzoate (4.75 g).

(-)ESI-MS m/z: 277 (KH- Pra~,&ratlom 29 To a solution of methyl 3-hydxoxy-4-iodobenzoate (1.00 2-propanol (410 pil) and trIphanyipliosphIns (1.42 g) in tetrabydrofuran (25 m'j was added diethyl azodIcarbo nc.atm (849 pl) dxopwise. The mixture was stirred at room temperature for 3 hours and evaporated. The residue was dissolved with ether and hexane and the solid was filtered of f. The solution was evaporated and the residue was purified with silica gel column chromatography to give me thyl 4-iodo-3-isopropoxybelzoate (1 .09 g).

(+)ESI-MS m/z 343 (M+Na)+ The following compound was obtained In a simnilar manner to that of Preparation 29.

Preparation Methyl 3- (cyclohexyloxy) -4-iodobenzoate (+)ESI-MS m/z: 383 (M+Na)+ PreparatIon 31 To a solution of methyl 4*-[2-[benzyl(tert-butoxycarbonyl) amino] ethyl] -2-isopropoxy-4 -biphenylcarboxy.ate (245 mg) in ethyl acetate (2.50 roL) was added 4N hydtoch3.oric acid (2.50 mL) and stirred at :room temperature+ +for 1 hour. The mixture was evaporated and dissolved with ethyl acetate and saturated sodium bicarbonate aqueous solution. ':The 'organic layer was washed with brine, dried over+ -magnesium sulfate and evaporated to give methyl. (benzy3.amlno )ethyl] isopropoxy- 4-biphenyvlcarboxylate .(197 mg).

(+)ESI-MS mfz; 404 (M+H) 4 The following compound was obtalned in a similar manner to that of Preparation 31..

Preparation 32 Methyl 4 E2- (benxylamino~ethylJ (cycl.ohsecyJloxy) -4biphenylcarbo~jlate (+)ESI-MS m/z: 444 (M+EH) 4 Preparation 33 To a mixture of (iR) -2-chloro-1- (2-pyrazinyl)ethanol (390 mg) in methanol (1.17 niL) was added 6N4 sodium hydroxide aqueous solution (0.47 mL) dropwise on ice cooling. The mixture was stirred at the same temperature for 1 hour. The mixture was warmed up to room temperature and stirred for 1 hour. 6N Sodium hydroxide aqueous solution (0.02 mL) was added the mixture and the resulting mixture was stirred at room temperature for 1 hour. The mixture was poured Into water (5 niL), and extracted with ethyl acetate twice. The extract was washed with brine, dried over sodium sulf ate and evaporated under reduced pressure to give oxiranyllpyrazine (266 mg) as a brown oil.

1 H'NAR '(200MHz,, DMSO-d 6 3.15-3.26 (2H, mn), 4.1 (1H, dd, J-2.5, 4.0Hz), 8.63-8.65 (3H, mn) Preparation 34 To a ,mixture of ethyl 2-(cyclohexyloxy)-4- [ethoxy( imino)methyllbenzoate hydrochloride (16.6.8 in -ethanol. (40f ml) !was. added dropwise 5.2M ammonia in ethanol (40 xL)if or. 30.mninutes, cooling with an ice bath. The miLxturewas.1 stirred at ambient temperature overnight. The- -precipitate w6!s removed by filtration and washed with hexane/ethanol The filtrate was evaporated under reduced pressure to give ethyl 4-[amino(imino)methyl]-2- (cyclohexyloxy)benzoate hydrochloride (14.9 g).

(+)ESI-MS m/z: 291 Pr-eparation 'IToamixtureocf 60t sodium hydride (3.34 g) in+N,Ndimethylformamide'(100 mLs) was added dropwise 4-cyano-2f3.uorobenzoic. aciLd (10.0 g) In K,N-diinethylformamiL:de (50 mL)3 mainta~iring the reaction teinparatura at 35-404C a~ver minutes under nit rogen'atmnosphere. To the mixture was added cyclohexanol (7.0 niL) In JNN-dimethylfarmamide (30 niL) maintaining the reaction temperature at 35-38 0 C over minutes and stirred vigorously f or 2 hours. To the mixture was added ethyl iodide (5.8 niL) in N.N-dimethylforrnamide niL) dropwise for 20 minutes, and the mixture was stirred vigorously at ambient temperature overnight. The mixture was poured into 1N hydrochloric acid (15 niL) and water (300 mL), and extracted with diisopropyl ether (200 niL x The combined extract was washed with water (100 niL) and brine (100 niL), dried over sodium sulfate and evaporated under reduced pressure to give oil (19.36 To a mixture of above oil in toluene (50 rnL) was added ethanol (3.9 rnL) and was bubbled wIth hydrogen chloride gas at approximately OOC for:1 hour. The mixture was stirred in refrigerator for 4 days. .The mixture was filtered to collect'precipitate and.

washed with diisopropyl ether to give ethyl 2- (cyclohexyloxy) [ethoxy( imino )methylJ benzoate hydrochloride (16.7 g).

(+)ESI-MS m/z: 296 (M+Na)+ Preparation 36 To .a cold 28%; amnmonium hydroxide (50,mL) was added.

(IR) -2-chloro-l1-(2-pyrazilyl) ethanlol In methanol: (20._mL).:deopwiLse at ambient temperature. for, 1 minutes.+ +The mixture was- stirred at room temperature_ overnight and .was evaporated under. reduced pressure. The residue wsprfe .by column-'chromatography on silica gel (chlorof orm/methanol/ anuonlim hydroxiLde=79/20./i) to give brown solid. The crude product was recrystallized from hot ethanol to give (1S)-2axino-1-(2-pyrazinyl)ethanol (1.84 g).

()ESI-MS M/Z: 140 Preparation 37 A mture, of athr.4 y 2clreh~~--y i~nl 2-(cyclohaxylary)benzoate (200 mg) and benzylamine (1.28 mL) In ethanol (1 niL) was stirred at 900C for 16 hours. The mixture was portioned to ethyl acetate P-nd saturated sodium bicarbonate aqueous solution. The organic layer was separated, washed-with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol-.

95/5) to give ethyl 4-[5-[2-(benzylamlno)ethyl]-2pyrimidinyl] (cyclohexy].oxy)benzoate (158 mg).

Preparation 38 To a mixture of ethyl 2-(cyclohexyloxy)-4-[4,6dichloro-5- .(2-chloroethyl)-2-pyrimidinyllbenzoate (314 mig) in 95% :ethanol.(3 niL) and tetrahydxofuran (3 niL) were added palladium on carbon (50% wet, 34 mg) and, triethylam-ine 2 1- The mixture was stirred at room-temperature under hydrogen atmosphere for 100 miLnutes. The mixture was 1s filtered through. celite pad and washed with,95% ethanol and ethyl acetate'.. The filtrate was evaporated under reduced pres sure. The res idde. was purif ied by column chromatography on silica- gel: (hexane/ ethyl acetate=80/20 to 70/30) to give ethyl 4- -chioroethyl) -2-pyrimidinyl] (cyclohexyloxy) benzoate (213 mg).

(+)ESI-MS m/z: 411 (M+Na)+ Preparation 39 dihydro-2-pyrimidinylJ -2-(cyclohexyloxy)benzoate.(5.18+ g) wvas. dissolved: in phosphoric trichioride (50 niL). +NN- Diethylaniline niL) was added to the mixture at ambient temperature.+ The niixture was refluxed for 21 hours. Excess phosphoric tridhloride was evaporated under reduced pressure.

The.i residue- was poured into ice and water, and extracted with ethyl acetate. The organic layer was separated, wmshed with, water, sturpted sodium bic5.rbonate aad briae, dried over magnesium sulfate and evaporated under reduced pressure.

The residue was purified by calumn chro~matography on silica gel (hexane/ethyl acetate-9/1) to give ethyl 2- (CycloheXyloxy)-4- (4,6-dich3.oro-5- (2-chloroethyl)-2pyriniidinyllbenzoate (2.62 g).

(+)ESI-MS m/z: 457 Preparation .To a solution of sodium ethanolate (320 mg) in ethanol (2 mL) was added ethyl 4-[amino(imiLno)methyl3-2- (cyclohexyloxy)berlzoate hydrochloride (500 mg) at room temperature under nitrogen atmosphere. The mixture was stirred at ambient temperature for 30 minutes. To the mixture.* was added diethyl (benzyloxy)ethyl malonate (610 mg)-.-in.ethano. nL). The mixture was stirred-at room temperature f or 4 days- and ref luxed f or -19 hours.

Concentrated hydrochloric acid (0.5 niL) was added to the mixture and the.:mixture was concentrated under reduced pressure'. .Water (1.5 mL) was added to the concentrate. .The precipitate was:.collected by filtration-and washed-.withi: ethanol to give ethyl: 4- 2-(benzyloxy)ethyl]-6-hydroxy-4obxo-1,4 -dih-ydro-2-pyrimidinyl] (cyclohexyloxy)belzoate...

(330 mg).

(-)ESI-MS 491 (MH- Preparation 41 To solution of. methyl 6-bromo-2-naphthoate (5.0 g)--in 1, 4 -dioxahe (50 mL) were added 4, 4, octamithyl-2,2'-bi-1,3,2-dioxaborolale (5.3 g), dichiorobis (triphenylphosphine )palladium( II) (1.3 g) and potassium acetat-e g) at room temperature under nitrogen, and the mixture was stiLrred at 90CC for 2 hours. The resulting miLxture was poured into water and the aqueous layer was ertracted with ethyl acetate. TIhe organic l~ayer was wzshed with brine, dried over anhydrous magnesium sulfate, evaporated under reduced pressure. The residue was purified by column chromatography on slitca gel Ceuerztz c-lloroform) to give methyl 6(.~~-erzlty132 dioxaborolan-2-yl) -2-naphthoate g).

(+)ESI-MS mhZ: 313 The following compounds from Preparation 42 to CI 5 Preparation 46 were obtained in a similar manner to that of Preparation 41.

Prl~tion 42 IND Methyl 6-(4,4,5,5-tetramethyl-13,2-doxaborolan-2-yl)- 1-naphthoate (4)ESI-MS m/z: 335 (1+Na)+ Prep2aration 43 Ethyl 5,5-tetzauethyl-1,3.,2-dioxaborolafl-2-yl)- 1H-Indole-2-carboxylate (+)ESI-MS mf/z: 316 Prep2aration 44 IMethyl l:-isopropyl-6-(4,4,5,5-tetramnethyl-1,.3,2dioxaborolan- 2-yl) H -indole carboxylate: (+)ESI-MS m/z: 366 Prep~aration -Isopropyl-NII-(methylsulfonyl)-6-(4 14, 1,3, 2 -dioxaborolan-2-yl) H-indole-3-carxboxamLde- (-)ESI-MS m/z: 405 Preparation 46 Ethyl+ [5.-(.4,4-,.5,5-tetramethyl-1,3,,2-;dioxaborolal-2-yl)- 1H-indol-1-yl]acetate (+)ESI-MS m/z: 352 Preparation 47 To a solution of methyl 6-hydroxy-1-naphthoate (4.5 g) and 2,6-lutidinte mL.) in dichlarometahne (90 mL) was added trifuoromethanesul.forxic anhydrids (7.9 mL) at SCC u-nder nitro~gen, and the resulting mixtura was stIrred at the same temperature for 6 hours. The resulting mixture was poured Into IN hydrochloric acid and the aqueous layer vas extracted with ethyl acetate. T2.,e organic layer was washed successively with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give methyl 6- [[(trifluoromethyl)sulfonyl oxyl-l-naphthoate (8.1 g).

1H NMR (CDC1 3 4.02 (3H, 7.50 (1H, dd, J=2.7, 7.6-7.65 (1H, 7.80 (1H, d, J-2.6Hz), 8.05 (1H, d, J-8.3Hz), 8.25-8.3 (1H, 9.11 (1H, d, The following compound was obtained in a similar manner to that of Preparation 47.

Preparation 48 Ethyl (trifluoromethyl)sulfonyloxy-1H-ilndole- 2 carboxylate (+)ESI-MS m/z: 338 (MH)+ Preparation 49 To a solution of 6-bromo-1-isoprpyl.-1H-idoJe-3+carboxylic acid. (1.94 g) in NN-dirnethylformamide, (97: rnL) were added potassium carbonate (1.43 g) and iodomethane (0.514 rnL) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 3.5. hours.,.

The resulting mixture was poured into water and the aqueous layer-was extracted. with ethyl acetate. The organic layer was washed:. snccessively with water three times and brine, dried over: anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography. on silica gel (hexane/ethyl acetate=10/1 to 5/1) to give mnethyl 6-bromo-1-isopropyl-1-inldole-3carboxylate (1.9 (+)ESI-MS mn/z: 318, 320 (M+Na)+ Preparation To a solution of methyl 6-eZ-[(ert-buta xycarbonyl)) (3 -cklorophenyl) -2-hydroxyethyl amino]ethyl pheyl L-isopropyl-1H-indole-3-carboxvlate (340 mg) in Ctdichloromethane (S mL) were added 3,4-dihydro-2{-pyral (0.105rnL) and a catalytic amount of pyridinium p-toluenesulfonate at room temperature under nitrogen, and the mixture was stirred at the same temperature for 12 hours.

