AU1890500A - Cyclic compound - Google Patents

Description

WO 00/40576 PCT/JPOO/00018 DESCRIPTION CYCLIC COMPOUND 5 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 10 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 a), to pharmaceutical compositions comprising the same, to use of the same as medicaments, and to methods for using the same 15 therapeutically in the treatment and/or the prevention of MMP- or TNF u-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 One object of the present invention is 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 25 pharmacological activities such as MMP- or TNF a- inhibitory activity and the like. Another object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said cyclic compound or a pharmaceutically 30 acceptable salt thereof. A further object of the present invention is to provide use of said cyclic compounds and pharmaceutically acceptable salts thereof as medicaments for prophylactic and therapeutic treatment of MMP- or TNF a-mediated diseases. 35 A still further object of the present invention is to WO 00/40576 PCT/JP00/00018 2 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 5 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 10 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 15 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 (e.g., osteoarthritis and rheumatoid arthritis, etc.), cerebral disease (e.g., stroke, etc.), tissue ulceration (e.g., corneal, epidermal and gastric ulcerations, etc.), abnormal wound healing, periodontal disease, bone disease 25 (e.g., 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 object compounds of the present invention are novel and can be represented by the following formula (I): 35 WO 00/40576 PCT/JPOO/00018 3 Y Z 5 R 1 -X-Ar-(CH2) m (CH2)n-R 2 (I) in which R 1 is lower alkyl, halogen, optionally substituted heterocyclic group or optionally substituted aryl, 10 R 2 is carboxy, protected carboxy or amidated carboxy, Ar is optionally substituted aryl or optionally substituted heterocyclic group, A is lower alkylene, 15 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 1<m+n<6, 20 and its salt. The object compounds of the present invention can be prepared by the following processes. 25 Process 1 Y Z Removal of the carboxy 30 Rl-X-Ar-(CH2) m (CH2) nR protective group (I-a) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 4 Y Z 5 R1-X-Ar-(CH2)m (CH2)n-COOH (I-b) or a salt thereof Process 2 10 Y Z Oxidation of vinyl

R

1 -X-Ar-(CH2)m (CH 2 )n-CH=CH2 group 15 (II) or a salt thereof Y Z 20

R

1 -X-Ar- (CH2)m (CH2)n-COOH (I-b) or a salt thereof 25 Process 3 Y Z 30 R-X-Ar-(CH2)m (CH2)n-R 2 Reduction (I-c) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 5 Y Z 5 Rl-X-Ar-(CH2)m (CH2)n-R 2 (I-d) or a salt thereof 10 Process 4 y z NH2-R 15 R-X-Ar-(CH2)m (CH2)n-COOH (IV) or its reactive (I-b) derivative at or its reactive derivative the amino-group, at the carboxy-group, or a salt thereof or a salt thereof 20 Y Z Rl-X--Ar- (CH2)m (CH2)CONH-OR 3 25 (I-e) or a salt thereof Process 5 30 HN r H2N> -y Cycli zation 200 RR-X-Ar--(CH 2 ) CH~R 2 a (III) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 6 Y Z R1-X-Ar-(CH2)m CH2-R 2 (I-f) or a salt thereof Process 6 10 Y Z Oprically active R1-X-Ar- (CH 2 ) m (CH 2 ) -COOH amine or its reactive 15 (I-b) derivative at or its reactive derivative the amino-group, at the carboxy-group, or a salt thereof or a salt thereof 20 R'-X--Ar-(CH2)m (CH2)n-%2 (I-g) or a salt thereof 25 Process 7 Y Z Removal of the RR-X-Ar--(CH2)m - r(CH2)nCONHOR 3 hydroxy-protective group 30 a (I-h) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 7 Y Z

R

1 -X-Ar--(CH2)m (CH2)n-CONHOH 5 (I-i) or a salt thereof Process 8 10 Ya Za R1-X-Ar-(CH2)m (CH2)n-R 2 Oxidation (I-j) 15 or a salt thereof Yb Zb

R

1 -X-Ar-(CH2)m (CH2)n-R 2 (I-k) or a salt thereof 25 Process 9 4-BR 5 Y- Z y z I--,R6 30 R-X-Ar-(CH2)m (CH2)n-R 2 (V) (I-c) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 8 Y Z R1-X-Ar- (CH2) m>(CH2) n-R 2 5 (I -1) or a salt thereof Process 10 10 Y0 Z R1-X-Ar-(CH2)ml-L (VII) 2 or a salt thereof C 15 (VI) or a salt thereof Y Z 20 R1-X-Ar-(CH2)ml Rc2 (I-m) or a salt thereof Process 11 25 H HO Z R1-X-Ar-(CH2)m (CH2)n-R 2 Cyclization 30 (VIII) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 9 z

R

1 -X-Ar-(CH2)m (CH2)n-R 2 5 (I-n) or a salt thereof Process 12 10 0 HS-A-SH R1-X-Ar-(CH2)m (CH2)n-R 2 (X) (IX) 15 or a salt thereof S S 20 R1-X-Ar-(CH2)m (CH2)n-R 2 (I-0) or a salt thereof 25 Process 13 Y Z 30 Rl-X-Ar--(CH2)m (CH2)n-R 2 Amidation (I-p) or its reactive derivative at the carboxy group, or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 10 Y Z 5 Rl-X-Ar-(CH2)m (CH2)n-R 2 5 e (I-q) or a salt thereof Process 14 10 Y Z Rl-X-Ar-(CH2)m (CH2)n-R 2 Acylation 15 (I-r) or its reactive derivative at the amino group, or a salt thereof 20 y z Rl-X-Ar-(CH 2 )m (CH2)n-R 2 25 (I-S) or a salt thereof Process 15 30 r_ Y z Removal of the

R

1 -X-Ar-(CH2)m (CH2)n-R 2 amino-protective group (I-t) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 11 Y Z Rl-X-Ar-(CH2) -R2 5 fM(CH2) 0 R (I-r) or a salt thereof Psrocess 16 10 Y z Removal of the R1-X-Ar-(CH2)m><CH2)n-R2 hydroxy-protective group 15 (I-u) or a salt thereof Y Z 20 R-X-Ar-(CH2)m >(CH2)n-R 2 (I-v) or a salt thereof 25 Process 17 Y Z

R

1 -X-Ar- (CH 2 )m ><CH 2 )n-2 Oxidation 30 k (I-w) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 12 Y Z Rl-X-Ar-(CH2)m><(CH 2 )n--R 2 51 (I-x) or a salt thereof Process 18 10 Y Z Rl-X-Ar-(CH2)m (CH2)n-R2 Reduction is ( (I-y) 15 or a salt thereof Y Z 20 Rl-X-Ar-(CH2)m CH)-R2 n M<C2)n (I-z) or a salt thereof 25 Process 19 Y Z 30 Rl-X-Ar-(CH2)m (CH2)n-R 2 Oxidation (I-aa) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 13 y z 5 RI-X-Ar-(CH2)m><(CH2)n-R2 (I-ab) or a salt thereof 10 Process 20 Y Z R1.-X-Ar-(CH2)m (CH2)n-R 2 Acylation 15 ] (I-v) or a salt thereof 20 y z Rl-X-Ar- (CH2)m> (CH2) n-R 2 (I-ac) or a salt thereof 25 Process 21 R1-L (XII) Y Z 30 R 5 or a salt thereof "'B-Ar- (CH2) (CH2)n-R 2 R6 (XI) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 14 Y Z

R

1 -Ar- (CH 2 ) CH2)n-R 2 (I-ad) or a salt thereof Process 22 10 Y Z Removal of the Rl-X-Ar-(CH 2 )n (CH2)n-R 2 carboxy-protective group (I-ae) 15 or a salt thereof 20 Y Z Rl-X-Ar-(CH2)m (CH2)n-R 2 (I-p) or a salt thereof 25 Process 23 Y Z Rl-X-Ar-(CH 2 )r (CH2)n-R 2 Substituted amine 30 (I-af) or a salt thereof 35 WO 00/40576 PCT/JPOO/00018 15 Y Z 5 Rt-XAr-(CH2)m (CH2)n-R 2 (I-ag) or a salt thereof in which R', R 2 , Ar, A, X, Y, Z, m and n are each as 10 defined above, R is haloaryl or halo, R is aryl, R is aryl at least substituted by optionally substituted aryl, 15 R is aryl at least having carboxy moiety, Ri aryl at least having amid moiety, R is aryl at least having amino moiety, i aryl at least having acylamino moiety, R is aryl at least having protected amino moiety, 20 R is aryl at least having protected hydroxy moiety, R is aryl at least having hydroxy moiety, ] R is aryl at least having thia moiety, Ris aryl at least having sulfinyl or sulfonyl moiety, 25 R is aryl at least having formyl moiety, R is aryl at least having hydroxy moiety, R is aryl at least having hin yl moiety, Ris aryl at least having vulinyl moety, on Ris aryl at least having 1,2-dihydroxyethyl moiety, 30 R is aryl at least having acyloxy moiety, p Rr is aryl at least having protected carboxy moiety, i Rs is aryl at least having halo(lower)alkanoyl moiety, R1 is aryl at least having substituted 35 amino(lower)alkanoyl moiety, WO 00/40576 PCT/JPOO/00018 16 R is protected carboxy, R2 is optically active amide, R is protected carboxy, R3 is hydrogen or hydroxy-protective group, 5 is hydroxy-protective group, R4 is optionally substituted aryl,

R

5 and R 6 are each hydrogen or combinedtogether to form lower alkylene, Ya is thia, sulfinyl or sulfonyl, 10 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, 15 provided that at least one of Yb and Zb is sulfinyl or sulfonyl, L is a leaving group, and ml is an integer of 1 to 6. 20 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 (I) to (I-ae) may be conventional non-toxic pharmaceutically acceptable 25 salts and include an acid addition salt such as an organic acid salt (e.g., acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, 30 nitrate, phosphate, etc.), or a salt with a base such as an amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.), an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, an organic WO 00/40576 PCT/JPOO/00018 17 base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), or the like. The object compounds and pharmaceutically acceptable 5 salts thereof may include solvates such as enclosure compounds (e.g., 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 10 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 15 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. 20 above-mentioned aryl, which is substituted by the group consisting of the following (Al) to (A35); (Al) halogen, (A2) lower alkyl, (A3) lower alkoxy, 25 (A4) halo(lower)alkyl, (A5) halo(lower)alkoxy, (A6) lower alkenyl, (A7) acyl, (A8) lower alkylthio, lower alkylsulfinyl, lower 30 alkylsulfonyl, (A9) C 6

-C

10 aryl (AlO) halo(C 6

-C

10 )aryl, (All) hydroxy, (A12) hydroxy(lower)alkyl, protected 35 hydroxy(lower)alkyl, WO 00/40576 PCT/JP0O/00018 18 (A13) amino, (A14) carboxy, (A15) protected carboxy, (A16) nitro(lower)alkenyl, 5 (A17) lower alkylenedioxy, (A18) acylamino, (A19) nitro, (A20) (C 6

-C

10 )aryl(lower)alkoxy, (A21) carbamoyl(lower)alkenyl optionally 10 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, 15 (A24) lower alkoxy(lower)alkanoyloxy, (A25) lower alkoxycarbonyloxy, (A26) lower alkenoyloxy optionally substituted by heterocyclic group of the above (1) to (14), (A27) lower cycloalkanecarbonyloxy, 20 (A28) lower alkoxy substituted by the group consisting of carboxy, protected carboxy, lower alkanoyl, lower cycloalkanecarbamoyl, and lower alkylcarbamoyl, (A29) lower alkylcarbamoyloxy(lower)alkyl, 25 (A30) lower alkoxycarbonylamino(lower)alkyl, (A31) amino(lower)alkyl, (A32) lower alkylcarbamoyl(lower)alkyl, (A33) heterocyclic-carbonylamino, the heterocyclic group being selected from the above (1) to 30 (14) and optionally being substituted N protective group, (A34) the above heterocyclic groups (1) to (14) being optionally substituted by lower alkyl, and 35 (A35) oxo.

