AU759900B2 - Cyclic compound - Google Patents

Description

DESCRIPTION

CYCLIC

COMPOUND

Field of the Invention The present invention relates to new compounds and pharmaceutically acceptable salts thereof.

More particularly, it relates to new compounds and pharmaceutically acceptable salts thereof which are useful as inhibitors of matrix metalloproteinases (hereinafter to be referred to as MMP) or the production of tumor necrosis factor a (hereinafter to be referred to as TNF to pharmaceutical compositions comprising the same, to use of the same as medicaments, and to methods for using the same therapeutically in the treatment and/or the prevention of MMP- or TNF a-mediated diseases.

Background Art Some compounds to be useful as metalloproteinase inhibitors, or the like are known (WO 97/20824, etc.).

20 Disclosure of the Invention It would be advantageous to provide new and useful cyclic compounds and pharmaceutically acceptable salts thereof, and to provide a process for preparing said new cyclic compound and salts thereof, which have pharmacological activities such as MMP- or TNF a- inhibitory activity and the like.

t would also be advantageous to provide a pharmaceutical composition comprising, as an active 30 ingredient, said cyclic compound or a pharmaceutically acceptable salt thereof.

It would also be advantageous to provide use of said cyclic compounds and pharmaceutically acceptable salts thereof as medicaments for prophylactic and therapeutic SLreatment of MMP- or TNF a-mediated diseases.

It would also be advantageous to provide a method for using the same for the treatment and/or the prevention of MMP- or TNF a-mediated diseases in mammals, especially humans.

The compounds of the present invention have inhibitory activity on MMP or the production of TNF a, and are useful for the treatment and/or prevention of diseases such as stroke, arthritis, cancer, tissue ulceration, decubitus ulcer, restenosis, periodontal disease, epidermolysis bullosa, scleritis, psoriasis and other diseases characterized by matrix metalloproteinase activity, as well as AIDS, sepsis, septic shock and other diseases caused by the production of TNF a.

There are a number of structurally related metalloproteases which effect the breakdown of structural proteins. Matrix-degrading metalloproteases, such as gelatinase (MMP-2, MMP-9), stromelysin (MMP-3) and collagenase (MMP-1, MMP-8, MMP-13), are involved in tissue matrix degradation and have been implicated in many pathological conditions involving abnormal connective tissue 20 and basement membrane matrix metabolism, such as arthritis osteoarthritis and rheumatoid arthritis, etc.), cerebral disease stroke, etc.), tissue ulceration corneal, epidermal and gastric ulcerations, etc.), abnormal wound healing, periodontal disease, bone disease Paget's disease and osteoporosis, etc.), tumor metastasis or invasion and HIV-infection.

A tumor necrosis factor is recognized to be involved in many infections and autoimmune diseases. Furthermore, it has been shown that TNF is the prime mediator of the 30 inflammatory response seen in sepsis and septic shock.

The compounds of the present invention are novel and can be represented by the following formula P:\OPERJgc\18905-0X spc.do-.12/02)3 Y z

R

1 -X-Ar- (CH2)m> ~(CH 2 )n-R2 in which R 1 is lower alkyl, halogen, optionally substituted heterocyclic group or optionally substituted aryl,

R

2 is carboxy, protected carboxy or amidated carboxy, Ar is optionally substituted aryl or optionally substituted heterocyclic group, A is lower alkylene, X is oxa or a single bond, Y is thia, sulfinyl or sulfonyl, Z is methylene, thia, sulfinyl or sulfonyl, m and n are each an integer of 0 to 6, and l+n 6, and its salt.

20 In an aspect of the invention there is provided a compound of the formula: Y Z

R

1 -X-Ar-(CH2)m (CH 2 )n-R 2 in which R 1 is Ci-C6 alkyl, optionally substituted heterocyclic group or optionally substituted C6-Cio aryl,

R

2 is carboxy, protected carboxy, hydroxyaminocarbonyl, tetrahydropyranyloxyaminocarbonyl, or phenyl (Ci-C 6 alkylaminocarbonyl, P:\OPERJgc\18905-X) spec.doc-12/02/03 3A Ar is optionally substituted C 6

-C

10 aryl or optionally substituted heterocyclic group, A is Ci-C 6 alkylene, X is oxa or a single bond, Y is thia, sulfinyl or sulfonyl, Z is methylene, m and n are each an integer of 0 to 6, and lm+n 6, and its salt, wherein the heterocyclic group of R 1 and Ar are selected from the group consisting of the following to (14), unsaturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms, too.

S: unsaturated condensed 7- to 13-membered, heterocyclic group containing 1 to 5 nitrogen atoms, 20 unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, unsaturated 3- to 8-membered, heteromonocyclic 25 group containing 1 or 2 oxygen atoms and 1 to S. 3 nitrogen atoms, unsaturated condensed 7- to 13-membered, heterocyclic group containing 1 or 2 oxygen atoms, unsaturated condensed 7- to 13-membered, A heterocyclic group containing 1 or 2 sulfur atoms, P:\OPER\Jgc\18905-4X) spec.doc-12/2/)3 3B saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, (11) unsaturated condensed 7- to 13-membered, heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, (12) unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, (13) saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, and (14) unsaturated condensed 7- to 13-membered, heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, and each of the above-mentioned heterocyclic group and @0 S: C 6 -Cio aryl group are optionally substituted by the group consisting of the following (Al) to (A35) 0 20 (Al) halogen, (A2) Ci-C6 alkyl, (A3) Cl-C6 alkoxy, (A4) halo (Ci-CE) alkyl, (A5) halo (Cl-CE) alkoxy, 25 (A6) C2-C6 alkenyl, *0 (A7) acyl, (A8) CI-C6 alkylthio, Ci-C6 alkylsulfinyl, Ci-C6 alkylsulfonyl, *i (A9) CE-Cio aryl, (A10) halo (C 6

-C

1 0 aryl, CR (All) hydroxy, P:\OPER\gc\18954) sp..doc-12A)2/03 3C (A12) hydroxy (01-06) alkyl, protected hydroxy (01- 06) alkyl, (A13) amino, (A14) carboxy, (A15) protected carboxy, (A16) nitro (02-06) alkenyl, (A17) C 1

-C

6 alkylenedioxy, (A18) acylamino, (A19) nitro, (A20) (06-Cia) aryl. (01-06) alkoxy, (A21) carbamoyl (0 2

-C

6 alkenyl optionally Nsubstituted by the group consisting of 01-06 alkyl, 06-C1O aryl, 01-06 alkoxy (06-Cia) -aryl, and halo (06-010) aryl, (A22) 01-06 alkylaminocarbonyloxy, (A23) 01-06 alkanoyloxy, :(A24) 01-06 alkoxy (01-06) alkanoyloxy, (A25) 01-06 alkoxycarbonyloxy, (A26) 02-06 alkenoyloxy optionally substituted by heterocyclic group of the above to (14), (A27) 03-06 cycloalkanecarbonyloxy, (A28) 01-06 alkoxy substituted by the group consisting of carboxy, protected carboxy, Cj- 06 alkanoyl, 03-06 cycloalkanecarbamoyl, and 01-06 alkylcarbamoyl, :(A29) 01-06 alkylcarbamoyloxy (01-06) alkyl, (A30) 01-06 al1koxyca rbonyl amino (01-06) alkyl, o~oo (A31) amino (01-06) alkyl, o~eoo:(A32) 01-06 alkylcarbamoyl (01-06) alkyl, (A33) heterocyclic-carbonylamino, the heterocyclic P-A, Itpgroup being selected from the above to (14) and optionally being substituted N- PA\OPER~gd\S9054(X) spw.do.-I2/02/03 3D protective group, (A34) the above heterocyclic groups to (14) being optionally substituted by Cj-C 6 alkyl, and (A35) oxo.

The compounds of the present invention can be prepared by the following processes.

WO 00/40576 PCT/JPOOOO0i 8 Y Z RI-X-Ar- (CH2) nCOOH (I-b) or a salt thereof Process 2 Y Z Oxidation of vinyl 'Rl-X-Ar- (CH2)mr><(CH2)nCH=CH 2 group 0

(II)

or a salt thereof RI-X-Ar- (CH 2 )Ifl>KCH 2 nCOOH (I-b) or a salt thereof Process 3 r z C2nR Reduction (I-c) or a salt thereof WO 00/40576PC/O/OI8 PCT/JPOO/00018 R -X-Ar- (CH2)m>K (CH 2 nR2 (I-d) or a salt thereof Process 4 Y Z Rl-X-Ar- (CH2) m><,CH~ 2 n-COOH (I-b) or its reactive derivative at the carboxy-group, or a salt thereof

NH

2

-OR

3

(IV)

or its reactive derivative at the amino-group, or a salt thereof Y Z Rl-X-Ar- (CH2)m ff (CH 2 n-CONH-OR 3 (I-e) or a salt thereof Process R I-X-Ar- (CR 2 Ur__ CH.R 2 a or a salt thereof Cycli zatiori

Y><

R

1 (CH2)rr 9 <C2-R or a salt thereof Process 6 y z Rl-X-Ar-

(CH

2 (CH 2 nrCOOH (I-b) or its reactive derivative at the carboxy-group, or a salt thereof Optically active amine or its reactive derivative at the amino-group, or a salt thereof r y z Rl-X-Ar- (CH 2 )n(>KSCH 2 )n n~ 2 (I-g) or a salt thereof Process 7 Y Z Removal of the Rl-X-Ar- (CH2)m><CH2)nCONH.OR3 hydroxy-protective group _M 30 a (I-h) or a salt thereof WO 00/40576 WO 0040576PCT/JPOO/00018 7 Y Z Rl-X-Ar- (CH2)m,>Ki(CH 2 n-CONHOH (I-i) or a salt thereof Process 8 u K

A

Ya Za Rl-X-Ar- (CH 2

K(CH

2 )n-R 2 Oxidation (I-i) or a salt thereof Yb Zb

H)

Rl-X--Ar- (CH2)m,~ (C -R 2 (I-k) or a salt thereof Process 9 y- B

(V)

Rl--Ar(CH2)-N(CH2) rR 2 a A-m (I-c) or a salt thereof WO 00/40576 WO 0040576PCT/JPOO/0001 8 Y Z Rl-X-Ar- (CH2)m> 2 )R2 or a salt thereof Process Y Z 2 c Rl-X-Ar- (CH2)mliL

(VII)

or a salt thereof

(VI)

or a salt thereof r z Rl-X-Ar- (CH 2 )m>KR2 (I-rn) or a salt thereof Process 11

HO

Rl-X-Ar-(CH2)m>K (CH 2 )n-R2 Cyclization

(VIII)

or a salt thereof WO 00/40576 WO 0040576PCT/JPOO/OO1 8 z Rl-X-Ar-(CH2)m (CH2)n-R 2 (I-n) or a salt thereof Process 12 0

HS-A-SH

Rl -X-Ar- (CH2) mI (CH2) nR 2 M(0)

(IX)

or a salt thereof

(S

Rl -X-Ar- (CR2) CR2) n-R 2 (1-o) or a salt thereof Process 13 z 30RI-X-Ar-(CH2)m><(CH 2 )n-R2 (I-p) or its reactive derivative at the carboxy group, or a salt thereof Amidat ion WO 00/40576 WO 0040576PCT/JPOO/000I 8 Y Z R4-X-Ar-(CH2)m

KICH

2 )n~R (I -q) or a salt thereof Process 14 Y Z

R

1 -X-Ar- (CH2)m>'K(CH 2 )n-R2 f or its reactive derivative at the amino group, or a salt thereof Acylation Rl'X-Ar- (CH2)m><(CH2)n-R2 g or a salt thereof Process Y Z Rl-X-Ar-(CH2)

><C

2

R

Removal of the amino-protective group (I-t) or a salt thereof WO 00/40576 WO 0040576PCT/JPOO/00018 z Rl-X-Ar- (CH2) M<(CH 2 )-R2 or a salt thereof Psrocess 16 Y Z R~l-X-Ar-(CR2) M><(CH2) n-R 2 .1 Removal of the hydroxy-protective group_ (I-u) or a salt thereof r z 2 n-R 2 3 (I-v) or a salt thereof Process 17 Y Z Rj-X-A r- (CH 2 m CH 2

,-R

2 Oxidat ion (I -W) or a salt thereof WO 00/40576 WO 0040576PCT/JPOO/O0oI 8 z Rl-X-Ar-

(CH

2

I>K(CH

2 n-R 2

I

(I -X) or a salt thereof Process 18 rz-

R

1 Ar Reduction mlX-r (CH2) M><CH 2 n-R 2 is or a salt thereof Ri A- (C2 .'LL (H)-R 2

(I-Z)

or a salt thereof Process 19 r z Rl-X-Ar- (CH2) m<CH 2 R2 OxidationIN (I-aa) or a salt thereof WO 00/40576 WO 0040576PCT/JPOO/000i 8 13 Y Z Rl-X-Ar- (CH2) -KCH)R2 (I-ab) or a salt thereof Process Y Z RI--X-Ar- (CH2) M><(CH 2 n-R 2 Acylation

(I-V)

or a salt thereof z Rl-X-Ar- (CR2) q M>(CH2) ,Rr1 2 (I-ac) or a salt thereof Process 21 R5 yAr z R6IBAr (CH2) r> CH2) n-R2

(XI)

or a salt thereof Rl-L (XII) or a salt thereof WO 00/40576 PCTJPOOOOOI 8 14 Y Z ~Rl-Ar- (CH2) ri <CH 2 n-R 2 (I-ad) or a salt thereof Process 22 y Z Removal of the R1-X-Ar-(CH2)?K..(CH 2 )R2 carboxy-protective group (I-ae) or a salt thereof RI-X-Ar- (CH2)m>K(CH 2 )n-R2 (I-p) or a salt thereof Process 23 z Rl-X-Ar- (CH2)m>K(CH 2 )n-R2 Substituted amine (I-af) or a salt thereof WO 00/40576 PCT/JP00/00018 Y Z

R

1 -X-Ar-(CH2)m

(CH

2 )n-R2 (I-ag) or a salt thereof in which R 1

R

2 Ar, A, X, Y, Z, m and n are each as defined above, Ra is haloaryl or halo, Rb is aryl, Rc is aryl at least substituted by optionally substituted aryl, is aryl at least having is aryl at least having is aryl at least having is aryl at least having is aryl at least having is aryl at least having is aryl at least having is aryl at least having is aryl at least having moiety, is aryl at least having is aryl at least having is aryl at least having is aryl at least having moiety, carboxy moiety, amido moiety, amino moiety, acylamino moiety, protected amino moiety, protected hydroxy moiety, hydroxy moiety, thia moiety, sulfinyl or sulfonyl formyl moiety, hydroxymethyl moiety, vinyl moiety, 1,2-dihydroxyethyl R1 is aryl at least having acyloxy moiety,

R

1 is aryl at least having protected carboxy moiety, Rs is aryl at least having halo(lower)alkanoyl moiety, R is aryl at least having substituted amino(lower)alkanoyl moiety, WO 00/40576 PCT/JP00/00018 16 Ra is protected carboxy,

R

2 is optically active amide, R is protected carboxy,

R

3 is hydrogen or hydroxy-protective group, R3 is hydroxy-protective group,

R

4 is optionally substituted aryl,

R

5 and R 6 are each hydrogen or combinedtogether to form lower alkylene, Ya is thia, sulfinyl or sulfonyl, Za is methylene, thia, sulfinyl or sulfonyl, provided that at least one of Ya and Za is thia or sulfinyl, Yb is thia, sulfinyl or sulfonyl, Zb is methylene, thia, sulfinyl or sulfonyl, provided that at least one of Yb and Zb is sulfinyl or sulfonyl, L is a leaving group, and m 1 is an integer of 1 to 6.

The starting compounds used in the above processes can be prepared according to the following Preparations or by a conventional method.

Suitable salts of the object compounds to (I-ae) may be conventional non-toxic pharmaceutically acceptable salts and include an acid addition salt such as an organic acid salt acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with a base such as an amino acid arginine, aspartic acid, glutamic acid, etc.), an alkali metal salt sodium salt, potassium salt, etc.), an alkaline earth metal salt calcium salt, magnesium salt, etc.), an ammonium salt, an organic WO 00/40576 PCT/JP00/00018 17 base salt trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), or the like.

The object compounds and pharmaceutically acceptable salts thereof may include solvates such as enclosure compounds hydrate, etc.).

Suitable examples and illustrations of the various definitions, which the present invention includes within its scope and which are shown in the above and subsequent descriptions of the present specification, are as follows.

The term "lower" is intended to mean up to 6 carbon atoms, preferably up to 4 carbon atoms, unless otherwise indicated.

Suitable "aryl" and aryl moiety in the term "optionally substituted aryl" may include an aryl having 6 to 10 carbon atoms, such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl and the like, preferably phenyl and naphthyl.

Suitable "optionally substituted aryl" may include.

above-mentioned aryl, which is substituted by the group consisting of the following (Al) to (Al) halogen, (A2) lower alkyl, (A3) lower alkoxy, (A4) halo(lower)alkyl, halo(lower)alkoxy, (A6) lower alkenyl, (A7) acyl, (A8) lower alkvlthio, lower alkvylsulfin, 1i.l,- (A9) (All) (A12) alkylsulfonyl,

C

6

-C

1 0 aryl halo(C 6

-C

1 0 )aryl, hydroxy, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, (A13) amino, (AN4) carboxy, protected carboxy, (A16) nitro (lower) alkenyl, (A17) lower alkylenedioxy, (A18) acylamino, (A19) nitro, (C 6 -C 10 )aryl (lower) alkoxy, (A21) carbamoyl (lower)alkenyl optionally N-substituted by the group consisting of lower alkyl, C 6

C

10 aryl lower alkoxy- (C 6

C

10 )aryl, and halo(C 6

C.

10 )aryl, (A22) lower alkylaminocarbonyloxy, (A23) lower alkanoyloxy, (A24) lower alkoxy(lower)alkanoyloxy, lower alkoxycarbonyloxy, (A26) lower alkenoyloxy optionally substituted by heterocyclic group of the following to (14), (A27) lower cycloalkanecarbonyloxy, (A28) lower al koxy substituted by the group consisting of carboxy, protected carboxy, lower alkanoyl, lower cycloalkanecarbamoyl, and lower alkylcarbamoyl, (A29) lower alkylcarbamoyloxy(lower) alkyl, (A30) lower alkoxycarbonylamino(lower)alkyl, (A31) amino(lower)alkyl, (A32) lower alkylcarbamoyl (lower) alkyl, (A33) heterocyclic-carbonylamino, the heterocyclic group being selected from the following to (14)-and optionally being substituted

N-

protective group, (A34) the following heterocyclic groups to (14) being optionally substituted by lower alkyl, and A (A 35.) oxo.

WO 00/40576 PCT/JPO0000018 19 Suitable "heterocyclic group" in the term "optionally substituted heterocyclic group" means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as oxygen atom, sulfur atom, nitrogen atom and the like.

Preferable heterocyclic groups are following to (14): unsaturated 3- to 8-membered, preferably 5- or 6membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl 4 H-1,2,4-triazolyl, 1H-l,2,3-triazolyl, 2 H-1,2,3-triazolyl, etc.), tetrazolyl 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl 4,5-dihydro-l,2,4triazinyl, 2 5 -dihydro-l,2,4-triazinyl, and the like); saturated 3- to 8-membered, preferably 5- or 6membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperidino, pyrazolidinyl, piperazinyl, and the like); unsaturated 3- to 8-membered, preferably 5- or 6membered, heteromonocyclic group containing 1 or 2 sulfur atoms (thienyl, and the like); unsaturated condensed (preferably bicyclic) 7- to 13-membered, preferably 9- or heterocyclic group containing 1 to 5 nitrogen atoms (indolyl, isoindolyl, indolizinyl, benzimidazolyl, WO 00/40576 PCT/JP00/00018 qinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl etc.), dihydrotriazolopyridazinyl, and the like); unsaturated 3- to 8-membered, preferably 5- or 6membered, heteromonocyclic group containing 1 or 2 oxygen atoms (furyl, and the like); saturated 3- to 8-membered, preferably 5- or 6membered, heteromonocyclic group containing 1 or 2 oxygen atoms (oxolanyl, and the like); unsaturated 3- to 8-membered, preferably 5- or 6membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (oxazolyl, isoxazolyl, oxadiazolyl 1,2,4oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), and the like); unsaturated condensed (preferably bicyclic) 7- to 13-membered, preferably 9- or heterocyclic group containing 1 or 2 oxygen atoms (benzofuranyl, benzodihydrofuranyl, benzodioxolenyl, and the like); unsaturated condensed (preferably bicyclic) 7- to 13-membered, preferably 9- or heterocyclic group containing 1 or 2 sulfur atoms (benzothienyl, dihydrobenzothienyl, and the like); saturated 3- to 8-membered, preferably 5- or 6membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (morpholinyl, morpholino, and the like); (11) unsaturated condensed (preferably bicyclic) 7- to 13-membered, preferably 9- or heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms WO 00/40576 PCT/JP00/00018 21 (benzoxazolyl, benzoxadiazolyl, and the like); (12) unsaturated 3- to 8-membered, preferably 5- or 6membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms (thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl 1,2,4-thiadiazolyl, 1,3,4thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3thiadiazolyl, etc.), and the like); (13) saturated 3- to 8-membered, preferably 5- or 6membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms (thiazolidinyl, and the like); (14) unsaturated condensed (preferably bicyclic) 7- to 13-membered, preferably 9- or heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms (benzothiazolyl, benzothiadiazolyl, and the like); etc.

These heterocyclic groups may have one or more substituents. Examples of the substituents for substituted heterocyclic group may be the same as those for "optionally substituted aryl" (above-mentioned (Al) to Suitable "lower alkyl" may include a straight or branched alkyl having 1 to 6 carbon atoms, and exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, hexyl and the like, and the most preferably methyl for R 1 Suitable "lower alkenyl" may include a straight or branched alkenyl having 2 to 6 carbon atoms, and exemplified by ethenyl, 1-propenyl, 2 -propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl and the like.

Suitable "lower alkoxy" may include a straight or branched alkenyl having 1 to 6 carbon atoms, and exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like.

Suitable "hydroxy-protective group" may include a conventional protective group, for example, substituted lower alkyl such as lower alkoxy(lower)alkyl methoxymethyl), lower alkoxy(lower)alkoxy(lower)alkyl methoxyethoxymethyl) and substituted or unsubstituted aryl(lower)alkyl benzyl, nitrobenzyl); acyl such as lower alkanoyl acetyl, propionyl, pivaloyl), aroyl benzoyl, fluorenecarbonyl), lower alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertbutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl), substituted or unsubstituted aryl(lower)alkoxycarbonyl benzyloxycarbonyl, bromobenzyloxycarbonyl), arenesulfonyl benzenesulfonyl, tosyl) and alkanesulfonyl methanesulfonyl, ethanesulfonyl); tri(lower)alkylsilyl trimethylsilyl); tetrahydropyranyl; and the like, preferably 20 tetrahydropyranyl.

tot' Suitable "halogen" includes fluorine, bromine, chlorine and iodine.

Suitable acyl and acyl moiety of "acylamino" includes acyl such as aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted by aromatic or heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic acids.

The aliphatic acyl includes saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower 30 alkanoyl formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl, N-alkylcarbamoyl WO 00/40576 PCT/JPOO/00018 23 methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertbutoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl acryloyl, methacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like.

The aromatic acyl may include C 6

-C

10 aroyl benzoyl, toluoyl, xyloyl, etc.), N-(C 6 -Cl0)arylcarbamoyl N-phenylcarbamoyl, N-tolylcarbamoyl, N-naphthylcarbamoyl, etc.), C 6

-C

10 arenesulfonyl benzenesulfonyl, tosyl, etc.), and the like.

The heterocyclic acyl may include heterocyclic-carbonyl furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.

The aliphatic acyl substituted by aromatic group(s) may include aralkanoyl such as phenyl(lower)alkanoyl phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl benzyloxycarbonyl, phenethyloxycarbonyl, etc.), aryloxyalkanoyl such as phenoxy(lower)alkanoyl phenoxyacetyl, phenoxypropionyl, etc.), and the like.

The aliphatic acyl substituted by heterocyclic group(s) may include heterocyclic-alkanoyl such as heterocyclic- (lower)alkanoyl thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, etc.), and the like.

These acyl groups may be further substituted by one or more suitable substituents as those for "optionally substituted aryl" (above-mentioned (Al) to WO 00/40576 PCT/JP00/00018 24 Suitable "protected carboxy" includes esterified carboxy wherein "esterified carboxy" is as defined below.

Suitable examples of the ester moiety of the esterified carboxy are lower alkyl ester methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.) and the like, which may have at least one suitable substituent. Examples of the substituted lower alkyl ester are lower alkanoyloxy(lower)alkyl ester acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l-(or 2 -)acetoxyethyl ester, l-(or 2- or 3 -)acetoxypropyl ester, l-(or 2- or 3- or acetoxybutyl ester, l-(or 2 -)propionyloxyethyl ester, l-(or 2- or 3 -)propionyloxypropyl ester, 1-(or butyryloxyethyl ester, 1-(or 2 -)isobutyryloxyethyl ester, l-(or 2 -)pivaloyloxyethyl ester, 1-(or 2 -)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2 -ethylbutyryloxymethyl ester, 3 3 -dimethylbutyryloxymethyl ester, 1-(or pentanoyloxyethyl ester, etc.], lower alkanesulfonyl(lower)alkyl ester 2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester 2-iodoethyl ester, 2 2 ,2-trichloroethyl ester, etc.); lower alkoxycarbonyloxy.(lower)alkyl ester methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, tert-butoxycarbonyloxymethyl ester, l-(or 2 -)methoxycarbonyloxyethyl ester, l-(or 2-)ethoxycarbonyloxyethyl ester, l-(or 2 -)isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene(lower)alkyl ester, (5-lower alkyl-2-oxo-1,3dioxol-4-yl) (lower)alkyl ester (5-methyl-2-oxo-1,3dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4yl)methyl ester, (5-propyl-2-oxo-l, 3 -dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester vinyl ester, allyl ester, WO 00/40576 PCT/JP00/00018 etc.); lower alkynyl ester ethynyl ester, propynyl ester, etc.); ar(lower)alkyl ester which may have at least one suitable substituent benzyl ester, 4methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3 4 -dimethoxybenzyl ester, 4-hydroxy-3,5-di-tertbutylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.

More preferable example of the protected carboxy thus defined may be C 1

-C

4 alkoxycarbonyl, and the most preferable one may be methoxycarbonyl, ethoxycarbonyl, and t-butoxycarbonyl for R 2 Said "amidated carboxy" can be referred to the ones as mentioned below.

Suitable examples of the amidated carboxy may include optionally substituted carbamoyl such as -carbamoyl, -N-hydroxycarbamoyl, -N-(protected hydroxy)carbamoyl, wherein said hydroxyprotective group may be the same as mentioned above tetrahydropyranyl, etc.), -mono(or di) (lower)alkylcarbamoyl wherein the lower alkyl group may be the same as those mentioned above (e.g.

methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, 3 -methylbutylcarbamoyl, isobutylcarbamoyl, pentylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), -N-(aryl(lower)alkyl)carbamoyl such as phenyl(lower)alkylcarbamoyl l-phenylethylcarbamoyl, (R)-(+)-l-phenylethyl, etc.), -cyclo(C 3

-C

7 )alkylcarbamoyl cyclohexylcarbamoyl, etc.), WO 00/40576 PCT/JPOO/00018 26 -carbamoyl substituted by amino or di(lower)alkylamino [e.g.

N-aminocarbamoyl, N-(dimethylamino)carbamoyl, etc.], -lower alkyleneaminocarbonyl pyrrolidin-l-ylcarbonyl, hexahydro-1H-azepin-1-ylcarbonyl, etc.), said alkylene being optionally substituted by carboxy or protected carboxy as mentioned above such as lower alkoxycarbonyl [e.g.

carboxypyrrolidin-1-ylcarbonyl, (methoxycarbonyl)pyrrolidin-l-ylcarbonyl, (ethoxycarbonyl)pyrrolidin-l-ylcarbonyl, etc.], or said lower alkylene being optionally interrupted by other hetero atom(s) such as nitrogen, oxygen or sulfur (e.g.

morpholinocarbonyl, etc.), -lower alkylsulfonylcarbamoyl methylsulfonylcarbamoyl, etc.), -arenesulfonylcarbamoyl benzenesulfonylcarbamoyl, etc.), and the like.

Preferable example of the amidated carboxy thus defined may be N-hydroxycarbamoyl, N-tetrahydropyranyloxycarbamoyl, and N-(phenylethyl)carbamoyl for R 2 Suitable "leaving group" may include halogen as mentioned above, acyloxy such as sulfonyloxy mesyloxy, tosyloxy, etc.), alkoxy tert-butoxy, etc.), aralkoxy benzyloxy, etc.), and the like, preferably halogen and the most preferably bromine.

Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene, WO 00/40576 PCT/JP00/00018 27 hexamethylene, and the like, in which more preferable one may be C 1

-C

4 alkylene, and the most preferable one may be ethylene, l-methyltrimethylene, and trimethylene.

Suitable "halo(lower)alkyl" may be above-mentioned lower alkyl substituted by halogen as mentioned above, in which more preferable one may be halo(C 1

-C

4 )alkyl.

Suitable "halo(lower)alkoxy" may be above-mentioned lower alkoxy substituted by halogen as mentioned above, in which more preferable one may be halo(C 1

-C

4 )alkoxy.

Suitable "lower alkylthio" may be thio group substituted by above-mentioned lower alkyl, in which more preferable one may be C 1

-C

4 alkylthio methylthio, ethylthio, etc.).

Suitable "lower alkylsulfinyl" may include methylsulfinyl, ethylsulfinyl, and the like, in which more preferable one may be C 1

-C

4 alkylsulfinyl (e.g.

methylsulfinyl, etc.).

Suitable "lower alkylsulfonyl" may include methylsulfonyl, ethylsulfonyl, and the like, in which more preferable one may be C 1

-C

4 alkylsulfonyl (e.g.

methylsulfonyl, etc.).

Suitable "haloaryl may be aforementioned aryl substituted by halogen as mentioned above, in which more preferable one may be halo(C 6

-C

10 )aryl, and the most preferable one may be 4 -fluorophenyl.

Suitable "hydroxy(lower)alkyl" may be above-mentioned lower alkyl substituted by hydroxy as mentioned above, in which more preferable one may be hydroxy(C 1

-C

4 )alkyl.

WO 00/40576 PCT/JP00/00018 28 Suitable "protected hydroxy(lower)alkyl" may be abovementioned hydroxy(lower)alkyl group protected by a conventional hydroxy-protective group such as acyl, (lower alkyl) (diaryl)silyl group (t-butyl) (diphenyl)silyl, etc.), and the like.

Suitable "aryl(lower)alkoxy" may include benzyloxy, phenylethoxy, and the like, in which more preferable one may be phenyl(C 1

-C

4 )alkoxy benzyloxy, etc.).

Suitable "carbamoyl(lower)alkenyl" may include carbamoylethenyl, carbamoylallyl, and the like, in which more preferable one may be carbamoyl(C 2

-C

4 )alkenyl (e.g.

carbamoylethenyl, etc.).

Suitable "lower alkoxyaryl" may include methoxyphenyl, ethoxyphenyl, and the like, in which more preferable one may be C 1

-C

4 alkoxyphenyl methoxyphenyl, etc.).

Preferable examples of "carbamoyl(lower)alkenyl optionally N-substituted by the group consisting of lower alkyl, aryl, lower alkoxyaryl and haloaryl" may include lower alkylcarbamoyl(lower)alkenyl carbamoylethenyl, methylcarbamoylethenyl, ethylcarbamoylethenyl, propylcarbamoylethenyl, isopropycarbamoylethenyl, dimethylcarbamoylethenyl, etc.),

C

6 arylcarbamoyl(lower)alkenyl phenylcarbamoylethenyl, etc.), lower alkoxy(C6-Cl0)arylcarbamoyl(lower)alkenyl (e.g.

methoxyphenylcarbamoylethenyl, etc.), haloarylcarbamoyl(lower)alkenyl (e.g.

fluorophenylcarbamoylethenyl, etc.), and the like.

Suitable "lower alkylaminocarbonyloxy" may include methylaminocarbonyloxy, ethylaminocarbonyloxy, and the like, in which more preferable one may be C1-C 4 alkylaminocarbonyloxy methylaminocarbonyloxy, ethylaminocarbonyloxy, etc.).

Suitable "lower alkanoyloxy" may include acetyoxy, propanoyloxy, and the like, in which more preferable one may be C 1

-C

4 alkanoyloxy propanoyloxy, etc.).

Suitable "lower alkoxy(lower)alkanoyloxy" may include methoxyacetyloxy, ethoxyacetyloxy, and the like, in which more preferable one may be C 1

-C

4 alkoxy(C 1

-C

4 )alkanoyloxy methoxyacetyloxy, etc.).

Suitable "lower alkoxycarbonyloxy" may include methoxycarbonyloxy, ethoxycarbonyloxy, and the like, in which more preferable one may be C 1

-C

4 alkoxycarbonyloxy ethoxycarbonyloxy, etc.).

Suitable "lower alkenoyloxy" may include acryloyloxy, and the like, in which more preferable one may be C 2

-C

4 alkenoyloxy acryloyloxy, etc.).

Preferable examples of "lower alkenoyloxy optionally substituted by heterecyclic group" may include lower 25 alkenoyloxy optionally substituted by the above-mentioned heterocyclic group pyridyl, etc.) such as pyridylacryloyloxy, and the like.

Suitable "lower cycloalkanecarbonyloxy" may include 30 C 3

-C

7 cycloalkanecarbonyloxy such as cyclopropanecarbonyloxy, cyclobutanecarbonyloxy, and the like, in which more preferable one may be C 3

-C

6 cycloalkanecarbonyloxy (e.g.

cyclopropanecarbonyloxy, etc.).

oooo* Suitable "lower cycloalkanecarbamoyl" may include C 3

-C

7 WO 00/40576 PCT/JPOO/00018 cycloalkanecarbamoyl such as cyclopropanecarbamoyl, cyclobutanecarbamoyl, and the like, in which more preferable one may be C 4

-C

6 cycloalkanecarbamoyl (e.g.

cyclopropanecarbamoyl, etc.).

Suitable "lower alkylcarbamoyl" may include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and the like, in which more preferable one may be C1-C4 alkylcarbamoyl methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, etc.).

Preferable examples of "lower alkoxy substituted by the group consisting of carboxy, protected carboxy, lower alkanoyl, lower cycloalkanecarbamoyl, lower alkylcarbamoyl may include arboxy(lower)alokoxy carboxymethoxy, etc.), lower alkoxycarbonyl(lower)alkoxy (e.g.

ethoxycarbonylmethoxy, butoxycarbonylmethoxy, etc.), lower alkanoyl(lower)alkoxy propanoylmethoxy, etc.), lower cycloalkanecarbamoyl(lower)alkoxy (e.g.

cyclopropylcarbamoylmethoxy, etc.), loweralkylcarbamoyl(lower)alkoxy (e.g.

methylcarbamoylmethoxy, ethylcarbamoylmethoxy, propylcarbamoylmethoxy, etc.), and the like.

Suitable "lower alkylcarbamoyloxy(lower)alkyl" may include methylcarbamoyloxymethyl, ethylcarbamoyloxymethyl, and the like, in which more preferable one may be C1-C 4 alkylcarbamoyloxy(C 1

-C

4 alkyl methylcarbamoyloxymethyl, etc.).

Suitable "lower alkoxycarbonylamino(lower)alkyl" may include methoxycarbonylaminomethyl, t-butoxycarbonylaminomethyl, and the like, in which more preferable one may be C 1

-C

4 alkoxycarbonylamino(C 1

-C

4 )alkyl methoxycarbonylaminomethyl, 31 t-butoxycarbonylaminomethyl, etc.).

Suitable "amino(lower)alkyl" may include aminomethyl, aminoethyl, and the like, in which more preferable one may be amino(C 1

-C

4 )alkyl (e.g aminomethyl, etc.).

Suitable "lower alkylcarbamoyl(lower)alkyl" may include methylcarbamoylmethyl, methylcarbamoylethyl, ethylcarbamoylmethyl, ethylcarbamoylethyl, and the like, in which more preferable one may be C 1

-C

4 alkylcarbamoyl-

(C

1

-C

4 )alkyl methylcarbamoylmethyl, etc.).

Suitable "heterocyclic-carbonylamino" may include carbonylamino group substituted by the above-mentioned heterocyclic group and pyrrolidinyl, tetrahydroisoquinolyl, furyl, etc.) such as pyrrolidinylcarbonylamino, 1,2,3,4tetrahydroisoquinolylcarbonylamino, furylcarbonylamino, and the like.

Preferable examples of "optionally substituted heterocyclic-carbonylamino" may include above-mentioned heterocyclic-carbonylamino optionally the heterocyclic group being substituted by N-protective group acyl such as 25 alkoxycarbonyl, etc.) such as pyrrolidinylcarbonylamino, 1,2,3, 4 -tetrahydroisoquinolylcarbonylamino, butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolyl)carbonylamino, furylcarbonylamino, and the like.

30 Suitable "nitro(lower)alkenyl" may be above-mentioned lower alkenyl substituted by nitro, in which more preferable one may be nitro(C 2

-C

4 )alkenyl.

Suitable "lower alkylenedioxy" may include straight or branched one such as methylenedioxy, ethylenedioxy, WO 00/40576 PCT/JP00/00018 32 trimethylenedioxy, propylenedioxy, tetramethylenedioxy, ethylethylenedioxy, pentamethylenedioxy, hexamethylenedioxy, and the like, in which more preferable one may be C1-C 4 alkylenedioxy.

Suitable "amido" may be the same as those for "amidated carboxy", and preferably lower alkylcarbamoyl, and the most preferably methylcarbamoyl.

Suitable "acylamino" may be amino substituted by acyl as mentioned above.

Suitable "substituted amine" may include amino group substituted by the above-mentioned substituent (A2) to (A12), (A14) to (A17), (A20) to (A32) and (A34).

Preferable examples may be hydroxy (lower)alkylamine hydroxyethylamine, etc.), above-mentioned N-containing heterocyclic group morpholino, etc.), lower alkenylamine allylamine, etc.),

C

6

-C

10 aryl(lower)alkylamine e.g. benzylamine, etc.), lower alkylamine t-butylamine, pentylamine, etc.), heterocyclic(lower)alkylamine such as pyridyl(lower)alkylamine pyridylmethylamine, etc.), lower alkoxy(lower)alkylamine ethoxyethylamine, etc.), and the like.

Preferable examples of the formula: Y Z is one of the following formulae: WO 00/40576 PCT/JPOO/0001 8 9

Q

02

OQ

n or 02 02 and the like.

In the object compounds the preferred one may be the compounds wherein m and n are each 0 or 1, and (ii) the more preferred one may be the compounds of the above item wherein A is ethylene, l-methyltrimethylene, or trimethylene.

The more preferred object compounds are: (iii) The compounds having the following formula: Y Z (CH 2) M <(CH 2 n R

(IA)

wherein a group of the formula: is one of the following formulae: WO 00/40576 PTJ0/01 PCT/JPOO/00018 34

CH

3 >K or 02n0<2 Ri is lower alkyl, phenyl, halophenyl, or (halo) (phenyl)phenyl, R 2is carboxy or hydroxyarinocarbonyl, and m and n are each an integer of 0 or 1, and rn+n=l.

(iV) The compounds having the following formula: Y Z Ri.- cH (IB)

S

wherein a group of the formula: is one of the following formulae: 13 02 0 102 OQ2 '0 WO 00/40576 PCT/JP00/00018 Sor 02 O R2 is carboxy or hydroxyaminocarbonyl, m and n are each an integer of 0 or 1, and m+n=l, R is halogen; heterocyclic group consisting of pyridyl, thienyl, furyl, benzofuranyl or benzothienyl, wherein the heterocyclic group is optionally substituted by the group consisting of lower alkanoyl, lower alkyl, lower alkoxy, lower alkoxycarbonylamino and lower alkylcarbamoyl; naphtyl or phenyl optionally substituted by the group consisting of the following (Cl) to (C31); (Cl) halogen, (C2) lower alkyl, (C3) lower alkoxy, (C4) halo(lower)alkyl, (C5) halo(lower)alkoxy, (C6) lower alkenyl, (C7) lower alkylcarbamoyl, carbamoyl, phenyl(lower)alkylcarbamoyl, lower alkanoyl, (C8) lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, (C9) phenyl, naphthyl, halophenyl, (Cll) hydroxy, (C12) mono- or dihydroxy(lower)alkyl, phenoxycarbonyloxy(lower)alkyl (C13) amino, (C14) carboxy, lower alkylenedioxy, (C16) lower alkanoylamino, phenyl(lower)alkanoylamino, WO 00/40576 WO 0040576PCT/JPOO/0001 8 36 ha lophenyl (lower) al1kanoyl amino, lower alkoxy (lower) alkanoylanino, lower alkoxy (lower) alkanoylamino, phenoxy (lower) alkanoylamino, lower alkoxyphenoxy (lower) alkanoylamino, lower alkyiphenoxy (lower) alkanoylanino, halophenoxy (lower) alkanoylamino, carboxy (lower) alkanoylamino, lower alkoxycarboriyl (lower) alkanoylamino, lower alkylcarbamoyl (lower) alkanoylamino, halo (lower) alkanoylamino, lower alkenyl (lower) alkanoylamino, lower alkoxy (lower) alkanoylanino, phenyl (lower) alkoxy (lower) alkanoylamino, pipericlinyloxy (lower) alkanoylamino, N-lower alkoxycarbonylpiperidinyloxy- (lower) alkanoylamino, pyridyloxy (lower) alkanoylamino, hydroxy (lower) alkanoylamino, lower alkanoyloxy (lower) alkanoylanino, lower alkylcarbamoyloxy (lower) alkanoylamino, N,N-di (lower alkyl) carbamoyloxy, piperidino-carbonyloxy (lower) alkanoylamino, phenyl (lower) al1kyl carbamoyloxy (lower) alkanoylamino, lower alkoxycarbonylanino (lower) alkanoylamino, amino (lower) al1kanoyl amino, lower alkoxycarbonylamino (lower) alkanoylamino, f luorenylmethoxyca rbonyl amino (lower) alkanoylamino, lower alkylamino (lower) alkanoylanino, [N,N-di (lower alkyl) amino] (lower) alkanoylamino, [N-lower alkyl-N- (lower alkoxycarbonyl) amino] (lower) alkanoylanino, [N-lower alkyl-N-(fluorenylmethoxycarbonyl) WO 00/40576 WO 0040576PCT/JPOO/OO1 8 37 amino] (lower) alkanoylamino, [N-lower alkyl-N-(mono- or di(lower)alkylcarbamoyl)amino] (lower)alkanoylamino, [N-(mono- or di(lower alkyl)carbamoyl)amino] (lower)alkanoylamino, benzoylamino (lower) alkanoylamino, lower alkanoylamino(lower)alkanoylamino, lower alkanesulfonylamino (lower) alkanoylamino, lower alkoxy (lower) alkanoylamino- (lower) alkanoylamino, cyclo (lower) alkyloxycarbonylamino- (lower) alkanoylamino, pyridylcarbonylamino (lower) alkanoylamino, morpholinocarbonylamino (lower) alkanoylamino, phenyl (lower) alkoxycarbonylamino- (lower) alkanoylanino, lower alkoxyphenylsulfonylamino- (lower) alkanoylamino, hydroxy (lower) alkylamino (lower) alkanoylamino, morpholino (lower) alkanoylamino, oxooxazolidinyl (lower) alkanoylamino, oxopyrrolidinyl (lower) alkanoylamino, trimethyihydantoinyl (lower) alkanoylamino, lower alkenylamino (lower) alkanoylamino, lower alkoxy(lower)alkylamino(lower)alkanoylamino, phenyl (lower) alkylamino (lower) alkanoylamino, pyridyl (lower) alkylamino (lower) alkanoylamino, lower alkoxycarbonylamino, phenyl (lower) alkoxycarbonylamino, lower alkoxy (lower) alkoxycarbonylamino, halo (lower) alkoxycarbonylamino, amino (lower) alkoxycarbonylamino, phthalimido (lower) alkoxycarbonylamino, carbamoylamino, WO 00/40576 PCT/JPOO/00018 38 (mono- or di (lower alkyl) carbamoylamino, naphthyl carbamoylamino, halophenylcarbamoylamino, lower alkoxyphenylcarbamoylamino, lower alkenylcarbamoylamino, cyclo (lower) alkyl (lower) al1kylcarbamoyl amino, phenyl (lower) alkylcarbarnoylamino, halo (lower) alkylcarbamoylamino, lower alkoxy (lower) alkylcarbamoylamino, hyclroxy (lower) alkylcarbamoylamino, (lower alkyl) (diphenyl) silyloxy (lower) alkylcarbarnoylamino, carboxy (lower) alkylcarbamoylamino, lower al koxycarbonyl (lower) al kylcarbamoylamino, lower alkylcarbamoyl (lower) alkylcarbamoylamino, or pyridylcarbamoylamino, lower alkylsulfonylamino, lower alkenoylamino, lower cycloalkanecarbonylamino, lower alkenyloxycarbonylamino, phenoxycarbonylamino, lower alkyithiocarbonylamino, (C17) phenyl (lower) alkoxy, (C18) lower alkenyl, mono- or di(lower alkyl) carbamoyl (lower) alkenyl, (2- (methylcarbamoyl) ethenyl, 2- (ethylcarbamoyl)ethenyl, 2- (propylcarbamoyl) ethenyl, 2- (isopropylcarbamoyl) ethenyl, 2- (dimethylcarbamoyl) ethenyl,) phenylcarbamoyl (lower) alkenyl, lower alkoxycarbamoyl (lower) alkenyl, ha lophenylcarbamoyl (lower) alIkenyl, (C19) lower alkylaminocarbonyloxy, lower alkanoyloxy, (C21) lower alkoxy(lower) alkanoyloxy, (C22) lower alkoxycarbonyloxy, (C23) pyridyl (lower)alkenoyloxy (C24) lower cycloalkanecarbonyloxy, carboxy(lower)alkoxy, lower alkoxycarbonyl (lower) alkoxy, lower alkanoyl(lower)alkoxy, lower cycloalkanecarbamoyl (lower) alkoxy, lower alkylcarbamoyl (lower) alkoxy, (C26) lower alkylcarbamoyloxy(lower)alkyl, (C27) lower alkoxycarbonylamino(lower)alkyl, (C28) amino (lower) alkyl, (C29) lower alkylcarbamoyl(lower)alkyl, (C30) furylcarbonylamino, tetrahydroisoquinolylcarbonylamino, N-lower alkoxycarbonyltetrahyclroisoquinolylcarbonylamino, pyrrolidinyl carbonylamino, (C31) oxazolyl, lower alkyloxadiazolyl.

The compounds of the above in which a group of the formula: y is one of the following formulae: S0 2

S

.:s *.2 WO 00/40576 WO 0040576PCT/JPOO/00018 Ris hyciroxyaminocarbonyl, m is 0 and n is 1, a group of the formula: R

S

is one of the group of the following formulae to (a) R 1 1 wherein Ris halo bromo, etc.), naphtyl 2-naphthyl, etc.), phenyl phenyl, etc.), mono- or dihalophenyl 3(or 4)-chiorophenyl, 2(or 3 or 4) -fluorophenyl, 3, 4-dichiorophenyl, difluorophenyl, etc.), mono- or di (lower) alkylphenyl 3 (or 4)-methylphenyl, 4-ethyiphenyl, 4isopropyiphenyl, 4-(t-butyl)phenyl, 3,4dimethyiphenyl, etc.), lower alkoxyphenyl 4methoxyphenyl, 4-ethoxyphenyl, etc.), trihalo(lower)alkylphenyl 4trifluoromethylphenyl, etc.), trihalo(lower)alkoxyphenyl 4trifluoromethoxyphenyl, etc.), lower alkenylphenyl 4-ethenyiphenyl, etc.), lower alkylcarbamoylphenyl 4-methylcarbamoylphenyl, 4-ethylcarbamoylphenyl, etc.), carbamoylphenyl (e.g.

4-carbamoylphenyl, etc.), phenyl (lower)alkylcarbamoylphenyl 4ben zylca rbamoylphenyl, etc.), lower alkanoylphenyl 4-acetyiphenyl, etc.), lower alkylthiophenyl, lower alkylsulfinylphenyl, lower alkylsulfonylphenyl 4-methylthiophenyl, 4-ethylthiophenyl, 4methylsulfinylphenyl, 4-methylsulfonylphenyl, etc.), 41 phenyiphenyl 4-phenyiphenyl, etc.), (halo) (phenyl)pheny. 4 -phenyl-3-fluoropheny.

etc.), halophenyiphenyl 4-(4fluorophenyl)pheiy etc.) hydroxyphenyl 3(or 4)-hydroxyphenyl, etc.), mono- or dihydroxy (lower) alkyiphenyl, phenoxycarbonyloxy(lower)alkylpheny., 3 (or 4)hydroxymethyiphenyl, 4- (l,2-dihyctroxyethyl)phenyl,.

4 -(phenoxycarbonyloxymethyljphenyl, etc.), aminophenyl 3 (or 4 )-aminophenyl, etc.), carboxypheny. 4-carboxyphenyl, etc.), lower alkylendioxyphenyl 3, 4 -methylendioxypheny., etc.), lower alkanesulfonylaminophenyl (e.g.

4- (methanesulfonylamino)phenyl etc.), lower alkenoylaminophenyl, 3- 2 -butenoylamino)phenyl, etc.), lower cycloalkanecarbonylaminophenyl (e.g.

3- (cyclopropanecarbonylamino) phenyl, 3- (cyclobutanecarbonylamino) phenyl, 3- (cyclopentanecarbonylamino)phenyl, etc.) phenyl(lower)alkoxypheny. 4 -benzyloxyphenyl, etc.), carbamoyl (lower) alkenylphenyl, mono- or di (lower alkyl)carbamoy.(lower)alkenylpheny. (e.g.

4- (methylcarbamoyl) ethenyl) phenyl, (2-(ehycrbmolethenyl)phnl 25 4- (propylcarbamoyl)ethenyl)phenyl, 4- (isopropycarbamoyl) ethenyl) phenyl, 4-2- (dimethylcarbamoyl) ethenyl) phenyl, etc.) phenylcarbanoyl (lower) alkenyiphenyl (e.g.

4- (phenylcarbamoyl)etheny.)phenyl, etc.), lower alkoxycarbamoyl(lower)alkenylphenyl (e.g.

4- (methoxyphenylcarbamoyl)ethenyl)phenyl, etc.), halophenylcarbamoyl (lower) alkenylpheny1 g.

4 -fluorophenylcarbamoyl)ethenyl)phenyl, etc.) lower alkylcarbamoyloxyphenyl (e.g.

4- (methylaminocarbonyloxy)phenyl, 4- (ethylaminocarbonyloxy)phenyl, etc.), lower alkanoyloxyphenyl 4 -propanoyloxyphenyl, etc.) lower alkoxy(lower)alkanoyloxyphenyl (e.g.

4- (methoxyacetyloxy)phenyl, etc.) lower alkoxycarbonyloxypheny. (e.g.

4- (ethoxycarbonyloxy) phenyl, etc.) pyridyl (lower) alkenoyloxyphenyl (e.g.

4- (3-pyridyl) acryloyloxy) phenyl, etc.), cyclo (lower) alkylcarbonyloxyphenyl (e.g.

4- (cyclopropylcarbonyloxy)phenyl, etc.), carboxy (lower) alkoxyphenyl (e.g.

4- (carboxymethoxy)phenyl, etc.) lower alkoxycarbonyl(lower)alkoxyphenyl (e.g.

4- (ethoxycarbonylmethoxy) phenyl, 4- (t-butoxycarbonylmethoxy)phenyl, etc.), lower alkanoyl (lower)alkoxyphenyl (e.g.

4- (propanoylmethoxy)phenyl, etc.), lower cycloalkanecarbamoyl (lower) alkoxyphenyl (e.g.

4- (cyclopropylcarbamoylmethoxy)phenyl, etc.), lower alkylcarbamoyl(lower)alkoxyphenyl (e.g.

4- (methylcarbanoylrnethoxy) phenyl, 4- (ethylcarbamoylmethoxy) phenyl, 4- (propylcarbamoylmethoxy) phenyl, etc.), lower alkylcarbamoyloxy(lower)alkylphenyl (e.g.

25 3 (or (methylcarbamoyloxymethyl)phenyl, etc.), lower alkoxycarbonylamino(lower)alkylphenyl (e.g.

4- (methoxycarbonylaminomethyl) phenyl, 4- (t-butoxycarbonylaminomethyl)phenyl, etc.), amino (lower) alkylphenyl 4-aiinomethylphenyl, 30 etc.), lower alkylcarbamoyl(lower)alkylpheny1 (e.g.

4 -(rnethylcarbamoylmethyl)phenyl, etc.), fuyc.bnlaiopey 123 4 -tetrahydroisoquinolylcarbonylaminophenl N-Boc-1, 2,3,4tetrahydroisoquinoylcarbonylaminophenl pyrrolidinylcarbonylaminophenyl (e.g.

3- (2 (or 3) -furyl carbonylamino) phenyl, 3- 4 -tetrahydroisocquinolylcarbonylamino) phenyl, 3-(N-(t-butoxycarbonyl)-1,2,3,4tetrahydroisoquinolylcarbonylamino) phenyl, 3 -(pyrrolidinylcarbonylamino)phenyl, etc.), oxazolyiphenyl 4-(1,3-oxazolyl)phenyl, etc.), lower alkyloxadiazolyiphenyl, l, 2 ,4-oxacliazol-3-yl)phenyl, etc.), (b) R 1 2 -C-HN S wherein R2is lower alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, etc.) optionally substituted by the group consisting of phenyl phenyl, etc.), halophenyl 4-chlorophenyl, etc.), lower **:alkoxyphenyl 4-methoxyphenyl, etc.), lower alkoxy methoxy, ethoxy, propoxy, butoxy, isopropyloxy, etc.), phenoxy phenoxy, etc.), lower alkoxyphenoxy 3(or 4)-methoxyphenoxy, 25 etc.), halophenoxy 4-fluoro(or chloro)phenoxy, etc.), lower alkylphenoxy 3(or 4)methyiphenoxy, etc.), carboxy carboxy, etc.), lower alkoxycarbonyl methoxycarbonyl, tbutoxycarbonyl, etc.), lower alkylcarbamoyl (e.g.

methylcarbamoyl, etc.), halo chloro, etc.), lower alkenyloxy allyloxy etc.), lower alkoxy(lower)alkoxy 2-ethoxyethoxy, etc.), phenyl(lower)alkoxy benzyloxy, etc.), ~piperidinyloxy 4-piperidinyloxy, etc.), N-tbutoxycarbonylpiperidinyloxy N-t- WO 00/40576 WO 000576PT/JP0001I8 44 butoxycarbonyl-4-piperidinyloxy, etc.) pyridyloxy 3 (or 4) -pyridyloxy, etc. hydroxy (e.g.

hydroxy, etc.), lower alkanoyloxy acetoxy etc.), mono- or di (lower) alkylcarbamoyloxy (e.g.

methylcarbamoyloxy, N-methyl--N-ethylcarbamoyloxy, etc.), piperidinylcarbonyloxy (e.g.

piperidinocarbonyloxy, etc.), phenyl (lower) alkylcarbarnoyloxy (e.g.

benzylcarbamoyloxy, etc.), lower al1koxyca rbonyl amino met hoxyca rbonyl amino, ethoxycarbonylamino, propoxycarbonylamino, tbut oxyca rbonyl amino, etc.), amino amino, etc.), lower alkoxycarbonylamino (e.g.

methoxycarbonylamino, t-butoxycarbonylamino, etc.), fluorenylrnethoxycarbonylamino (e.g.

fluorenylmethoxycarbonylamino etc.), mono- or di (lower)alkylamino methylamino ethylamino dimethylamino, N-methyl-N-ethylanino t-butylamino, pentylamino etc.), N-lower alkyl-N-(lower alkoxycarbonyl) amino N-methyl-Nmethoxycarbonylamino, N-rnethyl-N-tbutoxycarbonyl amino N-ethyl t-but oxycarbonylamino, etc.), N-lower alkyl-N- (fluorenylmethoxycarbonyl) amino N-methyl-N- (fluorenylmethoxycarbonyl)amino etc.), N-lower alkyl-N- (mono- or di (lower)alkylcarbamoyl)amino N-methyl-N- (dimethylcarbamoyl) amino, etc.), N-(mono- or di(lower alkyl)carbamoyl)amino (e.g.

dimethylcarbamoylamino N- (ethylcarbamoyl) amino, etc.), benzoylamino benzoylamino, etc.), lower alkanoylamino acetylamino, isobutyrylamino, pivaloylamino, etc.), lower alkanesulfonylamino methanesulfonylamino, etc.), lower alkoxy(lower)alkanoylamino (e.g.

methoxyacetylamino, etc.), WO 00/40576 PCT/JPOO/OO0i 8 cyclo (lower) alkyloxycarbonylamino (e.g.

cyclopent yloxyca rbonyl amino, etc.) pyridylcarbonylamino pyr idyl ca rbonyl amino, etc.), morpholinocarbonylamino (e.g.

morpholinocarbonylamino, etc.), phenyl (lower) alkoxycarbonylamino (e.g.

ben zyloxycarbonylamino, etc.), lower alkoxyphenylsulfonylamino 4methoxyphenyl sul fonyl amino, etc.), hydroxy (lower) alkylamino 2 -hydroxyethylamino, etc.), morpholino morpholino, etc.), oxooxazolidinyl 2-oxo-l, 3 -oxazolidin---yl, etc.), oxopyrrolidinyl 2 -oxopyrrolidin-l-yl, etc.), trimethyihyiantoinyl 3,4,4trimethylhydantoin-1lyl, etc.), pyridyl 3(or 4)-pyridyl, etc.), lower alkenylamino (e.g.

allylamino, etc.), lower alkoxy (lower) alkylamino 2 -ethoxyethyl amino, etc.), phenyl (lower) alkylarnino benzylamino, etc.), pyridyl (lower) alkylamino 3-pyridylmethylamino, etc.), and cyclo (lower) alkyl cyclohexyl, etc.),

(C)

0

N

R

1 3 -M

S

wherein M is oxygen or sulfur,

R

13 is lower alkyl methyl, ethyl, propyl, isopropyl, etc.), phenyl (lower) alkyl (e.g.

benzyl, etc.), lower alkoxy (lower) alkyl (e.g.

2 -methoxyethyl, etc.), halo (lower) alkyl (e.g.

46 2-chioroethyl, etc.), amino(lower)alkyl, 2aminoethyl, etc.) phthalimido(lower)alkoxycarbonylamino 2phthalimidoethyl, etc.), lower alkenyl (e.g.

allyl, etc.), phenyl phenyl, etc.), (d) 0

S

wherein

R

15 is hydrogen, or lower alkyl methyl, etc.), R4is hydrogen, lower alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.), naphthyl 1-naphthyl, etc.), halophenyl 3(or 4)-chlorophenyl etc.), lower alkoxyphenyl 4 -methoxyphenyl, etc.), lower alkenyl allyl, etc.), cyclo(lower)alky± (lower)alkyl (e.g.

cyclohexylmethyl, etc.), phenyl(lower) alkyl (e.g.

benzyl, etc.), halo(lower)alkyl. 2-chioroethyl, lower alkoxy(lower)alkyl methoxymethyl, 2-methoxyethyl, etc.), hydroxy(lower)alkyl 2hydroxyethyl, etc.), (lower alkyl) (diphenyl)silyloxy(lower)alkyl 2- butyl) (diphenyl)silyloxy)ethyl, etc.), carboxy(lower)alkyl carboxymethyl, etc.), lower alkoxycarbonyl(lower)alkyl ethoxycarbonylmethyl, etc.), lower alkylcarbamoyl (lower)alkyl (e.g.

metylcrbaoylethletc.), or pyridyl 3- A pyridyl, etc.), WO 00/40576 PC'r/JPOO/ooi 8 47 R 1 6

S

wherein

R

1 6 is benzothienyl 2 -benzothienyl, etc.), benzofuranyl 2 -benzofuranyl, etc.), thienyl 2(or 3)-thienyl, etc.), furyl 2-furyl, etc.), pyridyl 3-pyridyl, etc.), lower alkylpyriclyl l-methyl-4-pyridyl, 6-methyl--3pyridyl, etc.), lower alkoxypyridyl 6methoxy-3-pyridyl, etc.), lower alkoxycarbonylaminopyridyl methoxycarbonylamino-3pyridyl, etc.), lower alkanoylthienyl 5-acetyl-2-thienyl, etc.), lower alkylcarbamoylbenzofuranyl 2etc.).

(vi) The compounds of the above wherein a group of the formula:R

S

is the same group as and of claim 7, and the following formula (b) 0

R

1 2

S

wherein R2is lower alkyl, phenyl(lower)alkyl, halophenyl (lower) alkyl, lower alkoxyphenyl (lower) alkyl, lower alkoxy (lower) alkyl, phenoxy (lower) alkyl, lower alkoxyphenoxy (lower) alkyl, halophenoxy (lower) alkyl, 48 lower alkylphenoxy (lower) alkyl, carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, lower alkylcarbamoyl (lower)alkyl, halo(lower)alkyl, lower alkenyloxy(lower)alkyl, lower alkoxy(lower)alkoxy(lower)alkyl, phenyl (lower) alkoxy(lower) alkyl, piperidinyloxy (lower) alkyl, N-t-butoxycarbonylpiperidinyloxy (lower) alkyl, pyridyloxy(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyloxy(lower)alkyl, mono- or li (lower) alkylcarbamoyloxy (lower) alkyl, piperidinylcarbonyloxy (lower) alkyl, phenyl (lower) alkylcarbamoyloxy(lower) alkyl, amino (lower) alkyl, fluorenylmethoxycarbonylamino (lower)alkyl, mono- or di (lower) alkylamino(lower) alkyl, N-lower alkyl-N- (lower alkoxycarbonyl)amino(lower)alkyl, N-lower aJlkyl-N- (ffluorenylmethoxycarbonyl) amino (lower) alkyl, N-lower alkyl-N-(mono- or di(lower)alkylcarbamoyl)amino(lower)alkyl, N- (mono- or di (lower alkyl)carbamoyl)amino(lower)alkyl, b e z y a i o l w r a k l l owe benoylamino (lower) alkyl, lower alkanosoylamino (lower) alkyl, lower alkanesulfwe~akanylmin~lweraly (lwe~akloycrower) ino, ower~akl ahlxy aoycronylamino((orlkwr~lklloe yco oer alkyoxyarb onylamino (lower) alkyl, pydridylarnylamino (low) alkyl, mophlin(lower)alkyarboylaioli(lower)alkyl we akoxoypheinylloyno(lower) alkyl, oxopetyrrlidnl n(lower) lkyl, WO 00/40576 PCT/JpoO/OO0i S 49 pyridyl (lower) alkyl, lower alkenylamino (lower) alkyl, lower alkoxy (lower) alkylamino (lower) alkyl, phenyl (lower) alkylarnino (lower) alkyl, pyriciyl (lower) alkylamino(lower)alkyl, cycl (lower) oalkyl, (amino) (phenyl) (lower) alkyl (e.g.

2 -phenyl-l-aminoethyl, etc.), (lower al koxycarbonyl amino) (phenyl) (lower) al kyl 1amino- 1-phenylmethyl, 1l-t -butoxyca rbonyl amino-1 phenylmethyl, 1l-amino- 2-phenylethyl, 1-tbut oxyca rbonylamino-2..phen ylethyl, etc.) (amino) (lower alkoxy) (lower)alkyl 1-amino-2methoxyethyl, etc.), (lower alkoxycarbonylamino)- (lower alkoxy) (lower)alkyl 1-tbut oxyca rbonyl amino- 2-met hoxyethyl, etc.) (amino) (carboxy) (lower)alkyl, (lower al1koxyca rbonyl amino) (carboxy) (lower) alkyl, (amino) (lower alkoxycarbonyl) (lower) alkyl, (lower alkoxycarbonylamino) (lower alkoxycarbonyl) (lower)aJlkyl l-amino-3-carboxypropyl, 1-tbut oxyca rbonyl amino- 3-ca rboxypropyl, 1-amino-3- (tbutoxycarbonyl) propyl, l-t-butoxycarbonylamino-3-tbutoxycarbonylpropyl, etc.) (amino) (phenyl (lower) al koxy) (lower) alkyl, (lower alkoxycarbonylamino) (phenyl (lower) alkoxy) (lower)alkyl 1l-amino- 2-ben zyl oxyethyl, 1-tbutoxycarbonylamino-2..benzyloxyaminoethyl, etc.), (amino) (pyridyl) (lower)alkyl, (lower al1koxycarbonyl amino) (pyriclyl) (lower) al kyl 1amino-2- 3 -pyridyl) ethyl, l-t-butoxycarbonylamino- 2 (3-pyridyl) ethyl, 1l-amino- 2 -pyridyl) ethyl, 1t -but oxyca rbonyl amino- 2 (4 -pyridyl) ethyl, etc.), (amino) (hydroxy) (lower)alkyl, (lower alkoxycarbonylamino) (hydroxy) (lower) alkyl 1amino-2-hyciroxyethyl, l-t-butoxycarbonylamino-2hydroxyethyl, etc.), (amino) (amino) (lower) alkyl, WO 00/40576 PCT/JPOO/000i 8 (lower alkoxycarbonylamino) (amino) (lower)alkyl, (amino) (lower alkoxycarbonylamino) (lower)alkyl, (lower alIkoxyca rbonyl amino) (lower al koxycarbonyl amino) (lower)alkyl diaminopentyl, aminopentyl, 1, 5-bi s (t -butoxycarbonylamino) pent yl, (t-butoxycarbonylamino)pentyl, etc.), (amino) (lower cycloalkane) (lower)alkyl, (lower al1koxycarbonyl amino) (lower cycloalkane) (lower) al kyl l-amino-2-cyclohexylethyl, 1-tbutoxycarbonylamino-2-cyclohexylethyl, etc.).

(vii) The compounds of the above wherein a group of the formula:

RT

is the group of the following formula to (a) wherein R1is bromo, 2 -naphthyl, phenyl, 3(or 4 )-chlorophenyl, 2(or 3 or 4)-fluorophenyl, 3, 4 -dichloropheny, 3, S-difluorophenyl, 3 (or 4 )-methylphenyl, 4-ethylphenyl, 4 -isopropylphenyl, 4 -(t-butyl)phenyl, 3, 4 -dimethylphenyl, 4 -methoxyphenyl, 4-ethoxyphenyl, 4 -trifluoromethylphenyl, 4 -trifluoromethoxyphenyl, 4 -ethenylphenyl, 4 -methylcarbamoylphenyl, 4 -ethylcarbamoylphenyl, 4carbamoylphenyl, 4 -benzylcarbamoylphenyl, WO 00/40576 PCT/JPOOOO0i 8 51 4-acetyiphenyl, 4 -rethylthiophenyl, 4-ethyithiophenyl, 4 -methylsulfinylphenyl, 4 -methylsulfonylphenyl, phenyiphenyl, 4-phenyl-3fluorophenyl, 4- 4 -fluorophenyl)phenyl, 3(or 4)hydroxyphenyl, 3 (or 4) -hydroxymethylphenyl, 4- 2-dihyciroxyethyl) phenyl, 4- (phenoxycarbonyloxymethyl)phenyl, 3 (or 4)aminophenyl, 4 -carboxyphenyl, 3, 4 -methylendioxyphenyl, 4- (methanesulfonylamino) phenyl, 3- (2-butenoylamino) phenyl, 3- (cyclopropanecarbonylamino) phenyl, 3- (cyclobutanecarbonylamino) phenyl, 3- (cyclopentanecarbonylamino) phenyl, 4 -benzyloxyphenyl, 4- (methylcarbamoyl) ethenyl)phenyl, 4- (ethylcarbamoyl) ethenyl) phenyl, 4- (propylcarbamoyl) ethenyl) phenyl, 4- (isopropylcarbamoyl) ethenyl)phenyl, 4-2- (dimethylcarbamoyl)ethenyl)phenyl, 4- (phenylcarbamoyl) ethenyl) phenyl, 4- (methoxyphenylcarbamoyl) ethenyl) phenyl, 4- 4 -fluorophenylcarbamoyl) ethenyl)phenyl, 4- (methylaminocarbonyloxy) phenyl, 4- (ethylaminocarbonyloxy)phenyl, 4 -propanoyloxyphenyl, 4- (methoxyacetyloxy) phenyl, 4- (ethoxycarbonyloxy) phenyl, 4- (3-pyridyl) acryloyloxy) phenyl, 4- (cyclopropylcarbonyloxy) phenyl, 4- (carboxymethoxy) phenyl, 4- (ethoxycarbonylmethoxy) phenyl, 4- (t-butoxycarbonylmethoxy) phenyl, 4- (propanoylmethoxy) phenyl, 4- (cyclopropylcarbamoylnethoxy) phenyl, 3 (or 4) -(methylcarbamoylmethoxy) phenyl, 4- (ethylcarbamoylnethoxy) phenyl, 4-('propylcarbarnoylmethoxy) phenyl, 3 (or (.methylcarbamoyloxymethyl) phenyl, 4- (rethoxycarbonylaminomethyl) phenyl, 4- (t-butoxycarbonylaminomethyl)phenyl, 4 -amiriomethylphenyl, 4- (methylcarbamoylmethyl) phenyl, 3 -(2(or 3 )-furylcarbonylamino) phenyl, 3-(1,2,3,4tetrahydroisoquinoylcarbflylajf 0 phenyl, 3-(N-(t-butoxycarbonyl)123, 4 tetrahydroisoquinolylcarbonylamjf 0 phenyl, 3- (pyrrolidin-ylcarbonylamino) phenyl, 4- 3 -oxazolyl)phenyl, 4 -(5-methyl-1,2,4-oxadiazo13-y)phenyl, (b) 0

S

wherein R is methyl, ethyl, propyl, isopropyl, butyl, *isobutyl, t-butyl, neopentyl, phenylie thyl, 4 -chlorophenylmethyl, 4 -methoxyphenylmethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, isopropyloxymethyl, 1-methoxyethyl, 2 -methoxyethyl, phenoxyrnethyl, 2 -phenoxyethyl, 3 (or 4) -methoxyphenoxymethyl, 4-fluoro (or chlouro)phen'oxymetnyl, 3(or 4)-mbthylj..)enoxymethyl, 2-abxehl 2 -methoxycarbonylethyl,2t 2 -methylcarbamoylethyl, 2 -chloroethyl, chloroinethyl, allyloxymethyl, '-ALq 2 -ethoxyethoxy)methyl, benzyloxymethyl, rz-F 5 LU 4 -piperidinyloxymethyl, (N-t-butoxycarbonyl-4.

piperidinyl) oxymethyl, 3 (or 4) -pyridyloxymethyl, hydroxymethyl, 2-hyciroxyethyl, acetoxymethyl, l-acetoxyethyl, methylcarbamoyloxymethyl, 1- (Nmethyl-N-ethylcarbanoyloxy) methyl, (piperidinocarbonyloxy)methyl, (benzylcarbamoyloxy)methyl, (t-butoxycarbonylamino)methyl, aminomethyl, 1-aminoethyl, 1- (t-butoxycarbonylamino) ethyl, 2-aminoethyl, methoxycarbonylaminomethyl, 2- (methoxycarbonylamino) ethy'l, ethoxycarbonylaminomethyl, propoxycarbonylaninomethyl,, 1- (fluorenylmethoxycarbonylamino)methyl, 2- (t-butoxycarbonylamino) ethyl, 2- (fluorenylmethoxycarbonylamino) ethyl, 1-aminoisopropyl, 1-aminopropyl, 1- (t-butoxycarbonylamino) propyl, 1- (t-butoxycarbonylamino) isopropyl, 1, 5-ciarinopentyl, 1, 5-bis (t-butoxycarbonylamino) pentyl, methylarninomethyl, ethylaminomethyl, 2- (N-methyl-N-ethylamino) ethyl, dimethylaminomethyl, pentylaminomethyl, t-butylaminomethyl, 2-methylaminoethyl, .(N-methyl--N-methoxycarbonylamino)methyl, *t h l N t b u o y a b o y a i o e h l 1-(N-ethyl-N-t-butoxycarbonylamino) methyl, 2- (N-methyl-N- (fluorenylmethoxycarbonyl) amino) ethyl, 2- (N-methyl-N- (t-butoxycarbonyl) amino) ethyl,.