NI 5 The resulting mixture was poured Into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium IND bicarbonate and brine,* dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl. acetate=4/1) to give methyl 6- [2-[C(tertbutoxycarbonxyl) I (2R) (3-chlorophenyl).-2.- (tetrahydro-2Hpyran- 2 -yoy)ethyl]I amino]I ethyl] phenyl] 1-isopropyl-lHindole-3-carboxylate (310 mg).

(+)ESI-MS m/z: 697 (M+Na)~ The follobwing compound was obtained in a similar manner to that of Example 68.

Prep~aration 51 4-[2-U..tert-Butoxycarboflyl) ((2R)-2-(3-chlorophenyl)- 2- (tetkAiyd~o"'-'2-p yran- 2 -yloxy) ethyl]I aminojI ethyl Iphenlyl] -1isopropyl- 1H-indole- 3-carboxylic acid (-)ESI-MS m/z: 659, 661 Preparation 52 To a sodlutin of+' 6-(4-[2-((tert-butoxycarbofl)K2R)-2- 3-chloropheiyl) (tetrahydro-2H-pyral-2-yloxy) ethyl] amino] ethyl) ]ph'e'nyll 1-isopropyl- 1H- indole-3-carboxylic acid (131' mg) i:n+ N,N-dimethylformamiLde (2 inL) was added 1,1V- -carxbonYldi:Uiizole (35 mg) at room temperature under nitrogen, and the mixture was stirred at the same te-.mperatuxe for 2.5 hours. Ts thIs one were added methainesulffonamilde (46 mg.) and 1,a-diazabicyalo[5.4.OP-7undecene (72 mg) at room temperature, and the mixture was stirred a-t 60"C for 10 hours. The resulting mixture wa-s poured into 0.1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid three times and brine, dried over anhydrous magnesium sulfate and evaporated 1 5 under reduced pressure. The residue was purified by column S chromatography on silica gel (chloroform/methanol=200/1 to S100/1) to give tert-butyl [((2R)-2-(3-chlorophenyl)-2- 0 (tetrahydro-2H-pyran-2-yloxy)ethyl][2-(4-[1-isopropyl-3- [[(methylsulfonyl)amino]carbonyl]-1H-indol-6-yl]henyl] LO ethyl]carbamate (134 mg).

(-)ESI-MS m/z: 736, 738 (M-H) The following compound was obtained in a similar manner to that of Preparation 52.

Preparation 53 6-Bromo-1-isopropyl-N-(methylsulfonyl)-1H-indole-3carboxamide (-)ESI-MS m/z: 357, 359 (M-H) Preparation 54 <To a'solution of 5-bromo-1H-indole (5.0 g) in N,Naimethylformamide .(50 mL) were added potassium carbonate (4.2 g) and iodomethane (4.7 g) at room temperature under nitrogen., and the mixture was stirred at 60*C for 3.5 hours.

.The.resulting mixture was poured into water and the aqueous layer was extiracted with ethyl acetate. The organic layer was washed successively with water three times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on. silica gel (hexane/ethyl acetate=10/1 to 4/1) to give ethyl (5-bromo-1H-indol-1-yl)acetate (5.8 g) (+)ESI-MS m/s: 304, 306 (M+,4aj' Preparation To a solution of (1R)-2-[[2-(4-iodophenoxy)ethyllam.ino) (4-nitrophenyl) ethanol (7.52 g) In tetrahydrofuran xnL) was added di-tert-butyl dicarbonate (4.44 mL) and the mixture was stirred for 16 hours. The solvent was removed by evaporation and the residue was chromatographed NI 5 on silica gel (eluent: hexane/ethy. acetate) to give tertbutyl [(2R)-2-hydroxy-2-(4-nitrophenl)ethyl]E2-(4iodophenoxy)ethylcarbamate (3.48 g) as an orange paste.

(+)ESI-MS m/z: 551 (M+Na)4 The following compound was obtained according to a simiLlar manner to that of Preparation Preparation 56 [(tert-butyl(dimethyl)silylJoxylethyl] (4-bromophenyl) ethyl] earbamate (+)ESI-MS m/z: 614, 616 (M+Na)+ Preparation 57 To-a miLxture of (2R)-2-16-(acetylamino)-3-pyridyl]-2- ((tert-butyl~dimethyl) silyl]oxy]ethy1. 4-methylbenze-.

nesulfoniate (3.50 [2-(4-bromophnyl)ethylafike (3.01 g)+ and+dimethyl-sufoxIde (1.75 mL) was added N,N-diisopropylethylainine (1.31-.mL) and the mIxture was stiLrred at 8+0 0 C for 24 hours.*. After.cooliLng to room temperature, the mixture was diLluted with ethyl acetate (35 mL) and water and the, organic layer was separated. The organic layer was washed with water (35 mL x 2) and brine (35 mL). and dried over magnosium sulfate. Filtration followed by evaporation gave a yellow paste (5.36 S) which was chroinatographed on silIca-gel (eluent: hexane/ethyl acetate) to give N-[Sbutyl( dimethyl)s lylloxy12ethyll -2-py'rid-yllacetami-de (3 33 g)' as a colorless paste..

(+)ESI-ViS m/z: 492, 494 (M*IH)+ Preparaition 58 To a solution of E4-(2-[benzyl(tert-butoxycarboflyl)amino Iethyl lphenyl ]boroflic acid g) in 1,2dimethoxyethane (45 mL) were added methyl 3-nitro-4-.

[[(trifluoronethyl)sulfoflyl]oxylbezoate (3.0 g), tetrakls(triphenylphosphr18)palladiumf (800 mg) and aqueous solution of sodium carbonate (2M, 9.1 niL), and the mixture 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 was purified by column chromatography on silica gel (hexan6/6thy. acetate=3/1) to give methyl 4'42- [benzyl(tert-butoxycarbol)amiflo]ethyl] -2-nltro-4biLphenylcarboxylate (3.05 g).

MS m/z: 491 ~PFaatIon 59 A mixture of tert-butyl ((2R)-2-hydroxy-2-+ 47iodophenoxy) ethyl ]oarbamate (250 mg), (3etbo~ky-4-Ift (methylsulf onyl) amino] carbonyljphenyl] boronic acid' (223,mg), -bis(diphenylphosphilferrocel]d~ichloropalladium(II), complex with dichlorometbane (1;1, 114img), b:Ls(dLiphenylphosphino)ferrocenle (32 N,Ndirnethylformamide. (5 mL), and 2N sodium carbonate solution (0.99 !nuL).,was stirred at 800C for 1 hour. After cooling to room-temperaturef the mixture was quenched by the addition of lN hydrochloric acid (1.99 mL) and partitioned between ethl. cette(20 niL) and water (20 The organic layer was: separated, washed with water (20 mL x 2) and brine mL,, and driled over magnesium sulfate. Filtration followed by aeTaporat:Lca gave a brown foam which wa clromatographed on silica gel (eluent: hexarie/ethyl acetate) to give tertbutyl (3c-ethoy-4-[ECmethylsl-foflyl)aflaO!carbonll..

4 biohanylyl I oxyl ethyl][ -2-hydroxy-2 -phenylethyl3carbamlate (84.5 mg) as a pale orange solid.

(-)ESI-MS m/z; 597 (M-H- The following compound was* obtained according to a similar manner to that of Preparation 59.

Preparation tert-Butyl ((2R)-2-(6-(acetylamino)-3-pyridyl-2- [(tert-butyl)(dimethyl)silylloxylethyl[2-[3'- (cyclohexyloxy)-4'-[[(methylsulfonyl)aninolcarbonyl -4biphenylyll ethyl carbaiate (-)ESI-MS m/z: 807 (H-H- Example 1 To a solution of tert-butyl ((2R)-2-6-(acetylamino)-3pyridyl [tert-butyl (dimethyl) silyl]oxy ethyl] ethoxy-4'-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl :ethyl]carbamate (237 mg) in ethanol (2.4 mL) was added 1N sodium hydroxide. (3..14 mL) and the mixture was refluxed for 18 -hours. After. cooling to room temperature', the mixture, was.quenched&.by the., addition of 1N hydrochloric acid (3.14 mL). and the solvent was removed-by evaporation. To.the residue: Vere added .4 14 hydrogen* chloride in dioxane. (4 iL) ,and methanol- and the mixture was stirred at, room.

temperature for..15 hours. The solvent was concentrated-in .vacuo and. the *residue was dissolved in water (5 niL) and treated with activated carbon. After stirring for 2 hours, the mixture was filtered and the pH of the filtrate was* adjusted to.7 by the addition of 1N sodium hydroxide.. The precipitates. were collected by filtration, washed with water, and dried under reduced pressure at 50C to give 4'-E2- (6 -amtno-3-pyridyl) -2-hydrxyethyll aminio)ethy21-3ethoxy-N- (methylstif onyl- -Q4-biphenyrlcanrbamide (123 mg)' as.

a off-white solid.

NR *R (400 z, DMSO-d, 6)g 1,27 (3H, t, J-7.OH), 2.88-3.14 (9R. 4.15 (2H, q, J=7,OHz,) 4.67 (1H, t, 3=6.6Hz), 5.73 (111, br), 5.92 (2H, brs), 6.43 (1H, d, 3=8.4Hz), 7.18-7.20 (21H, in), 7.32 (2H, d, 3=8.4Hz), 7.37 (1H, dd, J=2.2, 8.4Hz), 7.46 (1H, d, 3=8.4Hz), 7.65 (2H1, d, 3=8.4Hz), 7.88 (1H, d, 3=2.2Hz) (-)ESI.-MS in/z: 497 The following compounds from. Example 2 to Example 4 were obtained in a similar manner to that of Example 1.

Example 2 LO 4*-12-[[(2R)-2-(6-Amino-3-pyridyl)-2-hydroxyethyl)amTino) ethyl] -3-(isopropylthio) (methylsulfonyl) -4biphenylcarboxamide L.H-NMR (400kHz, DMSOd 6 1.26 (611, d, J-6..6Hz),.

2.96-3,24 (9H1, 3.*64 (1H1, heptuplet, J=6.6Hz), 4.77 (111, mn), 5.97 d, 3-3.7Hz), 6.03 (2H, 6.47 (1Hd dF J= 8.41U)j,7.36-1.42 (3H, mn), 7.48,(111, d, J=8. .4Hz), 7.61 (1H1, 7.'66-7.70 (3H1, in), 7.90 d, J=2.2Hz), 8.74 (2H,.br) (-)ESI-MS in/Z: 527 (M-H)-F Rxample 3 4.'-[3-1[(2R)-%2-(6-Amino-3-pyridyl)-2-hydroxyethyl~amilpropyl] -3-(cy'clohexyloxy) (methylsu3.fonyl) -4-biphenylcarboxazu~de 1H1 NMR (400MHz,-DMSO-d 6 1.31-2.02 (12H, in), 2.68, (2H,t'.tJ=7.3Hz),.2 .93 (2H1, t, J=7.7Hz), 3.00-3.09 4455 mn) -4.6 (1H, mn), 5.87 (111, br), 5.96 (2H, br), 6.43 (1Ho d, J=8.4Hz), 7.22-7.26 (2K1, in), 7.31 (2H1, d, J-8. 1Hz), 7.38 (114,- dd, J=2.2, 8.4Hz), 7.52 (1H1, d, J=7.7Hz) 7.63 d,*J=8.1Hz), 7.88 (111, d, 3=2.2Hz), 8.96 (2H, br.) (-)ESI-MS infz: 565 Example 4 4' (soprpytAic n-4 -pheylcahrboxyylic a :Lo IM NMR (400M4iz 0 Dl(SO-d 6 1.29 (6H1, t, J-6.6Hz).

2.87-3.07 (6H1, mn), 3.71 (IH. hepttzplet,. 3=6.6Hz), 4-G9 (l11, t, T=6.2H1z), 5.89 (2H1, bra), 6.43 d, 3=8.4Hz), 7.33- 7.43 (4H, in), 7.54 (1H, 7.65 (2H, d, J=8.4Hz), 7.83-7.90 (2H1, m) (-)ESI-MS m/z: 450 Example To a solution of tert-butyl ((2R)-2-[6-(acetylamino)-3pyridyll-2-([tert-butyl(dimethyl)silyl]oxy]ethyl][2-[3'- (cyclohexyloxy) -4'-[[(methylsulfonyl)amino~carbonylJ -4biphenylyllethyl~carbamate (236 mg) In tetrahydrofuran (2.4 znL) was added 1.0 M solution of tetrabutylarmonium fluoride in tetrahydrofuran (0.321 mL) at room temperature and the mixture.-was. stirred for 1.5 hours. An additional portion of l.0.M solution of tetrabutylanmoniun fluoride in tetrahydrofuran 321 mL) was added and the mixture was stirred for .16. hours. The mixture was quenched by the addition of pH.6.86-buffer (20 niL) and extracted with ethyl acetate (20'mL) The' extract was washed with brine (20 mL) and. dried. over. magnesium sulfate. .Filtration followed by evaporation gave a pale yellow paste which was chromnatographed on silica gel (hexane/ethyl acetate) to give A-ert-butyl, (acetylamrino) .3-pyridyl] -2-hydroxyethyl3(2-[31-(cyclohexyloxy)-4'-([(methylsulfonyl)-amiLno]carbonyl]-4-biphenylyllethyllcarbamate (187.mg) as a whiLte foam.