WO 00/40576 PCT/JPOO/00018 19 Suitable "heterocyclic group" in the term "optionally substituted heterocyclic group" means saturated or unsaturated, monocyclic or polycyclic heterocyclic group 5 containing at least one hetero atom such as oxygen atom, sulfur atom, nitrogen atom and the like. Preferable heterocyclic groups are following (1) to (14): 10 (1) unsaturated 3- to 8-membered, preferably 5- or 6 membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, 15 pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2 H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4 triazinyl, 2 ,5-dihydro-1,2,4-triazinyl, etc.), and 20 the like); (2) saturated 3- to 8-membered, preferably 5- or 6 membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (azetidinyl,.pyrrolidinyl, imidazolidinyl, 25 piperidinyl, piperidino, pyrazolidinyl, piperazinyl, and the like); (3) unsaturated 3- to 8-membered, preferably 5- or 6 membered, heteromonocyclic group containing 1 or 2 sulfur atoms 30 (thienyl, and the like); (4) unsaturated condensed (preferably bicyclic) 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 to 5 nitrogen atoms 35 (indolyl, isoindolyl, indolizinyl, benzimidazolyl, WO 00/40576 PCT/JPOO/00018 20 qinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-blpyridazinyl, etc.), dihydrotriazolopyridazinyl, and the like); 5 (5) unsaturated 3- to 8-membered, preferably 5- or 6 membered, heteromonocyclic group containing 1 or 2 oxygen atoms (furyl, and the like); (6) saturated 3- to 8-membered, preferably 5- or 6 10 membered, heteromonocyclic group containing 1 or 2 oxygen atoms (oxolanyl, and the like); (7) unsaturated 3- to 8-membered, preferably 5- or 6 membered, heteromonocyclic group containing 1 or 2 15 oxygen atoms and 1 to 3 nitrogen atoms (oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4 oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), and the like); (8) unsaturated condensed (preferably bicyclic) 7- to 20 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 oxygen atoms (benzofuranyl, benzodihydrofuranyl, benzodioxolenyl, and the like); (9) unsaturated condensed (preferably bicyclic) 7- to 25 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 sulfur atoms (benzothienyl, dihydrobenzothienyl, and the like); (10) saturated 3- to 8-membered, preferably 5- or 6 membered, heteromonocyclic group containing 1 or 2 30 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 10-membered, heterocyclic group containing 1 or 2 oxygen atoms 35 and 1 to 3 nitrogen atoms WO 00/40576 PCT/JPOO/00018 21 (benzoxazolyl, benzoxadiazolyl, and the like); (12) unsaturated 3- to 8-membered, preferably 5- or 6 membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms 5 (thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4 thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3 thiadiazolyl, etc.), and the like); (13) saturated 3- to 8-membered, preferably 5- or 6 10 membered, 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 10-membered, 15 heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms (benzothiazolyl, benzothiadiazolyl, and the like); etc. 20 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 (A35)) 25 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, tert butyl, pentyl, hexyl and the like, and the most preferably methyl for Ri. 30 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 35 branched alkenyl having 1 to 6 carbon atoms, and exemplified WO 00/40576 PCT/JPOO/00018 22 by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like. Suitable "hydroxy-protective group" may include a 5 conventional protective group, for example, substituted lower alkyl such as lower alkoxy(lower)alkyl (e.g., methoxymethyl), lower alkoxy(lower)alkoxy(lower)alkyl (e.g., methoxyethoxymethyl) and substituted or unsubstituted aryl(lower)alkyl (e.g., benzyl nitrobenzyl); acyl such as 10 lower alkanoyl (e.g., acetyl, propionyl, pivaloyl), aroyl (e.g., benzoyl, fluorenecarbonyl), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl), 15 substituted or unsubstituted aryl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, bromobenzyloxycarbonyl), arenesulfonyl (e.g., benzenesulfonyl, tosyl) and alkanesulfonyl (e.g., methanesulfonyl, ethanesulfonyl); tri(lower)alkylsilyl (e.g., trimethylsilyl); tetrahydropyranyl; and the like, preferably 20 tetrahydropyranyl. Suitable "halogen" includes fluorine, bromine, chlorine and iodine. Suitable acyl and acyl moiety of "acylamino" includes acyl such as aliphatic acyl, aromatic acyl, heterocyclic 25 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 (e.g., formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g., mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, 35 hexylsulfonyl, etc.), carbamoyl, N-alkylcarbamoyl (e.g., WO 00/40576 PCT/JPOO/00018 23 methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower 5 alkenyloxycarbonyl (e.g., vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g., acryloyl, methacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g., cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the 10 like. The aromatic acyl may include C 6

~C

10 aroyl (e.g., benzoyl, toluoyl, xyloyl, etc.), N-(C 6

-C

10 )arylcarbamoyl (e.g., N-phenylcarbamoyl, N-tolylcarbamoyl, N-naphthylcarbamoyl, etc.), C 6 -C1 0 arenesulfonyl (e.g., 15 benzenesulfonyl, tosyl, etc.), and the like. The heterocyclic acyl may include heterocyclic-carbonyl (e.g., furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like. 20 The aliphatic acyl substituted by aromatic group(s) may include aralkanoyl such as phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 25 aryloxyalkanoyl such as phenoxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.), and the like. The aliphatic acyl substituted by heterocyclic group(s) may include heterocyclic-alkanoyl such as heterocyclic (lower)alkanoyl (e.g., thienylacetyl, imidazolylacetyl, 30 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 35 substituted aryl" (above-mentioned (Al) to (A35)).

WO 00/40576 PCT/JPOO/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 (e.g., methyl ester, ethyl 5 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 [e.g., acetoxymethyl 10 ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or 3-)acetoxypropyl ester, 1-(or 2- or 3- or 4-) acetoxybutyl ester, 1-(or 2 -)propionyloxyethyl ester, 15 1-(or 2- or 3 -)propionyloxypropyl ester, 1-(or 2-) butyryloxyethyl ester, 1-(or 2 -)isobutyryloxyethyl ester, 1-(or 2-)pivaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3 ,3-dimethylbutyryloxymethyl ester, 1-(or 2-) 20 pentanoyloxyethyl ester, etc.], lower alkanesulfonyl(lower) alkyl ester (e.g., 2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester (e.g., 2-iodoethyl ester, 2 ,2,2-trichloroethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester [e.g., 25 methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, tert-butoxycarbonyloxymethyl ester, 1-(or 2 -)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 30 1-(or 2-)isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene(lower)alkyl ester, (5-lower alkyl-2-oxo-1,3 dioxol-4-yl) (lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3 dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4 yl)methyl ester, (5-propyl- 2 -oxo-1,3-dioxol-4-yl)ethyl ester, 35 etc.]; lower alkenyl ester (e.g., vinyl ester, allyl ester, WO 00/40576 PCT/JPOO/00018 25 etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); ar(lower)alkyl ester which may have at least one suitable substituent (e.g., benzyl ester, 4 methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, 5 trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent (e.g., phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, 10 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 15 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 20 -carbamoyl, -N-hydroxycarbamoyl, -N-(protected hydroxy)carbamoyl, wherein said hydroxy protective group may be the same as mentioned above (e.g. tetrahydropyranyl, etc.), 25 -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, 30 diethylcarbamoyl, etc.), -N-(aryl(lower)alkyl)carbamoyl such as phenyl(lower) alkylcarbamoyl (e.g. 1-phenylethylcarbamoyl, (R)-(+)-1-phenylethyl, etc.), -cyclo(C 3

-C

7 )alkylcarbamoyl (e.g. cyclohexylcarbamoyl, 35 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 (e.g. pyrrolidin-1-ylcarbonyl, hexahydro-1H-azepin-1-ylcarbonyl, etc.), 5 said alkylene being optionally substituted by carboxy or protected carboxy as mentioned above such as lower alkoxycarbonyl [e.g. carboxypyrrolidin-1-ylcarbonyl, (methoxycarbonyl)pyrrolidin-1-ylcarbonyl, 10 (ethoxycarbonyl)pyrrolidin-1-ylcarbonyl, etc.], or said lower alkylene being optionally interrupted by other hetero atom(s) such as nitrogen, oxygen or sulfur (e.g. 15 morpholinocarbonyl, etc.), -lower alkylsulfonylcarbamoyl (e.g. methylsulfonylcarbamoyl, etc.), -arenesulfonylcarbamoyl (e.g. benzenesulfonylcarbamoyl, etc.), and the like. 20 Preferable example of the amidated carboxy thus defined may be : N-hydroxycarbamoyl, N-tetrahydropyranyloxycarbamoyl, and N-(phenylethyl)carbamoyl for R 2 . 25 Suitable "leaving group" may include halogen as mentioned above, acyloxy such as sulfonyloxy (e.g., mesyloxy, tosyloxy, etc.), alkoxy (e.g., tert-butoxy, etc.), aralkoxy (e.g., benzyloxy, etc.), and the like, preferably halogen 30 and the most preferably bromine. Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, 35 propylene, tetramethylene, ethylethylene, pentamethylene, WO 00/40576 PCT/JPOO/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, 1-methyltrimethylene, and trimethylene. 5 Suitable "halo(lower)alkyl" may be above-mentioned lower alkyl substituted by halogen as mentioned above, in which more preferable one may be halo(Cl-C 4 )alkyl. Suitable "halo(lower)alkoxy" may be above-mentioned 10 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 15 preferable one may be C 1

-C

4 alkylthio (e.g. methylthio, ethylthio, etc.). Suitable "lower alkylsulfinyl" may include methylsulfinyl, ethylsulfinyl, and the like, in which more 20 preferable one may be CI-C 4 alkylsulfinyl (e.g. methylsulfinyl, etc.). Suitable "lower alkylsulfonyl" may include methylsulfonyl, ethylsulfonyl, and the like, in which more 25 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 30 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 35 which more preferable one may be hydroxy(Cl-C 4 )alkyl.