1- (N-methyl-N- (dimethylcarbam oyl) amino) methyl, 1- (cimethylcarbamoylamino) methyl, l-(N-(ethylcarbamoyl)amino)methyl, 2- (ethylcarbamoyl) amino) ethyl, benzoylaminomethyl, 2-benzoylaminoethyl, acetylaminomethyl, isobutyrylaminomethyl, pivaloylaminomethyl,, A t/,41- (methanesulfonylamino)methyl, WO 00/40576 WO 0040576PCT/JPOO/0001 8 54 2- Cmethanesulfonylarnino)ethyl, methoxyacetylaminomethyl, cyclopentyloxycarboiylaminomethyl, pyridylcarbonylaminomethyl, morpholinocarbonylaninomethyl, benzyloxycarbonylaminomethyl, 1- (4-methoxyphenylsulfonylamino)methyl, 1- (2-hydroxyethylamino)methyl, rnorpholinomethyl, 1-(2-oxo-1, 3-oxazolidin-1yl)methyl, l-(2-oxopyrrolidin-1-yljmethyl, 1- 3 4 ,4-trimethylhydantoin-1-yl)methyl, allylaminomethyl, l-(2-ethoxyethylamino)methyl, benzylaminomethyl, 1- (3-pyridylmethylamino)methyl, 2-phenyl-l-aminoethyl, 1-amino-1-phenylmethyl, l-t-butoxycarbonylamino-l-phenylmethyl, 1-amino-2-phenylethyl, 1-t-butoxycarbonylamino-2phenylethyl, 1-amino-2-methoxyethyl, 1-t-butoxycarbonylamino-2-nethoxyethyl, 1-amino-3carboxypropyl, 1-t-butoxycarbonylamino-3carboxypropyl, 1-amino-3- (t-butoxycarbonyl)propyl, l-t-butoxycarbonylamino-3-t-butoxycarbonylpropyl, etc.), l-amino--2-benzyloxyethyl, l-t-butoxycarbonylanino-2-benzyloxyaminoethyl, 1-amino-2- (3-pyridyl)ethyl, 1-tbutoxycarbonylamino-2- (3-pyridyl)ethyl, 1-amino-2- (4-pyridyl)ethyl, 1-t-butoxycarbonylamino-2- (4pyridyl) ethyl, l-amino-2-hydroxyethyl, l-t-butoxycarbonylamino-2-hyiroxyethyl, 5-diaminopentyl, aminopentyl, 1, S-bis(t-butoxycarbonylamino)pentyl, (t-butoxycarbonylamino)pentyl, 1-amino-2cyclohexylethyl, l-t-butoxycarbonylamino-2cyclohexylethyl, (c) WO 00/40576 PCT/JPOO/0001 8 0

R

1 3 -11-t-H

/IN

wherein M=0 and R 13 is methyl, ethyl, propyl, isopropyl, benzyl, 2-methoxyethyl, 2 -choloroethyl, 2-aminoethyl, 2phthalimidoethyl, allyl, phenyl, or M=S and R 13 is methyl, ethyl, (d) 0 155 wherein hydrogen and R14 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, 1-naphthyl, 3(or 4) -chlorophenyl, 3 -methoxyphenyl, allyl, cyclohexylmethyl, benzyl, 2-chloroethyl, methoxymethyl, 2 -methoxyethyl, 2-hydroxyethyl, 2- (t-butyl) (diphenyl) silyloxy) ethyl, carboxymethyl, ethoxycarbonylmethyl, met hyl ca rbamoylmethyl, or 3-pyridyl,

R

1 4 is ethyl and R5is methyl, (e) wherein

R

1 6 is 2-benzothienyl, 2 -benzofuranyl, 2(or 3)-thienyl, WO 00/40576 PCT/JPOO/00018 56 2-furyl, 3-pyridyl, l-methyl-4-pyridyl, 6-methyl-3pyridyl, 6-methoxy-3-pyridyl, 5-methoxycarbonylamino-3-pyridyl, 5-acetyl-2-thienyl, 2 The processes for preparing the object compounds are explained in detail in the following.

Process 1 The object compound or a salt thereof can be prepared by subjecting a compound or a salt thereof to removal reaction of the carboxy-protective group.

Suitable salts of the compounds and can be referred to the ones as exemplified for the compound This reaction is carried out in accordance with a conventional method such as solvolysis including hydrolysis, reduction or the like.

The solvolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable base may include an inorganic base and an organic base such as an alkali metal sodium, lithium, potassium, etc.], an alkaline earth metal magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, hydrazine, trialkylamine trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]- 1, 4 -diazabicyclo[2.2.2]octane, 1, 8 -diazabicyclo[5.4.0]undec-7-ene, or the like.

Suitable acid may include and organic acid formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e.g.

hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, boron trifluoride diethyl etherate, hydrogen iodide, etc.].

The removal reaction using Lewis acid such as trihaloacetic acid trichloroacetic acid, WO 00/40576 PCT/JP00/00018 57 trifluoroacetic acid, etc.] or the like, is preferably carried out in the presence of cation trapping agents [e.g.

anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, an alcohol methanol, ethanol, etc.], methylene chloride, chloroform, carbon tetrachloride, dioxane, tetrahydrofuran, N,N-dimethylformamide, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

The reduction method applicable for the removal reaction may include chemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction may include a combination of metal tin, zinc, iron, etc.] or metallic compound chromium chloride, chromium acetate, etc.] and an organic or inorganic acid formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g.

platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalysts reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts reduced cobalt, Raney cobalt, etc.], iron catalysts reduced iron, Raney iron, etc.], copper catalysts reduced copper, Raney copper, Ullman copper, etc.] and the like, and these catalysts may be used in a combination with ammonium formate a WO 00/40576 PCT/JPOO/00018 58 combination of palladium on carbon and ammonium formate, etc.).

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the abovementioned acid to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.

Process 2 The compound or a salt thereof can be prepared by oxidating the compound (II) or a salt thereof.

Suitable salts of the compound (II) may be the same as those for the compound Oxidation is carried out in a conventional manner, which is capable of oxidating a vinyl group to a carboxy group, and suitable oxidizing reagent may be oxygen acid such as periodate sodium periodate, potassium periodate, etc.), peroxy acid such as perbenzoic acid perbenzoic acid, m-chloroperbenzoic acid, etc.), OXONE (2KHSO 5

-KHSO

4

-K

2 S0 4 potassium permanganate, a combination of titanium (III) chloride and hydrogen peroxide, a combination thereof a combination of potassium permanganate and sodium periodate, etc.), and the like.

This reaction can be carried out in the presence of a suitable base as mentioned above potassium carbonate, etc.).

The reaction is usually carried out in a conventional WO 00/40576 PCT/JP00/00018 59 solvent such as water, alcohol methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction.

Among these solvents, hydrophilic solvents may be used in a mixture with water.

The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

Process 3 The compound or a salt thereof can be prepared by subjecting the compound or a salt thereof to a reduction reaction.

Suitable salts of the compounds and may be the same as those for the compound The reduction method applicable for this reaction may be the same as Process 1, which is capable of converting haloaryl group to aryl group a combination of palladium on carbon and ammonium formate, etc.).

Process 4 The compound or a salt thereof can be prepared by reacting the compound or its reactive derivative at the carboxy group, or a salt thereof with compound (IV) or its reactive derivative at the amino group, or a salt thereof.

Suitable reactive derivative at the amino group of the compound (IV) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (IV) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (IV) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (IV) with phosphorus trichloride or phosgene, and the like.

Suitable salts of the compound (IV) and its reactive derivative can be referred to the acid addition salts as exemplified for the compound Suitable salts of the compound may be the same as those for the compound Suitable reactive derivative at the carboxy group of the compound may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride which an acid such as substituted phosphoric acid [e.g.

dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid methanesulfonic acid, etc.], aliphatic carboxylic acid acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or o. .aromatic carboxylic acid benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with S 25 imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.

cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl

[(CH

3 2 N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2 4 -dinitrophenyl ester, 30 trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, Sp-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8 -quinolyl thioester, etc.], or an ester with a N-hydroxy SMYcompound N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)- WO 00/40576 PCT/JP00/00018 61 pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound to be used.

The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;.

l-ethyl- 3 -(3-dimethylaminopropyl)carbodiimide

(WSCD);

N,N'-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7hydroxybenzisoxazolium salt; isoxazolium hydroxide intramolecular salt; N-hydroxybenzotriazole; 1-(p-chlorobenzenesulfonyloxy)-6chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, WO 00/40576 PCT/JP00/00018 62 phosphorus oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic or organic base as mentioned above such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, alkali metal hydroxide, or the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

Process The object compound or a salt thereof can be prepared by cyclizing the compound (III) or a salt thereof.

Suitable salts of the compounds and (III) may be the same as those for the compound This reaction is preferably carried out in the presence of hydrogen halide hydrogen iodide, etc.) or alkali metal halide sodium iodide, etc.).

This reaction can be carried out in the presence of a suitable base as mentioned above such as alkali metal hydroxide.

The reaction can be carried out in a conventional solvent, which does not adversely influence the reaction as mentioned above such as water, tetrahydrofuran, alcohol (e.g.

methanol, ethanol, etc.), a mixture thereof, and the like.

The reaction temperature is not critical and the reaction can be carried out under from warming to heating.

Process 6 The compound or a salt thereof can be prepared by reacting the compound or its reactive derivative at the carboxy group, or a salt thereof, with an optically active amine or its reactive derivative at the amino group, or a salt thereof.

Suitable "optically active amine" may include a conventional one which is capable of separating the starting 63 racemic compound into each optically active compound such as (R)-(+)-a-methylbenzylamine, and the like.

Suitable salts of the compound may be the same as those exemplified for the compound Suitable salts of the optically active amine may be acid addition salts as mentioned for the compound The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.

This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal lithium, sodium, potassium, etc.), alkaline earth metal calcium, etc.), alkali metal hydride sodium hydride, etc.), alkaline earth metal hydride calcium hydride, etc.), alkali metal hydroxide sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal 25 alkanoic acid sodium acetate, etc.), trialkylamine triethylamine, etc.), pyridine compound pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, and the like.

Suitable reactive derivative at the amino group of 30 optically active amine may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the said amine with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the said amine with a silyl compound such as S 35 is(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, WO 00/40576 PCT/JP0/00018 64 bis(trimethylsilyl)urea or the like; a derivative formed by the reaction of the said amine with phosphorus trichloride or phosgene, and the like.

Suitable reactive derivative at the carboxy group and salts of the compound may be the same as mentioned above.

The reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-( 4 -diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; l-ethyl-3-(3-dimethylaminopropyl)carbodiimide; N,N'-carbonylbis-( 2 -methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; l-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate ethyl chloroformate, isopropyl chloroformate); triphenylphosphine; 2 -ethyl- 7 -hydroxybenzisoxazolium salt; hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6chloro-lH-benzotriazole; l-hydroxybenzotriazole; or socalled Vilsmeier reagent prepared by the reaction of N,Ndimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

Process 7 The compound or a salt thereof can be prepared by subjecting the compound or a salt thereof to a removal reaction of the hydroxy protective group.

Suitable salts of the compounds and may be.

the same as those exemplified for the compound The reaction of this process can be carried out in a manner similar to that in Process 1.

Process 8 The compound and a salt thereof can be prepared by oxidating the compound or a salt thereof.

Suitable salts of the compounds and may be the same as those exemplified above with regard to the compound Suitable method of this oxidation includes conventional ones, which can convert thia group to sulfinyl or sulfonyl group, or sulfinyl to sulfonyl group, such as exemplified for Process 2.

Process 9 The compound or a salt thereof can be prepared by reacting the compound or a salt thereof with the compound Suitable salts of the compound may be the same as those exemplified for the compound 25 The reaction is usually carried out in a conventional s.olvent such as water, acetone, dioxane, acetonitrile, chloroform, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any 30 other organic solvents which do not adversely affect the reaction.

This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal f lithium, sodium, potassium, etc.), alkaline earth metal 3 calcium, etc.), alkali metal hydride sodium WO 00/40576 PCT/JP00/00018 66 hydride, etc.), alkaline earth metal hydride calcium hydride, etc.), alkali metal hydroxide sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid sodium acetate, etc.), trialkylamine triethylamine, etc.), pyridine compound pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, alkali metal halide sodium iodide, potassium iodide, etc.), alkali metal thiocyanate sodium thiocyanate, potassium thiocyanate, etc.), di(lower)alkyl azodicarboxylate diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.), and the like.

The reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N'-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; l-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate ethyl chloroformate, isopropyl chloroformate); triphenylphosphine; etrakis(triphenylphosphine)palladium(0); 2 -ethyl-7-hydroxybenzisoxazolium salt; WO 00/40576 PCT/JP00/00018 67 sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-IH-benzotriazole; 1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride.

The reaction temperature is not critical, and the reaction is usually carried out under from warming to heating.

Process The compound or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.

Suitable salts of the compound may be the same as those exemplified for the compound The reaction of this process can be carried out in a manner similar to that in Process 9.

Process 11 The compound or a salt thereof can be prepared by cyclizing the compound (VIII) or a salt thereof.

Suitable salts of the compounds and (VIII) may be the same as those exemplified for the compound This reaction can be carried out in the presence of a suitable acid as exemplified for Process 1, wherein preferable one may be trifluoroacetic acid, and the like.

The reaction can be carried out in a conventional solvent, which does not adversely influence the reaction as mentioned above such as water, tetrahydrofuran, alcohol (e.g.

methanol, ethanol, etc.), a mixture thereof, and the like.

The reaction temperature is not critical and the reaction can be carried out under cooling to warming.

Process 12 WO 00/40576 PCT/JP00/00018 68 The compound or a salt thereof can be prepared by reacting the compound (IX) or a salt thereof with the compound Suitable salts of the compounds and (IX) may be the same as those exemplified for the compound This reaction can be carried out in the presence of a suitable acid as exemplified for Process 1, wherein preferable one may be boron trifluoride diethyl etherate, and the like.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.

The reaction temperature is not critical and the reaction can be carried out under cooling to warming.

Process 13 The compound or a salt thereof can be prepared by amidating the compound or its reactive derivative at the carboxy group, or a salt thereof.

Suitable salts of the compounds and may be the same as those for the compound Suitable reactive derivative of the compound may be the same as those for the compound The amidation reaction applicable to this process may include a conventional amidation reaction which can convert a carboxy-group to an amido-group, for example, reaction with an optionally substituted amines such as mono- or di(lower)alkylamine methylamine, etc.), and the like.

And the reaction can be carried out in substantially the same manner as described in Process 4.

WO 00/40576 PCT/JP00/00018 69 Process 14 The compound or a salt thereof can be prepared by acylating the compound or its reactive derivative at the amino group, or a salt thereof.

Suitable salts of the compounds and may be the same as those for the compound Suitable acylating agent used in this reaction may be a conventional acylating agent which is capable of introducing the acyl group as mentioned before such as carboxylic acid, carbonic acid, sulfonic acid and their reactive derivative, for example, an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Preferable example of such reactive derivative may include acid chloride, acid bromide, a mixed acid anhydride with an acid such as substituted phosphoric acid dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonate methyl carbonate, ethyl carbonate, propyl carbonate, etc.), aliphatic carboxylic acid pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid benzoic acid, etc.), a symmetrical acid anhydride, an activated acid amide with a heterocyclic compound containing imino function such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole and tetrazole, an activated ester p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyridyl ester, piperidinyl ester, 8-quinolyl thioester, or an ester with a N-hydroxy compound such as N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, WO 00/40576 PCT/JPOO/00018 N-hydroxyphthalimide, 1-hydroxybenzotriazole, l-hydroxy-6chlorobenzotriazole, etc.), isocyanic acid or a salt thereof sodium isocyanate, etc.), lower alkylisocyanate (e.g.

methylisocyanate, ethylisocyanate, etc.), and the like.

This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal lithium, sodium potassium, etc.), alkaline earth metal calcium, etc.), alkali metal hydride sodium hydride, etc.), alkaline earth metal hydride calcium hydride, etc.), alkali metal hydroxide sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid sodium acetate, etc.), trialkylamine triethylamine, etc.), pyridine compound pyridine, lutidine, picoline, 4 -dimethylaminopyridine, etc.), quinoline, and the like.

In case that the acylating agent is used in a free form or its salt in this reaction, the reaction is preferably carried out in the presence of a condensing agent such as a carbodiimide compound N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-( 4 -diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N'-diisoopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.], a ketenimine compound N,N'-carbonylbis(2methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ether compounds (e.g.

ethoxyacetylene, -chlorovinylethyl ether), a sulfonic acid ester of N-hydroxybenzotriazole derivative 1-(4chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole, etc.], WO 00/40576 PCT/JP00/00018 71 a combination of trialkylphosphite or triphenylphosphine and carbon tetrachloride, disulfide or diazenedicarboxylate (e.g.

diethyl diazenedicarboxylate, etc.), a phosphorus compound ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride, etc.), thionyl chloride, oxalyl chloride, N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate, a reagent (referred to a so-called "Vilsmeier reagent") formed by the reaction of an amide compound such as N,N-di(lower)alkylformamide dimethylformamide, etc.), N-methylformamide or the like with a halogen compound such as thionyl chloride, phosphoryl chloride, phosgene or the like, and the like.

The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol methanol, ethanol, etc.), tetrahydrofuran, pyridine, N,N-dimethylformamide, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.

Process The compound or a salt thereof can be prepared by subjecting the compound or a salt thereof to a removal reaction of the amino-protective group.

Suitable salts of the compound may be the same as those for the compound The reaction of this process can be carried out in a manner similar to that in Process 1.

Process 16 The compound or a salt thereof can be prepared by subjecting the compound or a salt thereof to a removal reaction of the hydroxy-protective group.

WO 00/40576 PCT/JP00/00018 72 Suitable salts of the compounds and may be the same as those for the compound (I) The reaction of this process can be carried out in a manner similar to that in Process 1.

Process 17 The compound,(I-x) or a salt thereof can be prepared by oxidating the compound or a salt thereof.

Suitable salts of the compounds and may be the same as those for the compound The reaction of this process can be carried out in a manner similar to that in Process 8.

Process 18 The compound or a salt thereof can be prepared by reducing the compound or a salt thereof.

Suitable salts of the compounds and may be the same as those for the compound The reaction of this process can be carried out in.a manner similar to that in Process 3.

Process 19 The compound (I-ab) or a salt thereof can be prepared by oxidating the compound (I-aa) or a salt thereof.

Suitable salts of the compounds (I-aa) and (I-ab) may be the same as those for the compound The reaction of this process can be carried out in a manner similar to that in Process 2.

Process The compound (I-ac) or a salt thereof can be prepared by acylating the compound or a salt thereof.

Suitable salts of the compound (I-ac) may be the same as those for the compound WO 00/40576 PCT/JP00/00018 73 The reaction of this process can be carried out in a manner similar to that in Process 14.

Process 21 The compound (I-ad) or a salt thereof can be prepared by reacting the compound (XI) or a salt thereof with the compound (XII) or a salt thereof.

Suitable salts of the compounds (XI) and (XII) may be the same as those for the compound The reaction of this process can be carried out in a manner similar to that in Process 9.

Process 22 The compound or a salt thereof can be prepared by subjecting the compound (I-ae) or a salt thereof to a removal reaction of the carboxy-protective group.

Suitable salts of the compound (I-ae) may be the same as those for the compound The reaction of this process can be carried out in. a manner similar to that in Process 1.

Process 23 The compound (I-ag) or a salt thereof can be prepared by reacting the compound (I-af) or a salt thereof with a substituted amine.

Suitable salts of the compounds (I-af) and (I-ag) may be the same as those for the compound The reaction of this process can be carried out in a manner similar to that in Process 4.

The compounds obtained above can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation and the like.

The object compounds can be transformed into their WO 00/40576 PCT/JP00/00018 74 salts in a conventional manner.

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

Collagenases initiate the degradation of collagen in vertebrates and, in addition to their normal function in the metabolism of connective tissue and wound healing, they have been implicated to be involved in a number of pathological conditions such as joint destruction in rheumatoid arthritis, periodontal disease, corneal ulceration, tumor metastasis, osteoarthritis, decubitus restenosis after percutaneous transluminal coronary angiopsty, osteoporosis, psoriasis, chronic active hepatitis, autoimmune keratitis, and the like, and therefore the compounds of the present invention are useful for treating and/or preventing such pathological conditions.

Inhibitory activity of MMP can be assayed by a conventional test method as mentioned below.

Test Methods: Test Method 1: Inhibitory activity of human MMP-1 Human collagenase was prepared from the culture medium of human skin fibroblast stimulated with interleukin-lp (1 ng/ml). Latent collagenase was activated by incubation with tryspin (200 pg/ml) at 37 0 C for 60 minutes and the reaction was stopped by adding soybean trypsin inhibitor (800 [tg/ml).

Collagenase activity was determined using FITC-labeled calf skin type I collagen. FITC-collagen (2.5 mg/ml) was incubated at 37C for 120 minutes with the activated collagenase and test compound in 50 mM Tris buffer (containing 5 mM CaC12, 200 mM NaCl and 0.02% NaN 3 pH After stopping the enzyme reaction by adding the equal WO 00/40576 PCT/JP00/00018 volume of 70% ethanol-200 mM Tris buffer (pH the reaction mixture was centrifuged, and collagenase activity was estimated by measuring the fluorescence intensity of supernatant at 495 nm (excitation) and 520 nm (emission).

Test Method 2: Inhibitory activity of human MMP-9 The inhibitory activity of test compounds against human MMP-9 were measured by using commercial kits (Yagai, Japan).

Gelatinolytic activity was determined by monitoring the degradation of FITC-labeled bovine type IV collagen after incubation for 4 hours at 42 0 C. The amount of degraded collagen was estimated by measuring the fluorescence intensity at 495 nm (excitation) and 520 nm (emission).

Test Method 3: Inhibitory activity of human MMP-13 The inhibitory potential of test compounds against human MMP-13 were assayed by using commercial kit (Chondrex, USA) contained truncated form of human recombinant MMP-13 and fluorogenic peptide substrate. Activity of human MMP-13 was determined by monitoring the degradation of fluorogenic peptide substrate after incubation for 1 hour at 35°C and estimated by measuring the fluorescence intensity of degraded peptide substrate at 495 nm (excitation) and 520 nm (emission).

Test Method 4: Inhibitory activity of human MMP-8 The inhibitory potential of test compounds against human MMP-8 were assayed by using commercial kit (Chondrex, USA) contained recombinant human pro-MMP-8 and FITC-labeled telopeptide-free soluble bovine type I collagen as a substrate. Recombinant human pro-MMP-8 was activated by a sequential incubation with mercury compound and proteinase WO 00/40576 PCT/JP00/00018 76 at 35 0 C for 1 hour. Reaction mixture containing the activated MMP-8, substrate and test compounds were incubated at 35°C for 2 hours. After stopping the enzyme reaction by adding the stop solution (o-phenathroline), the reaction mixture was centrifuged and MMP-8 activity was estimated by measuring the fluorescence intensity of supernatant at 490 nm (excitation) and 520 nm (emission) For therapeutic purposes, the compounds and pharmaceutically acceptable salts thereof of the present invention can be used in the form of a pharmaceutical preparation containing, as an active ingredient, one of said compounds in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, solutions, suspensions, emulsions, sublingual tablets, suppositories, ointments, and the like. If desired, there may be included, in these preparations, auxiliary substances, stabilizing agents, wetting agents, emulsifying agents, buffers and other commonly used additives.

While the dose of the compound will vary depending upon the age and condition of patient and the like, in the case of intravenous administration, a daily dose of 0.01 100 mg of the active ingredient per kg weight of a human being, and in the case of intramuscular administration, a daily dose of 0.05 100 mg of the same per kg weight of a human being, or in the case of oral administration, a daily dose of 0.1 100 mg of the same per kg weight of a human being, is generally given for the treatment of MMP or TNFa-mediated diseases.

In order to illustrate the usefulness of the object compound, the pharmacological test data of a representative compound of the compounds are shown in the following.

WO 00/40576 PCT/JP00/00018 Inhibitory activity of MMP 1. Test Method Inhibitory activity of human MMP-13 as mentioned above.

2. Test Compound Compound of Example 3. Test Resut Inhibitory activity Test Compound E p[IC50 (nM)] Example 15 2.2 The following Preparations and Examples are given for the purpose of illustrating the present invention in detail.

The abbreviations used in this description are, for examplee, as follows.

Aib: Abu: 4PyAla: aminoisobutyric acid aminobutyric acid 4-pyridylalanine WO 00/40576 PCT/JPO/00018 78 Preparation 1-1) N-Chlorosuccinimide (2.67 g) was added gradually over minutes to a stirred solution of tetrahydro-2H-thiopyran .(2.04 g) in benzene (20 ml). The temperature was maintained at 20-300C by intermittent external cooling. The mixture was stirred for 1 hour and rapidly filtered to remove succinimide. The filtrate was added to a solution of 4-anisylmagnesium bromide in diethyl ether which was prepared from 4-anisyl bromide (7.48 g) and magnesium turnings (0.875 g) in diethyl ether (36 ml) in a usual manner. The rate of addition was such that the temperature of the reaction was maintained between 10-15°C. The resultant mixture was stirred at room temperature for 17 hours and decomposed by the addition of ice and a aqueous solution of sulfuric acid. The organic layer was separated, washed twice with water, once with 1N sodium hydroxide solution, twice with water, then once with brine, and dried over magnesium sulfate. Removal of the solvent, followed by washing with methanol, gave 3,4,5,6-tetrahydro- 2 4 -methoxyphenyl)-2H-thiopyran (1.22 g) as a colorless powder.

mp: 82-85°C IR (KBr): 1610, 1514, 1252 cm-1 NMR (DMSO-d 6 1.35-1.65 (2H, 1.7-2.1 (4H, m), 2.56-2.64 (1H, 2.73-2.86 (1H, 3.72 (3H, s), 3.84 (1H, dd, J=11.0, 2.7Hz), 6.87 (2H, d, J=8.7Hz), 7.24 (2H, d, J=8.7Hz) Anal. Calcd. for C 12

H

16 0S: C 69.19, H 7.74 Found: C 69.59, H 7.68 Preparation 1-2) 1.OM Solution of boron tribromide in dichloromethane (8.27 ml) was added dropwise to a stirred solution of 3,4,5, 6 -tetrahydro-2-(4-methoxyphenyl)-2H-thiopyran (718 mg) in dichloromethane (10 ml) under ice cooling and the WO 00/40576 PCT/JP00/00018 79 resulting mixture was stirred for 3 hours while the temperature was allowed to rise to room temperature. The reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (eluent: toluene ethyl acetate) over silica gel (15.4 g) to afford 3 ,4,5,6-tetrahydro-2-(4hydroxyphenyl)-2H-thiopyran (600 mg) as a colorless powder.

mp: 138-140.5°C IR (KBr): 3421 1241 cm 1 NMR (DMSO-d 6 1.35-1.65 (2H, 1.7-2.05 (4H, m), 2.58 (1H, br d, J=13.3Hz), 2.71-2.85 (1H, 3.78 (1H, dd, J=10.8, 2.5Hz), 6.68 (2H, d, 7.11 (2H, d, J=8.5Hz), 9.32 (1H, s) Preparation 1-3) A mixture of 3,4,5,6-tetrahydro-2-(4-hydroxyphenyl)-2Hthiopyran (578 mg), 4-bromochlorobenzene (683 mg), 8-hydroxyquinoline (17.3 mg), potassium carbonate (247 mg), and copper chloride (11.8 mg) in 1,3-dimethyl-2imidazolidinone (1.73 g) was stirred at 150 0 C under a nitrogen atmosphere for 21 hours and cooled to room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide and brine, dried over magnesium sulfate, and evaporated in vacuo.

The residue was chromatographed (eluent: n-hexane-toluene) over silica gel to afford 2 4 4 -chlorophenoxy)phenyl]- 3 4 ,5, 6 -tetrahydro-2H-thiopyran (417 mg) as a colorless powder.

mp: 69.5-70.5 0

C

IR (KBr): 1274 cm- 1 NMR (CDC13, 1.45-1.77 (2H, 1.83-2.2 (4H, m), 2.66 (1H, 2.81-2.95 (1H, 3.84 (1H, dd, WO 00/40576 PCT/JPO/00018 J=11.6, 2.6Hz), 6.88-6.97 (4H, 7.23-7.36 (4H, m) Preparation 1-4) An aqueous solution (23 ml) of OXONE (2KHSO 5

-KHSO

4

-K

2

SO

4 1.82 g) was added dropwise to a suspension of chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran (600 mg) in methanol (23 ml) under ice cooling and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was mixed with an aqueous solution (10 ml) of sodium sulfite (746 mg) at room temperature, stirred at the same temperature for a while, and concentrated in vacuo.

The residue was partitioned between ethyl acetate and water.

The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was washed with n-hexane to afford 2 -[4-(4-chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran 1,1-dioxide (636 mg) as a colorless powder.

mp: 151.5-152°C IR (KBr): 1313, 1247, 1120 cm- 1 NMR (CDC13, 1.65 (1H, 2.04-2.26 (4H, 2.37- 2.56 (1H, 2.96-3.13 (1H, 3.24 (1H, m), 4.01 (1H, dd, J=12.8, 3.1Hz), 6.92-7.03 (4H, m), 7.28-7.42 (4H, m) APCI MS m/z: 336 Preparation Solution of lithium diisopropylamide mono tetrahydrofuran in cyclohexane (1.47 ml) was added dropwise to a stirred suspension of 2 4 -(4-chlorophenoxy)phenyl]- 3 4 5 ,6-tetrahydro-2H-thiopyran 1,1-dioxide (621 mg) in tetrahydrofuran (9 ml) under a nitrogen atmosphere and dry ice acetone cooling and the resultant suspension was stirred under the same conditions for 25 minutes. A solution of allyl bromide (491 mg) in tetrahydrofuran ml) was added dropwise therein and the resultant mixture was WO 00/40576 PCT/JP00/00018 81 stirred under the same conditions for 2 hours and 30 minutes.

After addition of a saturated aqueous solution of ammonium chloride under the same conditions, the reaction mixture was extracted with ethyl acetate. The extract was washed successively with IN hydrochloric acid, brine, and a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (eluent: toluene ethyl acetate) over silica gel to afford 2-allyl-2-[4-(4-chlorophenoxy)phenyl]- 3 ,4,5,6-tetrahydro-2H-thiopyran 1,1-dioxide (419 mg) as a colorless oil.

IR (Film): 1639, 1311, 1243, 1126 cm- 1 NMR (CDC13, 1.81-1.86 (2H, 2.09-2.21 (3H, m), 2.53-2.68 (1H, 2.86-3.09 (2H, 3.17-3.35 (2H, 5.02-5.09 (1H, 5.14-5.31 (2H, m), 6.94-7.05 (4H, 7.31 (2H, d, J=9.0Hz), 7.61 (2H, d, API-ES MS m/z: 399 and 401 (M++Na) Preparation 1-6) Solution of lithium diisopropylamide mono tetrahydrofuran in cyclohexane (0.34 ml) was added dropwise to a stirred solution of 2-allyl-2-[4-(4chlorophenoxy)phenyl]-3,4,5, 6 -tetrahydro-2H-thiopyran 1,1dioxide (162 mg) in tetrahydrofuran (2.5 ml) under a nitrogen atmosphere and dry ice acetone cooling and the resultant solution was stirred under the same conditions for minutes. A solution of methyl iodide (134 mg) in tetrahydrofuran (0.5 ml) was added dropwise therein and the resultant mixture was stirred under the same condition for 1 hour and 20 minutes. After addition of a saturated aqueous solution of ammonium chloride under the same conditions, the reaction mixture was extracted with ethyl acetate. The extract was washed successively with IN hydrochloric acid and brine, dried over sodium sulfate, and evaporated in WO 00/40576 PCT/JP/nn/nnn 82 vacuo. The residue was chromatographed (eluent: toluene ethyl acetate) over silica gel (8.1 g) to afford 2 -allyl-2- [4-(4-chlorophenoxy)phenyl]-3,4,5, 6-tetrahydro-6-methyl-2Hthiopyran 1,1-dioxide (78 mg) as a paste.

IR (KBr): 1639, 1284, 1244, 1126 cm- 1 NMR (CDC13, 1.38 (3H, d, J=6.7Hz), 1.82-2.25 2.61 (1H, 2.99 (1H, dd,=14.3, 7.7Hz), 3.32-3.39 (2H, 5.02-5.08 (1H, 5.16-5.29 (2H, 6.95-7.03 (4H, 7.28-7.33 (2H, m), 7.57-7.64 (2H, m) APCI MS m/z: 391 and 393 Preparation 2 2-[4-(4-Chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2Hthiopyran (148 mg) was prepared from 3 ,4,5,6-tetrahydro-2- 4 -hydroxyphenyl)-2H-thiopyran (292 mg) and 4chloroiodobenzene (430 mg) in a similar manner to that of Preparation 1-3).

mp: 69.5-70.5°C Preparation 3 2-[4-(4-Chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2Hthiopyran (97 mg) was prepared from tetrahydro-2H-thiopyran (510 mg) and 4 -bromo-4'-chlorodiphenyl ether (2.12 g) in a similar manner to that of Preparation 1-1).

mp: 69.5-70.5 0

C

Preparation 4-1) chloride (17.1 g) was added dropwise to a stirred suspension of aluminum chloride (14.7 g) in dichloromethane (125 ml) under a nitrogen atmosphere and ice cooling over 5 minutes and the resulting solution was stirred under the same conditions for 10 minutes, then therein a solution of 4 -chlorodiphenyl ether (20.5 g) in dichloromethane (115 ml) was added dropwise over 20 minutes.

WO 00/40576 PCT/JP00/00018 83 The resulting mixture was stirred under the same conditions for 1 hour and 15 minutes, and poured into a mixture of 7% hydrochloric acid and ice. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The oily residue was powdered from n-hexane to afford 4-(5-chlorovaleryl)-4'-chlorodiphenyl ether (30.9 g) as a colorless powder.

mp: 59.5-60.5°C IR (KBr): 1672, 1250 cm- 1 NMR (CDC1 3 1.85-1.91 (4H, 2.94-3.02 (2H, m), 3.55-3.62 (2H, 6.96-7.05 (4H, 7.36 (2H, d, 7.95 (2H, d, J=8.9Hz) API-ES MS m/z: 345, 347 and 349 (M++Na) Preparation 4-2) A solution of sodium borohydride (2.16 g) in water (59 ml) was added dropwise to a stirred suspension of chlorovaleryl)-4'-chlorodiphenyl ether (30.8 g) and sodium bicarbonate (9.61 g) in ethanol (480 ml) under a nitrogen atmosphere at room temperature over 10 minutes and the resulting mixture was stirred under the same conditions for 3 hours. After removal of ethanol, the reaction mixture was acidified with 3N hydrochloric acid (70 ml) and extracted with toluene. The extract was washed successively with water, a saturated aqueous solution of sodium bicarbonate, and brine, dried over sodium sulfate, and evaporated in vacuo to afford 4 -(5-chloro-l-hydroxypentyl)-4'chlorodiphenyl ether (31.1 g) as a yellow oil.

IR (Film): 3383 1242 cm- 1 NMR (CDC13, 1.43-1.89 (7H, 3.53 (2H, t, J=6.6Hz), 4.67 (1H, 6.89-7.01 (4H, 7.24- 7.34 (4H, m) API-ES MS m/z: 347, 349 and 351 311 and 313 (M+-HCl+Na) WO 00/40576 PCT/JPO/00018 84 Preparation 4-3) Thionyl chloride (31.2 g) was added dropwise to a stirred solution of 4 -(5-chloro-l-hydroxypentyl)-4'chlorodiphenyl ether (31.0 g) in chloroform (383 ml) under ice cooling and the resulting solution was stirred under reflux for 4 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was partitioned between toluene and water. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (twice) and brine, dried over sodium sulfate, and evaporated in vacuo to afford 4-chloro-4'-(1,5dichloropentyl)diphenyl ether (33.7 g) as a pale brown oil.

IR (Film): 1242 cm-1 NMR (CDC1 3 1.47-1.85 (4H, 2.02-2.19 (2H, m), 3.53 (2H, t, J=6.5Hz), 4.85 (1H, dd, J=7.9, 6.6Hz), 6.91-7.00 (4H, 7.27-7.38 (4H, m) Preparation 4-4) Sodium sulfide nonahydrate (21.8 g) was added gradually to a stirred solution of 4-chloro-4'-(1,5-dichloropentyl)diphenyl ether (24.0 g) in N,N-dimethylformamide (DMF, 240 ml) under ice cooling and a nitrogen atmosphere, and the resulting mixture was stirred under the same conditions for 2 hours and at room temperature for 3 days, then the reaction mixture was filtered. The filtrate was concentrated in vacuo and partitioned between water and toluene. The organic layer was separated, washed twice with brine, dried over magnesium sulfate, and evaporated in vacuo.

The residue was chromatographed (eluent: n-hexane toluene) over silica gel to afford chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2Hthiopyran (13.8 g) as a colorless powder.

mp: 69.5-70.5°C Preparation 5-1) WO 00/40576 PCT/.TJP/fnnnl n 5-(4-Chlorophenyl)-2-(5-chlorovaleryl)thiophene (3.75 g) was obtained in a similar manner to that of Preparation 4-1).

NMR (CDC1 3 1.86-1.95 (4H, 2.95 (2H, dd, J=6.9, 6.9Hz), 3.59 (2H, dd, J=6.9, 6.9Hz), 7.30 (1H, d, J=3.9Hz), 7.39 (2H, d, J=8.4Hz), 7.58 (2H, d, J=8.4Hz), 7.67 (1H, d, J=3.9Hz) Preparation 5-2) Ethyl 7-chloro-3-[5-( 4 -chlorophenyl)-2-thienyl]hept-2enoate (4.2 g) was obtained in a similar manner to that of Preparation 8-2).

NMR (CDC13, 1.21-1.34 (3H, 1.61-1.93 (4H, m), 2.53-2.57 (1H, 3.06-3.11 (1H, 3.52-3.60 (2H, 4.12-4.23 (2H, 5.88 (0.5H, 6.23 7.21-7.34 (4H, 7.51-7.53 (2H, m) Preparation 6-1) Potassium tert-butoxide (1.34 g) was gradually added to a stirred solution of 4 diphenyl ether (3.44 g) and thiobenzoic acid (1.66 g) in N,N-dimethylformamide (48 ml) under ice cooling and a nitrogen atmosphere over 5 minutes, and the resulting mixture was stirred at the same temperature for 2 hours and at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo.

The oily residue (4.63 g) was chromatographed (eluent: nhexane toluene) over silica gel to afford 4-(1benzoylthio-5-chloropentyl)-4'-chlorodiphenyl ether (1.16 g) as a pink oil.

IR (Film): 1660, 1242 cm- 1 NMR (CDC13, 1.36-1.65 (2H, 1.75-1.90 (2H, WO 00/40576 PCT/JPO/00018 86 1.99-2.12 (2H, 3.52 (2H, t, J=6.6Hz), 4.77 (1H, t, J=7.8Hz), 6.90-6.98 (4H, 7.25-7.57 (7H, 7.90-7.96 (2H, m) API-ES MS m/z: 467, 469 and 471 (M++Na) Preparation 6-2) 28% Solution of sodium methoxide in methanol (96.5 mg) was added dropwise to a stirred solution of 4-(1benzoylthio-5-chloropentyl)-4'-chlorodiphenyl ether (223 mg) in methanol (1.1 ml) and acetonitrile (1.1 ml) under ice cooling and the resulting mixture was stirred at the same temperature for 2 hours, then additional 28% solution of sodium methoxide in methanol (96.5 mg), methanol (1.0 ml) and sodium iodide (7.5 mg) were added therein and the mixture was stirred at room temperature for 15 hours. The reaction mixture was acidified with 3N hydrochloric acid ml) under ice cooling. The acidic mixture was extracted with toluene. The extract was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue (197 mg) was chromatographed (eluent: n-hexane toluene) over silica gel (3.9 g) to afford 2-[4- 4 -chlorophenoxy)phenyl]-3,4,5, 6 -tetrahydro-2H-thiopyran (114 mg) as a colorless powder.

mp: 69.5-70.5°C Preparation 7-1) 4-( 4 -Chlorobutyryl)-4'-chlorodiphenyl ether (6.12 g) was prepared from 4-chlorobutyryl chloride (3.10 g) and 4-chlorodiphenyl ether (4.09 g) in a similar manner to that of Preparation 4-1).

IR (Film): 1680, 1250 cm 1 NMR (CDC13, 2.22 (2H, 3.14 (2H, t, 3.68 (2H, t, J=6.2Hz), 6.96-7.05 (4H, 7.31- 7.40 (2H, 7.93-8.01 (2H, m) WO 00/40576 PCT/JPeOnO/01 87 Preparation 7-2) 4 -(4-Chloro-1-hydroxybutyl)-4'-chiorodiphenyl ether 14 g) was prepared in a similar manner to that of Preparation 4-2).

NMR (CDCl 3 6) 1. 76-2. 01 (4H, m) 3. 51-3. 64 (2H, in), 4 .70 (1H, mn), 6. 90-7 .00 (4H, mn), 7 .24-7. 34 m) ()API-ES MS m/z: 333, 335 and 337 (M++Na) Preparation 7-3) 4 -Chloro- 4 '-(1,4-dichlorobutyl)diphenyl ether (5.75 g) was prepared in a similar manner to that of Preparation 4-3) IR (Film): 1244 cm- 1 NMR (CDCl 3 6) 1. 72-2. 30 m) 3. 57 (21H, t, J=6.4Hz), 4.88 (1H, t, J=7.2Hz), 6.89-7.00 (4H, mn), 7.24-7.39 (4H, mn) ()API-ES MS m/z: 293 and 295 (M+-Cl) Preparation 7-4) 2- 4 -Chlorophenoxy) phenyl] -2,3,4,5tetrahydrothiophene (3.63 g) was prepared in a similar manner to that of Preparation 4-4).

IR (Film) 1238 cmf 1 NMR (CDCl 3 6) 1.87-2.02 (2H, mn), 2.23-2.44 (2H, in), 2.99-3.17 (2H, in), 4.50 (1H, dd, J=8.4, 6.88-6.97 (4H, in), 7.23-7.31 mn), 7.38 (2H, d, Preparation 2 4 (4-Chlorophenoxy) phenyl 3,4, tetrahycirothiophene 1, 1-dioxide 05 g) was prepared in a similar manner to that of Preparation 1-4).

inp: 74.5-78.5'C IR (Film) 1315, 1234, 1169, 1126 cm- 1 NMR (CDCl 3 6) 2. 18-2. 55 mn), 3.12-3.36 (2H, in), 4.14 dd, J=11. 7, 7. 3Hz) 6.92-7. 05 in), WO 00/40576 PCT/JP00/00018 88 7.28-7.39 (4H, m) APCI MS m/z: 323 and 325 Preparation 8-1) To a suspension of aluminum chloride (3.58 g) in methylene chloride (20 ml) was added a solution of chloride (4.17 g) in methylene chloride ml) dropwise at 0°C. After being stirred for 30 minutes at the same temperature, a solution of 4-chlorodiphenyl ether (6 g) in methylene chloride (5 ml) was added therein and the mixture was stirred under ice-bath cooling for 2 hours.

After 4N hydrochloric acid was added carefully to decompose excess aluminum chloride, the organic layer was separated and the aqueous layer was extracted with chloroform (20 ml x The combined organic layer was washed with water and brine, and concentrated under reduced pressure. The resulting residue was washed with hexane to give chlorovaleryl)-4'-chlorodiphenyl ether (6.89 g) as a slightly yellow solid.

NMR (DMSO-d 6 1.84-1.95 (4H, 2.99 (2H, t, J=7Hz), 3.42 (2H, t, J=7Hz), 6.99 (2H, d, J=9Hz), 7.00 (2H, d, J=9Hz), 7.37 (2H, d, J=9Hz), 7.96 (2H, d, J=9Hz) Preparation 8-2) To a suspension of sodium hydride (60% oil dispersion, 3.14 g) in tetrahydrofuran (160 ml) was added a solution of triethyl phosphonoacetate (5.23 ml) in tetrahydrofuran ml) at 0°C. After being stirred 30 minutes at the same temperature, a solution of 4 -(5-chlorovaleryl)-4'chlorodiphenyl ether (48 g) in tetrahydrofuran (60 ml) was added therein, and the reaction mixture was refluxed overnight. The mixture was cooled to room temperature, poured into water, and concentrated under reduced pressure.

The residue was extracted with ethyl acetate (200 ml x 3).

WO 00/40576 PCT/JPOO/00018 89 The combined extract was washed with brine, dried over magnesium sulfate and concentrated to give ethyl 7-chloro-3- 4 4 -chlorophenoxy)phenyllhept-2-enoate (E:Z 1:1 mixture) (67.4 g) as a yellow oil.

NMR (CDCl 3 8) 1. 14 (1-5H, t, J=7Hz) 1. 26 5H, t, J=7Hz) 1.29-1.40 (2H, in), 1.50-1.67 (2H, in), 1.74-1.89 (2H, mn), 2.45 (1.5H, t, J=7Hz), 3.09 t, J=7Hz), 3.51 (1H, t, J=7Hz), 3.53 (1H, t, J=7Hz), 4.03 (1H, q, J=7Hz), 4.14 (1H, q, J=7Hz), 5.89 (0.5H, 6.04 (0.5H, 6.90-7.01 (4H, in), 7.14 (2H, d, J=8Hz), 7.28 (1H, d, J=8Hz), 7.30 (1H, d, J=8Hz), 7.42 (2H, d, J=8Hz) Preparation 8-3) A solution of sodium iodide (128 g) and ethyl 7-chioro- 3 4 4 -chlorophenoxy)phenyl]hept-2-enoate (67.4 g) in acetone (200 ml) was refluxed for 24 hours. The resulting mixture was poured into water (300 ml) and extract with ethyl acetate (100 ml x The combined organic layer was washed with water and brine, and dried over magnesium sulfate to give ethyl 3 -[4-(4-chlorophenoxy)phenyl]-7-iodohept-2-enoate (67.8 g) (E:Z 1:1 mixture) as a yellow oil.

NMR (CDCl 3 6) 1. 14 5H, t, J=7H-z) 1. 26 (1-5H, t, J=7Hz), 1.29-1.37 (2H, in), 1.46-1.62 (2H, in), 1.78-1.94 (2H, mn), 2.44 (1.5H, t, J=7Hz), 3.12 t, J=7Hz), 3.18 (3H, t, J=7Hz), 4.04 (1H, qi, J=7Hz), 4.20 (1H, q, J=7Hz), 5.88 (0.5H, 6.04 6.89-7.00 (4H, mn), 7.14 (2H, d, J=8H-z), 7.26-7.36 (3H, in), 7.42 (2H, d, J=8Hz) Preparation 8-4) A mixture of ethyl 3 4 -(4--chlorophenoxy)phenyl]-7iodo-hept-2-enoate (59.8 g) and thiourea (9.39 g) in ethanol (123 ml) was refluxed for 24 hours. The resulting mixture was cooled and evaporated to give ethyl 7-amidinothio-3-[4- WO 00/40576 PCT/JPOO/00018 C4-chlorophenoxy)phenyl]hept-2-enoate hydroiodide (70.2 g) (E:Z 1:1 mixture) as slightly yellow oil.

NMR (DMSO-d 6 1.05 (1.5H, t, J=7Hz), 1.24 t, J=7Hz), 1.33-1.68 (4H, mn), 2.48 (1H, t, J=7Hz), 3.05-3.16 (3H, in), 3.96 (1H, q, J=7Hz), 4.12 (1H, q, J=7Hz), 5.93 6.07 (0.5H, 6.96- 7.13 (4H, mn), 7.20 (1H, d, J=8Hz), 7.46 (1H, d, J=8Hz), 7.43 (1H, d, J=8Hz), 7.60 (1H, d, J=3Hz) MS in/z: 433 (M-H) Preparation 9-1) 4- (5-Chlorovaleryl) -4'-fluorodiphenyl ether (3.86 g) was obtained in a similar manner to that of Preparation 4-1).

NMR (ODC1 3 1.81-1.92 (4H, m) 2.97 (2H, dd, J=7, 7Hz), 3.53-3.6 (2H, in), 6.94-7.12 (6H, in), 7.92- 7.95 (2H, in) Preparation 9-2) Ethyl 7-chloro-3- (4-fluorophenoxy)phenyllhept-2.enoate 90 g) was obtained in a similar manner to that of Preparation 8-2).

NMR (CDCd 3 6:1. 31 (3H, dd, J=7, 7Hz) 1. 54-1.64 (2H, in), 1.78-1.88 (2H, in), 3.12 (2H, dd, 3.53 (2H, dd, J=7, 7Hz), 4.20 ddd, J=7, 7, 7Hz), 6.03 (1H, 6.93-7.09 (6H, in), 7.39-7.42 (2H, in) Preparation 10-1) 4- (5-Chlorovaleryl)-4'-bromodiphenyl. ether (6.71 g) was obtained in a similar manner to that of Preparation 4-1).

NMR (CDCl 3 1.82-1.94 (4H, in), 2.99 (2H, t, 3.60 (2H, t, J=6.5Hz), 6.95 (2H, d, J=9Hz), 7.00 (2H, d, J=9Hz), 7.51 (2H, d, J=9Hz), 7 .95 (2H, d, J=9Hz) WO 00/40576 PCT/JPOO/00018 91 Preparation 10-2 Ethyl 3-[4-(4-bromophenoxy)phenyll-7-chlorohept-2enoate (7.55 g) was obtained in a similar manner to that of Preparation 8-2).

NMR (ODC1 3 14 5H, t, J=7Hz) 1. 21-1. 39 5H, in), 1. 49-1. 65 (2H, in), 1. 74-1. 88 (2H, m), 2. 47 (1H, t, J=7Hz) 3. 12 (1H, t, J=7Hz) 3. 47- 3. 56 (2H, in), 4 .03 (1H, qj, J=7Hz) 4. 20 (1H, q, J=7Hz) 5. 89 SH, s) 6. 04 5H, s) 6. 86-6. 99 (4H, in), 7.39-7.50 (4H, in) Preparation 10-3) Ethyl 3-[4-(4-bromophenoxy)phenyl]-7-iodohept-2-enoate (7.85 g) was obtained in a similar manner to that of Preparation 8-3).

NMR (CDCl 3 14 5H, t, J=7Hz) 1. 21-1. 39 mn), 1.49-1.65 (2H, mn), 1.74-1.88 (2H, in), 2.47 (l1H, t, J=7Hz), 3.12 (1H, t, J=7Hz), 3.47- 3.56 (2H, in), 4.03 (1H, q, J=7Hz), 4.20 (1H, q, J=7Hz) 5. 89 5H, s) 6. 04 5H, s) 6. 86-6. 99 (4H, mn), 7.39-7.50 (4H, in) Preparation 10-4) Ethyl 7-amidinothio-3-[4- (4-bromophenoxy)phenyl]hept-2enoate hydroiodide (10.4 g) was obtained in a similar manner to that of Preparation 8-4).

NMR (DMSO-c1 6 1.06 (1.5H, t, J=7Hz), 1.24 t, J=7Hz), 1.35-1.52 (2H, mn), 1.54-1.75 (2H, in), 3.06-3.17 (2H, in), 3.39-3.49 (2H, in), 3.94 (1H, q, J=7Hz), 4.15 (1H, q, J=7Hz), 5.94 (0.5H, 6.07 6.96-7.11 (4H, mn), 7.56-7.64 (4H, in), 9.01-9.15 (4H, in) MS (ESI+) m/z: 479, 563 (+TFA) Preparation 11-1) WO 00/40576 PCT/JP00/00018 92 Methyl 4-(5-chlorovaleryl)phenyl ether (8.77 g) was obtained in a similar manner to that of Preparation 4-1).

NMR (CDC1 3 1.84-1.94 (4H, 2.97 (2H, t, J=7Hz), 3.59 (2H, t, J=6.5Hz), 3.88 (3H, 6.94 (2H, d, J=9Hz), 7.95 (2H, d, J=9Hz) Preparation 11-2) To a stirred solution of lithium diisopropylamide in tetrahydrofuran (prepared from diisopropylamine (2.32 g) and n-butyl lithium (14.3 ml, 1.6M in n-hexane) in tetrahydrofuran (14 ml) was added dropwise ethyl acetate (2.80 g) while maintaining -60 0 C on a dry-ice acetone bath.

The mixture was stirred for 1 hour at -60 0 C and quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The obtained organic phase was washed with saturated aqueous ammonium chloride three times and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluted with 5 to 10% ethyl acetate in n-hexane) to give ethyl 7-chloro-3-hydroxy-3-(4methoxyphenyl)-heptanoate (3.56 g) as an oil.

NMR (CDC13, 1.12 (3H, t, J=7.5Hz), 1.16-1.30 (1H, 1.39-1.56 (1H, 1.62-1.82 (4H, 2.77 (1H, d, J=16Hz), 2.94 (1H, d, J=16Hz), 3.45 (2H, t, J=6.5Hz), 3.80 (3H, 4.04 (2H, q, 4.38 (1H, 6.86 (2H, d, J=9Hz), 7.31 (2H, d, J=9Hz) Preparation 11-3) A mixture of ethyl 7 -chloro-3-hydroxy-3-(4methoxyphenyl)heptanoate (3.55 potassium thioacetate (1.42 g) and catalytic amount of tetrabutyl ammonium iodide (n-Bu 4 NI) (150 mg) in N,N-dimethylformamide (30 ml) was stirred for 6 hours at room temperature. The mixture was poured into saturated aqueous ammonium chloride and WO 00/40576 PCT/JPO/00018 93 extracted with ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride three times and brine, dried over sodium sulfate and evaporated in vacuo to give ethyl 7 -acetylthio-3-hydroxy-3-(4methoxyphenyl)heptanoate (3.61 g) as an oil.

NMR (CDC1 3 1.12 (3H, t, J=7Hz), 1.33-1.55 (4H, 1.66-1.80 (2H, 2.30 (3H, 2.72-2.81 (3H, 2.93 (1H, d, J=15.5Hz), 3.80 (3H, 4.03 (2H, q, J=7Hz), 4.36 (1H, 6.85 (2H, d, J=9Hz), 7.30 (2H, d, J=9Hz) Preparation 11-4) A mixture of ethyl 7 -acetylthio-3-hydroxy-3-(4methoxyphenyl)heptanoate (3.60 g) and potassium carbonate (1.40 g) in ethanol (54 ml) was stirred for 6 hours at room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1% aqueous citric acid.

The separated organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo to give ethyl 3hydroxy-3-(4-methoxyphenyl)-7-mercaptoheptanoate (3.01 g) as an oil.

NMR (CDC1 3 1.12 (3H, t, J=7.5Hz), 1.26 (1H, t, 1.35-1.60 (4H, 1.65-1.82 (2H, m), 2.40-2.57 (2H, 2.77 (1H, d, J=16Hz), 2.94 (1H, d, J=16Hz), 3.80 (3H, 4.04 (2H, q, 4.36 (1H, 6.86 (2H, d, J=9Hz), 7.30 (2H, d, J=9Hz) Preparation 12-1) 5-( 4 -Fluorophenyl)-2-(5-chlorovaleryl)thiophene (2.03 g) was obtained in a similar manner to that of Preparation 4-1).

NMR (CDC1 3 1.79-1.99 (4H, 2.95 (2H, t, J=7Hz), 3.59 (2H, t, J=7Hz), 7.12 (2H, dd, J=8, 8Hz), 7.59-7.68 (4H, m) WO 00/40576 PCT/JPOO/0001 8 94 Preparation 12-2) Ethyl 7 -chloro-3-[5-(4-fluorophenyl)2thienyl~hept-2 enoate (1.71 g) (E:Z 1:1 mixture) was obtained in a similar manner to that of Preparation 8-2).

NMR (ODC1 3 1.24 (1.5H, 1.37 (1.5H, t), 1.63-1.98 (4H, in), 2.56 (0.5H, t, J=7Hz), 2.87- 3. 00 (1H, in), 3. 08 (0.5H, t, J=7H-z) 3. 53 (1H, t, J=7Hz), 3.61 (1H, t, J=7Hz), 4.10-4.24 (2H, mn), 5.87 (0.5H, 6.22 (0.5H, 7.04-7.31 (3H, in), 7.55-7.69 (3H, in) Preparation 12-3) Ethyl 3 4 -fluorophenyl)-2-thienyl].7.iodohept-2enoate (1.94 g) was obtained in a similar manner to that of Preparation 8-3).

NMR (CDC1 3 1.06 (1.5H, t, J=7Hz), 1.32 (1.5H, t, J=7Hz), 1.67-2.08 (4H, in), 3.24 (2H, t, J=7Hz), 4.18 (2H, q, J=7Hz), 6.22 (1H, 6.92-7.30 .(4H, mn), 7.48-7.60 (2H, m) Preparation 12-4) Ethyl 7-aiidinothio-3-[5- 4 -fluorophenyl)-2thienyllhept-2-enoate hydroiodide (1.57 g) was obtained in a similar manner to that of Preparation 8-4).

NMR (CDC1 3 1.05 (3H, t, J=7Hz), 1.57-1.82 (4H, in), 3.18 (2H, t, J=7Hz), 4.14 (2H, q, J=7Hz), 4.36 (2H, t, J=7Hz), 6.19 (1H, 7.24-7.69 (6H, m) MS (ES1+) m/z 407 (M+H) Preparation 13-1) 4 -(S-Chlorovaleryl)biphenyl (1.35 g) was *obtained in a similar manner to that of Preparation 4-1).

NMR (CDCl 3 1.90-1.93 (4H4, in), 3.06 (2H, dd, J=6, 6Hz), 3.61 (2H, dd, J=7, 7Hz), 7.40-7.50 (3H, mn), WO 00/40576 PCT/JPOO/00018 7. 63 d, J=8Hz) 7. 69 di, J=8Hz) 8. 03 (2H, di, J=8Hz) Preparation 13-2) Ethyl 3 4 -biphenylyl)-7-chlorohept-.2-enoate (1 g) was obtained in a similar manner to that of Preparation 8-2).

NMR (CDCl 3 1) 1.10 5H, dci, J=7, 7Hz) 1. 33 dd, J=7, 7Hz), 1.55-1.68 (1H, in), 1.76-1.90 (1H, in), 2.51 (1H, dcl, J=7.5, 7.5Hz), 3.18 (1H, dci, J=7.5, 7.5Hz), 3.52 dd, J=6.5, 6.5Hz), 3.54 (1H, dci, J=6.5, 6.5Hz), 4.02 (1H, ddd, J=7, 7, 7Hz), 4.22 (1H, dcid, J=7, 7, 7Hz), 5.92 (0.5H, s), 6.13 (0.5H, 7.24-7.65 (9H, m) Preparation 14-1) 41 -Chloro-4-(5-chlorovaleryl)biphenylyl (3.29 g) was obtained in a similar manner to that of Preparation 4-1).

NMR (ODCd 3 1.90-1.93 (4H, mn), 3.05 (2H, dd, J= 6, 6Hz), 3.60 (2H, dd, J=6, 6Hz), 7.44 (2H, d, J=8Hz), 7.56 (2H, ci, J=8Hz), 7.65 (2H, di, J=8Hz), 8.03 (2H, ci, J=8Hz) Preparation 14-2) Ethyl 7-chloro-3- (4 '-chloro-4--biphenylyl) hept-2-enoate (0.70 g) was obtained in a similar manner to that of Preparation 8-2).

NMR (CDCl 3 1.11 (1.5H, dci, J=7, 7Hz), 1.32 dci, J=7, 7Hz), 1.50-1.58 (1H, in), 1.58-1.65 (1H, in), 2.49 (1H, cid, J=7, 7Hz), 3.17 (1H, dd, J=7, 7Hz), 3.50 (1H, dci, J=6, 6Hz), 3.54 (1H, cid, J=6, 6Hz), 4.01 (1H, ddd, J=7, 7, 7Hz), 4.22 (1H, cicd, J=7, 7, 7Hz), 5.93 (0.5H, 6.12 (0.5H, s), 7.40-7.58 (8H, m) Preparation 15-1) WO 00/40576 PCT/JPOO/0001 8 96 4 '-Bromo-4- (5-chlorovaleryl)biphenyl (1.97 g) was obtained in a similar manner to that of Preparation 4-1).

NMR (ODC1 3 1.90-1.93 (4H, in), 3.05 (2H, dd, J=7, 7HZ), 3.60 (2H, dd, J=6, 6Hz), 7.49 (2H, d, J=8Hz), 7.60 (2H, d, J'=8Hz), 7.65 (2H, d, J=8Hz), 8.03 (2H, d, J=8Hz) Preparation 15-2) Ethyl 7-chloro-3- (4 '-bromo-4-biphenylyl)hept-2enoate 64 g) was obtained in a similar manner to that of Preparation 8-2).

NMR (00013, 1 1.11 5H, dd, J=7, 7Hz) 1. 33 dd, J=7, 7Hz) 1. 52-1. 67 (2H, mn), 1. 75-1. 89 (2H, mn), 2. 50 (1H, dd, J=7, 7Hz) 3. 17 (1H, dd, J=8, 8Hz) 3. 51 (1H, dd, J=7, 7Hz) 3. 54 (1H, dd, J=7, 7Hz), 4.02 (1H, ddd, J=7, 7, 7Hz), 4.22 (1H, ddd, J=7, 7, 7Hz), 5.93 (0.5H, 6.11 (0.5H, s), 7.24-7.60 (8H, in) Preparation 16-1) 4 '-Fluoro-4- (5-chlorovaleryl)biphenyl (2.95 g) was obtained in a similar manner to that of Preparation 4-1).

NMR (CDCl 3 1.89-1.95 (4H, in), 3.05 (2H, dd, J=7, 7Hz), 3.60 (2H, dd, J=6, 6Hz), 7.13-7.19 (2H, in), 7.57-7.65 (2H, in), 8.03 (2H, d, J=8.4Hz) Preparation 16-2) Ethyl 7-chloro-3- (4 '-fluoro-4-biphenylyl) hept-2-enoate (1.07 g) was obtained in a similar manner to that of Preparation 8-2).

NMR (CDC1 3 1.33 (3H, dd, J=7, 7Hz), 1.59-1.67 (2H, in), 1.81-1.90 (2H, in), 3.17 (2H, dd, 3.54 (2H, dd, J=7, 7Hz), 4.22 (2H, ddd, J=7, 7, 7Hz) 6. 12 (1H, s) 7. 14 (2H, dd, J=8, 8Hz), 7.50-7.59 (6H, m) WO 00/40576 PCT/JP00/00018 97 Preparation 17) Methyl 3,4,5,6-tetrahydro-2H-thiopyran-2-carboxylate 1,1-dioxide (844 mg) was obtained in a similar manner to that of Preparation 1-4).

mp: 78-82°C NMR (CDC1 3 1.44-1.80 (3H, 1.83-1.96 (1H, m), 2.10-2.42 (2H, 2.72-2.85 (1H, 3.14-3.78 (1H, 5.57 (1H, dd, J=3, 8Hz), 3.82 (3H, s) MS (ESI-) m/z: 191 (M-H) Preparation 18) To a solution of potassium ethyl malonate (16.7 g) in acetonitrile (4 ml) was added triethylamine (15.1 g) and magnesium chloride (11.1 g) at 0°C and the reaction mixture was stirred at ambient temperature for 2.5 hours. To the resulting slurry was added phenoxybenzoyl chloride (10.86 g) [prepared from 4-phenoxybenzoic acid (10 g) and thionyl chloride (20 ml)] dropwise over 25 minutes at 0°C and the reaction mixture was stirred at ambient temperature for hours. After the reaction mixture was concentrated in vacuo, toluene and 13% aqueous hydrochloric acid (60 ml) was added therein cautiously while keeping the temperature below 25 0

C.

The organic layer was washed with 13% aqueous hydrochloric acid and concentrated in vacuo to give ethyl 3-oxo-3-(4phenoxyphenyl)propanoate as a yellow oil (14 g).

NMR (CDC1 3 1.27 (3H, t, J=7.0Hz), 3.95 (2H, s), 4.24 (2H, q, J=7.0Hz), 6.99 (2H, d, 7.07 (2H, d, J=8.0Hz), 7.18 (1H, dd, 8.0Hz), 7.41 (2H, dd, J=8.0, 8.0Hz), 7.92 (2H, d, MS (ESI-) m/z: 283.1 (M-H) Preparation 19-1) 5-Bromo-2-(5-chlorovaleryl)thiophene (13.4 g) was WO 00/40576 PCT/JPOO 0018 98 obtained in a similar manner to that of Preparation 4-1) NMR (CDCl 3 8) 1. 86-1. 91 (4H, in), 2.88 (2H, dd, J=6. 9, 6. 9Hz) 3. 55 (2H, dd, J=6. 6, 6. 6Hz) 7. 11 (iH, d, J=4.2Hz), 7.45 (1H, d, J=4.2Hz) Preparation 19-2) Ethyl 7 -chloro-3- (5-bromo-2-thienyl)hept2enoate (12.5 gwas obtained in a similar manner to that of Preparation 8-2).

NMR (CDC1 3 1.22-1.59 (3H, in), 1.65-1.92 (4H, in), 3.01-3.06 in), 3.50-3.59 in), 4.10-4.23 (2H, in), 5.85 (0.5H, 6.09 (0.5Hz, 6.98- 7.07 (2H, mn) Preparation 20-1) tert-Butyl 7 -chloro-3-hydroxy-3-(5-bromo-2thienyl)heptanoate (244 g) was obtained in substantially the same manner as that of Preparation 11-2) NMR (ODC1 3 8) 1. 36 (9H, s) 1. 38-1. 57 (2H, in), 1. 68- 1.80 (4H, in), 2.70 d, J=15.6Hz), 2.79 (1H, d, J=I15.6Hz), 3.49 (2H, t, J=6.9Hz), 5.00 (1H, s), 6.59 d, J=3.9Hz), 6.89 (1H, d, J=3.9Hz) Preparation 20-2) tert-Butyl 7 -acetylthio-3-hydroxy.3 (5-bromo-2thienyl)heptanoate (267 g) was obtained in substantially the same manner as that of Preparation 11-3).

NMR (CDC1 3 1.35 (9H, 1.39-1.57 (4H, in), 1.66- 1.80 (2H, in), 2.31 (3H, 2.67 (1H, d, J=15.9Hz), 2.76 (1H, d, J=15.9Hz), 2.82 (2H, t, 4.96 (1H, 6.58 (1H, d, J=3.9Hz), 6.88 (1H, d, J=3. 9Hz) Preparation 20-3) tert-Butyl 3-hydroxy-3- (S-bromo-2-thienyl) -7- WO 00/40576 PCT/JPnnl/00nnnl 99 mercaptoheptanoate (277 g) was obtained in substantially the same manner as that of Preparation 11-4).

NMR (CDC1 3 1.30 (1H, t, J=7.8Hz), 1.31-1.39 (9H, 1.40-1.65 (4H, 1.67-1.83 (2H, 2.49 (2H, dd, J=7.8, 15Hz), 2.70 (1H, d, J=16H), 2.79 (1H, d, J=16Hz), 4.98 (1H, 6.59 (1H, d, J=4.2Hz), 6.89 (1H, d, J=4.2Hz) Preparation 21-1) To a solution of 4 -bromophenol (300 mg) in acetone was added potassium carbonate (264 mg) and bromoacetic acid t-butyl ester (0.28 ml) at room temperature. After being stirred at the same temperature overnight, the reaction mixture was concentrated in vacuo. The resulting residue was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo to give 4 -bromophenoxy acetic acid t-butyl ester (450 mg) as an oil.

NMR (DMSO-d 6 1.42 (9H, 4.66 (2H, 6.88 (2H, d, J=4.5Hz), 7.45 (2H, d, Preparation 21-2) To a solution of 4 -bromophenoxyacetic acid t-butyl ester (4 g) in dichloromethane (10 ml) was added trifluoroacetic acid (30 ml) at room temperature. After being stirred at the same temperature for 3 hours, the reaction mixture was concentrated in vacuo. The resulting residue was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give 4 -bromophenoxy acetic acid (2.1 g) as a power.

NMR (DMSO-d 6 4.67 (2H, 6.89 (2H, d, J=9Hz), 7.45 (2H, d, J=9Hz) MS 230 (M-H) Preparation 21-3) WO 00/40576 PCT/JPO/00018 100 N-Ethyl-2-(4-bromophenoxy)acetamide (110 mg) was obtained in substantially the same manner as that of Example 32.

NMR (DMSO-d 6 1.03 (3H, t, J=7.2Hz), 3.10-3.19 (2H, 4.45 (2H, 6.93 (2H, d, J=9Hz), 7.47 (2H, d, J=9Hz), 8.11 (1H, br) Preparation 21-4)- 4-(Ethylaminocarbonylmethoxy) benzeneboronic acid pinacol cyclic ester (130 mg) was obtained in substantially the same manner as that of Preparation 24-2).

The product was used for the next reaction without further purification.

Preparation 22 4-(t-Butyloxycarbonylmethoxy)benzeneboronic acid (200 mg) was obtained in substantially the same manner as that of Preparation 21-1).

NMR (DMSO-d 6 1.42 (9H, 4.65 (2H, 6.84 (2H, d, J=9.0Hz), 7.71 (2H, d, J=9.0Hz), 7.88 (2H, s) Preparation 23-1) 4-Chloro-l-(5-bromo-2-thienyl)butan-l-one (8.0 g) was obtained in substantially the same manner as that of Preparation 8-1).

NMR (CDC1 3 2.21 (2H, quintet, J=7Hz), 3.05 (2H, t, J=7Hz), 3.66 (2H, t, J=7Hz), 7.11 (1H, d, J=4Hz), 7.50 (1H, d, J=4Hz) Preparation 23-2) tert-Butyl 6-chloro-3-hydroxy-3-(5-bromo-2thienyl)hexanoate (4.46 g) was obtained in substantially the same manner as that of Preparation 11-2).

NMR (CDC13, 1.37 (9H, 1.64-1.80 (1H, m), WO 00/40576 PCT/JPO/00018 101 1.82-1.98 (3H, 2.70 (1H, d, J=16Hz), 2.80 (1H, d, J=16Hz), 3.48-3.55 (2H, 5.02 (1H, 6.61 (1H, d, J=4Hz), 6.90 (1H, d, J=4Hz) Preparation 23-3) tert-Butyl 6-acetylthio-3-hydroxy-3-(5-bromo-2thienyl)hexanoate (4.77 g) was obtained in substantially the same manner as that of Preparation 11-3).

NMR (CDC1 3 1.36 (9H, 1.45-1.60 (1H, m), 1.62-1.94 (3H, 2.31 (3H, 2.68 (1H, d, J=16Hz), 2.77 (1H, d, J=16Hz), 2.85 (2H, t, J=7Hz), 4.98 (1H, 6.59 (1H, d, J=4Hz), 6.88 (1H, d, J=4Hz) Preparation 23-4) tert-Butyl 3-hydroxy-3-(5-bromo-2-thienyl)-6mercaptohexanoate (4.0 g) was obtained in substantially the same manner as that of Preparation 11-4).

NMR (CDC13, 1.30 (1H, t, J=8Hz), 1.36 (9H, 1.44- 1.62 (1H, 1.66-1.93 (3H, 2.44-2.55 (2H, m), 2.70 (1H, d, J=16Hz), 2.79 (1H, d, J=16Hz), 4.99 (1H, 6.60 (1H, d, J=4Hz), 6.89 (1H, d, J=4Hz) Preparation 24-1) A mixture of 4-bromobenzaldehyde (5.00 tosylmethyl isocyanide (5.43 g) and potassium carbonate (5.60 g) in methanol (50 ml) was refluxed for 2 hours and concentrated.

The residue was taken up between ethyl acetate and saturated aqueous ammonium hydrochloride. The separated organic layer was washed with water and brine, dried over sodium sulfate and filtered. The filtrate was treated with silica gel and the obtained residue was triturated with n-hexane to give 4 -bromophenyl)oxazole (4.06 g) as a solid.

NMR (CDC1 3 7.37 (1H, 7.51-7.58 (4H, m), 7.93 (1H, s) WO 00/40576 PCT/JPOO/00018 102 MS 224 (M+H) Preparation 24-2) A mixture of 5-( 4 -bromophenyl)oxazole (672 mg), bis(pinacolato)diborane (762 mg) dichlorobis(triphenylphosphine) palladium (11) (42.1 mg) and potassium acetate (883 mg) in dioxane (15 ml) was stirred for 14 hours at 80'C to form 4 -(S-oxazolyil)benzeneboronic acid pinacol cyclic ester.

After cooling to room temperature, the mixture was used to next reaction without further purification.

Preparation 4 -(Methoxycarbonylaminomethy1)phenyl)boronic acid mg) was obtained from 4 -aminomethylphenyl)boronic acid hydrochloride in a similar manner to that of Example 130.

NMR (DMSO-d 6 3. 53 (3H, s) 4. 18 di, J=7. 7. 20 di, J=8.5SHz) 7 .66-7. 75 (3H, mn), 8. 00 (2H, s) Preparation 26 4 -(Cyclopropylcarbonyloxy)phenyl)boronjc acid (77 mg) was obtained from 4 -hydroxyphenyl) boron ic acid in a similar manner to that of Preparation 21-1).

NMR (DMSO-d 6 1.00-1.07 (4H, in), 1.85-1.94 (1H, mn), 7.08 (2H, d, -J=8.5Hz), 7.81 (2H, di, J=8.5Hz), 8.09 (2H, s) Preparation 27 (Ethoxycarbonylmethoxy)phenyl)boronic acid (100 mg) was obtained in a similar manner to that of Preparation 21- 1).

NMR (DMSO-d 6 1.21 (3H, dd, J=7.2, 7 4.17 cicd, J=7.2, 7.2, 7.2Hz), 4.78 (2H, 6.87 d, 7.72 (2H, di, J=8.5Hz), 7.88 s) WO 00/40576 PCT/JPOO/00018 103 Preparation 28 4 -(Ethyl carbonylmethoxy) phenyl) borolic acid (95 mg) was obtained in a similar manner to that of Preparation 21- 1).

NMR (DMSO-c1 6 0.97 (3H, dcl, J=7.2, 7.2Hz), 2.49-2.54 (2H, in), 4.82 (2H, 6.84 (2H, d, J=8.5Hz), 7.71 (2H, d, J=8.5Hz), 7.87 (2H, s) Preparation 29 4 -Cyclopropylaminocarbonylmethoxyphenyl, boronic acid (160 mg) was obtained in a similar manner to that of Example 32.

NMR (DMSO-d 6 0.46-0.50 mn), 0.61-0.64 (2H, in), 2.65-2.72 (1H, mn), 4.43 (2H, 6.88 (2H, d, J=8.5Hz), 7.72 d, J=8.5Hz), 7.88 (2H, s), 8.13 (1H, br) Preparation 0 0 Br S 10 0 H

H

2 N-O\ I 0

H

(b) To a solution of (2S) (5-bromo-2-thienyl) -3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (4.24 g) in N,N-dimethylformamide (60 ml) was added 1-hydroxy- WO 00/40576 PCT/JPO/00018 104 benztriazole (1.62 g) and diisopropylcarbodiimide (1.88 ml) at ambient temperature. After 1 minute, the solution was added to hydroxylamine trityl crowns (a)(14.4 pmol/crown x 100), the reaction mixture was left overnight at ambient temperature. The crowns were washed with N,N-dimethylformamide, methanol and dichloromethane, successively and air dried to give (2S)-N-[2-[2-(5-bromo-2-thienyl)-l,1dioxo-3,4,5,6-tetrahydro-2H-thiopyran-2-yl]acetyl hydroxylamine trityl crowns (10.0 pmol/crown x 100).