(-)ESI-MS m/z: 693 Example 6 To a solution of tert-butyl [(2R)-2-[6-(acetylamin o)-3pyridyl)-2-hydroxyethyl] E2-E3' -(cyclohexyloxy)-4' 3 0 E[ (methylsulf onyl.) amiLno]I carbonyl I 4 -biphenyly. I ethyl] carbamate (177 mg) In 1,4-dioxcana (1.8 1mL vras a~ded 4M hydrogen chi ride in diaae C1.3 mL) and the mix-tare w'as stIrred at room temperature for k.5 hours. The precipitates were collected by filtration and washed with dioxane and dried under reduced pressure at 50*C to give 4'-r2-E[(ZR)-2- E 6- (acetylanino) 3-pyridy. I -2-hydroxyethyl]I amino]I ethyl]1 -3- (cyclohexyloxy) (methylsulfonyl) -4 -biphenylcarboxamide dihydrochioride (141 mg) as a white solid.

114 NMR (400MHz, DMSO-d 6 1.31-1.64 (6H, in), 1.69- 1.78 (2H, mn), 1.91-1.99 (2H, in), 2.12 (3H4, 3.01-3.28 (6H4, in), 3.39 (3H, 4.82 (1H4, heptuplet, J=4.OHz), 5.04 (1H, d. J-2.9, 9.9Hz), 7.35-7.43 (414, mn), 7.74 (2H, d, 3.28.4Hz), 7.78 (1H4, d, 3.28.1Hz). 7.87 (1H, dd, J-2.2, 8.8Hz), 8.34 (1H4, d, Jm2.2Hz), 8.99 (1H4, br), 9.25 (1H4, br), 10.8 (1H, brs), 11.2 (1H4, brs) (-)ESI-MS m/z: 594 .To'a solution of methyl 4'-E2-[(2R)-2-[6L (acetylamnino) -3-pyridyl] [tert-butyl(dimethyl)silyl]oxy]-ethyl] (ter 't-butoxycarboriyl)amino]ethyl] -3-ethoxy-4biphenylcarboxylate (191 mng) In -ethanol inL) was added 1N s odium: hydroxide 76 mL) and the. mixture was ref luxed for. 27 -hours., After cooling to room. temperature, the mixture. was quenched by the addition of 1N hydrochloric acid (2.76 inL) and, the -'solvent was removed. by evaporation. To the residue werei* added 4 N hydrogen' Clloride in. I1P 4 dioxane (4 niL) and methanol. (1 mL) and the mixture was stirred at room temperature for'5 hours. The solvent was concentrated in vacuo: and the residue was chroznatographed on octadecylfunctionalied silica gel (eluerit: water/methanol). The fractions containing the product were combined and acidified with IN hydrochloric acid and then concentrated In vacua to give 4.'-[2-(([(2R)-2-(6-amrnno-3-pyriLdyl)-2-hydroxyethyl)amino Iethyl! -3-ethoxy-4-bipheny2.carboxylic acId dihydrochloride (36.1 mng) as a white solid.

JH NZMR (4,OM{z, DRSO-d 6 L,36 (3H, t, 3.02-3.25 (6H, ml), 4.21 (2H, q, J=7.OHz)r 4.98 (1H, dd, 8.SHz), 6.47 (1H, br), 7.05 (1H4, d, J=9.214z), 7.26- 7.31 (214, mn), 7.38 (214, d, J=8.Hz), 7,71-7.73 (3F4, mn), 7.95-7.98 (2H, mn), 8.20 (1H1, br), 9.07 (1H1, br), 9.21 (1H, br), 12.6 (1H1, br), 14.0 br) (-)ESI-M4S m/z: 420 The following compounds from Example 8 to Example 9 were obtained In a similar manner to that of Example 7.

ExaMple 8 [(2R)-2-(6-Amino-3-pyridyl) -2-hydroxyethyllamino]ethyl] -3 -isobutyl- 4-biphenylcarboxyliLc acid dihydrochioride 1HNMR (400MHz, DMSO-d 6 0.88 (6H, d, J=6.6Hz), 1.85 (1H,.heptuplet, 3=6.6Hz), 2.91 (2H, d, J=6.6Hz), 3.04-3.22 (6R, mn), 4.98(l1 d, 3=7.3Hz),, 6.45 (1H, brs), 7.03 (1H, d, 7.38 (2H, J=8.lHz), 7.52 (1H, 7.58 dd, J=1.8, 8.1Hz), 7.70 (2H, d, 3=8.1Hz), 7.87 (1H, d, J=8.1Hz), -7.93-7.98 (2H, rnm) 8.14 (2H, br), 9.07 (1H, br), 9.21 (1H, br), 12.8 (1Hi, br), 14.0 (1H, br) (-)ESI-MS m/z: 432 (M-H)-F Exampe 9 [3-([1(2R)-2-(6-Amino-3-pyridyl)-2-hyroxyetyl..

amino] propyl] (cyclohexyloxy) -4-blphenylcarboxylic acid dihydrochioride .'HNMR,(400MHz.,. DMSO-d 6 13-05(12H, 2.67.

3.19,(6H, in), 4.65-(lH, heptuplet, J-3.7Hz), 4.96 dd, J=3.3,-8.8Hz), 6.43 (1H, br), 7.04 (1H, d, 3=9.2Hz), 7.25.

J=1.1, 8.1Hz), 7.32-7.36 (3H1, mn), 7.66 (2H, d, ,J=8.lHZ) 7.70 (1H1., d, 3=8.1Hz), 7.93-7.97 (2H, in), 8.21 (11H, br). 9.00 (1H, br),.9.19 (1H, br)F 12.6 (1H4, br), 14.1 (1H, br) (-)LSI-MS rn/Z: 488 Enal2e To a Solhtlon of nty..-2-()2-G (acetylamino) -3-p-yriLdyl] -2-[Etert-butyl(dinethyllsiLlyll oxy 3ethyl] (tr-t -butoxycarbonyl )aminolIethyl] -3 -cyclopentyl= d biphenylcarboxylate (307 mg) in 1,4-dioxane (3.1 nL) was Ct added 4N hydrogen chloride in 1,4-dioxane (3.1 niL) and the mixture was stirred at room temperature for 5 hours. The precipitates were collected by filtration, washed with 1,4dioxane, and dried under reduced pressure to give methyl 4- (2-(U(2)-2-[6-(acetylamino)-3-pyridyl]-2-hydroxyethyl]amino] ethyl] -3 -cyclopentyl- 4-biphenylcarboxylate dihydrochloride (136 mg) as a white solid.

The following compounds from Example 11 to Example 12 were obtained in a similar manner to that of Example Example 11 .Methyl 4"'-(3-[[(2R)-2-(6-(acetylamino)-3-pyridylJ-2hydroxyethyl I amino] propyl I -3 -isopropoxy..- 4biphenylcarboxylate dihydrochioride Example 12 Methyl. 4'.-(2-.[U2R)-2-[6-(acetylamino)-3-pyridylJ-2hydroxyethyl I amino] ethoxy J 3 -isobutyl- 4 -biphenylcarboxylate dihydro chloride Example 13 To!a. solution of methyl (acetylamino.) -3 -pyridyl -2 -hydrokcyethyl] amino.] ethyl] -3cyclopentyl biphenylcarboxylate dihydrochloride (136 mig) in water (3.fnL) was added SN sodium hydroxide. (1.5 niL). The mixture was heated to 100 0 C and stirred for. 16 hours. After cooling to room temperature, the mixture was diluted with water- mL) and the pH of the solution was adjusted to The precipitated solid was collected by filtration, washed 'with water, and dried under reduced pressure at CO*C Z'0 to give a: White solid (145 mg). To the solid were added IN htydrochloric acid (3 mL) and water (2 and tkhe suspensfon was heated to OC which turned to. a sol~ution. The saltlon .was allowed to cool to room temperature and stirred for 2 hours. The precipitates were collected by filtration, washed wiLth a small amount of water, and dried under reduced pressure at 50'C to give 4'-[2-[U(2R)-2-(6-anno-3-pyridyl)- 2-hydroxyethyl. amino] ethyl] 3-cyclopentyl- 4-biphenylcarboxylic acid dihydrochioride (135 mg) as a white solid.

1 Hl NNR (40014Hz, DMSO-d 6 6) 1.59-1.70 (4H, in), 1.76-1.86 (2H, mn), 1.99-2-.07 (2K1, mn), 3.00-3.26 (6H, in), 3.75-3.83 (1H, 4.98 (1H, dd, J-3.3, 8.8Hz), 6.46 (1H, br), 7.05 (1H, d, J=9.2Hz), 7.38 (2H, d, J-8.4Hz), 7.52 (1H1, dd. J-1-8, 8.1Hz).

7.64 (1H, d, J-1.8Hz), 7.69 (1H, d, J=8.4Hz), 7.74 (1H1, d, J=B.lHz), 7.95-7.98 (2H1, mn), 8.18 (2H, brs), 9.07 (1H1, brs), .9.21 (1H, brs), 12.9 (1H, br), 14.0 (1H, brs) (-)ESI-MS m/z: 444 The-.following compounds from Example 14 to Example were obtained in asiLmilar manner to that of Example 13.

Example 14 [-[[R)2-6-mno-3-pyridyl) -2-hydroxyethyl] amitio ].propyl J 3- isopropoxy- 4-biphenylcarboxylic acid.

dihydrochloride 1 H-NMR '(40014Hz, DMSO-d 6 1.31 (6H, d, J=6.2Hz), 2.02 (1H, in),.2,.72 (2H, t, J-7.7Hz). 2.92-3.20 (4H; mn), 4.82 (1H1, haptuplet,.7':-6.2Hz), 4.97 (111, dd, J=3.3, 8.8Hz), 6.43 (1H,.

br), 7.04 7.26 (1H, dd, 8.1Hz), 7.32 J=l.5Hz), 7.35 (111, d, J=8.4Hz),.7.66-7-70 (311, in), .7.93-7.97 (2Hz, mn), 8.23 (2H1, brs).,.9.04. (1H, br), 9.23 (1H, br), 12.5 (111, br), 14.1 (1H1, br) (-)ESI-MS m/z: 448 Example 2-(6 -Amino 3-pyzdyl) 2-hydroxyetiyl] amino) ethoxy]I- 3-isobutyl-4-bipheaylcarboxylic a~cid dihydrochiorlds INMR (401YThz, DMSO-d6, 6) 0.88 (6H, J6.6HZ) 0 1.85 7.49 (1H, d, J=I.BHz), 7.55 (111. dd, S 0 1Hz), 7.70 (Z2W, 53.

d, J=8.8Hz), 7.85 (1H, d, J=8.lHz), 7.93-7.97 (2H1, in), 8.20 (2H, brs), 9.27 (1H, br), 9.40 (1H, br), 12.8 (1H, br), 14.2 (1H, br) (-)ESI-MS m/z: 444 Example 16 To a solution of tert-butyl [2-[(4-bromophenyl)aminolethyl] ((2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]carbamate (200 mng), (3-isobutoxy- 4- (methoxycarbonyl )phenyl] boronic acid,(134 mng), potassium phosphate (198 mg) in ethanol (2.0 mL) was added bis(dicyclohexylamine)palladium(II) acotate-(24.9 mg) and the mixture was stirred 0 C for 3 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was stirred for 2 -days. -The mixture Was filtered through celite cake and the filtrate-, was-partitioned between ethyl acetate and water.

The-.separated .organic layer was washed with bri:ne and dried over magnesiLum sulfate. Piltration followed by evaporation under. reduced pressure gave the crude product which was purLf ied by. column. chromatography on silica gel (eluent: hexane/ethyl-acetate=1/l to To- the resulting solid were. added'.tetrahydrofuiran (2.0 methanol mL) and 1N aqueous sodium hydroxide solution (1.27 niL) and the mixture was stirred. at 45"C for 3.5 hours.' -After cooling to room temperature the reaction mixture was *stirred overnight.

The pH value was adjusted to 5.0-6.0 by addition of 1N hydrochloric. acid. and the mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesiumsulfate.- Filtration followed by evaporation under reduced pressure. gave the crude product which was purif ied by column chromatography.'on silica gel (aluent. heae/ethyl acetate-lf I to 1/3) to give fL-[-(etbtxczoy) E(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyety]amino~ethy.lJamiLno]-3-iLsobutoxy-4-b:ipheiylcarbox-yliLc ac-ld (24.9 mg) a~s a yellow paste.

(-)ESI-MS M/z: 582 The following compounds from Example 17 to Example were obtained in a sim~ilar manner to that of Example 16.