WO 00/40576 PCT/JPO0/00018 28 Suitable "protected hydroxy(lower)alkyl" may be above mentioned hydroxy(lower)alkyl group protected by a conventional hydroxy-protective group such as acyl, (lower 5 alkyl) (diaryl)silyl group (e.g. (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 10 be phenyl(Cl-C 4 )alkoxy (e.g. 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. 15 carbamoylethenyl, etc.). Suitable "lower alkoxyaryl" may include methoxyphenyl, ethoxyphenyl, and the like, in which more preferable one may be C 1

-C

4 alkoxyphenyl (e.g. methoxyphenyl, etc.). 20 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 (e.g. carbamoylethenyl, 25 methylcarbamoylethenyl, ethylcarbamoylethenyl, propylcarbamoylethenyl, isopropycarbamoylethenyl, dimethylcarbamoylethenyl, etc.),

C

6

-C

10 arylcarbamoyl(lower)alkenyl (e.g. phenylcarbamoylethenyl, etc.), lower alkoxy(C 6

-C

10 )arylcarbamoyl(lower)alkenyl (e.g. 30 methoxyphenylcarbamoylethenyl, etc.), haloarylcarbamoyl(lower)alkenyl (e.g. fluorophenylcarbamoylethenyl, etc.), and the like. Suitable "lower alkylaminocarbonyloxy" may include 35 methylaminocarbonyloxy, ethylaminocarbonyloxy, and the like, WO 00/40576 PCT/JPOO/0001 8 29 in which more preferable one may be Cl-C4 alkylaminocarbonyloxy (e.g. methylaminocarbonyloxy, ethylaminocarbonyloxy, etc.). 5 Suitable "lower alkanoyloxy" may include acetyoxy, propanoyloxy, and the like, in which more preferable one may be C 1

-C

4 alkanoyloxy (e.g. propanoyloxy, etc.). Suitable "lower alkoxy(lower)alkanoyloxy" may include 10 methoxyacetyloxy, ethoxyacetyloxy, and the like, in which more preferable one may be C 1

-C

4 alkoxy(Cl-C 4 )alkanoyloxy (e.g. methoxyacetyloxy, etc.). Suitable "lower alkoxycarbonyloxy" may include 15 methoxycarbonyloxy, ethoxycarbonyloxy, and the like, in which more preferable one may be C 1

-C

4 alkoxycarbonyloxy (e.g. ethoxycarbonyloxy, etc.). Suitable "lower alkenoyloxy" may include acryloyloxy, 20 and the like, in which more preferable one may be C2-C4 alkenoyloxy (e.g. 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 (1) (e.g. 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 4

-C

6 alkanecarbonyloxy (e.g. cyclopropanecarbonyloxy, etc.). 35 Suitable "lower cycloalkanecarbamoyl" may include C3-C7 WO 00/40576 PCT/JPOO/00018 30 cycloalkanecarbamoyl such as cyclopropanecarbamoyl, cyclobutanecarbamoyl, and the like, in which more preferable one may be C 4

-C

6 cycloalkanecarbamoyl (e.g. cyclopropanecarbamoyl, etc.). 5 Suitable "lower alkylcarbamoyl" may include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and the like, in which more preferable one may be Cl-C4 alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, 10 propylcarbamoyl, etc.). Preferable examples of "lower alkoxy substituted by the group consisting of carboxy, protected carboxy, lower alkanoyl, lower cycloalkanecarbamoyl, lower alkylcarbamoyl 15 may include arboxy(lower)alokoxy (e.g. carboxymethoxy, etc.), lower alkoxycarbonyl(lower)alkoxy (e.g. ethoxycarbonylmethoxy, butoxycarbonylmethoxy, etc.), lower alkanoyl(lower)alkoxy (e.g. propanoylmethoxy, etc.), lower cycloalkanecarbamoyl(lower)alkoxy (e.g. 20 cyclopropylcarbamoylmethoxy, etc.), loweralkylcarbamoyl(lower)alkoxy (e.g. methylcarbamoylmethoxy, ethylcarbamoylmethoxy, propylcarbamoylmethoxy, etc.), and the like. 25 Suitable "lower alkylcarbamoyloxy(lower)alkyl" may include methylcarbamoyloxymethyl, ethylcarbamoyloxymethyl, and the like, in which more preferable one may be Cl-C4 alkylcarbamoyloxy(Ci-C 4 )alkyl (e.g. methylcarbamoyloxymethyl, etc.). 30 Suitable "lower alkoxycarbonylamino(lower)alkyl" may include methoxycarbonylaminomethyl, t-butoxycarbonylaminomethyl, and the like, in which more preferable one may be Cl-C 4 alkoxycarbonylamino(Ci-C 4 )alkyl 35 (e.g. methoxycarbonylaminomethyl, WO 00/40576 PCT/JPOO/00018 31 t-butoxycarbonylaminomethyl, etc.). Suitable "amino(lower)alkyl" may include aminomethyl, aminoethyl, and the like, in which more preferable one may 5 be amino(CI-C 4 )alkyl (e.g aminomethyl, etc.). Suitable "lower alkylcarbamoyl(lower)alkyl" may include methylcarbamoylmethyl, methylcarbamoylethyl, ethylcarbamoylmethyl, ethylcarbamoylethyl, and the like, in 10 which more preferable one may be C 1

-C

4 alkylcarbamoyl (Cl-C 4 )alkyl (e.g. methylcarbamoylmethyl, etc.). Suitable "heterocyclic-carbonylamino" may include carbonylamino group substituted by the above-mentioned 15 heterocyclic group (2), (4) and (5) (e.g. pyrrolidinyl, teretahydroisoquinolyl, furyl, etc.) such as pyrrolidinylcarbonylamino, 1,2,3,4 teretahydroisoquinolylcarbonylamino, furylcarbonylamino, and the like. 20 Preferable examples of "optionally substituted heterocyclic-carbonylamino" may include above-mentioned heterocyclic-carbonylamino optionally the heterocyclic group being substituted by N-protective group (e.g. acyl such as 25 alkoxycarbonyl, etc.) such as pyrrolidinylcarbonylamino, 1,2,3, 4 -teretahydroisoquinolylcarbonylamino, (N-(t butoxycarbonyl)-1,2,3, 4 -teretahydroisoquinolyl) 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 35 branched one such as methylenedioxy, ethylenedioxy, WO 00/40576 PCT/JPOO/00018 32 trimethylenedioxy, propylenedioxy, tetramethylenedioxy, ethylethylenedioxy, pentamethylenedioxy, hexamethylenedioxy, and the like, in which more preferable one may be C1-C4 alkylenedioxy. 5 Suitable "amido" may be the same as those for "amidated carboxy", and preferably lower alkylcarbamoyl, and the most preferably methylcarbamoyl. 10 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), 15 (A14) to (A17), (A20) to (A32) and (A34). Preferable examples may be hydroxy (lower)alkylamine (e.g. hydroxyethylamine, etc.), above-mentioned N-containing heterocyclic group (e.g. morpholino, etc.), lower 20 alkenylamine (e.g. allylamine, etc.),

C

6

-C

10 aryl(lower)alkylamine e.g. benzylamine, etc.), lower alkylamine (e.g. t-butylamine, pentylamine, etc.), heterocyclic(lower)alkylamine such as pyridyl (lower)alkylamine (e.g. pyridylmethylamine, etc.), 25 lower alkoxy(lower)alkylamine (e.g. ethoxyethylamine, etc.), and the like. Preferable examples of the formula: 30 Y Z is one of the following formulae: 35 WO 00/40576 PCT/JPOO/00018 33 S , 2 '

CH

3 5 OQ , ' 02 1 or 02n 0 ' 10 2<> and the like. In the object compounds (I), 15 (i) the preferred one may be the compounds (I) wherein m and n are each 0 or 1, and (ii) the more preferred one may be the compounds of the above item (i) wherein A is ethylene, 1-methyltrimethylene, or trimethylene. 20 The more preferred object compounds (I) are: (iii) The compounds (I), having the following formula: 25 R1-X Y Z

(CH

2 )m (CH2 -R 2 (IA) 30 wherein a group of the formula: Y Z 35 is one of the following formulae: WO 00/40576 PCT/JPOO/00018 34 S 02 '

CH

3 10 or 02 2 Ri is lower alkyl, phenyl, halophenyl, or (halo) (phenyl)phenyl, R2 is carboxy or hydroxyaminocarbonyl, and 15 m and n are each an integer of 0 or 1, and m+n=1. (iV) The compounds (I), having the following formula: 20 Y Z 0 R 1

(CH

2 ) m<(CH 2 )R2 (TB) S wherein a group of the formula: 25 Y Z is one of the following formulae: 30 , 2 ' 0 0 02 35 O

Q)