Preparation 31-1) To a suspension of 3-nitrophenylboronic acid (2.33 g) and tetrakis(triphenylphosphine)palladium (1.29 g) in degassed N,N-dimethylformamide (50 ml) was added a solution of sodium carbonate (8.5 g) in degassed water (20 ml) and (2S)-N-2[2-[2-(5-bromo-2-thienyl)-l,l-dioxo-3,4,5,6tetrahydro-2H-thiopyran-2-yl]acetyl]hydroxylamine trityl crowns (202 pmol, 10.1 pmol/crown x 20) in an atmosphere of nitrogen. After the resulting mixture was heated for 48 hours at 60 0 C, the crowns were washed with degassed N,Ndimethylformamide, a solution of sodium diethylditiocarbamate (1.0 g) and diisopropylethylamine ml) in N,N-dimethylformamide (200 ml), N,N-dimethylformamide, methyl sulfoxide, water, methanol and dichloromethane, successively to give (2S)-N-[2-[2-(5-(3-nitrophenyl)-2thienyl)-1,l-dioxo-3,4,5,6-tetrahydro-2H-thiopyran-2yl]acetyl]hydroxylamine trityl crowns (202 pmol, 10.1 Wmol/crown x Preparation 31-2) To a solution of 2M tin (II) chloride dihydrate (7.67 g) in N,N-dimethylformamide (17 ml) was added (5-(3-nitrophenyl)-2-thienyl)-1,1,-dioxo-3,4,5,6-tetrahydro- 2 H-thiopyran-2-yl]acetyl]hydroxylamine trityl crowns (304 amol, 13.2 pmol/crown x 23). The reaction mixture was left WO 00/40576 PCT/JP00/00018 105 overnight at ambient temperature. The crowns were washed with N,N-dimethylformamide, water, methanol and dichloromethane, successively and air dried to give (2S)-N- [2-[2-(5-(3-aminophenyl)-2-thienyl)-1,1-dioxo-3,4,5,6tetrahydro- 2 H-thiopyran-2-yllacetyl]hydroxylamine trityl crowns (13.2 pmol/crown x 23).

The following compounds were obtained from 6-methyl-3- (trifluoromethanesulfonyloxy)pyridine in a similar manner to that of Preparation 24-2).

Preparation 32 6-Methylpyridine-3-boronic acid pinacol cyclic ester Preparation 33 6 -Methoxypyridine-3-boronic acid pinacol cyclic ester Preparation 34 4 -(5-Methyl-l,2,4-oxadiazol-3-yl)benzeneboronic acid pinacol cyclic ester Preparation 5-(Methoxycarbonylamino)pyridine-3-boronic acid pinacol cyclic ester Preparation 36 2 2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide Preparation 37 4-(Methylaminocarbonylmethyl)benzeneboronic acid pinacol cyclic ester Preparation 38 WO 00/40576 PCT/JP00/00018 106 acid pinacol cyclic ester Example 1 1.5M Lithium diisopropylamide mono tetrahydrofuran in cyclohexane (0.28 ml) was added dropwise to a stirred suspension of 2 4 4 -chlorophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran 1,1-dioxide (117 mg) in tetrahydrofuran (2.4 ml) under dry ice acetone cooling and a nitrogen atmosphere, and the mixture was stirred under the same conditions for 15 minutes, then a solution of tert-butyl bromoacetate (75 mg) in tetrahydrofuran (0.2 ml) was added dropwise therein and the resulting mixture was stirred under the same conditions for 2 hours. A saturated aqueous solution of ammonium chloride was added to the stirred reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo.

The residue was chromatographed (eluent: toluene ethyl acetate) over silica gel to afford a mixture (86 mg) of t-butyl 2 4 -(4-chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetate 1,1-dioxide and the starting material.

A solution of trifluoroacetic acid (560 mg) and the obtained mixture (79 mg) in dichloromethane (3.0 ml) was allowed to stand at room temperature for 3 days and evaporated in vacuo. The residue was dissolved in ethyl acetate and extracted five times with a. saturated aqueous solution of sodium bicarbonate. The aqueous extracts were combined, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford 2 4 -(4-chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetic acid 1,1-dioxide (44 mg) as a colorless powder.

mp: 191-193°C WO 00/40576 PCT/JP0nn/nnn18 107 IR (KBr): 1711, 1290, 1244, 1124 cm- 1 NMR (CDC1 3 1.75-2.05 (2H, 2.15 (2H, 2.6- 2.85 (2H, 3.08-3.15 (2H, 3.21 (1H, d, J=15.6Hz), 3.60 (1H, d, J=15.6Hz), 6.94-7.01 (4H, 7.31 (2H, dd, J=6.7, 2.1Hz), 7.59 (2H, d, API-ES MS m/z: 393 Anal. Calcd. for C 19

H

19 CIO5S: C 57.79, H 4.85 Found: C 57.88, H 4.83 Example 2 A mixture of ethyl 2 -(4-methoxyphenyl)-3,4,5,6tetrahydro-2H-thiopyran-2-acetate (100 mg) and lithium hydroxide monohydrate (42.8 mg) in a mixture of methanol and water was stirred for 4 hours at 60 0 C. After cooling to room temperature, the mixture was acidified with 4N hydrochloric acid and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo to give 2-(4methoxyphenyl)-3,4,5,6-tetrahydro-2H-thiopyran-2-acetic acid (93 mg) as a crystalline solid.

NMR (DMSO-d 6 1.44-1.80 (4H, 2.26-2.54 (3H, 2.62-2.79 (2H, 3.00 (1H, d, J=14.5Hz), 3.75 (3H, 6.89 (2H, d, J=9Hz), 7.48 (2H, d, J=9Hz) MS (ESI-) m/z: 265 (M-H) Example 3 To a solution of ethyl 2 -[5-(4-f!uorophenyl)-2thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetate (315 mg) in methanol (4 ml) was added 1N sodium hydroxide aqueous solution (1.3 ml) at 0°C and the mixture was stirred for hours at room temperature. The resulting mixture was evaporated to remove methanol. The residue was acidified WO 00/40576 PCT/JP00/00018 108 with 1N hydrochloric acid (HC1) and extracted with ethyl acetate The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 2-[5-(4-fluorophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetic acid (296 mg) as white solid.

NMR (CDC13, 1.58-1.92 (4H, 2.20-2.32 (1H, m), 2.57-2.68 (2H, 2.70-2.81 (1H, 2.89 (1H, d, J=14Hz), 2.97 (1H, d, J=14Hz), 6.97-7.08 (4H, m), 7.48-7.56 (2H, m) MS (ESI-) m/z: 335 (M-H) Example 4 To a solution of methyl 2 4 -phenoxybenzyl)-3,4,5,6tetrahydro-2H-thiopyran-2-carboxylate 1,1-dioxide in methanol (MeOH) (5 ml) was added solution of lithium hydroxide monohydrate (375 mg) in water (H 2 0) (5 ml) at room temperature. After being stirred at 60C for 2 hours, the mixture was concentrated in vacuo to remove MeOH. The residual solution was acidified by 1M hydrochloric acid and extracted with ethyl acetate (AcOEt) (20 ml x The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give 2-(4phenoxybenzyl)-3,4,5, 6 -tetrahydro-2H-thiopyran-2-carboxylic acid 1,1-dioxide (320 mg) as an amorphous powder.

NMR (CDC1 3 1.70-1.84 (2H, 1.95-2.20 (3H, m), 2.25-2.37 (1H, 3.11-3.25 (3H, 3.16 (1H, d, J=14Hz), 6.91 (2H, d, J=8Hz), 7.00 (2H, d, J=8Hz), 7.11 (1H, t, J=8Hz), 7.20 (2H, d, J=8Hz), 7.33 (2H, t, J=8Hz) MS (ESI-) m/z: 359 (M-H) Example 2-(4-Phenoxybenzyl)-3,4,5,6-tetrahydro-2H-thiopyran-2carboxylic acid (280 mg) was obtained in a similar manner to that of Example 4.

WO 00/40576 PCT/JPO/00018 109 NMR (CDC1 3 1.45-2.02 (5H, 2.35-2.46 (1H, m), 2.52-2.65 (1H, 2.68-2.85 (1H, 3.07 (2H, dd, J=3, 14Hz), 6.90 (2H, d, J=8Hz), 6.99 (2H, d, J=8Hz), 7.09 (1H, t, J=8Hz), 7.13 (2H, d, J=8Hz), 7.32 (2H, t, J=8Hz) MS (ESI-) m/z: 327 (M-H) Example 6 To a solution of ethyl 2-(4-phenoxyphenyl)-1,3dithiane-2-acetate (370 mg) in ethanol (4 ml) was added IN sodium hydroxide aqueous solution (2 ml) and the mixture was stirred at 50 0 C for 3 hours. The resulting mixture was evaporated to remove ethanol. The residue was acidified with 1N HC1 and extracted with diethyl ether. The organic layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated to give 2-(4phenoxyphenyl)-l,3-dithiane-2-acetic acid (280 mg) as white crystal.

NMR (CDC1 3 2.03 (2H, br), 2.83 (4H, br), 3.22 (2H, br), 6.93-7.05 (4H, 7.13 (1H, d, 7.41-7.48 (2H, 7.82-7.86 (2H, m) MS (ESI-) m/z: 345.1 (M-H) Example 7 1.5M Solution of lithium diisopropylamide monotetrahydrofuran in cyclohexane (1.60 ml) was added dropwise to a stirred solution of 2 -[4-(4-chlorophenoxy)phenyl]- 2 3 4 ,5-tetrahydrothiophene 1,1-dioxide (646 mg) in tetrahydrofuran (6.5 ml) under a nitrogen atmosphere and dry ice acetone cooling, and the resultant solution was stirred under the same conditions for 35 minutes.

A

solution of allyl bromide (532 mg) in tetrahydrofuran (1.9 ml) was added dropwise therein and the resultant mixture was stirred under the same conditions for 1 hour and 30 minutes.

After addition of a saturated aqueous solution of ammonium WO 00/40576 PCT/JP00/00018 110 chloride (10 ml) under the same conditions, the reaction mixture was extracted with ethyl acetate. The extract was washed successively with IN hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and evaporated in vacuo to afford an oil (0.68 g).

Potassium permanganate (259 mg), sodium periodate (1.75 and potassium carbonate (618 mg) was successively added to a stirred emulsion of the obtained oil in tert-butyl alcohol (22 ml) and water (38 ml) at room temperature and the resulting mixture was stirred at the same temperature for 1 hour and 40 minutes. The reaction mixture was acidified to pH c.a. 1.0 with 1N hydrochloric acid (10 ml) under ice cooling, and then sodium bisulfite was added portionwise therein under the same condition till the mixture became yellow. The yellow mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bisulfite and brine, dried over sodium sulfate, and evaporated in vacuo. The powdery residue was washed with a mixture of diisopropyl ether diethyl ether to afford a colorless powder (401 mg), 388 mg of which was chromatographed (eluent: toluene ethyl acetate acetic acid) over silica gel to afford an oil. The obtained oil was powdered from n-hexane to afford chlorophenoxy)phenyl]-2,3,4,5-tetrahydrothiophene-2-acetic acid 1,1-dioxide (306 mg) as a colorless amorphous powder.

mp: 45-50 0

C

IR (KBr): 2750-2400, 1734, 1716, 1300, 1244, 1126 cm- 1 NMR (DMSO-d 6 2.16-2.25 (2H, 2.65-2.77 (2H, 3.08-3.41 (4H, 7.00-7.10 (4H, 7.41- 7.51 (4H, 12.38 (1H, br) API-ES MS m/z: 379 and 381 Anal. Calcd. for C 18

H

17 C105S: C 56.76, H 4.50 Found: C 57.32, H 5.04 WO 00/40576 PCT/JPO/00018 111 Example 8 Potassium permanganate (172 mg), sodium periodate (1.28 and potassium carbonate (409 mg) was successively added to a stirred emulsion of 2 -allyl-2-[4-(4-chlorophenoxy)phenyl]- 3 ,4,5,6-tetrahydro-2H-thiopyran 1,1-dioxide (372 mg) in tert-butyl alcohol (15 ml) and water (26 ml) at room temperature and the resulting mixture was stirred at the same temperature for 1 hour and 30 minutes. The reaction mixture was acidified to pH c.a. 1.0 with conc. hydrochloric acid under ice cooling, and then sodium bisulfite was added portionwise therein under the same condition till the mixture became yellow. The yellow mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatogrphed (eluent: toluene ethyl acetate acetic acid) over silica gel to afford a colorless powder (277 mg), which was washed with n-hexane to afford chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetic acid 1,1-dioxide (250 mg) as a colorless powder.

mp: 191-193°C Example 9 2 4 -(4-Chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-6methyl-2H-thiopyran-2-acetic acid 1,1-dioxide (59 mg) was prepared in a similar manner to that of Example 8.

IR (KBr): 3442, 1735, 1714, 1284, 1245, 1124 cm- 1 NMR (DMSO-d 6 1.16 (3H, d, J=6.6Hz), 1.62-1.98 (4H, 2.47-2.63 (2H, 3.2-3.59 (3H, m), 6.98-7.10 (4H, 7.46 (2H, d, J=9.0Hz), 7.55 (2H, d, API-ES MS m/z: 407 and 409 Example A suspension of (2R or 2

S)-

2 -[4-(4-chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-N-((lR)-1-phenylethyl)-2H- WO 00/40576 PCT/JP00/00018 112 thiopyran-2-acetamide 1,1-dioxide (diastereomer A, 149 mg) obtained in Example 31 in a mixture of 14N sulfuric acid ml) and 1,4-dioxane (4.2 ml) was stirred under reflux for 21 hours and cooled to room temperature. The reaction mixture was partitioned between ethyl acetate and water.

The organic layer was washed with water and brine (twice), dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (eluent: dichloromethane methanol) over silica gel to afford (2R or chlorophenoxy)-phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetic acid 1,1-dioxide (an optical isomer A, 109 mg) as a crude brown gum.

IR (KBr): 1734, 1716, 1284, 1244, 1122 cm-1 NMR (CDC13, 1.93 (2H, 2.14 (2H, 2.6-2.85 (2H, 3.08-3.16 (2H, 3.22 (1H, d, J=15.6Hz), 3.62 (1H, d, J=15.6Hz), 6.95-7.04 (4H, 7.28- 7.35 (2H, 7.60 (2H, d, API-ES MS m/z: 393 and 395 [a] 2 5 -32.3° MeOH) Analytical chiral HPLC: column: Chiralpak AS (4.6 x 250 mm, Daicel Chemical Industries, Ltd.) eluent: n-hexane-ethanol-TFA (700:300:1) flow rate: 1.0 ml/minute detection: 220 nm retention time: 50.0 minutes Example 11 (2R or 2

S)-

2 4 -(4-Chlorophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (an optical isomer B, 77 mg) was prepared from (2R or 4 4 -chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-N-((1R)-1phenylethyl)-2H-thiopyran-2-acetamide 1,1-dioxide (diastereomer B, 133 mg) obtained in Example 31 in a similar manner to that of Example WO 00/40576 PCT/JPO/00018 113 IR (KBr): 1711, 1290, 1242, 1122 cm- 1 NMR (CDC13, 1.82-1.95 (2H, 2.10-2.15 (2H, m), 2.62-2.80 (2H, 3.03-3.11 (2H, 3.21 (1H, d, J=15.6Hz), 3.60 (1H, d, J=15.6Hz), 6.92-7.01 (4H, 7.28-7.34 (2H, 7.59 (2H, d, API-ES MS m/z: 393 Analytical chiral HPLC: column: Chiralpak AS (4.6 x 250 mm, Daicel Chemical Industries, Ltd.) eluent: n-hexane-ethanol-TFA (700:300:1) flow rate: 1.0 ml/minute detection: 220 nm retention time: 8.96 minutes Example 12 To a solution of 2 4 4 -chlorophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (16.8 g) in ethyl acetate (420 ml) was added methylbenzylamine (2.84 g) at room temperature. After being stirred overnight at the same temperature, the resulting crystal was filtrated and washed with ethyl acetate to give (2R or 2S)-2-[4-(4-chlorophenoxy)phenyl]-3,4,5,6-tetrahydro- 2 H-thiopyran-2-acetic acid l,1-dioxide methylbenzylamine salt (9.43 A suspension of resulting salt in ethyl acetate (200 ml) was washed with 1N hydrochloric acid (100 ml x water and brine, and concentrated to give the free acid. This procedure was repeated three times (second:amine 0.75 eq; third:0.85 eq) to give the optically resoluted (2R or chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetic acid (an optical isomer A) (4.75 g) as a white solid.

[a] 2 5 -32.30 MeOH) Optical purity: 91% ee Analytical chiral HPLC: WO 00/40576 PCT/JP00/00018 114 column: Chiralpak AS (4.6 x 250 mm, Daicel Chemical Industries, Ltd.) eluent: n-hexane-ethanol-TFA (700:300:1) flow rate: 1.0 ml/minutes detection: 220 nm retention time: 50.0 minutes Example 13 To a solution of 2 -(5-bromo-2-thienyl)-3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (1 g) in ethanol (8 ml) was added (R)-(+)-a-methylbenzylamine (185 mg) at room temperature. After being stirred overnight at the room temperature, the resulting crystal was filtrated and washed with ethanol to give 2-(5-bromo-2-thienyl)- 3,4,5,6-tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (R)-(+)-a-methylbenzylamine salt. A suspension of resulting salt in ethyl acetate was washed with 1N hydrochloric acid and brine, and concentrated to give the free acid. This procedure was repeated two times to give the optically resoluted (2R or 2 S)-2-(5-bromo-2-thienyl)-3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (300 mg) as a white solid.

NMR (DMSO-d 6 1.74-1.87 (4H, 2.30-2.37 (1H, 3.07-3.56 (5H, 7.02 (1H, d, J=4.2Hz), 7.21 (1H, d, J=4.2Hz) MS (ESI-) m/z: 351 (M-H) [a]2 5 -25.30 MeOH) Optical purity: 95% ee Analytical chiral HPLC: column: Chiralpak AS (4.6 x 250 mm, Daicel Chemical Industries, Ltd.) eluent: n-hexane-ethanol-trifluoroacetic acid (TFA) (700:300:1) flow rate: 1.0 ml/minute detection: 220 nm WO 00/40576 PCT/JPO/00018 115 retention time: 20.2 minutes Example 14 A mixture of 2 4 -(4-chlorophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (98.7 mg), ammonium formate (78.8 mg), and 10% palladium carbon wet, 60 mg) in ethanol (5 ml) was stirred under reflux for 3 hours and 20 minutes, and filtered. The filtrate was evaporated in vacuo and the residue was partitioned between ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was powdered from diisopropyl ether to afford 3,4,5,6-tetrahydro-2-(4phenoxyphenyl)- 2 H-thiopyran-2-acetic acid 1,1-dioxide (87 mg) as a colorless powder.

mp: 208.5-209.5°C IR (KBr): 2750-2550, 1707, 1290, 1246, 1124 cm- 1 NMR (CDC13, 1.75-2.25 (4H, 2.74 (2H, 3.11 (2H, 3.21 (1H, d, J=15.6Hz), 3.61 (1H, d, J=15.6Hz), 6.97-7.07 (4H, 7.14 (1H, t, J=7.4Hz), 7.36 (2H, t, J=7.7Hz), 7.59 (2H, d, API-ES MS m/z: 359 Example A solution of oxalyl chloride (76.2 mg) in dichloromethane (0.7 ml) was added dropwise to a stirred suspension of 2 4 -(4-chlorophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (118 mg) and N,N-dimethylformamide (1.10 mg) in dichloromethane (1.2 ml) under ice cooling and a nitrogen atmosphere, then the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and evaporated in vacuo.

The residue was dissolved in dichloromethane (1.6 ml) and the solution was added dropwise to a stirred mixture of WO 00/40576 PCT/JP00/00018 116 hydroxylammonium chloride (125 mg), IN aqueous solution of sodium hydroxide (1.8 ml), tetrahydrofuran (3.6 ml), and tert-butyl alcohol (1.8 ml) at room temperature and the resulting mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (eluent: toluene ethyl acetate acetic acid) over silica gel (2.6 g) to afford a colorless powder, which was washed with diisopropyl ether to afford 2 4 -(4-chlorophenoxy)phenyl]-3,4,5,6tetrahydro-N-hydroxy-2H-thiopyran-2-acetamide 1,1-dioxide (88 mg) as a colorless powder.

mp: 179-180 0 C (dec.) IR (KBr): 3421, 3315, 3220, 1652, 1284, 1248, 1119 cm- 1 NMR (DMSO-d 6 1.74-1.99 (4H, 2.5 (1H, 2.87 (1H, br d, J=13.8Hz), 3.01-3.55 (4H, 6.87-7.12 (4H, 7.42-7.59 (4H, 8.73 (1H, 10.48 (1H, s) API-ES MS m/z: 432 (M++Na) Anal. Calcd. for C 19

H

2 0 C1NO 5 S: C 55.68, H 4.92, N 3.42 Found: C 55.67, H 5.28, N 3.23 Example 16 A solution of oxalyl chloride (55.8 mg) in dichloromethane (0.5 ml) was added dropwise to a stirred solution of crude (2R or 2 S)-[4-(4-chlorophenoxy)phenyl]- 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (an optical isomer A, 87 mg) obtained in Example 12 and N,N-dimethylformamide (0.80 mg) in dichloromethane (0.88 ml) under ice cooling and a nitrogen atmosphere, then the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and 30 minutes, and evaporated in vacuo. The residue was dissolved in WO 00/40576 PCT/JPO/00018 117 dichloromethane (0.9 ml) and the solution was added dropwise to a stirred mixture of hydroxylammonium chloride (91.7 mg), IN aqueous solution of sodium hydroxide (1.3 ml), tetrahydrofuran (2.6 ml), and tert-butyl alcohol (1.3 ml) at room temperature and the resulting mixture was stirred at the same temperature for 1 hour and 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (eluent: toluene ethyl acetate acetic acid) over silica gel (1.9 g) to afford a pale brown powder (67 mg), which was washed with diisopropyl ether to afford (R or S)-(-)-2-[4-(4-chlorophenoxy)phenyl]-3,4,5,6tetrahydro-N-hydroxy-2H-thiopyran-2-acetamide 1,1-dioxide (optical isomer A, 55 mg) as a colorless powder.

mp: 183.5-187°C (dec.) [a]28: (C=0.71, MeOH) IR (KBr): 3446, 3423, 1653, 1284, 1250, 1119 cm-1 NMR (DMSO-d 6 1.75-2.05 (4H, 2.5 (1H, m), 2.87 (1H, br d, J=12.9Hz), 3.01-3.5 (4H, 7.00 (2H, d, J=8.9Hz), 7.08 (2H, d, J=8.9Hz), 7.46 (2H, d, J=8.9Hz), 7.56 (2H, d, J=8.9Hz), 8.73 (1H, s), 10.48 (1H, s) API-ES MS m/z: 432 and 434 (M++Na) API-ES MS m/z: 408 and 410 Analytical chiral HPLC: column: Chiralpak AS (4.6 x 250 mm, Daicel Chemical Industries, Ltd.) eluent: n-hexane-ethanol-TFA (700:300:1) flow rate: 1.0 ml/minute detection: 220 nm retention time: 18.2 minutes Example 17 (R or 2 -[4-(4-Chlorophenoxy)phenyl]-3,4,5,6- WO 00/40576 PCT/JPOO/00018 118 tetrahydro-N-hydroxy-2H-thiopyran-2-acetamide 1, 1-dioxide (41 mg) was prepared from crude (2R or chiorophenoxy) phenyl 4, 5, 6-tetrahydro-2H-thiopyran-2acetic acid 1,1-dioxide (an optical isomer B, 87 mg) obtained in Example 11 in a similar manner to that of Example 16.

mp: 187-188*C (dec.) [a]2 8 10.50 (C=0.56, MeOH) IR (KBr) :3444, 3423, 3317, 3224, 1655, 1284, 1250, 1122 cm- 1 NMR (DMSO-d 6 6) 1. 75-2. 05 (4H, in), 2. 5 (1H, in), 2. 87 (1H, br d, J=13. 6Hz) 3. 01-3. 52 (4H, in), 7.00 (2H, d, J=8 .9Hz) 7. 08 (2H, di, J=8. 9Hz) 7 .46 (2H, d, J=8.9Hz), 7.56 (2H, d, J=8.9H-z), 8.73 (1H, s), 10.48 (1H, s) +)API-ES MS m/z: 432 and 434 (M ++Na) ()APT-ES MS m/z: 408 and 410 Analytical chiral HPLC: column: Chiralpak AS (4.6 x 250 mm, Daicel Chemical Industries, Ltd.) eluent: n-hexane-ethanol-TFA (700:300:1) flow rate: 1.0 mi/minute detection: 220 nin retention time: 27.9 minutes Example 18 2- (4-Chlorophenoxy) phenyl] 4, 5, 6-tetrahydro-Nhydroxy-6-methyl-2H-thiopyran-2-acetamiie 1, 1-dioxide mg) was prepared from 2- (4-chlorophenoxy) phenyll -3,4,5,6tet rahydro- 6-methyl -2H-thiopyran-2 -acetic acid 1, 1-dioxide mg) in a similar manner to that of Example mp: 10200 (dec.) IR (KBr): 3446 and 3421 1668, 1282, 1246, 1124 cm'1 NMR (DMSO-d 6 1.17 (3H, di, J=6.6Hz), 1.5-2.05 (4H, WO 00/40576 PCT/JPOO/00018 119 in), 2.4 (iR, in), 2.8-2.95 (1H, br d) 3.09 (1H, d, OHz) 3. 23 (1H, d, J=15. OHz) 3 .54 (1H, in), 7.00 (2H, d, J=8.8Hz), 7.08 (2H, d, J=8.9Hz), 7. 42-7. 49 (2H, mn), 7. 56 (2H, d, J=8. 9Hz) 8 .73 (1H, 10.49 (1H, s) ()API-ES MS in/z: 446 and 448 (Me-INa) Example 19 3,4,5, 6-Tetrahydro-N-hydroxy-2- (4-phenoxyphenyl) -2Hthiopyran-2-acetamide 1,1-dioxide (41 ing) was prepared from 3,4,5, 6-tetrahydro-2- (4-phenoxyphenyl) -2H-thiopyran-2-acetic acid 1,1-dioxide (66 mg) in a similar manner to that of Example mp: 182-183*C (dec.) IR (KBr): 3446 and 3423 1655, 1288, 1246, 1115 cm- 1 NMR (DMSO-d 6 6) 1. 75 05 (4 H, in), 2. 4 (1H, in), 2.8 7 (1H, br d, J=13.OHz), 3.04-3.55 (4H, in), 6.96 (2H, d, J=8.9Hz), 7.06 (2H, d, J=7.5Hz), 7.19 (1H, t, J=7.3Hz), 7.43 (2H, t, J=7.4Hz), 7.54 (2H, d, J=8.9Hz), 8.74 (1H, 10.48 (1H, s) APCI MS m/z: 376 343 (M+-NHOH) -)API-ES MS m/z: 374 Example 2- (4-Chlorophenoxy)phenyl]>2,3,4, hydroxy-2-thiophene-2-acetamide 1,1-dioxide (88 ing) was prepared from 2 4 4 -chlorophenoxy)phenyl--2, 3,4,5tetrahydrothiophene-2-acetic acid 1, 1-dioxide (122 ing) in a similar manner to that of Example inp: 63-68"C (dec. IR (KBr): 3423 (br) 1662, 1296, 1244, 1126 cm- 1 NMR (DMSO-d 6 8) 2.19-2.23 (2H, m) 2. 56-3. 28 (6H, in), 6. 99-7 .10 (4H, in), 7. 38-7 .48 (4H, in), 8. 73 (1H, 10.40 (1H, s) WO 00/40576 PCT/JPOO/000i 8 120 +)APCI MS m/z: 396 and 398 363 and 365 -NH-OH) Anal. Calcd. for C 1 8

H

1 8 ClNO 5 S: C 54.61, H 4.58, N 3.54 Found: C 55.20, H 5.06, N 3.26 Example 21 To a solution of potassium hydroxide (400 g) in water (200 ml) was added a solution of ethyl 7-amidinothio-3-[4- 4 -chlorophenoxy)phenylhept2enoate hydroiodide (70.1 g) in tetrahydrofuran (100 ml), and the mixture was refluxed overnight. After the solution was cooled and acidified with 1N HCl, the mixture was extracted with ethyl acetate (100 ml x 3) The combined organic layer was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2 4 -(4-chlorophenoxy)phenyl]- 3,,,-erhdo2Htiprn2aei acid (60 g) as an yellow oil.

NMR (CDCl 3 1.51-1.90 (4H, in), 2.26-2.38 (1H, in), 2.48-2.68 (3H, in), 2.90 (2H, d, J=l4Hz), 2.98 (2H, d, J=l4Hz), 6.94 (4H, d, J=8Hz), 7.27 (2H, d, J=8Hz), 7.57 (2H, d, J=8Hz) MS m/z: 361 (M-H) Example 22 4 -Bromophenoxy)phenyl] 6-tetrahydro-2Hthiopyran-2 -acetic acid (3.99 g) was obtained in a similar manner to that of Example 21.

NMR (CDCl 3 1.50-1.87 (4H, mn), 2.27-2.49 (1H, in), 2.47-2.70 (3H, in), 2.90 (1H, d, J=l5Hz), 3.00 (1H, d, J=15Hz), 6.96 (4H, di, J=9Hz), 7.44 (4H, d, J=9Hz) MS (ESI-) m/z: 407 CM-H) Example 23 Ethyl 2 4 fluorophenyl)2thienylp-3,45,6 WO 00/40576 PCTP00/0001 8 121 tetrahydro-2H-thiopyran-2-acetate (117 mg) was obtained from 7-amidinothio-3-[5-(4-fluorophenyl)-2-thienyl]hept-2-enoate hydroiodide in a similar manner to that of Example 21.

NMR (CDC1 3 1.12 (3H, t, J=7Hz), 1.49-1.92 (4H, 2.18-2.30 (1H, 2.55-2.68 (2H, 2.73- 2.82 (1H, 2.81 (1H, d, J=14Hz), 2.89 (1H, d, J=14Hz), 4.01 (2H, q, J=7Hz), 6.93-7.11 (4H, m), 7.49-7.56 (2H, m) Example 24 To a solution of ethyl 3-(4-biphenylyl)-7-chlorohept-2enoate (0.90 g) in acetone (15 ml) was added Nal (1.55 g) at 0 C. After being stirred overnight, the reaction mixture was cooled, concentrated in vacuo, diluted with water, and extracted with ether. The ether extract was washed with brine, dried over MgSO 4 and concentrated in vacuo. A mixture of this residue and thiourea (158 mg) in ethanol (EtOH) (15 ml) was refluxed with stirring for 24 hours. -The resulting mixture was cooled and concentrated in vacuo to yield the isothiouronium salt. To a solution of potassium hydroxide (KOH) (1.74 g) in water was added this isothiouronium salt, and the mixture was refluxed with stirring for 8 hours. The reaction mixture was cooled at 0 C and was quenched by cautions dropwise addition of a solution of 50% aqueous sulfuric acid (H 2

SO

4 until acidic. The mixture was extracted with ether, and the organic layers were washed with water and brine, dried over magnesium sulfate (MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: methanol (MeOH) in chloroform (CHC13) to give 2-(4biphenylyl)-3,4,5,6-tetrahydro-2H-thiopyran-2-acetic acid (335 mg) as an amorphous.

NMR (CDC13, 1.60-1.85 (4H, 2.30-2.39 (1H, m), 2.50-2.70 (3H, 2.94 (1H, d, J=14.7Hz), 3.01 (1H, d, J=14.7Hz), 7.34 (1H, dd, J=7, 7Hz), 7.56- WO 00/40576 PCT/JPOO/00018 122 7. 61 (4H, in), 7 .68-7. 71 (2H, m) MS (ESI-) in/z: 311 (M-H) Example 2 (4-Fluorophenoxy) phenyl] 4, 5, 6-tetrahydro-2Hthiopyran-2-acetic acid (200 mng) was obtained in a similar manner to that of Example 24.

NMR (CDC1 3 6) 1. 60-1. 84 (4H, mn), 2.27-2. 36 (1H, in), 2. 50-2. 67 (3H, in), 2. 88 (1H, d, J=l5Hz) 2. 97 (11-, d, J=l6Hz), 6.91 (2H, d, J=9Hz), 6.99-7.06 (4H, in), 7. 56 (2H, d, J=9Hz) MS (ESI-) m/z: 345 (M-H) Example 26 2 (4-Chlorophenyl) phenyl]1-3, 4,5, 6-tetrahydro-2Hthiopyran-2-acetic acid (310 mg) was obtained in a similar manner to that of Example 24.

NMR (CDCl 3 6) 1. 60-1. 85 (4H, mn), 2.29-2. 38 (1H, in), 2. 52-2. 69 (3H, in), 2. 94 (1H, d, J=14. 7Hz) 3. 01 (1H, d, J=14.7Hz), 7.39 (2H, d, J=8Hz), 7.50-7.54 (4H, in), 7. 69 (2H, d, J=8Hz) MS (ESI-) m/z: 345 (M-H) Example 27 2 4 (4-Bromopheny1) phenyl] 4, 5, 6-tetrahydro-2Hthiopyran-2-acetic acid (120 mng) was obtained in a similar manner to that of Example 24.

NMR (CDC1 3 1.61-1.85 (4H, mn), 2.29-2.36 (1H, in), 2.51-2.69 mn), 2.94 (1H, d, J=14.7Hz), 3.01 (iR, d, J=14.7Hz), 7.45 (2H, d, J=9Hz), 7.51-7.57 (4H, mn), 7. 69 (2H, d, J=9Hz) MS (ESI-) m/z: 389 (M-N) Example 28 2 -[4-(4-Fluorophenyl)phenyl]-3, 4,5, 6-tetrahydro-2H- WO 00/40576 WO 0040576PCT/JPOO/noni x 123 thiopyran-2-acetic acid (200 mg) was obtained in a similar manner to that of Example 24.

NMR (ODC1 3 1.60-1.85 (4H, in), 2.29-2.38 (1H, mn), 2.53-2.67 (2H, in), 2.94 (1H, d, J=l5Hz), 3.01 (1H, d, Jl16Hz), 7.07-7.12 (2H, mn), 7.51-7.56 (4H, mn), 7.69 (2H, d, MS (ESI-) m/z: 329 (M-H) Example 29 2 -[S-(4-Chlorophenyl)-2-thienyl]-3,4,5,6tetrahydro-2Hthiopyran-2-acetic acid (2.5 g) was obtained in a similar manner to that of Example 24.

NMR (DMSO-d 6 6) 1. 55-1. 75 (4H, in), 2.25-2. 32 (1H, in), 2.45-2.63 (3H, in), 2.74 (1H, d, J=l4Hz), 3.97 (1H, d, J=14Hz), 7.02 (1H, d, J=3.6Hz), 7.40 (1H, d, J=3.6Hz), 7.45 (2H, d, J=8.7Hz), 7.64 (2H, d, J=8.7Hz) MS (ESI-) in/z: 351 (M-H) Example 2- (5-Bromo-2-thienyl) 3 4 1 -tetrahydro-2H-thiopyran- 2-acetic acid (8.5 g) was obtained in a similar manner to that of Example 24.

NMR (DMSO-d 6 45-1.73 (4H, in), 2. 12-2. 20 (1H, in), 2.45-2.70 (4H, in), 2.87 (1HI, d, J=14.4Hz), 6.84 d, J=4.2Hz), 7.08 (1H, d, J=4.2Hz) Example 31 l -Ethyl 3 -diiethylaiinopropyl) carbodiimide

(WSCD)

hydrochloride (205 mg) was added to a stirred mixture of 2- 4 4 -chlorophenoxy)phenyl..3,4, 5 6 -tetrahydro-2H--thiopyran- 2-acetic acid 1, 1-dioxide (326 ing), -a-methylbenzylamine (105 ing) and l-hydroxybenzotriazole (123 mng) in dichlorornethane (8 ml) under ice cooling, and then the resulting mixture was stirred at the same temperature for 2 WO 00/40576 PCT/JPOO/00018 124 hours and at room temperature for 2 hours and extracted with dichioromethane. The extract was washed successively with water, 0.1N hydrochloric acid, water, and a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (eluent: toluene ethyl acetate) over silica gel to afford diastereomer A (180 mg) and diastereomer B (181 mg) of 2 4 -(4--chlorophenoxy)phenyl]- 3, 4,5, 6-tetrahydro-2H-thiopyran-2-N- (IR) -1phenylethyl]acetamide 1,1-dioxide as a colorless solid and colorless crystals, respectively.

Diastereomer

A:

mp: 138-160.5*C D 31.00 (C=0.52, MeOH) IR (KBr) 3421 (br) 1651, 1288, 1244, 1124 cm- 1 NMR (CDCl 3 1.06 d, J=6.8Hz), 1.94-2.15 (4H, in), 2.68-2.74 (2H, in), 2.99-3.26 (4H, mn), 4.72- 4.87 (1H, in), 5.21 (1H, br d, J=8.OHz), 6.97 (2H-, d, J=9.OHz), 7.00-7.11 (4H, in), 7.19-7.37 in), 7.70 (2H, d, J=9.OHz) APCT MS m/z: 498 and 500 Diastereomer

B:

mp: 82.5-89'C [az]2 7 53.40 (C=0.50, MeOH) IR (KBr) 3365 (br) 1651, 1288, 1246, 1122 crrJ 1 NMR (00013, 1.32 (3H, d, J=6.9Hz), 1.91 (2H, in), 2.13 (2H, in), 2.62 (2H, in), 2.99-3.30 in), 4.85 (1H, in), 5.31 (1H, br d, J=8.OHz), 6.74-6.80 (2H, in), 6.90-6.99 (4H, mn), 7.15-7.36 (5H, in), 7.58 (2H, d, J=9.OHz) +)APCI MS m/z: 498 and 500 (M+f1) Example 32 To a solution of (2R or 2

S)-

2 4 -(4-chlorophenoxy)- WO 00/40576 PCT/JP00/00018 125 phenyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (4.75 g) obtained in Example 10, 0-(2tetrahydropyranyl)hydroxylamine (2.11 and l-hydroxybenzotriazole (1.95 g) in N,N-dimethylformamide ml) was added WSCD hydrochloride (2.77 After being stirred for 4 hours at room temperature, the solvent was evaporated in vacuo, and the resulting residue was dissolved in ethyl acetate (60 ml). The solution was washed with aqueous citric acid solution, saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give (2R or 2S)-N-( 2 -tetrahydropyranyloxy)-2-[4-(4-chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (6.52 g) as a slightly yellow oil.

NMR (CDC1 3 1.46-2.22 (10H, 2.77 (1H, br), 3.02-3.28 (4H, 3.38-3.55 (1H, 3.65-3.78 (1H, 4.37 (0.5H, 4.77 (0.5H, 6.95 (2H, d, J=8Hz), 7.00 (2H, d, J=8Hz), 7.29 (2H, d, J=8Hz), 7.65 (2H, d, J=8Hz), 8.28 (1H, br) MS (ESI-) m/z: 493 (M-H) The following compounds were obtained in a similar manner to that of Example 32.

Example 33 2 -[4-(4-Chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetamide (140 mg) NMR (CDC13, 1.42-1.91 (10H, 2.23-2.36 (1H, 2.49-2.72 (4H, 2.74-2.83 (1H, 3.45- 3.58 (1H, 3.71-3.83 (1H, 4.55 (1H, s), 4.79 (0.5H, 6.89-7.03 (4H, 7.27 (2H, d, J=8Hz), 7.60 (2H, d, J=8Hz), 7.96 (0.5H, 8.16 s) MS (ESI-) m/z: 460 (M-H) WO 00/40576 PCT/JP00/000i 8 126 Example 34 N- 2 -Tetrahydropyranyloxy) (4 -fluorophenoxy) phenyl]-3,4,5,6tetrahydro2Hthiopyran-2acetamide 1,1dioxide (307 mg) NMR (C~DC 3 1.53-1.70 (10H, in), 2.08-2.17 (2H, in), 2.73-2.76 (2H, mn), 3.02-3.23 (4H, mn), 3.42-3.52 (1H, in), 6.98-7.05 (6H, in), 7.64 (2H, d, J=9Hz) MS (ESI-) m/z: 476 (M-H) Example N- 2 -Tetrahydropyranyloxy) (4-fluorophenoxy) phenylI- 3 ,4,5,6tetrahydro2Hthopyran2acetaide (250 mg) NMR (C~DC 3 1.50-1.64 (6H, mn), 1.74-1.78 (4H, mn), 2.25-2.34 (2H, mn), 2.52-2.70 (4H, mn), 2.76-2.82 (1H, in), 3.49-3.57 (1H, in), 3.72-3.83 (1H, mn), 6.95-7.04 (6H, in), 7.59 (2H, d, J=9Hz) MS (EST-) m/z: 444 (N-H) Example 36 N- 2 -Tetrahydropyranyloxy) 2 4 -(4-fluorophenoxy)phenyll-3,4, 5, 6 -tetrahydro-2H-thiopyran2acetamide 1-oxide (152 ing) NMR (C~DC 3 1.54-1.81 (10H, mn), 2.45-2.56 (2H, in), 2.75-2.96 (5H, in), 3.53-3.59 (iN, mn), 3.81-3.87 (1N, mn), 6.95-7.04 mn), 7.39 (2H, di, J=9Hz) MS (ESI-) m/z: 460 (N-H) Example 37 N- 2 -Tetrahydropyranyloxy) (4-fluorophenoxy) phenyl]-3,4,5,6-tetrahycro2thiopyran-2acetanide 1,1dioxide (173 ing) NMR (C~DC 3 1.45-1.75 (6H, in), 1.89-2.01 (2H, mn), 2.06-2.20 (2H, in), 2.68-2.80 (2H, in), 3.00-3.24 (4H, in), 3.40-3.55 (1H, in), 3.64-3.75 (1H, in), 4.49 (0.5H, br 4.75 (0.5H, br 6.93 (2H, di, WO 00/40576 PCT/JPOO/00018 127 J=9Hz) 7 .04 d, J=9Hz) 7. 45 (2H, d, J=9Hz) 7. 67 (2H, d, J=9Hz) 7 .77 (2H, d, J=9H-z) 7. 77 br 7.90 br s) MS (ESI-) in/z: 536 (M-H) Example 38 N- (2-Tetrahydropyranyloxy) 4- (4-f luorophenyl) phenoxy] phenyl] 4, 5, 6-tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (122 ing) NMR (CDCl 3 6) 1. 45-1. 79 in), 1. 88-2. 02 in), 2.06-2.24 (2H, in), 2. 66-2 .82 (2H, in), 3. 00-3. (4H, in), 3.40-3.56 (1H, mn), 3. 64-3. 77 (1H, in), 4.41 (0.5H, br 4.75 (0.5H, br 7.00-7.18 (6H, mn), 7.42-7.56 (4H, in), 7 .67 d, J=9Hz) 7.75 (0.5H, br 7.89 (0.5H, br s) MS (ESI-) m/z: 552 Example 39 N- (2-Tetrahydropyranyloxy) (4-inethoxyphenyl) 4, 5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (113 mg)' NMR (CDC1 3 1.41-1.72 (6H, in), 1.87-2.01 (2H, in), 2.06-2.21 (2H, in), 2.59-2.81 (2H, in), 3.00-3.25 (4H, mn), 3.32-3.73 (2H, in), 3.81 (3H, 4.37- 4.44 (0.5H, mn), 4.69-4.79 (0.5H, mn), 6.91-7.03 (2H, mn), 7.53-7.69 (2H, in), 7.70-7.91 (1H, in) MS (ESI-) in/z: 396 (M-H) Example N- (2-Tetrahydropyranyloxy) 5- (4 -f luorophenyl) -2thienyll-3,4,5, G-tetrahydro-2H-thiopyran-2-acetanide (145 ing) NMR (CDC1 3 1.45-1.99 (10H, in), 2.17-2.32 (1H, mn), 2.50-2.97 (3H, in), 3.40-3.51 in), 3.71-3.86 (1H, mn), 4.70 (0.5H, 4.86 (0.5H, 6.93-7.19 (4H, mn), 7.52-7.67 mn), 8.09 (0.5H, 8.22 WO 00/40576 PCT/JPOO/00018 128 s) MS (ESI-) in/z: 434 (M-H) Example 41 N- 2 -Tetrahydropyranyloxy) 2 5- (4 -fluorophenyl) -2thienyl] 4,5, G-tetrahydro-2H-thiopyran-2acetamide 1, 1dioxide (345 ing) NMR (CDCl 3 1.39-1.79 (6H, mn), 1.89-2.00 (2H, mn), 2.05-2.27 (2H, mn), 2.64-2.92 (2H, mn), 3.06 (1H, s), 3.09-3.16 (lH, mn), 3.27-3.50 (1H, in), 3.61-3.73 (1H, mn), 4. 53 5H, br s) 4 .82 (1H, br s) 7. 02- 7.11 (2H, in), 7.16-7.27 (2H, in), 7.55 (1H, d, J=8Hz) 7. 57 (1H, d, J=8Hz) 7. 97 (0.5H, 8. 13 (1H, br s) Example 42 N- 2 -Tetrahydropyranyloxy) (4-biphenylyl) -3,4,5,6tetrahydro-2H-thiopyran.2-acetamide (330 mg) NMR (CDC1 3 1.45-1.81 (10H, mn), 2.29-2.38 (TH, mn), 2.52-2.96 (7H, mn), 3.58-3.75 (1H, in), 7.35-7.37 (1H, mn), 7.42-7.47 (2H, in), 7.56-7.64 (4H, mn), 7.71-7.75 (2H, mn) MS (ESI-) m/z: 410 CM-H) Example 43 N- 2 -Tetrahydropyranyloxy) (4-biphenylyl) -3,4,5,6tetrahydro-2H-thiopyran2acetanide 1,1-dioxide (390 mg) NMR (CDC1 3 1.38-1.66 (6H, mn), 1.95-2.03 (2H, mn), 2.12-2.21 (2H, in), 2.73-2.84 (2H, mn), 2.89 (1H, s), 2.96 (1H, 3.04-3.31 (4H, mn), 3.50-3.62 (1H, in), 7.35-7.47 (3H, mn), 7.58-7.60 (2H, in), 7.65-7.70 (2H. in), 7.77-7.81 (2H, in) MS (ESI-) rn/z: 442 (M-H) Example 44 WO 00/40576 PCT/JPOO/00018 129 N- (2-Tetrahydropyranyloxy) -2-114- (4chiorophenyl) phenyl]) 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (300 mg) NMR (CDC1 3 8) 1.60-1.66 (6H, mn), 1.94-2.03 (2H, in), 2.13-2.21 (2H, mn), 2.-76-2.84 (2H, in), 2.89-2.96 (2H, in), 3.07-3.27 (4H, mn), 3.53-3.65 (1H, mn), 7.41 (2H, d, J=8.5Hz), 7.51 (2H, d, 7.60-7.64 (2H, in), 7.76-7.80 (2H, mn) MS (ESI-) m/z: 476 (M-H) Example N- (2-Tetrahydropyranyloxy) (4-broinophenyl)phenyl] 3, 4 5 ,6-tetrahydro-2H-thiopyran-2-acetamiie 1,1-dioxide (100 mg) NMR (CDC1 3 1.44-1.62 (10H, in), 2.10-2.20 (2H, mn), 2.76-2.84 (2H, mn), 3.05-3.31 (4H, mn), 3.53-3.65 (1H, mn), 7.45 (2H, d, J=9Hz), 7.56-7.64 (4H, in), 7.70-7.77 (2H, m) MS (ESI-) m/z: 520 Example 46 N- (2-Tetrahydropyranyloxy) (4f luorophenyl) phenyl 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (230 mg) NMR (CDCl 3 6) 1. 45-1. 70 (10H, mn), 2. 12-2. 19 (2H, in), 2. 79-2. 81 (2H, 05-3 .32 (4H, mn), 3. 55-3. 64 (1H, mn), 7. 13 (2H, dd, J=9, 9Hz) 7. 52-7. 61 (4H, in), 7.73-7.78 (2H, in) MS (ESI-) in/z: 460 (M-H) Example 47 N- (2-Tetrahydropyranyloxy) (4-phenoxybenzyl) 4, 5, 6tetrahydro-2H-thiopyran-2-carboxamide 1, 1-dioxide (360 ing) NMR (CDC1 3 6) 1. 45-2. 31 (12H, in), 2 .42-2.63 (1H, in), 3. 03-3. 20 (3H, mn), 3. 43 1H-, d, J=l4Hz) 3. 57-3. WO 00/40576 PCT/JPOO/00018 130 (1H, mn), 3. 84-4 .02 (1H, in), 4 .91, 5. 11 (1H, s), 6. 91 (2H, d, J=8Hz) 6. 97-7. 14 (3H, in), 7 .19 (2H, t, J=8Hz) 7. 28-7 .48 (2H, mn), 9. 99, 10. 07 (1H, s) MS (ESI-) m/z: 458 (M-H) Example 48 N- (2-Tetrahydropyranyloxy) (4-phenoxybenzyl) -3,4,5,6tetrahydro-2H-thiopyran-2-carboxamide (320 ing) NMR (ODC1 3 1.33-2.00 (12H, in), 2.47-2.59 (1H, mn), 2.64-2.90 (3H, in), 3.08-3.22 (1H, in), 3.50-3.65 (1H, mn), 3.75-4.00 (1H, in), 4.70, 4.98 s), 6.87-7.20 (7H, in), 7.32 (2H, t, J=8Hz), 9.70 (1H, s) MS (ESI-) m/z: 426 (M-H) Example 49 N- (2-Tetrahydropyranyloxy) (4-biphenylylinethyl) 3,4,5, 6 -tetrahydro-2H-thiopyran-2-carboxamide 1,1-dioxide (152 ing) NMR (CDCd 3 1.54-2.35 (12H, in), 2.45-2.66 (1H, mn), 3.08-3.25 (3H, mn), 3.33-3.55 (1H, mn), 3.56-3.70 (1H, mn), 3.82-4.08 (1H, in), 4.95, 5.14 (1H, s), 7.23-7.36 (3H, in), 7.42 (2H, t, J="8Hz), 7.47-7.67 (4H, in), 10.01, 10.08 (1H, s) MS (ESI-) m/z: 442 (M-H) Example N- (2-Tetrahydropyranyloxy) (4-phenoxyphenyl) -1,3cithiane-2-acetamide (150 mng) NMR (DMSO-d 6 1.47-1.62 (6H, mn), 1.85-1.90 (2H, in), 2.73 (2H, 2.89 (4H, br), 3.33 (2H, mn), 4.57 (1H, 6.98 (2H, d, J=8.OHz), 7.03 (2H, d, J=8.OHz), 7.16 (1H, dd, J=8.0, 8.0Hz), 7.40 (2H, dd, J=8.0, 8.0Hz), 7.83 (2H, d, J=8.1-z) MS (ESI-) in/z: 444.1 (M-H) WO 00/40576 PCT/JPOO/00018 131 Example 51 N- (2-Tetrahydropyranyloxy) 2 (4-chlorophenylj -2thienyll- 3 ,4,5,6-tetrahydro-2H.thiopyran2.acetamide 1,1dioxide (250 mg) NMR (CDCl 3 1.45-1.67 (10H, m) 1.90-1.97 (2H, in), 2.67-3.12 (6H, mn), 3.62-3.68 (1H, in), 7.24-7.26 (2H, in), 7.35 (2H, d, J=8.7Hz), 7.52 (2H, d, J=8.7H-z) MS (ESI-) in/z: 482 (M-H) Example 52 N- (2-Tetrahydropyranyloxy) (5-bromo-2-thienyl) 3 4 ,5,6-tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (190 mng) NMR (CDCl 3 1.50-2.17 (11H, mn), 2.65-3.10 (6H, in), 3.47-3.58 (1H, mn), 3.72-3.81 (1H, in), 7.00-7.05 (2H, in) MS (ESI-) in/z: 450 (M-H) Example 53 (2R or 2S)-N- 2 -Tetrahydropyranyloxy)-2-(5..brono-2thienyl) 4, 5, 6-tetrahydro-2H-thiopyran-2-acetamide 1, 1 dioxide (80 mng) from (2R or 2S) 2 -(5-broino-2-thienyl)- 3,4,5, G-tetrahydro-2H-thiopyran-.2acetic acid 1, 1-dioxide (63 mng) obtained in Example 13 NMR (CDCl 3 1.50-2.17 (11H-, in), 2.65-3.10 (6H, in), 3.47-3.58 (1H, in), 3.72-3.81 (1H, in), 7.00-7.05 (2H, in) MS (ESI-) in/z: 450 (M-H) Example 54 To a mixture of (2R or 2 2 -tetrahydropyranyloxy)- 2 4 4 -chlorophenoxy)phenyllj-3,4,5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (6.51 g) obtained in Example 32 in methanol (40 ml) was added 10% hydrogen WO 00/40576 PCT/JP00/00018 132 chloride in methanol (10 ml) at room temperature. After being stirred for 30 minutes, the solution was concentrated.

The residue was purified with silica gel column chromatography (eluent: hexane-EtOAc 1:1) to give (2R or 2S)-(-)-N-hydroxy-2-[4-(4-chlorophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (optical isomer A, 4.72 g) as white crystalline.

[a] 2 5 -13.7 0 C (C=0.98, MeOH) Analytical chiral HPLC: column: Chiralpak AS (4.6 x 250 mm, Daicel Chemical Industries, Ltd.) eluent: n-hexane-ethanol-TFA (700:300:1) flow rate: 1.0 ml/minute detection: 220 nm retention time: 18.2 minutes The following compounds were obtained in a similar manner to that of Example 54.

Example N-Hydroxy-2-[4-( 4 -chlorophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetamide (61 mg) NMR (DMSO-d 6 1.32-1.78 (4H, 2.30-2.58 (4H, 2.60-2.73 (2H, 6.96-7.08 (4H, 7.43 (2H, d, J=8Hz), 7.55 (2H, d, J=8Hz), 10.19 (1H, s) MS (ESI-) m/z: 376 (M-H) Example 56 N-Hydroxy-2-[4-( 4 -fluorophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (220 mg) NMR (DMSO-d 6 1.75-2.03 (4H, 2.99 (1H, d, J=14Hz), 3.19 (1H, d, J=14Hz), 3.34-3.50 (4H, m), 6.94 (2H, d, J=9Hz), 7.09-7.14 (2H, 7.23-7.29 (2H, 7.53 (2H, d, J=9Hz), 8.74 (1H, s) MS (ESI-) m/z: 392 (M-H) WO 00/40576 PCT/JPOO/00018 133 Example 57 N-Hydroxy-2- 4 -f luorophenoxy) phenyl]1 4,5, 6tetrahydro-2H-thiopyran-2-acetamide (143 mg) NMR (DMSO-d 6 1.46-1.73 (4H, in), 2.35-2.49 (4H, in), 2.64-2.71 (2H, in), 6.93 (2H, d, J=9Hz), 7.05- 7.09 (2H, in), 7.20-7.26 (2H, mn), 7.53 (2H, d, J=9Hz), 8.62 (1H, 10.18 (1H, s) MS (ESI-) m/z: 360 (M-H) Example 58 N-Hydroxy-2-[4-(4-fluorophenoxy)phenyl]>3,4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1-oxide (80 mg) NMR (DMSO-d 6 1.47-1.65 (4H, in), 1.95-2.02 (1H, in), 2.25-2.44 (3H, mn), 2.57 (1H, d, J=14Hz), 2.70 (1H, d, J=l4Hz), 6.96 (2H, d, J=9Hz), 7.07-7.12 (2H, mn), 7.22-7.28 (2H, mn), 7 .40 (2H, d, J=9Hz) 8.64 (1H, 10.31 (1H, s) MS (ESI-) m/z: 376 (M-H) Example 59 N-Rydroxy-2- (4-bromophenoxy) phenyll 4,5, 6tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide (104 ing) NMR (CDC1 3 6) 1. 86-1. 97 (2H, mn), 2. 02-2.23 (2H, m) 2. 60-2. 80 (2H, mn), 3. 01-3.-24 (4H, in), 6. 93 (2H, d, J= 9H 7. 01 (2 H, d, J= 9H z) 7. 46 (2 H, d, J= 9Hz) 7. 64 (2H, d, J=9Hz) MS (ESI-) in/z: 452 (M-H) Example N-Hydroxy-2- [4 4 -f luorophenyl) phenoxyl phenyl] 3, 4, 5, 6 -tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide (63 mng) NMR (CDC1 3 6:1. 87-2. 00 (2H, mn), 2. 04-2. 25 (2H, m) 2. 60-2. 82 (2H, mn), 3. 01-3. 25 (4H, mn), 7. 00-7 .19 WO 00/40576 PCT/JPOO/0001 8 134 (6H, in), 7 .47-7 .57 (4H, mn), 7. 64 (2H, d, J=9Hz) MS (ESI-) m/z: 468 (M-H) Example 61 N-Hydroxy-2- (4-methoxyphenyl) 4, 5,6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (21 mg) NMR (DMSO-d 6 S, 1.70-2.05 (4H, mn), 2.39-2.52 (1H, mn), 2.81-2.91 (1H, mn), 2.95-3.22 (4H, mn), 3.26 (3H, 6.91 (2H, d, J=9Hz), 7.45 (2H, d, J=9Hz), 8.70 (1H, 10.46 (1H, s) MS (ESI-) m/z: 312 (M-H) Example 62 N-Hydroxy-2- (4-fluorophenyl) -2-thienyl] -3,4,5,6tetrahydro-2H-thiopyran-2-acetamide (87 mg) NMR (CDC1 3 1.45-1.85 (4H, m) 2.35-2.74 (4H, mn), 2.46 (1H, d, J=l4Hz), 2.66 (1H, d, J=l4Hz), 7.17- 7.33 (3H, mn), 7.45 (1H, d, J=3Hz), 7.64-7.77 (2H, 8.74 (1H, s) MS (ESI-) m/z: 350 (M-H) Example 63 N-Hydroxy-2- (4-fluorophenyl) -2-thienyl]-3, 4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (286mig) NMR (CDCl 3 1.'69-2.07 O4H, mn), 2.35-2.48 (2H, mn), 2.94-3.54 (4H, in), 7.17-7.33 (3H, mn), 7.45 (1H, d, J=3Hz), 7.64-7.77 (2H, in), 8.74 (1H, s) MS (ESI-) m/z: 382 (M-H) Example 64 N-Hydroxy-2- (4-biphenylyl) 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide (230 mng) NMR (DMSO-d 6 6) 1. 61-1. 79 (4H, mn), 2. 39-2. 56 (2H, mn), 2.65-2.75 (3H, mn), 2.89 (1H, 7.36 (1H, dd, J=7, 7Hz), 7.47 (2H, dd, J=7, 7Hz), 7.64-7.69 (6H, WO 00/40576 PCT/JPOO/00018 135 in), 8.63 (1H, s) MS (ESI-) m/z: 326 (M-H) Example N-Hydroxy-2- (4-biphenylyl) 4, 5, 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (230 mg) NMR (DMSO-d 6 6) 1. 77-2 .05 (4H, mn), 2. 49-2. 51 (2H, mn), 3. 19-3.41 (4H, in), 7. 41 (1H, dd, J=7. 5, 7. 5Hz) 7. 49 (2H, dd, J=7. 5, 7. 5Hz) 7. 65-7. 71 (6H, m) 8.74 (1H, s) MS (ESI-) m/z: 358 (M-H) Example 66 N-Hydroxy-2- 4- (4-chiorophenyl) phenyl] 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (150 ing) NMR (DMSO-d 6 6) 1. 78-2.04 (4H, in), 2. 91-3. 10 (2H, mn), 3. 17-3. 36 (4H, in), 7. 54 (2H, d, J=9Hz) 7. 61- 7.69 (4H, in), 7.73 (2H, d, J=9Hz), 8.72 (1H, s) Example 67 N-Hydroxy-2- (4-bromophenyl) phenyl] -3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (70 ing) NMR (DMSO-d 6 1.77-2.06 (4H, mn), 2.93-3.08 (2H, mn), 3.19-3.36 (4H, in), 7.61-7.70 (8H, in), 8.74 (1H,

S)

MS (ESI-) m/z: 436 CM-H) Example 68 N-Hydroxy-2- (4-fluorophenyl) phenyl] -3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (160 mng) NMR (DMSO-d 6 1.77-2.05 (4H, mn), 2.93-3.54 (6H, mn), 7.31 (2H, dd, J=9, 9Hz), 7.63-7.77 (6H, mn), 8.73 (1H, 10.53 (1H, s) MS (ESI-) m/z: 376 (M-H) WO 00/40576 PCT/JPOO/00018 136 Example 69 N-Hydroxy-2- (4-phenoxybenzyl) 4, 5, 6-tetrahydro-2Hthiopyran-2-carboxamidie 1,1I-dioxide (199 mg) NMR (CDCl 3 1.47-2.20 (5H, mn), 2.46-2.62 (1H, in), 2.96-3.20 (3H, mn), 3.43 (1H, di, J=l4Hz), 6.89 (2H, di, J=8Hz), 6.98 (2H, d, J=8Hz), 7.05-7.18 (3H, mn), 7.33 (2H, d, J=8Hz), 7.96 (1H, br 9.98 (1H, br

S)

MS (ESI-) m/z: 374 (M-H) Example N-Hydroxy-2- (4-phenoxybenzyl) 6-tetrahydro-2Hthiopyran-2-carboxamide (203 mg) mp: 124-126'C NMR (CDCl 3 8) 1. 22-1. 38 (1H, in), 1. 45-1. 66 (2H, in), 1. 70-1. 83 (1H, in), 1. 88-1 .98 (iH, in), 2. 43-2. (1Hl, in), 2.60-2.75 (2H, in), 2.80 (1M, di, J=14Hz), 3. 15 (1H, d, J=l 4Hz) 6. 90 (2H, di, J=8Hz) 7 .0.0 (2H, di, J=8Hz), 7.05-7.15 (3H, in), 7.33 (2H, t, J=8Hz), 9.47 (1H, s) MS (ESI-) in/z: 342 CM-H) Example 71 N-Hydroxy-2- (4-biphenylylmethyl) 4, 5,6tetrahydro-2H-thiopyran-2-carboxanide 1,1-dioxide (78 ing) mp: 101-104'C NMR (DMSO-d 6 58-2. 18 (6H, in), 3. 06-3. 17 (1H, mn), 3. 39 (1H, di, J=14Hz) 3. 49-3. 64 (1H, in), 3. (1H, d, J=l4Hz), 7.31 (2H, d, J=8Hz), 7.37 (1H, d, J=8Hz), 7.46 (2H, t, J=8Hz), 7.59 (2H, d, J=8Hz), 7. 65 (2 H, di, J= 8H z) 9. 20 (1 H, s) MS (ESI-) in/z: 358 (M-M) Example 72 N-Hydroxy-2- (4-phenoxyphenyl) 3-dithian-2-acetamide WO 00/40576 PCT/JPOO/0001 8 137 (8 8 mg) NMR (DMSO-d 6 7 38 (2 H, in), 3. 43 (2 H, s), 3.60-3.67 (2H, in), 3.80-3.88 (2H, in), 7.00 (2H, d, J=8.OHz), 7.10 (2H, d, J=8.0Hz), 7.22 (1H, dd, J=8.0, 8.0Hz), 7.45 (2H, dd, J=8.0, 8.0Hz), 8.04 (2H, d, J=8.OHz), 8.94 (1H, s) MS (ESI) in/z: 360.1 CM-H) Example 73 N-Hydroxy-2- 4 -chlorophenyl)-2-thienyl]-3,4,5, 6tetrahydro- 2 H-thiopyran-2acetanide 1, 1-dioxide (200 mng) NMR (DM30-cl 6 1.74-2.02 (4H, in), 2.96-3.52 (6H, in), 7.22 (1H, di, J=3.6Hz), 7.47-7.53 (3H, mn), 7.67 (2H, d, J=8.7Hz), 8.85 (1H, 10.59 (1H, s) MS (ESI-) in/z: 398 CM-H) Example 74 N-Hydroxy-2- (S-broino-2-thienyl) 4, 5, 6-tetrahydro-2Hthiopyran-2-acetainide 1, 1-dioxide (140 ing) NMR (DMSO-d 6 6) 1. 73-2. 00 (4H, mn), 2.26-2. 33 (1H, mn), 2.86-2.96 (2H, mn), 3.11-3.23 (2H, in), 3.40- 3.45 (1H, in), 7.03 di, J=3.9Hz), 7.22 (1H, d, J=3.9Hz), 8.86 (1H, 10.57 (1H, s) MS (ESI-) m/z: 366 (M-H) Example (2R or 2S) -N-Hydroxy-2- (5-bromo-2-thienyl) -3,4,5,6tetrahydro-2H-thiopyran-2acetaiie 1,1-dioxide (65 mng) from (2R or 23)-N- 2 -tetrahydropyranyloxy) (5-broino-2-thienyl) 3,4,5, 6 -tetrahydro-2H-thiopyran-2acetaie 1,1-dioxide ing) obtained in Example 53 [aID2: -1 7.1 0 C (C=0.485, DMF) NMR (DMSO-d 6 73-2. 00 (4H, in), 2. 26-2. 33 (1H, mn), 2. 86-2. 96 (2H, in), 3. 11-3.23 (2H, mn), 3.40- 3.45 (1H, in), 7.03 (1H, di, J=3.9Hz), 7.22 (1H, ci, WO 00/40576 PCT/JPOO/00018 138 J=3. 9Hz) 8 .86 (1H, s) 10. 57 (1H, s) MS (EST-) m/z: 366 (M-H) Optical purity: 95% ee Analytical chiral HPLC: column: Chiralpak AS (4.6 x 250 mm, Daicel Chemical Industries, Ltd.) eluent: n-hexane-ethanol-TFA (700:300:1) flow rate: 1.0 ml/minute detection: 220 nm The following compounds were obtained in a similar manner to that of Preparation 1-4).

Example 76 2 4 -(4-Fluorophenoxy)phenyl] -3,4,5,6-tetrahydro-2Hthiopyran-2--acetic acid 1,1-dioxide (450 mg) NMR (ODC1 3 6) 1. 87-2.21 (4H, in), 2. 67-2. 85 (2H, in), 3.03-3.15 (2H, in), 3.21 d, J=l6Hz), 3.62 -(lH, d, J=l6Hz), 6.94-7.04 (6H, in), 7.59 (2H, d, J=9Hz) MS (ESI-) m/z: 377 (M-H) Example 77 2 -[4-(4-Bromophenoxy)phenyl]-3,4, 5,6-tetrahydro-2Hthiopyran-2-acetic acid 1,1-dioxide NMR (ODC1 3 1.75-2.02 (4H, in), 2.08-2.21 (2H, in), 2.63-2.85 (2H, in), 3.02-3.16 (2H, in), 3.21 (1H, d, J=l6Hz), 3.60 (1H, d, J=l6Hz), 6.92 (2H, d, J=9Hz), 7.00 (2H, d, J=9Hz), 7.46 (2H, d, J=9Hz), 7.60 (2H, d, J=9Hz) MS (ESI-) in/z: 439 (M-H) Example 78 2- (4-Methoxyphenyl) 4, 5, 6-tetrahydro-2H-thiopyran-2acetic acid NMR (CDCd 3 6) 1. 71-2. 00 (4H, in), 2. 07-2. 20 (2H, m) WO 00/40576 PCT/JPOO/00018 139 2. 60-2. 86 (2H, mn), 2 .99-3 .14 (2H, mn), 3. 19 (1H, d, 5Hz) 3. 60 (1H, d, J=15 .5Hz) 3. 81 (3H, s) 6. 82 (2H, di, J=9Hz) 7. 56 (2H, d, J=9Hz) MS (ESI-) m/z: 297 (M-H) Example 79 2- (4-Eiuorophenyl) -2-thienyl] 6-tetrahydro-2Hthiopyran-2-acetic acid NMR (CDCl 3 1.70-2.02 (2H, mn), 2.09-2.24 (2H, mn), 2.67-2.86 (2H, in), 3.02-3.20 (2H, in), 3.19 (1H, di, 3.46 (1H, d, J=l5Hz), 7.06 (2H, cid, J=8Hz, 8Hz), 7.15 (1H, d, J=3Hz), 7.21 (1H, d, J=3Hz), 7.46-7.62 (2H, m) MS (ESI-) m/z: 367 (M-H) Example 2- (4-Biphenylyl) 4, 5, G-tetrahydro-2H-thiopyran-2acetic acid 1, 1-dioxide 33 g) NMR (OD1 3 8) 1. 80-2. 01 (2H, in), 2. 11-2. 19 (2H, in), 2. 69-2. 76 (1H, mn), 2. 82-2 .92 (1H, mn), 3. 02-3. 16 (2H, in), 3. 24 (1H, di, J15 6Hz) 3. 67 (1H, di, 6Hz) 7 .37-7 .46 (2H, in), 7. 58-7. 63 (4H, m) 7. 71 (2H, d, J=9Hz) MS (ESI-) m/z: 343 (M-H) Example 81 2- 4 -Chlorophenyl)phenyl]-3, 4,5, 6-tetrahydro-2Hthiopyran-2-acetic acid 1,1-dioxide (275 mg) NMR (CDC1 3 1.79-2.00 (2H, in), 2.10-2.18 (2H, in), 2.66-2.89 (2H, in), 3.02-3.14 (2H, in), 3.23 di, J=16H-z), 3.65 (1H, di, J=16Hz), 7.40 (2H, di, J=9Hz), 7.50 (2H, d, J=8.5Hz), 7.57 (2H, di, J=8.5Hz), 7.70 (2H, di, J=9Hz) MS (ESI-) m/z: 377 (M-H) WO 00/40576 PCT/JPO/00018 140 Example 82 2-[4-(4-Bromophenyl)phenyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetic acid 1,1-dioxide (105 mg) NMR (CDC1 3 1.70-2.20 (4H, 2.72-2.92 (2H, m), 3.05-3.16 (2H, 3.25 (1H, d, J=16Hz), 3.67 (1H, d, J=16Hz), 7.44 (2H, d, J=9Hz), 7.55-7.58 (4H, m), 7.71 (2H, d, J=9Hz) MS (ESI-) m/z: 421 (M-H) Example 83 2-[4-(4-Fluorophenyl)phenyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetic acid 1,1-dioxide (220 mg) NMR (CDC13, 1.80-2.18 (4H, 2.69-2.91 (1H, m), 3.04-3.16 (3H, 3.24 (1H, d, J=16Hz), 3.66 (1H, d, J=16Hz), 7.12 (2H, dd, J=9, 9Hz), 7.52-7.58 (4H, 7.70 (2H, d, MS (ESI-) m/z: 361 (M-H) Example 84 A mixture of 2-[4-(4-chlorophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid (56 potassium permanganate (48.8 g) and benzyltrimethylammonium chloride (2.87 g) in water-methylene chloride 1.5 Q) was stirred for 3 hours at room temperature. After the reaction mixture was poured into saturated sodium sulfite solution (500 ml), the solution was acidified with 4N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with chloroform (400 ml x The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography (eluent: chloroform-methanol 10:1) to give chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetic acid 1,1-dioxide (17.2 g) as colorless crystal.

mp: 191-193°C WO 00/40576 PCT/JP00/00018 141 Example N-Hydroxy-2-(4-phenoxyphenyl)-1, 3 -dithiane-2-acetamide 1,1,3,3-tetraoxide (56 mg) was obtained in a similar manner to that of Preparation 1-4).

NMR (DMSO-d 6 2.27-2.38 (2H, 3.43 (2H, s), 3.60-3.67 (2H, 3.80-3.88 (2H, 7.00 (2H, d, 7.10 (2H, d, J=8.0Hz), 7.22 (1H, dd, 8.0Hz), 7.45 (2H, dd, J=8.0, 8.0Hz), 8.04 (2H, d, J=8.0Hz), 8.94 (1H, s) MS (ESI-) m/z: 424.1 (M-H) Example 86 To a solution of 2 -[4-(4-fluorophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid (300 mg) in MeOH was added dropwise titanium (III) chloride (2.67 ml) (10 wt. solution in hydrochloric acid) in MeOH and hydrogen peroxide (0.69 ml)(30% aqueous solution) at room temperature. After being stirred for 15 minutes, the reaction is stopped by adding water. The reaction mixture is extracted with EtOAc and the solution was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: 5% MeOH in CHCl 3 to give 4 -fluorophenoxy)phenyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetic acid 1-oxide (150 mg) as an amorphous.

NMR (CDC13, 1.55-1.76 (4H, 2.45-2.62 (4H, m), 3.05-3.07 (2H, 6.95-7.07 (6H, 7.39 (2H, d, J=9Hz) MS (ESI-) m/z: 361 (M-H) Example 87 2-[5-(4-Chlorophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetic acid l,l-dioxide (1.95 g) was obtained in a similar manner to that of Preparation 1-4).

NMR (DMSO-d 6 1.76-1.90 (4H, 3.16-3.55 (6H, WO 00/40576 PCT/JPOO/0001 8 142 in), 7.19 (1H, d, J=3.6Hz), 7.47-7.52 (3H, in), 7.68 (2H, d, J=8.4H-z) Example 88 2 -(5-Bromo-2-thienyl)-3,4, S,6-tetrahydro-2H-thiopyran- 2-acetic acid 1,1-dioxide (6.0 g) was obtained in a similar manner to that of Preparation 1-4).