Ex mple 17 Methyl 4'-C[2-U(tert-butoxycarbonyl)[(2R)-2-(3chlorophenyl) 2-hydroxyethyl]I amino]I ethyl amino) -3-Ls obutoxy- 4 bi~phenylcarboxylate (+)ESI-MS m/z: 597 620 (M+Na)+ Example 18 Methyl 4'-7(2-(trt-butoxycarbonyl)[(2R)-2-(3chiorophenyl) 2 -hydroxyethyl I amino ethyl] amino)I -3- (cyclohexyloxy) biphenylcarboxylat e (+)SIMSm/z: 623 646 (M+Na)+ Example 19 Methyl (2-U(tert-butoxycarbonyl)[ chlorophenyl)-- 2-hydroxyethyl I amino]I ethyl ]amino] -3-propoxy-4blphenylcarboxylate '(+)ESI-MS m/z: 584 606 Example Methyl- 4.-[2-[(tert-butoxycarbonyl)[(2R)-2-(4chlOrophenyl) 2-hydroxyethyl ]amino] ethyl] amino] -3 (cyclohexyloxy) -4-biphenylcarboxylate (+)ESI-MS m/z: 624 .646 .(M4-Na)+ Example 21 .To a solution of 4'-[2-1(tert-butoxycarbonyl)[(2R)-2- (6 -chloro-"'3 -pyridyl) 2-hydzoxyethyl Iamino Iethyl Iamino]I -3 isobutocy.-4-biptienylcarboxylic acid (24.5 mg) In methanol (0.*490-mL) and water (0.049 inL) were added ammonlum formate (13-.2 mg) and 5% palladium on activated carbon (vet, t4.6 The Mixtur wras refluxed. Zor 30 mtinutes. After cooling to room temperature, the mixture was filtered through celite cake and the filtrate wras concentrated under reduced pressure. To thie resIdae was added vater (2.0 mL) and the pH value was adjusted to 5. 80 by addition of 0.1IN hydrochloric acid, extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. After filtration, the solvent was removed by evaporation under reduced pressure. To the resulting residue were added ethyl acetate (0.245 mL) and 414 hydrogen chloride in ethyl acetate (0.245 mL) and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried in vacuo at 55 0 C to give 4'-[[2-(((2R)-2-hydroxy-2-(3pyridyl )ethyl] amino] ethyl] amino) -3-isobutoxy- 4-biphenylcarboxylic acid trihydrochloride (7.5 mg) as a gray powder.

1NMR (4001M{z,.DMSO-d 6 1.02 d, J=7.2Hz), 2.1 (iH, in), 3.12-3.30 (3H, 3.38-3.46 (1H1, mn), 3.50-3.53 (2H, in), 3.91 (2H, d, J=6.6Hz), 5.31-5.34 (1H1, in), 6.77 (2H, d, 7.17-7.20 (2H, in), .7.56 (2H, d, J=8.8Hz). 7.68 d, J=8.OHz)P, 8.04-8.07 (1H, Mn), .8.56-8.158 (1H, in), 8.87-8.93.(2W, mn), 9.25 (1H, brs), .9.42 (iH, brs) (+)ESI-MS m/z: 450 (M-iH)+ Example 22 Tox a solution of methyl (tert-butoxycarbonyl) C (2R) -2-(3-chlorophenyl) -2-hydroxyethyllazninolethyllamilno]- 3- cycoheyloy) 4-iphnylarbxylte(125 mg) in methanol (1.750 niL) and tetrahydrofuran (0.900 niL) was-added 1N4 aqueous+ sodium hydroxide solution (1.05 mL) and the mixture was-stirred at room temperature for 1 day. To the reaction mixture, was added 1N aqueous sodium hydroxide solution .(0.900 niL) and the mixture was stirred at room temperature for 3 days.. The reaction mixture was concentrated unde~r reduced pressure and to the residue were added ethyl acetate mW) and water (20~ nL). The pH{ valu.e was adjusted to 5.70 by additioan of C.1N hydroahloric acid amnd the spa~ated organic layer was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation gave [2-[(tert-butoxycarbomyl)E(2R)-2-(3-chlorophenryl)-Zhycoxyethyl]I amino]I ethyl)] amino)] 3- (cyclohexyloxy) -4 biphenylcarboxylic acid (123 mg) as a yellow foam.

(-)ESI-MS m/z: 607 (M-HV- The following compounds from Examnple 23 to Example 24 were obtained in a similar manner to that of Example 22.

Example 23 4'-[[2-((tert-Butoxycarbolyl)[(2R)-2-(3-chlorophelyl)- 2-hydroxyethyl] amino] ethyl] amino] -3-isobutoxy- 4-biphenylcarboxylic acid (-)ESI-MS m/z: 582 Example 24 -[I(tert -Butoxycarbonyl) C 2- (A4-chlorophenyl) 2-hydroxyethyl Iamino Iethyl Iamino]I 3- (cyclohexyloxy) -4 biphenylcarboxylic acid (+)ESX-MS m/z: 609 (M+H) 4 632.(M+Na)++ ExaMple To a solution of methyl (acetylamino.)?-31- pyridyl -2 tert -butyl (dimethyl) silyl] oxy ethyl (tert -butoxycarbonyl) amino]I propyl]I 3 -isobutyl- 4 .blphenylcarboxylate. (352 mg) in 1,4-dioxane (1.76 niL) was added. 4N hydrogen: chloride in ethyl- acetate 52 niL) and the mixture was' stirred at room temperature for 4.5 hours.

To the reaction mixture was added. methanol. 50 niL) and the mixture was stirred at room temperature overnight. The reaction -mixture was concentrated under reduced pressure.

The resulting residue was dissolved in water (7.40 niL) with +ref luxing and to the solution was added 5N aqueous sodium hydroxide solution (2.94 niL) and. the mixture was ref luxed overnight. After cooling to room temnperature, the pH value was adjusted to 7.C~ by addition of IF lay zochloaric acld. The precIpit -ate was collected by filtration, dried in vacuo at and purified by column claromatograpby on octadecyluctoaiesiiagl(eluent: water/methanol-90/1O to 30/70). The fraction containing the product was acidified with 114 hydrochloric acid and concentrated to'give [[(2R)-2-(6-amino-3-pyridy)-2-hydoxyethylaminopropyl.3isobutyl-4-biphenylcarboxylic acid dihydrochioride, (128 mg) as a white powder.

INMR (40014Hz, DMSO-d 6 0.088 (6H, d, J=6.6Hz), 1.8-1.9 (1H, in), 1.97-2.07 (2H, in), 2.72 (2H, t, 2.9-3.0 (4H, in), 3.02-3.21 (2H, mn), 4.95-4.98 (1H, in), 6.41 (1H, brs), 7.03 (1H, d, J=9.2Hz), 7.35 (2H, d. J-8.OHz), 7.51 7.53 7.56-7.59 (1H, mn), 7.67 (2H, d, J- 3 Hz), 7.86 (1H, d, J=8.4Hz), 7.97-7.92 (2H, in), 8.19 (2H, .brs), 9.01 (111,.brs), 9.19 (1H, brs), 12.83 brs), 14.1 (1H, brs) (+)ESI-MSinfz: 448 Example 26 To a -solution. of methyl 4'-[2-[(tert-butoxycarbonyl) (4chroen) -2-hydroxyethyl Iamino Iethyl ]ainno I 3-propoxy-4-biphenylcarboxylate (94.0 mg) in methanol (1.13 rnmL)-and tetrahydrofuran (0.564 inL) was added IN4 aqueous *sodlium hydroxide. solution (0.806 mL) and the mixture was stiredat room*.temperature for overnight. +The reaction .mixture was concentrated under reduced pressure and to the residue were; added ethyl acetate and water.- The pH value wsadjusted to- 5.70 by addition of 0.1N4 hydrochloric acid and the separated-organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was removed by evaporation under reduced pressure. To a solution of~the resulting residue in ethyl acetate (0.940 inL) was. added. 4Whydrogen chloride in ethyl acetate mL) and the mixture was stirred at room tamparatuxe for overnight. The reaction mixftuze was dIlluted vith atliyl3 acetate and the precipitate was collected by filtration and dried In vacuo at W0C to give cblorophenyl) -2-hydxyethyl I aminc ethyl]I amino] -3-proponry-4~biphenylcarboxylic acid dihydrockiloriLde (71.4 mg) as a white powder.

1H1 NMR (200MHz, DMSO-.d 6 1.02 O3H, t, 1.66-1.86 (2H, mn), 2.94-3.29 (4H, mi), 3.44-3.56 (2H, in), 4.09 (2H1, t, J-6.3Hz), 5.01-5.08 (1H, in), 6.78 (2H1, d, Jem8.SHz), 7.16-7.24 (2H1, mn), 7.41-7.47 (4H, mn), 7.56 (2H, d, 7.68 (1H1, d, J-S.Hz), 8.95 (1H1, brs), 9.42 (111, brs) (-)ESI-MS in/z: 467 Example 27 To a solution of 4'-1[2-U(tert-butoxycarbonyl)[(2R)-2- (3-chiorophenyl) -2-hydroxyethyl] amino] ethyl) amino] -3- (cyclohexyloxy)-4-biphenylcarboxylic acid (30.0 mg) In ethyl acetate (0-.500 mL) was added 4N hydrogen chloride in ethyl.

acetate (0.'500 niL) and the mixture was stirred at room temperature for 1.5 hours. The reactiLon in:xture was diluted with ethyl acetate and the precipitate .was collected by filtration and dried in vacuo at 50*C.to 2- (3-chiorophenyl) -2-hydroxyethyl]aminolethyllamino]-3- (cyclokiexyloxy) -4-bJiphenylcaxboxylic acid dihydrochloride (23.4 mig) as a white powder.

1 H-NMR (400MHz, DMSO-d 6 1.30-1.42 (3H1, in), 1.44- 1.51.(1, .1.521-1.63 (2H1, mn), 1.69-1.79'(21, in), 1.81- 1.91.(2H1, mn), 3.02-3.19 (3H, mn), 3.22-3.31.(1H, mn), 3.49 (2H, 4.58-4.65,(111, in), 5.04-5.01 (1H1, mn), 6.75 (2H1, d, J-8;8Hz), 7.17-7.24 (2H1, mn), 7.36-7.48 (4H1, mn), 7.53 (2H, d, J-8.8Hz), 7.67 (1H, d, J-S8Hz), 8.88 (1H1, brs), 9.26 (1H, brs) (-)ESI-MS m/z: 507 (-1 The f oll.owing compound~s from ZamL~le 28i to Mxwitp3.G 29wezes obtain~ed in a- similar manner to that of Example 27.

Example 28 4'-[[2-U[(2R)-2-(3-Chlorophnyl)-2-hdroxyethyl~aaino ethyl] amino]- 3-isobutoxy-4-biphenylcarboxylic acid dihydrochioride 1NMR (400MHz, DMSO-d 6 1.02 (6H, d, J=6.6Hz), 2.00-2.10 (1H, mn), 3.02-3.20 (3H, in), 3.22-3.30 (1H, mn), 3.51 (2H, t, J-6-6Hz), 3.91 (2H, d, J=6.2Hz), 5-03-5-07 (iM, rn), 6.78 (2H, d, J-8.8Hz), 7.17-7.21 (2H, mn), 7.36-7.48 (4H, mn), 7.56 (2H, d, J-8.8Hz), 7.68 (1H, d, J-7.6Hz), 8.95 (1H1, O brs), 9.41 (1H, brs) .(-)ESI-MS xn/z: 482 Example 29 4'-[[2-[[E(2R)-2-(4-Chlorophenyl)-2-hydroxyethyllamino]ethyl] amino] (cyclohexyloxy) -4 -biphenylcarboxylic acid dihydrochioriLde 1 H NMR. (200MHz, DMSO-d 6 1.26-1.94 (10H, mn), 2.95- ;3.30. (4H rn),.3.44-3.55 (2H, in),.4.55*-4.69 in), 4-99- 5.06. (1H, 6.76 (2H, d, J=8.5Hz), 7.16-7.24 (2H, in), 7.41-7.47(4H, mn), 7.53 (2H, d, J-8.5Hz),.7.67 (1H, d, J=811z), 8.90 (iH, brs), 9.33 (1H, brs).

(-)ESI-MS m/z: 508 The following compound was obtained in a similar manner to that of Example 16.

Example Methyl 4'-12-['(tert-butoxyoarbonyl) ((2R)-2-hydroxy-2- (3-pyridyl)ethyllaminolethyl]-3-(cyclohexylamino)-4biphenylcearboxylate (+)ESI-MS in/z: 574 Exgmple 31 -To a solution of methyl 4'-E2-[(tert-butoxyoarbony1)- C (2R) -2-hydroy-2-(3-pridyltyJ-axnino2ethyyl1-3-* (Qyccy-lain) -4-bih~nya~ro:~yate(300 mg) In Erethanol (6 zrrL was added IN sodium hydroxide aqueoxis solution (3.14 mL.) at room temperature and stirred at 55 0 C overnIght. To the solution was added IN hydrochlorlc acid C(3.14 inL) and the solution was diluted with ethyl acetate, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified with silica gel colunn chromatography to give 2=1 (tert-butoxycarbonyl) -2hydroxy- 2- (3-pyridyl )ethyl] amino] ethyl] (cyclohexylamino) 4-biphenylcarboxylic acid (272 mg).

(-)ESI-MS m/z: 558 (H-HF- Example 32 To a solution of 4'-[2-U(tert-butoxycarbonyl)[(2R)-2hydroxy- 2-(3 -pyridyl) ethyl] aminolJethyl) -3-(cyclohexylamino) 4-biphenylcarboxylic acid (265 mg) in 1.4-dioxane (2.50 mL) .was added 4N hydrbgen.'chloride in 1,4-dioxane (2.50 niL) and stixred .at room temperature for 5 hours. The-mixture was diluted with ethyl 'acetate, and the solid was collected by filtration'and dried to give 3- (cyclohexylamino) 2- [[(2R.)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-.4bipheriylcarboxylic acid dihydrochioride (210 mg).