WO 00/40576 PCT/JPOO/00018 35 or 02n O2 5 R2 is carboxy or hydroxyaminocarbonyl, m and n are each an integer of 0 or 1, and m+n=1, R is halogen; heterocyclic group consisting of pyridyl, thienyl, furyl, benzofuranyl or 10 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 15 group consisting of the following (Cl) to (C31); (Cl) halogen, (C2) lower alkyl, (C3) lower alkoxy, (C4) halo(lower)alkyl, 20 (C5) halo(lower)alkoxy, (C6) lower alkenyl, (C7) lower alkylcarbamoyl, carbamoyl, phenyl(lower)alkylcarbamoyl, lower alkanoyl, (C8) lower alkylthio, lower alkylsulfinyl, lower 25 alkylsulfonyl, (C9) phenyl, naphthyl, (ClO) halophenyl, (Cl) hydroxy, (C12) mono- or dihydroxy(lower)alkyl, 30 phenoxycarbonyloxy (lower) alkyl (C13) amino, (C14) carboxy, (C15) lower alkylenedioxy, (C16) lower alkanoylamino, 35 phenyl(lower)alkanoylamino, WO 00/40576 PCT/JPOO/00018 36 halophenyl(lower)alkanoylamino, lower alkoxy(lower)alkanoylamino, lower alkoxy(lower)alkanoylamino, phenoxy(lower)alkanoylamino, lower 5 alkoxyphenoxy(lower)alkanoylamino, lower alkylphenoxy(lower)alkanoylamino, halophenoxy(lower)alkanoylamino, carboxy(lower)alkanoylamino, lower alkoxycarbonyl(lower)alkanoylamino, 10 lower alkylcarbamoyl(lower)alkanoylamino, halo(lower)alkanoylamino, lower alkenyl(lower)alkanoylamino, lower alkoxy(lower)alkanoylamino, phenyl(lower)alkoxy(lower)alkanoylamino, 15 piperidinyloxy(lower)alkanoylamino, N-lower alkoxycarbonylpiperidinyloxy (lower)alkanoylamino, pyridyloxy(lower) alkanoylamino, hydroxy(lower)alkanoylamino, 20 lower alkanoyloxy(lower)alkanoylamino, lower alkylcarbamoyloxy(lower)alkanoylamino, N,N-di(lower alkyl)carbamoyloxy, piperidino-carbonyloxy(lower)alkanoylamino, phenyl(lower)alkylcarbamoyloxy(lower) 25 alkanoylamino, lower alkoxycarbonylamino(lower)alkanoylamino, amino(lower)alkanoylamino, lower alkoxycarbonylamino(lower)alkanoylamino, fluorenylmethoxycarbonylamino(lower) 30 alkanoylamino, lower alkylamino(lower)alkanoylamino, [N,N-di(lower alkyl)amino](lower)alkanoylamino, [N-lower alkyl-N-(lower alkoxycarbonyl)amino](lower)alkanoylamino, 35 [N-lower alkyl-N-(fluorenylmethoxycarbonyl)- WO 00/40576 PCT/JPOO/00018 37 amino] (lower)alkanoylamino, [N-lower alkyl-N-(mono- or di(lower) alkylcarbamoyl)amino](lower)alkanoylamino, [N-(mono- or di(lower alkyl)carbamoyl) 5 amino](lower)alkanoylamino, benzoylamino(lower)alkanoylamino, lower alkanoylamino(lower)alkanoylamino, lower alkanesulfonylamino(lower)alkanoylamino, lower alkoxy(lower)alkanoylamino 10 (lower)alkanoylamino, cyclo(lower)alkyloxycarbonylamino (lower)alkanoylamino, pyridylcarbonylamino(lower)alkanoylamino, morpholinocarbonylamino(lower)alkanoylamino, 15 phenyl(lower)alkoxycarbonylamino (lower)alkanoylamino, lower alkoxyphenylsulfonylamino (lower)alkanoylamino, hydroxy(lower)alkylamino(lower)alkanoylamino, 20 morpholino(lower)alkanoylamino, oxooxazolidinyl(lower)alkanoylamino, oxopyrrolidinyl(lower)alkanoylamino, trimethylhydantoinyl(lower)alkanoylamino, lower alkenylamino(lower)alkanoylamino, 25 lower alkoxy(lower)alkylamino(lower) alkanoylamino, phenyl(lower)alkylamino(lower)alkanoylamino, pyridyl(lower)alkylamino(lower)alkanoylamino, lower alkoxycarbonylamino, 30 phenyl(lower)alkoxycarbonylamino, lower alkoxy(lower)alkoxycarbonylamino, halo(lower)alkoxycarbonylamino, amino(lower)alkoxycarbonylamino, phthalimido(lower)alkoxycarbonylamino, 35 carbamoylamino, WO 00/40576 PCT/JPOO/00018 38 (mono- or di(lower alkyl)carbamoylamino, naphthylcarbamoylamino, halophenylcarbamoylamino, lower alkoxyphenylcarbamoylanino, 5 lower alkenylcarbamoylamino, cyclo (lower) alkyl (lower) alkylcarbamoylamino, phenyl (lower) alkylcarbamoylamino, halo (lower) alkylcarbamoylamino, lower alkoxy (lower) alkylcarbamoylamino, 10 hydroxy (lower) alkylcarbamoylamino, (lower alkyl) (diphenyl) silyloxy (lower) alkyl carbamoylamino, carboxy (lower) alkylcarbamoylamino, lower alkoxycarbonyl (lower)alkylcarbamoylamino, 1s lower alkylcarbamoyl (lower) alkyl carbamoylamino, or pyridylcarbamoylamino, lower alkylsulfonylamino, lower alkenoylamino, 20 lower cycloalkanecarbonylamino, lower alkenyloxycarbonylamino, phenoxycarbonylamino, lower alkyithiocarbonylamino, (C17) phenyl(lower)alkoxy, 25 (C18) lower alkenyl, mono- or di(lower alkyl) carbamoyl(lower)calkenyl, (2 (methylcarbamoyl)ethenyl, 2 (ethylcarbamoyl)ethenyl, 2 (propylcarbamoyl)ethenyl, 2 30 (isopropylcarbamoyl)ethenyl, 2 (dimethylcarbamoyl)ethenyl,) phenylcarbamoyl(lower)alkenyl, lower alkoxycarbamoyl(lower)alkenyl, halophenylcarbamoyl(lower)alkenyl, 35 (C19) lower alkylaminocarbonyloxy, WO 00/40576 PCT/JP00/00018 39 (C20) lower alkanoyloxy, (C21) lower alkoxy(lower)alkanoyloxy, (C22) lower alkoxycarbonyloxy, (C23) pyridyl(lower)alkenoyloxy 5 (C24) lower cycloalkanecarbonyloxy, (C25) carboxy(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy, lower alkanoyl(lower)alkoxy, lower cycloalkanecarbamoyl(lower)alkoxy, 10 lower alkylcarbamoyl(lower)alkoxy, (C26) lower alkylcarbamoyloxy(lower)alkyl, (C27) lower alkoxycarbonylamino(lower)alkyl, (C28) amino(lower)alkyl, (C29) lower alkylcarbamoyl(lower)alkyl, 15 (C30) furylcarbonylamino, teretahydroisoquinolylcarbonylamino, N-lower alkoxycarbonyl teretahydroisoquinolylcarbonylamino, pyrrolidinylcarbonylamino, 20 (C31) oxazolyl, lower alkyloxadiazolyl. (V) The compounds (I) of the above (iv), in which a group of the formula: 25 yz is one of the following formulae: 30 S 02 s 35 WO 00/40576 PCT/JPOO/00018 40 R2 is hydroxyaminocarbonyl, m is 0 and n is 1, a group of the formula: R r S 5 is one of the group of the following formulae (a) to (e); (a) 10 Rll S wherein R is halo (e.g. bromo, etc.), naphtyl (e.g. 2-naphthyl, etc.), phenyl (e.g. phenyl, etc.), mono- or 15 dihalophenyl (e.g. 3(or 4)-chlorophenyl, 2(or 3 or 4)-fluorophenyl, 3,4-dichlorophenyl, 3,5 difluorophenyl, etc.), mono- or di(lower)alkylphenyl (e.g. 3(or 4)-methylphenyl, 4-ethylphenyl, 4 isopropylphenyl, 4-(t-butyl)phenyl, 3,4 20 dimethylphenyl, etc.), lower alkoxyphenyl (e.g. 4 methoxyphenyl, 4-ethoxyphenyl, etc.), trihalo(lower)alkylphenyl (e.g. 4 trifluoromethylphenyl, etc.), trihalo(lower)alkoxyphenyl (e.g. 4 25 trifluoromethoxyphenyl, etc.), lower alkenylphenyl (e.g. 4-ethenylphenyl, etc.), lower alkylcarbamoylphenyl (e.g. 4-methylcarbamoylphenyl, 4-ethylcarbamoylphenyl, etc.), carbamoylphenyl (e.g. 4-carbamoylphenyl, etc.), 30 phenyl(lower)alkylcarbamoylphenyl (e.g. 4 benzylcarbamoylphenyl, etc.), lower alkanoylphenyl (e.g. 4-acetylphenyl, etc.), lower alkylthiophenyl, lower alkylsulfinylphenyl, lower alkylsulfonylphenyl (e.g. 4-methylthiophenyl, 4-ethylthiophenyl, 4 35 methylsulfinylphenyl, 4-methylsulfonylphenyl, etc.), WO 00/40576 PCT/JPOO/00018 41 phenylphenyl (e.g. phenylphenyl, etc.), (halo) (phenyl)phenyl (e.g. 4-phenyl-3-fluorophenyl etc.), halophenylphenyl (e.g. 4-(4 fluorophenyl)phenyl etc.) hydroxyphenyl (e.g. 3(or 5 4)-hydroxyphenyl, etc.), mono- or dihydroxy(lower)alkylphenyl, phenoxycarbonyloxy(lower)alkylphenyl, (e.g. 3(or 4) hydroxymethylphenyl, 4-(1,2-dihydroxyethyl)phenyl, 4-(phenoxycarbonyloxymethyl)phenyl, etc.), 10 aminophenyl(e.g. 3(or 4)-aminophenyl, etc.), carboxyphenyl (e.g. 4-carboxyphenyl, etc.), lower alkylendioxyphenyl (e.g. 3,4-methylendioxyphenyl, etc.), lower alkanesulfonylaminophenyl (e.g. 4 -(methanesulfonylamino)phenyl etc.), lower 15 alkenoylaminophenyl, (e.g. 3- (2-butenoylamino)phenyl, etc.), lower cycloalkanecarbonylaminophenyl (e.g. 3-(cyclopropanecarbonylamino)phenyl, 3-(cyclobutanecarbonylamino)phenyl, 3-(cyclopentanecarbonylamino)phenyl, etc.) 20 phenyl(lower)alkoxyphenyl (e.g. 4-benzyloxyphenyl, etc.), carbamoyl(lower)alkenylphenyl, mono- or di(lower alkyl)carbamoyl(lower)alkenylphenyl (e.g. 4-(2-(methylcarbamoyl)ethenyl)phenyl, 4-(2-(ethylcarbamoyl)ethenyl)phenyl, 25 4-(2-(propylcarbamoyl)ethenyl)phenyl, 4-(2-(isopropycarbamoyl)ethenyl)phenyl, 4-2-(dimethylcarbamoyl)ethenyl)phenyl, etc.) phenylcarbamoyl(lower)alkenyl (e.g. 4-(2-(phenylcarbamoyl)ethenyl)phenyl, etc.), 30 lower alkoxycarbamoyl(lower)alkenyl (e.g. 4-(2-(methoxyphenylcarbamoyl)ethenyl)phenyl, etc.), halophenylcarbamoyl(lower)alkenyl (e.g. 4-(2-( 4 -fluorophenylcarbamoyl)ethenyl)phenyl, etc.) lower alkylcarbamoyloxyphenyl (e.g. 35 4-(methylaminocarbonyloxy)phenyl, WO 00/40576 PCT/JPOO/00018 42 4-(ethylaminocarbonyloxy)phenyl, etc.), lower alkanoyloxyphenyl (e.g. 4-propanoyloxyphenyl, etc.) lower alkoxy(lower)alkanoyloxyphenyl (e.g. 4-(methoxyacetyloxy)phenyl, etc.) 5 lower alkoxycarbonyloxyphenyl (e.g. 4-(ethoxycarbonyloxy)phenyl, etc.) pyridyl(lower)alkenoyloxyphenyl (e.g. 4-(3-(3-pyridyl)acryloyloxy)phenyl, etc.), cyclo(lower)alkylcarbonyloxyphenyl (e.g. 10 4-(cyclopropylcarbonyloxy)phenyl, etc.), carboxy(lower)alkoxyphenyl (e.g. 4-(carboxymethoxy)phenyl, etc.) lower alkoxycarbonyl(lower)alkoxyphenyl (e.g. 4-(ethoxycarbonylmethoxy)phenyl, 15 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.), 20 lower alkylcarbamoyl(lower)alkoxyphenyl (e.g. 4-(methylcarbamoylmethoxy)phenyl, 4-(ethylcarbamoylmethoxy)phenyl, 4-(propylcarbamoylmethoxy)phenyl, etc.), lower alkylcarbamoyloxy(lower)alkylphenyl (e.g. 25 3(or 4)-(methylcarbamoyloxymethyl)phenyl, etc.), lower alkoxycarbonylamino(lower)alkylphenyl (e.g. 4-(methoxycarbonylaminomethyl)phenyl, 4-(t-butoxycarbonylaminomethyl)phenyl, etc.), amino(lower)alkylphenyl (e.g. 4-aminomethylphenyl, 30 etc.), lower alkylcarbamoyl(lower)alkylphenyl (e.g. 4-(methylcarbamoylmethyl)phenyl, etc.), furylcarbonylaminophenyl, 1,2,3,4-teretahydro isoquinolylcarbonylaminophenyl, N-Boc-1,2,3,4 teretahydroisoquinolylcarbonylaminophenyl, 35 pyrrolidinylcarbonylaminophenyl (e.g.