NMR (DMSO-d 6 1.74-1.87 (4H, in), 2.30-2.37 (1H, in), 3.07-3.56 (SH, in), 7.02 (1H, d, J=4.2Hz), 7.21 (1H, d, J=4.2Hz) MS (ESI-) in/z: 351 (M-H) Example 89 A mixture of 2 4 -(4-bromophenoxy)phenyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (130 mg), 4 -fluorobenzeneboronic acid (49.7 mng) and tetrakis(triphenylphosphine)palladium(0) (3.4 mg) in a mixture of l,2-diinethoxyethane (0.5 ml) and 2M aqueous sodium carbonate (0.5 ml) was refluxed for 6 hours. The mixture was acidified with 4N hydrochloric acid to pH 3 *and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo to give 2-[4-114-(4fluorophenyl)phenoxylphenyl.3, 4,5,6tetrahydro-2H-thiopyran.2-acetic acid 1,1-dioxide (116 mg) as an oil.

NMR (ODC1 3 1.75-2.02 (4H, in), 2.08-2.21 (2H, mn), 2.64-2.84 in), 3.01-3.17 (2H, in), 3.23 (1H, d, 3.62 (lE, d, J=l5Hz), 7.04 (2H, d, J=9Hz), 7.07-7.16 (4H, in), 7.41-7.56 (4H, in), 7.61 (2H, d, J=9Hz) MS (ESI-) m/z: 453 (N-H) Example 1.6M n-Butyl lithium in hexane (1.63 ml) was added WO 00/40576 PCT/JPOO 00018 143 dropwise to a solution of diisopropylamine (261 mg) in THF ml) under ice-bath cooling and a nitrogen atmosphere.

After being stirred under the same condition for 30 minutes, a solution of methyl 3 4 ,5, 6 -tetrahydro-2H-thiopyran-2carboxylate 1,1-dioxide (450 mg) in THF (8 ml) was added therein and the mixture was stirred for 45 minutes under dry ice-acetone cooling. A solution of 4-phenoxybenzyl bromide (719 mg) in THF (8 ml) was added to this mixture under the same condition. After the mixture was stirred for 2 hours under the same temperature for 2 hours under ice-bath cooling and for 2 hours at room temperature, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The resulting mixture was extracted with AcOEt. The extract was washed with 5% hydrochloric acid, 1M sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel (SiO 2 column chromatography (eluent: hexane-AcOEt, 6:1) to give methyl 2-(4-phenoxybenzyl)- 3,4,5,6-tetrahydro-2H-thiopyran-2-carboxylate 1,1-dioxide (745 mg) as an oil.

NMR (CDC1 3 1.68-1.92 (2H, 2.02-2.34 (4H, m), 3.10-3.30 (2H, 3.17 (1H, d, J=14Hz), 3.74 (1H, d, J=14Hz), 3.83 (3H, 6.91 (2H, d, J=8Hz), 7.00 (2H, d, J=8Hz), 7.06-7.18 (3H, 7.34 (2H, t, J=8Hz) Example 91 Methyl 2 -(4-phenoxybenzyl)-3,4,5,6-tetrahydro-2Hthiopyran-2-carboxylate (605 mg) was obtained in a similar manner to that of Example NMR (CDC13, 1.46-1.82 (4H, 1.86-1.96 (1H, m), 2.28-2.40 (1H, 2.52-2.62 (1H, 2.69-2.80 (1H, 3.07 (2H, 3.71 (3H, 6.89 (2H, d, J=8Hz), 7.00 (2H, d, J=8Hz), 7.06-7.14 (3H, m), 7.33 (2H, t, J=8Hz) WO 00/40576 PCT/JP00/00018 144 Example 92 Methyl 2 -(4-biphenylylmethyl)-3,4,5,6-tetrahydro-2Hthiopyran-2-carboxylate 1,1-dioxide (250 mg) was obtained in a similar manner to that of Preparation NMR (CDC1 3 1.72-1.93 (2H, 2.06-2.20 (3H, m), 2.25-2.37 (1H, 3.12-3.30 (2H, 3.24 (1H, d, J=14Hz), 3.81 (1H, d, J=14Hz), 3.86 (3H, 7.23 (2H, d, J=8Hz), 7.30-7.38 (1H, 7.43 (2H, t, J=8Hz), 7.49-7.58 (4H, m) Example 93 To a stirred solution of ethyl 3-hydroxy-3-(4methoxyphenyl)- 7 -mercaptoheptanoate (3.00 g) in dichloromethane (20 ml) was added trifluoroacetic acid (1 ml) at room temperature under nitrogen. After 1 hour, the mixture was quenched by the addition of triethylamine (1 ml) with ice cooling and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The separated organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The obtained oil was purified by column chromatography on silica gel (eluted with 5 to 10% ethyl acetate in n-hexane) to give ethyl 2-(4-methoxyphenyl)- 3,4,5,6-tetrahydro-2H-thiopyran-2-acetate (2.216 g) as an oil.

NMR (CDC13, 1.05 (3H, t, J=7Hz), 1.50-1.84 2.25-2.36 (1H, 2.45-2.71 (2H, 2.79 (1H, d, J=14Hz), 2.91 (1H, d, J=14Hz), 3.81 (3H, s), 3.93 (2H, q, J=7Hz), 6.88 (2H, d, J=9Hz), 7.55 (2H, d, J=9Hz) Example 94 To a mixture of ethyl 3 -oxo- 3 -(4-phenoxyphenyl)propanoate (500 mg) and 1, 3 -propanedithiol (2 ml) was added WO 00/40576 PCT/JP00/00018 145 boron trifluoride diethyl etherate (2 ml) at 0°C. After being stirred at ambient temperature for 3 hours, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel 60 (50 g) (eluent: ethyl acetate:hexane to give ethyl 2-(4phenoxyphenyl)-1,3-dithian-2-acetate (370 mg) as a yellow oil.

NMR (CDC1 3 1.12 (3H, t, J=7.0Hz), 1.94-2.01 (2H, 2.75-2.81 (4H, 3.13 (2H, 4.00 (2H, q, 6.98 (2H, d, J=8.5Hz), 7.03 (2H, d, 7.12 (1H, dd, J=7.0, 7.0Hz), 7.34 (2H, dd, J=7.0, 7.0Hz), 7.88 (2H, d, MS (ESI-) m/z: 374 (M-H) Example A mixture of tert-Butyl 2-(5-bromo-2-thienyl)-3,4,5,6tetrahydro-2H-thiopyran-2-acetate (199 g) and aqueous trifluoroacetic acid (1.0 1) was stirred for 2 hours at room temperature. The mixture was diluted with water (1.5 1) and stirred for 1 hour with ice cooling. The separated solid was collected and washed with water (500 ml) to give bromo-2-thienyl)-3,4,5,6-tetrahydro-2H-thiopyran-2-acetic acid (166.2 g).

NMR (DMSO-d 6 1.45-1.73 (4H, 2.12-2.20 (1H, m), 2.45-2.70 (5H, 2.87 (1H, d, J=14.4Hz), 6.84 (1H, d, J=4.2Hz), 7.08 (1H, d, J=4.2Hz) MS 319 (M-H) Example 96 To a solution of 2 S)-N-(2-tetrahydropyranyloxy)-2-[5- 3 2 -(tert-butyl) (diphenyl)sillyloxy)ethylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5, 6-tetrahydro-2H-thiopyran-2- WO 00/40576 PCT/JP00/00018 146 acetamide 1,1-dioxide (500 mg) in tetrahydrofuran (3 ml) was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 ml) at 0°C and the reaction mixture was stirred at ambient temperature for 3 hours. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo.

The residue was purified by flash column chromatography on silica gel 60 (eluent: 6% methanol-chloroform) to give (2S)-

N-(

2 -tetrahydropyranyloxy)-2-[5-(3- ((2-hydroxyethyl)aminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (70 mg) as a white amorphous.

NMR (CDC13, 1.46 (2H, br), 1.52-1.68 (4H, 1.94 (2H, br), 2.04-2.24 (2H, 2.67-2.88 (2H, m), 3.00-3.06 (2H, 3.11 (2H, 3.30-3.47 (2H, m), 3.72 (2H, td, J=7.0, 7.0Hz), 4.24 (2H, td, 4.52 (1/2H, br), 4.82 (1/2H, br), 6.80 (1H, 7.18-7.46 (6H, 7.60 (1H, 8.32 (1/2H, 8.46 (1/2H, s) MS 550.5 (M-H) Example 97 To a solution of 2-(5-bromo-2-thienyl)-3,4,5,6tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (140.0 g) in a mixture of acetonitrile (560 ml) and ethanol (800 ml) was added a solution of R-(+)-a-methylbenzylamine (28.8 g) in ethanol (40 ml) at 50 0 C. After been allowed to cool to ambient temperature over the time of 2 hours, the mixture was stirred for 2 hours at ambient temperature and for 2 hours with ice cooling additionally. The separated solid was collected and washed with acetonitrile (140 ml) to give (5-bromo-2-thienyl)-3,4,5,6-tetrahydro-2H-thiopyran- 2 -N-[(R)-1-phenylethyl]acetamide 1,1-dioxide (66.2 g).

WO 00/40576 PCT/JPOO/00018 147 The absolute configuration was determined by X ray crystallography analysis.

NMR (DMSO-d 6 8) 1. 35 (3H, d, J=6. 6Hz) 1. 60-2. 04 (4H, in), 2. 18-2. 32 (1H, mn), 2 .86-3. 10 in), 3. 24 (1H, d, J=15.6Hz), 3.36-3.52 (2H, in), 4.15 (1H, qj, J=6.6Hz), 6.96 (1H, d, J=4.2Hz), 7.14 (1H, d, J=4.2Hz), 7.24-7.43 (5H, in) The following compounds were obtained in substantially the same manner as that of Example 54.

Example 98 (2S) -N-Hydroxy-2- (3-methylphenyl) -2-thienyl] 3 4

,S,

6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (120 mng) NMR (DMSO-d 6 1.75-2.06 (4H, mn), 2.35 (3H, s), 2.95-3.52 in), 7.13 (1H, d, J=7.5Hz), 7.20 (1H, d, J=5Hz), 7.30 (1H, dd, J=7.5, 7.5Hz), 7.42-7.45 (3H, in), 8.84 (1H, s) MS 378 (M-H) Example 99 (2S) -N-H-ydroxy-2- [5-(4-methyiphenyl) -2-thienyl] 3 4 ,5, 6 -tetrahydro-2H-thiopyran-2-acetamiie 1,1-dioxide (82 mng) NMR (DMSO-d 6 1.74-2.04 mn), 2.32 (3H, s), 2.47-2.53 (1H, in), 2.95-3.25 (4H, in), 3.43-3.53 (1H, in), 7.16 (1H, d, J=3.OHz), 7.23 (2H, d, J==7.OHz), 7.40 (1H, d, J=3.0Hz), 7.53 (2H, d, J=7.OHz), 8.85 (1H, s) MS 378.0 (M-H) Example 100 (2S) -N-Hydroxy-2- (4-ethylphenyl) -2-thienyl] -3,4,5,6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (115 mng) WO 00/40576 PCT/JPOO/00018 148 NMR (ODCd 3 24 (3H, t, J=7Hz) 1. 74-1. 93 (2H, in), 1. 96-2. 16 (2H, mn), 2 .57-2 .73 (2H, in), 2. 65 (2H, q, J=7Hz) 2. 94-3. 15 (4H, mn), 7 .114-7. 24 (4H, in), 7 (2H, cd, J=8Hz) 8 .52 (1H, s) MS 392 (M-K) Example 101 (2S) -N-Hyclro~y-2- (4-iethoxyphenyl) -2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (970 mng) NMR (DM30-cl 6 1.72-2.06 (4H, mn), 2.34-2.45 (1H, mn), 2.94-3.26 (4H, mn), 3.39-3.56 (1H, mn), 3.78 (3H, s), 6.98 (2H, di, J=7Hz), 7.16 (1H, d, J=3Hz), 7.34 (1K, d, J=3Hz), 7. 57 (2H, d, J=7Hz) 8. 85 (1H, s) 10.58 (1H, s) MS (ESI-) 394 (M-H) Example 102 (2S) -N-Hydroxy-2- (4-hydroxyinethyiphenyl) -2-thienyl] 3, 4,5, 6-tetrahydro-2K-thiopyran-2-acetamide 1, 1-dioxide mng) NMR (DM30-cl 6 6:1. 67-2. 08 (4H, mn), 2.33-2. 48 (1K, in), 2. 92-3. 28 (4H, in), 3 .39-3. 54 (1K, mn), 4. 50 (2K, cd, J=6Kz) 5. 24 (1H, t, J=6Hz) 7.20 (1K, di, J=3Hz) 7 .36 (2H, d, J=7Hz) 7. 44 (1K, di, J=3Hz) 7. 60 (2K, c, J=7Hz), 8.86 (1H, s) MS (ESI-) 394 (M-H) Example 103 (2S) -N-Hydroxy-2- (2-thienyl) -2-thienyl])-3, 4,5, 6tetrahydlro-2K-thiopyran-2-acetamide 1,1-dioxide (130 mg) NMR (DMS0-cl 6 1.72-2.04 (4K, in), 2.93-3.51 (6K, mn), 7.10 (1K, dci, J=4.5, 4.5Hz), 7.15 (1K, ci, J=4.O~z), 7.26 (1K, ci, J=4.OHz), 7.29 (1K, cd, J=4.5Hz), 7.53 (1H, cd, J=4.5Hz), 8.32 (1H, s) WO 00/40576 PCT/JPOO/00018 149 MS 370 (N-H) Example 104 (2S) -N-Hydroxy-2- (2-furyl) -2-thienyl] -3,4,5,6tetrahydro-2H--thiopyran-2-acetamide 1, 1-dioxide (12 mg) NMR (CDCi 3 8) 1. 80-1. 97 (2H, mn), 2. 00-2. 25 (2H, in), 2.56-2.69 in), 2.74-2.89 (1H, mn), 2.96-3.20 (4H, mn), 6.43-6.47 (1H, mn), 6.52-6.56 (1H, mn), 7.15-7.22 (2H, mn), 7.39-7.44 (1H, mn), 8.12 (1H, br s) MS 354 CM-H) Example 105 (2S) -N-Hydroxy-2- (4-methylcarbarnoylphenyl) -2thienyl]-3,4,5, 6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (46 mg) NMR (DMSO-d 6 1.68-2.10 (4H, mn), 2.33-2.48 (1H, mn), 2.79 (3H, d, J=4Hz), 2.92-3.32 (4H1, in), 3.40-3.57 in), 7.26 (1H, d, 3=3Hz), 7.60 (1H, d, J=3Hz), 7.74 (2H, d, J=8Hz), 7.88 (2H, J=8Hz), 8.50 (1H, Mn) MS (ESI-) 421 (N-H) Example 106 2 S)-N-Hydroxy-2-II5-(4-ethylcarbamoylphenyl) -2thienyl]-3,4,5,6-tetrahydro-2H-thiopyran2-acetanide 1,1dioxide (740 ing) NMR (DMSO-d 6 1.13 (3H1, t, J=7.5Hz), 1.75-2.05 (4H, in), 2.36-2.45 (1H1, in), 2.95-3.03 (2H, mn), 3.13- 3.47 (5H, in), 7.24 d, J=5.0Hz), 7.60 (1H1, d, 3=5.0Hz), 7.73 (2H1, d, 3=9.0Hz), 7.87 (2H, d, 8.51 (1H, t, J=3.OHz) MS 435.2 (N-H) Example 107 WO 00/40576 PCT/JPOO/00018 150 -N-Hydroxy-2 5- (3 -a cet yl aiinophenyl) -2 -thi enyl] 3,4,5, G-tetrahyclro-2H-thiopyran-2-acetamide, 1,1-dioxide (2 g) NMR (DMSO-d 6 1.74-2.01 (4H, mn), 2.06 (3H, s), 2.35-2.46 (1H, mn), 2.94-3.50 (5H, in), 7.20 (1H, d, J=3.OHz), 7.33 (2H, d, J=5.0Hz), 7.39 (1H, d, 7.44-7.49 (1H, mn), 7.94 (1H, s) MS 42*1.1 (M-H) Example 108 (2S) -N-H-ydroxy-2- [5-(3-aminophenyl) -2-thienyli -3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide hydrochloride (87 ing) NMR (DMSO-d 6 1.69-2.09 (4H, mn), 2.34-2.56 (1H, mn), 2.95-3.07 mn), 3.11-3.32 (2H, in), 3.40-3.57 (1H, in), 7.17 (1H, d, J=8Hz), 7.24 (1H, d, J=3Hz), 7.42-7.60 (4H, mn), 10.63 (1H, s) MS 379 (M-H) Example 109 (2S) -N-Hydroxy-2- (3-ethylcarbanoylaminophenyl) -2thienyl 1-3, 4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide NMR (DMSO-d 6 1.06 (3H, t, Jh7.2Hz), 1.69-2.09 (4H, mn), 2.31-2.53 (1H, in), 2.93-3.55 (7H, in), 6.14 (1H, t, J=4.5Hz), 7.12-7.30 (4H, mn), 7.38 (1H, d, 7.84 (1H, 8.56 (1H, 8.72-8.95 in), 10.60 (1H, s) MS 450 (M-H) Example 110 (2S) -N-Hydroxy-2- 3 -methoxycarbonylaninophenyl) -2thienyl 1-3, 4,5, G-tetrahydro-2H-thiopyran-2-acetanide 1, 1dioxide (82 ing) NMR (DMSO-d 6 1.70-2.07 (4H, mn), 2.34-2.53 (lH, mn), WO 00/40576 PCT/JPOO/00018 151 2.94-3.08 (211, in), 3.10-3.27 (211, mn), 3.30-3.55 (1H, in), 3.69 (3H, 7.20 (1H1, d, J=3.511z), 7.27-7.41 (41H, mn), 7.83 (1H1, 9.76 (1H, s) MS 456 (M+H-+N11 3 Example 111 (2S) -N-Hyciroxy--2-r5- 3 -carbamoylaminophenyl) -2thienyl] £-tetrahydro-21-thiopyran2.acetainide 1,1dioxide (45 mg) NMR (DMSO-d 6 70-2. 08 (411, in), 2. 32-2. 55 (1H, in), 2.93-3.07 (211, in), 3.09-3.30 (2H, mn), 3.39-3.55 (111, 5.90 (211, 7.16-7.23 (211, in), 7.24- 7. 39 (211, in), 7. 37 (1H1, d, J=3. 5Hz) 7. 78 (1H1, s), 8.66 (1H, 8.84 (1H1, s) MS 422 (M-H) Example 112 (2S) -N-Hydroxy-2- 3 -methylcarbanoylaininophenyl) -2thienyll-3,4,5,6-tetrahydro-2H-thiopyran-2acetanide 1,1dioxide (77 mng) NMR (DMSO-d 6 74-2. 05 (4H1, in), 2. 38-2.46 (1H1, in), 2.66 (3H1, d, J=4.OHz), 2.95-3.26 (411, in), 3.42- 3.52 (1H1, mn), 6.06 (1H, q, J=4.OHz), 7.17-7.20 mn), 7.22-7.26 (211, mn), 7.36 (1H1, d, J=3.5Hlz), 7.82 (1H1, 8.65 8.83 (1H, s) MS 436.2 (M-H) Example 113 WO 00/40576 PCT/JP00/00018 152 0 0 Br S

SHN

O NH

H

(d) To a solution of pyridine-3-boronic acid 1,3propanediol cyclic ester (130 mg) in degassed N,Ndimethylformamide (0.5 ml) were added a suspension of tetrakis(triphenylphosphine)-palladium (103 mg) in degassed N,N-dimethylformamide (2.5 ml), a solution of sodium carbonate (424 mg) in degassed water (1 ml) and (5-bromo-2-thienyl) -1,1-dioxo-3,4,5,6-tetrahydro-2Hthiopyran-2-yl]acetyl]hydroxylamine trityl crowns (4 mmol, 10.0 rpmol/crown) in an atmosphere of nitrogen. After resulting mixture was heated for 48 hours at 60 0 C, the crowns were washed with degassed N,N-dimethylformamide, a solution of sodium diethyldithiocarbamate (500 mg) and diisopropylethylamine (0.5 ml) in N,N-dimethylformamide (100 ml), N,N-dimethylformamide, methyl sulfoxide, water, methanol and dichloromethane, successively. The crowns were treated with 5% trifluoroacetic acid in dichloromethane for 1 hour at ambient temperature and removed from the solution.

After the solution was evaporated under a stream of nitrogen, the residue was purified by reverse phase HPLC (0.1% trifluoroacetic acid in acetonitrile, 0-20% gradient) to give (2S)-N-hydroxy-2-[5-(3-pyridyl)-2-thienyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (10 mg) as a powder.

WO 00/40576 PCT/JPOO/00018 153 NMR (DMSO-d 6 ):1.25-2.05 (4H, in), 2.87-2.93 (1TH, n), 2.97-3.50 (5H, mn), 7.28 (1H, d, J=4.OHz), 7.53- 7.58 (1H, in), 7.65 (1H, d, J=4.0Hz), 8.16 (1H, d, 8.56 (1H, br), 8.95 (1H, br) MS (ESI-) 365.0CM-H) Example 114 (2S) (2-Tetrahydropyranyloxy) (3inethylcarbainoylaminophenyl) -2-thienyll 6-tetrahydro- 2H-thiopyran-2-acetanide 1,1-dioxide (132 mng) NMR (CDC'1 3 8) 1.45 (4H, br) 1. 62-1.66 (2H, in), 1. 93 (2H, br), 2.07-2.17 (2H, in), 2.77-2.81 (5H, mn), 2.98-3.03 (1H, in), 3.10-3.15 (3H, mn), 3.32-3.50 (1H, in), 3.70-3.78 (1H, mn), 4.59 (1l~xl/2, 4.83 (lHxl/2, 7.00 (1H, d, J=3.5Hz), 7.07-7.08 (1H, mn), 7.12-7.21 (4H, in), 7.30-7.40 (2H, in), 9.16 (lHxl/2, 9.35 (lHxl/2, s) MS (ESI-) 520.2 (M-H) The following compounds were obtained in substantially the same inanner as that of Example 89.

Example 115 (2-Tetrahydropyranyloxy) (3-methyiphenyl) 2-thienyl]-3,4,5, 6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (200 mg) NMR (C~DC 3 40-1.73 (10H, mn), 2. 37 (3H, s) 2. 69- 2. 88 (2H, in), 3. 06- 3.16 (4H, in), 3. 30-3. 45 (1H, m), 3.61-3.75 (2H, mn), 7.11 (1H, d, J=7.SHz), 7.24- 7.28 (3H, in), 7.38--7.41 (2H, in) Example 116 (2-Tetrahydropyranyloxy)-2-[5-(4-mnethylphenyl)- 2-thienyl]-3,4, 5, 6-tetrahydro-2H--thiopyran-2-acetanide 1,1dioxide (142 mg) WO 00/40576 PCT/JPOO/nnni R 154 NMR (CDC1 3 6) 1 .4 3 (2H, br) 1. 65-1. 69 (2H, in), 1. (2H, br) 2. 07-2.18 (2H, in), 2. 37 (3H, s) 2. 63- 2. 80 (2H, in), 3. 06 (2H, br s) 3. 10-3. 16 (2H, in), 3.40-3.50 (2H, in), 3.58-3.76 in), 4.53 (lHxl/2, 4.80 (lHxl/2, 7.15-7.24 (4H, mn), 7.46 (21-, d, J=8.OHz), 7.39 (1Hxl/2, 8.06 C11-xl/2, s) MS CESI-): 462.1 CM-H) Example 117 2 -Tetrahydropyranyloxy)2-5(4ethylphel) -2thienyl)-3,4,5, G-tetrahydro-2H-thiopyran-2.acetanide 1,1dioxide NMR (CDC1 3 1.25 (3H, t, J=8Hz), 1.35-1.76 (6H, mn), 1.87-2.00 mn), 2.04-2.23 (2H, mn), 2.60-2.91 (4H, in), 3.00-3.19 (4H, in), 3.27-3.50 (1H, in), 3.60-3.77 (1H, in), 4.53, 4.71 (1H, 7.15-7.28 (4H, in), 7.51 d, J=8Hz), 8.10, 8.25 (1H, s) MS CESIf) 478 CM+H) Example 118 (2S) C 2 -Tetrahydropyranyloxy) (4-iethoxyphenyl) 2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2acetanide 1,1dioxide (1.85 g) NMR (CDC1 3 1.36-1.82 in), 1.98-2.02 (2H, in), 2.10-2.25 (2H.1 in), 2.62-2.88 (2H, in), 2.98-3.20 (4H, in), 3.26-3.50 (1H, mn), 3.57-3.72 (1H, in), 3.83 O3H, 6.90 (2H, d, J=8Hz), 7.13, 7.15 (1H, d, J=3Hz), 7.22, 7.24 d, J=3Hz), 7.52 (2H, d, J=8Hz), 8.11, 8.25 (1H, s) MS 478CM-H) Example 119 (2-Tetrahydropyranyloxy) (4hydroxymethyiphenyl) -2-thienyl]1 4, 5, 6 -tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (181 ing) WO 00/40576 PCT/JPOO/00018 155 NMR (C~DC 3 36-1.78 (6H, mn), 1. 85-2.03 (2H, n), 2.06-2.55 (2H, in), 2.66-2.93 (2H, mn), 2.98-3.21 (4H, in), 3.26-3.50 (1H, in), 3.62-3.73 (1H, in), 4.52, 4.82 (1H, mn), 4.70 (1H, 7.22-7.30 (1H, mn), 7.35 (2H, d, J=8Hz), 7.42-7.62 (1H, in), 7.57 (2H, d, J=8Hz), 8.25, 8.35 (1H, s) MS 478 CM-H) Example 120 (2-Tetrahydropyranyloxy) -2-[5-(2-thienyl)-2thienyl]-3,4, 5, G-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (200 mng) NMR (C~DC 3 1.41-1.75 (10H, in), 2.65-2.82 (2H, mn), 3.04-3.17 (4H, mn), 3.30-3.74 (3H, in), 7.00-7.02 (1H, mn), 7.11-7.13 (1H, in), 7.17-7.19 (3H, in) MS 454 (M-H) Example 121 (2S) (2-Tetrahydropyranyloxy) (2-furyl) -2thienyl]-3, 4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (95 mg) NMR (CDCl 3 1.41-1.77 (6H, in), 1.85-2.00 (2H, in), 2.03-2.25 (2H, in), 2.61-2.91 (2H, in), 3.00-3.06 (2H, in), 3.07-3.16 (2H, mn), 3.28-3.53 (1H, in), 3.61-3.75 (1H, in), 4.51 (0.5H, 4.80 (0.5H, s), 6.42-6.47 (1H, in), 6.50-6.56 (1H, in), 7.17-7.24 (2H, in), 7.38-7.42 (1H, in), 7.93 (0.5H, 8.09 s) MS (EST-) 438 CM-H) Example 122 (2S) (2-Tetrahydropyraiyloxy) (4-carboxyphenyl) 2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (910 ing) NMR (C~DC 3 1.36-1.73 (6H, in), 1.85-2.25 (4H, mn), WO 00/40576 PCT/JPOO/00018 156 2.76-2.88 (2H, mn), 3.02-3.25 (4H, mn), 3.28-3.53 (1H, in), 3.69-3.81 (1H, mn), 4.56, 4.87 (1H, s), 7.57 (1H, d, J=8Hz) 7.36-7.44 in), 7.72-7.83 (2H, in), 8.00 (2H, d, J=8Hz) MS (ESI-) :492 (M-H) Example 123 (2S) (2-Tetrahydropyranyloxy) (4ethyl carbamoylphenyl) -2-thienyl]1 4, 5, 6-tetrahydro-2Hthiopyran-2-acetainide 1, 1-dioxide (984 mng) NMR (CDCl 3 6) 1. 28 (3H, t, J=7 .OH 1. 4 4-1. 55 (4 H, mn), 1.64-1.68 (2H, mn), 1.95 (2H, br), 2.06-2.23 (2H, in), 2. 67-2. 91 (2H, mn), 3. 01-3. 16 (4H, in), 3. 27-3. 33 (1H, mn), 3. 46-3. 55 (2H, in), 3. 62-3. (1H, mn), 4.50 (lHxl/2, 4.82 (lHxl/2, 7.28 (1H, d, J=4. OHz) 7. 33 (1H, d, J=4. OHz) 7. 62 (2H, d, J=8.OHz), 7.75 (2H, d, J=8.OHz), 8.19 (lHxl/2, 8.27 (lHxl/2, s) MS 519.2 (M-H) Example 124 (2S) (2-Tetrahydropyranyloxy) (3acetylaininophenyl) -2-thienyl]1 4, 5, 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (2.63 g) NMR (CDC1 3 6) 1. 43 (2H, br) 1. 55-1. 64 (4H, in), 1. 93 (2H, br), 2.04-2.15 (2H, in), 2.19 (3H, 2.80- 2.85 (2H, mn), 3.02-3.16 (4H, in), 3.44-3.48 (1H, mn), 3.66-3.73 (1H, in), 4.55 (lHxl/3, 4.85 (lHx2/3, 7.08-7.11 (1H, in), 7.16-7.23 (3H, mn), 7.38 (1H, br 7.57 (1H, d, J=7.OHz), 7.94 (1H, 8.93 (lHxl/3, 9.02 (lHx2/3, s) MS 505.4 (M-H) Example 125 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-aninophenyl)-2- 157 thienyl]-3,4, S,6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (214 mg) NMR (C~DC 3 1.36-1.80 (6H, in), 1.84-2.25 (4H, in), 2.61-2.92 (2H, in), 2.98-3.20 (4H, in), 3.27-3.89 (4H, mn), 4.54 (0.5H, 4.81 (0.5H, 6.62 (1H, dd, J=2.3, 8Hz), 6.91 (1H, 6.99 (1H, di, J=8Hz), 7.15 (1H, t, J=8Hz), 7.20-7.29 (2H, in), 7.98 8.15 (0.5H, s) MS 463 (M-H) Example 126 tert-Butyl2- (5-bromo-2-thienyl) 6-tetrahydro-2Hthiopyran-2-acetate (199 g) was obtained in substantially the same manner as that of Example 93.

NMR (C~DC 3 1,34 (9H, 1.46-1.91 (5H, in), 2.10- 2.22 (1H, in), 2.49-2.62 (2H, in), 2.66 (1H, d, J=13.2Hz), 2.75 (1H, d, J=13.2Hz), 6.74 (1H, di, J=3.9Hz), 7.45 (1H, d, J=3.9Hz) Example 127 (2S) (5-Bromo-2-thienyl) 6-tetrahydro-2Hthiopyran-2-N-[(R)-1-phenylethyl]acetanide 1,1-dioxide (78 es..g) was partitioned between ethyl acetate (500 ml) and aqueous 1N hydrochloric acid (300 ml) The separated 25 organic phase was washed with aqueous 1N hydrochloric acid *Vgo: (100 ml) and brine (100 ml), dried over sodium sulfate and concentrated in vacuo to give (2S)-2-(5-bromo-2-thienyl)- 3, 4,5, G-tetrahydro-2H-thiopyran-2-acetic acid 1, 1-dioxide (57.5 g) as an solid.

:00, 30 mp: 189 0 C (dec. oleo*NMR (DMSO-d 6 1.74-1.87 (4H, in), 2.30-2.37 (lH, in), 3.07-3.56 (5H, in), 7.02 (1H, di, J=4.2Hz), 7.21 (1H, di, J=4.2Hz) xanp 9 WO 00/40576 PCT/JPO/00018 158 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4methylcarbamoylphenyl) -2-thienyl]-3,4,5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (68 mg) was obtained in substantially the same manner as that of Example 32.

NMR (DMSO-d 6 1.35-1.64 (6H, 1.71-2.08 (4H, m), 2.36-2.53 (1H, 2.79 (3H, d, J=4Hz), 2.88-3.32 (4H, 3.40-3.53 (2H, 3.74-3.92 (1H, m), 4.45, 4.75 (1H, 7.22-7.30 (1H, 7.55-7.64 (1H, 7.74 (2H, d, J=8Hz), 7.88 (2H, d, J=8Hz), 8.50 (1H, d, J=4Hz), 11.25 (1H, s) MS 505 (M-H) Example 129 To a mixture of (2S)-N-(2-tetrahydropyranyloxy)-2-[5- (3-aminophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran- 2-acetamide 1,1-dioxide (110 mg) in dichloromethane (1.5 ml) was added a solution of ethylisocyanate (21.9 mg) in dichloromethane (0.5 ml) with ice cooling. The mixture was allowed to warm to room temperature and stirred for 3 hours.

The resulted mixture was purified by chromatography on silica gel (methanol in chloroform, 0.5 to 3% gradient) to give (2S)-N-(2-tetrahydropyranyloxy)-2-[5-(3ethylcarbamoylaminophenyl) -2-thienyl] 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (100 mg) as an amorphous solid.

NMR (CDC1 3 1.08-1.18 (3H, 1.38-1.75 (6H, m), 1.86-2.00 (2H, 2.02-2.24 (2H, 2.76-2.90 (2H, 2.96-3.17 (4H, 3.20-3.55 (3H, m), 3.70-3.85 (1H, 4.61 (0.5H, 4.84 (0.5H, s), 5.25-5.40 (1H, 6.95-7.34 (5H, 7.36-7.50 (1H, 9.13 (0.5H, 9.35 (0.5H, s) MS 534 (M-H) Example 130 To a mixture of 2 S)-N-(2-tetrahydropyranyloxy)-2-[5- WO 00/40576 PCT/JP00/00018 159 3 -aminophenyl)-2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran- 2 -acetamide 1,1-dioxide (110 mg) and pyridine (28.1 mg) in dichloromethane (1.5 ml) was added a solution of methyl chloroformate (26.8 mg) in dichloromethane (0.5 ml) with ice cooling. The mixture was allowed to warm to room temperature and stirred for 3 hours. The resulted mixture was washed with aqueous 0.5% citric acid and brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified by chromatography on silica gel (methanol in chloroform, 0.5 to 3% gradient) to give 2 -tetrahydropyranyloxy)-2-[5-(3methoxycarbonylaminophenyl)-2-thienyl] -3,4,5,6-tetrahydro- 2 H-thiopyran-2-acetamide 1,1-dioxide (101 mg) as an amorphous solid.

NMR (CDC13, 1.35-1.56 (4H, 1.59-1.75 (2H, m), 1.86-2.00 (2H, 2.05-2.26 (2H, 2.63-2.93 (2H, 3.01-3.17 (4H, 3.27-3.51 (1H, m), 3.58-3.74 (1H, 3.79 (3H, 4.54 (0.5H, s), 4.82 (0.5H, 6.74 (1H, br 7.15-7.21 (1H, m), 7.23-7.37 (4H, 7.62 (1H, br 8.10 (0.5H, s), 8.24 (0.5H, s) MS 521 (M-H) The following compound was obtained in substantially the same manner as that of Example 129.

Example 131 2 -Tetrahydropyranyloxy)-2-[5-(3aminocarbamoylphenyl)-2-thienyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetamide l,1-dioxide (170 mg) NMR (DMSO-d 6 1.36-1.65 (6H, 1.69-2.10 (4H, m), 2.34-2.48 (1H, 2.89-3.32 (4H, 3.39-3.54 (2H, 3.72-3.91 (1H, 4.43 (0.5H, 4.75 5.90 (2H, 7.16-7.30 (4H, 7.32- 7.49 (1H, 7.79 (1H, 8.66 (1H, s) WO 00/40576 PCT/JPOO/00018 160 MS 506 (M-H) Example 132 (2S) (2-Tetrahydropyranyloxy) (4-f luorophenyl) 2-thienyl] 5-tetrahydrothiophene-2-acetamide 1,1dioxide (272 mg) was obtained in a similar manner to that of Example 32.

NMR (CDCl 3 1.39-1.84 (6H, m) 2.27-2.41 (2H, m), 2.82-3.00 (4H, m) 3.13-3.25 (2H, m) 3.35-3.63 (TH, in), 3.68-3.80 (1H, in), 4.55-4.64 (0.5H, mn), 4.81-4.89 (0.5H, in), 7.03-7.11 (2H, in), 7.13-7.40 (2H, in), 7.49-7.58 (2H, in), 8.20 (0.5H, 8.30 s) MS 452 (M-H) The following compounds were obtained in substantially the same manner as that of Example 54.

Example 133 (2S) -N-Hydroxy-2- 5- (3-ethoxyacetylaminophenyl) -2thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (4.62 g) NMR (DMSO-d 6 1.20 (3H, t, J=7Hz), 2.35-2.48 (1H, in), 2.94-3.28 (4H, in), 3.42-3.53 (1H, in), 3.58 (2H, q, J=7Hz), 4;04 (2H, 7.21 (1H, d, J=3Hz), 7.32-7.44 (3H, in), 7.57-7.63 (1H, mn), 8.03 (1H, s), 8.85 br), 9.81 (1H, s) MS 465 (M-H) Example 134 (2S) -N-Hydroxy-2- 3 -propionylaminophenyl) -2thienyl] G-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (76 mg) NMR (DMSO-d 6 1.09 (3H, t, J=7Hz), 2.35 (2H, q, J=7Hz), 2.37-2.48 (1H, in), 2.90-3.52 (5H, in), 7.21 WO 00/40576 PCT/JPOO/00018 161 (1H, d, J=3Hz) 7. 28-7. 53 mn), 8. 00 (1H, s), 9. 98 (1H, s) 10. 61 (1H, s) MS (ESI-) 435 (M-H) Example 135 (2S) -N-Hydroxy-2- 5- 3 -propylaminocarbonylaminophenyl) 2-thienyl]--3,4, 5 ,6-tetrahydro-2H-thiopyran.2acetaie 1,1dioxide (75 mg) NMR (DMSO-d 6 0.88 (3H, t, J=7Hz), 1.44 (2H, q, J=7Hz), 1.68-2.10 in), 2.34-2.48 (1H, mn), 2.90-3.58 (7H, mn), 6.22 (1H, br), 7.11-7.30 (4H-, in), 7.48 di, J=3Hz), 7.84 (1H, 8.60 (1H, s) 10. 61 (1H, s) MS 464 (N-H) Example 136 (2S) -N-Hydroxy-2- 3 -butyrylaminophenyl) -2-thienyl] 3,4,5, G-tetrahydro-2H-thiopyran.2-.acetanide 1,1-dioxide (79 mng) NMR (DMSO-d 6 0.92 (3H, t, J=7Hz), 1.55-1.68 (2H, in), 1.69-2.10 (4H, in), 2.30 (2H, t, J=7Hz), 2.35- 2.48 (1H, mn), 2.92-3.65 (5H, mn), 7.20 (1H, d, J=3Hz), 7.34 (2H, d, J=3Hz), 7.40 (1H, di, J=3Hz), 7.44-7.53 (1H, in), 8.00 (1H, s) MS (ESI-) 449 Example 137 (2S) -N-Hydroxy-2- 5- 2 -met hoxyethoxycarbonylamino) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (64 mg) NMR (DMSO-d 6 1.70-2.11 (4H, in), 2.34-2.50 (1H, in), 2.92-3.26 (4H, in), 3.29 (3H, 3.40-3.66 (3H, in), 4.15-4.28 (2H, in), 7.20 (1H, di, J=3Hz), 7.26-7.42 in), 7.85 (1H, 8.84 (1H, 9.87 (1H, s), 10.60 (1H, s) WO 00/40576 PCT/JPOO/00018 162 MS (ESI-) 481 (M-H) Example 138 (2S) -N--Hydroxy-2- (2methoxycarborlylaminoacetylamino)phenyl)-2-thienyl]-3,4, 5,6tetrahydro-211-thiopyran-2-acetamiie 1,1-dioxide (58 mg) NMR (DMSO-d 6 8) 1. 69-2.07 (4H, in), 2.32-2.48 (1H, m), 2.92-3:50 (511, mn), 3.56 (31H, 3.80 (211, di, J=8Hz), 7.19 (1H1, d, J=311z), 7.30-7.52 (5H, mn), 7.97 (1H1, 8.82 (1H1, s) MS (ESI-) 494 (M-H) Example 139 (2S)-N-Hydroxy-2-[5-(3- (phenoxyacetylamino)phenyl)-2thienyl]-3,4,5, 6-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (3.8 g) NMR (DMSO-d 6 70-2. 09 (411, mn), 2. 35-2. 50 (111, m) 2. 92-3. 55 (511, mn), 4 .72 (211, s) 6. 94-7. 05 (311, in), 7. 21 (111, di, J=3Hz) 7. 28-7. 44 (511, in), 7. 52-7 (111, in), 8.03 (1H1, 8.84 (1H1, 10.21 (111, s), 10.60 (1H, s) MS 513 (M-H) Example 140 (2S) -N-Hydroxy-2-[5- (propoxyacetylainino)phenyl)-2thienyl]-3,4,5, G-tetrahydro-2H--thiopyran-2-acetamide 1,1dioxide (2.28 g) NMR (DMSO-d 6 0.91 (311, t, J=811z), 1.54-1.67 (211, mn), 1.70-2.11 (411, mn), 2.36-2.49 (1H1, in), 2.94- 3.29 (411, mn), 3.43-3.58 (111, in), 3.48 (211, t, J=811z), 4.05 (211, 7.21 (111, di, J=3Hz), 71.32- 7.45 (31, in), 7.54-7.62 (1H1, in), 8.03 (1H1, s), 8.85 (111, 9.81 (111, 10.60 (111, s) MS (ESI-) 479 (M-11) WO 00/40576 PCT/JPO/0001 8 163 Example 141 (2S)-N-Hydroxy-2-[5-[3-(2-propen-lyloxy)acetylaiinolphenyl]-2-thienyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (9.32 g) NMR (DMSO-d 6 1.70-2.09 (4H, 2.35-2.56 (1H, 2.94-3.08 (2H, 3.10-3.29 (2H, 3.30-3.55 (1H, 4.07 (2H, 4.10 (2H, d, J=6Hz), 5.22 (1H, d, J=9Hz), 5.34 (1H, d, J=l5Hz), 5.89-6.04 7.21 (1H, d, J=3.5Hz), 7.31-7.44 (3H, m), 7.55-7.61 (1H, 8.03 (1H, 8.85 (1H, br s), 9.86 (1H, 10.6 (1H, br s) MS 477 (M-H) Example 142 2 S)-N-Hydroxy-2-[5-[4-(5-oxazolyl)pheny 1]2thl 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (331 mg) NMR (DMSO-d 6 1.72-2.10 (4H, 2.36-2.49 (1H, m), 2.95-3.09 (2H, 3.11-3.30 (2H, 3.42-3.56 (1H, 7.24 (1H, d, J=3.9Hz), 7.57 (1H, d, J=3.9Hz), 7.76 (1H, 7.77 (4H, 8.48 (1H, s) MS 431 (N-H) Example 143 (2S)-N-Hydroxy-2-[5- 3-(n-butyloxyacetyl 2-thieryl]-3,4,5,6-tetrahydro-2H-thiopyran2acetamide 1,1dioxide (90 ig) NMR (DMSO-d 6 0.92 (3H, t, J=7.OHz), 1.47 (2H, tq, 7.0Hz), 1.60 (2H, dd, J=7.0, 7.0Hz), 1.74- 2.06 (4H, 2.37-2.47 (1H, 2.96-3.30 (4H, 3.38-3.45 (1H, 3.52 (2H, t, J=7.OHz), 4.05 (2H, 7.22 (1H, d, J=4.OHz), 7.32-7.37 (2H, 7.41 (1H, d, J=4.OHz), 7.55-7.60 (1H, 8.02 (1H, s), 8.84 (1H, 9.80 (1H, 10.59 (1H, s) MS 493.2 (M-H) WO 00/40576 PCT/JPOO/00018 164 Example 144 (2S) -N-Hydroxy-2- ethoxycarbonylaminoacetylanino) phenyl }-2-thienyl 1-3, 4,5,6tetrahydro-2H.-thiopyran-2-acetamide 1, 1-dioxide (2.3 g) NMR (DMSO-d 6 6) 1.18 (3H, t, J=7. OHz) 1. 74-2. 05 (4H, in), 2.36-2.46 mn), 2.95-3.26 (4H, mn), 3.40- 3.53 (1H, mn), 3.79 (2H, d, J=6.0Hz), 4.02 (2H, q, J=7. OHz) 7. 21 (1H, di, J=4. OHz) 7. 35-7. 40 (3H, in), 7.40 (1H, di, J=4 .OHz) 7.45-7.49 (1H, mn), 7. 97 (1H, s) 8. 84 (1H, s) 10. 08 (1H, s) MS (ESI-) :508.3 (M-H) Example 145 (2S)-N-Hydroxy-2-[5-f3-(2chloroethylaminocarbonylamino)phenyl..2thienyl] .3,4,5,6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (72 mg) NMR (DMSO-d 6 6) 1. 72-2. 04 (4H, mn), 2. 36-2. 45 (1H, mn) 2.93-3.23 (4H, in), 3.39-3.46 (3H, in), 3.67 (2H, t, J=6.OHz), 6.44 (1H, t, J=6.OHz), 7.17-7.30 (4H, mn), 7.38 (1H, d, J=4.OHz), 7.84 (1H, 8.81 (1H, s), 8.84 (1H, s) MS (ESI-) 484.3 Example 146 (2S) -N-Hydroxy-2- (3-methoxypropionylamino) phenyl I-2-thienyl] 6-tetrahydro-2H-thiopyran-2acetainide 1,1-dioxide (3.4 g) NMR (DMSO-d 6 1.72-2.05 (4H, mn), 2.38-2.47 (1H, in), 2.56 (2H, t, J=6.OHz), 2.95-3.21 (4H, mn), 3.27 (3H, 3.36-3.52 mn), 3.64 (2H, t, J=6.OHz), 7.20 (1H, di, J=4.0J-z), 7.31-7.36 (2H, in), 7.40 d, J=4.OHz), 7.45-7.49 (1H, in), 8.01 10.07 (1H, 10.60 s) MS (ESI-) 479.2 (M-H+Na) WO 00/40576 PCT/JPOO/00018 165 Example 147 (2S) -N-Hydroxy-2- [5-13- (methoxyacetylainino) phenyl}J-2thienyll- 3 ,4,5,6-tetrahydro-28.-thiopyran-2-acetamide 1,1dioxide (2.5 g) NMR (DMSO-d 6 1.74-2.06 (4H, mn), 2.37-2.48 (1H, in), 2.95-3.26 (4H, in), 3.41 (3H, 3.43-3.53 (1H, mn), 4.02 (2H, 7.20 (1H, d, J=4.0Hz), 7.32-7.38 (2H, in), 7.42 (1H, d, J=4.OHz), 7.58-7.63 (1H, mn), 8.04 (1H, 8.84 (1H, 9.87 (1H, 10.60 (1H, s) MS 451.2 (M-H) Example 148 (2S) -N-Hydroxy-2- 5- (3-hydroxymethyiphenyl) -2-thienyl] 3 4 ,5, 6 -tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide mg) NMR (DMSO-d 6 1.71-2.08 (4H, mn), 2.37-2.46 (1H, in), 2.95-3.54 (5H, mn), 4.54 (2H, d, J=5.5Hz), 5.29 (1H, dd, J=5.5, 5.5Hz), 7.21 (1iH, d, J=4.OHz), 7.25 (1H, d, J=8.OHz), 7.38 (18, dd, J=8.0, 8.0Hz), 7.46 (1H, d, J=4.OHz), 7.53 (1H, d, J=8.OHz), 7.59 (1H, s), 8.85 (1H, 10.6 (1H, s) MS (ESI-) 394 (M-H) Example 149 (2S) -N-Hydroxy-2- (cis-1, 2-dihydroxyethyl) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran-2acetainide 1,1-dioxide (100 ing) NMR (DMSO-d 6 1.73-2.07 (4H, in), 2.35-2.46 (1H, mn), 2.95-3.50 (5H, in), 4.51-4.56 mn), 4.70-4.80 (1H, br), 5.24-5.35 (1H, br), 7.20 d, J=4.OHz), 7.39 (2H, d, J=8.OHz), 7.44 (1H, d, J=4.OHz), 7.58 (2H, d, J=8.OHz), 8.83 (1H, s), 10.58 (1H, s) MS (ESI-) 424 CM-H) WO 00/40576 PCT/JPO/00018 166 Example 150 (2S)-N-Hydroxy-2-[5-(3-(methylaminocarbonyloxymethyl)phenyl) -2-thienyl]-3,4,5, 6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (100 mg) NMR (DMSO-d 6 1.70-2.06 (4H, 2.35-2.46 (1H, m), 2.59 (3H, d, J=5.OHz), 2.96-3.54 (5H, 5.05 (2H, 7.22 (1H, d, J=4.0Hz), 7.29 (1H, d, J=8.OHz), 7.42 (1H, dd, J=8.0, 8.0Hz), 7.49 (1H, d, 7.59-7.61 (2H, 8.84 (1H, br), 10.59 (1H, br) MS 451 (M-H) Example 151 (2S)-N-Hydroxy-2-[5-(4-( 2 -iethylaminocarbonylethenyl) phenyl) -2-thieny-3,4,5, 6-tetrahydro-2H-thiopyran- 2 -acetamide 1,1-dioxide (170 mg) NMR (DMSO-d 6 1.72-2.09 (4H, 2.38-2.48 (1H, m), 2.71 (3H, d, J=5Hz), 2.98-3.51 (5H, 6.63 (1H, d, J=1SHz), 7.23 (1H, d, J=4Hz), 7.42 (1H, d, J=15Hz), 7.55 (1H, d, J=4Hz), 7.60 (2H, d, J=8.4Hz), 7.69 (2H, d, J=8.4Hz), 8.05 (1H, d, 10.60 (1H, s) MS 447 (M-H) Example 152 (2S)-N-Hydroxy-2-[5-(4-( 2 -ethylaminocarbonylethyl)phenyl) -2-thienylj 6-tetrahydro-2H-thiopyran-2.

acetaiide l,1-dioxide (200 ig) NMR (DMSO-d 6 1.08 (3H, t, J=7.2Hz), 1.73-2.12 (4H, 2.39-2.48 (1H, 2.96-3.05 (2H, 3.11- 3.54 (5H, 6.63 (iR, d, J=l5Hz), 7.24 (1H, d, J=4Hz), 7.41 (1H, d, J=15Hz), 7.55 (1H, d, J=4Hz), 7.60 (2H, d, J=8.4Hz), 7.69 (2H, d, J=8.4Hz), 8.10 (1H, dd, J=7.2, 7.2Hz), 10.6 (1H, s) MS (ESI-) 461 (M-H) WO 00/40576 PCT/JPOO/00018 167 Example 153 (2S) -N-Hydroxy-2- (isopropylaminocarbonylamino) phenyl) -2-thienyl] 4, 5, 6 -tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (82 mg) NMR (DMSO-d 6 8) 1.-10 (6H, d, J=8Hz) 1. 65-2. 11 (4H-, in), 2.30-2.45 (1H, mn), 2.85-3.26 mn), 3.36- 3.56 (1H, in), 3.65-3.88 (1H, mn), 6.08 (1H, br s), 7.07-7.45 (6H, in), 7.84 (1H, 8.50 (1H, s), 10.62 (iN, s) MS 464 (M-H) Example 154 (2S) -N-Hydroxy-2-[5-[3-[ 2 -hydroxyethylamino)acetylaminolphenyl]-2-thienyl]p3,4,5, 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide hydrochloride (82 mg) NMR (DMSO-d 6 1.70-2.10 (4H, in), 2.32-2.53 (1H, mn), 2.94-3.06 (2H, in), 3.09-3.20 (2H, in), 3.21-3.30 (2H, mn), 3.40-3.88 (3H, in), 3.98-4.05 (2H, mn), 7.23 (1H, d, J=3.SHz), 7.37-7.53 (4H, in), 7.93- 8.00 (2H, in), 8.93-9.07 s) MS 482 (M+H) Example 155 (2S)-N-Hydroxy-2-[*5-[3-[( 4 -rorphoiino)acetylainino]phenyl] -2-thienyl] 6 -tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide hydrochloride (75 mg) NMR (DMSO-d 6 1.70-2.10 (4H, in), 2.32-2.52 (1H, in), 2.90-3.06 (2H, in), 3.09-3.37 (4H, in), 3.41-3.58 (5H, in), 3.62-4.03 (2H, in), 4.25 (2H, 7.23 (1H, d, J=3.SHz), 7.40-7.54 (5H, in), 8.03 (1N, s) MS (ESI 508 (M+H) Example 156 (2S)-N-Hydroxy-2-[5- 4 -methoxyphenyl)acetylamino)- WO 00/40576 PCT/JPOO/00018 168 phenyl) -2-thienyl] 4, 5, 6-tetrahydro-21--thiopyran-2acetamide 1,1-dioxide (105 mg) NMR (DMSO-d 6 1.70-2.08 (4H, in), 2.34-2.48 (1H, in), 2 .92-3. 30 (4H, in), 3 .42-3 .54 (1H, in), 3. 58 (2H, s) 3. 73 (3H, s) 6. 90 (2H, d, J=9Hz) 7. 20 (1H, di, J=3Hz) 7. 26 (2H, d, J=9Hz) '7.32-7. 38 (2H, m) 7.40 (1H, di, J=3Hz), 7.44-7.53 (1H, in), 7.99 (1H, 8.84 (1H, br 10.24 (1H, 10.60 (1H, s) MS 527 (M-H) Example 157 (2S) -N-Hydroxy-2- 5- (3-methoxyphenoxy) acetylamino) phenyl) -2-thienyll 4, 5, 6-tetrahydro-2H-thiopyran-2acetainide 1,1-dioxide (110 ing) NMR (DMSO-d 6 1.68-2.11 (4H, mn), 2.32-2.50 (1H, in), 2 .90-3. 66 (5H, in), 4. 71 (2H, s) 6. 49-6. 66 (2H, in), 7.13-7.26 (2H, in), 7.31-7.47 (2H, in), 7.52-7.72 (2H, in), 7.94-8.14 (1H, in), 8.70 (2H, br 10.23 (1H, 10.62 (1H, s) MS 543 (M-H) Example 158 (23S) -N-Hydroxy-2 5- (3-phenoxypropionylanino) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran-2acetainide 1,1-dioxide (78 mng) NMR (DMSO-d 6 1.69-2.12 (4H, mn), 2.35-2.50 (iH, in), 2.82 (2H, t, J=7Hz), 2.92-3.56 (5H, in), 4.28 (2H, t, J=7Hz) 6. 95 (3H, di, J=9Hz) 7. 21 (iH, di, J=3Hz), 7.29 (2H, t, J=8Rz), 7.34-7.55 (4Hl, m), 8.03 (1H, 8.84 (1H, 10.21 (1H, 10.60 (1H, s) MS 527 (M-H) Example 159 2 S)-N-Hydroxy-2-[5-(3-(4-fluorophenoxy)acetylamino)- WO 00/40576 PCT/JPOO/00018 169 phenyl) -2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (75 mg) NMR (DMSO-d 6 1. 69-2. 11 (4H, in), 2. 34 49 (1H, mn) 2. 92-3. 56 (5H, in), 4. 71 (2H, s) 6. 97-7. 36 (5H, in), 7. 83-7. 46 (3H, in), 7. 52-7. 62 (1H, in), 8. 02 (1H, s) 8. 84 s) 10. 20 (1H, s) 10. 60 (1H, s) MS 531 (M-H) Example 160 2 S) -N-Hydroxy-2- (4 -methoxyphenoxy) acetylamino) phenyl) -2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran-2acetainide 1,1-dioxide (89 mg) NMR (DMSO- d 6 6) 1.6 8 08 (4IH, in), 2. 35 50 (1 H, in), 2. 94-3. 30 (4H, mn), 3. 41-3. 54 (1H, mn), 3. 70 (3H, s) 4. 65 (2H, s) 6. 90 (2H, d, J=lOHz) 6. 98 (2H, cd, J=lOHz) 7. 21 (1H, di, J=3Hz) 7. 33-7. 45 (3H, in), 7.54-7.62 (1H, in), 8.03 (1H, 8.84 (1H, s), 10.17 (1H, 10.60 (1H, s) MS 543 (M-H) Example 161 (2S) -N-Hydroxy-2- 5- (methylarinocarbonyloxy) acetylamino) phenyl) -2-thienyl]1-3, 4, 5, 6-tetrahydro-2Hthiopyrari-2-acetamiie 1,1-dioxide (68 mg) NMR (DMSO-d 6 6) 1. 64-2. 08 (4H, in), 2. 32-2. 51 (1H, in), 2.61 (3H, 2.92-3.56 (5H, mn), 4.57 (2H, s), 7.12-7.54 (7H, mn), 7.98 (1H, 10.14 (1H, s), 10.61 (1H, s) MS (ESI-) :494 Example 162 (2S) -N-Hydroxy-2- (5-phenyl-2-thienyi) -3,4,5,6tetrahydro-2H-thiopyran-2-acetaie 1, 1-dioxide (51 ing) NMR (DMSO-d 6 6) 1. 70-2. 07 (4H, mn), 2. 34-2. 52 (iH, in), WO 00/40576 PCT/JPO/00018 170 2.94-3.07 (2H, 3.10-3.27 (2H, 3.30-3.50 (1H, 7.21 (1H, di, J=3.5Hz), 7.29-7.36 (1H, 7.43 (2H, t, J=8Hz) 7.48 (1H, d, J=3.5Hz), 7.65 (2H, d, J=8Hz), 8.85 (1H, br s) MS (ESI-) 364 (M-H) Example 163 (2S) -N-Hydroxy-2- 4 -ethylaminnocarbonyiiethoxy) phenyl) -2-thienyl] 4, 5, 6 -tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (35 mg) NMR (DMSO-d 6 1.04 (3H, t, J=7.2Hz), 1.71-2.08 (4H, m) 1.35-1.45 (1H, m) 2.95-3.50 (7H, 4.89 (2H, s) 7.00 (2H, d, J=9. OHz) 7.17 (1H, d, J=4.OHz), 7.35 (1H, d, J=4.OHz) 7.58 (2H, d, J=9.OHz), 8.12 (iN, br), 8.84 (1H, 10.59 (1H, s) Example 164 (2S) -N-Hydroxy-2- (methylaminocarbonylmethoxy) phenyl)-2-thienyl] 6-tetrarahydro-2H-thiopyran2acetamide 1,1-dioxide (450 mg) NMR (DMSO-d 6 1.70-2.07 (4H, 2.35-2.45 (1H, m), 2.65 (3H, d, J=4.5Hz), 2.95-3.50 (5H, 4.50 (2H, 7.01 (2H, d, J=9.OHz), 7.16 (1H, d, J=4.OHz), 7.35 (1H, d, J=4.0Hz), 7.57 (2H, d, J=9.OHz), 8.06 (1H, br), 8.84 (1H, 10.57 (1H, s) MS 451 (M-H) Example 165 (2S)-N-Hydroxy-2-[5-( 4 -fluorophenyl)-2-thienyl]- 2 3 4 ,5-tetrahydrothiophene-2-acetamide i,1-dioxide (200 mg) NMR (DMSO-d 6 2.14-2.35 (2H, 2.55-2.68 (1H, m), 2.80 (1H, d, J=l5Hz), 2.90 (1H, d, J=15Hz), 3.05- 3.40 (3H, 7.17 (1H, d, J=4Hz), 7.26 (2H, d, J=9Hz), 7.45 (iR, d, J=4Hz), 7.70 (2H, dd, 9Hz), 8.88 (1H, 10.60 (1H, s) WO 00/40576 PCT/JPOO/00018 171 MS 368 (M-H) Example 166 (2S) (2-Tetrahydropyranyloxy) (3- (acetoxyacetylamino)phenyl) -2-thienyl]-3,4,5, 6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (110 mg) was dissolved in 50% trifluoroacetic acid in dichioromethane (10 ml) and the reaction mixture was stirred at room temperature for 1 hour. After the mixture was concentrated in vacuo, the residue was purified by Si0 2 column chromatography (eluent: 2% MeOH in CHC1 3 to afford (2S)-N-hydroxy-2-[5-(3- (acetoxyacetylamino)phenyl)-2-thienyll-3,4,5, 6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (65 mg) as a powder.

NMR (DMSO-d 6 1.69-2.07 (4H1, in), 2.14 (3H, s), 2.32-2.47 (1H1, in), 2.92-3.55 (511, in), 4.67 s), 7.22 d, J=3Hz), 7.32-7.52 (3H, in), 7.97 (1H,

S)

MS 479 (M-H) Example 167 (2S) -N-Hydroxy-2- -2acet oxypropi onyl amino) phenyl) -2-thienyl 4, 5, 6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (50 mng) NMR (DMSO-d 6 1. 44 (3H, d, J=8Hz) 1 .72-2. 08 (4H, in), 2.33-2.49 (1H1, in), 2.93-3.32 (4H1, in), 3.40- 3.56 (1H, in), 5.04 (1H1, qj, J=8Hz), 7.22 (1H1, d, J=3Hz), 7.32-7.53 (4H, mn), 7.97 (1H1, 8.84 (111, 10.19 (1H, 10.59 (1H, s) MS 493 (M-H) Example 168 WO 00/40576 PCT/JP00/00018 172 Br S C1

OH

H

To a solution of 3-chlorophenylboronic acid (125 mg) in degassed N,N-dimethylformamide (0.5 ml) was added a suspension of tetrakis(triphenylphosphine)palladium (103 mg) in degassed N,N-dimethylformamide (2.5 ml), a solution of sodium carbonate (424 mg) in degassed water (1 ml) and N-[2- [2-(5-bromo-2-thienyl)-1,l-dioxo-3,4,5,6-tetrahydro-2Hthiopyran-2-yl]acetyl]hydroxylamine trityl crowns (59.2 Pmol, 14.8 pmol/crown) in an atmosphere of nitrogen. After resulting mixture was heated for 48 hours at 60 0 C, the crowns were washed with degassed N,N-dimethylformamide, a solution of sodium diethylditiocarbamate (500 mg) and diisopropylethylamine (0.5 ml) in N,N-dimethylformamide (100 ml), N,N-dimethylformamide, methyl sulfoxide, water, methanol and dichloromethane, successively. The crowns were treated with 5% trifluoroacetic acid in dichloromethane for 1 hour at ambient temperature and removed from the solution.

After the solution was evaporated under a stream of nitrogen, the residue was purified by HPLC trifluoroacetic acid in 30% ethanol-hexane) to give (2S)-N-hydroxy-2-[5-(3chlorophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (4.5 mg) as a powder.

MS 400.2 (M+H) WO 00/40576 PCT/JP00/00018 173 The Object Compounds listed in the Table were obtained from the Starting Compounds 1 and 2 in a similar manner to that of Example 168 according to the following reaction scheme.

Reaction Scheme: (Examples 169 to 190) R-B(OH)2 Starting Compounds 2 Starting Compounds 2 Object Compounds Starting Compounds 1 WO 00/40576 WO 0040576PCT/JPOO/00018 174 Table Example Object Compounds Nos. R Physicochemical Data

F

169 /b MS (ESI+) 384.3 (M+H)

F

170 6 -MS (ESI+) :384.3 (M+H) 171 cl MS (ESI+) :434.2 (M+H) 172 MS (ESI+) :402.2 (M+14) 173 MS (ESI+) 422.4 (M+H) CH 3 CH H3C 174 MS (ESI+) :408.2 (M+H) CH3- WO 00/40576PC/OiOi8 PCT/JPOO/0001 8 175 Example Nos.

Object Compounds R 1 Phvsicochemical Data~ 175 C3MS 394.2 (M+H) CH3--b 176 S MS (ESI 372.2 (M+H) 177 SMS (ESI+) :422.2 (M+H) 178 0MS 568.4 (M-H) 179 MS (ESI+) :434.3 (M+H) F3C 180 F3C-O MS 450.2 (M+H) 181 CH3CO MS CESI+): 408.3 (M+H) (2R or 2S) WO 00/40576 Example Nos.

176 PCT/JPOO/Oo0l 8 -r Object Compounds R 1 Physicochemical Data 187 2 MS (EST+) 412.3 (M+H)

CH

3 S 183 \MS (ESI+) :426.2 (M+H) 184 MS 442.3 (M+H)

F

185 MS 501.2 (M+H) 186 MS (ESI-) 568.4 (N-H) 187 20-/ MS 513.3 CH2O (M+H+CH 3

CN)

188 MS (ESIi) 382.3 (M+H) HO (2R or 2S) WO 00/40576 WO 0040576PCT/JPOO/OOOI 8 177 Example Object Compounds Nos. R Physicochemical Data 189 MS 416.3 (M+H) 190 0MS (ESI+) 410.3 (M+H) The following compounds were obtained in a similar manner to that of Example 54.

Example 191 (23) -N-Hydroxy-2- (3-aminoacetylamino) phenyl) -2thienyll-3, 4,5, 6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide hydrochloride (3.0 g) from tetrahydropyranyloxy) (t-butoxycarbonylamino) acetylamino)phenyl)-2-thienyl]-3,4, 5,6-tetrahydro-2Hthiopyran-2-acetamide 1, 1-dioxide NMR (DMSO-d 6 1.68-2.10 (4H, in), 2.34-2.48 (1H, in), 2.92-3.62 (5H, in), 3.76-3.88 (2H, in), 7.23 (1H, d, J=3Hz), 7.36-7.46 (3H, mn), 7.49-7.56 (1H, in), 7.99 (1H, 10.69 (1H, 10.92 (1H, s) MS 438 (M+H) Example 192 (2S) -N-Hydroxy-2- (N-methylamino) propionylainino)phenyl)-2-thienyl]-3,4, 5,6-tetrahydro-2Hthiopyran-2-acetainide 1,1-dioxide hydrochloride (112 mng) from (2S)-N-(2-tetrahydropyranyloxy)-2-[5-(3-(3-(N-tbutoxycarbonyl-N-methylamino) propionylanino) phenyl) -2- WO 00/40576 PCT/JPOO/00018 178 thienyl] 6 -tetrahydro-2H-thiopyran-2-acetamiie 1,1dioxide NMR (DMSO-d 6 1.68-2.11 (4H, in), 2.32-2.47 (1H, in), 2.61 (3H, t, J=4Hz), 2.78 (2H, t, J=7Hz), 2.90- 3.30 (6H, mn), 3.38-3.62 (1H, mn), 7.22 (1H, di, J=3Hz), 7.32-7.50 (4H, in), 8.04 (1H, 8.36-8.58 (2H, mn), 10. 33 (1H, s) 10 .61 (1H, s) MS 466 (M+H) Example 193 (2S) -N-H-ydroxy-2- -2-amino-3- (3pyridyl) propionyl) amino) phenyl)} -2-thienyl]1 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide hydrochloride (500 mng) f rom 2 S) (2-tetrahydropyranyloxy) 2 5 3 (t-but oxycarbonyl amino) pyridyl)propionylamino) pheny1-2-.thieny1> 3, 4,5, 6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide NMR (DMSO-d 6 1.74-2.06 (4H, in), 2.35-2.46 (iR, in), 2.97-3.34 (4H, in), 3.46-3.55 (3H, in), 4.24 (1H, br), 7.23 (lH, di, J=4.OHz), 7.41-7.44 (3H, in), 7.56 (1H, d, J=7.OHz), 7.88 (1H, dcl, J=7.0, 7.95 (1H, 8.38 (1H, d, J=7.OHz), 8.48 (2H, br), 8.77 (1H, br), 8.87 (1H, br s) MS 529.1 (M+H) Example 194 (2S) -N-Hydroxy-2- (N-iethylamino) acetylanino) phenyl) -2-thienyl] 6 -tetrahydro-2H-thiopyran-2acetainide 1,1-dioxide hydrochloride (78 ing) from tetrahydropyranyloxy) (3(2-.(N.t-butoxycarbonylanino) acetylamino) phenyl) -2-thienyl 4, 5, 6-tetrahyciro-2Hthiopyran-2-acetamiie 1, i-dioxide NMR (DM80-cl 6 1.65-2.08 (4H, in), 2.31-2.49 (1H, in), 2.63 (2H, t, J=7Hz), 2.92-3.52 (5H, in), 3.92- 4.00 (2H, mn), 7.23 (1H, d, J=3Hz), 7.34-7.45 (3H, WO 00/40576 PCT/J'POO/00018 179 in), 7 .49-7 .57 (1H, mn) 798 (lH, s) 8.97-9. 14 (2H, 10. 67 (1H, 10. 94 (1H, s) MS 454 (M+H) Example 195 (2S) -N-Hydroxy-2- arinopropiony 1amino) phenyl) 2-thienyl]-3,4,5, 6-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide hydrochloride (78 mng) from tetrahydropyranyloxy) 5- (t -butoxyca rbonyl amino) propionylainino)phenyl)-2-thienyl]-3, 4,5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 1.68-2.09 (4H, mn), 2.32-2.50 (1H, in), 2.78 (2H, d, J=8Hz), 2.92-3.62 in), 7.23 (1H, d, J=3Hz), 7.32-7.57 (4H, mn), 7.92-8.16 (4H, mn), 10.45 (1H, 10.67 (1H, s) MS 454 (M+H) Example 196 (2S)-N-Hydroxy-2-[5-[3-(((2S)-2-anino-3methoxypropionyl) amino) phenyl] -2-thienyl] 4, 5, 6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide hydrochloride (1.64 g) from (2-tetrahydropyranyloxy)- 2- (t-butoxycarbonylainino) -3met hoxypropionyl) amino) phenyl -thienyl-3, 4, 5, 6tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide NMR (DMSO-d 6 1.70-2.10 (4H, mn), 2.34-2.53 (1H, in), 2.94-3.06 (2H, in), 3.10-3.56 (6H, mn), 3.74-3.86 (2H, mn), 4.17-4.29 (1H, mn), 7.22 (1H, d, 7.38-7.46 (3H, in), 7.53-7.59 (1H, mn), 7.95 (1H, s), 8.30-8.44 (2H, mn), 8.84 br 10.63 (1H, s), 10.85 (1H, br s) MS 482 (M+H) Example 197 WO 00/40576 PCT/JPOO/0001 8 180 (2S) -N-Hydroxy-2- 5- (2 -hydroxya cetyl amino) phenyl) -2thienyl] 6-tetrahydro-2H-thiopyran-2-acetamiie 1, 1dioxide (58 mg) from (2S) -N-(2-tetrahydropyranyloxy)-2-[5- (2-methoxycarbonyloxyacetylamino) phenyl) -2 -thienyl] 3, 4, 5,6-tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide NMR (DMSO-d 6 1.70-2.12 (4H, in), 2.32-2.49 (1H, mn), 2.91-3.28 (4H, in), 3.39-3.55 (1H, mn), 4.01 (2H, d, J=7Hz), 5.71 (1H, t, J=7Hz), 7.22 (1H, di, j=3Hz), 7.38-7.40 (2H, in), 7.40 (1H, d, J=3Hz), 7.60-7.72 (1H, in), 8.08 (1H, 8.85 (1H, 9.79 (1H, s), 10.61 (1H, s) MS 437 (M-H) Example 198 (2S)-N-H-ydroxy-2-[5-(3-(((2S)-2-hydroxypropionyl)amino) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (65 mng) from tetrahydropyranyloxy)-2-[5-(3-( -2acetoxypropionyl) amino) phenyl) -2-thienyll]-3, 4, 5, 6tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide NMR (DMSO-d 6 6) 1. 33 (3H, br s) 1. 67-2. 12 (4H, m) 2. 30-2 .48 (1H, mn), 2. 90-3 .71 (5H, in), 4 .09-4. 24 (1H, in), 7.21 br 7.38-7.48 (3H, mn), 7.68- 7.75 (1H, in), 8. 11 s) 9.26 (1H, s) 10. (1H, s) MS 451 (M-H) Example 199 To a solution of (2S)-N-2-(tetrahydropyranyloxy)-2-[5- (3 -aiinopropionyl amino) phenyl) -2 -thi enyl I- 3,4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (180 ing) in chloroform (5 ml) and pyridine (1 ml) was added a solution of methoxycarbonyl chloride (38.1 mg) at room temperature.

After being stirred at the same temperature overnight, the mixture was concentrated in vacuo. The residue was WO 00/40576 PCT/JP00/00018 181 dissolved in ethyl acetate (10 ml) and the solution was washed successively with a 5% citric acid solution, a saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. After the residue was dissolved in 1% hydrogen chloride in methanol ml), the mixture was stirred at room temperature for minutes and concentrated in vacuo. The residue was purified by SiO 2 column chromatography (eluent: 2% MeOH in CHC13) to afford (2S)-N-hydroxy-2-[5-(3-(3- (methoxycarbonylamino)propionylamino)phenyl)-2-thienyl]- 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (63 mg) as a powder.

NMR (DMSO-d 6 1.22-2.11 (4H, 2.35-2.56 (3H, m), 2.94-3.33 (6H, 3.42-3.58 (1H, 7.20 (1H, d, J=3Hz), 7.21-7.38 (1H, 7.32-7.38 (2H, 7.40 (1H, d, J=3Hz), 7.42-7.50 (1H, 8.01 (1H, s), 8.85 (1H, m) MS 508 (M-H) Example 200 To a solution of (2S)-N-(2-tetrahydropyranyloxy)-2-[5- (4-(t-butyloxycarbonylmethoxy)phenyl)-2-thienyl] -3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (220 mg) in tetrahydrofuran (THF):H 2 0= 2:1 (3 ml) was added lithium hydroxide monohydrate (23.9 mg) at room temperature. After being stirred at the same temperature overnight, the reaction mixture was concentrated in vacuo. The resulting residue was diluted with ethyl acetate, washed with 1% citric acid solution and brine, dried over sodium sulfate and concentrateed in vacuo to give tetrahydropyranyloxy)-2-[5-(4-carboxymethoxyphenyl)-2thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (190 mg) as an amorphous solid.