'H.NMR (200MHz,. DMSO-d 6 1.14-1.76 (8H, in, 1.88- 2.4(2f, in), 3-01-3.52 (6H, 3.52-3.70 (1H, in), 5.35 (1Hi, d 1 3J=5 .OHz), 6.80 (1H, d, J=8.5Hz),.6.92 (1H, 7.37 (2H, d-0 3=8.5Hz), 7.65 (2H, d, 3=8.0Hz), 7.85 (1H, d, (111 dd 8.0Hz), 8.62.(1W, J=8.5Hz), 8.90 (1H, d, J=5.5Hz), 8.95 (1H, 9.38 (2H, brs) (-)ESI-MS in/z: 458 (M-HV- Exwnple 33 Almixture 'of methyl 4'-(2-(banzylamino)et-hyI]-2isopropoxy -4-biphenylcarboxrylate (190 mg), 2-chloro-S- C(2R) 2-oxiranylipyridIne (110 mg) and, ethanol (3,80 mL) was ref luxed fo~r 24 houzs The tiztuira was evapozated and thie residue was purified with silica gel column ohromatography to give methyl 4'-[2-EbenzylU(2R)-2-(6-chloro-3-pyridyl)-2hydroxyethyl] amilno) ethyl] -2 -isopropoxy-4 -biphenylcarboxylate (216 mg).

(+)ESI-MS M/z: 559 The following compounds from Example 34 to Example were obtained In a similar manner to that of Example 33.

Example _3 4 Methyl 4'-2-benzyl((2R)-2-(6-chloro-3-pyridyl)-2hydroxyethyl Jamino Jethyl] (cyclohexyloxy) -4biphenylcarboxylate (+)ESI-MS m/z; 599 Example .Ethyl 4'-[2-[benzyl[(2R)-2-(6-chloro-3-pyridyl)-2hydroxyethyl] amino Iethyl] -2-butyl- 4-biphenylcarboxylate (+)ESI-MS m/z: 571 Example 36 A mixture of methyl 4'-(2-[benzyl((2R)-2-(6-chloro-3pyridyl) -2 -hydroxyethyl] amino ethyl] isopropoxy- 4biphenylcarboxylate (210 mg), amnmonium formate (237 mg), palladium oncarbon -(501 wet, 105 mg) and methanol (4.20 mL) was-refluxed for.. 1.5 .hours. The solid was filtered off and the-solution was evaporated to give crude amine product.

The..residue was dissolved with tetrahydrofuran (2.10 mL) and *w~ter-(2.10 niL), added di-tert-butyl dicarbonate (98 mg) and the pH was- adjusted to 8.0-9.0 with 3N sodium hydroxide aqueous: solution. The mi-xture was.stirred at room temperature for 1 hour and poured into ethyl acetate and water. The organiLc layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue -was purif11ied with:- silica gel column chromatography to give methyl 4'-C2-1(tert-butoxycarbonyl)C(2R)-2-hydrox-y-2-(3carboxylsate (129 mg).

The following compounds from Example 37 to Example 38 were obtained in a similar manner to that of Example 36.

Example 37 Methyl 4'-(2-((tert-butoxycarbonyl)[(2R)-2-hydroxy-2- (3-pyridyl)ethyl]amino]ethyl]-2-(cyclohexyloxy)-4biphenylcarboxylate.

(+)ESI-MS m/z: 575 Example 38 Ethyl 4'-[2-(tert-butoxycarbofyl)[(2R)-2-hydroxy-2-(3pyridyl) ethyl] amino] ethyl] 2-butyl-4-biphenylcarboxyl.ate (+)ESI-MS mfz: 569 (M+Na)+ Example 39 To a solution of methyl 4'-[2-[.(.tert-butoxycarbonyl)- (2R)-2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl]1 -2isopropoxy-4-biphenylc8.rboxylate (125 mg) in methanol (2.50 nmL) was'added iN sodium hydroxide aqueous solution (700 )al) and stirred at 50 0 C overnight. To the mixture was added 1N hydrochloric acid (.700 jil) and the.mixture was poured into water and ethyl acetate. The organic solution* was separated, washed.' wth-+brine, dried over magnesium sulfate and evaporated-to 'give crude carboxylic acid product+. The residue was dissolved with 1,4-dioxane (1.25 and to the mixture was added 4N hydrochloric acid aqueous solution (1.25 mL) dxopwise at room temperature. The mixture was stirred overnight, diluted with ethyl acetate and the resulting. solid was collected by filtration. The solid was dried to++ give I(2R) 2 -hydroxy- 2 (3 -pyridyl) ethyl]aminao Bethy1]i 2-isoprpoxr- 4- biphenylcarboxylic acid dihydrochloride (80 mg).

IM CFA 200z, DMSO-d6 1.24 d. 3.00-3.54 (6H, F 4.0- .72 mn), 5.31 dlq, d, 3-G.C9),- 7.33 (2H, d, J=8 0 0Mz), 7.41 (1H, d, J=8.OHz), 7.52-7.61 (4H, 7.9 dd, Jz5.5, .90z), 8,49 (1H, d, J- 82Evz 8.50- (1H, d, J=4.5Hz, 8.90 9.30 (2H, brs) (-)ESI-MS m/z: 419.4 The following compounds from Example 40 to Example 41.

were obtained In a similar manner to that of Example 39.

Exqpe4 2-(Cyclohexyloxy)-4'-(2-[[(2R)-2-hydroxy-2-(3pyridyl )ethyl] amino Iethyl] -4 -biphenylcarboxylic acid dihydrochioride 1H NM (200MHz, DMSO-d 6 1.16-1.67 (8H, in), 1.75- 1.94 (2H1, mn), 3.00-3.49 (6H, in), 4.36-4.53 (1H, mn), 5.26 (1H, d, J-6.OHz), 7.33 (2H, d, J=8.OHz), 7.42 (1H, d, 7.53-7.60 (4H, in), 7.91 (111, dd, J=5.0, 8.0Hz), 8.39 (1H, d, 3=8.0OHz), 8.80 (1H, d, 3=4.0Hz), 8.86 (1H, 9.19 (211, bra) (-)ESI-MS mlz: 459 Example 41 2-Butyl-4'. CC(2R) -2-hydroxy-2- (3.-pyridyl) ethylJI andio]ethiyl) -4 -biphenylcarboxylic acid dihydrochioride 1 WHNMR -(200M~z,. DMSO-d 6 0.75 (3H, 3=7.3Hz), 1.07 -L1.25- (2H, r -33-1.4 8 (2H, mn), 2.56--2.64.(2H, in), 3.02- 3.48 (6H, Mn) 0 5'.27 (111. d, J=6.0Hz), 7.24-7.39 (5H, in), 7.80 (1H, .dd. 7.89 (1H, d, J3=1.5Hz)., 7.92 (1H, dd, 3=S55 8.0Hz). 8.41 (1H1, d, 3=8.0Hz), 8.81 (111, dd, 8.87 d, J=1.0Hz),:9.21 (2H, brs) (-)ESI-MS in/z; 417 Example 42 To..a mixture of methyl 4'-[2-[(tert-butoxycarbonyl)- E -2-hyd-toxy-2- (2-pyrazinyl) ethyl Iamnino Iethyl]j-3- (cyclolexyloxy)-4-biphenylcarboxylate (260 mng) in methanol mL.) and tetrahydrofuran (1.5 rnL) was aded IN sodiAUM hydroxide aqueou. solutlon mrL) dropw~'se and the milxtura was stirred at room temperature overnight. The mixture was acidiffied with IN hydrochlorla acid (2 znL) &nd partiticned to ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate-15/85) to give 4'-[2-[(tert-butoxycarbonyl) 1(2S)-2hydroxy--2- (2-pyrazinyl)ethyllamino]ethyl] (cyclohexyloxy) 4-biphenylcarboxylic acid (230 mg).

(-)ESI-MS m/z: 560 Example 43 A mixture of.(lS)-2-amino-1l-(2-pyrazinyl)ethanoI (61 mg), 4'-(2-bromoethyl) (cyclohexyloxy) (methylsulfonyl) 4-biphenylcarboxamide (105 mg), potassium bicarbonate (136 mg) nad- potassium iodide (7 mg).in 1-methyl-2-pyrrolidone (1 mL) was stirred at. 100"C for 1.5 hours. To the mixture was added iN Hydrochloric acid (1.5 nit). The resulting mixture was poured into pH 7 buffer solution, extracted with :.cbloxoform/methanol dried over sodium sulfate and evaporated under-reduced pressure. :The residue was purified byreverse column chromatography on Daisogel SP-120 (water/methanol),.to. give 3-(cyclohexyloxy)-4'-[.2-.[[(2S)-2- .hydroxy-2- (2-pyrazinyl)ethyl]amino]ethyl]

-N-

(methylsulfonyl) -t-biphenylcarboxamilde hydrochloriLde (13 mg).

NMR (20I DMSO-d 6 1.34-1.81 (BH, mn), 1.90- :2.03 3.-03-3.48 (6H, mn), 3.3.9 (3H, 4.78-4.86 (1H, 2S. in), 5.16* (1H, dd,* J=2.8, 9.5Hz), 7.35-7.42 (4H, mn), 7.72- (3H, mn)- 8.64-(2H, 8.84 (1H, 9.02 brs).

9.37 (1W, brs), 11.21 (1H, s) (-)BSI-MS in/z: 537 The followinkg compound was obtained In a similar namnr to that of Example 43.

Example 44 3-(Cyclohexyloxy)-4'-L2-[[(..S,2R)-2-hydroxy-2-(4hydroxyphenyl) -1-methylethyl) aminxo lethyl] -N- SS~ (methylsulfonyl) -4-biphenylcarboxami-de hydrochlorlde 1H NMR (200MHz, CDCl 3 (3H, d, J6.5Hz), 1.23- 1.96 (10H, 3.00-3.65 (5W, 3.17 (3H, 4.70-4.95 (1H, 5.08 (1H, 6.76 (2H, d, 3=8.4Hz), 7.17 (2H, d, 3=8.4Hz), 7.32-7.49 (5H, 7.72-7.95 (3H, 8.88 (2H, s) (-)ESI-Ms m/z: 565 (free) Example To a mixture of ethyl 4-(5-[2-Ebenzyl[(2R)-2-(6chioro- 3-pyridyl) 2-hydroxyethy 3 amino] ethyl] -2pyrmidinyl-2-(cyclohexyloxy)benzoate (48 mg) and ammonium formate (50 mg) in methanol (1 mL) was added 10% palladium on carbon (50% wet,.24 mg). The mixture was stirred at 70 0

C

for 90 minutes. The mixture was filtered through celite pad and the filtrate was evaporated under reduced pressure.

The residue was purified by column chromatography (chloroformfmethanol=98/2) to give ethyl 2-(cyclohexyloxy)- 4 2 2 R)-2-hydroxy-2(3pyriyl)ethylamnoethyl.2pyrimidinylbenzoate (47 mg).

(+)ESI-MS m/z: 491 The following compound was obtained in a similar manner to that of Example Example 46 Ethyl 2 -(cyclohexyloxy)-4-(5-2*-[[(2R)-2-ydroxy-2phenylethyl] amino] ethyl] -2 -pyrimidinyl] ]benzoate (+)ESI-MS m/z: 490 Example 47 To a mixture of 4-E5-[2-((tert.-butoxycarbonyl)[(aFR)-2hydroxy-2-phenyle^thyl amio i ethyl]- 2-pyrimtdinyl] -2- (cyclohexyloxy)beazoic acid (60 mg) in ethyl acetate mU WaS added 4M hydrgen chloride in ethyl acetate (I mLj and the mixture was stirred at room temperature for 3 hours.

The precipitate was collected by filtratior and washed with diisopropyl ether, The precipitate waras dried under reduced pressure to give 2-(cyclohexyloxy)-4-[5-[2-([(R)-2-hyrOXy- 2-phenylethyl amino ethyl] -2-pyrimidinyl]benzoic -acid hydrochloride (38 mg).

1H MR (200MHz, DMSO-d 6 1.35-1.95 (1OH, 3.40 (6H, 4.50-4.62 (1H, 5.02 (1H, dd, 10.5Hz), 7.30-7.42 (5H, 7.74 (1H, d, J=8.0Hz), 8.00 (1H, dd; J=1.0, 8.0Hz), 8.07 (1H, brs), 8.89 (2H, 9.00 (1H, brs), 9.41 (1H, brs) (-)ESI-MS m/z: 460 The following compound was obtained in a similar manner to that of Example 47.

Example 48 2-(Cyclohexyloxy)-4-[5-[(2-U(2R)-2-hydroxy-2phenylethyl i amino] ethyl] -2 -pyrimidinyl i-N- (methylsulfonyl) benzamide hydrochloride 1H NMR (200MHz, DMSO-d 6 1.26-2.04 (10H, 3.02- 3.41 (6H, 3.39 (3H, 4.49-4.72 (2H, 5.02 (1H, dd, 10.0Hz), 7.32-7.46 (5H, 7.78 (1H, d, 8.05 (1H, brs), 8.1 (1H, d, J=3.OHz), 8.91 (2H, 8.99 (1H, brs), 8.41 (1H, brs), 11.49 (1H, s) (+)ESI-MS m/z: 539 Example 49 A mixture of ethyl 4-(5-(2-(benzylamino)ethyl]-2pyrimidinylj-2-(cyclohexyloxy)benzoate (149 mg) and (2R)-2phenyloxirane (0.05 nL) in ethanol (2 mL) was refluxed for 28 hours. The mixture was evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel (hexane/ethyl acetate-80/20) to give ethyl Ebenzyl[(2R)-2-hydroxy-2-phenylethy:Iamninolethyl)-2pyzrimFdlnyll (cya.c1hxyloxy)benzoa. t 15 Img) (+)ESI-MS M/z: 580 The Zollowing compound was obtaned in a si-milar manner ct to that of Example 49.