WO 00/40576 PCT/JPOO/00018 43 3-(2(or 3)-furylcarbonylamino)phenyl, 3-(1,2,3,4-teretahydroisoquinolylcarbonylamino) phenyl, 3-(N-(t-butoxycarbonyl)-1,2,3,4 teretahydroisoquinolylcarbonylamino)phenyl, 5 3-(pyrrolidinylcarbonylamino)phenyl, etc.), oxazolylphenyl (e.g. 4-(1,3-oxazolyl)phenyl, etc.), lower alkyloxadiazolylphenyl, (e.g. 4-(5-methyl 1,2,4-oxadiazol-3-yl)phenyl, etc.), (b) 10 0 R1 2 -C-HN S 15 wherein R12 is lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, etc.) optionally substituted by the group consisting of phenyl (e.g. phenyl, etc.), 20 halophenyl (e.g. 4-chlorophenyl, etc.), lower alkoxyphenyl (e.g. 4-methoxyphenyl, etc.), lower alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, isopropyloxy, etc.), phenoxy (e.g. phenoxy, etc.), lower alkoxyphenoxy (e.g. 3(or 4)-methoxyphenoxy, 25 etc.), halophenoxy (e.g. 4-fluoro(or chloro)phenoxy, etc.), lower alkylphenoxy (e.g. 3(or 4) methylphenoxy, etc.), carboxy (e.g. carboxy, etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, t butoxycarbonyl, etc.), lower alkylcarbamoyl (e.g. 30 methylcarbamoyl, etc.), halo (e.g. chloro, etc.), lower alkenyloxy (e.g. allyloxy etc.), lower alkoxy(lower)alkoxy (e.g. 2-ethoxyethoxy, etc.), phenyl(lower)alkoxy (e.g. benzyloxy, etc.), piperidinyloxy (e.g. 4-piperidinyloxy, etc.), N-t 35 butoxycarbonylpiperidinyloxy (e.g. N-t- WO 00/40576 PCT/JPOO/00018 44 butoxycarbonyl-4-piperidinyloxy, etc.), pyridyloxy (e.g. 3(or 4)-pyridyloxy, etc.), hydroxy (e.g. hydroxy, etc.), lower alkanoyloxy (e.g. acetoxy etc.), mono- or di(lower)alkylcarbamoyloxy (e.g. 5 methylcarbamoyloxy, N-methyl-N-ethylcarbamoyloxy, etc.), piperidinylcarbonyloxy (e.g. piperidinocarbonyloxy, etc.), phenyl(lower)alkylcarbamoyloxy (e.g. benzylcarbamoyloxy, etc.), lower 10 alkoxycarbonylamino (e.g. methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, t butoxycarbonylamino, etc.), amino (e.g. amino, etc.), lower alkoxycarbonylamino (e.g. methoxycarbonylamino, t-butoxycarbonylamino, etc.), 15 fluorenylmethoxycarbonylamino (e.g. fluorenylmethoxycarbonylamino etc.), mono- or di(lower)alkylamino (e.g. methylamino ethylamino dimethylamino, N-methyl-N-ethylamino t-butylamino, pentylamino etc.), N-lower alkyl-N-(lower 20 alkoxycarbonyl)amino (e.g. N-methyl-N methoxycarbonylamino, N-methyl-N-t butoxycarbonylamino N-ethyl-N-t-butoxycarbonylamino, etc.), N-lower alkyl-N (fluorenylmethoxycarbonyl)amino (e.g. N-methyl-N 25 (fluorenylmethoxycarbonyl)amino etc.), N-lower alkyl-N-(mono- or di(lower)alkylcarbamoyl)amino (e.g. N-methyl-N-(dimethylcarbamoyl)amino, etc.), N-(mono- or di(lower alkyl)carbamoyl)amino (e.g. dimethylcarbamoylamino N-(ethylcarbamoyl)amino, 30 etc.), benzoylamino (e.g. benzoylamino, etc.), lower alkanoylamino (e.g. acetylamino, isobutyrylamino, pivaloylamino, etc.), lower alkanesulfonylamino (e.g. methanesulfonylamino, etc.), lower alkoxy(lower)alkanoylamino (e.g. 35 methoxyacetylamino, etc.), WO 00/40576 PCT/JPOO/00018 45 cyclo(lower)alkyloxycarbonylamino (e.g. cyclopentyloxycarbonylamino, etc.), pyridylcarbonylamino (e.g. pyridylcarbonylamino, etc.), morpholinocarbonylamino (e.g. 5 morpholinocarbonylamino, etc.), phenyl(lower)alkoxycarbonylamino (e.g. benzyloxycarbonylamino, etc.), lower alkoxyphenylsulfonylamino (e.g. 4 methoxyphenylsulfonylamino, etc.), 10 hydroxy(lower)alkylamino (e.g. 2-hydroxyethylamino, etc.), morpholino (e.g. morpholino, etc.), oxooxazolidinyl (e.g. 2 -oxo-1,3-oxazolidin-1-yl, etc.), oxopyrrolidinyl (e.g. 2-oxopyrrolidin-1-yl, etc.), trimethylhydantoinyl (e.g. 3,4,4 15 trimethylhydantoin-1-yl, etc.), pyridyl (e.g. 3(or 4)-pyridyl, etc.), lower alkenylamino (e.g. allylamino, etc.), lower alkoxy(lower)alkylamino (e.g. 2 -ethoxyethylamino, etc.), phenyl(lower)alkylamino (e.g. benzylamino, etc.), 20 pyridyl (lower) alkylamino (e.g. 3-pyridylmethylamino, etc.), and cyclo(lower)alkyl cyclohexyl, etc.), (c) 25 0

R

1 3 -M-C-HN S 30 wherein M is oxygen or sulfur, R 13 is lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, etc.), phenyl(lower)alkyl (e.g. benzyl, etc.), lower alkoxy(lower)alkyl (e.g. 35 2-methoxyethyl, etc.), halo(lower)alkyl (e.g.

WO 00/40576 PCT/JPOO/00018 46 2-choloroethyl, etc.), amino(lower)alkyl, phthalimido(lower)alkoxycarbonylamino (e.g. 2 aminoethyl, 2-phthalimidoethyl, etc.), lower alkenyl (e.g. allyl, etc.), phenyl (e.g. 5 phenyl, etc.), (d) 10 0 R1 4 -N-C-HN S R15 wherein R1 5 is hydrogen, or lower alkyl (e.g. methyl, etc.), 15 R14 is hydrogen, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.), naphthyl (e.g. 1-naphthyl, etc.), halophenyl (e.g. 3(or 4)-chlorophenyl etc.), lower alkoxyphenyl (e.g. 4-methoxyphenyl, etc.), lower 20 alkenyl (e.g. allyl, etc.), cyclo(lower)alkyl(lower)alkyl (e.g. cyclohexylmethyl, etc.), phenyl(lower)alkyl (e.g. benzyl, etc.), halo(lower)alkyl (e.g. 2-chloroethyl, etc.), lower alkoxy(lower)alkyl (e.g. methoxymethyl, 25 2-methoxyethyl, etc.), hydroxy(lower)alkyl (e.g. 2 hydroxyethyl, etc.), (lower alkyl) (diphenyl)silyloxy(lower)alkyl (e.g. 2-((t butyl) (diphenyl)silyloxy)ethyl, etc.), carboxy(lower)alkyl (e.g. carboxymethyl, etc.), 30 lower alkoxycarbonyl(lower)alkyl (e.g. ethoxycarbonylmethyl, etc.), lower alkylcarbamoyl(lower)alkyl (e.g. methylcarbamoylmethyl, etc.), or pyridyl (e.g. 3 pyridyl, etc.), 35 (e) WO 00/40576 PCT/JPOO/00018 47 RI 6 5 wherein R1 6 is benzothienyl (e.g. 2-benzothienyl, etc.), benzofuranyl (e.g. 2-benzofuranyl, etc.), thienyl (e.g. 2(or 3)-thienyl, etc.), furyl (e.g. 2-furyl, etc.), pyridyl (e.g. 3-pyridyl, etc.), lower 10 alkylpyridyl (e.g. 1-methyl-4-pyridyl, 6-methyl-3 pyridyl, etc.), lower alkoxypyridyl (e.g. 6 methoxy-3-pyridyl, etc.), lower alkoxycarbonylaminopyridyl (e.g. 5 methoxycarbonylamino-3-pyridyl, etc.), lower 15 alkanoylthienyl (e.g. 5-acetyl-2-thienyl, etc.), lower alkylcarbamoylbenzofuranyl (e.g. 2 methylcarbamoyl-5-benzofuranyl, etc.). (vi) The compounds (I) of the above (v), wherein 20 a group of the formula: R S is the same group as (a), (c), (d) and (e) of claim 7, and the following formula (b): 25 (b) 0