NMR (DMSO-d 6 1.35-1.60 (6H, 1.66-1.71 (2H, m), WO 00/40576 PCT/JPOO 00018 182 1.73-2.05 (2H, 2.34-2.46 (1H, 2.90-3.50 (6H, 3.72-3.90 (1H, 4.45, 4.75 (1H, s), 4.72 (2H, 6.96 (2H, d, J=9.0Hz), 7.16 (1H, d, 7.32 (1H, d, J=4.0Hz), 7.56 (2H, d, J=9.0Hz), 11.2 (1H, s) MS 522 (M-H) Example 201 To the reaction mixture of 4 benzeneboronic acid pinacol cyclic ester obtained in Preparation 24-2) was added 2 S)-N-(2-tetrahydropyranyloxy)- 2-(5-bromo-2-thienyl)-3,4,5,6-tetrahydro-2H-thiopyran-2acetamide l,l-dioxide (679 mg), tetrakis(triphenylphosphine)palladium(0) (8.67 mg) and aqueous 2M sodium carbonate (7.5 ml) at room temperature.

The mixture was stirred for 3 hours at 80°C and taken up between ethyl acetate and 3% aqueous sodium bicarbonate.

The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (eluted with to 3% methanol in chloroform) to give tetrahydropyranyloxy)-2-[5-[4-(5-oxazolyl)phenyl]-2thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide l,l-dioxide (795 mg) as an amorphous solid.

NMR (CDC13, 1.40-1.55 (4H, 1.61-1.75 (2H, m), 1.91-2.02 (2H, 2.05-2.25 (2H, 2.70-2.94 (2H, 3.01-3.17 (4H, 3.29-3.51 (1H, m), 3.64-3.74 (1H, 4.53 (0.5Hz, 4.82 (0.5H, s), 7.26-7.34 (2H, 7.39 (1H, 7.65 (4H, s), 7.94 (1H, 8.25 (0.5H, 8.37 (0.5H, s) MS 515 (M-H) The following compounds were obtained in a similar manner to that of Example 89.

WO 00/40576 PCT/JPOO/00018 183 Example 202 (2S) (2-Tetrahydropyranyloxy) (3-formyiphenyl) 2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2acetamide 1,1dioxide (0.9 g) NMR (CDCl 3 1.40-1.75 (6H, in), 1.90-2.02 (2H, mn), 2.05-2.26 (2H, mn), 2.70-2.93 (2H, in), 3.01-3.19 (2H, in), 3.28-3.53 (1H, in), 3.62-3.75 (1Hi, in), 4.53, 4.83 (1H, 7.26-7.37 (2H, mn), 7.56 (1H, dd, J=8. 0, 8.0OHz) 7.80-7.85 (2H, in), 8.09 (1H, s), 10.05 (1H, s) MS 476 (M-H) Example 203 (2S) 2 -Tetrahydropyranyloxy) (4-ethenyiphenyl) 2-thienyl]-3,4, 5 ,6-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (2.1 g) NMR (CDC1 3 1.37-1.75 (6H, in), 1.86-2.00 (2H, mn), 2.05-2.25 (2H, in), 2.65-2.91 (2H, in), 3.00-3.17 (4H, in), 3.26-3.49 (1H, mn), 3.59-3.70 (1H, mn), 4.51, 4.81 (18, 5.28 (1H, d, J=11Hz), 5.78 (1H, d, J=17.7Hz), 6.66-6.75 (1H, mn), 7.41 (2H, d, J=8.08z), 7.55 (2H, d, J=8.OHz) MS 474 (M-H) Example 204 (2S) 2 -Tetrahydropyranyloxy) (2carboxyetheny) pheny)-2-thienyl] 3, 4, 5, 6-tetrahydro-2Hthiopyran-2-acetainide l,1-dioxide (1.1 g) NMR (CDCl 3 6) 1. 41-1 .71 (6H, in), 1. 92-2. 25 (48, in), 2. 76-2 .88 (2H, in), 3. 05-3 .19 (4H, in), 3. 30-3. 51 (1H, mn), 3. 69-3. 76 (18, mn), 4. 54, 4. 84 (1H, s) 6. 40 (1H, d, J=15Hz) 7. 45-7 .74 (7H, in) MS (ESI-) 518 (M-H) Example 205 WO 00/40576 PCT/JPOO/0001 8 184 (2S) 2 -Tetrahydropyranyloxy) (5-phenyl-2-thienyl) 3, 4,5, 6-tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide (93 mg) NMR (CDCl 3 39-1. 75 (6H, in), 1. 90-2. 00 (2H, mn), 2. 04-2. 24 (2H, in), 2. 63-2. 91 (2H, in), 3. 03-3 .18 (4H, mn), 3. 27-3. 50 (1H, in), 3 .59-3. 70 (1H, m) 4 53 5H, s) 4. 80 5H, s) 7.2 4 41 (5H, in), 7. 56-7. 63 (2H, mn), 7. 95 5H, s) 8. 12 5H-, s) MS 448 (M-H) Example 206 (2S) (2-Tetrahydropyranyloxy) (tbutyloxycarbonylmethoxy) phenyl) 2-thienyl]-3, 4 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (3.8 g) NMR (DMSO-d 6 1.35-1.60 (15H, mn), 1.65-1.71 (2H, in), 1.73-2.04 (2H, mn), 2.34-2.45 (1H, in), 2.90- 3.50 (6H, mn), 3.72-3.90 (1H, in), 4.45, 4.75 (1H, 4.73 7.01 (2H, d, J=9.OHz), 7.15 (1H, d, J=4.OHz), 7.33 (1H, d, J=4.OHz), 7.55 (2H, d, J=9.OHz) Example 207 (23) (2-Tetrahydropyranyloxy) 5- (4- (ethyl ami noca rbonylnet hoxy) phenyl) -2-thienyl 4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (65 ing) was obtained in a similar manner to that of Example 201.

NMR (DMSO-d 6 6) 1. 04 (3H, t, J=7. 2Hz) 1. 37-1. 63 (6H-, mn), 1.69-1.81 mn), 1.83-2.04 in), 2.35- 2.47 (1H, mn), 2.87-3.51 (8H, mn), 3.74-3.90 (1H, in), 3.95, 4.75 (1H, 4.49 (2H, 7.00 (2H, d, J=9.OHz), 7.15-7.20 (1H, in), 7.33-7.36 (1H, in), 7.58 (2H, d, J=9.OHz), 8.13 (1H, br) Example 208 (23) (2-Tetrahydropyranyloxy) 5- (3- WO 00/40576 PCT/JPOO/00018 185 (propylarinocarbonylamino)phenyl) -2-thienyl]1-3,4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (140 mg) NMR (DMSO-d 6 8) 88 t, J=7Hz) 1. 26-2. 09 (12H, in), 2.43-2.46 (1H, in), 2.78-3.56 (6H, mn), 3.72-3.92 (1H, mn), 4.44, 4.75 (1H, 6.11-6.24 (1H, in), 7.09-7.42 (6H, in), 7.85 (1H, 8.55 (1H,

S)

MS 548 (M-H) The following compounds were obtained in a similar manner to that of Example 129.

Example 209 (2S) 2 -Tetrahydropyranyloxy) 5- (3- (isopropylaminocarbonylainino) phenyl) -2-thienyl] 4, 5, 6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (160 mg) NMR (DMSO-d 6 8) 1. 10 (6H, mn), 1. 30-2. 10 (10H, in), 2. 34-2. 47 in), 2. 83-3. 30 (5H, in), 3. 40-3. 53 (1H, in), 3. 18-3. 90 (2H, in), 4. 36, 4 .44 (1H, s) 6. 04 (1H, d, J=8Hz) 7. 09-7 .40 (6H, in), 7. 85 (1H, 8.44 (1H, s) MS 548 (M-H) Example 210 2 S) (2-Tetrahydtopyranyloxy)2-[ 5-f3-(2.

chloroethylaininoca rbonyl amino) phenyl -2-thienyl] 4,5, 6tetrahydro-2H-thiopyran-2acetaide 1,1I-dioxide (335 ing) NMR (CDC1 3 6) 1 .46 (2H, br) 1. 62-1. 67 in), 1.84-1.96 in), 2.74-2.88 (2H, mn), 2.96-3.06 (211, in), 3.08-3.14 (2H, in), 3.31-3.41 (2H, mn), 3.49-3.54 (1H1, in), 3.55-3.60 in), 3.66 (21H, t, J=6.OHz), 3.70-3.80 in), 4.48 (1/2H1, br), 4.84 (1/2H, br), 7.17-7.24 (4H1, in), 7.30-7.50 (5H, in) MS 568.4 (M-H) WO 00/40576 PCT/JPO/00018 186 Example 211 To a solution of 2 S)-N-(2-tetrahydropyranyloxy)-2-[5- 3 -aminophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran- 2 -acetamide 1,1-dioxide (7.00 ethoxyacetic acid (2.04 g) and l-hydroxybenzotriazole (2.65 g) in N,N-dimethylformamide ml) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD HC1) (3.75 g) at room temperature. After being stirred at the same temperature overnight, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (200 ml) and the solution was washed successively with 5% citric acid solution, a saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by SiO 2 column chromatography (eluent 1% MeOH in CHCl 3 to afford (2S)-N- 2 -tetrahydropyranyloxy)-2-[5-(3-(2ethoxyacetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (7.00 g).

NMR (DMSO-d 6 1.20 (3H, t, J=7Hz), 1.33-1.62 (6H, 1.70-2.12 (4H, 2.35-2.50 (1H, 2.88- 3.22 (5H, 3.38-3.52 (1H, 3.58 (2H, q, J=7Hz), 3.75-3.92 (1H, 4.44, 4.75 (1H, s), 7.18-7.25 (1H, 7.34-7.45 (3H, 7.55-7.64 (1H, 8.03 (1H, 9.81 (1H, 11.24 (1H, s) MS 549 (M-H) The following compounds were obtained in substantially the same manner as that of Example 211.

Example 212 2 -Tetrahydropyranyloxy)-2-[5-(3-(2- (methylaminocarbonyloxy)acetylamino)phenyl)-2-thienyl]- 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (144 mg) NMR (DMSO-d 6 1.36-2.10 (10H, 2.36-2.51 (1H, WO 00/40576 PCT/JPOO/00018 187 in), 2. 60 (3H, d, J=6Hz) 2 .87-3. 30 (5H, in), 3. 3. 54 mn), 3. 72-3. 90 (1H, in), 4 .4 3, 4 .7 6 (1H, mn), 4 .57 (2H, s) 7 .18-7. 30 (2H, in), 7 .35-7. 52 (4H, in), 7 .99 (1H, s) 10. 14 (1H, s) 11 .25 (1H, s) MS CESI-): 578 CM-H) Example 213 (2S) N- (2-Tetrahydropyranyloxy) 5- (2S) (tertbutoxycarbonylanino) -3-inethoxypropionylanino) phenyl]1 -2thienyl] 6-tetrahydro-2H-thiopyran-2-acetamide 1, 1dioxide (2.90 g) NMR (CDC1 3 1.37-1.51 (11H, in), 1.59-2.01 (6H, mn), 2.04-2.25 (2H, in), 2.64-2.91 (2H, mn), 3.00- 3.17 (4H, mn), 3.26-3.50 (4H, mn), 3.53-3.72 (2H, in), 3.80-3.94 (1H, mn), 4.34-4.45 (1H, in), 4.53 4.82 (0.5H, 5.45-5.59 (1H, mn), 7.20-7.36 mn), 7.43-7.51 (1H, in), 7.75-7.83 (1H, in), 8.18 (0.5H, 8.31 (0.5H, 8.49 (1H, br s) MS 683 (M+H+NH 3 Example 214 (2S) (2-Tetrahydropyranyloxy) (4iethoxyphenyl) acetylamino) phenyl) -2-thienyl]1-3, 4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (160 ing) NMR (CDCl 3 1..36-1.76 (8H, in), 1.86-1.98 (2H, in), 2.04-2.22 (2H, mn), 2.69-2.92 (2H, in), 3.02-3.17 (2H, in), 3.26-3.51 (1H, mn), 3.62-3.73 (1H, mn), 3. 68 (2H, s) 3. 82 (3H, s) 4 .52, 4 .72 (iRH, s) 6.87-6.95 (2H, mn), 7.13-7.32 (6H, mn), 7.45-7.56 (3H, mn), 8.56, 8.59 (1H, s) MS CESI-): 611 CM-H) Example 215 (2S) (2-Tetrahydropyranyloxy) (tertbutoxycarbonylamino) acetyl) amino) phenyl) -2-thienyl] 4, 5,6- WO 00/40576 PCT/JPOO/0001 8 188 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (246 ing) NMR (DMSO-d 6 1.26-1.63 (6H, mn), 1.40 (9H, s), 1.68-2.06 (4H, in), 2.35-2.48 (1H, in), 2.88-3.30 in), 3.36-3.53 (1H, in), 3.74 (2H, d, J=7Hz), 3.72-3.92 (1H, in), 4.43, 4.75 (1H, 7.03-7.12 (1H, mn), 7.18-7.24 (1H, m) 7.40-7.53 (4H, m), 7.98 (1H, 10.05 (1H, 11.25 (1H, s) MS (ESI-) 620 CM-H) Example 216 (2S) (2-Tetrahydropyranyloxy) 5- (3propoxyacetylamino)phenyl) -2-thienyl] 4,5, 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (3.68 g) NMR CCDCl 3 1.01 (3H, t, J=7Hz), 1.36-1.78 (10H, mn), 1.88-1.99 (2H, in), 2.03-2.25 (2H, in), 2.65-2.93 (2H, mn), 2.98-3.18 (2H, in), 3.28-3.52 (1H, in), 3.58 (2H, t, J=7Hz), 3.62-3.74 (1H, mn), 4.07 (2H, 4.52, 4.82 (1H, 7.23-7.38 (4H, in), 7.52- 7.59 (1H, in), 7.80 (1H, 8.19, 8.32 (1H, s), 8.56 (1H, s) MS (ESI-) 563 (M-H) Example 217 (2S) (2-Tetrahydropyranyloxy) 5-{13- (nbutyloxyacetylamino)phenylp-2.thienyl]>3,4,5, 6-tetrahydro- 2 H-thiopyran-2-acetanide 1,1-dioxide (140 mng) NMR (CDC1 3 1.95 (2H, br), 2.08-2.23 (2H, mn), 2.64- 2.88 (2H, in), 3.06 (2H, 3.16 (2H, br), 3.39- 3.50 (2H, mn), 3.62 (2H, t, J=7.5Hz), 4.06 (2H, s), 4.54 (1/2H, br), 4.80 (1/2H, br), 7.21-7.30 (2H, mn), 7. 34-7. 36 (2H, mn), 7. 52-7 .56 (1H, in), 7. 80 (1H, 7.94 (1/2H, 8.12 (1/2H, 8.34 (1H, s) MS (ESI-) 577.3 (M-H) Example 218 WO 00/40576 PCT/JPOO/00018 189 (2S) (2-Tetrahydropyranyloxy) 5- f3- (3methoxypropionyl amino) phenyl .2-thienyl]1 4, 5, 6-tetrahydro- 2 H-thiopyran-2-acetamide 1, 1-dioxide 34 g) NMR (CDCl 3 1.46 (2H, br), 1.57-1.70 (2H, in), 1.95 (2H, br), 2. 07-2.20 (2H, in), 2. 66 (2H, t, J=6. OHz) 2.70-2.89 (2H, in), 3.06 (2H, 3.10-3.16 (2H, in), 3.26-3.44 (1H, in), 3.47 (3H, 3.62-3.70 (2H, in), 3.75 (2H, t, J=6.OHz), 4.52 (1/2H, br), 4.82 (1/2H, br), 7.20-7.25 (2H, in), 7.28-7.31 (2H, mn), 7.46- 7.51 (1H, mn), 7.70-7.73 (1H, in), 8.18 (1/2H, s), 8.31 (1/2H, 8.31 (1H, s) MS 549.4 (N-H) Example 219 (2S) (2-Tetrahydropyranyloxy) 5-{3- (iethoxyacetylainino) phenyl -2-thienyl 4, 5, 6-tetrahydro- 2 H-thiopyran-2-acetamjde 1, 1-dioxide 24 g) NMR (CoDC 3 8) 1. 46 (4H, br) 1. 55-1.58 (2H, in), 1. 94 (2H, br) 2. 07-2.20 (2H, mn), 2 .66-2. 88 (2H, in), 3.05 (2H, 3.09-3.14 (2H, mn), 3.27-3.48 (1H, im), 3.53 (3H, 3.60-3.72 (1H, mn), 4.04 (2H, s), 4.52 (1/2H, br), 4.81 (1/2H, br), 7.23-7.30 (2H, mn), 7.43-7.46 in), 7.55-7.59 (1H, in), 7.80 (1H, 8.04 (1/2H, 8.20 (1/2H, 8.30 (1H, s) MS 535.3 (N-H) Example 220 (2S) 2 -Tetrahydropyranyloxy) 5- (9fl1uorenylmethoxyca rbonyl amino) propionylamino) phenyl) -2thienyl 1-3,4,5, 6 -tetrahydro-2H-thiopyran2acetamide 1, 1dioxide (2.70 g) NMR (CoDC 3 1.31-1.81 (8H, in), 1.84-2.28 (4H, in), 2.58-2.76 (21H, mn), 2.92-3.22 (4H, in), 3.30-3.84 (4H, in), 4.02-4.22 (2H, mn), 4.37-4.49 (1H, mn), 4.62, 4.94 (1H, 6.89-7.90 (13H, mn), 7.99-8.14 WO 00/40576 PCT/JPOO/00018 190 (2H, in), 8.66, 8.78 (1H, 10.00, 10.46 (1H, s) MS (ESI-) 756 (M-H) Example 221 (2-Tetrahydropyranyloxy) phenoxyacetylanino) phenyl) -2-thienyl] 4,5, 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (4.90 g) NMR (CDC1 3 1.37-1.76 (8H, in), 1.88-1.99 (2H, mn), 2.05-2.26 (2H, in), 2.67-2.92 in), 2.98-3.18 (2H, in), 3.28-3.51 (1H, in), 3.62-3.75 (1H, mn), 4.62 (2H, 4.52, 4.82 (1H, 6.98-7.11 (3H, mn), 7.23-7.30 (2H, in), 7.32-7.40 (4H, in), 7.58- 7.62 (1H, in), 7.79 (1H, 8.24, 8.35 (1H, s), 8.36 (1H, s) MS 597 (M-H) Example 222 (2S) 2 -Tetrahydropyranyloxy) 5- (3iethoxyphenoxy) acetylaiino) phenyl) 2-thienyl] 4, 5,6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (140 ing) NMR (DMSO-d 6 1.34-1.77 (8H, in), 1.86-1.99 (2H, in), 2.05-2.24 (28, in), 2.66-2.90 (2H, in), 3.03-3.17 (2H, mn), 3.28-3.52 (1H, mn), 3.62-3.74 (1H, in), 3.82 (3H, 4.52, 4.82 (1H, 4.61 (2H, s), 6.52-6.65 (3H, in), 7.22-7.30 (3H, in), 7.33-7.42 (2H, mn), 7.55-7.62 (1H, in), 7.72-7.82 (1H, in), 8.26-8.42 (2H, in) MS (ESI-) 627 (M-H) Example 223 (2S) 2 -Tetrahydropyranyloxy) (3phenoxypropionylanino)phenyl) -2-thienyl] 5, 6-tetrahydro- 2 H-thiopyran-2-acetamide 1,1-dioxide (135 ing) NMR (CDCl 3 1.32-1.78 (8H, mn), 1.86-1.98 (2H, in), 2.06-2.25 (2H, in), 2.71-2.92 (2H, in), 2.86 (2H, t, WO 00/40576 PCT/JPOO/00018 191 J=7Eiz) 3. 01-3.20 (2H, in), 3. 28-3. 52 (1H, mn), 3. 63-3. 77 (1H, n) 4. 35 (2H, t, J=7Hz) 4. 54, 4. 84 (1H, s) 6. 78-7. 03 (4H, mn), 7 .12-7. 36 (5H, m) 7. 47-7. 65 (2H, in), 8. 13 (1H, s) 8. 73 (1H, s) MS (ESI-) 644 (M-H) Example 224 (2S) (2-Tetrahydropyranyloxy) 5- (4 f luorophenoxy) acetylainino) phenyl) -2-thienyl] 4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (158 ing) NMR (C~DC 3 8) 1. 35-2. 01 (10H, in), 2. 05-2. 23 (2H, in), 2. 66-2. 94 (2H, mn), 3. 01-3. 19 (2H, mn), 3. 29-3. 53 (1H, in), 3. 62-3. 26 (1H, in), 4 .53, 4 .82 (1H, s) 4 .58 (2H, s) 6. 92-7. 10 (5H, mn), 7 .24-7. 39 (3H, m) 7.56-7.62 (1H, mn), 7.73-7.77 (1H, in), 8.34 (1H, s), 8.39, 8.49 (1H, s) MS (EST-) 615 (M-H) Example 225 (2S) (2-Tetrahydropyranyloxy) (4methoxyphenoxy) acetylarnino) phenyl) -2-thienyl]1 4,5, 6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (150 mng) NMR (00013, 6) 1. 36-1. 78 (8H, in), 1. 87-2. 01 (2H, m) 2. 06-2. 26 (2H, in), 2. 65-2. 94 (2H, in), 3. 02-3. 23 (2H, in), 3.27-3.56 (1H, in), 3. 62-3. 36 (1H, im) 3.80 (3H, 4.52, 4.83 (1H, 4.57 (2H, s), 6.84-7.03 (4H, in), 7.24-7.43 (4H, in), 7.54-7.67 (1H, in), 7.80 (1H, 8.28-8.49 (2H, m) MS (ESI-) 627 (M-H) Examnple 226 (2S) (2-Tetrahydropyranyloxy) 5- (N-tertbutoxycarbonyl-N-methylanino) propionylamino) phenyl) -2thienyll-3,4,5, 6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (160 ing) WO 00/40576 PCT/JPOO/00018 192 NMR (CDC'1 3 ):1.38-1.75 (8H, mn), 1.48 (9H, s) 1.88- 2 .01 (2H, in), 2. 06-2. 24 (2H, mn), 2. 62-2. 88 (4H, m) 2 .91 (3H, s) 3. 02-3. 17 (2H, in), 3. 27-3. 50 (1H, m) 3. 58-3. 75 O3H, mn), 4. 53, 4 .32 (1H, s) 7 .18-7. 31 (6H, in), 7.52-7.59 in), 7.70-7.83 (1H, mn) MS (ESI-) 648 (M-H) Example 227 (2S) (2-Tetrahydropyranyloxy) [5-f 3- (t~rtbutoxycarbonylanino) (3-pyridyl) propionylamino) phenyl 1-2thienyl]-3, 4, S, 6 -tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (1.54 g) NMR (DMS0-cl 6 1.22-1.27 (2H, in), 1.43 (9H, s), 1.63-1.68(4H, in), 1.98 (2H, br), 2.07-2.25 (2H, in), 2.74-2.98 (2H, mn), 3.04-3.20 (6H, in), 3.41-3.48 (1H, in), 3.66-3.76 (1H, mn), 4.45 (1/2H, br), 4.54- 4.63 (1H, br), 4.86 (1/2H, br), 5.31-5.45 (1H, mn), 6.82-7.00 (2H, in), 7.04-7.20 (3H, in), 7.22-7.27 (2H, in), 7.52-7.65 (2H, in), 8.43-8.59 (3H, in) MS 713.1 (M+H) Example 228 (2S) (2-Tetrahydropyranyloxy-2- 15- (2-propen-1yloxy)acetyllaminophenyl]-2-thienyl]-3, 4,5,6-tetrahydro-2Hthiopyran-2-acetainide 1,1-dioxide (14.6 g) NMR (CDC1 3 1.37-1.76 (6H, in), 1.88-2.01 in), 2.04-2.26 (2H, in), 2.64-2.92 (2H, in), 3.00-3.17 (4H, in), 3.27-3.51 (1H, in), 3.61-3.72 (1H, in), 4.08 (2H, 4.16 (2H, d, J=6Hz), 4.52 (0-5H, s), 4.81 (0.5H, 5.33 (1H, d, J=9Hz), 5.37 (1H, d, J=16.5Hz), 5.90-6.04 (1H, in), 7.23-7.39 (5H, in), 7.53-7.60 (1H, in), 7.80 (1H, 8.16 (0.5H, s), 8. 22 (0.S5H, s) 8. 35 (1H, s) MS (ESI-) 561 (M-H) WO 00/40576 PCT/JPOO/00018 193 Example 229 (2S) (2-Tetrahydropyranyloxy) f5-{3- (2- (ethoxycarbonyl amino) acetylaminno) phenyl)-2-thienyl] 5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (4 g) NMR (CDC1 3 8) 1. 28 (3H, t, J=7. 5Hz) 1. 41 (2H, br) 1. 92 (2H, br) 2. 04-2. 17 (2H, in), 2. 55 (4H, br) 2. 73-2. 91 (2H, in), 3. 02-3 .13 (48, in), 3. 28-3. 49 (1H, mn), 3.64-3.74 (18, in), 4.03-4.05 (2H, in), 4.20 (2H, q, J=7.5Hz), 4.52 (1/2H, br), 4.83 (1/2H, br), 7.11-7.21 (3H, in), 7.37-7.43 (1H, in), 7.48- 7.56 (2H, mn), 7.74-7.80 (1H, in), 8.46 (1H, br) MS (ESI-) 628.2 (M-H+C1) Example 230 2 S) (2-Tetrahydropyranyloxy) (N-tertbutoxycaronyl-N-methylanino) acetylamino) phenyl) -2-thienyl] 3 4 1 ,,-tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (119 mng) NMR (C~DC 3 1.35-1.74 (88, in), 1.51 (9H, s), 1.88-2.00 (28, in), 2.05-2.55 (28, mn), 2.18-2.92 (2H, in), 3.03 (38, 3.05-3.16 (2H, mn), 3.28- 3.50 (18, mn), 3.62-3.76 (1H, mn), 3.99 (2H, s), 4.53, 4.83 (18, 7.22-7.34 (48, mn), 7.43 (18, br 7.67-7.85 (18, mn), 8.42, 8.50 (18, s) MS (ESI-) 634 (M'H) Example 231 (2S) (2-Tetrahydropyranyloxy) 5- (tertbutoxycaronylanino) propionylainino) phenyl) -2-thienyl 3, 4, 5, 6 -tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide (150 mng) NMR (C~DC 3 6) 1. 3 5-1. 72 (88H, mn), 1. 44 (9H, s) 1.88-2.01 (28, mn), 2.05-2.23 (28, in), 2.57-2.67 (28, in), 2.75-2.89 (28, in), 3.00-3.17 (48, in), 3.28-3.56 (38, mn), 3.65-3.76 (18, mn), 4.54, 4.84 WO 00/40576 PCT/JPOO/00018 194 (1H, s) 5.28 (1 H, br s) 7 .13-7.28 (4H, mn), 7. 48- 7.-6 6 (2 H, in), 8. 14 (1 H, br s) 8. 75, 8. 78 (1 H, s) MS 634 (M-H) The following compounds were obtained in a similar manner to that of Example 130.

Example 232 (2S) 2 -Tetrahydropyranyloxy) 5- (3- (propionylamino) phenyl)-2thienyl 3, 4 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (160 mg) NMR (DMSO-d 6 8) 1.-09 (3H, t, J=7Hz) 1 .32-2. 07 in), 2. 36 (2H, q, J=7Hz) 2 .37-2.47 (iR, mn), 2. 88- 3.22 (5H, in), 3. 35-3. 54 (1H, mn), 3. 74-3. 92 (1H, in), 4 .44, 4. 75 (1H, s) 7. 17-7. 25 (1H, in), 7 .30-7 .42 in), 7. 43-7. 52 (1H, in), 8 .00 s) 9. 98 (1H, 11.36 (1H, s) MS (ESI-) 519 (M-H) Example 233 (2S) 2 -Tetrahydropyranyloxy) (3- (butyrylamino) phenyl) -2-thienyl] 5, 6-tetrahydro-2Hthiopyran-2-acetainide'1, 1-dioxide (166 mg) NMR (CDCl 3 6) 1. 01 (3H, t, J=7Hz) 1.35-1. 84 mn), 2 .O05-2. 25 in), 2. 37 (2H, t, J=7Hz) 2. 66- 2.92 (2H, in), 2.97-3.17 (2H, in), 3.27-3.52 (1H, in), 3.60-3.77 (1H, in), 4.54, 4.74 (1H, 7.08-7.32 in), 7.48-7.66 (2H, in), 8.64 (1H, br) MS 533 (M-H) Example 234 2 S)-N-(2-Tetrahydropyranyloxy)2[S-( 3 2 methoxyethoxyca rbonyl amino) phenyl) 2 thienyl]I 3,4,5, 6tetrahydro-2H-thiopyran2acetamide 1, i-dioxide (120 mng) NMR (C~DC 3 1.37-1.78 (8H, in), 1.89-2.00 (2H, in), WO 00/40576 PCT/JPOO/00018 195 2. 05-2. 25 (2H, mn), 2. 67-2. 94 (2H, in), 3. 02-3. 18 (3H, in), 3. 26-3. 52 (1H, in), 3 .58-3. 69 (2H, m) 3.66 4.25-4.32 (2H, in), 4.52, 4.83 (1H, s) 6. 90-7 .00 (1H, mn), 7. 20-7 .32 (5H, mn), 7 .63 (1H, 8.34, 8.46 s) MS (ESI-) 565 (M-H) Example 235 C2S) 2 -Tetrahyciropyranyloxy) (9fluorenylmethoxycarbonylanino) acetylamino)phenyl) -2thienyl]-3, 4,5, G-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (486 ing) NMR (DMSO-d 6 34-1. 62 (6H, mn), 1. 71-2. 08 (4H, mn), 2. 36-2 .47 (1H, mn), 2. 88-3. 34 (5H, in), 3. 39- 3. 52 (2H, mn), 3. 74 92 (3H, mn), 4 .19-4. 37 (3H, in), 4.42, 4.77 (1H, 7.18-7.27 (1H, mn), 7.32-7.52 (7H, in), 7.62-7.70 (1H, in), 7.75 (2H, d, J=7Hz), 7.92 (2H, d, J=7Hz), 8.02 (1H, s) Example 236 (2S) 2 -Tetrahydropyranyloxy) (3- (acetoxyacetylamino)phenyl)-2-.thienyl-34, 5 6-tetrahydro- 2 H-thiopyran-2-acetanide 1,1-dioxide (260 ing) NMR (CDC1 3 1.35-1.77 (8H, mn), 1.86-2.00 (2H, in), 2.03-2.24 (2H, in), 2.71-2.92 (2H, in), 3.00-3.20 (2H, mn), 3.38-3.54 (1H, mn), 3.65-3.78 (1H, in), 4.52, 4.72 (1H, 4.72 7.14-7.35 (4H, mn), 7.52, 7.59 (1H, 7.56-7.67 (1H, mn), 8.06-8.15 (1H, in), 8.59-8.70 (1H, in) MS (ESI-) 563 CM-H) Example 237 2 S)-N-(2-Tetrahydropyranyloxy)-2[5..(3-((2S)-2acetoxypropionylanino)phenyl) -2-thienyl] 6-tetrahydro- 2 H-thiopyran-2-acetainide 1,1-dioxide (313 ing) WO 00/40576 PCT/JPOOni0018 196 NMR (CDC1 3 1 .38-1.78 (8H, mn), 1.-49, 1. 57 (3H, d, J=8Hz) 1.88-2 .00 (2H, mn), 2. 07-2. 22 (2H, in), 2.72-2.92 (2H, in), 3.03-3.19 (2H, in), 3.29-3.56 (1H, rn), 3.64-3.78 (1H, in), 4.53, 4.82 s), 5.06, 5.34 (1H, q, J=8Hz) 7.18-7.36 (4H, m), 7.53-7.68 (2H, in), 8.10 (1H, br 8.55, 8.59 (1H-,

S)

MS (ESI-) 577 (N-H) Example 238 (2S) 2 -Tetrahyclropyranyloxy) (3- (chloroacetylamino) phenyl) 2-thienyl 4 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1, 1-dioxide (201 mg) NMR (CDC1 3 6) 1. 40-1. 54 (4H, in), 1. 60-1. 73 (2H, m) 1. 88-2. 00 (2H, mn), 2. 06-2. 25 (2H, mn), 2. 67-2 .91 (2H, in), 3. 02-3. 18 (4H, in), 3. 29-3. 51 (1H, m) 3. 62-3. 75 (1H, in), 4.21 (2H, s) 4. 53 5H, s) 4 .82 5H, s) 7. 23-7. 29 (2H1, mn), 7. 32-7. 41 (2.H, mn), 7.51-7.59 (1H1, mn), 7.70-7.76 (1H, in), 8.22 (0.5H, 8.28-8.36 (1.5H1, s) MS (ESI-) 539 (N-H) Example 239 (2S) 2 -Tetrahydropyranyloxy) 5- (9- (f luorenylmethoxycarbony lamino) acetylamino) phenyl) -2thienyl] 6 -tetrahydro-2H-thiopyran-2acetanide 1, 1dioxide (478 ing) was dissolved in a solution of piperidine in N,N-dimnethylforinamide (8 ml) at room temperature. After being stirred at the same temperature for 1 hour, the reaction mixture was concentrated in vacuo.

The residue was purified by SiC 2 column chromatography (eluent: 1-5% MeCH in CHC1 3 to give tetrahydropyranyloxy) 5- 2 -aminoacetylanino) phenyl) -2theyl3456ttayro2-hoya--ctmd 1,1dioxide (335 mng).

WO 00/40576 PCT/JPOO/00018 197 NMR (DMSO-d 6 37-1. 65 (6H, in), 1. 70-2. 08 (4H, m), 2. 34-2. 50 (1H, mn), 2. 87-3 .52 (8H, in), 3. 72-3. (1H, in), 4. 44, 4. 75 (1H, s) 7. 18-7. 25 (1H, in), 7. 32-7. 44 (3H, mn), 7. 52-7 .60 (iN, mn), 8. 02 (1N, s) MS 522 (M+H) Example 240 (2S) (2-Tetrahydropyranyloxy) (3aminopropionylamino)phenyl) -2-thienyl] 6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (1.56 g) was obtained in a similar manner to that of Example 239.

NMR (DMSO-d 6 8) 1. 32-2. 09 (10H, mn), 2. 32-2. 48 (3H, in), 2 .72-3. 56 (8H, in), 3. 72-3 .90 (1H, in), 4 .45, 4. (1N, 7.17-7.24 (1N, in), 7.28-7.51 (3H, mn), 7.43-7.54 (1H, mn), 8.01 (1H, 12.4 (1H, br s) MS 534 (M-H) Example 241 (2S) (2-Tetrahydropyranyloxy) (2- (methoxycarbonylamino)acetylamino)phenyl)-2-thienyl]- 3, 4, 5, 6 -tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide (88 mg) was obtained in a similar manner to that of Example 130.

NMR (CDCl 3 8) 1. 36-1. 72 (8H, mn), 1. 87-1. 99 (2H, in), 2.07-2.27 (2H, in), 2.79-2.92 in), 3.00- 3.23 in), 3.28-3.52 (1H, in), 3.68-3.76 (1H, mn), 3.75 (3H, 3.96-4.12 (2H, in), 4.53, 4.84 (1H, 5.76-5.88 (1H, in), 7.05-7.22 (5N, in), 7.36- 7.55 (2H, in), 8.40 (iH, s) MS 578 (M-N) Example 242 To a solution of 2 S)-N-(2-tetrahydropyranyloxy)-2-[5- (3-formyiphenyl) -2-thienyl] 6-tetrahydro-2H-thiopyran- 2-acetainide 1,1-dioxide (100 mng) in tetrahydrofuran (1.5 ml) was added dropwise sodium borohydride (8.71 mng) in water WO 00/40576 PCT/JP00/00018 198 (0.7 ml) at room temperature. After being stirred for minutes, the reaction is stopped by adding 1% aqueous citric acid solution. The reaction mixture is extracted with ethyl acetate and the solution was washed with brine, dried over MgSO 4 and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: 0.5-3% methanol in chloroform) to give tetrahydropyranyloxy)-2-[5-(3-hydroxymethylphenyl)-2thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (96 mg) as an amorphous solid.

NMR (CDC13, 1.38-1.72 (6H, 1.81-2.00 (2H, m), 2.03-2.25 (2H, 2.67-3.17 (6H, 3.29-3.51 (1H, 3.61-3.72 (1H, 4.52, 4.81 (1H, s), 4.72 (2H, d, J=6.0Hz), 7.25-7.41 (4H, 7.52 (1H, d, J=8.5Hz), 7.60 (1H, s) MS 478 (M-H) Example 243 A solution of (2S)-N-(2-tetrahydropyranyloxy)-2-[5-(4ethenylphenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (200 mg), microencapsulated osmium tetraoxide (5.34 mg) and N-methylmorphorine N-oxide (98.5 mg) in a mixture of H 2 0-acetone-acetonitrile ml) was stirred at room temperature for 12 hours. After the reaction was completed, the catalyst was separated by filtration. After washing with methanol, combined filtrates were concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: 0.5-3% methanol in chloroform) to give tetrahydropyranyloxy)-2-[5-(4-(cis-1,2dihydroxyethyl)phenyl) -2-thienyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide as an amorphous solid (200 mg).

NMR (CDC13, 1.38-1.75 (6H, m) 1.90-2.00 (2H, m), 2.07-2.23 (2H, 2.60-2.89 (2H, 3.09-3.17 WO 00/40576 PCT/JP00/00018 199 (4H, 3.25-3.50 (1H, 3.59-3.71 (1H, m), 3.73-3.82 (1H, 4.52, 4.80 (1H, 4.80-4.88 (1H, 7.34-7.40 (3H, 7.54-7.59 (3H, m) MS 508 (M-H) Example 244 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3- (phenoxycarbonyloxymethyl)phenyl)-2-thienyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (620 mg) was obtained from (2S)-N-(2-tetrahydropyranyloxy)-2-[5-(3hydroxymethylphenyl)-2-thienyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (500 mg) in a similar manner to that of Example 130.

NMR (CDC1 3 1.38-1.75 (6H, 1.90-2.01 (2H, m), 2.06-2.23 (2H, 2.65-2.90 (2H, 3.04-3.17 (4H, 3.30-3.50 (1H, 3.62-3.70 (1H, m), 4.53, 4.81 (1H, 5.28 (2H, 7.19 (2H, d, 7.25-7.31 (4H, 7.37-7.42 (4H, m), 7.59-7.61 (1H, 7.66 (1H, s) MS 598 (M-H) Example 245 To a solution of (2S)-N-(2-tetrahydropyranyloxy)-2-[5- (3-(phenoxycarbonyloxymethyl)phenyl)-2-thienyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (200 mg) in N,N-dimethylformamide (3 ml) was added 40% aqueous methylamine (0.17 ml). After being stirred for 3 hours at the same temperature, the mixture was concentrated in vacuo.

The residue was diluted with ethyl acetate, washed with 1% aqueous citric acid solution, sat. NaHCO 3 solution and brine, dried over MgSO 4 and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: CHC1 3 to give (2S)-N-(2-tetrahydropyranyloxy)-2- [5-(3-(methylaminocarbonyloxymethyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2- WO 00/40576 PCT/JPOO/00018 200 acetamide 1, 1-dioxide (150 mg) as an amorphous solid.

NMR (CDCl 3 37-1. 75 (6H, mn), 1. 90-2. 00 (2H, m) 2. 05-2. 23 (2H, in), 2. 83 (3H, d, J=5.-OHz) 2. 89- 3.17 (6H, in), 3.29-3.50 (1H, in), 3.61-3.71 (1H, mn), 4.53, 4.81 (1H, 5.11 (2H, 7.25-7.31 (2H, in), 7.36 (1H, dd, J=8.0, 8.0Hz), 7.51-7.59 (3H, mn) MS 535 (M-H) Example 246 (2S) (2-Tetrahydropyranyloxy) 5- (4 (2- (methylaminocarbonyl) ethenyl) phenyl) -2-thienyl.] 4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (270 mg) was obtained from 2 S)-N-(2-tetrahydropyranyloxy)-2-[5-(4-(2carboxyethenyl) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamije 1,1-dioxide (300 mng) in a similar manner to that of Example 32.

NMR (CDCl 3 1.38-1.73 mn), 1.88-2.02 (2H, in), 2.09-2.25 (2H, in), 2.78-2.89 (2H, in), 2.96 (3H, d, J=SHz), 3.05-3.19 (4H, in), 3.29-3.51 (1H, in), 3.65-3.75 (1H, in), 4.54, 4.84 (1H, 6.40 (1H, d, J=lSHz) 7.20-7.59 (7H, in), 8.78 (1H, d, Example 247 (2S) 2 -Tetrahydropyranyloxy) (2- (ethyl aminocarbonyl) ethenyl)phenyl) 2 thienyl 4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (280 mng) was obtained in a similar manner to that of Example 32.

NMR (DMSO-d 6 1.23 (3H1, t, J=7.2Hz), 1.38-1.73- (6H, mn), 1.90-2.01 (211, mn), 2.07-2.23 in), 2.78- 2.88 (2H, mn), 3.02-3.20 (4H1, mn), 3.38-3.48 (3H, mn), 3.67-3.76 (111, in), 4.54, 4.84 (1H1, 6.41 d, 7.21-7.59 (7H, in), 8.78 (1H, br) Example 248 2 S) (2-Tetrahydropyranyloxy) WO 00/40576 PCT/JPOO/00018 201 (methylaminocarbonylmethoxy) phenyl) -2-thienyll1-3, 4, 5, 6tetrahydro-2H-thiopyran-2acetamide 1, 1-dioxide (720 mg) was obtained in a similar manner to that of Example 247.

NMR (DMSO-d 6 1.37-1.62 (6H, m) 1.67-1.81 (2H, m), 1.82-2.05 (2H, in), 2.33-2.45 (1H, mn), 2.66 (3H, d, 2.90-3.50 (6H, in), 3.73-3.91 (1H, in), 4.45, 4.75 (TH, 4.50 (2H, 7.01 (2H, d, J=9.OHz), 7.16 (1H, d, J=4.OHz), 7.32 (1H, d, 7.59 (2H, d, J=9.OHz), 8.07 (1H, br), 11.23 s) Example 249 A mixture of 2 2 -tetrahydropyranyloxy-2[-3- (chloroacetylamino) phenyl]I -2-thienyl 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (98 mg), n-tetrabutylamionium iodide (5 mg) and 2-aminoethanol (27. 7 mg) in N,N-dimethylformamide (1.5 ml) was stirred for 14 hours at room temperature. The mixture was concentrated in vacuo and taken up between ethyl acetate and saturated aqueous sodium bicarbonate. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo to give 2 2 -tetrahydropyranyoxy)2-5[3 2 -hydroxyethyl amino) acetylamino ]phenyl 2thienyl 3,4,5, G-tetrahydro-2H-thiopyran2acetamide 1,1-dioxide (100 mg) as an amorphous solid.

NMR (CDCl 3 1.38-1.77 (6H, mn), 1.89-2.00 (2H, mn), 2.05-2.24 (2H, in), 2.68-2.91 (4H, in), 3.00-3.18 (4H, in), 3.29-3.52 (3H, mn), 3.62-3.80 (3H, in), 4.53 (0.5H, 4.82 (0.5H1, 7.22-7.32 (4H, in), 7.59-7.67 (1H, in), 7.69-7.75 (1H, in), 8.01 (111, s), 9.48 (1H, s) MS 564 (M-H) Example 250 2 S)-N-(2-Tetrahydropyranyloxy)2[5[3q (4- WO 00/40576 202 PT.fnnn morpholi no) acetylami no] phenyl] -2-thienyl] 4,5, 6tetrahydro-2H-thiopyran2acetamide 1,1-dioxide (96 mg) was obtained in a similar manner to that of Example 249.

NMR (CDC1 3 5) 1. 40-1. 56 (4 H, in), 1. 61-1. 73 in), 1.89-2.01 (2H, mn), 2.06-2.32 (2H, in), 2.61-2.87 (6H, in), 3.05-3.19 mn), 3.31-3.51 in), 3.62-3.74 (1H, in), 3.77-3.85 (41H, mn), 4.53 4.81 (0.5H, 7.25-7.31 (2H, in), 7.33-7.38 (2H, mn), 7.52-7.61 (1H, in), 7.74-7.80 in), 8.00-8.23 (1H, in), 9.10 (1H, s) MS (ESI-) 590 (M-H) The following compounds were obtained in a similar manner to that of Example 54.

Example 251 (2S) -N-Hydroxy-2- -aiinocarbonyiphenyl) -2-thienyl] 3 4 ,5, 6 -tetrahydro-2H-thiopyran-2acetanide 1,1-dioxide mng) NMR (DMSo-d 6 1.74-2.04 (4H, in), 2.37-2.46 (1H, mn), 2.96-3.27 (4H, mn), 3.4-3.54 (1H, in), 7.25 (1H, d, J=4.OHz), 7.48 (1H, br), 7.59 d, J=4.OHz), 7.74 d, J=7.5Hz), 7.92 d, J=7.SHz), 8.02 (1H, br) 8.85 br) MS (ESI-) 407.1 (M-H) Example 252 (2S) -N-Hydroxy-2- 4 -benzylaininocarbonyl) phenyl) -2thienyl] G-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (20 mng) NMR (DMSO-d 6 1.74-2.08 (4H, mn), 2.37-2.45 (1H, in), 2.95-3.26 (4H, m) 3.43-3.52 (1H, in), 4.49 (2H, d, J=6.OHz), 7.24 (2H, in), 7.31-7.34 (4H, in), 7.61 (1H, d, J=3.OHz), 7.75 (2H, d, J=7.5Hz), 7.95 (2H, d, J=7.5Hz), 8.84 (1H, 9.10 (1H, t, J=6.OHz) WO 00/40576 PCTUP00/00018 203 MS 523.1(M±H+Na) Example 253 (2S) -N-Hydroxy-2- 5- (et hoxyca rbonyl amino) phenyl) -2thienyl] 4,5, G-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (115 ing) NMR (DMSO-d 6 1.28 (3H, t, J=7.OHz), 1.73-2.05 (4H, mn), 2.37-2.45 (1H, mn), 2.96-3.25 (4H, mn), 3.42- 3.53 (1H, in), 4.15 (2H, q, J=7.OHz), 7.20 (1H, d, J=4.0Hz), 7.28-7.34 (3H, in), 7.48 (1H, d, J=4.OHz), 7.82 (1H, 8.84 (1H, br), 9.85 (1H, 10.60 (1H, br) MS 451.2 (M-H) Example 254 (2S) -N-Hydroxy-2- f[5- (ben zylaininocarbonyl) phenyl) -2thieny]3,4,5,6tetrahydro2 Htthio opyr2acetide 1,1dioxide (50 mg) NMR (DMSO-d 6 1.73-2.05 mn), 2.36-2.47 (1H, in), 2.95-3.25 (4H, in), 3.41-3.52 (1H, mn), 4.31 (2H di, 6.68 (1H, t, J=7.OHz), 7.18-7.38 in), 7. 86 (1 H, s) 8. 72 (1 H, s) 8. 84 (1 H, s) MS 512.3 (M-H) Example 255 (2S) -N-Hydroxy-2- 5- (n-propyloxycarbonylamino) phenyl) -2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran.2.

acetamide l,1-dioxide (120 mg) NMR (DMSO-d 6 0.95 (3H, t, J=7.OHz), 1.66 (2H, qt, J=7. 0, 7.0OHz) 1. 72-2. 05 in), 2. 35-2. 46 (1H, mn), 2. 94-3. 29 (4H, mn), 3. 40-3. 53 (1H, mn), 4. 05 (2H, t, J=~7.0OHz) 7. 20 d, J=4 .OHz) 7 .29-7 .34 (3H, mn), 7.38 (1H, di, J=4.0Hz), 7.83 (1H, 8.83 (1H, 9.73 (1H, 10.59 (iR, s) MS 465.3 (M-H) WO 00/40576 PCT/JPOO/00018 204 Example 256 (2S) -N-Hydroxy-2- (isopropoxycarbonylamino) phenyl) -2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (90 mg) NMR (DMSO-d 6 8) 1.26 (6H, d, J=6. OHz) 1.74-2.04 (4H, in), 2.35-2.55 (1H, in), 2.94-3.25 (4H, in), 3.40- 3. 51 (1H, in), 4. 40 (1H, qq, J=6. 0, 6.0OHz) 7. (1H, d, J=4.0OHz) 7.29-7. 33 (3H, in), 7. 36 (1H, d, J=4.OHz), 7.85 (1H, 8.83 (1H, 9.67 (1H, s), 10.59 (1H, s) MS 465.3 (M-H) Example 257 (2S) -N-Hydroxy-2- (2-chloroethoxycarbonyl amino) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (100 mng) NMR (DMSO-d 6 1.75-2.05 (4H, in), 2.36-2.47 (iR, in), 2.94-3.29 (4H, mn), 3.42-3.52 (1H, mn), 3.88 (2H, d, J=6.OHz), 4.35 (2H, d, J=6.OHz), 7.21 (1H, d, J=4.OHz), 7.32-7.36 (2H, mn), 7.40 (1H, d, J=4.OHz), 7.84 (1H, 8.83 (1H, 9.94 (1H, 10.08 (1H, s) MS 485.2 (M-H) Example 258 (2S) -N-Hydroxy-2- (3-valerylarninophenyl) -2-thienyl] 3 4

,S,

6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (102 ing) NMR (DMSO-d 6 0.91 (3H, t, J=8Hz), 1.24-1.41 (2H, mn), 1.52-1.66 (2H, in), 1.69-2.08 (4H, mn), 2.33 (2H, t, J=8Hz), 2.32-2.48 (1H, mn), 2.92-3.28 (4H, in), 3.37-3.54 (1H, in), 7.20 (1H, d, J=3Hz), 7.34 (2H, d, J=3Hz), 7.40 (1H, d, J 3Hz), 7.42-7.52 (1H, in), 7.99 (1H, 10.00 (1H, 10.60 (1H, s) WO 00/40576 PCT/JPOO/00018 205 MS 463 (M-H) Example 259 (2S) -N-Hydroxy-2- 5- (ethyl thioca rbonylamino) phenyl) -2-thienyl] 4, 5, 6 -tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (92 mg) NMR (DMSO-d 6 6) 1. 26 (3H, t, J=8Hz) 1. 72-2. 08 (4H, mn), 2.36-2.49 mn), 2.89 (2H, q, J=8Hz), 2.94- 3.30 (4H, in), 3.39-3.55 mn), 7.21 (1H, d, J=3Hz), 7.32-7.44 mn), 7.90 (1H, 8.85 (1H, 10.39 (1H, 10.60 (1H, s) MS 469 (M+H) Example 260 (2S) -N-Hydroxy-2- 3 (met hyl thiocarbonylamino) phenyl) -2-thienyl.] 4, 5, 6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (130 mg) NMR (DMSO-d 6 1.68-2.08 (4H, mn), 2.33 (3H, 2.35- 2.46 in), 2.92-3.38 (4H, mn), 3.39-3.53 (1H, in), 7.21 (1H, d, J=3Hz), 7.29-7.46 (4H, in), 7.90 (1H,

S)

MS 453 Example 261 (2S) -N-Hydroxy-2- 3 (ben zyloxycarbonylamino) phenyl) -2-thienyl 1-3, 4, 5, 6 -tetrahydro-2H-thiopyran.2acetamide 1, 1-dioxide (60. 2 mg) NMR (DMSO-d 6 8) 1. 68-2. 07 (4H, mn), 2. 32-2. 48 (1H, in), 2.92-3.34 (4H, in), 3.52-3.65 (1H, in), 5.18 (2H, s), 7.21 (1H, d, J=3Hz) 7.26-7.50 (1OH, m) 7.85 (iH, 9.91 (1H, 10.60 (1H, s) MS 513 (M-H) Example 262 (2 )NHdo y2 oy abnlmn WO 00/40576 PCT/JPOO/00018 206 a cetylIainino) phenyl) -2-thienyl]1 5, 6-tetrahydro-2Hthiopyran-2-acetaiie 1,1-dioxide (40 ing) NMR (DMSO-d 6 40 (9H, s) 1. 66-2. 08 (4H, in), 2. 2. 48 (1H, in), 2. 92-3. 32 (4H, in), 3. 45-3. 53 (1H, in), 3.73 (2H, d, J=7Hz), 7.07 (1H, t, J=7Hz), 7.22 (1H, d, J=3Hz), 7.32-7.54 (4H, in), 7.97 (1H, 10.05 (1H, s) 10. 61 (4H, s) MS 536 (M-H) Example 263 (2S) -N-Hydroxy-2- (4-chiorophenoxy) acetylainino)phenyl) -2-thienyl] 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (90 ing) NMR (DMSO-d 6 1.71-2.09 (4H, mn), 2.35-2.49 (1H, in), 2.94-3.29 in), 3.42-3.55 (1H, in), 4.74 (2H, 7.00-7.12 (2H, mn), 7.22 (1H, br 7.32-7.47 in), 7.51-7.62 (1H, mn), 8.02 (1H, 8.84 (1H, 10.22 (TH, 10.60 (1H, s) MS 547 (M-H) Example 264 (2S) -N-Hydroxy-2- 5- (phenoxyca rbonylanino) phenyl) -2-thienyl]1 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide ('88 mng) NMR (DMSO-d 6 1.68-2.09 (4H, mn), 2.32-2.48 (1H, mn), 2.92-3.30 (4H, in), 3.56-3.72 (1H, mn), 7.17-7.30 (4H, mn), 7.31-7.51 (6H, in), 7.89 (1H, 10.37 (1H, 10.61 (1H, s) MS 499 (M-H) Example 265 2 S) -N-Hydroxy- 2 (4-chlorophenyl) acetylanino) phenyl)-2-thienyl]-3, 4,5, G-tetrahydro-2H-thiopyran-2acetarnide 1,1-dioxide (95 ing) NMR (DMSO-d 6 1.68-2.09 (4H, mn), 2.35-2.48 (1H, mn), WO 00/40576 PCT/JPOO/00018 207 2. 92-3. 32 (4H, in), 3. 54-3. 66 (1H, mn), 3. 68 (2H, s), 7. 20 (1H, d, J=3Hz) 7 .28-7 .52 (8H, mn), 7. 99 (1H, s) 10. 33 (1H, s) 10. 60 (1H, s) MS 531 (M-H) Example 266 (2S) -N-Hydroxy-2- 4 -morpholinocarbonylamino) acetylamino)phenyl)2thienyl34,S6-tetrahydro-2Hthiopyran-2-acetamide l,l-dioxicle (50 mng) NMR (DMSO-d 6 6) 1. 71-2. 08 (4H, mn), 2. 36-2. 48 (1K, m) 2.94-3.62 (13H, in), 3.82 (2H, di, J=7Hz), 6.96 (1H-, t, J=7Hz), 7.21 (1H, d, J=3Hz), 7.31-7.49 (4H, in), 8.02 (1H, 8.84 (1H, br s) MS 549 (M-H) Example 267 (23) -N-Hydroxy-2- (N-ethyl-N-methylaininocarbonyloxy) acetylainino) phenyl) -2-thienyl] -3,4,5,6tetrahydro-2H-thiopyran-2acetaie 1,1-dioxide (133 ing) NMR (DMSO-d 6 6) 1.-05, 1. 12 (3H, t, J=8Kz) 1. 68-2.07 (4H, in), 2.35-2.48 (1H, mn), 2.76-3.36 (9H, in), 3.39-3.54 (1H, mn), 4.63 (2H, 7.21 (1H, d, J=3Hz) 7. 32-7 .47 (4H, mn), 8. 00 (1H, s) 8. 85 (1H, 10.18 (1H, 10.61 (1H, s) MS 522 (M-H) Example 268 (2S) -N-Hydroxy-2- (isopropoxyacetylanino) phenyl) -2-thienyl] 6 -tetrahydro-2H-thiopyran-2acetainide 1,1-dioxide (204 ing) NMR (DMSO-.d 6 1.78 (6H, d, J=8Hz), 1.72-2.08 (4H, mn), 2.35-2.49 (1H, in), 2.94-3.31 (4H, mn), 3.42- 3.56 (1H, mn), 3.63-3.77 (1H, mn), 4.04 (2H, s), 7.22 di, J=3Hz), 7.32-7.43 (2H, mn), 7.40 (1H, di, J=3Hz), 7.56-7.64 (1H, mn), 8.02 (1H, 8.85 WO 00/40576 WO 0040576PCT/WOninnni R 208 (iN, s) 9. 68 (1H, s) 10 .60 (1H, s) MS 482 (M+H) Example 269 2 S) -N-Hydroxy-2- [5(3 (2(2oxo1, 3-oxazolidinyl- 3 yl) acetyiainino) phenyi) -2-thienyl 4,5, 6-tetrahydro-2thiopyran-2-acetamide 1, 1-dioxide (480 mg) NMR (DMSO-d 6 6) 1. 65-2. 09 (4H, mn), 2. 32-2. 51 (1H, mn), 2. 88-3. 53 (5H, in), 3. 66 (2H, t, J=8Hz) 4 .04 (2H, 4.34 (2H, t, J=8Hz), 7.21 (1H, d, J=3Hz), 7.30-7.51 (4H, in), 8.03 10.37 (1H, s), 10.62 (1H, s) MS 506 (M-H) Example 270 (2S) -N-Hydroxy-2- 4 -methoxyphenylaminocarbonylN aminio) phenyl) -2-thienyl] 4, 5, 6 -tetrahydro-2H-thiopyran2acetainide 1,1-dioxide (140 mg) NMR (DMSO-c1 6 1.73-2.04 (4H, mn), 2.38-2.45 (1H, in), 2.95-3.26 (4H, mn), 3.39-3.54 (iH, mn), 3.72 (3H, s), 6.86 (2H, d, J=7.5Hz), 7.20 (iN, d, J=4.OHz), 7.23-7.32 (3H, in), 7.37 (2H, d, J=7.5Hz), 7.50 (1H, d, J=4.OHz), 7.87 (1H, 8.50 (1H, 8.72 (1H, 8.84 (1H, 10.59 (1H, s) MS 528.3 (M-H) Example 271 (2S) -N-Hydroxy-2- 3 -pyridylaininocarbonylamino) phenyl) -2-thienylj 4, 5, 6 -tetrahydro-2H-thiopyran2 acetamide 1,1-dioxide (70 ing) NMR CDMSO-d 6 1.75-2.05 (4H, in), 2.37-2.48 (1H, mn), 2.96-3.25 (4H, in), 3.58-3.69 (1H, mn), 7.21 (iH, d, J=4.OHz), 7.30-7.36 (3H, mn), 7.42 (iH, d, 7.82 (iH, dd, J=7.5, 5.0Hz), 7.90 (1H, 8.29 (12H, d, J=7.5Hz), 8.45 (1H, d, J=5.OHz), 9.03 (1H, WO 00/40576 PCT/JPOO/00018 209 s) 9. 48 (1H, s) 9. 85 (1H, s) 10. 60 (1H, s) MS 499.2 (N-H) Example 272 (2S)-N-Hydroxy-2-[5-{3-( 2

S)-

2 aiinopropionyl)amino)phenyl}-2-thienyl] G-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide hydrochloride (120 ing) from tetrahydropyranyloxy)-2-[5-{3-(C((2S)-2-tertbutoxycarbonylaminopropionyl) amino) phenyl}-2-thieiyl] 3,4, 5, 6 -tetrahydro-2H-thiopyran-2-acetamiie 1,1-dioxide NMR (DMSO-d 6 50 (3H, di, J=7. OHz) 1. 72-2. 03 (4H, mn), 2.35-2.46 (1H, mn), 2.95-3.27 (4H, mn), 3.43- 3.54 (1H, in), 4.05 (1H, br t, J=7.OHz), 7.21 (1H, di, J=4.0Hz), 7.37-7.43 mn), 7.55 (1H, d, J=7.5Hz), 7.95 (1H, 8.28-8.32 (3H, mn), 10.63 (1H, 10.81 (1H, s) MS (ESI-) :450.7 (M-H) Example 273 (2S) -N-Hyclroxy-2-[5-{3-( (tert-butoxycarbonylamino) propionyl)amino)phenyl}.2-thienyl]>3,4, 5, 6-tetrahyciro- 2 H-thiopyran-2-acetamiie 1,1-dioxide (30 mng) NMR (DMSO-d 6 6) 1.27 (3H, di, J=6. OHz) 1. 38 (9H, s), 1.74-2.04 (4H, mn), 2.37-2.42 (1H, mn), 2.95-3.25 (4H, mn), 3.38-3.51 (1H, in), 4.08-4.15 (1H, mn), 7.10 (1H, di, J=7.OHz), 7.20 (1H, di, J=4.OHz), 7.31-7.36 (2H, in), 7.40 (1H, di, J=4.OHz), 7.50 (1H, br), 7.96 (1H, 8.83 (1H, 10.04 (1H, s), 10.60 (TR, s) MS 550.3 (N-H) Example 274 (2S)-N-Hydroxy-2-[5-13-( ((2R)-2-aminopropionyl)amino)phenyl }-2-thienylj 6 -tetrahyclro-2H-thiopyran-2acetamide 1,l-ciioxide (130 mg) from WO 00/40576 PCT/JPOO001i8 210 tetrahydropyranyloxy)2- 5-13- (2R) -2-tertbut oxyca rbonyl ami nopropionyl) amino) phenyl -2 -thienyl] 3,4,5, G-tetrahydro-2H-thiopyran-2acetamiie l,l-dioxiie NMR (DMSO-d 6 1.50 (3H, di, J=7.OHz), 1.72-2.03 (4H, in), 2.35-2.46 (1H, mn), 2.95-3.27 (4H, in), 3.43- 3. 54 (1H, in), 4 .05 (1H, br t, J=7. OHz) 7.21 (1H, di, J=4.OHz), 7.37-7.43 (3H, mn), 7.55 (1H, di, J=7. 5Hz) 7. 95 (1H, s) 8.28-8.32 (3H, mn), 10.63 (1H, 10.81 (1H, s) MS (ESI-) 4 52. 1 CM-H) Example 275 (2S) -N-Hydroxy-2- [5-13- (4-methyiphenoxy) acetylaiino) phenyl}.2thienyl> 3, 4 5 ,6-tetrahydro-2Hthiopyran-2-acetamiie l,1-dioxide (150 mng) NMR (DMSO-d 6 6) :1 .74-2. 04 (4H, mn), 2. 24 (3H, s) 2. 37- 2.45 (1H, in), 2.95-3.26 (4H, in), 3.44-3.53 (1H, in), 4. 67 (2H, s) 6. 90 (2H, di, J=7. 5Hz) 7. 11 (2H, di, 7.21 (1H, di, J=4.OHz), 7.34-7.37 (2H, in), 7.42 (1H, di, J=4.OHz), 7.56 (1H, di, J=6.0Hz), 8.01 (1H, s) 8. 82 (1H, s) 10. 17 (1H, s) 10. 59 (1H,

S)

MS 528.1 CM-H) Example 276 (2S) -N-Hydroxy-2- 5- f 3- N-diinethylamino) acetylanino) phenyly...2-thielyl] 4, 5, 6 -tetrahydro-2Hthiopyran-2-acetamiie 1, 1-cioxicie (65 mg) NMR (DMSO-d 6 1. 74 05 (4H, in), 2. 36-2. 45 (1H, in), 2. 89 (6H, s) 2. 96-3. 27 (4H, mn), 3. 44-3. 54 (1H, in), 4 .17 (2H, s) 7. 22 (1H, di, J=4 .0Hz) 7. 38-7. 42 (2H, mn), 7.50 (1H, di, J=5.OHz), 7.95 (1H, 8.84 (1H, br), 9.88 (1H, br), 10.60 (1H, 10.82 (1H, s) MS CESI-): 464.3 CM-H) WO 00/40576 PCT/JPOO/0001 8 211 Example 277 (2S) -N-Hydroxy-2-[f5- (allyloxycarbonylamino) phenyl) -2-thienyll-3, 4,5, 6-tetrahydro-2H-thiopyran-2acetainide 1,1-dioxide (50 mg) NMR (DMSO-d 6 1.73-2.04 (4H, in), 2.36-2.45 (1H, mn), 2.95-3.25 (4H, mn), 3.41-3.49 (1H, in), 4.63 (2H, d, 5.25 (1H, d, J=8.OHz), 5.38 (1H, d, J=8. OHz) 5. 93-6. 06 (1H, in), 7. 20 (1H, d, J=4 .OHz) 7 .30-7. 35 in), 7. 49 (TH, d, J=4 .OHz) 7 .84 (1H, 8.83 (1H, 9.85 (1H, s) MS (EST-) 4 63. 3 (N-H) Example 278 (2S) -N-Hydroxy-2- 5 3 -ethoxycarbonylmethylaminocarbonylamino)phenyl) -2-thienyl] 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (40 ing) NMR (DMSO-d 6 1.23 (3H, t, J=7.SHz), 1.73-2.05 (4H, mn), 2.36-2.47 (1H, in), 2.94-3.25 (4H, in), 3.42- 3.54 (1H, mn), 3.87 (2H, d, J=7.OHz), 4.13 (2H, q, J=7.5Hz), 6.50 (1H, t, J=7.OHz), 7.18 (1H, d, J=4 .OHz) 7. 21-7. 30 (3H, in), 7. 37 (TR, d, J=4 .OHz) 7. 83 (1 H, s) 8. 83 (1H, s) 8 .9 6 (1iH, s) MS 508.3 (M-H) Example 279 (2S) -N-Hydroxy-2- (benzyloxyacetylamino)phenyl) -2thienyl] 4,5, G-tetrahydro-2H-thiopyran-2-acetanide 1, 1dioxide (55 mg) NMR (DMSO-d 6 1.75-2.06 (4H, in), 2.36-2.46 (1H, mn), 2.95-3.25 (4H, in), 3.42-3.53 (1H, in), 4.11 (2H, s), 4.64 (2H, 7.21 (1H, d, J=4.OHz), 7.28-7.43 (8H, in), 7.54-7.57 (1H, in), 8.01 (1H, 8.82 s), 9.90 (1H, 10.60 (1H, s) MS (ESI-) 527.3 (N-H) WO 00/40576 PCT/JPOO/00018 212 Example 280 (2S) -N-Hydroxy-2- 5- (cyclopent yl carbonyl amino) phenyl) -2-thienyl 1-3, 4, 5, 6-tetrahydro--2H-thiopyran-2acetamide 1,1-dioxide (120 mg) .NMR (DMSO-d 6 8) 1. 52-2.06 (12H, mn), 2.36-2.47 (1H, m) 2. 78 (1H, tt, J=7. 0, 7 .0Hz) 2. 95-3. 25 (4H, in), 3.40-3.54 (1H, in), 7.20 (1H, d, J=4.OHz), 7.32- 7.34 (2H, in), 7.40 (1H, d, J=4.0Hz), 7.45-7.49 (1H, in), 8.03 (iR, 8.84 (1H, 9.98 (1H, s), 10.61 (1H, s) MS 475.3 (M-H) Example 281 (2S) -N-Hydroxy-2- (2-hydroxyethyl) ami noca rbonyl amino) phenyl) -2-thienyl J-3, 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1, 1-dioxide (20 mng) NMR (DMSO-d 6 6) 1. 72-2.04 (4H, in), 2. 40-2. 45 (1H, m), 2.93-3.25 (6H, mn), 3.41-3.50 (3H, in), 4.75 (1H, t, 6.22 (1H, t, J=5.OHz), 7.16-7.25 (3H, mn), 7.35 (1H, d, J=4.OHz), 7.82 (1H, 8.71 8.83 (1H, s) MS 466.4 (M-H) Example 282 (2S)-N-Hydroxy-2-[5- (2-aminoethoxy)carbonylamino)phenyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide hydrochloride (20 rmg) NMR (DMSO-d 6 1.74-2.07 (4H, in), 2.35-2.44 (1H, in), 2.95-3.27 (4H, in), 3.48-3.66 (SH, in), 7.12-7.51 (4H, in), 7.86-7.90 (2H, in), 8.00-8.08 (2H, in), 9. 10 (1H, s) 9. 85 (1H, S) 10.-62 s) MS 468.3 (M+H) Example 283 (2S)-N-H-ydroxy-2-[5- 3 -chloropropionylamino)phenyl)- WO 00/40576 WO 0040576PCTJPOoO 08 213 2 -thienyl]-3,4,5,6-tetrahydro2H-~thiopyran2-acetamide 1,1dioxide (95 mng) NMR (DMSO-d 6 1.73-2.06 in), 2.37-2.46 (1H, mn), 2.84 (2H, t, J=6.OHz), 2.95-3.26 (4H, mn), 3.43- 3.56 mn), 3.90 (2H, t, J=6.OHz), 7.21 (18, d, J=4.OHz), 7.35-7.40 (2H, in), 7.42 (1H, d, J=4.OHz), 7.47-7.52 (1H, in), 8.00 (1H, 8.85 (1H, s) MS 469.1 Example 284 (2S) -N-H-ydroxy-2- (methanesulfonylamino)phenyl) -2thienyl]-3, 4,5, G-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (40 ing) NMR (DMSO-d 6 1.72-2.05 (48, in), 2.34-2.44 (18, mn), 2.89 (38, 2.93-3.23 (48, mn), 3.41-3.51 (1H, in), 7.12 (2H, d, J=7.5Hz), 7.15 (1H, d, J=4.08z), 7.31 (18, d, J=4.OHz), 7.50 (28, d, MS 457.3 (M-H) Example 285 (2S) -N-Hydroxy-2- (phenylaminocarbonyl) ethenyl) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran- 2-acetainide 1,1-dioxide (40 ing) NMR (DMSO-d 6 1.73-2.07 (4H, m) 2.38-2.48 (18, m), 2.97-3.54 (58, mn), 6.86 (1H, d, J=16Hz), 7.06 (18, dd, J=8.0, 8.0Hz), 7.24 (1H, d, J=4.08z), 7.34 (2H, dd, J=8.0, 8.0Hz), 7.56 (1H, d, J=4.OHz), 7.61 (18, d, J=l6Hz), 7.65-7.75 (6H, mn), 8.85 (18, 10.2 (1H, 10.6 (1H, s) Example 286 (2S) -N-Hydroxy-2 5- (4 4 -met hoxyphenylaninocarbonyl) ethenyl)phenyl) -2-thienyl]-3, 4,5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (100 ing) NMR (DMSO-d 6 o, 1.72-2.07 (4H, in), 2.37-2.46 (18, mn), WO 00/40576 PCT/JPOO/00018 214 2. 97-3. 52 in), 3. 74 (3H, s) 6. 83 (1H, d, J=l6Hz) 6. 92 (2H, di, J=8 .5Hz) 7. 24 (1H, d, J=4 .OHz) 7. 54-7. 75 (8H, mn), 8. 85 (iR, s) 10. 08 (1H, 10.6 (1H, s) Example 287 (2S) -N-Hydroxy-2- (4-f luorophenylaminocarbonyl) ethenyl) phenyl) -2-thienyl] 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide l,1-dioxide (80 ing) NMR (DMSO-d 6 8) 1. 73-2. 07 (4H, in), 2. 37-2. 46 (1H, m) 2. 98-3. 53 (5H, in), 6. 83 (1H, d, J=l 6Hz) 17. 18 (2H, cid, J=8.5, 8.5Hz), 7.24 (1H, di, J=4.OHz), 7.57- 7.75 (8H, in), 8.85 (1H, 10.3 (1H, 10.6 (1H,

S)

Example 288 (2S) -N-Hydroxy-2- (ethylcarbonyloxy) phenyl) -2thienyl]-3,4, 5, G-tetrahydro-2H-thiopyran.2-acetaiie 1,1dioxide (100 ing) NMR (DMSO-c1 6 1.13 (3H, cid, J=7.5, 7.5Hz), 1.71-2.07 (4H, in), 2.36-2.46 (1H, in), 2.62 (2H, ddd, 7.5Hz), 2.96-3.52 (5H, in), 7.20-7.21 (3H, mn), 7.46 (1H, di, J=4.OHz), 7.68 (2H, di, J=8.5Hz), 8.85 (1H, s) MS (ESI-) 436 (M-14) Example 289 (23) -N-Hydroxy-2- (methoxycarbonylaminoinethyl) phenyl) -2-thienyl]1 4, 5, 6 -tetrahydro-2H-thiopyran-2 acetainide 1,1-dioxide (45 mg) NMR (DMSO-d 6 6) 1. 70-2. 06 (4H, in), 2. 35-2. 45 (1H, mn), 2.96-3.50 mn), 3.56 (3H, 4.19 (2H, di, J=7.OHz), 7.20 (1H, di, J=4.OHz), 7.29 (2H, di, 7.43 (1H, di, J=4.OHz), 7.60 (2H, di, J=8.5Hz), 7.70 (1H, t, J=7.OHz), 8.85 (1H, S), WO 00/40576 PCT/JPOO/00018 215 10.60 (1H, s) MS (ESI-) :451 CM-H) Example 290 (2S) -N-Hydroxy-2- (ethylcarbonylmethoxy) phenyl) -2thienyl] 4, 5, 6 -tetrahydro-2H-thiopyran-2-acetamiie 1, 1dioxide (120 mg) NMR (DMSO-d 6 0.98 (3H, t, J=7.2Hz), 1.70-2.07 (4H, mn), 2.33-2.45 (1H, in), 2.54 (2H, q, J=7.2Hz), 2.95-3.50 (5H, mn), 4.86 (2H, 6.95 (2H, d, 7.16 (1H, d, J=4.0Hz), 7.34 (1H, di, J=4.OHz), 7.55 (2H, d, J=8.5Hz), 8.84 (1H, br) MS 450 CM-H) Example 291 (2S) -N-Hydroxy-2- [5S- (4 (cyclopropylaminocarbonylmethoxy) phenyl) -2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran- 2-acetamide 1,1-dioxide (70 ing) NMR (DMSO-d 6 0.46-0.51 (2H, in), 0.60-0.66 (2H, in), 1.70-2.07 (4H, in), 2.34-2.45 (1H, in), 2.66-2.75 (1H, in), 2.95-3.50 (5H, in), 4.47 (28, 6.99 (2H, d, J=8.5Hz), 7.16 (1H, d, J=4.OHz), 7.35 (18, d, J=4.OHz), 7.57 (2H, d, J=8.SHz), 8.15 (18, br), 8.84 (18, 10.59 (18, s) Example 292 (2S) -N-Hydroxy-2- 5- (4 (n-propylaininocarbonylmethoxy)phenyl) -2-thienyl] 6 -tetrahydro-2H-thiopyran- 2-acetaiie 1,1-dioxide (70 mng) NMR (DMSO-d 6 0.82 (3H, t, J=7.5Hz), 1.39-1.50 (2H, mn), 1.73-2.07 (4H, mn), 2.35-2.45 (1H, mn), 2.95- 3.52 (7H, in), 4.50 (2H, 7.01 (2H, di, 7.17 (18, di, J=4.OHz), 7.35 (1H, d, J=4.OHz), 7.58 (2H, cd, J=8.5Hz), 8.11 (1H, br), 8.85 (1H, s), 10.59 (18, s) WO 00/40576 PCT/JPOO/00018 216 MS 479 (M-H) Example 293 (2S) -N-Hycroxy-2- (3-hydroxyphenyl) -2-thienyl] 3, 4, 5, 6-tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (120 mg) NMR (DMSO-d 6 6) 1. 70-2. 05 (4H, mn), 2. 36-2. 45 (1H, in), 2.95-3.50 (5H, in), 6.71-6.74 (1H, in), 7.00 (1H, s), 7.06 (1H, d, J=8.0Hz), 7.17-7.25 (2H, mn), 7.39 (1H, d, J=4.OHz), 8.85 (1H, 9.62 (1H, 10.60 (1H,