Example Ethyl 4-[5-(2-[benzylE(2R)-2-(6-chloro-3-pyridyl)-2hydroxyethyl Iamino] ethyl] -2-pyrimidinyl] -2- (cyclohexyloxy)benzoate (+)ESI-MS m/z: 615 IND Example 51 To a mixture of methyl 4'-(2-azninoethyl)-3- (cyclohexyloxy)-4-biphenylcarboxylate (376 mg) in diznethyl suif oxide (1.9 mL.) was added NNC-bis(trimethylsilyl)urea (272.mg) at room temperature and the mixture was stirred at 650C for 1 hour. After cooling down to**room temperature, was added 2-[(2R)-2-oxdranyl]pyrazine (175 mg), and then the mixture was stirred at 650C for 41 hours. Water (2 mL.) and concentrated hydrochloric acid (0.11 il.) were added on Ice cooling. iThe mixture was stirred at the same temperature for 30 minutes. warmed up to room temperature and stirred at room temperature for 30minutes. Chloroform/methanol (5/1) 2G (2 mL.) was added and the mixture was stirred at room temperature for 30 minutes. pH 7 Buffer solution was added and extracted with chloroform/methanol *The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over sodium sulfate and evaporated under reduced-pressure. To a mixture of above residue in tetrahydrofurai (1.8 mL.) and pH 7 buffer solution (1.8 mL.) was added di-tert-butyl dicarbonate (350 mg) in tetrahxydrofuran (0.3 mL.) at room temperature and the mixture was stirred at room temperature for.1.5 hours. The mixture wras partitIoned b'etween ethyl acetate and water. The organic layer was separated and washed with 11I1 hydrochlo.ic acid, saturated sodium bicarbonate aqueous solution znd brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was, purified by column chromatography on silica gel (ohlorofor /methanol-99/1) to give methyl 4'-[2-[(tert-butoxycarbonyl)(2S)-2-hydroxy-2- (2-pyrazinyl)ethyljamino]ethyl]-3-(cyclohexyloxy)-4biphenylcarboxylate (270 mg).

(+)ESI-MS m/z: 576 Cl The following compounds from Example 52 to Example 53 was obtained in a similar manner to that of Example 77.

Example 52 4'-[2-1[(2R)-2-(6-Chloro-3-pyridyl)-2-hydroxyethylazninolethylJ-3-(cyclohexyloxy)-N-(methylsulfonyl)-4biphenylcarboxamide hydrochloride 1H NMR (200OHz., DMSO-d 6 1.29-1.81 (81, 1.89- 2.03 (2H, 3.03-3.31 (6H, 3.39 (3H, 4.76-4.88 (1H, 5.09-5.18 (1H, 7.34-7.43 (4H, 7.57 (1H, d, J!8-.5Hz),7.72-7.80 (3H, 7.91 (1H, dd, J-2.3, 8.46 (1H, d, J=2.0Hz), 9.14 (1H, brs), 9.41 (1H, brs), 11.20 (IH, s) (+)ESI-MS m/z: 572 Example 53 3-(Cyclohexyloxy)-4'-(2-[((2S)-2-hydroxy-2-(2pyrazinyl)ethyl]amino]ethyl]-4-biphenylcarboxylic acid hydrochloride 1H NMR (200MHz, DMSO-d 6 1.33-1.91 (10H, 3.03-.

3.51 (6H, 4.59-4.71 (1H, 5.18 (1H, dd, J=3.3. 7.24-7.41 (4H, 7.68-7.72 (31, 8.64 (2H, 8.84 (1.

9.05 (1H, brs), 9.45 (1H, brs) (+)ESI-MS m/z: 462 (M+H) 4 Example 54 To a mixture of ethyl 2-(cyclohexyloxy)-4-[ 5-2-(E(2R)- 2-hydroy-2- pyridyl) ethyl amino ethyl-2 -pyriidiylbenzoate (47 mng) in tetrahydrofuran (I mL) and pH 7 buffer solution (1 mnL-) was added di-tert-butyl dicarbonate (35 mg) at ambient temperature. +The mixture was stirred at room temperature for I hour. The mixture was portioned to ethyl acetate and saturated sodium bicarbonate aqueous solution.

The organic layer was separated, washed with brine dried over sodium sulfate and evaporated under reduced pressure.

To a mixture of the above residue in ethanol (0.5 mL) and tetrahydrofuran (0.22 mL) was added 1N sodium hydroxide aqueous solution (0.48 mL) dropwise. The mixture was stirred at ambient temperature overnight. 1N Hydrochloric acid (0.48 mL) was added. The mixture was portioned to chloroform/methanol and pH 7 buffer solution. The organic layer was separated. The aqueous layer was extracted with chloroform/methanol three times. The combined organic layer was dried over sodium sulfate and evaporated under: reduced pressure. The residue was purified by column chromatography (chloroform/methanol-98/2) to give 4-[5-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)-.

ethyl]amino]ethyl]-2-pyrimidinyl]-2-(cyclohexyloxy)benzoic acid (24 mg).

(+)ESI-MS m/z: 563 The following compound was obtained in a similar manner to that of Example 54.

Example 4-[5-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2phenylethyl] amino] ethyl] -2-pyrimidinyl -2- (cyclohexyloxy)benzoic acid (+)ESI-MS m/z: 584 (M+Na)+ Example 56 To a mixture of 4-[5-[2-[(tert-butoxycarbonyl hydroxy-2- 3-pyridyl)sthyl]amino ethyl] -2-pyrimidinyl -2- (cyclohexylory)benzoic acid (24 mg) in ',N-dimethyformamide (0.24 mL) was added 1,1-carb onyldiimidaole (13 mg) at room temperature and stirred at room temperature for 1 hour.

Methansulfonamide (8 mg) and 1.8-diazabicyclo[5.4.0]undecene (0.01 mL) were added at room temperature and the mi-xture was stirred at room temperature 5 days. The mixture was poured into pH 7 buffer solution and extracted with chloroform/methanol (5 three times. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (chloroform/methanol=98/2). To a mixture of above product In 1. 4-dioxane (1 mL) was added 4N hydrogen chloride in 1,4dioxane (1 niL) and the mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure. The residue was triturated with ether to give 2-(cyclohexyloxy)-4-C5-E2-[U(2R)-2-hydroxy-2-(3pyrldyl) ethyl Jamino] ethyl] -2 -pyriLmidLny. I-N- (methylsulfonyl )benzamide dihydrochloride (5 mg).

1H NMR (20'011Hz, DMSO-d 6 6):.1.24-2.03 (10H, in),*3.09-.

3.37.(6H,mi), 3.38 4.60-4.70 mn), 5.22-5.29 (1H, mn), 7.78 (1H, d, J=8.OHz), 7.92 dd, J=5.3 8.05-8.11 (2H, mn), 8.4 (1H, d,.J=8.OHz), 8.80-8.90 (2H, in), .8.92 9.22 (1H. brs), 9.31 (1H, brs), 11.48 (1H, brs) (t)ESI-MS mhz: 540 The following compound was obtained In a similar manner to that of Example 56.

Example 57 tert-Dutyl [2-[2-[3-(cyclohexyloxy)-4- [(miethylsulfonyl) amino] carbonyl Iphenyl] -5 -pyrimidinyl] ethyl] -hydroxy- 2-phenylethyl 3carbainate (+)ESI-MS m/z: 661 ExaMple 58 To a solution of tert-butyl [2-(4-bromophenyl)ethyl] 3-chloropher.yl) hydL-r thllcbamate (56G mg) and methyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)-2-naphthoate (461 mng) in N,N-dimethylfomamide (5.6 niL) were added 1 -bis (diphenylphosphino) ferrocene] 71.

palladium(II) dichioride dichioromethane complex (151 mg), 1,1'-bis(diphenylphosphino)ferrocene (102 mg) and 2M sodium carbonate (2.0 mL) at room temperature, and the mixture was stirred at 80*C for 4 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water three times and brine, dried over anhydrous 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 6-[4-E2- ((tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl -2-naphthoate (514 mg).

(+)ESI-MS m/z: 582, 584 The following compounds from Example 59 to Example 67 were obtained in a similar manner to that of Example 58.

Example 59 Methyl 6-[4-[2-E(tert-butoxycarbonyl) (2R)-2-hydroxy-2- (3-pyridyl)ethyl]amino]ethylphenyl-2-naphthoate (+)ESI-MS m/z: 527 (M+H) 4 Example Methyl 6-[4-f2-[(tert-butoxycarbonyl)[(2R)-2-(3chlorophenyl) -2 -hydroxyethyl i amino] ethyl JphenylJ -1naphthoate (.)ESI-MS m/z: 582 (M+Na)+ Example 61 Methyl 6-(4-(2-[(tert-butoxycarbonyl)((2R)-2-hydroxy-2- (3-pyridyl)ethyl] amino] ethyl] phenyl] naphthoate (+)ESI-MS m/z: 527 Example 62 Ethyl 5- 4-E2-E(tert-butoxycarbonyl)E(+2R)-2-(3chlorophenyl) -2 hydroxyethyll amirno I ethyl Ip-henyll -indoile- 2-carboxylate (-)ESX-MS M/z: 561 Example 63 Ethyl 5-[4-[2-[(tert-Butoxycarbonyl) C(2R)-2-hydroxy-2- (3-pyridyl)ethyl]aminolethy.]phenyl] -lH-indole-2-carboxylate (+)ESI-MS m/z: 530 Ex~aple 64 Methyl 6-(4-(2-[(tert-butoxycaxbonyl)[(2R)-2-(3chiorophenyl) -2 -hydroxyethyl] amino] ethyl] phenyl isopropyl- 1H-indole-3-carboxylate (+)ESI-MS m/z: 613, 615 (M+Na)+ Example Methyl 6-[4-[2-[(tert-butoxycarbonyl) r(2R)-2-hydroxy-2- (3 -pyridyl.) ethyl]I amino] ethyl] phenyl J sopropyl-lH-indole- 3- carboxylate (+)ESI-MS m/z: 558 Exiamle 66 tert-Eutyl -2-hydroxy-2- (3-pyriLdyl) ethyl] .Isopropyl-3- E [(methylsulf onyl) amino] carbonyll -1H-iLndol-6yl )phenyllIethyll] arbamate (-)ESI-MS m/z: 619 Example 67 Ethyl (5-[4-[2-E(tert-butoxycarbonyl1)[(2R)-2-(3chiorophenyl) -2 -hydroxyethyl] amino) ethyl ]pheriylJ H-indol- 1yl] acetate (+)ESX-MS m/z: 599, 601 (M4.Na)+ Example 68 A mixture of methyl 6-[4-(2-[C(tert-butoxycarbonyl)- (3-chiorophenyl) -2 -hydxoxyethyl) amiLno]I ethyl Iphenyl] 2-naphthoate (105 mg) and lN sodium hydroxiLde (0.375 niL) in 1,4-dioxene (1 niL).was stirred at room temperature for 12 hours. To the resuilting mixture were added IN~ hydroch.loric acid (0.375 niL) and chloroform-methano2. After separation, the organic layer -was dried ove~r anhydrous magnesium sulfate, evaporated under reduced pressure. The residue was purified by column chromatography an silicaL gel (chlorofomfmathanol-10/f1) to give 6-E4-[2-[(tertbutoxycarbonyl) chiorophenyl) -2 -hydroxyethyl] amino]ethyllphenyl] -2-naphthoic acid (100 mg).

(-)ESI-MS m/z: 544, 546 The following compounds from Example 69 to Example 76 were obtained In a similar manner to that of Example 68.

Example 69 6-[4-[2-[(tert-Butoxycarbonyl)((2R)-2-hydroxy-2-(3pyridyl) ethyl] amino ]ethyl Iphenyl] -2 -naphthoic acid (-)ESI-MS m/z: 511 Example 6-[4-[2-[(tert-Butoxycarbonyl) ((2R)-2-(3-chlorophenyl)- 2 -hydroxyethyl] amino) ethyl] phenyl] -1-naphthoic acid (-)ESX-Ms m/z: 544, 546 (M-HF- Example 71 6-(.4-E2.-[tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3pyridyl) ethyl] aminolIethyl Iphenyl]-1l-naphthoic acid (-)ESI-MS m/z: 511 (MH- Example 72 .5-[4-[2-U(tert-Butoxycarbonyl) [(2R)-2-(3-chlorophenyl)- 2-hydroxcyethyl I amino) ethyl] phenyl] lH-indole-2-carboxylic acid (-)ESI-MS m/z: 533 (MH- Example 73 5-[4-[2,-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3pyridyl) ethyl] amino] ethyl] phenyl] H-indole-2-carboxyllc acid (-)ESI-MS M/Z: 500 (H-HF- Example 7 4 .6i.E4-[2-[(tert-Butoxcr.rbonyl) (2R)-Z-(3-chlorophenyl)- 2-hiyd.roxyethyl Iaminoethy1l phenyli -isop. pyl.- H-iLnidol3- 3- Oaxboylic 8LC~A (-)ESI-14S m/z: 575, 577 (M-H)F ExaM2le 6-[4-[2-E(tert-Butoxyobonyl)(2 )-2-yc5-zoxy..2-(..