R

1 2 -C-HN S 30 wherein R 1is lower alkyl, phenyl(lower)alkyl, halophenyl(lower)alkyl, lower alkoxyphenyl(lower)alkyl, lower alkoxy(lower)alkyl, phenoxy(lower)alkyl, lower 35 alkoxyphenoxy(lower)alkyl, halophenoxy(lower)alkyl, WO 00/40576 PCT/JPOO/00018 48 lower alkylphenoxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, lower alkylcarbamoyl(lower)alkyl, halo(lower)alkyl, lower alkenyloxy(lower)alkyl, lower 5 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 10 alkanoyloxy(lower)alkyl, mono- or di(lower)alkylcarbamoyloxy(lower)alkyl, piperidinylcarbonyloxy(lower)alkyl, phenyl(lower)alkylcarbamoyloxy(lower)alkyl, lower alkoxycarbonylamino(lower)alkyl, amino(lower)alkyl, 15 lower alkoxycarbonylamino(lower)alkyl, fluorenylmethoxycarbonylamino(lower)alkyl, mono- or di(lower)alkylamino(lower)alkyl, N-lower alkyl-N (lower alkoxycarbonyl)amino(lower)alkyl, N-lower alkyl-N-(fluorenylmethoxycarbonyl)amino(lower) 20 alkyl, N-lower alkyl-N-(mono- or di(lower) alkylcarbamoyl)amino(lower)alkyl, N-(mono- or di(lower alkyl)carbamoyl)amino(lower)alkyl, benzoylamino(lower)alkyl, lower alkanoylamino(lower)alkyl, lower 25 alkanesulfonylamino(lower)alkyl, lower alkoxy(lower)alkanoylamino(lower)alkyl, cyclo(lower)alkyloxycarbonylamino(lower)alkyl, pyridylcarbonylamino(lower)alkyl, morpholinocarbonylamino(lower)alkyl, 30 phenyl(lower)alkoxycarbonylamino(lower)alkyl, lower alkoxyphenylsulfonylamino(lower)alkyl, hydroxy(lower)alkylamino(lower)alkyl, morpholino(lower)alkyl, oxooxazolidinyl(lower)alkyl, oxopyrrolidinyl(lower)alkyl, 35 trimethylhydantoinyl(lower)alkyl, WO 00/40576 PCT/JPOO/00018 49 pyridyl (lower)alkyl, lower alkenylamino(lower)alkyl, lower alkoxy(lower)alkylamino(lower)alkyl, phenyl(lower)alkylamino(lower)alkyl, pyridyl(lower)alkylamino(lower)alkyl, 5 cycl(lower)oalkyl, (amino) (phenyl) (lower)alkyl (e.g. 2-phenyl-l-aminoethyl, etc.), (lower alkoxycarbonylamino) (phenyl) (lower)alkyl (e.g. 1 amino-l-phenylmethyl, 1-t-butoxycarbonylamino-l phenylmethyl, 1-amino-2-phenylethyl, 1-t 10 butoxycarbonylamino-2-phenylethyl, etc.), (amino) (lower alkoxy) (lower)alkyl (e.g. 1-amino-2 methoxyethyl, etc.), (lower alkoxycarbonylamino) (lower alkoxy) (lower)alkyl (e.g. 1-t butoxycarbonylamino-2-methoxyethyl, etc.), 15 (amino) (carboxy) (lower)alkyl, (lower alkoxycarbonylamino) (carboxy) (lower)alkyl, (amino) (lower alkoxycarbonyl) (lower)alkyl, (lower alkoxycarbonylamino) (lower alkoxycarbonyl) (lower)alkyl (e.g. 1-amino-3-carboxypropyl, 1-t 20 butoxycarbonylamino-3-carboxypropyl, 1-amino-3-(t butoxycarbonyl)propyl, 1-t-butoxycarbonylamino-3-t butoxycarbonylpropyl, etc.) (amino) (phenyl(lower)alkoxy) (lower)alkyl, (lower alkoxycarbonylamino) (phenyl(lower)alkoxy) 25 (lower)alkyl (e.g. 1-amino-2-benzyloxyethyl, 1-t butoxycarbonylamino-2-benzyloxyaminoethyl, etc.), (amino) (pyridyl) (lower)alkyl, (lower alkoxycarbonylamino) (pyridyl) (lower)alkyl (e.g. 1 amino-2-(3-pyridyl)ethyl, 1-t-butoxycarbonylamino 30 2 -(3-pyridyl)ethyl, 1-amino-2-(4-pyridyl)ethyl, 1 t-butoxycarbonylamino-2-(4-pyridyl)ethyl, etc.), (amino) (hydroxy) (lower)alkyl, (lower alkoxycarbonylamino) (hydroxy) (lower)alkyl (e.g. 1 amino-2-hydroxyethyl, 1-t-butoxycarbonylamino-2 35 hydroxyethyl, etc.), (amino) (amino) (lower)alkyl, WO 00/40576 PCT/JPOO/00018 50 (lower alkoxycarbonylamino) (amino) (lower)alkyl, (amino) (lower alkoxycarbonylamino) (lower)alkyl, (lower alkoxycarbonylamino) (lower alkoxycarbonylamino) (lower)alkyl (e.g. 1,5 5 diaminopentyl, 1-t-butoxycarbonylamino-5 aminopentyl, 1,5-bis(t-butoxycarbonylamino)pentyl, 1-amino-5-(t-butoxycarbonylamino)pentyl, etc.), (amino) (lower cycloalkane) (lower)alkyl, (lower alkoxycarbonylamino) (lower cycloalkane) (lower)alkyl 10 (e.g. 1-amino-2-cyclohexylethyl, 1-t butoxycarbonylamino-2-cyclohexylethyl, etc.). (vii) The compounds (I) of the above (vi), wherein 15 a group of the formula: R is the group of the following formula (a) to (e): (a) 20 Rl 25 wherein Ri is bromo, 2-naphthyl, phenyl, 3(or 4)-chlorophenyl, 2(or 3 or 4)-fluorophenyl, 3,4-dichloropheny, 3,5-difluorophenyl, 3(or 4)-methylphenyl, 4-ethylphenyl, 30 4 -isopropylphenyl, 4- (t-butyl)phenyl, 3,4-dimethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4 -trifluoromethylphenyl, 4 -trifluoromethoxyphenyl, 4-ethenylphenyl, 4 -methylcarbamoylphenyl, 4-ethylcarbamoylphenyl, 4 35 carbamoylphenyl, 4 -benzylcarbamoylphenyl, WO 00/40576 PCT/JPOO/00018 51 4-acetylphenyl, 4-methylthiophenyl, 4-ethylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl, phenylphenyl, 4-phenyl-3 fluorophenyl, 4-(4-fluorophenyl)phenyl, 3(or 4) 5 hydroxyphenyl, 3(or 4)-hydroxymethylphenyl, 4-(1,2-dihydroxyethyl)phenyl, 4-(phenoxycarbonyloxymethyl)phenyl, 3(or 4) aminophenyl, 4-carboxyphenyl, 3,4-methylendioxyphenyl, 10 4-(methanesulfonylamino)phenyl, 3-(2-butenoylamino)phenyl, 3-(cyclopropanecarbonylamino)phenyl, 3-(cyclobutanecarbonylamino)phenyl, 3-(cyclopentanecarbonylamino)phenyl, 15 4-benzyloxyphenyl, 4-(2-(methylcarbamoyl)ethenyl)phenyl, 4-(2-(ethylcarbamoyl)ethenyl)phenyl, 4-(2-(propylcarbamoyl)ethenyl)phenyl, 4-(2-(isopropylcarbamoyl)ethenyl)phenyl, 20 4-2-(dimethylcarbamoyl)ethenyl)phenyl, 4-(2-(phenylcarbamoyl)ethenyl)phenyl, 4-(2-(methoxyphenylcarbamoyl)ethenyl)phenyl, 4-(2-( 4 -fluorophenylcarbamoyl)ethenyl)phenyl, 4-(methylaminocarbonyloxy)phenyl, 25 4-(ethylaminocarbonyloxy)phenyl, 4 -propanoyloxyphenyl, 4-(methoxyacetyloxy)phenyl, 4-(ethoxycarbonyloxy)phenyl, 4-(3-(3-pyridyl)acryloyloxy)phenyl, 4-(cyclopropylcarbonyloxy)phenyl, 30 4-(carboxymethoxy)phenyl, 4-(ethoxycarbonylmethoxy)phenyl, 4-(t-butoxycarbonylmethoxy)phenyl, 4-(propanoylmethoxy)phenyl, 4-(cyclopropylcarbamoylmethoxy)phenyl, 35 3(or 4)-(methylcarbamoylmethoxy)phenyl, WO 00/40576 PCT/JPOO/00018 52 4-(ethylcarbamoylmethoxy)phenyl, 4-(propylcarbamoylmethoxy)phenyl, 3(or 4)-(methylcarbamoyloxymethyl)phenyl, 4-(methoxycarbonylaminomethyl)phenyl, 5 4- (t-butoxycarbonylaminomethyl)phenyl, 4-aminomethylphenyl, 4-(methylcarbamoylmethyl)phenyl, 3-(2(or 3 )-furylcarbonylamino)phenyl, 3-(1,2,3,4 teretahydroisoquinolylcarbonylamino)phenyl, 10 3-(N-(t-butoxycarbonyl)-1,2,3,4 teretahydroisoquinolylcarbonylamino)phenyl, 3-(pyrrolidinylcarbonylamino)phenyl, 4-(1, 3 -oxazolyl)phenyl, 4-(5-methyl-1,2, 4 -oxadiazol-3-yl)phenyl, 15 (b) 0 I R1 2 -C-HN S 20 wherein R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, phenylmethyl, 25 4-chlorophenylmethyl, 4 -methoxyphenylmethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, isopropyloxymethyl, 1-methoxyethyl, 2-methoxyethyl, phenoxymethyl, 2-phenoxyethyl, 3(or 4)-methoxyphenoxymethyl, 4-fluoro(or 30 chloro)phenoxymethyl, 3 (or 4) -methylphenoxymethyl, 2-carboxyethyl, 2 -methoxycarbonylethyl, 2-t butoxycarbonylethyl, 2 -methylcarbamoylethyl, 2-chloroethyl, chloromethyl, allyloxymethyl, (2-ethoxyethoxy)methyl, benzyloxymethyl, 35 4 -piperidinyloxymethyl, (N-t-butoxycarbonyl-4- WO 00/40576 PCT/JPOO/00018 53 piperidinyl)oxymethyl, 3(or 4)-pyridyloxymethyl, hydroxymethyl, 2-hydroxyethyl, acetoxymethyl, 1-acetoxyethyl, methylcarbamoyloxymethyl, 1-(N methyl-N-ethylcarbamoyloxy)methyl, (piperidino 5 carbonyloxy)methyl, (benzylcarbamoyloxy)methyl, (t-butoxycarbonylamino)methyl, aminomethyl, 1-aminoethyl, 1-(t-butoxycarbonylamino)ethyl, 2-aminoethyl, methoxycarbonylaminomethyl, 2-(methoxycarbonylamino)ethyl, 10 ethoxycarbonylaminomethyl, propoxycarbonylaminomethyl, 1-(fluorenylmethoxycarbonylamino)methyl, 2-(t-butoxycarbonylamino)ethyl, 2-(fluorenylmethoxycarbonylamino)ethyl, 15 1-aminoisopropyl, 1-aminopropyl, 1-(t-butoxycarbonylamino)propyl, 1-(t-butoxycarbonylamino)isopropyl, 1,5-diaminopentyl, 1,5-bis(t-butoxycarbonylamino) pentyl, methylaminomethyl, ethylaminomethyl, 20 3-(2-(N-methyl-N-ethylamino)methyl, 3-(dimethylaminomethyl, 3-(pentylaminomethyl, 3-(t-butylaminomethyl, 3-(3-methylaminoethyl, 3-(2-(N-methyl-N-methoxycarbonylamino)methyl, 1-(N-methyl-N-t-butoxycarbonylamino)methyl, 25 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, 30 1-(N-(ethylcarbamoyl)amino)methyl, 2-(N-(ethylcarbamoyl)amino)ethyl, benzoylaminomethyl, 2 -benzoylaminoethyl, acetylaminomethyl, isobutyrylaminomethyl, pivaloylaminomethyl, 35 1-(methanesulfonylamino)methyl, WO 00/40576 PCT/JPOO/00018 54 2-(methanesulfonylamino)ethyl, methoxyacetylaminomethyl, cyclopentyloxycarbonylaminomethyl, pyridylcarbonylaminomethyl, 5 morpholinocarbonylaminomethyl, benzyloxycarbonylaminomethyl, 1-(4-methoxyphenylsulfonylamino)methyl, 1-(2-hydroxyethylamino)methyl, morpholinomethyl, 1-(2-oxo-1,3-oxazolidin-1 10 yl)methyl, 1-(2-oxopyrrolidin-1-yl)methyl, 1-(3,4,4-trimethylhydantoin-1-yl)methyl, allylaminomethyl, 1-(2-ethoxyethylamino)methyl, benzylaminomethyl, 1-(3-pyridylmethylamino)methyl, 2-phenyl-l-aminoethyl, 1-amino-1-phenylmethyl, 15 1-t-butoxycarbonylamino-1-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 20 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, 1-t 25 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, (1,5-diaminopentyl, 1-t-butoxycarbonylamino-5 30 aminopentyl, 1,5-bis(t-butoxycarbonylamino)pentyl, 1-amino-5-(t-butoxycarbonylamino)pentyl, 1-amino-2 cyclohexylethyl, 1-t-butoxycarbonylamino-2 cyclohexylethyl, 35 (c) WO 00/40576 PCT/JPOO/00018 55 0 11 R1 3 -- M-C-HN / S 5 wherein M=O and R 1 3 is methyl, ethyl, propyl, isopropyl, benzyl, 2-methoxyethyl, 2-choloroethyl, 2-aminoethyl, 2 phthalimidoethyl, allyl, phenyl, or M=S and R1 3 is methyl, ethyl, 10 (d) 0 ||