S)

MS 380 (M-H) Example 294 (2S) -N-Hydroxy-2- (3 -but ylaminocarbonylamino) phenyl) 2-thienyl]-3,4,5, 6-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (170 mg) NMR (DMSO-d 6 0.90 (3H, dd, J=7.2, 7.2Hz), 1.27-1.37 (2H, in), 1.37-1.47 (2H, mn), 1.70-2.05 in), 2.37-2.45 (1H, mn), 2.95-3.50 (7H, mn), 6.16 dd, 7.0Hz), 7.17-7.28 (4H, mn), 7.37 (1H, d, J=4.OHz), 7.84 (1H, 8.55 1 10.6 (1H, s) MS (ESI-) 478 (M-H) Example 295 (2S) -N-Hydroxy-2- 5- (1-naphtyl) aminocarbonylamino) phenyl) -2-thienyl]1 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (250 ing) NMR (DMSO-d 6 1.72-2.07 (4H, in), 2.38-2.47 (1H, mn), 2.95-3.31 (5H, in), 7.22 (1H, d, J=4.OHz), 7.29- 7.37 (3H, in), 7.44 (1H, d, J=4.OHz), 7.47-7.68 (4H, in), 7.94-7.96 (2H, in), 8.02 (1H, d, J=8.3Hz), 8.15 (1H, d, J=8.3Hz), 8.85 (1H, 9.27 (1H, 10.6 (1H, s) MS (ESI-) 548 (M-H) WO 00/40576 PCT/JPOO/00018 217 Example 296 (2S) -N-Hydroxy-2- 5- (allylarninocarbonylamino) phenyl) -2-thienyl 4, 5, 6 -tetrahydro-2H-thiopyran-2acetamide 1,1I-dioxide (200 ing) NMR (DMSO-d 6 8) 1. 70-2. 07 (4H, in), 2. 36-2. 45 in), 2.96-3.25 (5H, mn), 3.72-3.76 (2H, mn), 5.02-5.19 (2H, m),.5.80-5.94 (1H, mn), 6.29-6.32 (1H, in), 7.18-7.26 (4H, in), 7.38 (1H, d, J=4.OHz), 7.84 (1H, 8.68 (1H, 10.6 (1H, s) MS 462 CM-H) Example 297 (2S) -N-Hydroxy-2- (i sobut yl1ami noca rbonyl amino) phenyl) -2-thienyl] 4, 5, 6 -tetrahydro-2H-thiopyran.2acetainide 1, 1-dioxide (170 ing) NMR (DMSO-d 6 6) 0. 88 (6H, d, J=6. 6Hz) 1. 65-2. 07 in), 2.40-2.47 (1H, mn), 2.94 (2H, dd, J=6.5, 3.00-3.50 (5H, in), 6.23 (1H, dd, J=6.5, 7.17-7.20 (3H, in), 7.37 (1H, d, J=4.OHz), 7.84 (1H, 8.54 (1H, 10.6 (1H, s) MS 478 CM-H) Example 298 (2S) -N-Hydroxy-2- (cyclohexylmethylaminocarbonylamnino) phenyl) -2-thienyl] 4, 5, 6 -tetrahydro-2H-thiopyran.2 acetamide 1,1-dioxide (110 ing) NMR (DMSO-d 6 0.83-0.95 (2H, in), 1.11-1.25 (3H, in), 1.60-1.75 (6H, in), 1.83-2.07 (4H, in), 2.37-2.45 in), 2.93-3.07 in), 3.08-3.30 (3H, in), 6.22 br), 7.19-7.28 mn), 7.3.7 d, J=4.OHz), 8.55 (1H, 10.6 s) MS (ESI-) 518 (M-H) Example 299 WO 00/40576 PCT/JPOO 0018 218 (2S) -N-Hydroxy-2- 2 -rnethoxyethylaiinocarbonylamino) phenyl) -2-thienyl 1 4, 5, 6-tetrahydro-2H-thiopyran2 acetarnide 1,1-dioxide (150 ing) NMR (DMSO-d 6 6) 1. 71-2. 06 (4H, in), 2. 37-2. 46 (1H, m) 2.95-3.01 (2H, in), 3.05-3.25 (3H, mn), 3.28 (3H, s), 3.35-3.51 (4H, in), 6.21-6.25 (1H, mn), 7.16-7.25 (4H, mn), 7.37 (1H, d, J=4.0Hz), 7.83 (1H, 8.68 (1H, 8.79-8.86 (1H, br), 10.6 (1H, s) MS 480 (N-H) Example 300 (2S) -N-Hydroxy-2- 5- (N-methyl-N-ethylaminocarbonyl) amino) phenyl) -2-thienyl 1 4, 5, 6-tetrahydro-2H--thiopyran-2acetainide 1,1-dioxide (55 ing) NMR (DMSO-d 6 1.08 O3H, t, J=7.OHz), 1.70-2.08 (4H, in), 2.37-2.45 (1H, mn), 2.94 (3H, 2.97-3.54 (7H, mn), 7.20 (1H, d, J=4.OHz), 7.25 (2H, d, J=8.OHz), 7.37 (1H, d, J=4.OHz), 7.45 (2H, d, J=8.OHz), 7.84 (1H, 8.84 (1H, 10.59 (1H, s) MS (ESI-) 464 (N-H) Example 301 (2S) -N-Hydroxy-2- (N,N-dimethylaminocarbonyl) ethenyl) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran- 2-acetamide 1,1-dioxide (180 ing) NMR (DMSO-d 6 1.70-2.08 (4H, mn), 2.37-2.45 (1H, in), 2.93 O3H, 2.94-3.10 (2H, mn), 3.17 (3H, s), 3.18-3.55 (3H, mn), 7.20 (1H, d, J=4.0Hz), 7.25 (1H, d, J=16Hz), 7.45 (1H, d, J=K16Hz), 7.55 (1H, d, J=4.OHz), 7.66 (2H, d, J=8.5Hz), 7.75 (2H, d, 8.84 (iH, br), 10.60 (1H, s) MS (ESI-) 461 (N-H) Example 302 (2S) -N-Hydroxy-2-[5- 2 -(isopropylaininocarbonyl)- WO 00/40576 WO 0040576PCT/JPOO/0001 8 219 ethenyl) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran- 2-acetamide 1,1-dioxide (110 ing) NMR (DMSO-d 6 1 1.11 (6H, d, J=6. 5Hz) 1. 70-2. 07 (4H, in), 2.36-2.44 (1H, in), 2.97-3.55 (5H, in), 3.40- 4.00 (1H, mn), 6.62 (1H, d, J=l6Hz), 7.23 (1H, d, J=4 .OHz) 7. 40 (1 H, d, J=l16H 7. 55 (1iH, d, J=4 .OHz) 7.58 (2H, d, J=8.5Hz), 7.69 (2H, d, 7.99 (1H, d, J=7.5Hz), 10.6 (1H, s) MS (ESI-) 475 (M-H) Example 303 (2S) -N-Hydroxy-2- 5- (4 (propylaminocarbonyl) ethenyl) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran- 2-acetamide 1,1-dioxide (120 ing) NMR (DMSO-d 6 0.88 (3H, t, J=7.5Hz), 1.47 (2H, q, 1.70-2.07 mn), 2.35-2.45 (1H, mn), 2.96-3.55 (7H, in), 6.65 (1H, d, J=l6Hz), 7.23 (1H, ci, J=4.OHz), 7.40 (1H, di, J=l6Hz), 7.55 (1H, d, J=4.OHz), 7.60 (2H, d, J=8.5Hz), 7.69 (2H, d, J=8.5Hz), 8.10 (1H, t, J=7-OHz), 10.6 (1H, s) MS 475 (M-H) Example 304 (2S) -N-Hydroxy-2- (methylaininocarbonyloxy)phenyl) 2-thienyl]-3,4,5, 6 -tetrahydro-2H--thiopyran-2-acetaiie 1,1dioxide (150 ing) NMR (DMSO-d 6 1.71-2.05 (4H, in), 2.35-2.45 (1H, in), 2.67 (3H, di, J=4.5Hz), 2.95-3.51 (5H, mn), 7.15 (2H, d, J=8.7Hz), 7.21 (1H, d, J=4.OHz), 7.43 (1H, d, J=4.OHz), 7.63 (2H, di, J=8.7Hz), 7.65-7.68 (1H, in), 8.85 (1H, 10.6 (1H, s) MS (ESI-) 437 (M-H) Example 305 (2S)-N-Hydroxy-2-[5- (ethylaminocarbonyloxy)phenyl)- WO 00/40576 PCT/JPOO/00018 220 2-thienyl]-3, 4

,S,

6 -tetrahydro-2-1-thiopyran-2-acetamcide 1,1dioxide (130 mg) NMR (DMSO-d 6 08 (3H, dd, J=7.2, 7. 2Hz) 1. 71-2. (4H, mn), 1.85-1.96 in), 2.95-3.30 (6H, mn), 3.41-3.53 (1H, mn), 7.15 (2H, di, J=8.7Hz), 7.20 (1H, d, J=4.OHz), 7.43 (1H, d, J=4.OHz), 7.63 (2H, d, J=8.7Hz), 7.80 (1H, dd, J=7.0, 7.0Hz), 8.85 (1H, 10.6 s) MS 451 (M-H) Example 306 (2S) -N-Hydroxy-2- (5-acetyl-2-thienyl) -2-thienyl] 3, 4,5, G-tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide mng) NMR (DMSO-d 6 1.68-2.07 mn), 2.35-2.45 (1H, mn), 2.53 (3H, 2.95-3.53 (5H, mn), 7.21 (1H, di, J=4.OHz), 7.44 (1H, d, J=4.OHz), 7.51 (1H, di, J=4.OHz), 7.91 (1H, d, J=4.OHz), 8.85 (1H, s) MS 412 (M-H) The following compounds were obtained in a similar manner to that of Example 166.

Example 307 (2S) -N-Hycroxy-2- 4 -methoxyacetoxy) phenyl) -2thienyl]-3,4, 5, 6 -tetrahydro-2H-thiopyran-2-acetamicie 1,1dioxide (100 mg) NMR (DMSO-d 6 1.71-2.05 (4H, in), 2.36-2.45 (1H, in), 2.97-3.28 (4H, mn), 3.41 (3H, 3.42-3.51 (1H, in), 4.36 (2H, 7.21 (1H, di, J=4.0Hz), 7.22 (2H, di, 7.48 (1H, di, J=4.0Hz), 7.70 (2H, di, J=8.SHz), 8.84 (1H, s) MS 452 (M-H) Example 308 WO 00/40576 PCT/JPOO/0001 8 221 (2S) -N-Hydroxy-2- [15- (ethoxycarbonyloxy) phenyl) -2thieriyl]-3,4,5, 6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (80 mg) NMR (DMSO-d 6 1.31 (3H, dd, J=r7.5, 7.5Hz), 1.70-1.93 (4H, mn), 2.36-2.47 (1H, in), 2.97-3.51 (5H, mn), 4.27 ddd, J=7.5, 7.5, 7.5Hz), 7.21 (1H, d, J=4.OHz), 7.30 (2H, di, J='8.5Hz), 7.49 (1H, cd, J=4.OHz), 7.69 (2H, d, MS 452 (M-H) Example 309 (2S) -N-Hydroxy-2- (cyclopropylcarbonyloxy)phenyl) 2-thienyl] 5, 6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (100 mg) NMR (DMSO-d 6 1.03-1.06 (4H, mn), 1.70-2.05 in), 2.36-2.47 (1H, in), 2.95-3.51 (5H, mn), 7.17- 7.21 (3H, in), 7.46 (1H, d, J=4.OHz), 7.66 (2H, cd, 8.84 (1H, 10.58 (1H, s) MS 448 (M-H) Example 310 (2S) -N-Hydroxy-2- 5- (4 (ethoxycarbonylnethoxy) phenyl) -2-thienyl 4, 5, 6-tetrahyclro-2H-thiopyran-2acetamide 1,1-dioxide (150 ing) NMR (DMSO-d 6 6):.1.22 (3H, t, J=7.2Hz), 1.70-2.07 (4H, mn), 2.35-2.45 (1H, mn), 2.95-3.52 (5H, mn), 4.17 (2H, q, J=7.2Hz), 4.82 (2H, 6.97 (2H, di, 7.16 (1H, di, J=4.OHz), 7.34 (1H, di, J=4.OHz), 7.56 (2H, d, J=8.5Hz), 8.83 (1H, s) 10. 6 (1H, s) Example 311 To a solution of 0.5M 4-chiorophenylisocyanate (192 ing) in dichioromethane (2.5 ml) was added aininophenyl) -2-thienyl) 1-clioxo-3, 4, 5, 6-tetrahydro-2Hthiopyran-2-yllacetyllhydroxylanine trityl crowns (26 [tmol, WO 00/40576 PCT/JP00/00018 222 13.2 (xmol/crown x The reaction mixture was left overnight at ambient temperature. The crowns were washed with N,N-dimethylformamide, methanol and dichloromethane, successively. The crowns were treated with trifluoroacetic acid in dichloromethane for 1 hour at ambient temperature and removed from the solution. After the solution was evaporated under a stream of nitrogen, the residue was purified by reverse phase HPLC (0.1% trifluoroacetic acid in acetonitrile, 10-40% gradient) to give (2S)-N-hydroxy-2-[5-(3-(4-chlorophenylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (1.6 mg) as a white powder.

MS 551.3 (M+H+NH 3 The following compounds were obtained in substantially the same manner as that of Example 311.

Example 312 (2S)-N-Hydroxy-2-[5-(3-(n-phenylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (1.2 mg) MS 492.3 (M-H) Example 313 (2S)-N-Hydroxy-2-[5-(3-(n-hexylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (3.0 mg) MS 506.4 (M-H) Example 314 (2S)-N-Hydroxy-2-[5-(3-(3-chlorophenylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (1.3 mg) MS 550.7 (M+H+NH 3 WO 00/40576 PCT/JPOO/00018 223 Example 315 (2S) -N-Hydroxy-2- 2 -amino-2-phenylacetyl) amino) phenyl) -2-thienyl] 4, 5, 6 -tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide hydrochloride (76 mg) was obtained in a similar manner to that of Example 54.

NMR (DMSO-d 6 1. 64-2. 11 (4H, in), 2. 32-2. 98 (1H, in), 2.87-3.62 (5H, mn), 5.30 (1H, br 7.22 (1H, s), 7.34-7.82 (10H, in), 7.97 (1H, 8.91 (2H, br s), 10.66 (1H, br 11.27 (1H, s) MS 514 (M+H) Example 316 (2S) -N-Hydroxy-2- 5- (benzoylamino) propionylamino) phenyl) -2-thienyl 3, 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (96 mng) was obtained in a similar manner to that of Example 199.

NMR (DMSO-d 6 6) 1.64-2.10 (4H, in), 2. 33-2. 48 (1H, in), 2.58-2.76 (2H, in), 2.88-3.56 (9H, mn), 7.21 (1H, br 7.30-7.64 (8H, in), 7.84 (2H, br 8.03 (1H, br 8.64 (1H, br s) MS (EST-) 554 (M-H) Example 317 (2S) -N-Hydroxy-2- (ethylaminocarbonylanino) propionylaiino) phenyl) -2 thienyl 4, 5, 6-tet rahydro-2Hthiopyran-2-acetamide 1,1-dioxide (98 mg) was obtained in a similar manner to that of Example 199.

NMR (DMSO-d 6 0.96 (3H, t, J=7Hz), 1.69-2.10 (4H, in), 2.33-2.48 in), 2.90-3.64 (11H, in), 7.19 (1H, d, J=3Hz), 7.28-7.51 (SH, in), 8.04 (1H, s) MS (ESI-) 521 (M-H) Example 318 (2S) -N-Hydroxy-2- (methanesulfonylanino) propionylaiino)phenyl)-2-thienyl] 6-tetrahydro-2H- WO 00/40576 PCT/JPOO/00018 224 thiopyran-2-acetamide 1, 1-dioxide (54 mg) was obtained in a similar manner to that of Example 199.

NMR (DMSO-d 6 1.22-2.12 (4H, in), 2.35-2.49 in), 2.-58 (2H, t, J=7Hz) 2. 99 s) 2. 94-3. 62 (7H, in), 7. 06-7. 16 (1H, in), 7. 22 (1H, d, J=3Hz) 7. 33- 7.39 (2H, in), 7.40 (1H, d, J=3Hz), 7.43-7.52 (1H, in), 8.01 (1H, s) MS 528 (M-H) Example 319 (2S) -N-Hydroxy-2- 4 -piperidinyloxy) acetylamino) phenyl) -2-thienyl 4, 5, 6 -tetrahydro-2H-thiopyran-2acetarnide 1,1-dioxide hydrochloride (55 mg) was obtained from 2 S)-N(2tetrahydropyranyloxy) [5-(3(j-er but oxyca rbonyl -4 -piper idinyl oxy)acetylaino)hl)- 2 thienyl]-3, 4,5, 6 -tetrahydro-2Hthiopyran.2-acetainide 1,1 dioxide in a similar manner to that of Example 54.

NMR (DMSO-d 6 1.68-2.11 (8H, in), 2.34-2.98 (1H, 2.89-3.56 (8H, in), 3.66-3.80 (1H, in), 4.14 (2H, s), 7.11-7.62 (5H, in), 8.00 (1H, 8.85 (1H, 9. 83 (1H, s) 10. 60 (1H1, s) MS 522 (M+H) The following compounds were obtained in a similar manner to that of Example 89.

Example 320 (2S) 2 -Tetrahydropyranyloxy) (4- (methane sul fonylami no) phenyl) 2 -thienyl] 4, 5, 6-tetrahydro- 2 H-thiopyran-2acetamide l,1-dioxide (70 mg) NMR (CDCl 3 6) 1. 32 (2H, br) 1. 40-1.49 (2H, in), 1. 64-1. 68 (2H, in), 1. 94 (2H, br) 2. 10-2.20 (2H, in), 2.76-2.80 (2H, in), 3.00 (2H, 3.06-3.10 in), 3.15 (2H, br), 3.33-3.51 (1H, mn), 3.65-3.74 (1H, in), 4.55 (1/2H, br), 4.82 (1/2H, br), 7.01 (1H, br), WO 00/40576 PCT/JPOO/00018 225 7.11-7.16 (3H, in), 7.45 (2H, d, J=7.5Hz), 8.25 (1/2H, 8.33 (1/2H, s) MS 541.4 (M-H) Example 321 (2S) (2-Tetrahydropyranyloxy) (4- (methoxycarbonylaminomethyl) phenyl) -2-thienyl]1-3, 4, 5, 6tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide (80 mg) NMR (DMSO-c1 6 8) 1. 37 (6H, in), 1 .69-1. 81 (2H, in), 1.82-2.07 (2K, mn), 2.35-2.45 (1H, mn), 2.90-3.50 (6H, mn), 3.57 (3H, 3.72-3.88 (1H, in), 4.20 (2K, d, J=7.0Hz), 4.45, 4.75 (1H, 7.20-7.22 (1H, in), 7.28 (2H, d, J=8.5Hz), 7.41-7.43 (1H, in), 7.61 (2H, d, J=8.5Hz), 7.72 (1H, t, MS 535 (M-H) Example 322 (23) (2-Tetrahydropyranyloxy) [57 (4- (cyclopropylcarbonyloxy) phenyl) -2-thienyll1 4,5, 6tetrahydro-2H-thiopyran-2-acetaiie 1,1-dioxide (150 mg) NMR (DMSO-d 6 1.03-1.07 (4H, mn), 1.39-1.64 (6H, mn), 1.70-2.05 (5H, mn), 2.35-2.45 (1K, mn), 2.90-3.51 (6H, in), 3.75-3.90 (1H, in), 4.45, 4.75 (1H, s), 7.02-7.05 (1H, in), 7.19 (2H, d, J=8.5Hz), 7.44- 7.47 (1H, in), 7.76 (2H, d, Example 323 (2S) (2-Tetrahydropyranyloxy) (4- (ethoxycarbonylinethoxy) phenyl) -2-thienyl] 4, 5, 6tetrahydro-2H-thiopyran-2-acetanide 1,1I-dioxide (220 mng) NMR (DMSO-d 6 6) 1. 22 (3K, t, J=7. O~z) 1. 35-1.62 (6H, mn), 1.66-2.05 (4H, mn), 2.35-2.45 (1H, in), 2.90- 3.50 (6H, in), 3.73-3.90 (1H, in), 4.18 (2H, q, J=7.OHz), 4.45, 4.75 (1H, 4.82 (2H, 6.98 (2H, d, J=8.5Hz), 7.16-7.21 (1H, mn), 7.32-7.36 (1H, WO 00/40576 PCT/JPOO/00018 226 mn), 7.57 (2H, d, Example 324 (2S) (2-Tetrahydropyranyloxy) (ethyl ca rbonylmet hoxy) phenyl) -2-thienyl]1 4, 5, 6-tetrahydro- 2 H--thiopyran-2-acetamide 1, 1-dioxide (200 mg) NMR (DMSO-d 6 0) 0.98 (3H, t, J=7. 2H-z) 1. 35-1. 65 (6H, in), 1 .67-2 .05 (4H, in), 2. 32-2. 45 (1H, mn), 2. 54 (2H, q, J=7.2Hz), 2.90-3.50 (6H, in), 3.74-3.89 (1H, in), 4 45, 4 75 (1H, s) 4 .8 6 (2H, s) 6. 95 (2H, d, 7.16-7.20 (1H, mn), 7.31-7.35 (1H, mn), 7.55 (2H, d, Example 325 (2S) 2 -Tetrahydropyranyloxy) (4- (cyclopropylaininocarbonylmethoxy) phenyl) -2-thienyl]) 4,5, 6tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide (140 mg) NMR (DMSO-dr., 6) 0. 45-0. 50 (2H, in), 0. 60-0. 65 (2H, m) 1.35-1.65 (6H, mn), 1.70-2.07 (4H, mn), 2.35-2.45 (1H, mn), 2.65-2.74 (1H, mn), 2.90-3.50 (6H, mn), 3.75-3.90 (1H, mi), 4.47 (2H, 4.45, 4.75 (1H, 6.98 (2H, d, J=8.5Hz), 7.15-7.20 (1H, in), 7.30-7.35 (1H, mn), 7.58 (2H, d, 8.15 (1H, br), 11.20 (1H, s) Example 326 (2S) (2-Tetrahydropyranyloxy) 5- (3-hydroxyphenyl) 2-thienyl]-3, 4,5, G-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (205 mg) NMR (DMSO-d 6 1.35-1.64 (6H, in), 1.66-2.05 (4H, in), 2.35-2.45 (1H, in), 2.90-3.50 (6H, in), 3.75-3.90 (1H, in), 4.45, 4.75 (1H, 6.70-6.73 (1H, mn), 7.00-7.07 (2H, mn), 7.16-7.21 (2H, in), 7.35-7.40 (1H, mn), 9. 61 (1H, s) WO 00/40576 PCT/JPOO/00018 227 Example 327 (2S) (2-Tetrahydropyranyloxy) (5-acetyl-2thienyl) -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (100 ing) NMR (CDCl 3 8) 1.43-1.78 (6H, mn), 1.85-1.98 m) 2.05-2.25 (2H, mn), 2.58 (3H, s) 2. 63-2.86 (2H, m) 2.95-3.17 (4H, in), 2.95-3.61 in), 3.65-3.82 (1H, in), 4.51, 4.83 (1H, 7.18 (1H, d, j=4.OHz), 7.57 (1H, d, J=4.OHz), 7.64 (1H, d, J=4.0Hz), 7.70 (1H, d, J=4.OHz) Example 328 (2S) (2-Tetrahydropyranyloxy) (4aininocarbonyiphenyl) -2-thienyl] 4,5, 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (49 mg) was obtained from (2S) 2 -tetrahydropyranyloxy) (4-carboxyphenyl) -2thienyl] 4, 5, 6 -tetrahydro-2H-thiopyran-2-acetanide 1, 1dioxide (133 ing) in a similar manner to that of Example 32.

NMR (CDCl 3 8) 1. 45 (2H, br) 1. 63-1. 68 (2H, in), 1. 94 (2H, br), 2.08-2.17 (2H, mn), 2.30-2.36 (2H, 3.00-3.22 mn), 3.26-3.47 (1H, in), 3.68-3.76 (1H, in), 4.55 (1/2H, br), 4.85 (1/2H, br), 7.43- 7.57 (5H, in), 7.63-7.70 (3H, in), 7.75-7.80 (1H, in) MS 493.6 (M+H) Example 329 (23) (2-Tetrahydropyranyloxy) (4- (benzylaininocarbonyl)phenyl) -2-thienyl] 6-tetrahydro- 2 H-thiopyran-2-acetanide 1,1-dioxide (85 ing) was obtained in a similar manner to that of Example 328.

NMR (CDC1 3 1.51-1.60 (2H, mn), 1.70-1.79 (4H, mn), 1.89-1.96 (2H, in), 2.08-2.18 (2H, in), 2.76-2.83 (2H, br), 2.97-3.14 (4H, in), 3.40-3.64 (1H, in), 3.72-3.92 (1H, mn), 4.60-4.65 (2H, in), 4.68 (1/2H, br), 4.84 (1/2H, br), 7.20-7.37 (7H, in), 7.56-7.83 WO 00/40576 PCT/JPOO/00018 228 mn) MS (ESI-) 581.2 (M-H) The following compounds were obtained in a similar manner to that of Example 130.

Example 330 (2S) (2-Tetrahydropyranyloxy) (3- (ethoxycarbonylamino) phenyl) -2-thienyl 6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (190 mug) NMR (CDC1 3 8) 1. 34 (1H, t, J=7. OHz) 1. 46 (2H, br) 1.64:-1.69 (4H, in), 1.94 (2H, br), 2.07-2.20 (2H, in), 2.67-2.88 (2H, in), 3.06 (2H, 3.11-3.16 (2H, in), 3.30-3.48 (1H, in), 3.60-3.70 (1H, in), 4.23 (2H, q, J=7.OHz), 4.53 (1/2H, br), 4.81 (1/2H, br), 6.69 (1H, 7.27-7.32 (5H, mn), 7.64 (1H, s), 8.05 (1/2H, 8.20 (1/2H, s) MS 535.2 (M-H) Example 331 (2S) (2-Tetrahydropyranyloxy) (npropoxyca rbonyl amino) phenyl) -2-thienyl]1 4, 5, 6-tetrahydro- 2H-thiopyran-2-acetainide 1, 1-dioxide (170 mg) NMR (CDC1 0.99 (3H, t, J=6.OHz), 1.45 (2H, br), 1.63-1.75 (6H, in), 1.95 (2H, br), 2.06-2.21 (2H, mn), 2.63-2.91 (2H, mn), 3.05 (2H, 3.12 (2H, br), 3.28-3.50 (1H, mn), 3.58-3.69 (1H, in), 4.07-4.15 (2H, in), 4.52 (1/2H, br), 4.80 (1/2H, br), 6.65 (1H, 7.20-7.30 (5H, in), 7.66 (1H, 7.96 (1/2H, 8.12 (1/2H, s) MS 549.4 (M-H) Example 332 (2S) (2-Tetrahydropyranyloxy) (3- (isopropoxycarbonylamino) phenyl) -2-thienyl 4, 5, 6- WO 00/40576 PCT/JPOO/000i 8 229 tetrahydro-2H-thiopyran2acetanide 1,1-dioxide (160 mg) NMR (CDCl 3 6) 1. 31 (6H, d, J=7. 5Hz) 1.45 (2H, br), 1. 64-1. 68 (4H, in), 1. 94 (2H, br) 2.05-2.21 (4H-, in), 2.64-2.86 (2H, in), 3.05 (2H, 3.10-3.15 (2H, mn), 3.30-3.38 (1H, mn), 3.60-3.70 in), 4.52 (1/2H, br) 4. 80 (1/2H, br) 5. 02 (1H, qq, J=7. 7. 5Hz) 6. 59 (1H, s) 7. 24-7. 28 in), 7. 67 (1H, 7.94 (1/2H, 8.10 s) MS 549.4 (M-H) Example 333 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5q3(2.

chloroethoxycarbonylanino) phenyl }-2-thienyl] 5,6tetrahydro-2H-thiopyran.2acetanide 1,1-dioxide (155 ing) NMR (CDC1 3 6) 1. 45 (2H, br) 1. 62-1. 68 (4H, mn), 1. (2H, br), 2.07-2.22 (2H, in), 2.63-2.89 (2H, in), 3.05 (2H, 3.10-3.16 (2H, mn), 3.28-3.48 (1H, in), 3.61-3.66 (1H, in), 3.75 (2H, t, J=5.OHz), 4.43 (2H, t, J5S.OHz), 4.52 (1/2H, br), 4.80 (1/2H, br), 6.80 (1H, 7.23-7.31 (5H, in), 7.65 (1H, S), 8.02 (1/2H, 8.17 (1/2H, s) MS 569.3 (M-H) Example 334 (2S) 2 -Tetrahyd'ropyranyloxy) (3- (valerylaminophenyl) -2-thienyl] 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (148 ing) NMR (CDC1 3 0.96 (3H, t, J=7Hz), 1.32-1.78 (12H, mn), 1.85-1.99 (2H, in), 2.03-2.25 (2H, in), 2.40 (2H, t, J=7Hz), 2.69-2.93 (2H, in), 2.98-3.18 (2H, mn), 3.28-3.51 in), 3.62-3.77 (1H, in), 4.55,. 4.83 (1H, 7.10-7.32 (4H, in), 7.47-7.69 (3H, in), 8.66 (1H, s) MS (ESI-) 547 (M-H) WO 00/40576 PCT/JPOO/00018 230 Example 335 (2S) 2 -Tetrahydropyranyloxy) (3- (ethyl thioca rbonylamino) phenyl) -2-thienyl]1 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (130 mg) NMR (CDC1 3 6) 1. 26 (3H, t, J=8Hz) 1. 39-1. 77 (8H, in), 1.34-2.00 (2H, nm), 2.06-2.75 (2H, mn), 2.71-2.96 (2H, in), 2. 99 (2H, q, JB~z), 3.04-3.17 (2H, mn), 3.29-3.52 (2H, mn), 3.64-3.76 (1H, in), 4.55, 4.84 (1H, 7.15-7.32 (4H, in), 7.38-7.54 (3H, mn), 8.49, 8.58 (1H, s) MS 551 (M-H) Example 336 (2S) (2-Tetrahydropyranyloxy) (3- (methyl thiocarbonyl amino) phenyl) -2 -thienyl I- 3, 4, 5, 6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (192 ing) NMR (CDCl 3 1.36-1.78 (8H, in), 1.86-2.00 (2H, in), 2.07-2.75 (2H, mn), 2.43, 2.45 (3H, 2.72-2.97 (2H, mn), 3.03-3.22 (2H, in), 3.30-3.54 (1H, mn), 3.64-3.76 (11H, in), 4.56, 4.74 (1H, br 7.12'- 7.32 (4H, in), 7.40-7.53 (2H, in), 7.62-7.71 in), 8.65, 8.72 (1H, s) MS 537 (M-H) Example 337 2 -Tetrahydropyranyloxy) (3- (ben zyloxycarbonylamino) phenyl) -2-thienyl 4, 5, 6tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide (87 ing) NMR (OD1 3 6) 1. 35-1. 72 (BH, in), 1. 86-1. 98 (28, in), 2. 02-2. 22 (28, mn), 2. 65-2 .92 (2H, in), 2. 98-3. 16 (2H, in), 3.28-3. 50 (1H, in), 3. 62-3. 73 (1H, m) 4. 52, 4. 71 (1H, s) 5.21 (2H, s) 6. 88 (18, br s) 7. 19-7. 46 (108, in), 7 .62 (1H, br s) 8. 26, 8. 38 (1H, s) MS (ESI-) 597 (M-H) WO 00/40576 PCT/JPOO/00018 231 Example 338 (2S) (2-Tetrahydropyranyloxy) (4chiorophenyl) acetylamino) phenyl) -2-thienyl] -3,4,5,6tetrahydro-2H-thiopyran-2-acetamiie 1,1-dioxide (158 mrg) NMR (CDCl 3 1.35-1.79 (8H, in), 1.87-1.99 (2H, in), 2.04-2.24 (2H, in), 2.17-2.93 (1H, mn), 3.02-3.17 (2H, 3.27-3.52 (1H, in), 3.63-3.74 (1H, mn), 4.53, 4.82 (1H, 4.59 (2H, 6.83 (1H, d, J=8Hz), 6.96 (2H, d, J=8Hz), 7.22-7.39 (5H, mn), 7.56-7.62 (1H, in), 7.22-7.28 (1H, mn), 8.30 (1H, s), 8.34, 8.45 (1H, s) MS (ESI+) 633, 634 (M+H) Example 339 (2S) (2-Tetrahydropyranyloxy) (3- (phenoxycarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (124 mng) NMR (CDC1 3 1.34 (8H, mn), 1.85-1.99 (2H, in), 2.03-2.24 (2H, in), 2.68-2.94 (2H, in), 3.00-3.2'0 (2H, in), 3.29-3.53 (1H, mn), 3.62-3.77 (1H, in), 4.53, 4.82 (1H, 7.11-7.47 (11H, mn), 7.63, 7.67 (1H, 8.49, 8.57 (1H, s) MS (ESI-) 583 (M-H) Example 340 (2S) (2-Tetrahydropyranyloxy) (4inorpholinocarbonylamino) acetylanino) phenyl) -2-thienyl] 3,4, 5, 6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide mg) NMR (DMSO-d 6 1.32-2.09 (10H, in), 2.34-2.51 (1H, in), 2.87-3.62 (14H, in), 3.73-3.92 (1H, mn), 3.80 (2H, d, J=7Hz), 4.43, 4.76 (1H, 6.96 (1H, t, J=7Hz), 7.17-7.26 (1H, in), 7.32-7.53 (4H, in), 8.02 (1H, s) MS (ESI-) 633 (M-H) WO 00/40576 PCT/JPOO/00018 232 Example 341 (2S) 2 -Tetrahydropyranyloxy) (N-ethyl-Nmethylaminocarbonyloxy) acetylamino) phenyl) -2-thienyl 3 4 6 -tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (220 mg) was obtained in a similar manner to that of Example 211.

NMR (ODC1 3 1.18, 1. 23 (3H, t, J=8Hz) 1. 37-1. 74 (8H, mn) 1. 89-2. 01 (2H1, in), 2. 06-2.23 (2H, in), 2. 72-2. 88 (2H1, in), 2. 99, 3. 03 (3H, s) 3. 05-3. 18 (2H, mn), 3. 15-3.28 (11, in), 4 .53, 4. 83 s) 4 .72, 4. 74 (2H, s) 7.-15-7.32 (4H, mn), 7. 52 (1H, br s) 7. 59, 7. 64 (1H, br s) 8.23 (1H, s) 8. 62- 8.75 (1H, m) MS (ESI-) :606 (M-H) The following compounds were obtained in a similar manner to that of Example 129.

Example 342 (2S) 2 -Tetrahydropyranyloxy) 5- (3- (ben zylaminnocarbonylamino) phenyl) -2-thienyl] 5, 6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (80 mg) NMR (CDC1 3 1.42 (2H, br), 1.60-1.66 in), 1.83-1.90 (2H1, in), 2.00-2.18 (2H, in), 2.74 (2H, br), 2.92-3.00 (2H, in), 3.04-3.10 (2H1, in), 3.30- 3.50 (1H, in), 3.68-3.78 (1H1, in), 4.33-4.42 (2H, i) 4.57 (1/2H, br), 4.72 (1/2H1, br), 6.93-7.12 (6H, in), 7.27-7.25 (2H1, in), 7.28-7.32 (4H1, m) MS 596.4 CM-H) Example 343 (23) (2-Tetrahydropyranyloxy) (4iethox yphenyl ami noca rbonyl amino) phenyl) -2-thienyl 4,5, 6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (224 mng) NMR (CDCl 3 1.43 (2H, br), 1.62-1.73 (4H1, mn), 1.90 WO 00/40576 PCT/JPOOOO0i 8 233 (2H, br), 2.03-2.20 (2H, in), 2.77 (2H, br), 2.96- 3.03 (2H, in), 3.08-3.14 (2H, mn), 3.33-3.54 (1H, in), 3.68-3.75 (1H, mn), 3.77 (3H, 4.61 (1/2H, br), 4.86 (1/2H, br), 6.80-6.93 (4H, in), 7.10-7.29 (6H, mn), 7.38-7.53 (2H, mn), 9.04 (1/2H, 9.42 (1/2H,

S)

MS 611.5 (M-H) Example 344 2 2 -Tetrahydropyranyoxy)2[5.(3(ethoxy.

carbonylinethylaininocarbonylanino) phenyl) -2-thienyl] -3,4,5,6tetrahydro-2H-thiopyran2acetanide 1,1-dioxide (490 mng) NMR (CDC1 3 1.22-1.33 (5H, mn), 1.42-1.47 (2H, mn), 1.62-1.70 (2H, mn), 1.94 (2H, br), 2.07-2.20 (2H, in), 2.74-2.86 (2H, in), 3.08-3.20 (2H, in), 3.49- 3.52 (2H, in), 3.68-3.78 (2H, in), 3.97-4.27 (4H, in), 4.58 (1/2H, br), 4.85 (1/2H, br), 5.68-5.80 (1H, in), 6.96-7.24 (5E, in), 7.28-7.34 (1H, in), 7.40- 7.46 (1H, mn), 9.12 (1/2H, 9.31 (1/2H, s) MS 592.3 (M-H) Example 345 (2S) 2 -Tetrahydropyranyloxy) (3- Cbutylaininocarbonylainino)phenyl) -2-thienyl]-3, 4,5,6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (330 ing) NMR (CDCl 3 0.90 (3H, dd, J=7.2, 7.2Hz), 1.26-1.74 mn), 1.85-1.99 (2H, mn), 2.02-2.21 (2H, in), 2.74-2.89 (2H, in), 2.97-3.26 (6H, in), 3.31-3.54 (1H, mn), 3.71-3.80 (1H, mn), 4.60, 4.83 (1H, s), 5.42-5.53 (1H, in), 6.95 d, J=4Hz), 7.01-7.30 mn), 7.38-7.43 (1H, mn), 9.3, 9.51 (1H, s) Example 346 (2S) (2-Tetrahydropyranyloxy) (1naphtylaininocarbonylainino)phenyl) -2-thienyl]-3, 4,5,6- WO 00/40576 PCT/JP00/00018 234 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (350 mg) NMR (CDC1 3 1.30-1.65 (6H, 1.75-1.92 (2H, m), 1.93-2.19 (2H, 2.70-2.88 (2H, 2.92-3.20 (4H, 3.30-3.46 (1H, m) 3.70 (1H, br), 4.56, 4.83 (1H, 6.93-7.80 (12H, 7.95 (1H, dd, Example 347 (2S)-N-(2-Tetrahydropyranyloxy)-2- (allylaminocarbonylamino)phenyl) -2-thienyl] -3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (300 mg) NMR (CDC1 3 1.35-1.70 (6H, 1.85-2.25 (4H, m), 2.75-2.88 (2H, 2.95-3.17 (4H, 3.30-3.52 (1H, 3.70-3.90 (3H, 4.59, 4.83 (1H, s), 5.10-5.23 (2H, 5.40-5.49 (1H, 5.80-5.94 (1H, 6.95-7.28 (6H, m) MS 546 (M-H) Example 348 To a solution of (2S)-N-(2-tetrahydropyranyloxy)-2-[5- (3-aminophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran- 2-acetamide 1,1-dioxide (150 mg) and thienylamine (163 mg) in N,N-dimethylformamide (3 ml) was added 3- (phenoxycarbonylamino)pyridine (83 mg) and the reaction mixture was stirred at ambient temperature for 14 hours.

The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel 60 (eluent: 3% methanol-chloroform) to give (2S)- N-(2-tetrahydropyranyloxy)-2-[5-(3-(3pyridylaminocarbonylamino)phenyl) -2-thienyl] -3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (150 mg) as a white amorphous.

WO 00/40576 PCT/JPOO/00018 235 NMR (CDC1 3 ri:1. 38 (2H, br) 1. 45-1. 62 (4H, mn), 1. 94 (4H, br) 2. 05-2.25 mn), 2. 92 (2H, br) 3. 02- 3.11 (4H, in), 3.32-3.50 in), 3.78 (1H, br), 4.20-4.23 (1H, mn), 4.62 (1/2H, br), 4.94 (1/2H, br), 6.89-7.27 (4H, mn), 7.30-7.46 (1H, in), 7.51- 7.72 (2H, mn), 8.03-8.21 (1H, mn), 8. 40 (1/2H, s) 8.45 (1/2H, s) MS 585.4 (M+H) The following compounds were obtained in a similar manner to that of Example 130.

Example 349 (2S) (2-Tetrahydropyranyloxy) (3- Callyloxycarbonylainino)phenyl)-2-thienyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (160 ing) NMR (CDCl 3 8) 1. 45 (2H, br) 1. 58-1. 68 (4H, in), 1. 94 (2H, 2. 07-2. 22 (2H, in) 2. 66-2. 90 (2H, mn) 3.04-3.52 (28, mn), 3.09-3.15 (28, mn), 3.30-3.49 (1H, mn), 3.63-3.72 (1H, in), 4.52 (1/2H, br), 4.'67 (2H, d, J=7.0Hz), 4.80 (1/2H, br), 5.27 (18, d, J=8.OHz), 5.38 (18, d, J=8.0Hz), 5.89-6.04 (18, mn), 6.83 (18, 7.24-7.34 (58, mn), 7.63 (1H, s), 8.20 (1/2H, 8.35 (1/2H, s) MS (ESiI-): 547.3 (M-H) Example 350 (2S) (2-Tetrahydropyranyloxy) 5- (2benzyloxyacetylanino) phenyl) -2-thienyl] 6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (410 mng) NMR (CDCl 3 1.45 (2H, br), 1.61-1.68 (4H, mn), 1.95 (28, br), 2.06-2.22 (28, mn), 2.64-2.87 (2H, in), 3.03 (2H, br 3.08-3.13 (28, mn), 3.28-3.47 (1H, mn), 3.61-3.67 (1H, mn), 4.08 (2H, d, J=7.5Hz), 4.52 (1/2H, br), 4.63 (18, 4.68 (1H, 4.67 (28, WO 00/40576 PCT/JPOO/00018 236 di, J=l5Hz) 4 .82 (l/2H, br) 7. 30-7 .40 (9H, in), 7 .53 (1H, d, J=5. OHz) 7 .77 (1H, s) 8 .01 (1H, s) 8.16 (1H, 8.34 (1H, s) MS 611.5 (N-H) The following compounds were obtained in a similar manner to that of Example 211.

Example 351 (2S) (2-Tetrahydropyranyloxy) (tertbutoxycarbonylamino) propionyl) amino) phenyl -2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (310 mng) NMR (CDCl 3 1.43-1.48 (14H, in), 1.65-1.68 (4H, in), 1.94 (42H, br), 2.04-2.20 (2H, in), 2.67-2.87 (2H, in), 3.04-3.07 (2H, in), 3.10-3.15 (2H, in), 3.28- 3.62 (1H, in), 3.63-3.75 (1H, mn), 4.32 (1H, br), 4.52 (1/2H, br), 4.82 (1/2H, br), 7.20-7.30 (4H, in), 7.40-7.50 (1H, in), 7.67 (1/2H, 7.77 (1/2H, 8.36 (1/2H, 8.54 (1/2H, s) MS 634.3 (N-H) Example 352 (2S) (2-Tetrahydropyranyloxy) (2R) (tertbutoxycarbonylamino) propionyl) amino) phenyl) -2-thienyll 3,4,5, 6-tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (475 mng) NMR (CDCl 3 1.43-1.48 (14H, mn), 1.65-1.68 (4H, mn), 1.94 (42H, br), 2.04-2.20 (2H, in), 2.67-2.87 (2H, in), 3.04-3.07 (2H, in), 3.10-3.15 (2H, in), 3.28- 3.62 (1H, in), 3.63-3.75 (1H, in), 4.32 (1H, br), 4.52 (1/2H, br), 4.82 (1/2H, br), 7.20-7.30 (4H, in), 7.40-7.50 in), 7.67 (1/2H, 7.77 (1/2H, 8.36 (1/2H, 8.54 (1/2H, s) MS 634.3 (N-H) WO 00/40576 PCT/JPOO/00018 237 Example 353 (2S) (2-Tetrahydropyranyloxy) (4methyiphenoxy) acetylamino) phenyl }-2-thienyl] -3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (230 mg) NMR (CDC1 3 1.44 (2H, br), 1.56-1.68 (4H, in), 1.95 (2H, br), 2.07-2.21 mn), 2.33 (3H, 2.63- 2.90 (2H, mn), 3.05 (2H, 3.11-3.13 (2H, br), 3.30-3.48 (1H, in), 3.60-3.70 (1H, in), 4.52 (1/2H, br), 4.60 (2H, 4.80 (1/2H, br), 6.90 d, J=8.OHz), 7.15 (2H, d, J=8.0Hz), 7.22-7.29 (2H, in), 7.33-7.36 (2H, in), 7.55-7.59 (1H, in), 7.80 (1H, s), 8. 00 (1/2H, s) 8. 14 (1/2H, s) 8. 32 (1H, s) MS 611.3 (M-H) Example 354 (2S) (2-Tetrahydropyranyloxy) Ndirnethylainino) acetylainino) phenyl }-2-thienyl] 4,5, 6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (90 ing) NMR (CDCl 3 6) 1. 46 (2H, br) 1. 62-1. 68 (4H, in), 1.'95 (4H, br), 2.04-2.23 (2H, in), 2.41 (6H, 2.65- 2. 88 (1H, mn), 3. 05 (2H, s) 3. 10 (2H, in), 3. 12- 3.15 (2H, in), 3.26-3.49 (1H, in), 3.62-3.72 mn), 4.52 (1/2H, br), 4.80 (1/2H, br), 7.23-7.29 (2H, in), 7.34 (2H, d, J=5.OHz), 7.60-7.66 (1H, mn), 7.76 (1H, br), 8.00 (1/2H, br), 8.18 (1/2H, br), 9.19 (1H, s) MS 550.3 (M+H) Example 355 (2S) (2-Tetrahydropyranyloxy) (4chiorophenyl) acetylanino) phenyl) -2-thienyl 4, 5, 6tetrahydro-2H-thiopyran-2-acetamiie 1,1-dioxide (158 ing) NMR (CDCl 3 1.34-1.98 (10H, in), 2.03-2.25 (2H, in), 2.69-2.88 (2H, in), 3.02-3.18 (2H, mn), 3.27-3.51 WO 00/40576 PCT/JPOO/00018 238 (1H, in), 3. 62-3. 26 (1H, in), 3. 68 (2H, s) 4. 53, 4 .83 (1H, br s) 7. 00-7 .66 (10H, mn), 7 .73, 7. 76 (iN, s) 8. 65-8 .75 (1H, mn) MS 616 (M-H) Example 356 (2S) (2-Tetrahydropyranyloxy) ((R)-2-tertbut oxyca rbonyl ami n'-2 -phenyl acet y1)amino) phenyl) -2-thienyl] 3, 4, 5, 6-tet rahyclro- 2H-t hi opyran- 2-ace tamide 1, 1-dioxide (117 ing) NMR (DMSO-d 6 6) 1. 20-1. 62 (6H, mn), 1. 40 (9H, s) 1. 68- 2.06 (4H, mn), 2.34-2.48 (1H, in), 2.86-3.32 (5H, mn), 3.73-3.86 (1H, in), 4.40, 4.75 (1H, br 5.86 (1H, d, J=8Hz), 7.16-7.23 (1H, mn), 7.28-7.61 (10H, mn), 7. 96 (1H, s) 10. 37 (1H, s) 11. 23 s) MS 696 (M-H) Example 357 (2S) (2-Tetrahydropyranyloxy) (2i sopropoxya cet yl amino) phenyl) -2-thienyl 4, 5, 6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (276 mng) NMR (CDC1 3 1.29 (6H, d, J=7Hz), 1.36-1.77 (8H, mn), 1.88-2.00 (2H, mn), 2.65-2.92 (2H, mn), 3.02-3.18 (2H, in), 3.28-3.51 (1H, mn), 3.62-3.73 (1H, in), 3.77 (1H, q, J=7Hz), 4.07 4.52, 4.82 (1H, br 7.23-7.48 (4H, in), 7.52-7.60 (iR, mn), 7.78 (1H, 8.18, 8.32 br 8.40 (1H, s) MS 565 (M+H) Example 358 (2S) (2-Tetrahydropyranyloxy) (1-tertbutoxycarbonyl-4 -piperidinyloxy) acetylainino) phenyl) -2thienyl] 6-tetrahydro-2H-thiopyran-2-acetanide 1, 1dioxide (360 mg) WO 00/40576 PCT/JP00/00018 239 2.01 (4H, 2.06-2.24 (2H, 2.68-2.92 (2H, m), 3.02-3.18 (4H, 3.28-3.52 (1H, 3.58-3.74 (2H, 3.79-3.92 (2H, m) 4.12 (2H, 4.53, 4.82 (1H, 7.22-7.38 (4H, 7.52-7.58 (1H, m), 7.76 (1H, 8.27, 8.84 (1H, 8.34, 8.38 (1H, s) MS 706 (M+H) Example 359 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(2-oxo-l,3oxazolidin- 3 -yl)acetylamino)phenyl)-2-thienyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (600 mg) NMR (DMSO-d 6 1.36-1.64 (6H, 1.69-2.06 (4H, m), 2.34-2.48 (1H, 2.88-3.32 (5H, 3.42-3.53 (1H, 3.66 (2H, t, J=8Hz), 3.73-3.90 (1H, m), 4.34 (2H, t, J=8Hz), 4.44, 4.75 (1H, 7.17-7.25 (1H, 7.33-7.48 (4H, 8.03 (1H, s) MS 590 (M-H) Example 360 To a suspension of 2 -tetrahydropyranyloxy)-2- [5-(3-aminophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (300 mg) and triethylamine (392 mg) in chloroform (4 ml) was added triphosgene (192 mg) at 0°C and the reaction mixture was stirred at ambient temperature for 30 minutes. To the mixture was added (2- ((tert-butyl)(diphenyl)sillyloxy)ethyl)amine (232 mg) at 0°C and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was poured into water and was extracted with chloroform. The organic layer was washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel 60 (eluent: 2% methanol-chloroform) to give (2S)- WO 00/40576 PCT/JPOO/00018 240 N- (2-tetrahydropyranyloxy) 5- (tertbutyl) (diphenyl) sillyloxy) ethyl arinoca rbonyl1amnino) phenyl) -2thienyl] G-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (350 mg) as a white amorphous.

NMR (ODC1 3 1.04 1.44 (2H, br), 1.62-1.68 (4H, in), 1.85-1.94 (2H, br), 2.05-2.19 (2H, mn), 2.69-2.90 (2H, in), 2.98-3.10 (4H, in), 3.31-3.44 in), 3.62-3.80 (3H, in), 4.56 (1/2H, br), 4.80 (1/2H, br), 6.64 (1H, 7.09-7.30 (5H, in), 7.32- 7.42 (71H, mn), 7.56-7.64 (4H, in), 8.62 (1H, s) MS 788.5 (M-H) The following compounds were obtained in a similar manner to that of Example 130.

Example 361 (2S) (2-Tetrahydropyranyloxy) [r5- (3- (cyc lopentylca rbonyl amino) phenyl) -2 -thi enyl I-3,4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (205 ing) NMR (00013, 1.46 (2H, br), 1.60-1.70 (6H, mn), l.'77- 1.84 (2H, in), 1.91-1.97 (6H, in), 2.07-2.21 (2H, mn), 2.66-2.89 (2H, mn), 2.71 (1H, tt, J=7.5, 3.05 (1H, 3.10-3.15 (2H, in), 3.30-3.49 (1H, mn), 3.63-3.70 (1H, mn), 4.54 (1/2H, br), 4.82 (1/2H, br), 7.20-7.30 (4H, in), 7.41 br), 7.52 (1H, br), 7.71 (1H, br), 8.25 (1/2H, 8.37 (1/2H, s) MS 559.4 Example 362 2 S)-N-(2-Tetrahydropyranyloxy) chioropropionylamino) phenyl) -2-thienyl] 5, 6-tetrahydro- 2 H-thiopyran-2-acetamide 1,1-dioxide (145 mg) NMR (OD1 3 1.45 (2H, br), 1.54-1.72 (4H, mn), 1.95 (4H, br), 2.09-2.24 (2H, mn), 2.72-2.82 (2H, mn), 2.85 (2H, t, J=6.4Hz), 3.00-3.08 (2H, mn), 3.11- WO 00/40576 PCT/JPOO/00018 241 3.16 (2H, in), 3. 29-3. 52 (1H, in), 3.63-3 .7 3 (1H, mn), 3.91 (2H, t, J=6. 5Hz), 4. 54 (1/2H, br) 4. 83 (1/2H, br) 7. 15-7. 30 (4H, 7. 54-7.72 (3H, in), 8. (1H, s) MS 553.3 (M-H) The following compounds were obtained in a similar manner to that of Example 360.

Example 363 (2S) (2-Tetrahydropyranyloxy) (3- (i sobutyl ami nocarbonylanino) phenyl) -2-thienyl]1 4,5, 6tetrahydro-21--thiopyran-2-acetamide 1, 1-dioxide (230 ing) NMR (CDC1 3 8) 0.-90 (6H, di, J=6. 6Hz) 1. 40-1. 70 (7H, mn), 1.88-1.97 (2H, in), 2.05-2.22 (2H, in), 2.99- 3.18 (6H, in), 3.31-3.51 (1H, in), 6.96-7.29 (6H, in), 7.47-7.53 (1H, mn), 9.25, 9.47 (1H, s) MS 562 (M-H) Example 364 (2S) (2-Tetrahydropyranyloxy) (cyclohexylinethylaiinocarbonylainino) phenyl) -2-thienyl] 5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (200 mng) NMR (CDCl 3 83-1. 00 (2H, in), 1. 10-1. 25 (4H, in), 1.35-1.54 (5H, mn), 1.55-1.79 (6H, in), 1.85-1.98 (2H, in), 2.01-2.22 (2H, in), 2.75-2.89 (2H, mn), 3.00-3.22 (6H, mn), 3.30-3.52 (1H, in), 3.66-3.82 (1H, in), 1.59, 4.84 (1H, 5.45-5.55 (1H, mn), 6.95-7.30 (6H, in), 7.40 (1H, br) Example 365 (2S) (2-Tetrahydropyranyloxy) (2met hoxyet hyl aminoca rbony1amnino) phenyl) -2-thienyl]1 4,5, 6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (220 ing) NMR (CDC1 3 1.38-1.68 (6H, in), 1.85-1.98 (2H, in), WO 00/40576 PCT/JPOO/00018 242 2.03-2.18 (2H, in), 2.75-2.90 (2H, in), 3.01-3.17 (4H, mn), 3.30-3.35 (1H, mn), 3.38 (3H, 3.42- 3.55 (4H, in), 3.66-3.77 (1Hi, mn), 4.55, 4.84 (1H, 5.51-5.60 (1H, in), 7.05-7.40 (6H, mn), 9.10, 9.20 (1H, s) MS (ESI-):564 (M-H Example 366 (2-Tetrahydropyranyloxy) (N-methyl-Nethylaininocarbonyl)amino)phenyl) -2-thienyl]-3, 4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (200 mg) NMR (CDCl 3 6) 1. 33 (3H, t, J=7. OHz) 1. 40-1. 75 (6H, in), 1.85-1.98 (2H, mn), 2.05-2.20 (2H, mn), 2.60- 2.90 (4H, mn), 3.00-3.20 (5H, mn), 3.29-3.50 (1H, in), 3.62-3.73 (1H, mn), 4.23 (2H, q, J=7.OHz), 4.53, 4.80 (1H, 7.15-7.35 (6H, m) MS 548 (M-H) Example 367 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-((2phthalimidoethoxy) carbonylamino) phenyl) -2-thienyl] 5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (155 mng) from (2-tetrahydropyranyloxy) f5-(3-aninophenyl) -2thienyl] 4, 5,6-tetrahydro-21--thiopyran-2-acetamide 1, 1dioxide (300 mg) and 2-phthaloylethanol NMR (ODd 3 1.42-1.70 (6H, mn), 1.81-1.96 (2H, mn), 2.02-2.23 (2H, in), 2.87-3.27 (4H, in), 3.49 (2H, br), 3.52-3.75 (2H, in), 4.04 (2H, br), 4.16-4.48 (1H, in), 5.05-5.23 (1H, in), 6.76-7.36 (8H, in), 7.66-7.74 (2H, mn), 7.79-7.87 (2H, mn) MS 680.5 (M-H) The following compounds were obtained in a similar manner to that of Example 32.

WO 00/40576 PCT/JPOO/00018 243 Example 368 (2S) 2 -Tetrahydropyranyloxy) (2phenylaminocarbonylethenyl) phenyl) 2-thienyl]1 4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (100 mg) NMR (DMSO-d 6 8) 1. 38-1. 62 (6H, in), 1. 72-2. 06 (4H, in), 2.38-2.47 (1H, in), 2. 90-3. 52 (6H, in), 3.75-3. (1H, in), 4. 45, 4 .7 5 (1H, 6. 86 (1H, d, J1l6Hz) 7. 06 (1H, dd, J=8. 0, 8 .0Hz), 7 .24-7 .27 (1H, in), 7. 34 (2H, d, J=8. 0, 8.0OHz) 7. 55-7. 58 (2H, in), 7.65-7.76 (6H, in) Example 369 2 S) 2 -Tetrahydropyranyoxy)2[ (4-ethoxyphenylaminocarbonyl) ethenyl)phenyl) 2-thienyl 1 3 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (150 ing) NMR (DMSO-d 6 1.37-1.64 (6H, mn), 1.71-2.08 (4H, in), 2.36-2.47 (1H, in), 2.90-3.51 (6H, in), 3.74 (3H, s), 3.75-3.90 (1H, in), 4.45, 4.75 (1H, 6.82 (1H, d, J=16Hz), 6.92 (2H, d, J=8.5Hz), 7.24-7.27 (1H, in), 7.54-7.75 (8H, in) Example 370 (2S) 2 -Tetrahydropyranyloxy) 5- (4-f luorophenylaminocarbonyl) ethenyl) phenyl) -2-thienyl 1 4,5, 6tetrahydro-2H-thiopyran-2-.acetanide 1,1-dioxide (150 ing) NMR (DMSO-d 6 8) 1. 37-1. 62 (6H, in), 1. 70-2. 08 (4H, in), 2. 36-2. 46 (1H, mn), 2 .91-3. 54 6H, mn), 3. 75-3. (1H, in), 4. 45, 4. 75 (1H, 6. 83 (1H, d, J=l6Hz), 7.18 (2H, dd, J=8. 5, 8. 5Hz), 7 .24-7.27 (1H, in), 7.55-7.75 (8H, in), 10.3 (1H, s) Example 371 2 S) (2-Tetrahydropyranyloxy)2[ 5(4-(2-(NNdimethylaminocarbonyl) ethenyl) phenyl) -2-thienyl] 4, 5,6tetrahydro-2H-thiopyran-2acetanide 1, 1-dioxide (250 mg) WO 00/40576 PCT/JPOO/00018 244 NMR (CDC1 3 35-1. 75 1. 88-2. 01 (2H, m), 2. 05-2.25 (2H, mn), 2. 65-3. 18 (9H, in), 3. 20 (3H, S), 3.26-3.49 (1H, in), 3.64-3.70 (1H, mn), 4.54, 4.83 (1H, 6.91 (iR, d, J=l6Hz), 7.29 (1H, d, J=4.OHz), 7.47-7.69 (6H, in) Example 372 (2S) (2-Tetrahydropyranyloxy) (2- (isopropylaminocarbonyl)ethenyl)phenyl) -2-thienyl]-3, 4,5,6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (220 ing) NMR (DMSO-d 6 1.11 (6H, d, J=5Hz), 1.37-1.64 (6H, in), 1.70-2.07 (4H, mn), 2.35-2.46 (iR, mn), 2.90- 3. 37 (5H, mn), 3. 40-3. 54 (1H, mn), 3. 74-3. 90 (1H, m) 3. 90-4. 01 (1H, mn), 4. 45, 4 .75 (1H, s) 6-.62 (1H, d, J=l6Hz), 7.21-7.25 (1H, mn), 7.40 (1H, d, J=l6Hz), 7.51-7.55 (1H, in), 7.57 (2H, d, J=8.5Hz), 7.69 (2H, d, J=8.SHz), 7.99 (1H, d, Example 373 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4(2- (propylaininocarbony'l) ethenyl)phenyl) -2-thienyll -3,4,5,6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (210 mng) NMR (DMSO-d 6 0.88 (3H, t, J=7.5Hz), 1.36-1.62 (8H, in), 1.70-2.06 (4H, in), 2.35-2.45 (1H, in), 2.40- 3.30 (7H, mn), 3.41-3.52 (1H, in), 3.74-3.90 (1H, mn), 4.45, 4.75 (1H, 6.65 (1H, d, J=l6Hz), 7.22- 7.25 (1H, mn), 7.40 (1H, d, J=l6Hz), 7.51-7.55 (1H, mn), 7.60 (2H, d, J=8.5Hz), 7.70 (2H, d, 8.10 (1H, t, J=7.OHz), 11.2 (1H, s) Example 374 (2S) (2-Tetrahydropyranyloxy) (npropyiaminocarbonylnethoxy) phenyl) -2-thienyl] -3,4,5,6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (140 ing) NMR (DMSO-d 3 0.82 (3H, t, J=7.SHz), 1.36-1.63 (8H, WO 00/40576 PCT/JPOO/00018 245 in1.70-2.05 in), 2.33-2.44 (1H, in), 2.93- 3.50 mn), 3.74-3.91 (1H, in), 4.45, 4.75 (1H, s) 4. 50 s) 7 .01 (2H, di, J=8. 5Hz) 7 .16-7. (1H, mn), 7.33-7.37 (1H, mn), 7.58 (2H, d, J=8.SHz), 8.10 (1H, br) Example 375 To a suspensibn of (2S) (2-tetrahydropyranyloxy) -2- (2-phthaliiidoethoxy) carbonylainino) phenyl) -2thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (155 mg) in methanol (4 ml) was added hydrazine inonohydrate (13.7 ing) and the reaction mixture was stirred at ambient temperature for 3 hours, the resulting mixture was filtrated and washed with methanol. The filtrate was concentrated in vacuo to give (2S)-N-(2-tetrahydropyranyloxy) 5- (2-aiinoethylaminocarbonylainino) phenyl) 2-thienyl]-3,4,5, 6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (125 mng) as a white amorphous.

NMR (CDCl 3 1.24-1.35 (2H, mn), 1.42-1.52 (2H, in), 1.62-1.73 (2H, in), 1.96 (2H, br), 2.08-2.25 (21H, in), 2.86 (2H, br), 3.01-3.05 (2H, in), 3.15 (2H, br), 3.44-3.50 (4H, in), 3.74-3.84 (1H, in), 4.22- 4.25 (1H, in), 4.45 (1/2H, br), 4.83 (1/2H, br), 7.22-7.30 (4H, in), 7.37-7.44 (1H, in), 7.68 (1H, br 7.83-7.86"(11-, in), 8.20-8.24 (1H, m) MS 552.3 (M+H) The following compounds were obtained in a similar manner to that of Example 130.

Example 376 (2S) (2-Tetrahydropyranyloxy) (4- (ethylcarbonyloxy) phenyl) -2-thienyl] 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (150 ing) NMR (DMSO-d 6 1.15 (3H, cid, 7.5Hz), 1.38-1.61 WO 00/40576 PCT/JPOO/00018 246 (6H, in), 1. 70-2. 07 (4H, in), 2. 37-2. 46 (1H, in), 2.58-2. 66 (2H, in), 2.90-3. 51 (6H, in), 3.75-3.88 (1H, mn), 4 .43, 4 .75 (1H, s) 7 .18-7. 25 (3H, m), 7.43-7.48 (1H, in), 7.68 (2H, d, MS 520 (M-H) Example 377 (2S) (2-Tetrahydropyranyloxy) (4- (methoxyacetoxy)phenyl) -2-thienyl]-3, 4, 5,6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (150 ing) NMR (DMSO-d 6 1.36-1.62 (6H, in), 1.69-2.05 (4H, mn), 2.34-2.43 (1H, in), 2.87-3.29 (5H, in), 3.38 s), 3.40-3.51 (1H, mn), 3.75-3.90 (1H, in), 4.37 (2H, s), 4.44, 4.75 (1H, 7.20-7.26 (3H, mn), 7.42-7.48 (1H, mn), 7.70 (2H, d, MS 536 (M-H) Example 378 (2S) (2-Tetrahydropyranyloxy) (4- (ethoxycarbonyloxyphenyl)phenyl) -2-thienyl]-3,4, 5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (150 ing) NMR (DMSO-d 6 1.30 (3H, dd, J=7.5, 7.5Hz), 1.38-1.65 (6H, in), 1.70-1.95 (4H, in), 2.36-2.45 mn), 2.90-3.51 (6H, mn), 3.72-3.90 (1H, mn), 4.27 (2H, ddd, J=7.5, 7.5, 7.5Hz), 7.43, 4.75 (1H, 7.20- 7.26 (1H, mn), 7.29 d, J=8.5Hz), 7.45-7.49 (1H, in), 7.69 (2H, di, MS 536 (M-H) The following compounds were obtained in a similar manner to that of Example 129.

Example 379 (2S) (2-Tetrahydropyranyloxy) (4- (rethylaminocarbonyloxy) phenyl) -2-thienyl]1-3, 4, 5,6- WO 00/40576 PCT/JPOO/00018 247 tetrahydro-2H-thiopyran--2-acetamide 1,1-dioxide (250 mg) NMR (DMSO-d 6 6) 1.3 7 62 (4 H, in), 1. 7 0-2. 05 (4 H, m) 2. 35 46 (1 H, mn), 2. 67 (3 H, d, J=4. 5H 2. 90 3.30 (5H, mn), 3.40-3.55 (1H, mn), 3.75-3.88 (1H, in), 4.44, 4.75 (1H, 7.15 di, J=8.7Hz), 7.18- 7.24 (1H, in), 740-7.45 (1H, mn), 7.63 (2H, d, J=8 .7Hz) MS (ESI-) 521 CM-H) Example 380 (2S) 2 -Tetrahydropyranyloxy) 5- (4- (ethylaininocarbonyloxy) phenyl) -2-thienyl 4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (230 mg) NMR (CDC1 3 6) 1. 23 (3H, dd, J= 7. 2, 7. 2H z) 1. 36- 1.7 in), 1.86-2.00 (2H, in), 2. 03-2.25 (2H, m) 2.65-2.87 (2H, in), 3.01-3.18 (4H, mn), 3.26-3.37 (2H, in), 3.60-3.69 (1H, mn), 4. 51, 4. 80 (1H, s) 5.01-5.09 (1H, mn), 7.14 (2H, di, J=8.7Hz), 7.16-- 7.25 (2H, in), 7.54 d, J=8.7Hz), 8.09, 8.24 (1H, s) MS (ESI-) 535 CM-H) Example 381 (2S) (2-Tetrahydropyranyloxy) 5- (4 -hyclroxyphenyl) 2-thienyl] 6 -tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (1 g) was obtained in a similar manner to that of Example 201.

NMR (CDC1 3 38-1. 66 mn), 1. 70-2. 04 (4H, in), 1. 84-1. 94 (1H, in), 2 .89-3. 48 (6H, in), 3. 75-3. (1H, in), 4.45, 4.75 (1H, 8.80 (2H, di, J=8.7Hz), 7.13-7.17 (1H, mn), 7.21-7.25 (1H, in), 7.45 (2H, d, J=8.7Hz), 9.68 (1H, s) The following compounds were obtained in a similar manner to that of Example 201.

WO 00/40576 PCT/JPOO/00018 248 Example 382 (2S) (2-Tetrahydropyranyloxy) 5- (6-methyl-3pyridyl) -2-thienyl] 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (99 mg) NMR (CDCl 3 6) 1. 40-1. 75 in), 1. 90-2. 00 (2H, in), 2.07-2.25 (2H, in), 2.59 (3H, 2.70-2.94 (2H, in), 3.05-3.17 (4H, in), 3.30-3.52 (1H, in), 3.63-3.74 (1H, in), 4.52 (0.5H, 4.81 (0.5H, 7.17 (2H, d, J=8Hz), 7.26-7.33 in), 7.75 (iH, dd, 8Hz), 8.12 (0.5H, 8.24 8.74 (1H, d, MS (ESI-) 463 (M-H) Example 383 (2S) (2-Tetrahydropyranyloxy) 5- (6-iethyl-3pyridyl) -2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (110 mg) NMR (CDC1 3 6) 1.40-1. 74 mn), 1. 88-2. 00 (2H, in), 2.07-2.20 (2H, mn), 2.67-2.87 (2H, in), 3.04-3.08* (2H, in), 3.09-3.18 (2H, mn), 3.30-3.52 (1H, in), 3.60-3.73 (1H, in), 3.96 (3H, 4.53 (0.5H, s), 4.81 (0.5H, 6.77 (1H, d, J=8Hz), 6.83 (1H, d, J=8Hz), 7.16-7.20 (lH, mn), 7.64-7.79 (1H, in), 7.99 (0.5H, 8.13 (0.5H, 8.39-8.42 (iN, in) MS (ESI-) 479 (M-H) The following compounds were obtained in a similar manner to that of Example 130.

Example 384 (2S) (2-Tetrahydropyranyloxy) (2-acetylainino) phenyl)I-2-thienyl] 4, 5, -tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (105 ing) NMR (CDCl 3 6) 1. 33-1.77 (8H, mn), 1. 87-2. 00 (2H, m) WO 00/40576 PCT/JPOO/00018 249 2. 11 (3H, mn), 2. 06-2. 77 (2H, in), 2. 85-3. 36 (5H, m), 3. 66-3. 83 (2H, mn), 4. 36-4. 48 (1H, in), 4 .53 (1/2H, br), 4.88 (1/2H, br), 7.12-7.37 (5H, in), 7.59-7.67 (1H, mn), 8. 82 (1/2H, br s) 8. 84 (1/2H, br s) 9.83 (1H, 10.04 (1H, s) MS 563.0 (M-H) Example 385 (2S) (2-Tetrahydropyranyloxy) (3- (iethoxycarbonyl) propionylaimno) phenyl....>thienyl 4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (130 mg) NMR (CDC1 3 1.44 (4H, br), 1.65-1.67 (2H, mn), 1.95 (2H, br), 2.08-2.21 (2H, in), 2.67-2.77 (6H, mn), 3.06-3.14 (4H, mn), 3.29-3.48 (1H, mn), 3.62-3.70 (1H, mn), 3.72 O3H, 4.53 (1/2H, br), 4.81 (1/2H, br), 7.20-7.27 (3H, in), 7.51 (1H, br), 7.60 (1/2H, 7.66 (1/2H, 7.80 (1/2H, br), 7.84 (1/2H, br), 8.40 (1/2H, 8.44 (1/2H, s) MS 577.2 (M-H) Example 386 (2-Tetrahydropyranyloxy)

(N-

mnethoxycarbonyl-N-inethylainino) acetyl amino) phenyl -2thienyl]-3,4,5, G-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (160 ing) NMR (CDC1 3 1.46 (2H, br), 1.68 (4H, br), 1.96 (2H, br), 2.07-2.24 (2H, in), 2.70-2.94 (2H, mn), 3.02- 3.09 (2H, in), 3. 10 (3H, s) 3. 16 (2H, br) 3. 31- 3.53 (1H, in), 3.65-3.75 mn), 3.80 (3H, s), 4.02-4.09 (2H, in), 4.54 (1/2H, br), 4.83 (1/2H-, br), 7.24-7.31 (SH, mn), 7.53 (1H, br), 7.63 (1/2H, 7.67 (1/2H, 8.44 (1/2H, 8.50 (1/2H, s) MS 592.1 (M-H) Example 387 WO 00/40576 PCT/JPOO/0001 8 250 (2S) (2-Tetrahydropyranyloxy) (3-pyridyl-2propenyloxy)phenyl}I-2-thienyl]-3, 4,5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (270 mg) NMR (DMSOd 6 b) 1. 36-1. 65 (6H, mn), 1. 70-2.06 (4H, in), 2.36-2.47 (1H, mn), 2.91-3.28 (SH, in), 3.41-3.52 (1H, in), 3.75-3.91 (1H, in), 4.45, 4.75 (1H, s), 7.07 (1H, di, Ch=l6Hz), 7.21-7.26 (1H, in), 7.30 (2H, di, J=8.OHz), 7.45-7.51 (2H, in), 7.72 (2H, d, J=8.OHz), 7.94 (1H, d, J=l6Hz), 8.28-8.32 (1H, in), 8.60-8.62 (1H, in), 8.99 (1H, s) MS 595 (M-H) The following compounds were obtained in a similar manner to that of Example 211.