Ct pyridy.)ethylamino]ethylpphenyl] isopropyl-1H-indole-3- E carboxylic acid (-)ESI-MS m/z: 542 Example 76 C 5 [5-(4-[2-[(tert-Butoxycarbonyl) [(2R)-2-(3-chlorophenyl) -2-hydroxyethyl aminolethyl pheyl] -1H-indol-1yl]acetic acid IND (-)ESI-MS m/z: 547, 549 (M-H) Example 77 To a solution of 6-(4-[2-[(tert-butoxycarbonyl)[(2R)-2- (3-chiorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-2naphtholc acid (98 mg) in 1,4-dioxane (2 mL) was added 4N hydrogen chloride in 1,4-dioxane (2 mL) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 12 hours. The resulting mixture was evaporated and dried in vacuo to give chlorophenyl)-2-hydroxyethylamino]ethyl)phenyl]-2-naphthoic acid hydrochloride (71 mg).

1H NMR (DMSO-d 6 3.00-3.50 (6H, 4.95-5.10 (1H.

7.35-7.55 (6H, 7.85 (2H, d, 3-8.2Hz), 7.90-8.10 (3H, 8.22 d, J-8.8Hz), 8.31 (1H, s) (+)ESI-MS i/z: 446,448 (M-HC1+H)+ The following compounds from Example 78 to Example 81 were obtained in a similar manner to that of Example 77.

Example 78 6-[4-[2-(U2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]aminolethyliphenyl]-1-naphthoic acid hydrochloride 1H NMR CDMSO-d 6 3.00-3.45 (6H, 4.95-5.00 (11-1, 7.3-7.50 (6H, 9.3 t, T=7.9Hz), 7.85 (29, d, J=8.2Hz, a-00 (1H, dd, 9.=z 3.1-.2 (1K, 8.24 (IR, d, J=8.111), 8.33 (1H, 8.97 (IR, d, m/z: 444, 446 (-HCl-H)- Example 79 (2R) (3-Chloropheiyl) -2-hydroxyethyl] amino] ethyl] phenyl] H-iLndole-2 -carboxylic acid hydrochloride INMR (DMSO-d 6 2.95-3.50 (6H, in), 4.90-5.10 (iH, in,7.14 (iR, in), 7.2-7.6 (BR, mn), 7.66 (2H, d, J=8.2Hz), 7.91 (1W, s) (-)ESI-MS in/z: 433 (M-H-Cl-H)- Example 6-E4-[2-[((2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino) ethyliphenyl) -l-isopropyl-1H-indole-3-carboxylic acid hydrochloride 11H NMR (DMSO-d 6 1.53 J=6.6Hz), 2.95-3.40 4.85-5.1 (2H1, mn), 7.3-7.55 (7H, in), 7.75 (2H, d, J=8.lHz), 7.88 (1H, 8.07 (1H, d, J=8.4Hz), 8.18 (1H, s) (+)ESI-MS m/z; 477, 479 (M-2HCl+H)+ Example 81 [5-[4-[2.(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino) ethyl Jphenylj -lH-indol-1J-yl 3acetic acid hydrochloride 1 H NMR'(DMSO--d 6 2.90-3.40 (6H, in), 4.90-5.10 (3H, mn), 6.50 (1H, d, J=3.1Hz), 7.25-7.50 (9H, in), 7.65 (2H, d, J-8.lHz), 7.81 (1H, s) (-)ESI-Ms m/z: 447 (4-HCl-H)- Example 82 To a'solution of 6-[4-[2-[(tert-butoxycarbonyl)C(2R)-2hydroxy-2- (3-pyridyl) ethyl] amino] ethyl]pheiy. I-l-naphthoic acid (67 mg) in 1,4-dioxane (2 mL) was added 6N hydrochloric acid (2 mL) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 12 hours.

The resulting mixcture was evaporated and dried in vacuo to give 6-[4-[2-[[(2R)-2-hyciroxy-2-(3-pyridyl)ethyllaminoJ-.

ethyl) phenyl] -1-napbhthoio acid dihydroch2.orlde (59 mug).

IH NMR (DMSO-d 6 3.00-3.60 (6K, in), 5.15-5.30 (IH, mn), 7.44 (2H, d, J=~8.2Hz), 7.67 (1H, t, J=7.81iz), 7.80-8.10 (4H, 8.10-8.50 (4H, in), 8.75-8.90 (2H1, mU), 89,97 (IR, d+ J=9.lHz) (-)ESI-MS n/z: 411 (M-2HCI-H)- The following compounds from Example 83 to Example 86 N 5 were obtained in a similar manner to that of Example 82.

Example 83 6-[4-[2-(r(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]- INDamino] ethyl]phenyl.] -2-naphthoic acid dihydrochioride 1H NMR (DMSO-d 6 3.00-3.60 (6H, 5.15-5.30 (1H, 7.44 (2H, d, 3-8.2Hz), 7.8-8.15 (7H, 8.22 (1H, d, 3=8.7Hz), 8.30-8.45 (21, 8.64 (11, 8.81 (1H, d, 3=5.0Hz), 8.87 (1H, s) (-)ESI-MS m/z: 411 (M-2HC-H)- Example 84 5 [2-([(2R)-2-Hydroxy-2-(3-pyridy1)ethyl amin Jethyl]phenyl] ,-H-indole-2-carboxylic acid dihydrochioride 11 NMR (DMSO-d 6 3.00-3.55 (6H, m) 5.15-5.30 (1H.

7.15 (1H, 7.35 (2H, d, 3=8.2Hz), 7.45-7.60 (2H, m), 7.66 (2H, d, 3-8.1Hz), 7.85-8.00 (2H, 8.35-8.50 (1H, m), 8.80-8.95 (2H, m) (-)ESI-MS m/z: 400 (M-2HC-HV- Example 6-[4-[2-([(2R)-2-Hydroxy-2-(3-pyridyl)ethylaminojethyl]phnyl-l-isopropyl-H-indole-3-carboxylic acid dihydrochloride 1H NMR (DMSO-d 6 1.53 (6H, d, J=6.6Hz), 3.00-3.50 (6H, 4.85-5.05 (1H, 5.15-5.30 (1H, 7.37 (2H, d, J8.lHz) 7.51 (1H, d, J=9.Hz), 7.75 (2H, d, Je8.lHz), 7.8- 7.95 8.07 (1H, d, 3=8.3Hz), 8.18 (11, 8.35 (1R, d, J=8.lHz), 8.75-8-90 (2H, m) (+)ESI-MS m/z: 444 (M-2HCl+H) 4 Example 86 6-E4-[2-EE(2R)-2-Hydoxy-2-(3-pyridyl)ethyl]axninojethyl]phenyl]-1-isopropyl-N- (iethylsilfonyl)-1H-ndole-3 carboxainide dihydrochioride 1NMR (DMSO-d 6 1.52 (6H1, d. J-6.5HZ), 3.00-3.60 (6H1, in), 3.40 (3H, 4.90-5.10 (1H1, in), 5.25-5.40 (1H, M), 7.38 (2H1, d, J=8.1Hz), 7.56 (1H1, d, J=8.5Hz), 7.76 (2H1, d, 7.92 (1H, 8.00-8.15 (1H, 8.19 (111, d, J=8.31z), 8.57 (1H1, d, J=8.0Hz), 8.68 (31H, 8.88 d, J-5.2Hz), 8.94 (1H, s) (-)ESI-MS m/z: 519 CM-2HCl-H)- Example 87 LO A mixture of tert-butyl ((2R)-2-(3-ch.oropheflyl).2- (tetrahydro-2H-PYran-2-yloxy) ethyl] I 1-iLsopropyl-3- U(metkiylsulfoflyl amino] carbonyl] -lH-indol- 6-yl]phenyl] ethyl]carbamfate (132 mg), 10* hydrogen chloride in methanol (2 niL) and 4N hydrogen chloride in 1,.4-dioxane (2 niL) was stirred at the same temperature f or 12 hours. The resulting mixture was evaporated under reduced pressure. The residue was .purified by'reverse phase column chromatography followed by treatment of N hydrochloric acid to give 6 -[E4 2 2 (3 chiorophenyl) 2 -hydroxyethyl -amino ethyl]I phenyl]I -1 isopropyl-N- (methylsulf onyl) 1H- Indole 3 -carboxaniide hydrochloride (81 mig).

1NMR (DMSO-d 6 1.52 (6H1, d, 3=6.5Hz), 3.00-3.45 (6H, in), 3.39 (3H, 4.90-5.10 (2H1, in), 7.30-7.60 (7H, mn), 7.76 (2H1, d, J=6.2Hz), 7.91 (1H1, s),.8.19 (1H1, d, 3=8.3Hz), 8.65 (1H1, s) (-)ESI-MS m/z: 552 (M-HC1-H)- Example 88 To a solution of tart-butyl C(2R)-2-[6-(acetylIi:Lno)-3pyridylJ-2-C rtert-butyl(dmetyl)silYloxY~etbYl1E2-d 3 (cyclohexyloxy) -4 E (methylsulfonyl )amino) carbonyl] -4b~hnllehylabmt (32S mig) in ethano2. (3.2S mL) was added I.N sodium hydroxide (4.05 niL) and the mixture was stirred at 100*C for 16 hours. After cooling to room temperature, IN hydrochloric acid (4.05 itL) was added and

\O

c 78.

the mixture was concentrated in vacuo. To the residue were added 4N hydrogen chloride in 1,4-dioxane (8 mL) and methanol (2 mL) and the mixture was stirred at room temperature for 40 hours. The solvent was removed by C 5 evaporation and the residue was purified by reverse-phase O chromatography (ODS column, eluent: water/methanol). The C fractions containing the product were combined, acidified IC with 1N hydrochloric acid (2 mL), and concentrated in vacuo to give 4 2 -[[(2R)-2-(6-amino-3-pyridyl)-2-hydroxyethyljaminoethyl]-3-(cyclohexyloxy)-N-(methylsulfonyl)-4biphenylcarboxamide dihydrochloride (149 mg) as a white solid.

1H NMR (400 MHz, DMSO-d 6 1.34-1.64 (6H, 1.68- 1.79 (2H, 1.91-2.01 (2H, 3.05-3.28 (6H, 3.39 (3H, 4.79-4.85 (1i, 4.99 (1H, d, J-6.2Hz), 6.47 (1H, br), 7.05 (1H, d, J-9.1Hz), 7.36-7.43 (4H, 7.74 (2H, d, J-8.lHz)., 7.78 (1H, d, J-8.1Hz), 7.95-7.98 (2H, 8.19 (1H, 9.12 (1H, br), 9.28 (1H, br), 11.2 (1H, br), 14.1 (1W, br) (-)ESI-MS m/z: 551 (free)

Claims (9)