R

1 4 -N-C-HN

R

1 5 S 15 wherein R15 is hydrogen and R 4 is hydrogen, methyl, ethyl, propyl, isopropyl, 20 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, 25 carboxymethyl, ethoxycarbonylmethyl, methylcarbamoylmethyl, or 3-pyridyl, R 4 is ethyl and R 15 is methyl, (e) 30 35 wherein R1 6 is 2-benzothienyl, 2-benzofuranyl, 2(or 3)-thienyl, WO 00/40576 PCT/JPOO/00018 56 2-furyl, 3-pyridyl, 1-methyl-4-pyridyl, 6-methyl-3 pyridyl, 6-methoxy-3-pyridyl, 5-methoxycarbonylamino-3-pyridyl, 5-acetyl-2-thienyl, 2 -methylcarbamoyl-5-benzofuranyl. 5 The processes for preparing the object compounds are explained in detail in the following. Process 1 10 The object compound (I-b) or a salt thereof can be prepared by subjecting a compound (I-a) or a salt thereof to removal reaction of the carboxy-protective group. Suitable salts of the compounds (I-a) and (I-b) can be referred to the ones as exemplified for the compound (I). 15 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. 20 Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, lithium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine, 25 triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0] non-5-ene, 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 [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, 30 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 35 trihaloacetic acid [e.g. trichloroacetic acid, WO 00/40576 PCT/JPOO/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 5 as water, an alcohol [e.g. 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 10 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 15 reduction. Suitable reducing agents to be used in chemical reduction may include a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid 20 [e.g. 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. 25 platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], 30 nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Ullman copper, etc.] and the like, and these catalysts may 35 be used in a combination with ammonium formate (e.g. a WO 00/40576 PCT/JP0O/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 5 as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above mentioned 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 10 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 15 cooling to heating. Process 2 The compound (I-b) or a salt thereof can be prepared by oxidating the compound (II) or a salt thereof. 20 Suitable salts of the compound (II) may be the same as those for the compound (I). 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 25 such as periodate (e.g. sodium periodate, potassium periodate, etc.), peroxy acid such as perbenzoic acid (e.g., perbenzoic acid, m-chloroperbenzoic acid, etc.), OXONE (2KHSO5-KHSO 4

-K

2

SO

4 ), potassium permanganate, a combination of titanium (III) chloride and hydrogen peroxide, a combination 30 thereof (e.g. 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 (e.g. potassium carbonate, etc.). 35 The reaction is usually carried out in a conventional WO 00/40576 PCT/JPOO/00018 59 solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other 5 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. 10 Process 3 The compound (I-d) or a salt thereof can be prepared by subjecting the compound (I-c) or a salt thereof to a reduction reaction. 15 Suitable salts of the compounds (I-c) and (I-d) may be the same as those for the compound (I). The reduction method applicable for this reaction may be the same as Process 1, which is capable of converting haloaryl group to aryl group (e.g. a combination of 20 palladium on carbon and ammonium formate, etc.). Process 4 The compound (I-e) or a salt thereof can be prepared by reacting the compound (I-b) or its reactive derivative at 25 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 30 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, 35 bis(trimethylsilyl)urea or the like; a derivative formed by WO 00/40576 PCT/JPOO/00018 60 reaction of the compound (IV) with phosphorus trichloride or phosgene, and the like. Suitable salts of the compound (IV) and its reactive 5 derivative can be referred to the acid addition salts as exemplified for the compound (I). Suitable salts of the compound (I-e) may be the same as those for the compound (I). Suitable reactive derivative at the carboxy group of 10 the compound (I-b) 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 acid such as substituted phosphoric acid [e.g. 15 dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic 20 acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with 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, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N-hydroxy 35 compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(lH)- WO 00/40576 PCT/JPOO/00018 61 pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-lH-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (I-b) to be used. 5 The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent 10 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 (I-b) is used in a free acid form or its salt form, the reaction is preferably 15 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; 20 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCD); N,N'-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; 25 ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7 30 hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl) isoxazolium hydroxide intramolecular salt; N-hydroxybenzotriazole; 1-(p-chlorobenzenesulfonyloxy)-6 chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with 35 thionyl chloride, phosgene, trichloromethyl chloroformate, WO 00/40576 PCT/JPOO/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, 5 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. 10 Process 5 The object compound (I-f) or a salt thereof can be prepared by cyclizing the compound (III) or a salt thereof. Suitable salts of the compounds (I-f) and (III) may be the same as those for the compound (I). 15 This reaction is preferably carried out in the presence of hydrogen halide (e.g. hydrogen iodide, etc.) or alkali metal halide (e.g. sodium iodide, etc.). This reaction can be carried out in the presence of a suitable base as mentioned above such as alkali metal 20 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. 25 The reaction temperature is not critical and the reaction can be carried out under from warming to heating. Process 6 The compound (I-g) or a salt thereof can be prepared by 30 reacting the compound (I-b) 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 35 conventional one which is capable of separating the starting WO 00/40576 PCT/JPOO/00018 63 racemic compound into each optically active compound such as (R)-(+)-c-methylbenzylamine, and the like. Suitable salts of the compound (I-g) may be the same as those exemplified for the compound (I). 5 Suitable salts of the optically active amine may be acid addition salts as mentioned for the compound (I). The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, 10 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 15 organic or inorganic base such as alkali metal (e.g. lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline earth metal hydride (e.g., calcium hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, 20 potassium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal 25 alkanoic acid (e.g., sodium acetate, etc.), trialkylamine (e.g., triethylamine, etc.), pyridine compound (e.g., 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 35 bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, WO 00/40576 PCT/JPOO/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 5 salts of the compound (I-b) 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; 10 N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-( 4 -diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; N,N'-carbonylbis-(2-methylimidazole); 15 pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); 20 phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g., ethyl chloroformate, isopropyl chloroformate); triphenylphosphine; 2 -ethyl- 7 -hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide 25 intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6 chloro-lH-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 30 oxalyl chloride. The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming. Process 7 35 The compound (I-i) or a salt thereof can be prepared by WO 00/40576 PCT/JPOO/0001 8 65 subjecting the compound (I-h) or a salt thereof to a removal reaction of the hydroxy protective group. Suitable salts of the compounds (I-h) and (I-i) may be the same as those exemplified for the compound (I). 5 The reaction of this process can be carried out in a manner similar to that in Process 1. Process 8 The compound (I-k) and a salt thereof can be prepared 10 by oxidating the compound (I-j) or a salt thereof. Suitable salts of the compounds (I-j) and (I-k) may be the same as those exemplified above with regard to the compound (I). Suitable method of this oxidation includes conventional 15 ones, which can convert thia group to sulfinyl or sulfonyl group, or sulfinyl to sulfonyl group, such as exemplified for Process 2. Process 9 20 The compound (I-1) or a salt thereof can be prepared by reacting the compound (I-c) or a salt thereof with the compound (V). Suitable salts of the compound (I-1) may be the same as those exemplified for the compound (I). 25 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 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 (e.g., lithium, sodium, potassium, etc.), alkaline earth metal 35 (e.g., calcium, etc.), alkali metal hydride (e.g., sodium WO 00/40576 PCT/JPOO/00018 66 hydride, etc.), alkaline earth metal hydride (e.g., calcium hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, 5 etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g., sodium acetate, etc.), trialkylamine (e.g., triethylamine, etc.), pyridine 10 compound (e.g., pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, alkali metal halide (e.g., sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g., sodium thiocyanate, potassium thiocyanate, etc.), 15 di(lower)alkyl azodicarboxylate (e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.), and the like. The reaction is preferably carried out in the presence of a conventional condensing agent such as 20 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; 25 N,N'-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus 30 oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g., ethyl chloroformate, isopropyl chloroformate); triphenylphosphine; etrakis(triphenylphosphine)palladium(0); 35 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m- WO 00/40576 PCT/JPOO/00018 67 sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole; 1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with 5 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. 10 Process 10 The compound (I-m) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof. 15 Suitable salts of the compound (I-m) may be the same as those exemplified for the compound (I). The reaction of this process can be carried out in a manner similar to that in Process 9. 20 Process 11 The compound (I-n) or a salt thereof can be prepared by cyclizing the compound (VIII) or a salt thereof. Suitable salts of the compounds (I-n) and (VIII) may be the same as those exemplified for the compound (I). 25 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 30 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. 35 Process 12 WO 00/40576 PCT/JPOO/00018 68 The compound (I-0) or a salt thereof can be prepared by reacting the compound (IX) or a salt thereof with the compound (X). Suitable salts of the compounds (I-0) and (IX) may be 5 the same as those exemplified for the compound (I). 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. 10 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 15 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. 20 Process 13 The compound (I-q) or a salt thereof can be prepared by amidating the compound (I-p) or its reactive derivative at the carboxy group, or a salt thereof. Suitable salts of the compounds (I-p) and (I-q) may be 25 the same as those for the compound (I). Suitable reactive derivative of the compound (I-p) may be the same as those for the compound (I-b). The amidation reaction applicable to this process may include a conventional amidation reaction which can convert 30 a carboxy-group to an amido-group, for example, reaction with an optionally substituted amines such as mono- or di(lower)alkylamine (e.g. methylamine, etc.), and the like. And the reaction can be carried out in substantially the same manner as described in Process 4. 35 WO 00/40576 PCT/JPOO/00018 69 Process 14 The compound (I-s) or a salt thereof can be prepared by acylating the compound (I-r) or its reactive derivative at the amino group, or a salt thereof. 5 Suitable salts of the compounds (I-r) and (I-s) may be the same as those for the compound (I). Suitable acylating agent used in this reaction may be a conventional acylating agent which is capable of introducing 10 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 15 bromide, a mixed acid anhydride with 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, 20 sulfuric acid, alkyl carbonate (e.g. methyl carbonate, ethyl carbonate, propyl carbonate, etc.), aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid (e.g. benzoic acid, etc.), a symmetrical 25 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 (e.g. p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, 30 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, 35 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, WO 00/40576 PCT/JPOO/00018 70 N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6 chlorobenzotriazole, etc.), isocyanic acid or a salt thereof (e.g. sodium isocyanate, etc.), lower alkylisocyanate (e.g. methylisocyanate, ethylisocyanate, etc.), and the like. 5 This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g. lithium, sodium potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), 10 alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, 15 etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamine (e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lutidine, picoline, 4 -dimethylaminopyridine, etc.), 20 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 25 carbodiimide compound [e.g. N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-( 4 -diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-( 3 -dimethylaminopropyl)carbodiimide, etc.], a ketenimine compound (e.g. N,N'-carbonylbis(2 30 methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ether compounds (e.g. ethoxyacetylene, 1-chlorovinylethyl ether), a sulfonic acid ester of N-hydroxybenzotriazole derivative [e.g. 1-(4 35 chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.], WO 00/40576 PCT/JPOO/00018 71 a combination of trialkylphosphite or triphenylphosphine and carbon tetrachloride, disulfide or diazenedicarboxylate (e.g. diethyl diazenedicarboxylate, etc.), a phosphorus compound (e.g. ethyl polyphosphate, isopropyl polyphosphate, 5 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 10 (e.g. 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 15 solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, pyridine, N,N-dimethylformamide, etc., or a mixture thereof. The reaction temperature is not critical and the 20 reaction is usually carried out under from cooling to heating. Process 15 The compound (I-r) or a salt thereof can be prepared by 25 subjecting the compound (I-t) or a salt thereof to a removal reaction of the amino-protective group. Suitable salts of the compound (I-t) may be the same as those for the compound (I). The reaction of this process can be carried out in a 30 manner similar to that in Process 1. Process 16 The compound (I-v) or a salt thereof can be prepared by subjecting the compound (I-u) or a salt thereof to a removal 35 reaction of the hydroxy-protective group.