Example 388 (2S) (2-Tetrahydropyranyloxy) [5-13- (2methoxyethoxy) acet yl amino) phenyl -2 -thienyl]I 3, 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (175 mg) NMR (CDCl 3 1.35-1.74 (8H, mn), 1.89-1.99 (2H, m), 2.06-2.25 (2H, mn), 2.68-2.89 (2H, in), 3.02-3.17 (2H, mn), 3.25-3.46 (1H, in), 3.52 (3H, 3.58- 3.67 (2H, in), 3.74-3.81 (2H, mn), 4.13 (2H, s), 4.52 (1/2H, br), 4.79 (1/2H, br), 7.22-7.38 (4H, in), 7.55-7.62 (1H, in), 7.83 (1H, br 8.04 (1/2H, s) 8. 19 (1/2H, s) 8. 97 (1H, s) MS 579.9 (M-H) Example 389 (2S) (2-Tetrahydropyranyloxy) (N-9f luorenylinethoxycarbonyl-N-nethylanino) acetylamino) phenyl- 2-thienyl]-3, 4,5, 6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (1.77 g) NMR (CDCl 3 1.42 (2H, br), 1.64 (4H, br), 1.95 (2H, br), 2.08-2.23 (2H1, in), 2.70-2.90 (2H, in), 3.00- WO 00/40576 PCT/JP00/00018 251 3.07 (5H, 3.10-3.16 (2H, 3.27-3.48 (1H, m), 3.60-3.70 (1H, 4.00-4.09 (1H, 4.28 (1H, br), 4.52 (2H, 4.56 (1/2H, br), 4.80 (1/2H, br), 7.21-7.48 (9H, 7.58-7.65 (3H, 7.75 (2H, br), 8.20 (1/2H, 8.32 (1/2H, s) MS 791.9 (M-H+C1) Example 390 2 -Tetrahydropyranyloxy)-2-[5-{3-(((2S)-2,6bis(tert-butoxycarbonylamino)hexanoyl)amino)phenyl}-2thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (290 mg) NMR (CDC1 3 1.45 (18H, 1.48-1.70 (14H, 1.95 (2H, br), 2.09-2.20 (2H, 2.68-2.92 (2H, m), 3.00-3.15 (4H, 3.25-3.49 (1H, 3.63-3.74 (1H, 4.16-4.28 (1H, 4.52 (1/2H, br), 4.65 (1/2H, br), 7.22-7.24 (2H, 7.27-7.30 (2H, m), 7.51 (1H, br), 7.62-7.82 (1H, m) MS 791.3 (M-H) Example 391 2 -Tetrahydropyranyloxy)-2-5-{3-(2-tertbutoxycarbonylamino-3-(3-pyridyl)propionylamino)phenyl}-2thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (1.54 g) NMR (DMSO-d 6 1.22-1.27 (2H, 1.43 (9H, 1.63- 1.68 (4H, 1.98 (2H, br), 2.07-2.25 (2H, m), 2.74-2.98 (2H, 3.04-3.20 (6H, 3.41-3.48 (1H, 3.66-3.76 (1H, 4.45 (1/2H, br), 4.54- 4.63 1 H br), 4.86 (1/2H, br), 5.31-5.45 (1H, m), 6.82-7.00 (2H, 7.04-7.20 (3H, 7.22-7.27 (2H, 7.52-7.65 (2H, 8.43-8.59 (3H, m) MS 713.1 (M+H) Example 392 WO 00/40576 PCT/JPOO/00018 252 (2S) (2-Tetrahydropyranyloxy) 3- (3carboxypropionylamino) phenyl}1-2-thienyl 1 4, 5, 6-tetrahydro- 2 H--thiopyran-2-acetamide 1, 1-dioxide (50 mg) was obtained in a similar manner to that of Example 3.

NMR (DMSO-d 6 1. 36-2. 06 (10H, mn), 2. 34-2. 63 (5H, in), 2.88-3.52 (6H, mn), 3.65-3.90 (1H, in), 4.43 (1/2H, br), 4.75 (1/2H, br), 7.17-7.32 (1H, in), 7.28-7.48 (4H, mn), '8.00 (lH, 10.08 (1H, 10.59 (1H, 11.22 (1H, 12.13 (iF, br s) MS 563.4 (N-H) Example 393 (2S) 2 -Tetrahydropyranyloxy) 5-1 3- (3- (methylaminocarbonyl) propionylamino) phenyl }-2-thienyl] 3,4,5, G-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide mg) was obtained in a similar manner to that of Example 32.

NMR (CDCl 3 48 (2H, br) 1 .62 (4H, br) 1. 96 (2H, br), 2.06-2.26 (2H, in), 2.62-2.66 (2H, in), 2.75 (3H, br 2.88 (2H, br), 3.05-3.22 (5H, in), 3.36-3.49 (1H, mn), 3.73-3.99 (1H, in), 4.15-4.25 (1H, mn), 4. 70 (1/2H, 4.95 (1/2H, 6.97-7.12 (4H, in), 7.32-7.43 (2H, in), 9.12 (1/2H, br), 9.24 (1/2H, br) MS 576.3 (N-H) Example 394 (23) 2 -Tetrahydropyranyloxy) 5- (tertbutoxycarbonylaninoinethyl) phenyl) -2-thienyl]1 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (200 mng) was obtained in a similar manner to that of Example 89.

NMR (CDCl 3 1.47 (9H, 1.52-1.68 (6H, in), 1.81-1.95 (2H, in), 2.06-2.23 (2H, in), 2.63-2.89 (2H, in), 3.05 (2H, br 3.08-3.13 (2H, in), 3.27- 3.50 (1H, mn), 3.61-3.70 (1H, mn), 4.24-4.39 (2H, in), 4.52 (1/2H, br), 4.80 (1/2H, br), 6.71-6.82 (1H, WO 00/40576 PCT/JPOO/0001 8 253 in), 7.14-7.70 (5H, in), 8.07 (1/2H, s) 8.24 (1/2H,

S)

MS 577.3 (M-H) Example 395 (2S) -N-(2-Tetrahydropyranyloxy) (2- (methylamino) acetylamino)phenyll-2-thienyl] -3,4,5,6tetrahydro-2H--thiopyran-2-acetamide 1,1-dioxide (915 mng) was obtained in a similar manner to that of Example 239.

NMR (DMSO-d 6 1.42-1.59 (6H, in), 1.73-2.05 (4H, in), 2. 32 (3H, s) 2. 37-2. 46 (1H, mn), 2 .89-3. 20 (4H, mn), 3.25 (2H, 3.42-3.48 (2H, mn), 3.75-3.78 1 m), 4.44 br), 4.75 (1/2H, br), 7.20-7.24 (1H, in), 7.34-7.36 (2H, in), 7.38-7.42 (1H, in), 7.55- 7.57 (iR, mn), 8.02 (1H, s) MS 536.3 (M+H) The following compounds were obtained in a similar manner to that of Example 54.

Example 396 (2S) -N-Hydroxy-2- (6-iethyl-3-pyridyl) -2-thienyl] 3,4,5, 6 -tetrahydro-2R-thiopyran-2-acetanide 1,1-dioxide hydrochloride (89 mg) NMR (DMSO-d 6 1.71-2.10 (4H, in), 2.35-2.54 (1H, mn), 2.68 (3H, 2.96-3.08 (2H, mn), 3.14-3.60 (3H, in), 7.32 (1H, d, J=3.5Hz), 7.74-7.81 (2H, in), 8.49 (1R, dd, J=1.5, 8Hz), 9.01 (iR, d, J=1.5Hz), 10.66 (1H,

S)

MS (ESI-) 379 (M-H) Example 397 -N-Rydroxy-2- [5-(6-methoxy-3-pyridyl) -2-thienyl] 3,4,5, 6 -tetrahydro-2R-thiopyran-2-acetanide, 1,1-dioxide mg) WO 00/40576 PCT/JPOO/00018 254 NMR (DMSO-d 6 71-2. 09 (4H, m) 2. 33-2 .52 (1H, M), 2.95-3.08 (2H, in), 3.10-3.29 (2H, in), 3.42-3.58 (1H, mn), 3.89 (3H, 6.89 (1H, d, J=8Hz), 7.21 (1H, d, J=3.5Hz), 7.43 (1H, d, J=3.5Hz), 7.97 (1H, dd, J=1.5, 8Hz), 8.47 (1H, di, MS 395 (N-H) Example 398 yl)phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (67 mg) NMR (DMSO-d 6 1.71-2.09 (4H, mn), 2.20-2.52 (1H, m), 2.68 (3H, 2.94-3.08 (2H, in), 3.11-3.33 (2H, mn), 3.36-3.56 (1H, in), 7.26 (1H, d, 7.63 (1H, d, J=3.5Hz), 7.84 (2H, d, J=8Hz), 8.03 (2H, d, J=8Hz), 8.84 (1H, s) MS (ESI-) 446 (N-H) Example 399 2 S)-N-Hydroxy-2-[5-{3-(2-(acetylanino)acetylanino)..

phenyl)} -2-thienyl 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (75 mg) NMR (DMSO-d 6 1.69-2.08 (4H, in), 1.89 (3H, s), 2.34-2.48 (1H, in), 2.94-3.30 (4H, in), 3.38-3.55 (1H, mn), 3.88 d, J=8.OHz), 7.21 (1H, d, J=4.OHz), 7.32-7.40 (2H, mn), 7.42 (1H, d, 7.44-7.51 (1H, in), 7.98 (1H, 8.22 (1H, t, J=8.OHz), 8.83 (1H, 10.08 (1H, 10.60 (1H, s) MS (ESI-) 478.3 (N-H) Example 400 (2S)-N-_Hydroxy-2- [5-13- 3 -rnethoxycarbonylpropjionylamino) phenyl) -2-thieny11 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (60 mg) WO 00/40576 PCT/JPOO/00018 255 NMR (DMS0-l 6 72-2.09 (4H, in), 2.33-2.48 (1H, in), 2 .63 (3H, s) 2. 77-3. 40 (6H, in), 3. 42-3.55 (1H, in) 7.21 (1H, d, J=4. OHz) 7. 28-7 .48 in), 7. 98 (1H, s) 8. 84 (1H, s) 10. 12 (1H, s) 10. 60 (1H, s) MS 493.4 (M-H) Example 401 (2S) -N-Hydroxy-2- (methylaminocarbonyl) propionylamino) phenyl l-2-thienyl 1 3, 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamije 1,1-dioxide (30 mng) NMR (DMSO-d 6 1.73-2.05 (4H, in), 2.40 (2H, t, J=6.OHz), 2.45-2.49 (1H, in), 2.53-2.58 (3H, in), 2.95-3.26 (4H, in), 3.40-3.54 mn), 7.20 (1H, d, J=4.OHz), 7.32 (2H, d, J=4.5Hz), 7.39 (1H, d, J=4.OHz), 7.43-7.47 (2H, mn), 7.82 (1H, br), 8.00 (1H, 10.08 1 10.60 (1H, s) MS 492.1 CM-H) Example 402 (2S) -N-Hydroxy-2-[5-{3-(2- (2-iethoxyethoxy)acetylamino) phenyl}I-2-thienyll>3, 4, 5, 6-tetrahydro-2thiopyran-2-acetaie 1,1-dioxide (120 ing) NMR (DMSO-d 6 1.70-2.07 (4H, in), 2.36-2.46 (1H, in), 2.94-3.28 (4H, in), 3.31 (3H, 3.48-3.51 (1H, mn), 3.52-3.58 (2H, in), 3.66-3.72 (2H, in), 4.10 (2H, s), 7.22 (1H, d, J=4.0Hz), 7.33-7.40 (1H, in), 7.40 (1H, d, J=4.0Hz), 7.52-7.62 (1H, mn), 8.00 (1H, 8.84 (1H, 9.76 (1H, 10.60 (1H, s) MS 495.3 (M-H) Example 403 (2S) -N-Hydroxy-2- 3 -aminoinethylphenyl) -2-thienyl] 3,4,5, G-tetrahydro-2H-thiopyran-2acetaie 1,1-dioxide (132 mg) from 2 2 -tetrahydropyranyloxy-25(3-(tertbutoxycarbonylaminoinethyl)phenyl)y2-thienll3, 4,5,6- WO 00/40576 PCT/JPOO/00018 256 tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide NMR (DMSO 6 6) 1. 73-2. 08 in), 2. 35-2. 45 (1H, m).

2. 95-3. 26 (4H, mn), 3. 43-3 .55 (1H, in), 4. 08 (2H, br) 7. 24 (1H, d, J=4 .0Hz) 7 .37-7. 39 (1H, m) 7 .45-7. 50 (2H, mn), 7. 68 1H, d, J=7 .5Hz) 7. 75 (1H, 8.115 (2H, br), 8.83 (1H, 10.60 (1H, s) MS 435.2 (M-H+CH 3

CN)

Example 404 (2S) -N-Hydroxy-2-[5-{3-(2- (N-methoxycarbonyl-Nmethylainino) acetylamino) phenyl I-2-thienyl] 6tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (110 mg) NMR (DMSO-d 6 1.75-2.06 (4H, in), 2.37-2.46 (1H, in), 2.90 (3/2H, 2.94 (3/2H, 2.95-3.26 (4H, in), 3.40-3.50 (1H, in), 3.56 (3/2H, 3.63 (3/2H, s), 4.05 (2H, 7.20 (1H, d, J=4.OHz), 7.32-7.39 (3H, in), 7.42 (1H, di, J=4.OHz), 8.02 (1H, 8.84 (1H,

S)

MS (ESI-) 508.4 CM-H) Example 405 (2S)-N-Hydroxy-2-[5-{3-( 6-diaininohexanoyl)ainino) phenyl}J-2-thienyl J 4, 5, 6 -tetrahydro-2H-thiopyran-2acetarnide 1,1-dioxide (200 mg) from tetrahydropyranyloxy)-2.t...3.j((2S) 6-bis(tertbutoxycarbonylanino) hexanoyl) amino) phenyl -2-thienyl] 3, 4, 5, 6 -tetrahydro-2H-thiopyran.2-acetainide 1, 1-dioxide NMR (DMSO-d 6 8) 1.33-1. 44 (2H, in), 1. 50-1. 60 (2H, n) 1.73-1.93 (4H, in), 1.95-2.07 (1H, mn), 2.35-2.45 (1H, in), 2.73-2.80 (2H, in), 2.95-3.28 (4H, in), 3.50-3.55 (1H, mn), 3.94 (1H, br), 7.22 (1H, di, J=4.OHz), 7.42-7.45 (3H, mn), 7.53 (1H, d, J=7.OHz), 7.94 (1H, 8.38 (1H, s) MS 509.3 (M+H) WO 00/40576 PCT/JPOO/00018 257 Example 406 (2S) -N-Hydroxy-2- 2 -amino-3- (3-pyriclyl) propionylamino)phenyl)-2-thienyll 6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (460 mng) from (2S)-N- (2-tetrahydropyranyloxy) (2-tertbu toxyca rbonyl amino- 3- 3 -pyridyl) propionylamino) phenyl) -2thienyl]-3,4,5, G-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide NMR (DMSO-d 6 1.74-2.07 mn), 2.36-2.46 (1H, mn), 2.96-3.32 (6H, in), 3.45-3.55 (1H, mn), 4.24 (1H, br), 7.22 (1H, d, J=4.OHz), 7.39-7.48 (4H, mn), 7.52-7.57 (1H, mn), 7.83-7.88 (2H, mn), 8.39 (2H, br), 8.56-8.60 (2H, mn), 10.57 10.60 (1H,

S)

MS 529.1 (M+H) Example 407 (2S) -N-Hydroxy-2 5- (4 3 -pyr idyl -2-propenyloxy) phenyl) -2-thienyl 4, 5, 6 -tetrahydro-2H--thiopyran-2acetainide 1,1-dioxide (180 mng) NMR (DMSO-d 6 1.70-2.06 in), 2.36-2.47 (1H, in), 2.96-3.56 (5H, mn), 7.16 d, J=l6Hz), 7.23 (1H, d, J=4.OHz), 7.30 (2H, d, J=8.5Hz), 7.49 (1H, d, J=l6Hz), 7.70-7.76 (3H, in), 7.97 (1H, d, 8.53-8.57 (1H, mn), 8.75 (1H, d, J=5Hz), 9.12 (1H, 10.6 (1H, s) MS 511 (M-H) Example 408 To a solution of 2

S)-

2 -tert-butoxycarbonylamino-3hydroxypropionic acid (66 mg), 1 l-hydroxybenzotriazole (44 mg) and I1-ethyl- 3- 3 -dimethylarninopropyl) carbodiimide hydrochloride (62 mng) in N,N-dimethylfornamide (1.3 ml) was added a solution of (2S) 2 -tetrahydropyranyloxy)-2-[5-(3aminophenyl)-2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2- WO 00/40576 PCT/JP00/00018 258 acetamide 1,1-dioxide (100 mg) in N,N-dimethylformamide ml) at ambient temperature. After being stirred at the same temperature overnight, the reaction mixture was added ethyl acetate and the solution was washed successively with water, a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and evaporated under a stream of nitrogen.

After the residue was dissolved in methanol (1 ml), the solution was added 4N hydrogen chloride in ethyl acetate.

The mixture was stirred at ambient temperature for 1 hour.

After the solution was evaporated under a stream of nitrogen, the residue was purified by reverse phase HPLC (0.1% trifluoroacetic acid in acetonitrile, 1-60% gradient) to give (2S)-N-hydroxy-2-[5-{3-(((2S)-2-amino-3hydroxypropionyl)amino)phenyl}-2-thienyl]-3,4,5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (30 mg) as a white powder.

NMR (DMSO-d 6 1.76-2.10 (4H, 2.38-2.46 (1H, m), 3.00 (2H, d, J=10Hz), 3.13-3.52 (4H, 3.82-3.93 (1H, 3.98-4.06 (1H, 7.23 (1H, d, 7.40-7.45 (3H, 7.50-7.54 (1H, 7.98 (1H, s), 8.32 (2H, br), 10.73 (1H, s) MS 468.3 (M+H) The following compound was obtained in a similar manner to that of Example 408.

Example 409 (2S)-N-Hydroxy-2-[5-{3-( 2 -dimethylaminocarbonyl)amino)acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (30 mg) from tetrahydropyranyloxy)-2-[5-{3-(( 2 -aminoacetyl)amino)phenyl}- 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (150 mg) and dimethylaminocarbonyl chloride.

NMR (DMSO-d 6 1.74-2.04 (4H, 2.35-2.44 (1H, m), WO 00/40576 PCT/JPOO/00018 259 2. 85 (6H, s) 2 .95-3.25 (4H, in), 3. 46-3.53 (1H, m), 3. 78 (2H, d, J=4 .0Hz) 6. 65 (1H, t, J=4.-OHz) 7. (1H, d, J=4 .OHz) 7 .34-7 .40 (2H, mn), 7 .40-7 .48 (2H, mn), 8.01 8.08 (1 H, br) 9. 98 (1H, S), 10.60 (1H, s) MS (ESI+) 509.2 (M+H) Example 410 (2S) -N-Hydroxy-2- 5- {13- (dimethylaminocarbonyl)

-N-

iethylamino) acetylamino) phenyl 2-thienyll>3, 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (30 mng) was obtained in a similar manner to that of Example 409.

NMR (DMSO-d 6 1.73-2.05 (4H, in), 2.37-2.48 (1H, in), 2. 74 (6H, s) 2 87 (3H, s) 2. 95-3. 25 (4 H, in), 3.44-3.52 (1H, mn), 3.91 (2H, 7.20 (1H, d, J=4.OHz), 7.34-7.45 (3H, in), 7.42 (1H, d, J=4.OHz), 8.02 (1H, 10.06 (1H, 10.60 (1H, s) MS 521.2 (M-H) Example 411 (2S) (2-Tetrahydropyranyloxy) 1,2, 4-oxadiazol-3-yl) phenyl] -2-thienyl] 6-tetrahydro- 2 H-thiopyran-2-acetamide 1,1-dioxide (113 mg) was obtained in a similar manner to that of Example 201.

NMR (CDC1 3 1.38-1.74 (6H, in), 1.90-2.01 (2H, in), 2.06-2.25 (2H, in), 2.67 (3H, 2.70-2.89 (2H, in), 3.03-3.08 (2H, mn), 3.10-3.18 (2H, in), 3.28-3.50 (TR, in), 3.59-3.72 (1H, in), 4.53 (0.5H, 4.81 7.28-7.32 (1H, in), 7.35-7.39 (1H, in), 7.71 (2H, d, J=8Hz), 7.99 (0.5H, 8.08 (2H, d, J=8Hz), 8.13 (0.5H, s) MS (ES1-) 530 (M-H) Example 412 WO 00/40576 PCT/JPOO/00018 260 tert-Butyl 2-(5-bromo-2-thienyl)-2,3,4,5tetrahydrothiophene-2-acetate (2.77 g) was obtained in substantially the same manner as that of Example 93.

NMR (CDCl 3 8) 1. 34 (9H, s) 1. 90-2. 05 (1H, in), 2. 07-2. 20 (2H, in), 2. 26-2 .36 (1H, in), 2. 83 (1H, ci, 2.98-3.09 (2H, mn), 3.12 (l1H, d, 6.70 (1H, di, J=4Hz), 6.87 (2H, d, J'=4Hz) Example 413 tert-Butyl 2-[5-(4-fluorophenyl)-2-thienyl]-2,3,4,5tetrahydrothiophene-2 -acetate (479 ing) was obtained in substantially the same manner as that of Example 100.

NMR (C~DC 3 8) 1. 34 (9H, s) 2. 02-2. 29 (3H, in), 2. 36- 2. 46 (1H, in), 3. 00 (1H, d, J=l 6Hz) 3. 01-3. 14 (2H, mn), 3.17 (1H, cd, Jl16Hz), 6.92 (1H, d, J=4Hz), 7.00-7.08 (3H, mn), 7.52 (2H, dci, J=4, 9Hz) Example 414 (4-Fluorophenyl) -2-thienyl] -2,3,4,5tetrahydrothiophene-2 -acetic acid (298 ing) was obtained 'in a similar manner to that of Example NMR (CDCl 3 8) 2. 02-2. 31 (3H, in), 2. 39-2. 50 (1H, in), 2.98-3.17 (3H, mn), 3.30 (1H, d, J=l6Hz), 6.93 (1H, ci, J=4Hz), 6.99-7.08 (3H, in), 7.50 (2H, dci, 9Hz) MS 321 (M-H) Example 415 2- (4-Fluorophenyl) -2-thienyl] -2,3,4,5tetrahydrothiophene-2 -acetic acid 1,1-dioxide (272 ing) was obtained in a similar manner to that of Preparation 1-4).

NMR (CoDC 3 2.18-2.43 (2H, m) 2.70-2.82 (1H, m), 2.89-3.01 (1H, in), 3.09 (1H, ci, J=l6Hz), 3.14-3.25 (2H, in), 3.36 (1H, ci, Jz=l6Hz), 7.07 (2H, t, J=9Hz), 7.13-7.18 (2H, in), 7.54 (2H, dci, J=5, 9Hz) WO 00/40576 PCT/JPOO/00018 261 The following compounds were obtained in a similar manner to that of Example 130.

Example 416 (2S) (2-Tetrahydropyranyloxy) 3- (2- (ben zyloxyca rbonyl amino) acetylamino) phenyl) 2-thienyl] 3, 4,5, 6-tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (230 mng) NMR (CDCl 3 8) 1. 43 (4H, br) 1. 63-1. 65 (2H, in), 1. 94 (2H, br), 2. 09-2. 23 (2H, in), 2. 82 (2H, br) 3. 06- 3.17 (4H, in), 3.27-3.50 (1H, in), 3.64-3.76 (1H, mn), 4.03-4 .05 (2H, in), 4.52 (1/2H, br), 4.83 (1/2H, br), 5.18 (2H, 7.10-7.22 (4H, in), 7.30-7.38 (6H, in), 7.45-7.55 (2H, in), 8.23 (1H, br), 8.77 (1/2H, br), 8.85 (1/2H, br) MS 654.2 (M-H) Example 417 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(4methoxybenzene sulf onyl amino) acetylamino)phenyl 2 thienylp 3,4,5, G-tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide (220 mg) NMR (CDCl 3 1.43 (4H, br), 1.62-1.72 (2H, mn), 1.95 (2H, br), 2.06-2.25 (2H, mn), 2.75-2.90 (2H, in), 3.00-3.18 (4H, in), 3.28-3.50 (1H, in), 3.64-3.70 (1H, in), 3.75 (2H, d, J=6.OHz), 3.82 (3H, 4.54 (1/2H, br), 4.85 (1/2H, br), 5.72-5.86 (1H, in), 6.98 (2H, d, J=8.OHz), 7.14-7.23 (4H, in), 7.85 (2H, d, J=8.OHz), 8.40 (1H, br), 8.78 (1/2H, 8.94 (1/2H, s) MS 690.1 (M-H) Example 418 2 S)-N-(2-Tetrahydropyranyloxy)2-[5.j3-.[>(l15,5.

WO 00/40576 PCT/JPOO/00018 262 trimethylhydantoin.-3-yl) a cetyl amino] phenyl] -2-thienyl] 3,4,5, G-tetrahydro-2H-thiopyran-2-.acetamide 1,1-dioxide (212 mg) was obtained in a similar manner to that of Example 211.

NMR (C~DC 3 1.38-1.75 (12H, mn), 1.87-2.05 (2H, in), 2.07-2.28 (2H, in), 2.77-2.96 (5H, in), 3.00-3.25 (4H, in), 3.27-3.54 in), 3.68-3.81 (1H, mn), 4.40 (2H, 4.53 (0.5H, 4.85 s), 6.93-7.06 (1H, in), 7.09-7.34 (4H, in), 7.54-7.66 (1H, mn), 8.25-8.35 (1H, in), 9.05 (0.5H, 9.20 (0.5H, s) MS 645 (M-H) Example 419 (2S) 2 -Tetrahydropyranyloxy)-2-[5- [4- (phenoxycarbonyloxymethyl)phenyl]-2-.thienyl]- 3 ,4,5,6tetrahydro-2H-thiopyran2acetanide 1,1-dioxide (120 mng) was obtained in a similar manner to that of Example 244.

NMR (CDCl 3 1.35-1.76 (6H, mn), 1.87-2.00 (2H, mn), 2.04-2.25 (2H, in), 2.65-2.91 (2H, in), 3.00-3.18 (4H, in), 3.25-3.51 (1H, in), 3.59-3.72 (1H, mn), 4.53 (0.5H, 4.81 (0.5H, 5.27 (2H, 7.17 (2H, d, J=8Hz), 7.23-7.32 (1H, in), 7.35-7.49 (6H-, in), 7.62 (2H, d, J=8Hz), 8.01 (0.5H, 8.15

S)

MS 598 (M-H) Example 420 (2S) 2 -Tetrahydropyranyloxy) -2-Es- [4- (methylaminocarbonyoxmethy)pheny12thienyl]- 3 ,4,5,6tetrahydro-2H-thiopyran2acetanide l,1-dioxide (70 mg) was obtained in a similar manner to that of Example 245.

NMR (C~DC 3 1.36-1.75 (6H, in), 1.86-2.01 (2H, mn), 2.05-2.24 (2H, in), 2.64-2.85 (SH, in), 3.01-3.18 (4H, in), 3.27-3.50 (1H, in), 3.56-3.70 (1H, in), 4.53 (0.5H, 4.61-4.74 (1H, in), 4.80 (0.5H, s), WO 00/40576 PCT/JPOO/00018 263 11 (2H, s) 7. 21-7 .29 in), 7 .36 di, J=8Hz) 7. 56 (2H, d, 3=8Hz) 7. 96 5H, s) 8. 11 5H, s) MS (ESI-) :535 (N-H) Example 421 (2S) (2-Tetrahydropyranyloxy-2-[5qs5 (iet hoxycarbonyl amino) 3 -pyridyll--2-thienyl] 5, 6tetrahydro-211-thiopyran-2.acetamide 1, 1-dioxide (170 mg) was obtained in a similar manner to that of Example 201.

NMR (CDC'l 3 8) 1. 40-1. 74 in), 1. 89-2. 01 (211, m) 2.05-2.25 (2H, in), 2-70-2.95 (211, in), 3.01-3.17 (4H, in), 3.30-3.56 (1H, mn), 3.62-3.76 (1H, in), 3.83 (3H, 4.53 (0.5H, 4.84 (0.5H, s), 6.97-7.06 (1H, mn), 7.25-7.33 (1H1, mn), 7.36-7.65 (1H, in), 8.10-8.19 (1H, mn), 8.40-8.56 (3H, in) MS 522 (N-H) Example 422 2 S)-N-(2-Tetrahydropyranyloxy)2[5-(3 (methylaininocarbonylinethylaminocarbonylanino) phenyl) -2thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2acetanide 1,1dioxide (45 ing) was obtained in a similar manner to that of Example 32.

NMR (CDCl 3 6) 40-1. 47 (4H, mn), 1. 64-1. 69 (2H, mn), 2. 15 (2H, br) 2.28 (2H1, br), 2.80 (3H, br s) 2. 81-2. 88 (211, mn), 2. 98-3. 15 (4H, in), 3. 25-3. 52 (1H1, in), 3. 72-3. 81 (1H, in), 3. 85-3. 94 (2H1, in), 4.50 (1/211, br), 4.85 (1/2H1, br), 5.27-5.43 (1H1, in), 7.12-7.19 (6H, mn), 7.48-7.55 (211, mn), 7.67- 7.72 (1H1, in) MS 577.2 (N-H) Example 423 2 S)-N-(2-Tetrahycropyranyloxy)2[5-( 3 WO 00/40576 PCT/JPOO/00018 264 (carboxymethylaminocarbonylamino)phenyl)2thjeny 1 3 ,4,5,6tetrahydro-2H-thiopyran2acetamide 1,1I-dioxide (130 mg) was obtained in a similar manner to that of Example 3.

NMR (CDCl 3 8) 1. 43-1. 50 (2H, in), 1. 64-1. 68 (4H, m) 1.92 (2H, br), 2.08-2.21 (2H, mn), 2.40-2.48 (2H, in), 2.95-3.14 (4H, in), 3.30-3.53 (1H, in), 3.75- 3.81 (1H, in), 4.00 (2H, br 4.45 (1/2H, br), 4.82 (1/2H, br), 7.15-7.22 (5H, mn), 7.53 s), 7.57 (1/2H, s) MS 565.0 (M-H) The following compounds were obtained in a similar manner to that of Example 249.

Example 424 (2S) 2 -Tetrahydropyranyloxy) (2- (allylamino) acetylamino) phenyl }-2-thienyl] -3,4,5,6tetrahydro-2thiopyran-2acetanide 1,1-dioxide (106 mg) NMR (CDCl 3 1.45 (2H, br), 1.64-1.68 (4H, in), 1.95 (2H, br), 2.06-2.24 (2H, in), 2.64-2.86 (2H, in) 3.07 (2H, br 3.13-3.16 (2H, in), 3.30-3.49 (1H, in), 3.46 (3H, d, J=7.OHz), 3.45 (2H, 3.62-3.71 (iR, in), 4.52 (1/2H, 4.80 (1/2H, 5.20-5.30 (2H, in), 5.85-5.98 in), 7.23-7.32 (4H, in), 7.56 (1H, br); 7.80 (1H, 9.40 (1H, s) MS 562.2 (M+H) Example 425 (2S) 2 -Tetrahydropyranyloxy) f5-{3- (2ethoxyethylamino)acetylain noppheyl- thiel>- 3 4 5 6tetrahydro-2H-thiopyran2acetamide 1, 1-dioxide (65 ing) NMR (CDCl 3 1.23 (3H, t, J=7.5Hz), 1.46 (2H, br), 1.65-1.80 (4H, in), 1.95 (2H, br), 2.05-2.25 (2H, in), 2..65-2.85 in), 2.88 (2H, t, J=6.OHz), 3.30-3.49 (1H, in), 3.44 (2H, 3.51-3.58 (4H, in), WO 00/40576 PCT/JPOO/00018 265 3. 62-3. 70 (1H, in), 4 .52 br) 4 .80 (1/2H, br) 7. 27-7. 35 (58, in), 7. 57-7. 61 (1H, mn), 7. 83 (1H, s) 8. 03 (1/2H, br) 8. 20 (1/2H, br s) 9. 52 (1H, s) MS 594.2 (M+H) Example 426 (2S) (2-Tetrahydropyranyloxy) (2- (ben zylainino) acetylamino) phenyl).-2..thi enyl 3 4, 5,6tetrahydro-2H-thiopyran-2.acetanide 1, 1-dioxide (95 ing) NMR (CDC1 3 8) 1.43 (2H, br) 1.52-1.68 (48, in), 1.96 (28, br), 2.10-2.22 (2H, in), 2.66-2.89 (28, in), 3.06 (2H, br s) 3.10-3. 16 (2H, mn), 3.29-3.50 (1H, in), 3.45 (2H, br s) 3.60-3.70 (1H, in), 3.88 (2H, 4.52 (1/2H, br), 4.80 (1/2H, br), 7.27-7.38 (1 OH, mn), 7. 52 (18, br) 7. 79 (18, br) 8. 05 (1/2H, br), 8.20 (1/2H, br), 9.33 (1H, s) MS 612.2 (M+H) Example 427 (2S) 2 -Tetrahydropyranyloxy) (2- (pentylainino) acetylanino) phenyl 2-.thieny 4, 5, 6tetrahydro-2H-thiopyran2-acetanide 1, 1-dioxide (83 ing) NMR (CDCl 3 8) 0.87-0.94 (58, in), 1.29-1.64 (6H, in), 1.42-1.64 (48, mn), 1.95 (28, br) 2.08-2.22 (28, in), 2.62-2.88 (28, in), 2.69 (28, t, J=7.OHz), 3.06 (2H, 3.10-3.14 (28, in), 3.24-3.50 (18, in), 3.39 (28, 3.61-3.69 (18, in), 4.54 (1/2H, br), 4.80 (1/2H, br), 7.25-7.33 (58, in), 7.56 (1H, br), 7.80 (18, 8.00 (1/2H, br), 8.16 (1/2H, s), 9.44 (1H, s) MS 592.3 (M+H) Example 428 2 S)-N-(2-Tetrahydropyranyloxy)2.j5{3.( (2R)-2-tert- WO 00/40576 PCT/JPOO/00018 266 butoxycarbonylamino-3-benzyloxypropionyl) aminophenyl thienyl]-3,4,5, G-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (400 mg) NMR (C~DC 3 1.40-1.48 (2H, br), 1.49 (9H, s), 1.60-1.68 (4H, mn), 1.94 (2H, br), 2.06-2.24 (2H, in), 2.65-2.90 (2H, in), 3.06 (1H, br 3.11-3.16 (2H, br), 3.27-3.47 (1H, mn), 3.63-3.70 (2H, in), 3.97-4.04 (1H, in), 4.44 (iR, br), 4.52 (1/2H, br), 4.55 d, J=11.OHz), 4.65 (1H, d, J=11.0Hz), 4.80 (1/2H, br), 5.50 (1H, br), 7.22-7.41 (11H, mn), 7.72 (1H, br), 8.07 (1/2H, 8.20 (1/2H, s), 8.47 (1H, br) MS 776.2 (M-H Cl) The following compounds were obtained in a similar manner to that of Example 54.

Example 429 (2S) -N-Hydroxy-2- 3 -cyclobutanecarbonylaminophenyl) 2-thienyl] 6 -tetrahydro-2H-thiopyran-2-acetanide 1'01dioxide (250 mg) NMR (DMSO-d 6 1.75-2.30 (1OH, in), 2.37-2.46 (1H-, in), 2.95-3.52 (5H, in), 7.20 (iN, d, J=4.OHz), 7.33-7.35 (2H, in), 7.40 (1H, d, J=4.OHz), 7.46- 7.50 (1H, mn), 8.02 (1H, 9.84 (1H, 10.60 (1H, s) MS (ESI-) 461 (M-H) Example 430 2 S)-Hydroxy-2-[5-[3-[2-(,5,5-trimethylhydantoin-3 yl) acetylainino] phenyl] -2-thienyl] 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (117 mng) NMR (DMSO-d 6 1.36 1.70-2.09 (4H, in), 2. 35-2 .54 (iN, in), 2 .84 (3H, s) 2. 94-3. 08 (2H, in), 3. 10-3. 29 (2H, in), 3.36-3. 55 (iN, in), 4.23 (2H, s), WO 00/40576 PCT/JPOO/00018 267 7.21 (1H, d, J=3. 5Hz) 7 .35-7. 43 (4H1, mn), 7. 95 (1H, s) 8 .8 3 (1H, s) 10 .41 (1H, s) 10. 60 (1H, s) MS (ESI-) :561 CM-H) Example 431 (2S) -N-Hydroxy-2- (methylaminocarbonyloxymethyl) phenyl] -2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (46 mg) NMR (DMSO-c1 6 5) 1. 67-2. 09 (4H, mn), 2. 34-2. 53 (1H, m) 2.59 (3H, di, J=4. 8Hz) 2 .94-3. 08 (28, mn), 3. 3.30 (2H, in), 3. 38-3. 55 (18, in), 5. 02 (2H, s) 7.21 (1H, d, J=3.5Hz), 7.38 (2H, di, J=8Hz), 7.48 (1H, d, J=3.5Hz), 7.64 (2H, d, J=8Hz), 8.85 (1H, br s) MS 451 CM-H) Example 432 (2S) -N-Hydroxy-2- (methoxycarbonylanino) -3pyridyl I-2-thienyl] 4,5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (94 ing) NMR (DMSO-d 6 1.71-2.09 (4H, mn), 2.35-2.56 (18, mn), 2.95-3.08 (2H, in), 3.11-3.32 (2H, in), 3.41-3.57 (1H, in), 3.74 (3H, 7.29 (18, di, J=3.5Hz), 7.65 (1H, d, J=3. 5Hz) 8. 32 (18, s) 8. 63 (1H, d, J=1.58z), 8.71 (1H, di, MS 440 (M+H) Example 433 (2S) -N-Hyciroxy-2- 2-durnethyipropionylamino) phenyl]I -2-thienyl]) 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (100 ing) NMR (DMSO-d 6 1.24 (9H, 1.71-2.08 (4H, in), 2.35-2.53 (1H, mn), 2.94-3.07 (2H, mn), 3.10-3.28 (2H, in), 3.39-3.55 (18, in), 7.20 (18, di, 7.30-7.39 (28, mn), 7.41 (18, di, J=3.5Hz), 7.59- WO 00/40576 PCT/JPOO/00018 268 7. 65 (1H, mn), 8.-01 s) 8. 84 br s) 9. (1H, s) MS 463 (M-H) Example 434 (2S)-N-Hydroxy-2-[5-[3-( (E)-2-butenoylainino)phenyl]-2thienyl] 5, 6-tetrahydro-2H-thiopyran-2-acetanide 1, 1dioxide (104 mg) NMR (DMSO-d 6 1.71-2.08 (7H, in), 2.36-2.55 (1H, mn), 2.94-3.08 in), 3.10-3.29 (2H, in), 3.39-3.85 in), 6.14 dd, J=1.5, 14Hz), 6.75-6.88 (1H, mn), 7.21 (1H, d, J=3.5Hz), 7.32-7.39 (2H, in), 7.41 (1H, d, J=3.5Hz), 7.50-7.56 (1H, in), 8.05 (1H, s), 10.08 (iR, 10.60 (1H, s) MS 447 (M-H) Example 435 (2S) -N-Hydroxy-2- 3- (benzyloxycarbonylamino) acetylainino)phenyl}-2-thienyl] 5,6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (150 ing) NMR (DMSO-d 6 1.75-2.06 (4H, in), 2.38-2.47 (1H, mn), 2.96-3.27 (4H, mn), 3.40-3.55 (1H, in), 3.83 d, 5.06 (2H, 7.22 (1H, d, J=4.OHz), 7.29-7.40 (8H, mn), 7.45-7.50 (1H, mn), 7.58 (1H, t, J=6.5Hz), 8.00 (1H, 8.84 (1H, br), 10.10 (1H, s) 10. 60 (1H, br) MS 570.1 (M-H) Example 436 (2S)-N-Hydroxy-2-[5-{3- (2-(4-iethoxybenzenesulfonylamino) acetylaiino) phenyl)}-2-thienyl 4, 5, 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (170 ing) NMR (DMSQ-d 6 1.73-2.05 (4H, mn), 2.35-2.46 (1H, mn), 2.95-3.26 (4H, mn), 3.49-3.53 (1H, in), 3.62 (2H, s), 3.77 7.08 (2H, d, J=8.OHz), 7.20 (1H, d, WO 00/40576 PCT/JPOO/00018 269 J=4 .0Hz) 7. 30-7 .38 (4H, in), 7 .75 (12H, di, J=8. OHz) 7 .8 4 (1H, s) 8 .8 4 (1H, br) 10. 02 (1H,

S)

MS 606.2 (M-H) Example 437 (2S) -N-Hyciroxy-2- ('ethylaiinocarbonylmethylaminocarbonyl amino) phenyl) -2-thienyl]1 4, 5, 6-tetrahyciro-2Hthiopyran-2-acetamide 1, 1-dioxide (25 mng) NMR (DMSO-d 6 6) 1. 72-2. 08 (4H, mn), 2. 36-2. 45 (1H, in), 2.61 (3H, d, J=4 .5Hz) 2. 95-3. 25 (4H, in), 3.42- 3. 50 (1H, in), 3. 70 (2H, di, J=6. 5Hz) 6. 45 (1H, t, 7 .17-7. 27 (4H, in), 7. 37 d, J=4 .0Hz) 7. 84 (4 H, s) 7. 88 (1lH, br) 8. 84 (1lH, br) 9.01 (1H, 10.63 (1H, s) MS 493.3 (M-H) Example 438 (2S) -N-Hydroxy-2- (2R) -2-arnino-3benzyloxypropionyl) amino) phenyl 2-.thienyl 3, 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide hydrochloride (125 mg) from 2 S)-N-(2-tetrahydropyranyloxy)- 2- 3- 2 -tert-butoxycarbonylamino-3benzyloxypropionyl) amino) phenyl. .2-.thienyl 1l3, 4, 5,6tetrahydro-2H-thiopyran-2-acetamiie 1, 1-dioxide NMR (DMSO-d 6 6) 1. 73-2. 06 (4H, in), 2. 36-2. 46 (1H, m), 2.95-3.26 (4H, mn), 3.40-3.55 (1H, in), 3.48 (2H, di, 4.26 (1H, br t, J=4.5Hz), 4.58 (2H, di, 7.23 (1H, di, J=4.OHz), 7.27-7.35 (6H, in), 7.40-7.44 (2H, in), 7.53 (1H, d, J=6.OHz), 7.94 (1H, 8.41 (2H, br), 8.83 10.62 (1H, s), 10.82 (1H, s) MS (ESI-) 558.3 (M-H) Example 439 WO 00/40576 PCT/JPOO/00018 270 (2S) -N-Hycroxy-2- (a llylami no) a cetyl amino) phenyl)}-2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1, 1-dioxide (70 mg) NMR (DMSQ.-d 6 8) 1. 75-2. 06 (4H, in), 2. 36-2. 45 (1H, m) 2. 96-3. 27 (4H, in), 3. 40- 3. 50 (1H, in), 3. 69 (2H, d, J=6. 0Hz) 3. 93 (2H, s) 5.-42-5. 54 mn), 5. 84- 5.98 (1H, in), 7.22 (1H, di, J=4.0Hz), 7.38-7.45 (3H, in), 7.48-7.52 (1H, in), 7.95 (1H, 8.85 (1H, br), 10.63 10.77 (1H, s) MS 476.1 (M-H) Example 440 (2S) -N-Hydroxy-2- 5-1{3- (2 -ethoxyethyl amino) acetylamino)phenyl-2-thienyl]-3,4, 5,6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (45 ing) NMR (DMSO-d 6 1.14 (3H, t, J=7.OHz), 1.74-2.06 (4H, in), 2.35-2.45 (1H1, in), 2.93-3.26 (4H1, mn), 3.41- 3.47 (1H1, in), 3.57 (2H, td, J=7.0, 7.0Hz), 3.55 (2H, t, J=4.5Hz), 3.65 (2H, 7.22 (1H, di, J=4.0Hz), 7.38-7.44 (3H, mn), 7.50-7.54 (1H, mn), 7.98 (1H, 8.84 (1H1, 10.33 (1H, br), 10.62 (1H, s) MS 508.2 (M-H) Example 441 (2S) -N-Hydroxy-2 (2 -pent ylamino) acetylanino) phenyl -2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (55 mg) NMR (DMSO-d 6 0.90 (3H, t, J=4.5Hz), 1.24-1.34 (4H, in), 1.63 (2H, br), 1.73-2.05 (4H, mn), 2.37-2.46 (1H, mn), 2.92-3.28 (6H, in), 3.43-3.53 (1H, in), 3.92 (21H, 7.22 (1H, d, J=4.OHz), 7.38-7.44 (3H, in), 7.50-7.54 (1H, in), 7.96 (1H1, 8.84 (2H, br 10.64 (1H, 10.75 (1H1, s) MS 508.1 (M+H) 271 Example 442 (2S) -N-Hydroxy-2- (3-isobutyrylaminophenyl) -2thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (250 mg) NMR (DMSO-d 6 1 1.11 (6H, d, J=7.OHz), 1.70-2.08 (4H, mn), 2.35-2.45 (1H, mn), 2.55-2.64 (1H, in), 2.95- 3. 54 (5H, mn), 7. 20 (1H, d, J=4. OHz) 7. 34-7.-35 (2H, in), 7.40 (1H, d, J=4.OHz), 7.46-7.51 (1H, in), 8.01 (1H, 8.84 (1H, s),.9.94 (1H, 10.60 (1H, s) MS (ESI-) :449 (M-H) Example 443 (2S) -N-Hydroxy-2- 3- (2-benzylamino) acetylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (55 ing) NMR (DMSO-d 6 1. 74-2. 06 (4H, in), 2. 35-2. 45 m), 2.95-3.28 (4H, in), 3.40-3.50 (3H, mn), 3.89 (1H, s), 4.24 (1H, 7.22 (1H, d, J=4.OHz), 7.36-7.55 (9H, mn), 7.92 (1H, 8.84 (1H, 10.62 (1H, s), 10.68 (1H, s) MS 528.1 (M-H) The following compounds were obtained in a similar manner to that of Example 408.

Example 444* (2S)-N-Hydroxy-2-(5-{3-( ((2S)-2-amino-3benzyloxypropionyl) amino)phenyl}-2-thienylj 6-' tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (40 ing) from L-Boc-Ser (bzl) -OH NMR (DMSO-d 6 1.73-2.06 (4H, in), 2.36-2.46 (1H, in), *6, 2.95-3.26 (4H, in), 3.40-3.55 (1H, mn), 3.48 (2H, d, 4.26 (1H, br t, J=4.5Hz), 4.58 (2H, d, J=5. OHz) 7. 23 (1H, d, J=4 .0Hz) 7 .27-7. 35 (6H, in), WO 00/40576 PCT/JPOO/00018 272 7 .40-7 .44 (2H, in), 7 .53 (1IH, d, J=6.0OHz) 7 .94 (1H, s) 8 .41 (2H, br) 8 .83 (1H, s) 10. 62 (1H, s) 10.82 (1H, s) MS 558.3 (M+H) Example 445 (2S) -N-Hydroxy-2- [5-13- (2S) -2-pyrrolidinylcarbonylamino) phenyl -2-th-ienyl]1 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (40 mng) from L-Boc-Pro-OH NMR (DMS0-cl 6 1.84-2.05 (7H, in), 2.35-2.45 (2H, mn), 2.95-3.30 (4H, in), 3.44-3.53 (3H, in), 4.35 (1H, br), 7.22 (1H, d, J=4.OHz), 7.39-7.50 (4H, in), 7.96 8.72 (1H, br), 8.83 (1H, 9.27 (1H, br) MS 468.3 (M+H) Example 446 (2S)-N-Hydroxy-2-[5-{3-(( (2S)-2--aiino-3cyclohexylpropionyl) amino) phenyl-2-thienyl] 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (50 mng) from L-Boc-CHA-OH NMR (DMSO-d 6 0.87-0.98 (2H, mn), 1.10-1.25 (4H, in), 1.40 (1H, br), 1.60-1.77 (6H, in), 1.85-2.06 (4H, in), 2.35-2.47 (1H, mn), 2.95-3.27 (4H, mn), 3.44- 3.53 (1H, mn), 3.96 (1H, br), 7.22 (1H, d, 7.40-7.48 (3H, in), 7.60 (1H, d, J=7.OHz), 7.90 (1H, 8.23 (2H, br), 8.84 (1H, 10.55 (1H, s), 10.60 (1H, s) MS 534.8 (M+H) Example 447 (2S)-N-Hydroxy-2-[5-{3-(C(2-amino-2-methylpropionyl)aiino) phenyl)-2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (20 ing) from L-Boc-AiB-OH NMR (DMSO-d 6 1.62 1.74-2.06 in), WO 00/40576 PCT/JPOO/00018 273 2. 35-2 .44 (1H, in), 2 .95-3. 27 (4H, in), 3. 37-3. 53 (1H, in), 7. 22 (1H, d, J=4 .OHz) 7. 38-7. 48 (3H, m) 7. 60 (1H, d, J=7. 5Hz) 7 .92 (1H, s) 8. 24 (2H, br) 8. 83 (1H, s) MS (ESI+) 466.3 (M+H) Example 448 (2S) -N--Hycroxy-2- 5- j 3- (2R) -2-methoxypropionyl) amino) phenyl -2-thienyll] 4, 5, 6-tetrahydro--2H-thiopyran-2acetamide 1, 1-dioxide (30 mng) NMR (DMSO-d 6 6) 1. 32 (3H, d, J=6. OHz) 1. 73-2. 06 (4H, mn), 2.36-2.43 in), 2.95-3.26 (4H, mn), 3.34 (3H, 3.45-3.54 (1H, in), 3.87 (1H, q, J=6.0Hz), 7.20 (1H, d, J=4.OHz), 7.32-7.35 (2H, in), 7.40 (1H, d, J=4.0Hz), 7.62 (1H, d, J=6.5Hz), 8.60 (1H, s), 9. 93 (1H, s) 10. 60 (1H, s) MS 465.2 (M-H) Example 449 (2S) -N-Hydroxy-2- 3-C -2-amino-4carboxybutyryl) amino) phenyl}I-2-thienyl 4, 5, 6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (33 ing) from L-Boc-Glu (tBu) -OH NMR (DMSO-d 6 1 1.74-2. 25 (6H, in), 2. 37-2. 46 (1H, in), 2. 95-3. 26 (4H, in), 3. 45-3. 62 (1H, in), 3. 95-4. 04 (3H, mn), 7.23 (1H, d, J=4.OHz), 7.40-7.45 (3H, in), 7.52 (1H, d, J=7.OHz), 7.90 (1H, 8.28 (2H, br), 8.84 (1H, br) MS 510.7 (M+H) Example 450 2 S) -N-Hydroxy-2- [5-13- (benzoylamino) acetylamino) phenyl}J-2-thienyl 1 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (42 ing) NMR (DMSO-d 6 1.72-2.04 (4H, in), 2.36-2.47 (1H, in), WO 00/40576 PCT/JPOO/00018 274 2. 95-3. 25 (4H, mn), 3 .43-3. 53 (1H, mn), 4. 09 (2H, d, 7. 20 (1H, d, J=4 .OHz) 7. 36-7. 39 (2H, mn), 7. 42 (1H, d, J=4 .OHz) 7 .47-7. 57 (4H, mn), 7. 92 (2H, d, J=7.5Hz), 8.30 (1H, 8.88 (1H, t, J=6.OHz), 10.20 (1H, 10.60 (1H, s) MS 541.3 (M-H) Example 451 (2S) -N-Hydroxy-2- (ethylamino)acetylamino) phenyl}-2-thienyl]-3,4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (60 ing) from 2-(N-ethyl-N-tertbutoxycarbonylamino) acetic acid NMR (DMSO-d 6 8) 1. 22 (3H, t, J=7. OHz) 1. 74 06 (4 H, in), 2.35-2.45 (1H, in), 2.95-3.27 (6H, in), 3.51- 3.57 (1H, in), 3.96 t, J=5.OHz), 7.22 (1H, d, J=4.OHz), 7.42-7.46 (3H, mn), 7.48-7.51 (1H, mn), 7. 93 (1H, s) 8. 87 br) 10. 60 (1H, s) 10. 54 (1H, s) MS 466.2 (M+H) Example 452 (2S) -N-Hydroxy-2-[f5- (aminobutyryl) amino) phenyl }-2-thienyl] 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (105 ing) from L-Boc-Abu-OH NMR (DMSO-d 6 8) 0. 98 (3H, t, J= 6.5H 1. 7 4-2. 06 (4 H, in), 1.89 (2H, qt, J=6.5, 6.5Hz), 2.36-2.45 (1H, in), 2.96-3.27 (4H, in), 3.44-3.54 (1H, in), 3.90 (1H, br), 7.22 (1H, d, J=4.OHz), 7.39-7.46 (3H, in), 7.52-7.56 (1H, in), 7.91 (1H, 8.32 (2H, br), 8.85 (1H, 10.56 (1H, 10.60 (1H, s) MS 467.2 (M+H) Example 453 (2S) -N-Hydroxy-2- 3- (piperizinocarbonyloxy) acetylamino)phenyl)-2-thienyl]-3, 4,5, 6-tetrahydro-2H- WO 00/40576 PCT/JPOO/00018 275 thiopyran-2-acetamide 1, 1-dioxide (47 mg) NMR (DMSO-d 6 48-1. 58 (6H, mn), 1. 75-2.05 (4H, m) 2.37-2.46 (1H, in), 2.95-3.26 (4H, mn), 3.46-3.55 in), 4.62 (2H, s) 7 .20 (1H, di, J=4.-OHz) 7. 35-7. 38 (3H, in), 7.62 (1H, d, J=4.0Hz), 8.00 (1H, 10.17 (1H, 10.60 (1H, s) MS 548.2 (M-H) Example 454 (2S)-N-Hydroxy-2-[5-{3- (2-(benzylaminocarbonyloxy)acetylamino) phenyl)} -2-thienyl 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1, 1-dioxide (55 mg) NMR (DMSO-d 6 8) 1 .73-2 .05 (4H, in), 2. 37-2. 46 (1H, in), 2. 94-3. 26 (4H, in), 3. 42-3. 53 (1H, in), 4. 22 (2H, d, J=5.OHz), 4.61 (2H, 7.20-7.48 (10H, in), 7.93- 7.97 (2H, mn), 8.84 (1H, br), 10.15 1 10.60 (1H, s) MS 570.1 (M-H) Example 455 2 S)-N-Hydroxy-2-[5-{3-(2-(3-methylphenoxy)acetylamino) phenyl 1-2-thienyl]1-3, 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1, 1-dioxide (30 mg) NMR (DMSO-d 6 1.73-2.06 (4H, in), 2.30 (3H, s), 2.37-2.47 (1H, mn), 2.95-3.26 (4H, in), 3.40-3.50 (1H, in), 4.70 (2H, 6.70-6.75 (3H, mn), 7.20- 7.22 (2H, in), 7.38-7.40 (2H, in), 7.43 (1H, di, 7.56 (1H, di, J=7.OHz), 8.03 (1H, s), 8. 84 (1H, s) 10. 17 (1H, s) 10. 60 (1H, s) MS 565.2 (M+H+C1) Example 456 (2S)-N-Hydroxy-2-I5-{3-(2-(3-pyridyloxy)acetylainino) phenyl) -2-thienyl 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,l1-dioxide (50 mg) WO 00/40576 PCT/JPOO/00018 276 NMR (DMSO-d 6 8) :1.72-2. 06 (4H, in), 2. 37-2. 48 (1H, in), 2. 96-3. 27 (4H, mn), 3. 40-3. 50 (1H, mn), 4 .90 (2H, s), 7. 20 (1H, d, J=4 .OHz) 7. 35-7. 42 (3H, mn), 7. 52- 7. 56 (2H, mn), 7. 64-7 .66 (1H, in), 8. 00 (1H, s), 8 .30 (1H, d, J=4. 5Hz) 8 .50 (1H, d, J=2.0OHz) 10.30 (1H, 10.60 (1H, s) MS 514.1 (M-H) Example 457 (2S)-N-Hydroxy-2-[5-{3-(2-(4-pyridyloxy)acetylanino)phenyl}-2-thienyl] 6-tetrahydro-2H-thiopyran-2acetarnide 1,1-dioxide (35 mg) NMR (DMSO-d 6 1. 72-2. 05 (4H, in), 2. 35-2. 44 (1H, m) 2. 95-3. 25 (4H, mn), 3. 42-3. 53 (1H, in), 5. 26 (2H, s) 7.07 (2H, d, J=7.OHz), 7.20 (1H, d, J=4.OHz), 7.40-7.42 (4H, in), 8.03 (1H, 8.41 (2H, d, J=7. 0Hz) MS 516.1 (M+H) Example 458 (2S) -N-Hydroxy-2- -2-amino-3- (4-pyridyl) propionyl)ainino)phenyll-2-thienyl]-3, 4,5,6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (160 ing) L-Boc4-PyAla-OH NMR (DMSO-d 6 1.72-2.06 (4H, in), 2.35-2.46 (1H, in), 2.96-3.39 (6H, mn), 3.44-3.55 (1H, mn), 4.30 (1H, br), 7.22 (1H, d, J=4.OHz), 7.42-7.48 (4H, mn), 7. 55 (1H, d, J=6. OHz) 7. 85 (1H, s) 8. 39 (2H, br) 8.70 (2H, J=5.5Hz), 10.60 (1H, 10.62 (1H,

S)

MS (ESIi): 529.2 Example 459 (2S)-N-Hydroxy-2-[5-13-(((2S)-2-anino-3phenyipropionyl) amino) phenyl }-2-thienyl] 6-tetrahydro- 2H-thiopyran-2-acetamide 1,1-dioxide (40 mg) from WO 00/40576 PCT/JPOO/00018 277 L-Boc-Phe-OH NMR (DMSO-d 6 74-2. 06 (4H, in), 2. 35-2. 44 (1H, in), 2.95-3.27 (6H, in), 3.43-3.53 (1H, in), 4.15 (1H, br), 7.22 (1H1, d, J=4.0Hz), 7.25-7.35 (5H, mn), 7.39-7.46 (4H, in), 7.80 (1H, 8.32 (2H, br), 8. 85 (1H, br) 10. 47 (1H, s) 10. 73 (1H, s) MS 528.3 (M+H) The following compounds were obtained in a similar manner to that of Example 130.

Example 460 (2S) (2-Tetrahydropyranyloxy) (2- (methanesulfonylamino) acetylarnino) phenyl) -2-thienyl] 3,4,5, 6-tetrahydro-2H-thiopyran-2-acetanide 1,1-dioxide mng) NMR (DMSO-d 6 1.46-1.72 (8H, mn), 1.87-1.99 (2H, mn), 2.06-2.24 (2H, mn), 2.81-2.92 (2H, in), 3.02 (3H, s), 3.05-3.21 (2H, mn), 3.28-3.52 (1H, mn), 3.68-3.80 (1H, in), 3.98-4.06 (2H, in), 4.53, 4.87 (1H, br s), 5.94-6.08 (1H, in), 7.06-7.21 (4H, mn), 7.42-7.52 (2H, in), 8.58, 8.59 (1Hi, br s) MS (ESI-) 598 (M-H) Example 461 (2S) (2-Tetrahydropyranyloxy) (3- (phenylacetylanino) phenyl) -2-thienyl] 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (132 ing) NMR (CDCl 3 1.30-1.73 (8H, mn), 1.84-1.97 (2H, in), 2.04-2.23 (2H, mn), 2.70-2.90 (2H, mn), 2.97-3.16 (2H, mn), 3.26-3.51 (1H, in), 3.63-3.73 (1H, in), 3.73 (2H, 4.52, 4.72 (iR, br 7.08-7.62 (12H, in), 8.68 (1H, br s) MS (ESI-) 580 (M-H) WO 00/40576 PCT/JPOO/00018 278 Example 462 (2S) 2 -Tetrahyclropyranyloxy) (3- (cycl opropaneca rbonyl amino) phenyl) -2-thienyl]1 4,5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (550 mg) NMR (DMSO-d 6 0.72-0.89 (4H, in), 1.32-1.64 (6H, in), 1. 67-2. 06 (5H, in), 2. 34 49 (1H, mn), 2. 87-3. in), 3.41-3.53 (1H, mn), 3.72-3.91 (1H, in), 4.44, 4.75 (1H, 7.16-7.26 (1H, in), 7.39-7.52 (4H, in), 8.02 (1H, s) MS 531 (N-H) Example 463 (2S) 2 -Tetrahydropyranyloxy) 5-{f 3- (propoxycarbonylamino) acetylamino) phenyl) -2-thienyl]1 4, 5,6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (93 ing) NMR (CDC1 3 6) 0. 93-0. 99 (3H, in), 1. 44 (2H, br) 1.65-1.75 (6H, in), 1.95 (2H, br), 2.04-2.26 (2H, in), 2.72-2.92 (2H, mn), 3.01-3.15 (4H, in), 3.28- 3.48 (1H, in), 3.70 (1Hi, br), 3.95-4.12 (4H, in), 4.53 (1/2H, 4.84 (1/2H, 5.54-5.64 7. 12-7.23 (4H, in), 7.50 (1H, br s) 7. 58 (1H, s) 8 .2 8 (1H, br) 8. 70-8.7 8 (1H, m) MS 606.1 (M-H) Example 464 (2S) (2-Tetrahydropyranyloxy) [5-1 3- (2- (cyclopentyloxyca rbonyl amino) acetylaino) phenyl l2-thienyl] 3 4 6 -tetrahydro-2H-thiopyran-2-acetanide 1,1I-dioxide (53 mg) NMR (CDCl 3 1.44 (4H, br), 1.60-1.74 (4H, in), 1.86-1.96 (6H, mn), 2.05-2.24 (2H, in), 2.70-2.89 (2H, in), 2.96-3.20 in), 3.29-3.52 m), 3.64-3.75 in), 3.94-4.02 in), 4.54 (1/2H], 4.83 5.16 br), 5.45-5.54 (1H, mn), 7.16-7.25 (3H, in), 7.51-7.60 (2H, mn), 8.30 (1H, WO 00/40576 PCT/JPOO/00018 279 br) MS 632.1 (M-H) The following compounds were obtained in a similar manner to that of Example 211.

Example 465 (2S) 2 -Tet-rahydropyranyloxy) (2oxopyrrolidinyl) acetylamino) phenyl) -2-thienyl]1-3, 4, 5,6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (520 mg) NMR (DMSO-d 6 6) 1. 32-1. 63 (6H, mn), 1. 68-2. 09 (6H, in), 2.28 (2H, t, J=7Hz), 2.35-2.48 in), 2.86-3.53 (6H, in), 3.46 (2H, t, J=7Hz), 3.22-3.40 (1H, in), 4.05 (2H, 4.44, 4.75 (1H, 7.16-7.25 (1H, in), 7.32-7.46 (4H, mn), 8.02 (1H, 10.20 (1H, s), 11.25 (1H, s) MS (ESI-) 588 (M-H) Example 466 2 2 -Tetrahydropyranyoxy)2[5(-( (3S)-N-tertbutoxycarbonyl-1, 2,3, 4 -tetrahydroisoquinoline-3carbonyl) amino) pheriyl) -2-thienyl] 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (135 ing) NMR (DMSO-d 6 1.18-2.06 (10H, in), 1.31 (9H, s), 2.34-2.47 (1H, in), 2.88-3.31 (7H, in), 3.38-3.54 (1H, mn), 3.72-3.88 (1H, mn), 4.36-4.85 (4H, in), 7.14-7.50 (9H, in), 7.88-8.00 (1H, in), 10.16 (1H, 11.24 (1H, s) MS 722 (M-H) Example 467 (2)N_(-erhdoyanyoy--5(-ooae2 carbonylamino)phenyl)-2thienylp.3,4, 5, 6-tetrahydro-2Hthiopyran-2-acetainide 1,1-dioxide (670 mng) NMR (DMSO-d 6 1.38-1.62 (6H, mn), 1.70-2.08 (7H, mn), WO 00/40576 PCT/JPOO/00018 280 2.14-2.78 (1H, in), 2.36-2.50 (1H, mn), 2.90-3.32 in), 3.4 0 53 in), 3. 74 90 (1H, dci, J=7Hz), 4.02 (1H, dci, J=7Hz), 4.42 (1H, dd, J=7Hz), 4.45, 4.75 (1H, s) 7.19-7.25 (1H, in), 7.31-7.44 (3H, in), 7 .65 (1H, d, J=8Hz) 8. 07 (1H, s) 9. 78 (1H, 11.25 (1H, s) MS (ESI-) :561 (M-H) Example 468 (2S) (2-Tetrahydropyranyloxy) (oxolane-3carbonylainino) phenyl) -2-t-hienyl] 4, 5, 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (700 mg) NMR (DMSO-d 6 1.33-1.63 (6H, in), 1.69-2.15 (4H, in), 2. 09 (2H, dd, J=8Hz) 2 .35-2. 48 (1H, in), 2. 86-3. 32 (4H, mn), 3. 39-3. 56 (1H, mn), 3. 65-3. 86 (4H, mn), 3. 88-4 .00 (1H, mn), 4. 45, 4 .75 (1H, s) 7. 18-7.25 (1H, in), 7. 30-7. 52 (4H, mn), 8. 02 (1H, s) 10. (1H, 11.24, 11.25 (1H, s) MS 561 (M-H) Example 469 (2S) (2-Tetrahydropyranyloxy) 3- (ethylaminocarbonylanino) acetylamino) phenyl -2-thienyl 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (4 .7 g) NMR (C~DC 3 8) 0. 85-0. 93 (3H, mn), 1. 45 (4H, br) 1. 55-1. 68 (2H, mn), 1. 92 (2H, br) 2.01-2.25 (2H, mn), 2.92-3.10 (7H, in), 3.26-3.75 (1H, in), 3.44- 3.54 (2H, in), 3.68-4.02 (2H, in), 4.30-4.40 (1H, in), 4.65 (1/2H, br), 4.92 (1/2H, br), 6.02 (1H, br), 7.07-7.26 (7H, mn), 7.54 (1/2H, 7.60 (1/2H, s), 9.27 (1/2H, 9.32 (1/2H, s) MS (ESI-) 591.2 (M-H) Example 470 (2S) (2-Tetrahydropyranyloxy) (3- WO 00/40576 PCT/JPOO/00018 281 is oval erylaininophenyl) -2-thienyll-3, 4, 5, 6-tetrahydro-2Hthiopyran-2-acetainide 1, 1-dioxide (200 mg) NMR (CDC1 3 04 (6R, d, J=6.0OHz) 1. 16 (2H, d, 1.45 (2H, br), 1.65-1.75 (2H, in), 1.92- 1.95 (2H, in), 2.07-2.30 (2H, in), 2.28 (2H, br), 2.30-2.40 (1H, in), 2.71-2.90 (2H, mn), 3.04-3.15 (4H, mn), 3.30-3.50 in), 3.64-3.75 (1H, in), 4.52 (1/2H, br s) 4 .82 (1/2H, br s) 7.20-7.30 (3H, in), 7.39-7.46 (1H, in), 7.50-7.57 (2H, in), 7.62-7.66 (1H, in), 8.37-8.47 (1H, mn) MS 547.1 (M-H) Example 471 (2S) (2-Tetrahydropyranyloxy) [5-13- (2- (methoxyacetylamino)acetylamino)phenyl}-2-thienyl]- 3 4 5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (195 ing) NMR (C~DC 3 1.45 (2H, br), 1.67 (4H, br), 1.97 (2H, br), 2.07-2.24 (2H, mn), 2.80-2.87 (2H, mn), 3.01- 3.06 (1H, in), 3.11-3.20 (3H, mn), 3.30-3.44 (1H, in), 3.46 (3H, 3.68-3.78 (1H, in), 4.04 (2H, 4.09-4.13 (1H, mn), 4.25-4.32 (1H, in), 4.53 (1/2H, 4.84 (1/2H, 7.08-7.24 (3H, in), 7.42 (2H, br), 7.48-7.54 (2H, mn), 8.56 (1H, br), 9.08 (1/2H, 9.18 (1/2H, br s) MS (ESI+) 591. 1 (M+H) Example 472 (2S) (2-Tetrahydropyranyloxy) 3- (3pyridylcarbonylanino) acetylarnino) phenyll -2-thienyl] 4, 5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (90 ing) NMR (C~DC 3 8) 1.36 (2H, br) 1. 65 (4H, br) 1. 94 (2H, br), 2.06-2.23 (2H, mn), 2.80-3.20 (7H, in), 3.55- 3. 72 (1H, mn), 4 .36 (1/2H, br s) 4 .37-4. 65 (2H, mn), 4.86 (1/2H, 7.13-7.30 (5H, in), 7.43-7.49 (1H, in), 7.54 (1H, br 7.75-7.81 (1H, in), 8.23 (1H, WO 00/40576 PCT/JPOO/00018 282 d, J=7 .5Hz) 8.76 (1H, br) 9.27 (1/2H, s) 9.31- 9. 34 (1H, in), 9. 40 (1/2H, s) MS (ESI+) 625.1 (M+H) Example 473 (2S) (2-Tetrahydropyranyloxy) 3- (met hoxymethylaninocarbonylafi no) phelyl}-2-thielyl] 3 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (100 mg) was obtained in a similar manner to that of Example 348.

NMR (CDCl 3 6) 1.25 (2H, br) 1. 43 (2H, br) 1. 64 (2H, br) 1. 93 br) 2. 05-2. 22 (2H, in), 2. 70-2. 88 (2H, in), 3.00-3.13 (4H, in), 3.37 (3H, 3.45- 3.52 (4H, in), 4.55 (1/2H, br), 4.81 (1/2H, br), 5.40-5.49 (1H, mn), 7.08-7.20 (6H, in), 7.27-7.40 (1H, in), 8.91 (1/2H, br), 8.98 (1/2H, br) MS (ESI-) 567.1 (M-H+NH 3 Example 474 (2S) (2-Tetrahydropyranyloxy) 5- 3- (3pyridylmethylamino)acetylamino)phenyl}-2-thienylV- 3 4 5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (100 ing) was obtained in a similar manner to that of Example 249.

NMR (CDCl 3 6) 1.42 (2H, br) 1.63-1.68 (4H, in), 1.95 (2H, br) 2. 07-2. 23 (2H, in), 2. 68-2. 95 (2H, in), 3.08 (2H, br 3.13 (2H, br), 3.27-3.44 (1H, in), 3. 46 (2H, s) 3. 62-3.70 (1H, in), 3. 90 (2H, s) 4. 52 (1/2H, br) 4 .82 (1/2H, br) 7. 24-7. 34 (6H, in), 7. 53-7. 57 (1H, in), 7. 65-7.70 (2H, mn), 8. 57 (1H, d, Jh5.OHz), 8.62 (1/2H, br), 8.65 (1H, 8.90 (1/2H, 9.17 (1H, d, J=6.OHz) MS (ESI+) 613.2 (M+H) Example 475 (2S) (2-Tetrahydropyranyloxy) [5-13- (tertbutylamino)acetylainino)phenyl}-2-thienyl]-3,4,5, 6 WO 00/40576 PCT/JPOO/00018 283 tetrahydro-2H-thiopyran-2-acetanide 1,1I-dioxide (95 mg) was obtained in a similar manner to that of Example 249.

NMR (CDCl 3 8) 1. 17 (9H, s) 1. 46 (2H, br) 1. 65-1. (4H, in), 1. 96 (2H, br) 2. 09-2.23 (2H, in), 2. 64- 2.86 (2H, in), 3.06 (2H, br 3.10-3.15 (2H, in), 3.36 (2H, br 3.43-3.70 (2H, in), 4.53 (1/2H, br), 4 .80 (1/2H, br) 7. 22-7 .34 (5H, mn), 7. 56-7. (1H, in), 7.78 (1H, 9.53 (1H, s) MS 593.6 (M-H+NH 3 The following compounds were obtained in a similar manner to that of Example 54.