1. A compound of the formula I]: OH R 3 Ry NX-D-E R 2 R' Rs wherein A is or N [I] D is E is or or X is bond, -CH 2 or -NH-, R 1 is hydrogen, halogen, hydroxy, amino or (lower alkanoyl)amino. R 2 R 4 and R 5 are each independently hydrogen or optionally substituted lower alkyl, R 3 is hydrogen or an amino protective group, R 6 is hydrogen, carboxy, lower alkoxycarbonyl or (lower alkylsulfonyl)carbamoyl, and R7 is -Y-R 8 in which Y is bond, or and RS is hydrogen, lower alkyl, cyclo(lower)alkyl, carboxy( lower) alkyl or (lower alkoxycarbonyl)(lower)alkyl. provided that when A is D is 0and Eis-a\ I c 5 then X is bond, Rl is hydroxy, R 2 is methyl, R 4 and R 5 .are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; X is -CH 2 or R 1 is halogen. R 2 R4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R8, in which Y is and R 8 is isobutyl or cyclohexyl; or (31 X is -CH 2 or Rl is para-chioro, R 2 is hydrogen or methyl, R 4 and R5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R7 Is y-R 8 in which Y is and R 8 is propyl, when A is is and E is_ then [11 X is bond, R 1 is amino, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and 7 ±.is -Y-R 8 in which Y is bond. or and R8 is ethyl, isopropyl. isobutyl or cyclopetyl; 12) X is bond, R 1 is amino, R 2 R 4 and R 5 are each hydrogen, R3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R7 is -Y-R 8 ir, which Y is or and R8 is ethyl or isopropyl [31 X ±z bond, RI is chloro or (low=er alkanoy) am-ino, R 2 R4 and R*5 are each hydrogen, R3 is hydrogen, R 6 is (methv1sufony1)carbamoy1, and R 7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; X is bond, R 1 is hydrogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, Cl 5 and R 7 is -Y-R 8 in which Y is and R 8 is O cyclo(lower) alkyl: 0D X is bond, R 1 is hydrogen, R 2 R 4 and R 5 are 0 each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 (substituted at 2' or 6' position in 4-biphenyl of in which Y is bond or and R 8 is isopropyl, butyl or cyclohexyl; X is -CH 2 R 1 is amino, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is and R 8 is cyclo( lower)alkyl; X is -CH 2 or R 1 is amino, R2, R 4 and R are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is bond or and R 8 is isobutyl or cyclohexyl: or X is R 1 is hydrogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is and R 8 is lower alkyl, when A is D is and E is then X is bond, R 1 is halogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy or (Lower alkysulfonyl)carbamoyl, and webR 7 is -y-R 8 in which Y is bond, and R 8 is hydrogen, or when A is D is and E is C i then X is bond, R 1 is hydrogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy or (lower alkysulfonyl)carbamoyl, and R7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen, or a prodrug thereof or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1, wherein A is or, __CN D is -or e is or F, X is bond, -CH 2 or -NH-, R 1 is hydrogen, halogen, hydroxy amino or (lower alkanoyl)amino, R2, 4 and. R 5 are each independently hydrogen or lower alkyl, R 3 is hydrogen, R 6 is hydrogen, carboxy or (lower alkylsulfonyl)carbamoyl, and, R7 is -Y-R 8 in which Y is b'ond, or and RS is hydrogen, lower alkyl, cyclo(loverjalkyl, carboxy (lower) alkyl or (lower alkoxycarbonyl)- (lower)alkyl, provided that when A is j D is and E is c- 5 O\ C-I C-I C-I then [11 X is bond, R 1 is hydroxy, R 2 is methyl, R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is and R 8 is cyclohexyl: X is -CH 2 or R 1 is halogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is and R 8 is isobutyl or cyclohexyl; or X is -CH 2 or R 1 is para-chloro, R 2 is hydrogen or methyl, R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is and R 8 is propyl, when A is D Is ,and E is then X is bond, R 1 is amino, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen-, R 6 is carboxy, and R 7 is.-Y-R 8 in which Y is bond, or and R 8 is ethyl, isopropyl, isobutyl or cyclopentyl; X is bond, R 1 is amino, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is or and R9 is ethyl or isopropyl: [31 X is bond, R 1 is chloro or.(lower alkanoyl)amino, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methysulfonyl)carbaoyl, and R 7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; X is bond, R 1 is hydrogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is and R 8 is cyclo(lower)alkyl: X is bond, R 1 is hydrogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 (substituted at 2' or 6' position in 4-biphenyl of in which Y is bond or and R 8 is isopropyl, butyl or cyclohexyl;- X is -CH 2 R 1 is amino, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is and R 8 is cyclo(lower)alkyl; X is -CH 2 or R I is amino, R 2 R 4 and R are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is bond or and R 8 is isobutyl or cyclohexyl: or X is R 1 is hydrogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is and R 8 is lower. alkyl, when A is D~ is and E F, S then X is bond, R 1 is halogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy or (loweralkysulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen, or C 5 when A is D is and E is 2 then X is bond, R 1 is hydrogen, R 2 R 4 and R 5 are each ND hydrogen, R 3 is hydrogen, R 6 is carboxy or (lower alkysulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen.

3. A compound of claim 2, wherein A is or D is E is or X is bond, -CH 2 or -NH-, R1 is hydrogen, chloro, hydroxy or amino, R 2 R 4 and R 5 are each independently hydrogen or methyl, R 3 is hydrogen, R 6 is hydrogen, carboxy or (lower alkylsulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is bond, or -NH-,'and R 8 is hydrogen, lower alkyl or oyclo(lower)- alkyl, provided that when A is D is and E is c- 5 then X is bond, R 1 is hydroxy, R 2 is methyl, R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is and R 8 is cyclohexyl: X is -CH 2 or R 1 is chloro, R 2 R 4 and R are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is and R 8 is isobutyl or cyclohexyl: or X is -CH 2 or R 1 is para-chloro, R 2 is hydrogen or methyl, R 4 and R 5 are each hydrogen. R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is and R 8 is propyl, when A is D is and E is then X is bond, R 1 is amino, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is bond, or and R 8 is ethyl, isopropyl, isobutyl or cyclopentyl; X is bond, R 1 is amino, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is or and R 8 is ethyl or isopropyl: is bond, R 1 is chloro, R 2 R 4 and R 5 are eac hydrogen, R 3 is hydrogen. R6 is (metlhy~lsufonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; [4j X is bond, R 1 is hydrogen, R 2 R 4 and R 5 are h each hydrogen, R 3 is hydrogen, R 6 is carboxy, and SR 7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; Cl 5 X is bond, R 1 is hydrogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and ID R 7 is -Y-R 8 (substituted at 2' or 6' position in 4-biphenyl of in which Y is bond or and R 8 is isopropyl, butyl or cyclohexyl: X is -CH2-, R 1 is amino, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; X is -CH 2 or R 1 is amino, R 2 R 4 and R are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is bond or and R 8 is isobutyl or cyclohexyl; or X is R 1 is hydrogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is and R 8 is isobutyl, when A is D is and E is then X is bond, R 1 is chloro, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R S in which Y is bond, and RS is hydrogen, or when A is D is -and E is then X is bond, R 1 is hydrogen, R 2 R 4 and R 5 are each C 5 hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen. ID

4. A compound of claim 3, wherein A is D is and E is X is bond. R 1 is hydroxy, R 2 is methyl, R 4 and R are each hydrogen, R 3 is hydrogen, R 6 is (methylsulfonyl)carbamoyl, and R 7 is -Y-R 8 in which Y is and R 8 is cyclohexyl; X is -CH 2 or R 1 is.chloro, R 2 R 4 and R 5 are each hydrogen. R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y is and R 8 is isobutyl or cyclohexyl; or X is -CH 2 or R 1 is para-chloro. R 2 is hydrogen or methyl, R 4 and RS are each hydrogen, R 3 is hydrogen. R 6 is carboxy, and R7 is -Y-R 8 in which Y is and R 8 is propyl, is D is and E is X is bond. R 1 is amino. R 2 R 4 and R5 are each hydrogen, R3 is hydrogen, R 6 is carboxy, and R7 is -Y-R 8 in which Y is bond, or and R is ethyl, isopropyl, isobutyl or cyclopentyl; E2] X is bond, R1 is anino, R 2 R 4 and R 5 are each hydrogen, R3 is hydrogen, R 6 is (methylsulfonyl)Carbamoyl, and Ris -Y-R 8 in which Y is or and R 8 is ethyl or isopropyl; X is bond, RI is chioro, R R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is NI 5 (methylsulfonyl)carbamoyl, and R7? is -y-R 8 In which Y is and R 8 Is cyclohexyl; IND X is bond, R 1 Is hydrogen, R R 4 and R 5 are each C)hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -Y-R 8 in which Y Is and R 8 Is cyclohexyl:- Xi:s bond, RI s hydrogen, R 2 R 4 and RS are each hydrogen, R 3 is hydrogen, R 6 is carboxy. and Ris -y-R 8 (substituted at 2' or 6' position in 4- biphenyl of in which Y is bond or and R8is Isopropyl, butyl. or cyclohexyl; is -CH 2 R 1 is amino, R R 4 and R 5 are each hydrogen, R 3 Is hydrogen, R 6 is (iethylsulfonyl) carbamoyl, and. R 7 is -y-R 8 in which Y Is and R 8 is cyclohexyl; [71 X is -CH 2 Or R 1 is amino, R 2 R 4 *and RS are each hydrogen, R 3 Is hydrogen, R 6 is carboxy, and Is -Y-R 8 in which Y Is bond or and R 8 is Isobutyl or cyclohexyl;- or 18] X Is R 1 is hydrogen, R 2 R 4 and R 5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and R 7 is -y-R 8 In which Y is and R 8 Is Isobutyl, K iLs D IS I X Is bond, R 1 is chioro, R 2 R 4 and RSare each hy-ogan,. R3is hydrogen, R 6 is carboxy, and. R7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen, or A is D\i ,Eis X is bond, Rl is hydrogen, R 2 R 4 and R5 are each hydrogen, R 3 is hydrogen, R 6 is carboxy, and c-R7 is -Y-R 8 in which Y is bond, and R 8 is hydrogen. A compound of claim 4, which is selected from a group Of 3-(Cyclohexloxy)-4-2-[(S,2R)-2-hydroxy-2-(4- hydroxyphenyl) -1-methylethyllJamnino] ethyl] -N- (methylsulfonyl) -4 -biphenylcarboxamide, 4'-1[(z-.[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]- amino] ethyl] amino] -3-isobutoxy- 4-biphenylcarboxylic acid, 4'-[[2.(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]- amino] ethyl) amino] (cyclohexyloxy) -4-biphenyl- carboxylic acid, 4'-E(21[(2R)-2-(4-Chlorophflyl)-2-hydtoxyethyl]- imiho] ethyl] amino] (cyclohexyloxy) -4-biphenyl- carboxcylic acid, .4'-[(2-[C(2R)-2-(4-Chlorophnyl)-2-hydroxyethylJ- aminolIethyl] amino] -3-propoxy- 4-biphenylcarboxylic acid, 4'[-[2)2(-mn--prLy)2hdoytyl amino] -ethyl) -3 -isobutyl- 4-biphenylcarboxylic acid, 4'[-E2)2(-mn--yiy)2hdoytyl amino] ethyl] (isopropylthio) biphenylcarboxylic acid, 4'-[2-[((2R)-2-(6-Amino-3-pyrdy-)-2-hydroxyethyXJ- amino] ethyl) -3-cyclopentyl-4-biphenyl-carbox~liO eacId, amino]ethyl] -3-ethoxy-4-biphenylcarboxylic acid, 4'[-12)2(-mn--yiy)2hdoytyl ami~no] ethyl] -3-(isopropylthio) (metkiylsu3.fonyl) -4- biphenylcarboxamide, (11) 4'[-C2)2(-mn--yly)2hdoytyl amino lethyll -3-ethoxy-N-(methylsulfofyl) -4- biphenylcarboxamide, (12) 4'-[2([1(2R)-2-(6-Chloro-3-pyridy)-2-ydrtoxyethylJ- amnino] ethyl] (cyclohexyloxy) (methylsulfony.) -4- biphenylcarboxanide, (13) 4'-E2-1:[(2R)-2-[6-(Acetylamino)-3-pyridyl]-2- hydroxyethyl] amino] ethyl] (cyclohexyloxy) -N- LO (methylsulfonyl) -4-bipheny3.carboxamide, (14) 3-(Cyolohexylamino)-4-[2-(((2R)-2-hydoxy- 2 (3- pyridyl )ethyl] amino] ethyl] -4 -biphenylcarboxylic acid, 4'E-[2)2Hdoy2(-yty~tylmnltyl 2- isopropoxy- 4- biphenylcarboxyliC acid, 2"(Cyclohexyloxy)-4'-(2-1[U2R)-2-hydroxy-2-(3-pyriLdyl) ethyl] aminojethyl) -4-biphenylcarboxylic acid, (17) 2-Butyl-4'-[2-[[(2R)-2-hydroxy-2-.(3-pyridyl)ethyl]- aznino]ethyl] -4-biphenylcarboxylic acid, (18) 4'1-[(R--6Aio3-yiyj2hdoytyl amino]propyl] (cyclohexyloxy) (methylsulfonyl) -4- biphenyl -carboxamide, 4'[-E2)2(-mn--yiy)2hdoytyl amino] propyl] -3-isobutyl- 4-biphenylcarboxylic acid, 4'-[3-[E(2R)-2-(6-Amhino-3-pyridyl)-2-hydroxyethyl]- amino]propyl 3-isopropoxy-4-biphefllcarboxylic acid, (21) 4,-31(R)2(-mn--priy)2hdoytyl amino] propyl] (cyclohexyloxy) -4-biphenylcarboxylic acid, (22) 4'-(2-[(2R)2-(6Aminl-3-pyridyl)-2-hydroxyethyl]- amino] ethoxy] -3-Isobutyl- 4-biphenylcaxboxylic acid, (23) 4'[2[(R--yrx--(-yiy~tylmnl ethyl! amino] -3-isobutoxy-4-bipheflyl-oarboxyliC eaciLd (24) 6-4[-J2)2(-hoopay)2hdoytyl aminolIethyl IphenyllI-2-naphthoic acid, (25) 6-4[-[2)2(-hoopay)2hdoytyl amino]ethyl]phenyl]-l-naphthoic acid, (26) 6-4-[2-[[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]mino]- ethyl]phenyl-2-naphthoic acid, and (27) 6-[4-[2-[((2R)-2-Hydroxy-2-(3-pyridyl)ethyl] amino]- S ethyl]phenyllfl-naphthoic acid, or a pharmaceutically acceptable salt thereof.

C

6. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a C 10 pharmaceuticallY acceptable salt thereof in admixture with pharmaceutically acceptabie carriers or excipients.

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

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

9. A compound of claim 1 or a pharmaceutically acceptable salt thereof.:for use as selective P3 adrenergic receptor agonists. A method for the prophylactic and/or the therapeutic -treatment of gastro-intestinal disorders, ulcer, overactive bladder, micturiation disorders, pancreatitis, obesity or diabetes which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human. being or an animal. DATED this 1 7 th day of May 2006 Astellas Pharma Inc. By DAVIES COLLISON CAVE S Patent Attorneys for the Applicant