Example 476 2 S) -N-Hydroxy-2- (N-methanesulf onylamino) acetylamino) phenyl) -2-thienyl] 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1, 1-dioxide (32 mg) NMR (DMSO- d 6 6) 1. 72 08 (4 H, mn), 2.3 3 48 (1lH, in), 2.92-3.56 (7H, in), 3.00 (3H, 3.87 (1H, d, J=7Hz) 7.21 (1H, d, J=3Hz), 7.34-7.52 (4H, i) 7.96 8.84 (iR, s) MS 514 (M-H) Example 477 2 S) -N-Hydroxy-2- 3 -phenylacetylamino) phenyl) -2thienyl]-3,4, 5, 6 -tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide (92 ing) NMR (DMSO-d 6 1.67-2.08 (4H, in), 2.32-2.51 (1H, mn), 2.89-3.54 (5H, in), 3.66 (2H, 7.17-7.53 (11H, in), 8. 00 (1H, s) 10. 30 (1H, s) 10. 60 (1H, s) MS 497 (M-H) Example 478 (2S) -N-Hydroxy-2- 2 -oxopyrrolidinyl) acetylamino) phenyl) -2thienyl 4, -5, 6 -tetrahydro-2H- WO 00/40576 PCT/JPOO/00018 284 thiopyran-2-acetamide 1, 1-dioxide (420 mg) NMR (DMSO-d 6 5) 1. 68-2. 12 (6H, mn), 2.19-2.48 (3H, in), 2. 90-3. 61 (7H, in), 4 .06 (2H, s) 7. 20 (1H, d, J=3Hz) 7. 31-7. 52 (5H, in), 8. 02 (1H, s) 10. 23 (1H, s) 10. 62 (1H, s) MS (ESI-) 504 (N-H) Example 479 (2S) -N-Hydroxy-2- 2, 3,4-tetrahydroisolquinoline-3-carbonyl) amino) phenyl) -2-thienyl 4, 5, 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide hydrochloride (88 mg) from (2S)-N-(2-tetrahydropyrariyloxy-2- 3 -(((3S)-N-tert-butoxycarbonyl-1,2,3,4tetrahydroisoquinoline-3-carbonyl) amino) phenyl) -2-thienyl] 3, 4, 5, 6-tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide NMR (DMSO-d 6 6) 1. 66-2.14 (4H, mn), 2. 32-2. 48 (1H, m) 2.86-3.92 (7H, in), 4.26-4.51 (3H, in), 7.12-7.52 (8H, in), 7.56-7.68 (1H, in), 8.03 (1H, 9.55 (1H, br s) 9. 96 (1H, br s) 10. 67 (1H, s) 11. 22' (1H,

S)

MS (ESI+) 540 (M+H) Example 480 (2S) -N-Hydroxy-2- 5- (cyc 1opropanecarbonyl amino) phenyl) -2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (410 ing) NMR (DMSO-d 6 8) 0. 70-0. 90 (4H, in), 1. 66-2. 10 (5H, in), 2. 34-2. 49 (1H, in), 3. 42-3. 55 (1H, in), 7. 21 (1H, d, J=3Hz) 7. 28-7. 39 (2H, mn), 7 .40 (1H, d, J=3Hz) 7.42-7.52 (1H, mn), 8.01 (1H, 10.33 (1H, s), 10.61 (1H, s) MS (ESI-) 447 (N-H) Example 481 (2S) -N-Hydroxy-2- 5- (oxo lane -2 -carbonyl amino) WO 00/40576 PCT/JPOO/00018 285 pheriyl) -2-thienyl] 6 -tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (340 mng) NMR (DMSO-d 6 6) 1. 7 1-2. 07 (71-H, mn), 2. 14 27 (1 H, in), 2.93-3.27 (4H, mn), 3.40-3.55 (1H, mn), 3.84 (1H, dd, J=7Hz), 4.00 (1H, dd, J=7Hz), 4.41 (1H, d, J=7Hz), 7.21 (1H, d, J=3Hz), 7.32-7.44 (3H, in), 7.65 (1H, d, J=8Hz) 8. 07 (1H, s) 8. 85 (1H, s) 9. 78 (1H, 10.60 (1H, s) MS 477 CM-H) Example 482 (2S) -N-Hydroxy-2- (oxolane-3-carbonylamino) phenyl) -2-thienyl]-3, 4,5, G-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (541 mng) NMR (DMSO-d 6 1.68-2.20 (4H, in), 2.09 (2H, dd, J=8Hz), 2.24-2.49 (1H, in), 2.92-3.31 (4H, mn), 3.43-3.54 (1H, mn), 3.65-3.76 (4H, in), 3.95 (1H, t, J=8Hz), 7.21 (1H, d, J=3Hz), 7.30-7.54 (4H, mn), 8.02 (1H, 10.17 (1H, 10.61 (1H, s) MS 477 (M-H) Example 483 2 S)-N-Hydroxy-2-[5-{3-(2-(ethyaninocarbonylanino)acetylainino)phenyl}-2-thienyl]-3, 4,5, 6-tetrahydro-2Hthiopyran-2-acetanide 1',1-dioxide (3.0 ing) NMR (DMSO-d 6 1.00 (3H, t, J=7.5Hz), 1.73-2.05 (4H, mn), 2.38-2.46 (1H, mn), 2.95-3.25 (6H, in), 3.43- 3.53 (1H, mn), 3.83 (2H, d, J=6.OHz), 6.10-6.18 (2H, mn), 7.20 (1H, d, J=4.0Hz), 7.35-7.37 (2H, mn), 7.40 (1H, d, J=4.OHz), 7.46-7.50 in), 7.97 (1H, s), 8.84 (1H, s) MS 507.2 (M-H) Example 484 (2S)-N-H-ydroxy-2-[5- 3 -isovalerylaminophenyl) -2- WO 00/40576 PCT/JPOO/00018 286 thienyl] G-tetrahydro-2H-thiopyran-2-acetamicie 1, 1dioxide (120 mg) NMR (DMSO-d 6 0.95 (6H, di, J=7.5Hz), 1.74-2.15 in), 2.20 (2H, di, J=7.OHz), 2.38-2.45 (1H, mn), 2.95-3.26 (4H, in), 3.40-3.53 (1H, in), 7.20 (1H, cd, J=4.OHz), 7.32-7.37 (2H, mn), 7.46-7.50 (1H, mn), 8.00 (1H, 9.97 (1H, 10.60 (1H, s) MS 46-3.0 (M-H) Example 485 (2S) -N-Hycroxy-2- 5- (methoxymethylaminocarbonylamnino) phenyl) -2-thienyl] 4, 5, 6-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (70 mng).

NMR (DMSO-d 6 1.73-2.04 (4H, in), 2.35-2.45 (1H, in), 2.95-3.28 (6H, mn), 3.26 (3H, 3.37-3.42 (1H, in), 6.24 (1H, t, J=7.OHz), 7.16-7.27 (4H, mn), 7.37 (1H, di, J=4.OHz), 7.83 8.67 (1H, s) MS 466.4 (M-H) Example 486 (2S) -N-Hydroxy-2- 3- (3-pyridylmethylamino) acetylamino)phenyl-2-thienyll 6-tetrahydro-2Hthiopyran-2-acetaiie l,l-dioxide (60 mg) NMR (DMS0-cl 6 1.72-2.06 (4H, in), 2.35-2.45 (1H, mn), 2.97-3.28 (4H. in), 3.42-3.50 (1H, in), 3.98 (2H, br), 4.35 (2H, br), 7.22 (1H, di, J=4.OHz), 7.38- 7.43 (2H, mn), 7.48-7.52 (1H, in), 7.68-7.73 (1H, mn), 7.93 (1H, s) 8. 23 (1H, di, J=7. OHz) 8. 74 (1H, di, J=6.OHz), 8.85 9.68 (1H, br) MS 527.1 (M-H) Example 487 (2S) -N-Hydroxy-2- 5- f(3- (propoxycarbonylamino) acetylamino) phenyl -2-thienyl 4 5, 6 -tetrahydro-2Hthiopyran-2-acetamiie 1, 1-dioxide (70 mg) WO 00/40576 PCT/JPOO/00018 287 NMR (DMSO-d 6 0.-91 (3H, t, J=7. OHZ) 1.-58 (2H, qt, 7.0Hz), 1.73-2.05 (4H, in), 2.37-2.48 (1H, in), 2. 94 27 (4H, in), 3. 44-3. 53 (1H, nm), 3. 79 (2H, di, J=6.OHz), 3.93 (2H, t, J=7.OHz), 7.21 (1H, di, J=4.OHz), 7.35-7.42 (4H, mn), 7.45-7.48 (1H, mn), 7.97 (1H, 8.84 (1H, 10.08 (1H, 10.61 (1H, s) MS 522.1 (M-H) Example 488 (2S) -N-Hydroxy-2- 3- (cyclopentyloxycarbonylamino) acetylamino)phenyl}-2-thienyl]-3, 4,5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-cijoxide (30 mng) NMR (DMSO-c1 6 6) 1.50-1.70 (6H, mn), 1. 75-2. 05 (6H, in), 2.37-2.48 (1H, in), 2.95-3.25 (4H, in), 3.43-3.53 (1H, in), 3.77 (2H, d, J=5.OHz), 4.97 (1H, br), 7.20 (1H, di, J=4.OHz), 7.30 (1H, t, J=7.OHz), 7.35-7.38 (2H, in), 7.41 (1H, d, J=4.OHz), 7.45- 7.48 1 in), 7.98 (1H, 8.83 (lH, br), 10.07 (1H, 10.60 br) MS 548.1 (M-H) Example 489 (2S) -N-Hydroxy-2- (3-(2-(iethoxyacetylainino) phenyl 1- 2-thienyl]-3, 4 5 6 -tetrahyciro-2H-thiopyran-2-acetamiie 1,1dioxide (70 mng) NMR (DMSO-d 6 8) 1.74 05 (4H, in), 2. 36-2. 48 (1H, in), 2.95-3.26 (4H, in), 3.37 (3H, 3.43-3.54 (1H, mn), 3.39 (2H, s) 3. 45 (2H, di, J=6. OHz) 7. 20 (1H, di, J=4.OHz), 7 .36-7 .40 (2H, in), 7. 42 (1H, di, J=4 .OHz) 7.43-7.48 (1H, in), 7.94 8.05 (1H, t, J=6.OHz), 8.84 (1H, 10.'13 (1H, 10.60 (1H,

S)

MS 508.1 (M-H) WO 00/40576 PCT/JPOO/0001 8 288 Example 490 (2S) -N-Hydroxy-2- [5-1 3- (tert -but ylami no) a cetyl amino) phenylI 2-thienyl 1 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1, 1-dioxide (50 mg) NMR (DMSO-d 6 5) 1.32 (9H, s) 1. 72-2. 06 (4H, in), 2.35-2.4 6 (1H, mn), 2 .96-3.28 (4H, mn), 3. 38-3. 52 (1H, mn), 3. 96 t, J=7. OHz) 7.22 d, J=4.OHz), 7.41-7.44 (3H, mn), 7.51-7.54 in), 7.97 (1H, 8.84 (1H, br), 8.95-8.98 (2H, br) MS 494.1 (M+H) Example 491 (2S) -N-Hydroxy-2- (3-pyridylcarbonylamino) a cetyl amino) phenyl}1-2 thienyl] 3, 4,5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (60 ing) NMR (DMSO-d 6 1.72-2.04 (4H, in), 2.37-2.45 (11-, in), 2.95-3.25 (4H, mn), 3.40-3.52 (1H, in), 4.00- 4.06 br), 4.13 (2H, d, J=7.OHz), 7.20 (1H, d, 7.32-7.39 (2H, mn), 7.42 (1H, d, 7.46-7.50 (1H, in), 7.59-7.64 (1H, in), 8.02 (1H1, s), 8.30-8.33 (1H, in), 8.77 (1H, d, J=6.OHz), 9.10 (1H, 9.15 (1H, t, MS 527.3 CM-H) Example 492 (2S) -N-Hydroxy-2- 3 -dirnethylbutyryl amino) phenyl) -2-thienyl] 4, 5, G-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (160 mg) was obtained from 3,3diinethylbutyric acid in a similar manner to that of Example 408.

NMR (DMSO-d 6 1.03 (9H, 1.66-2.10 (4H, in), 2.21 (2H, 2.34-2.48 (1H, in), 2.92-3.29 (4H, mn), 3.42-3.56 (1H, in), 7.20 (1H, d, J=3Hz), 7.28-7.38 (2H, in), 7.40 (1H, d, J=3Hz), 7.45-7.54 (iH, in), 7.99 (1H, 9.93 (1H, 10.61 (1H, s) WO 00/40576 PCT/JPOO/00018 289 MS 477 (M-H) Example 493 (2S) -N-Hydroxy-2- (4-ethoxyphenyl) -2-thienyl] 3,4,5, G-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide mg) was obtained in a similar manner to that of Example 168.

NMR (DMSO-d 6 1.35 t, J=7.0Hz), 1.73-2.04 (4H-, in), 2.34-2.44 (1H, mn), 2.95-3.25 mn), 3.62- 3.68 (1H, in), 4.06 (2H, q, J=7.OHz), 6.97 (2H, d, J=7.5Hz), 7.16 (1H, d, J=4.OHz), 7.33 (1H, d, 7.56 (1H, d, MS 410.2 (M+H) The following compounds were obtained in a similar manner to that of Example 130.

Example 494 (2S) (2-Tetrahydropyranyloxy) (3- (cyclobutylcarbonylainino)phenyl)-2-thienyl]-3,4, 5,6tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (340 mng) NMR (DMSO-d 6 1.37-1.65 (6H, in), 1.70-2.30 (10H, in), 2.37-2.46 (1H, in), 2.90-3.55 (7H, mn), 3.75-3.89 (1H, in), 4.44, 4.75 (1H, 7.19-7.22 in), 7.34-7.40 (3H, in), 7.45-7.51 (1H, in), 8.03 (1H, s), 9.83 (1H, s) Example 495 (2S) (2-Tetrahydropyranyloxy) -2-ES- (3- (isobutyrylaminophenyl) -2-thienyl] 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (330 ing) NMR (DMSO-d 6 1.11 (6H, d, J=7.OHz), 1.36-1.64 (6H, mn), 1.70-2.05 (4H, mn), 2.35-2.45 (1H, in), 2.55- 2.64 (1H, in), 2.90-3.54 (6H, in), 3.75-3.90 (1H, in), 4.45, 4.75 (1H, 7.20-7.23 (1H, in), 7.33-7.41 (3H, in), 7.45-7.51 (1H, in), 8.03 (1H, s) WO 00/40576 PCT/JPOO/00018 290 Example 496 (2S) (2-Tetrahydropyranyloxy) 2diiethylpropionylaino) phenylI 2thienyl34, 5 6tetrahydro-2H-thiopyran-2-acetamide 1, 1-dioxide (267 ing) NMR (DMSO-d 6 6) 1.24 s) 1. 36-1. 64 (6H, m) 1. 69-2. 09 (4H, in), 2.36-2.53 (1H, in), 2. 88-3.29 (4H, in), 3. 30-3. 51 (2H, in), 3. 74-3. 91 (1H, in), 4.44 (0.5H, 4.76 (0.5H, 7.19-7.24 (1H, in), 7.30-7.42 (3H, mn), 7.59-7.65 (1H, mn), 8.01 s), 9.30 (1H, s) MS (ESI-) 547 (N-H) Example 497 2 S)-N-(2-Tetrahydropyranyloxy)-2[5(3-((E)-2butenoylamino)phenyl]-2-thienyl] 6-tetrahydro-2Hthiopyran-2-acetanide 1,1-dioxide (160 mng) NMR (CDC1 3 1.37-1.76 (6H, mn), 1.86-2.02 (5H, in), 2.04-2.26 (2H, in), 2.68-2.94 (2H, in), 3.00-3.19 (4H, in), 3.30-3.51 (1H, in), 3.62-3.76 (1H, in), 4.55 (0.5H, 4.83 (0.5H, 6.00 (1H, dd, 15Hz), 6.94-7.09 (1H, mn), 7.13-7.33 (4H, in), 7.49-7.67 (3H, mn), 8.45-8.55 (1H, in) MS 531 (N-H) The following compounds were obtained in a similar manner to that of Example 201.

Example 498 WO 00/40576 PCT/JPOO/00018 291 Br 0" 0 '00 B s s N HC1 N-IS o .0 0 2 S) 2 -Tetrahydropyranyloxy)2 5(4pyridyl) 2thienyl]-3, 4,5, 6 -tetrahydro-2H-thiopyran-2acetanide 1,1dioxide (60 mng) NMR (ODC1 3 1.40-1.76 (6H, mn), 1.86-2.00 (2H, mn), 2.06-2.25 (2H, mn), 2.71-2.93 (2H, in), 3.00-3.19 (4H, mn), 3.25-3.55 (1H, mn), 3.60-3.799 (1H, mn), 4.50 (0.5H, 4.84 (0.5H, 7.16-7.35 (1H, in), 7.44-7.49 (3H, in), 8.21 (0.5H, 8.28 s), 8.59 (2H, d, J=8Hz) MS 451 (M+H) Example 499 (2S) (2-Tetrahydropyranyloxy) (4- (met hyl aiinocarbonylinethyl) phenyl] -2-thienyl] 4,5, 6tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide (67 mng) MS 519 (M-H) Example 500 (2S) 2 -Tetrahydropyranyloxy) (2- (methylaminocarbonyi) -5-benzofuranyl]I -2-thienyl]1 4, 5,6tetrahydro-2H-thiopyran-2-acetanide 1, 1-dioxide (283 ing) NMR (ODC1 3 1.38-1.76 mn), 1.88-2.02 mn), 2.04-2.25 (2H, mn), 2.65-2.93 (2H, mn), 3.01-3.18 WO 00/40576 PCT/JPOOOO0i 8 292 (71-H, in), 3. 26 51 (1 H, in), 3. 60-3. 74 (1 H, m), 4 .55 5H, s) 4 .83 (0 .5H, s) 6. 61-6. 71 (1H, in), 7. 21-7. 31 (2H, in), 7 .43-7. 50 (2H, in), 7. 60-7. 66 (1H, in), 7 .83-7. 88 (1H, mn), 8. 20 5H, s) 8. 27 5H, s) Example 501 (23) (2-Tetrahydropyranyloxy) (4methyithiophenyl) -2-thienyll] 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1, 1-dioxide (129 mng) was obtained in a similar manner to that of Example 89.

NMR (ODC1 3 6) 1. 38-1. 76 (6H, mn), 1. 86-2. 00 (2H, m) 2.05-2.24 (2H, mn), 2.51 (3H, 2.61-2.90 (2H, mn), 3.03-3.17 in), 3.26-3.50 (1H, in), 3.56-3.70 in), 4.52 (0.5H, 4.79 (0.5H, 7.20-7.36 (3H, in), 7.45-7.54 (2H, in), 7.62-7.68 (1H, mn), 7.98 (0.5H, 8.09-8.15 (0.5H, m) Example 502 2 S)-N-(2-Tetrahydropyranyloxy)2[5(4.

methanesulf onyl) phenyl ]-2-thienyl 4, 5, 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (57 ing) was obtained from (2S) 2 -tetrahydropyranyloxy) (4-iethyithiophenyl) -2thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetanide 1,1dioxide in a similar manner to that of Preparation 1-4).

NMR (00013, 1.40-1.59 (4H, in), 1.62-1.74 (2H, in), 1.88-2.02 (2H, in), 2.05-2.25. (2H, in), 2.76-2.88 (2H, rn), 3.04-3.20 (7H, mn), 3.40-3.54 (1H, in), 3.60-3.77 (1H, in), 4.54 (0.5H, 4.82 (0.5H, s), 7.26-7.35 (1H, in), 7.37-7.43 (1H, in), 7.73-7.80 (2H, in), 7.90-7.97 (2H, in), 8.14 (0.5H, 8.20 s) The following compounds were obtained in a similar manner to that of Example 54.

WO 00/40576 PCT/JPOO/00018 293 Example 503 (2S) -N-Hydroxy-2- 4 -methane sulfonyl) phenyl]1-2thienyl]-3,4,5, G-tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide (27 mg) NMR (DMSO-d 6 1.72-2.10 (4H, mn), 2.36-2.55 (1H, mn), 2.96-3.08 (2H, in), 3.12-3.36 in), 3.39-3.56 (1H, mn); 7.28 (1H, d, J=3.9Hz), 7.70 (1H, d, J=3.9Hz), 7.91 (2H, d, J=8Hz), 7.96 (2H, di, J=8Hz), 8.86 (1H, s) MS 442 (M-H) Example 504 (2S) -N-H-ydroxy-2- [I 5- 4 -methylaininocarbonylinethyl) phenyl]I-2-thienyl] 4, 5, 6 -tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide (25 mg) NMR (DMSO-d 6 1.70-2.06 (4H, in), 2.34-2.52 (1H, mn), 2.59 (3H, d, J=4.5Hz), 2.95-3.34 (4H, mn), 3.36- 3.54 O3H, mn), 7.20 (11H, di, J=3.9Hz), 7.29 (2H, d, J=8Hz), 7.43 (1H, di, J=3.9Hz), 7.56 (iH, d, J=8Hz), 7.94-8.02 (1H, mn), 8.85 (1H, s) MS (ESI-) 435 (M-H) Example 505 (2S) -N-Hydroxy-2- (4-pyridyl) -2-thienyll -3,4,5,6tetrahydro-2H-thiopyran-2acetaiie 1,1-dioxide (3.1 ing) MS 367 (M-H) Example 506 (2S) -N-Hydroxy-2- (met hyl aminoca rbonyl) benzofuranyl] -2-thienyl] G-tetrahydro-2H-thiopyran-2acetamide 1,1-dioxide hydrochloride (119 mg) NMR (DMSO-d 6 1.72-2.10 (4H, in), 2.36-2.56 (iH, in), 2.81 (3H, d, J=4.8Hz), 2.95-3.31 (4H, in), 3.40- 3.55 (1H, in), 7.22 (1H, di, J=3.9Hz), 7.49 (iH, di, WO 00/40576 PCT/JPOO/00018 294 J=3. 9Hz) 7. 53 (1H, s) 7. 69 (1H, di, J=8Hz) 7. (1H, d, J=8Hz) 8. 03 (1H, s) 8. 73 (1H, q, J=4.8Hz0, 8.86 (1H, br 10.60 (1H, br s) MS 461 (M-H) Example 507 (2S) (2-Tetrahydropyranyloxy) (methanesulfinyl)phenyl] -2-thienyl] 6-tetrahydro-2Hthiopyran-2-acetamide 1,1-dioxide (45 mg) was obtained from 2 S)-N-(2-tetrahydropyranyloxy)-2-[5-(4-methylthiophenyl)-2thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1dioxide in a similar manner to that of Preparation 1-4).

NMR (C~DC 3 1.38-1.76 (6H, in), 1.84-2.01 (2H, m),2.05-2.25 (2H, mn), 2.77 (3H, 2.77-2.88 (2H, m),3.00-3.18 (4H, in), 3.30-3.54 (1H, in), 3.64-3.79 (1H, in), 4.53 (0.5H, 4.83 (0.5H, 7.25-7.34 (2H, in), 7.65 (2H, di, J=8Hz), 7.70-7.78 (2H, in), 8.66 (0.5H, 8.71 (0.5H, s) MS (ESI-) 510 (M-H) Example 508 (2S) -N-Hydroxy-2- (methanesulfinyl)phenyl] -2thienyl] G-tetrahydro-2H-thiopyran-2-acetaie 1,1dioxide (11 mg) was obtained in a similar manner to that of Example 54.

NMR (DMSO-d 6 71-2. 10 (4H, in), 2. 35-2. 55 in), 2. 78 (3H, s) 2. 95-3. 08 (2H, in), 3. 11-3. 38 (2H, m) 3.41-3.55 (1H, in), 7.25 (1H, di, J=3.9Hz), 7.61 (1H, d, J=3.9Hz), 7.72 di, J=8Hz), 7.85 (2H, di, J=8Hz), 8.85 (1H, s) MS (ESI-) 426 (M-H) P:\OPERUgc\I905-(X spCc.doc-12/02/)3 294A Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form or suggestion that that prior art forms part of the common general knowledge in Australia.

It would be appreciated by a person skilled in the art the numerous variations and/or modifications may be made to the invention as shown the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

*e e 9*.

I

"2222 o Q ooo

Claims (12)

1. A compound of the formula: jA> Y Z R1-X-Ar-(CH 2 (CH 2 )n-R 2 (I) in which R 1 is CI-C 6 alkyl, optionally substituted heterocyclic group or optionally substituted C 6 -C 10 aryl, R 2 is carboxy, protected carboxy, hydroxyaminocarbonyl, tetrahydropyranyloxyaminocarbonyl, or phenyl (Ci-C 6 alkylaminocarbonyl, Ar is optionally substituted C 6 -Cio aryl or optionally substituted heterocyclic group, A is Ci-C 6 alkylene, X is oxa or a single bond, 20 Y is thia, sulfinyl or sulfonyl, Z is methylene, m and n are each an integer of 0 to 6, and l1m+n 6, and its salt, wherein the heterocyclic group of R 1 and Ar are selected from the group consisting of the following to (14), unsaturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, 0 unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms, S. unsaturated condensed 7- to 13-membered, P:\OPERJgc\I8')954-) spec.doc-12/2/)3 296 heterocyclic group containing 1 to 5 nitrogen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated condensed 7- to 13-membered, heterocyclic group containing 1 or 2 oxygen atoms, unsaturated condensed 7- to 13-membered, heterocyclic group containing 1 or 2 sulfur atoms, saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, (11) unsaturated condensed 7- to 13-membered, 20 heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, (12) unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, (13) saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, and (14) unsaturated condensed 7- to 13-membered, heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, and each of the above-mentioned heterocyclic group and w C6-Ci0 aryl group are optionally substituted by P:%OPERJgc\I895OX) spmcdoc-12/02A03 297 the group consisting of the following (Al) to (Al) halogen, (A2) Cl-C 6 alkyl, (A3) Cl-C 6 alkoxy, (A4) halo (Cl-C 6 alkyl, halo (Cl-C 6 alkoxy, (AM) C 2 -C 6 alkenyl, (A7) acyl, (A8) Cl-C 6 alkylthio, Cl-C 6 alkylsulfinyl, Cl-C6 alkylsulfonyl, (A9) C 6 -Cj 0 aryl, (AlO) halo (C 6 -C 10 aryl, (All) hydroxy, (A12) hydroxy (Cl-C 6 )alkyl, protected hydroxy (Cl- CO) alkyl, (A13) amino, (A14) carboxy, protected carboxy, (A16) nitro (C-C 6 alkenyl, Cl-C 6 alkylenedioxy, (A18) acylarnino, (A19) nitro, (C 6 -CIO) aryl (Cl-C 6 alkoxy, (A21) carbamoyl(C 2 -CO)alkenyl optionally N- substituted by the group consisting of Cl-C 6 alkyl, C 6 -Cj 0 aryl, Cl-C 6 alkoxy(C 6 -Cl)-aryl, :and halo (C 6 -Cl 0 aryl, (A22) Cl-CE alkylaminocarbonyloxy, (A23) Cl-C 6 alkanoyloxy, (A24) Cl-C 6 alkoxy(Cl-C 6 )alkanoyloxy, Cl-C 6 alkoxycarbonyloxy, P:\OPERUgc\1890)5-X spec.doc-10202/03 298 (A26) C2-C6 alkenoyloxy optionally substituted by heterocyclic group of the above to (14), (A27) C3-C6 cycloalkanecarbonyloxy, (A28) Ci-C6 alkoxy substituted by the group consisting of carboxy, protected carboxy, C1- C6 alkanoyl, C 3 -C6 cycloalkanecarbamoyl, and Ci-C6 alkylcarbamoyl, (A29) Ci-C 6 alkylcarbamoyloxy(Ci-C6)alkyl, Ci-C6 alkoxycarbonylamino(Cl-C6)alkyl, (A31) amino(Ci-C 6 )alkyl, (A32) Ci-C6 alkylcarbamoyl (Ci-C6) alkyl, (A33) heterocyclic-carbonylamino, the heterocyclic group being selected from the above to (14) and optionally being substituted N- protective group, (A34) the above heterocyclic groups to (14) being optionally substituted by Cl-C6 alkyl, and (A35) oxo.

2. The compound of claim 1, in which 1. R 1 is Cl-C6 alkyl; optionally substituted heterocyclic group consisting of the following to or optionally substituted C6-C10 aryl; R 2 is carboxy or hydroxyaminocarbonyl, Ar is phenyl or heterocyclic group of the following and m and n are each an integer of 0 or 1, and m+n=l or 2, wherein the heterocyclic group is; 30 unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 5- or 6-membered, heteromonocyclic group P:\OPERUg\c\89lS.05) spc.doc-12A)2/A) 299 containing 1 to 4 nitrogen atoms, unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, unsaturated bicyclic 9- or heterocyclic group containing 1 to 5 nitrogen atoms, unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms, saturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated bicyclic 9- or heterocyclic group containing 1 or 2 oxygen atoms, unsaturated bicyclic 9- or heterocyclic group containing 1 or 2 sulfur atoms, or (10) saturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, wherein the heterocyclic group being optionally substituted by the group consisting of the following (Bl) to (B8); (Bl) C1-C6 alkanoyl, (B2) Ci-C6 alkyl, 'e (B3) Cl-C6 alkoxy, S.(B4) CI-C6 alkoxycarbonylamino, (B5) carbamoyl or Ci-C6 alkylcarbamoyl, 30 (B6) Ci-C6 alkoxycarbonyl, (B7) halo, and (B8) oxo; P:WPERUgc\l8905-O spc.doc-12/02/03 300 and the above-mentioned aryl is optionally substituted by the group consisting of the (Al) to as defined in claim 1.

3. The compound of claim 2, in which a group of the formula: Y Z is one of the following formulae: S 02 a CH3 O 0 2 o r 2 R is Ci-C6 alkyl; optionally substituted heterocyclic 20 group consisting of the following to optionally substituted phenyl; or optionally substituted naphtyl; R 2 is the same as defined in claim 2, Ar is phenyl or thienyl, and m and n are each an integer of 0 or 1, and m+n=l or 2, wherein the above-mentioned heterocyclic group is pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, C. pyridyl, pyridyl N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, dihydrotriazinyl, ^/RAat azetidinyl, pyrrolidinyl, imidazolidinyl, Spiperidinyl, piperidino, pyrazolidinyl, PAOPER~gg\l8905-0O sp..doc-12/02A)3 301 piperazinyl, thienyl, inciolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, benzotriazolyl, tetrazolopyrilyl, tetrazolopyridazinyl, dihydrotriazolopyridazilyl, furyl, oxolanyl, oxazolyl, isoxazolyl, oxadiazolyl, benzofuranyl, benzodihyclrofuranyl, benzodioxolenyl, benzothienyl, dihydrobenzothienyl, or (10) morpholinyl, morpholino, wherein the heterocyclic group being optionally substituted by the group consisting of the (Bi) to (B8) as defined in :claim 2, and the above-mentioned phenyl or naphthyl is optionally substituted by the group consisting of following (Al) to (A34), (Al) halogen, (A2) Cj-C 6 alkyl, (A3) C 1 -C 6 alkoxy, (A4) halo (Cl-C6) alkyl, halo (Cl-C 6 alkoxy, C 2 -C 6 alkenyl, (A7) acyl, (A8) C 1 -C 6 alkylthio, Cl-C6 alkylsulfinyl, C 1 -C 6 A alkylsulfonyl, Zt (A9) C 6 -Cj 0 aryl, P:\OPERUgc\1805-4X) spwo.dom.12A)2A3 302 (AlO) halo (C 6 -ClO) aryl, (All) hydroxy, (A12) hydroxy(Cl-C 6 )alkyl or protected hydroxy(Cl- CE) alkyl, (A13) amino, (A14) carboxy, protected carboxy, (A16) nitro (C 2 -C 6 alkenyl, (A17) 01-06 alkylenedioxy, (A18) acylamino, (A19) nitro, (C 6 -C 1 0 aryl (Cl-C 6 alkoxy, (A21) carbamoyl (02-06) alkenyl optionally N- substituted by the group consisting of Cl-CE alkyl, (C 6 -Cl 0 aryl, C1-C6 alkoxy (C 6 -Cl 0 aryl, and halo (C6-Cla) aryl, (A22) 01-06 alkylaminocarbonyloxy, (A23) 01-06 alkanoyloxy, *(A24) 01-06 alkoxy (Cl-C 6 alkanoyloxy, (A25) Cl-CE alkoxycarbonyloxy, .(A26) 02-CE alkenoyloxy optionally substituted by the above heterocyclic group (A27) 03-CE cycloalkanecarbonyloxy, (A28) Cl-CE alkoxy substituted by the group consisting of carboxy, protected carboxy, Cl-CE alkanoyl, 03-CE cycloalkanecarbamoyl, and Cl-C 6 alkylcarbamoyl, (A29) Cl-C 6 alkylcarbamoyloxy (01-CE alkyl, Cl-0 6 alkoxycarbonylamino (Cl-C 6 alkyl1, (A31) amino (Cl-C 6 alkyl, *(A32) Cl-CE alkylcarbamoyl(Cl-0 6 )alkyl, (A33) heterocyclic-carbonylamino, the heterocyclic P:\OPERUB\jI9aW>. spc.doc-l2/Il2l3 303 group being selected from the above (4) and and optionally substituted by N- protective group, and (A34) the heterocyclic group of the above (7) being optionally substituted by C 1 -C 6 alkyl.

4. The compound of claim 3, having the following formula: R 1 -X Q mC2)Y 10 ((CH2) CH2)n-R2 wherein a group of the formula: Y is the same as defined in claim 3, R 1 is C 1 -C 6 alkyl, phenyl, halophenyl, or (halo) (phenyl)phenyl, 20 R 2 is the same as defined in claim 3, and m and n are each an integer of 0 or 1, and m+n=l. The compound of claim 3, having the following formula: R 1 (CH2)m (CH2)n-R2 wherein a group of the formula: P:AOPER~go I890S.O) SPw.doe-12AO2A)3 304 is the same as defined in claim 3, R2 is the same as defined in claim 3, m and n are each an integer of 0 or 1, and m+n=1, R 1 is heterocyclic group consisting of pyridyl, thienyl, furyl, benzofuranyl or benzothienyl, wherein the heterocyclic group is optionally substituted by the group consisting Of Cl-CE alkanoyl, Cj-C 6 alkyl, Cl-C 6 alkoxy, Cl-C6 al1koxyca rbonyl amino and C1-CE alkylcarbamoyl; naphtyl or phenyl, each of which is optionally substituted by the group consisting of the following (Cl) to (C31); (Cl) halogen, (C2) 01-06 alkyl, (03) Cl-CE alkoxy, (C4) halo (0 1 -0 6 alkyl, halo (C 1 -C 6 alkoxy, (C6) 02-06 alkenyl, (07) Cl-C 6 alkylcarbamoyl, carbamoyl, phenyl(Ci- 06) alkylcarbamoyl, Cl-CE alkanoyl, (08) Cl-CE alkylthio, Cl-C6 alkylsulfinyl, 01-06 alkylsulfonyl, (09) phenyl, naphthyl, (010) halophenyl, (C11) hydroxy, (012) mono- or dihydroxy(CI-C 6 )alkyl, phenoxycarbonyloxy (01-06) alkyl, (013) amino, *(014) carboxy, (015) 01-0 alkylenedioxy, (016) C 1 -C 6 alkanoylamino, phenyl (0 1 0C 6 )alkanoylamino, halophenyl(0 1 C6)alkanoylamino, C 1 -0 6 alkoxy(Cl- P:\OPER~gg%)9OS4) spwc.dow-12A)2101 305 C 6 )alkanoylamino, phenoxy (C 1 C 6 alkanoylamino, 01-06 alkoxyphenoxy (01- C 6 alkanoylamino, 01-06 alkyiphenoxy (C 1 06) alkanoylamino, halophenoxy (Cl- C 6 )alkanoylamino, carboxy(C 1 06) alkanoylamino, 01-06 alkoxycarbonyl (Cl- C 6 )alkanoylamino, C 1 -C 6 alkylcarbamoyl (Cl- 06) alkanoylamino, halo (01-06) alkanoylamino, 02-06 alkenyl (01-06) alkanoylamino, 01-06 alkoxy (01-06) alkanoylamino, phenyl (Cl- 06) alkoxy (01-06) alkanoylamino, piperidinyloxy (01-06) alkanoylamino, N-0 1 -0 6 alkoxycarbonylpiperidinyloxy (Cl- 06) alkanoylamino, pyriclyloxy (01- 0 6 )alkanoylamino, hydroxy(0i- 06) alkanoylamino, 01-06 alkanoyloxy (Cl- 06) alkanoylamino, 01-06 alkylcarbamoyloxy (Cl- 06) -alkanoylarnino, N, N-di (01-06 alkyl) carbamoyloxy, 01-06 alkanoylamino, piperidiono-carbonyloxy (01-06) to alkanoylamino, phenyl (Cl- 06) alkylcarbamoyloxy (0 1 -0 6 alkanoylanino, amino (01-06) alkanoylamino, 01-06 alkoxycarbonyl amino (01-06) alkanoylamino, f luorenylmethoxycarbonylamino (01-06)- alkanoylamino, 01-06 alkylamino (Ci- 06) alkanoylamino, [N,N-di (01-06 alkyl)amino] (01-06) al1kanoyl amino, [N-0 1 -0 6 alkyl-N- (01-06 alkoxycarbonyl) -amino] (01-06) alkanoylamino, [M,0 1 -0 6 alkyl-N- (fluorenylmethoxycarbonyl)aminoI (Cl- C 6 alkanoylamino, [N-Oi-0 6 alkyl-N- (mono- or P:%OPERJgo%189OS.4E spwo.doc-12O2AJ3 306 di (01-06) alkylcarbamoyl) amino] (Ci- 0 6 )alkanoylamino, [N-(mono- or di(0 1 -C 6 alkyl) carbamoyl) -amino] (01- C 6 alkanoylamino, benzoylamino (Cl- 0 6 )alkanoylamino, Cl-C 6 alkanoylamino (C 1 C 6 alkanoylamino, Cl-C 6 alkanesulfonylamino (C 1 -C 6 alkanoylamino, 01- C6 alkoxy (C 1 -C 6 alkanoylamino- (Cl- C 6 alkanoylamino, cyclo (03- C 6 alkyloxycarbonylamino- (01- 06) alkanoylamino, pyridylcarbonylamino (C 1 06) alkanoylamino, morpholinocarbonylamino (C 1 -C 6 alkanoylamino, phenyl (C 1 -C 6 alkoxyoxycarbonylamino (Cl- J5 06) alkanoylamino, 01-06 alkoxyphenylsulfonylamino (Cl- C 6 alkanoylamino, hyciroxy (Cl- C 6 alkylamino (CI-C 6 -alkanoylamino, so*, morpholino (01-06,) alkanoylamino, oxooxazolidinyl (01-06) alkanoylamino, *9 oxopyrrolidinyl (01-06) alkanoylamino, trimethyihydantoinyl (01-06) alkanoylamino, 02- 06 alkenylamino (01-06) alkanoylamino, 01-06 alkoxy (01-06) alkylamino (01-06) alkanoylamino, phenyl (01-06) alkylamino (01-06) -alkanoylamino, pyriclyl (01-06) alkylamino (01-06)- *alkanoylamino, 01-06 al1koxyca rbonyl amino,

9. 9.:phenyl (01-06) alkoxycarbonylamino, 01-06 00. aloy C0-6) alkoxycarbonylamino, halo (Cl- 06) alkoxycarbonylamino,, amino (Cl- 06) alkoxycarbonylamino, phthalimido (Ci- ,,tp06) alkoxycarbonylamino, carbamoylamino, P:NOPER'Jgc%189054X) sp.c.do.I12A)2O3 307 (mono- or di (Cl-C 6 alkyl) carbamoylamino, naphthylcarbamoylamilo, halophenylcarbamoylamino, Cl-C 6 alkoxyphenylcarbamoylamino, 02-06 alkenylcarbamoylamino, cyclo (C 3 -C 6 alkyl (01- 06) alkylcarbamoylamino, phenyl (C 1 C 6 alkylcarbamoylamino, halo (C 1 06) alkylcarbamoylamnio, 01-06 alkoxy (01- 06) alkylcarbamoylamino, hydroxy (Cl- C 6 )alkylcarbamoylamilo, (01-C6 alkyl) (diphenyl) silyloxy (Cl- 06) alkylcarbamoylamino, carboxy (Cl- 06) alkylcarbamoylamino, 01-06 alkoxycarbonyl (01-06) alkylcarbamoylamino, Cl- 06 alkylcarbamoyl (01-06) al1kyl -carbamoyl amino, or pyriclylcarbamoyl amino, 01-06 alkylsulfonylamino, 02-06 alkenoylamino, 03- 06 cycl1oal kane ca rbonyl amino, 02-06 :::so-al kenyloxycarbonylamino, Soes 4 :so 20 phenoxycarbonyl amino, 01-06 al kylthiocarbonylamino, (017) phenyl (01-06) alkoxy, (018) 02-06 alkenyl, mono- or di (Cl-0 6 alkyl) carbamoyl (02-06 alkenyl, (2- (methylcarbamoyl)ethenyl, 2- (ethylcarbamoyl) ethenyl, 2- to*S (propylcarbamoyl) ethenyl, 2 (isopropylcarbamoyl) ethenyl, 2- (dimethylcarbamoyl) ethenyl, phenylcarbamoyl (02-06) al kenyl, 01-06 alkoxycarbamoyl (C 2 -C 6 alkenyl, halophenylcarbamoyl (02-06) alkenyl, P:\OPEft~\18954) sp.m1A2) 308 (019) Cl-Cs alkylaminocarbonyloxy, (020) Cl-C6 alkanoyloxy, (021) Cl-C6 alkoxy (Cl-C 6 alkanoyloxy, (C22) Cl-Cs alkoxycarbonyloxy, (C23) pyridyl (C 2 -C6) alkenoyloxy, (024) 03-C6 cycloalkanecarbonyloxy, carboxy (Cl-C 6 alkoxy, Cl-C6 alkoxycarbonyl (Cl-OS) alkoxy, Cl-C6 alkanoyl (0 1 -C6) alkoxy, 03-06 cycloalkanecarbamoyl (01-06) alkoxy, Cl-CS alkylcarbamoyl (01-06) alkoxy, (026) Cl-Cs alkylcarbamoyloxy (Cl-CS) alkyl, (027) Cl-CS al koxyca rbonyl amino (Cl-CS) alkyl, (028) amino (0 1 -0)alkyl, (029) Cl-CS alkylcarbamoyl (C 1 alkyl, (030) furylcarbonylamino, tetrahydroisoquinolylcarbonylamino, N-0 1 -0 al koxycarbonyl- tetrahydroisoquinolylcarbonylamino, pyrrolidinylcarbonylamino, *(031) oxazolyl, Cl-CS alkyloxadiazolyl. .0 The compound of claim 5, in which a group of the formula: (AN one of the following formulae: 0 2 s 0 N2 PAOfPEfl~gckSI&904XI spmcdm. I 2/02A3 309 R 2 is the same as defined in claim m is 0 and n is 1, a group of the formula:R14 Y is the group of the following formulae to (a) Rl 1 __s wherein R" is halo, naphtyl, phenyl, mono- or dihalophenyl, mono- or di (Cl-C 6 )alkylphenyl, Cl-CE alkoxyphenyl, trihalo (Cl-C 6 alkylphenyl, trihalo (Cl- C 6 alkoxyphenyl, C 2 -C 6 alkenyiphenyl, C 1 -C 6 alkylcarbamoylphenyl, carbamoylphenyl, phenyl (Cl- C 6 al kylcarbamoylphenyl, C 1 -C 6 al kanoylphenyl, Cj- C 6 alkylthiophenyl, CI-C 6 alkylsulfinylphenyl, Cj- C 6 alkylsulfonyiphenyl, phenylphenyl, (halo) (phenyl)phenyl, halophenylphenyl, hydroxyphenyl, mono- or dihyciroxy(Cl-C 6 alkylphenyl, phenoxycarbonyloxy (C 1 -C 6 alkylphenyl, aminophenyl, carboxyphenyl, Cl-C 6 alkylendioxyphenyl, Cl-C 6 alkanesulfonylaminophenyl, C 2 -C 6 alkenoylaminophenyl, C 3 -C 6 cycloalkanecarbonylaminophenyl, phenyl (Cl- C 6 alkoxyphenyl, mono- or di (Cl-C 6 alkyl) carbamoyl (C 2 -C 6 alkenylphenyl, phenylcarbamoyl (C 2 -C 6 al kenylphenyl, Cl-C 6 alkoxycarbamoyl (C 2 -C 6 )alkenylphenyl, 7:,,Ahalophenylcarbamoyl (C 2 -C 6 alkenylphenyl, Cl-C 6 LLJ alkylcarbamoyloxyphenyl, Cj-C 6 alkanoylaoxyphenyl, P:%OPERUgc(lS8fl)5400 spec.doc-12AUt 310 01-06 alkoxy (Cl-C 6 alkanoyloxyphenyl, 01-06 alkoxycarbonyloxyphenyl, pyridyl (02- C 6 alkenoyloxyphenyl, cyclo (03- C 6 alkylcarbonyloxyphenyl, carboxy (01- C 6 )alkoxyphenyl, Cl-C 6 alkoxycarbonyl (Cl- C 6 alkoxyphenyl, 01-06 alkanoyl (Cl-C 6 al koxyphenyl, 03-06 cycloalkanecarbamoyl (0 1 -C 6 alkoxyphenyl, 01-06 alkylcarbamoyl (Cl-C 6 alkoxyphenyl, 01-06 alkylcarbamoyloxy (Cl-C 6 alkyiphenyl, 01-06 al1koxyca rbonyl amino (0 1 -C 6 alkyiphenyl, amino (C 1 06,)alkyiphenyl, 01-06 alkylcarbarnoyl (C 1 C 6 )alkylphenyl, furylcarbonylaminophenyl, 1,2,3,4- tetrahydroisoquinolylcarbonylaminophenyl, N-t- butoxycarbonyl, 1,2,3,4- tetrahydroisoquinolylcarbonylaminophenyl, pyrrolidinylcarbonylamiiophenyl, oxazolyiphenyl, Cl-C 6 alkyloxadiazolylphenyl, 0/\ R 1 2 -C S. wherein R 12is 01-06 alkyl optionally substituted by the group consisting of phenyl, halophenyl, 01-06 alkoxyphenyl, C1-C6 alkoxy, phenoxy, Cj-CG alkoxyphenoxy, halophenoxy, (01-06) alkyiphenoxy, carboxy, 01-06 al koxycarbonyl, 01-06 alkylcarbanoyl, halo, 006alkenyloxy,016 nALalkoxy (0-06alkoxy, phenyl alkoxy, gA~jjpiperidinyloxy, N-0 1 -0 6 alkoxycarbonyl- Uipipericlinyloxy, pyriclyloxy, hydroxy,010 P:QpERucAI3905Ain) spcv.doc-IZ02A)3 311 alkanoyloxy, mono- or di(C1-C6)alkylcarbamoyloxy, piperidinylcarbonyloxy, pheny (Cl- C 6 alkylcarbamoyloxy, amino, 01-06 a].koxycarbonylamino, fluorenylmethoxycarbonylamino, mono- or di (Cl- 06) alkylamino, N- 01-06 alkyl-N- (0 1 -C 6 alkoxycarbonyl) amino, N-Cl-C 6 alkyl-N- (fluorenylmethoxycarbonyl) amino, N-Cj-C 6 al.kyl-N- (mono- or di (Ol-0 6 -alkylcarbamoyl) amino, N- (mono- or di (01-06 alkyl) carbamoyl) amino, benzoylamino, 01-06 alkanoylamino, 01-06 alkanesulfonylamino, Cj- 06 alkoxy (01-06)alkanoylamino, cyclo (03- 06) alkyloxycarbonylamino, pyridylcarbonylamino, morpholinocarbonylamino, phenyl (Cl- C 6 alkoxycarbonylamino, 01-06 alkoxyphenylsulfonylanino, hydroxy (Cl- 06) alkylamino, morpholino, oxooxazoliclinyl, **oxopyrrolidinyl, trimethyihydantoinyl, pyridyl, 02-0s alkenylamino, 0-C6 aoy(1-C6) alkylamino, 2 C* .l o y C phenyl (C1-06)alkylamino, pyr idyl (CI-C6) al kylamino, and cyclo (03-06) alkyl, (C) 0 R I 3 -M-0-HN wherein M is oxygen or sulfur, R is 01-06 alkyl, phenyl (0i-0 6 alkyl, 1-6alkoxy(0 1 06) alky1, halo (01-06) alkyl, amino (01-06) alkyl, or phthalimido(0i-0 6 )alkoxycarbonylamino, 02-06 wj alkenyl, phenyl, PAOPERU~AIRW)S41I qp.dom.l2A)2A) 312 (d) Ri 4-N-C HN wherein R 15 is hydrogen or 01-06 alkyl, R 14 is hydrogen, 01-06 alkyl, naphthyl, halophenyl, 01-06 alkoxyphenyl, 02-C6 alkenyl, C 3 -C 6 cycloalyl (Cl- 06) alkyl, phenyl (Cl-C 6 alkyl, halo (Cl-C 6 alkyl, 0j- CE alkoxy (C 1 -C6) alkyl, hydroxy (Cl-C 6 alkyl, (Cl-CE alkyl) (diphenyl)Silyloxy(0 1 -C 6 )alkyl, carboxy(Cl- C 6 alkyl, Cl-CE alkoxycarbonyl (Cl-C 6 alkyl, 01-CE alkylcarbamoyl(Cl-C 6 )alkyl, or pyridyl, (e) R6-- wherein R 16 is benzothienyl, benzofuranyl, thienyl, furyl, 01-C6 alkylpyridyl, pyridyl, Cl-CE alkoxypyridyl, Cl-CE alkoxycarbonylaminopyridyl, 01-C6 alkanoylthienyl, alkylcarbamoylbenzofuranyl. 7. The compound of claim 6, wherein a group of the formula: R-3 is the same group as and of claim 7, 1' and the following formula PAOPERUcNlS954X) sp-cdo-.Z/2MA 313 (b) 0 R 1 2 -C HN- S wherein R 12 is C 1 -C 6 alkyl, phenyl(CI-C 6 )alkyl, halophenyl(Cl- CE) alkyl, Cl-C 6 alkoxyphenyl (Cl-C 6 alkyl, 01-06 alkoxy (Cl-C 6 alkyl, phenoxy (Cl-0 6 alkyl, 01-06 alkoxyphenoxy (Cl-CE) alkyl, halophenoxy (Cl-CE) alkyl, Cl-C 6 alkyiphenoxy (C 1 -C 6 alkyl, carboxy (01-06) alkyl, 01-06 alkoxycarbonyl (Cl-CE) alkyl, Cl-CE alkylcarbamoyl (Cl-C 6 )alkyl, halo (Cl-C 6 alkyl, C 2 -C 6 alkenyloxy alkyl, CI-0 6 alkoxy (C 1 -C 6 alkoxy (Cl- C 6 )alkyl, phenyl (Cl-C 6 alkoxy (Cl-CE) alkyl, piperidinyloxy (0 1 -C 6 alkyl, N-t-butoxycarbonylpiperidinyloxy (Cl-CE) alkyl, pyridyloxy (Cl-CE) alkyl, hyciroxy (Cl-CE) alkyl, Cl-CE alkanoyloxy (01-06) alkyl, mono- or di (01- 06,)alkylcarbamoyloxy (Cl-C6) alkyl, piperidinylcarbonyloxy(0 1 -0 6 )alkyl, pheny(0 1 C6)alkylcarbamoyloxy(Cl-C6)alkyl, amino(0 1 CE) alkyl, Cl-CE alkoxycarbonylamino (01-06) alkyl, f luorenylmethoxycarbonyl amino (01-06) al1kyl, mono- or di (Cl-CE) alkylamino (Cl-CE) alkyl, N- Cl-CE alkyl- N- (Cl-CE alkoxycarbonyl) amino (01-06) alkyl, N- Cl-CE alkyl-N- (fluorenylmethoxycarbonyl) amino- (Cl- 06) alkyl, N- Cl-CE alkyl-N- (mono- or di (Cl- 06) alkylcarbamoyl) amino (Cl-C6) alkyl, N- (mono- or di (Cl-CE alkyl) carbamoyl) amino (Cl-C6) alkyl, benzoylamino(0 1 -0 6 )alkyl, 01-06 alkanoylamino(0 1 CE) alkyl, 01-CE alkanesulfonylamino (Cl-CE) alkyl, Cj- 06 alkoxy (01-06) alkanoylamino (01-06) alkyl, cyclo (03- PAODPER\Jg,%I89O5.4JO spc.cIU)AJ 314 C 6 alkoxy (Cl-CE) alkanoylamino (Cl-C 6 alkyl, CYClo (C 3 CO) al1kyloxycarbonyl aminlo (Cl-C 6 alkyl, pyr idyl ca rbonyl amino (Cl-C 6 alkyl, morpholinocarbonylamilo (Cl-C 6 alkyl, phenyl (Cl- CO) al1koxyoxyca rbonyamnio (Cl-C 6 alkyl, Cl-C6 alkoxyphenylsulfonylamilo (Cl-C 6 alkyl, hydroxy (Cl- CE)alkylamino(Cl-C6)alkyl, morpholino(Ci-C6)alkyl, oxooxazolidinyl (Cl-C6) alkyl, oxopytrrolidinyl (Cl- C 6 alkyl, trimethyihydantoinyl (Cl-C6) alkyl, pyridyl (Cl-CE)alkyl, C 2 -C 6 alkenylamino (Cl-C 6 alkyl, lower alkoxy(Cl-CE)alkylamfiflo(Cl-C6)alkyl, phenyl (Cl-C 6 al1kyl amino (Cl-CE) al1kyl, pyridyl (Cl- C 6 )alkylamino(Cl-C 6 )alkYl, CYClo(C 3 -C 6 )alkyl, (amino) (phenyl) (Cl-C 6 al1kyl amino, Cl-C 6 alkoxycarbonylamino) (phenyl) (C-C 6 alkyl, (amino) (Cl-C 6 alkoxy) (Cl-C 6 )alkyl, (CI-C 6 alkoxycarbonylamino) (Cl-C 6 alkoxy) (Cl-C 6 )alkyl, :(amino) (carboxy) (Cl-C 6 alkyl, (Cl-C 6 al1koxyca rbonyl amino) (carboxy) (C 1 -C 6 )alkyl, (amino) (Cl-C 6 alkoxycarbonyl)-(Cl-C 6 )alkyl, (Cl-C 6 *a alkoxyca rbonyl amino) (Cl-C 6 alkoxycarbonyl) (Cl- o 0 C 6 )alkyl, (amino) (phenyl(Cl-C 6 )alkoxy) (C 1 C 6 alkyl, (Cl-C 6 al koxycarbonyl amino) (phenyl (C 1 C 6 )alkoxy) (Cl-C 6 alkyl, (amino) (pyridyl) (C 1 C 6 )alkyl, (Cl-C 6 alkoxycarbonylamino) (pyridyl) V. (Cl-C 6 )alkyl, (amino) (hydroxy) (Cl-C 6 )alkyl, (C 1 -C 6 alkoxycarbonylamino) (hydroxy) (iC)akl (amino) (amino) (Cl-C 6 alkyl, (Cl-C 6 *oo alkoxycarbonylamino) (amino) (C 1 -C 6 )alkyl, (amino) 030 (C 1 -C 6 alkoxycarbonylamino) (Cl-CO alkyl, (C 1 -C 6 al koxyca rbonyl amino) (Cl-C 6 al1koxycarbonyl amino) ALI 1 ~(Cl-C6) alkyl, (amino) (C 3 -CE cycloalkane) (C 1 P:XOPER~jgcIBW)S4K) spec.doc-IMf)M)3 315 CO) alkyl, (Cl-CE alkoxycarbonylamino) (C 3 -C 6 cycloalkane) (Cl-C 6 alkyl. 8. The compound of claim 6, in which ~a group of the formula: R s is the group of the following formula to (a) wherein R" is bromo, 2-naphthyl, phenyl, 3(or 4)-chlorophenyl, 2(or 3 or 4)-fluorophenyl, 3,4-clichioropheny, difluorophenyl, 3(or 4)-methyiphenyl, 4- ethyiphenyl, 4-isopropyiphenyl, 4- (t-butyl)phenyl, 3, 4-dimethyiphenyl, 4-methoxyphenyl, 4- ethoxyphenyl, 4-trifluoromethyiphenyl, 4- trifluoromethoxyphenyl, 4-ethenyiphenyl, 4- *ehlabmolhnl *-tycraoypey, mtcarbamoylphenyl, 4- ethzylcarbamoylphenyl, 4- acetyiphenyl, 4-methyithiophenyl, 4- ethyithiophenyl, 4-methylsulfinyiphenyl, 4- methylsulfonyiphenyl, phenyiphenyl, 4-phenyl-3- fluorophenyl, 4- (4-fluorophenyl)phenyl, 3 (or 4)- hydroxyphenyl, 3(or 4)-hyclroxymethyiphenyl, 4- 2-dihydroxyethyl) phenyl, 4- (phenoxycarbonyloxymethyl)phenyl, 3(or 4)- cj~ AL,~aminophenyl, 4-carboxyphenyl, 3, 4-methylendioxyphenyl, 316 4- (methanesulfonylamino) phenyl, 3- (2-butenoylamino) phenyl, 3- (cyclopropanecarbonylamino) phenyl, 3- (cyclobutanecarbonylamino)phenyl, 3- (cyclopentanecarbonylamino) phenyl, 4 -benzyloxyphenyl, 4- (methylcarbamoyl)'ethenyl) phenyl, 4- (ethylcarbamoyl) ethenyl) phenyl, 4- (propylcarbamoyl) ethenyl) phenyl, 4 -(2-(isopropylcarbamoyl)ethenyl)phenyl, 4-2- (dimethylcarbamoyl) ethenyl) phenyl, 4- (phenylcarbamoyl) ethenyl) phenyl, 4- (methoxyphenylcarbamoyl) ethenyl)phenyl, 4- (4-fluorophenylcarbamoyl) ethenyl) phenyl, 4- (methylaminocarbonyloxy)phenyl, 4- (ethylamiriocarbonyloxy)phenyl, 4-propanoyloxyphenyl, 4- (rethoxyacetyloxy)phenyl, 4- (ethoxycarbonyloxy) phenyl, 4- (3-pyridyl) acryloyloxy) phenyl, 4- (cyclopropylcarbonyloxy) phenyl, 4- (carboxyrnethoxy) phenyl, 4- (ethoxycarbonylmethoxy) phenyl, 4- (t-butoxycarbonylnethoxy) phenyl, 4- (propanoylmethoxy) phenyl, 4- Ccyclopropylcarbamoylmethoxy) phenyl, 3 (or (methylcarbamoylmethoxy)phenyl, 4- (ethylcarbamoylmethoxy) phenyl, 4- (propyl ca rbamoylrnethoxy) phenyl, 3 (or (methylcarbamoyloxymethyl)phenyl, 4-(methoxycarbonylaminomethyl)phenyl, 4- (t-butoxycarbonylaminomethyl) phenyl, 4 -arnilnomethyiphenyl, 4- (methylcarbamoylmethyl) phenyl, 3-(2(or 3 )-furylcarbonylamino)phenyl, 3-(1,2,3,4- .,ClR Atetrahydroisoquinolylcarbonylanino) phenyl, 317 3- (t-butoxycarbonyl) 2,3,4- tetrahyclroisoquinolylcarbonylamino) phenyl, 3- Cpyrrolidinylcarbonylamino) phenyl, 4- 3-oxazolyl) phenyl, 4 7(5-methyl-1,2,4-oxadiazol-3.yl)phenyl, (b) 0 11 R 12 -C-HT N S wherein R2is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, phenylmethyl, 4 -chlorophenylmethyl, 4-methoxyphenylmethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, isopropyloxymethyl, 1-methoxyethyl, 2- rnethoxyethyl, phenoxymethyl, 2-phenoxyethyl, 3(or 4) -methoxyphenoxymethyl, 4-fluoro (or chloro) phenoxymethyl, 3 (or 4) -methylphenoxymethyl, 2-carboxyethyl, 2 -methoxycarbonylethyl, 2-t- butoxycarbonylethyl, 2-methylcarbamoylethyl, 2-chloroethyl, chloromethyl, allyloxymethyl, 2 -ethoxyethoxy)methyl, benzyloxymethyl, 4-pipe ridinyloxymethyl, (N-t-butoxycarbonyl-4- piperidinyl) oxymethyl, 3 (or 4) -pyridyloxymethyl, hydroxymethyl, 2-hydroxyethyl, acetoxymethyl, l-acetoxyethyl, methylcarbamoyloxymethyl, 1-(N- methyl-N-ethylcarbamoyloxy)methyl, (piperidino- carbonyloxy)methyl, (benzylcarbamoyloxy)methyl, .(t-butoxycarbonylaomino), aminomethyl, 1-aminoethyl, 1- (t-butoxycarbonylamino) ethyl, 2-aminoethyl, methoxycarbonylaminomethyj, 41 2- (methoxycarbonylamino) ethyl, 318 ethoxycarbonylarninomethyl, propoxycarbonylaminomethyl, 1- (fluorenylmethoxycarbonylamino) methyl, 2- (t-butoxycarbonylamino) ethyl, 2- (fluorenylmethoxycarbonylamino)ethyl, 1-arninoisopropyl, 1-aminopropyl, 1- (t-butoxycarbonylamino) propyl, 1- (t-butoxycarbonylamino) isopropyl, 1, 5-diaminopentyl, 1, 5-bis (t-butoxycarbonylamino) perityl, methylaminonethyl, ethylaminomethyl, 2- (N-methyl-N-ethylamino)methyl, dimethylaminomethyl, pent ylaminomethyl, t-butylaminomethyl,, 2-methylaminoethyl, 1- (N-methyl -N-methoxycarbonylamino) methyl, 1- (N-methyl-N-t-butoxycarbonylamino)methyl, 1- (N-ethyl-N-t-butoxycarbonylamino) methyl, 2- (N-methyl-N- (fluorenylmethoxycarbonyl) amino) ethyl, 2- (N-methyl-N- (t-butoxycarbonyl) amino) ethyl, 1- (N-methyl-N- (dimethylcarbamoyl) amino) methyl, 1- (dimethylcarbamoylamino)methyl, 1- (ethylcarbamoyl)amino)methyl, 2- (ethylcarbamoyl)amino) ethyl, benzoylaminomethyl, *2-benzoylaminoethyl, acetylaminomethyl, isobutyrylaminomethyl, pivaloylaminomethyl, l-(methanesulfonylamino)methyl, 2- (methanesulfonylamino) ethyl, methoxyacetylaminomethyl, cyclopentyloxycarbonylaminomethyl, pyridylcarbonylaminomethyl, morpholinocarbonylaminomethyl, benzyloxycarbonylaminomethyl, 1 4 -methoxyphenylsulfonylamino)methyl, 2 -hydroxyethylamino) methyl, morpholinomethyl, 1- (2-oxo-1, 3-oxazolidin-1- yl)methyl, l-( 2 -oxopyrrolidin-l-yl)methyl, 319 1-(3,4,4-trimethylhydantoin-1-yl)methyl, allylaminomethyl, 1- (2-ethoxyethylamino)methyl, benzylaminomethyl, 1- (3-pyridylrnethylamino)methyl, 2-phenyl--1-aminoethyl, 1-amino-1-phenylmethyl, 1-t-butoxycarbonylaniino-l-phenylmethyl, 1-amino-2-phenylethyl, 1-t-butoxycarbonylamino-2- phenylethyl, 1-amino-2-methoxyethyl, 1-t-butoxycarbonylamino-2-methoxyethyl, 1-amino-3- carboxypropyl, 1-t-butoxycarbonylamino-3- carboxypropyl, 1-amino-3- (t-butoxycarbonyl)propyl, 1-t-butoxycarbonylamino-3-t-butoxycarbonylpropyl, etc.), 1-amino--2-benzyloxyethyl, 1-t-butoxycarbonylamino-2 -benzyloxyaminoethyl, 1-amino-2- (3-pyridyl) ethyl, l-t-butoxycarbonylamino- 2- (3-pyridyl)ethyl, 1-amino-2- (4-pyridyl)ethyl, 1-t- butoxycarbonylamino-2- (4-pyridyl) ethyl, 1-amino-2- hydroxyethyl, 1-t-butoxycarbonylamino-2-hydroxyethyl, 5-diaminopentyl, aminopentyl, 1, 5-bis (t-butoxycarbonylamino)pentyl, l-amino- 5- (t-butoxycarbonylamino) pentyl, l-amino-2- cyclohexylethyl, 1-t-butoxycarbonylamino-2- cyclohexylethyl, fe 25 (c) 0 R1 3 1-H1N/\ wherein and R is methyl, ethyl, propyl, isopropyl, benzyl, 2-methoxyethyl, 2-oholoroethyl, 2-aminoethyl, 2- 7 phthalimidoethyl, allyl, phenyl, or M=S and R1 3 is methyl, ethyl, 320 (d) 0 Rl4 1 1 4N--HNI\ R 1 5 S wherein R 15 is hydrogen and R 14 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, 1-naphthyl, 3(or 4)- chlorophenyl, 3-methoxyphenyl, allyl, cyclohexylmethyl, benzyl, 2-chloroethyl, methoxymethyl, 2-methoxyethyl, 2-hydroxyethyl, (t-butyl) (diphenyl)silyloxy) ethyl, carboxymethyl, ethoxycarbonylmethyl, methylcarbamoylmethyl, or 3-pyridyl, R 14 is ethyl and R 15 is methyl, (e) R16 wherein 16is 2-benzothienyl, 2-benzofuranyl, 2(or 3)-thienyl, 2-furyl, 3-pyridyl, 1-methyl-4-pyridyl, 6-methyl-3- pyridyl, 6-methoxy-3-pyridyl, 5-methoxycarbonylamino-3-pyridyl, 5-acetyl-2-thienyl, A process for the preparation of a compound of the formula: Y Z _b 1 V Rl-X-Ar- (CH 2 )m>K%(CH 2 )n-R2() 321 in which R 2 Ar, A, X, Y, Z, m and n are each as defined in Claim 1, which comprises subjecting a compound of the formula: Rl-X--Ar- (CH 2 )m>K(CH 2 nRa2 (I-a) or a salt thereof to removal reaction of the carboxy- protective group, to give a compound of the formula: (A> Rl-X-Ar- (CH2)m <(CH2) nCOOH (I-b) or a salt thereof; or 00 00 0 00. 0 0000 0 000. 000. 0* 00 0 9 00 00 000. 0 00 00 0 S 0030 0 0000 05 0 S S SO 5500 0 0,00 0 0505 *000 0 000005 0 0 oxidating the vinyl group of a compound of the formula: Y Z R 1 -X-Ar- (CH2)m><(iCH2) nCH=CH2 (I I) or a salt thereof, to give a compound of the above formula or a salt thereof; or reducing a compound of the formula: Y Z RlXar(CH 2 )m>K(CH 2 nR 2 Ic) 322 or a salt thereof, to give a compound of the formula: rz Rb-X-Ar-(CH2)m/> (CH2)n-R2 (I-d) or a salt thereof; or reacting a compound of the above formula or its reactive derivative at the carboxy-group, or a salt thereof, with a compound of the formula: NH 2 -OR 3 (IV) or its reactive derivative at the amino-group, or a salt thereof, to give a compound of the formula: z Y Z Rl-X-Ar-(CH2)m (CH2) n-CONH-OR 3 (I-e) or a salt thereof; or cyclizing a compound of the formula: *HN 2 30 HN R 1 -X-Ar-(CH 2 m CH m 2 (III) a or a salt thereof, to give a compound of the formula: 323 Y z R 1 -X-Ar-(CH2) CH 2 -R2 (I-f) or a salt thereof; or reacting a compound of the above formula or its reactive derivative at the carboxy-group, or a salt thereof, with an optically active amine or its reactive derivative at the amino-group, or a salt thereof, to give a compound of the formula: Y Z^ Y R1-X-Ar-(CH2)m -(CH2)n-R (I-g) or a salt thereof; or subjecting a compound of the formula: Y z R1-X-Ar-(CH2)m (CH2)n-CONH-OR3 (I-h) 1 a 25 or a salt thereof to removal reaction of the hydroxy- protective group, to give a compound of the formula: Y Z R1-X-Ar-(CH2)m> (CH2)n-CONHOH (I-i) *o or a salt thereof; or *oe* oxidating a compound of the formula: Ya Z -X-A R 1 -X-Ar- (CH2)m CH 2 )nR 2 (I-j) S324 or a salt thereof, to give a compound of the formula: Yb Z Rl-X-Ar-(CH2)m CH2)n-R 2 (I-k) or a salt thereof; or reacting a compound of the above formula (I-c) or a salt thereof, with a compound of the formula: R4-B<R (V) 20 to give a compound of the formula: SR-X-Ar-(CH2)mr CH2)n-R 2 (1-1) or a salt thereof; or (10) reacting a compound of the formula: o SY Z (VI) 2 c or a salt thereof, with a compound of the formula: 325 R'-X-Ar- (CH2)ml-L (VII) or a salt thereof, to give a compound of the formula: z or a salt thereof; or (11) cyclizing a compound of the formula: R 1 XA-(H2 m (H)nR (VIII) *or a salt thereof, to give a compound of the formula: R'-X-Ar-(CH-2)m (8)-R 2 (I-n) or a salt thereof; or 326 (12) amidating a compound of the formula: or its reactive derivative at the carboxy group, or a salt thereof, to give a compound of the formula: r or a salt thereof; or 1s (13) acylating a compound of the formula: Rl-X-A-A C2m (C2nR (I-r) 327 or its reactive derivative at the amino group, or a salt thereof, to give a compound of the formula: Y Z Rl-X-Ar-(CH 2 )m <(CH 2 )n-R 2 (I-s) or a salt thereof; or (14) subjecting a compound of the formula: R -X-Ar-(CH2) \(CH2)n-R2 (I-t) or a salt thereof to a removal reaction of the amino- protective group, to give a compound of the formula: or a salt thereof; or subjecting a compound of the formula: 30 R-X-Ar-(CH2) (CH2)n-R2 (I-u) z or a salt thereof to a removal reaction of the hydroxy- protective group, to give a compound of the formula: 328 RI-X-Ar- (CR2) rr <(CH2) n-R 2 (I1v) or a salt thereof; or (16) oxidating a compound of the formula: r Rj-X-Ar- (CH2) CH2) n-R2 (I-w) or a salt thereof, to give a compound of the formula: Rj-X-Ar C2 C R (I-X) *or a salt thereof; or (17) reducing a compound of the formula: Rl-X-Ar-(CH 2 o a alt herofto give a compound of the formula: RA-X-Ar -(OH 2 rr CH2)n2(Iz or a salt thereof; or (18) oxidating a compound of the formula: Y Z or a salt thereof, to give a compound of the formula: Rp-X-Ar-CH2)n><C 2 )n.R2 CI-ab) or a salt thereof; or (19) acylating a compound of the formula: R Ar (C2) <CH2) n-R2 Iv or a salt thereof, to give a compound of the formula: r Rl-X-Ar- (CH2)M><(CH2)n~R (I-ac) :or a salt thereof; or reacting a compound of the formula: Y Z (XI) R 6 330 or a salt thereof, with a compound of the formula: R 1 -L (XII) or a salt thereof, to give a compound of the formula:, Rl-Ar- (CH2) <(CH 2 n-R2 (I-ad) or a salt thereof; or (21) subjecting a compound of the formula: r2 (H)Rl-X-A-C R (I-ae) or a salt thereof, to a removal reaction of the carboxy- 5:95.:protective group, to give a compound of the formula: y z :or a salt thereof; or (22) reacting a compound of the formula: !RAR1-X-Ar-(CH 2 llf>CH2)n-R 2 (I-af) 331 or a salt thereof, with a substituted amine, to give a compound of the formula: Y Z R1EX-Ar-(CH2)m>.(CL2)n-R2 (I-ag) or a salt thereof, in which R 1 R 2 Ar, A, X, Y, Z, m and n are each as defined above, Ra is haloaryl or halo, Rb is aryl, Rc is aryl at least substituted by optionally substituted aryl, Sis aryl at least having carboxy moiety, Rd is aryl at least having amido moiety, R1 is aryl at least having amino moiety, Sis aryl at least having acylamino moiety, Rh is aryl at least having protected amino moiety, RI is aryl at least having hydroxy moiety, R4 is aryl at least having thia moiety, Rj is aryl at least having sulfinyl or sulfonyl moiety, R1 is aryl at least having formyl moiety, Rl is aryl at least having hydroxymethyl m R1 is aryl at least having vinyl moiety, Rp is aryl at least having 1,2-dihydroxyet Rq is aryl at least having acyloxy moiety, R1 is aryl at least having protected carboxy moiety, RS is aryl at least having halo (C 1 -C 6 alka moiety, oiety, hyl moiety, noyl 332 R1 is aryl at least having substituted amino (Cl-C 6 alkanoyl moiety, Ra is protected carboxy, Rb is optically active amide, R2 is protected carboxy, 3 is hydrogen or hydroxy-protective group, R3 is hydrogen or hydroxy-protective group, Ra is hydroxy-protective group, R 4 is optionally substituted aryl, R 5 and R 6 are each hydrogen or combinedtogether to form Ci-C 6 alkylene, Ya is thia, sulfinyl or sulfonyl, Za is methylene, thia, sulfinyl or sulfonyl, provided that at least one of Ya and Za is thia or sulfinyl, Yb is thia, sulfinyl or sulfonyl, Zb is methylene, thia, sulfinyl or sulfonyl, provided that at least one of Yb and Zb is sulfinyl or sulfonyl, L is a leaving group, and 20 ml is an integer of 1 to 6.

10. A pharmaceutical composition which comprises the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

11. A process for preparing a pharmaceutical composition which comprises admixing the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof with a 30 pharmaceutically acceptable carrier or excipient.

12. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as a medicament.

13. Use of the compound of any one of claims 1 to 9 or a P:\OPERJgcl18905-4I spec.doc-122/03 333 pharmaceutically acceptable salt thereof as an inhibitor of matrix metalloproteinases (MMP) or tumor necrosis factor a (TNF a).

14. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating and/or preventing MMP- or TNF a- mediated diseases.

15. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for treating and/or preventing MMP- or TNF a-mediated diseases.

16. The compound of claim 1 substantially as hereinbefore described with reference to the Examples. "to. DATED this 12 h day of February, 2003 Fujisawa Pharmaceutical Co., Ltd. By DAVIES COLLISON CAVE Patent Attorneys for the Applicants O 9 **0