WO 00/40576 PCT/JPOO/00018 72 Suitable salts of the compounds (I-u) and (I-v) 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. 5 Process 17 The compound (I-x) or a salt thereof can be prepared by oxidating the compound (I-w) or a salt thereof. Suitable salts of the compounds (I-w) and (I-x) may be 10 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 8. Process 18 15 The compound (I-z) or a salt thereof can be prepared by reducing the compound (I-y) or a salt thereof. Suitable salts of the compounds (I-y) and (I-z) may be the same as those for the compound (I). The reaction of this process can be carried out in.a 20 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. 25 Suitable salts of the compounds (I-aa) and (I-ab) 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 2. 30 Process 20 The compound (I-ac) or a salt thereof can be prepared by acylating the compound (I-v) or a salt thereof. Suitable salts of the compound (I-ac) may be the same as those for the compound (I).

WO 00/40576 PCT/JPOO/00018 73 The reaction of this process can be carried out in a manner similar to that in Process 14. Process 21 5 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 (I-ad), (XI) and (XII) may be the same as those for the compound (I). 10 The reaction of this process can be carried out in a manner similar to that in Process 9. Process 22 The compound (I-p) or a salt thereof can be prepared by 15 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 (I). The reaction of this process can be carried out in.a 20 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 25 substituted amine. Suitable salts of the compounds (I-af) and (I-ag) 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 4. 30 The compounds obtained above can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation and the like. 35 The object compounds can be transformed into their WO 00/40576 PCT/JPOO/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 5 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 10 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, 15 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 20 conventional test method as mentioned below. Test Methods: Test Method 1: Inhibitory activity of.human MMP-l 25 Human collagenase was prepared from the culture medium of human skin fibroblast stimulated with interleukin-1l (1 ng/ml). Latent collagenase was activated by incubation with tryspin (200 tg/ml) at 37'C for 60 minutes and the reaction was stopped by adding soybean trypsin inhibitor (800 [tg/ml). 30 Collagenase activity was determined using FITC-labeled calf skin type I collagen. FITC-collagen (2.5 mg/ml) was incubated at 37'C for 120 minutes with the activated collagenase and test compound in 50 mM Tris buffer (containing 5 mM CaCl 2 , 200 mM NaCl and 0.02% NaN 3 , pH 7.5). 35 After stopping the enzyme reaction by adding the equal WO 00/40576 PCT/JP0O/00018 75 volume of 70% ethanol-200 mM Tris buffer (pH 9.5), 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). 5 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). 10 Gelatinolytic activity was determined by monitoring the degradation of FITC-labeled bovine type IV collagen after incubation for 4 hours at 42'C. The amount of degraded collagen was estimated by measuring the fluorescence intensity at 495 nm (excitation) and 520 nm (emission). 15 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, 20 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 25 degraded peptide substrate at 495 nm (excitation) and 520 nm (emission). Test Method 4: Inhibitory activity of human MMP-8 30 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 35 sequential incubation with mercury compound and proteinase WO 00/40576 PCT/JPO0/00018 76 at 35'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 5 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 10 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 15 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 20 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 25 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 30 100 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 35 compound of the compounds are shown in the following.

WO 00/40576 PCT/JPOO/00018 77 Inhibitory activity of MMP 1. Test Method Inhibitory activity of human MMP-13 as mentioned above. 5 2. Test Compound Compound of Example 15 3. Test Resut 10 Inhibitory activity Test Compound [C (nM)] Example 15 2.2 The following Preparations and Examples are given for the purpose of illustrating the present invention in detail. 15 The abbreviations used in this description are, for examplee, as follows. Aib: aminoisobutyric acid Abu: aminobutyric acid 20 4PyAla: 4-pyridylalanine 25 30 35 WO 00/40576 PCT/JPOO/00018 78 Preparation 1-1) N-Chlorosuccinimide (2.67 g) was added gradually over 30 minutes to a stirred solution of tetrahydro-2H-thiopyran (2.04 g) in benzene (20 ml). The temperature was maintained 5 at 20-30*C 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 10 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 20% 15 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 20 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 , 6): 1.35-1.65 (2H, m), 1.7-2.1 (4H, m), 25 2.56-2.64 (1H, m), 2.73-2.86 (1H, m), 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 30 Preparation 1-2) 1.OM Solution of boron tribromide in dichioromethane (8.27 ml) was added dropwise to a stirred solution of 3

,

4 ,5, 6 -tetrahydro-2-(4-methoxyphenyl)-2H-thiopyran (718 mg) 35 in dichloromethane (10 ml) under ice cooling and the WO 00/40576 PCT/JPOO/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 5 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-(4 hydroxyphenyl)-2H-thiopyran (600 mg) as a colorless powder. 10 mp: 138-140.5'C IR (KBr): 3421 (br), 1241 cm-1 NMR (DMSO-d 6 , 8): 1.35-1.65 (2H, m), 1.7-2.05 (4H, m), 2.58 (1H, br d, J=13.3Hz), 2.71-2.85 (1H, m), 3.78 (1H, dd, J=10.8, 2.5Hz), 6.68 (2H, d, J=8.5Hz), 15 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)-2H thiopyran (578 mg), 4-bromochlorobenzene (683 mg), 20 8-hydroxyquinoline (17.3 mg), potassium carbonate (247 mg), and copper (I) chloride (11.8 mg) in 1,3-dimethyl-2 imidazolidinone (1.73 g) was stirred at 150'C under a nitrogen atmosphere for 21 hours and cooled to room temperature. The reaction mixture was partitioned between 25 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] 30 3

,

4 ,5,6-tetrahydro-2H-thiopyran (417 mg) as a colorless powder. mp: 69.5-70.5'C IR (KBr): 1274 cm- 1 NMR (CDCl 3 , 8): 1.45-1.77 (2H, m), 1.83-2.2 (4H, m), 35 2.66 (1H, m), 2.81-2.95 (1H, m), 3.84 (1H, dd, WO 00/40576 PCT/JPOO/00018 80 J=11.6, 2.6Hz), 6.88-6.97 (4H, m), 7.23-7.36 (4H, m) Preparation 1-4) An aqueous solution (23 ml) of OXONE (2KHS05-KHS04-K 2

SO

4 , 5 1.82 g) was added dropwise to a suspension of 2-[4-(4 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) 10 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 15 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 20 NMR (CDCl 3 , 8): 1.65 (1H, m), 2.04-2.26 (4H, m), 2.37 2.56 (1H, m), 2.96-3.13 (1H, m), 3.24 (1H, m), 4.01 (lH, dd, J=12.8, 3.1Hz), 6.92-7.03 (4H, m), 7.28-7.42 (4H, m) (+) APCI MS m/z: 336 (M++H) 25 Preparation 1-5) 1.5M Solution of lithium diisopropylamide mono tetrahydrofuran in cyclohexane (1.47 ml) was added dropwise to a stirred suspension of 2-[4-(4-chlorophenoxy)phenyll 30 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 (2.5 35 ml) was added dropwise therein and the resultant mixture was WO 00/40576 PCT/JPOO/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 5 successively with 1N 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] 10 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 (CDCl 3 , 6): 1.81-1.86 (2H, m), 2.09-2.21 (3H, m), 2.53-2.68 (1H, m), 2.86-3.09 (2H, m), 3.17-3.35 15 (2H, m), 5.02-5.09 (1H, m), 5.14-5.31 (2H, m), 6.94-7.05 (4H, m), 7.31 (2H, d, J=9.OHz), 7.61 (2H, d, J=9.OHz) (+) API-ES MS m/z: 399 and 401 (M++Na) 20 Preparation 1-6) 1.5M Solution of lithium diisopropylamide mono tetrahydrofuran in cyclohexane (0.34 ml) was added dropwise to a stirred solution of 2-allyl-2-[4-(4 chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran 1,1 25 dioxide (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 35 minutes. A solution of methyl iodide (134 mg) in tetrahydrofuran (0.5 ml) was added dropwise therein and the 30 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 1N hydrochloric acid 35 and brine, dried over sodium sulfate, and evaporated in WO 00/40576 PCT/JPOO/00018 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-2H thiopyran 1,1-dioxide (78 mg) as a paste. 5 IR (KBr): 1639, 1284, 1244, 1126 cm 1 NMR (CDCl 3 , 8): 1.38 (3H, d, J=6.7Hz), 1.82-2.25 (5H, m), 2.61 (1H, m), 2.99 (1H, dd,=14.3, 7.7Hz), 3.32-3.39 (2H, m), 5.02-5.08 (1H, m), 5.16-5.29 (2H, m), 6.95-7.03 (4H, m), 7.28-7.33 (2H, m), 10 7.57-7.64 (2H, m) (+) APCI MS m/z: 391 and 393 (M++H) Preparation 2 2-[4-(4-Chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H 15 thiopyran (148 mg) was prepared from 3,4,5,6-tetrahydro-2

(

4 -hydroxyphenyl)-2H-thiopyran (292 mg) and 4 chloroiodobenzene (430 mg) in a similar manner to that of Preparation 1-3). mp: 69.5-70.5'C 20 Preparation 3 2-[4-(4-Chlorophenoxy)phenyl]-3,4,5,6-tet-rahydro-2H thiopyran (97 mg) was prepared from tetrahydro-2H-thiopyran (510 mg) and 4 -bromo-4'-chlorodiphenyl ether (2.12 g) in a 25 similar manner to that of Preparation 1-1). mp: 69.5-70.5'C Preparation 4-1) 5-Chlorovaleryl chloride (17.1 g) was added dropwise to 30 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 35 dichloromethane (115 ml) was added dropwise over 20 minutes.

WO 00/40576 PCT/JPOO/0001 8 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 5 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 10 NMR (CDCl 3 , 8): 1.85-1.91 (4H, m), 2.94-3.02 (2H, m), 3.55-3.62 (2H, m), 6.96-7.05 (4H, m), 7.36 (2H, d, J=9.0Hz), 7.95 (2H, d, J=8.9Hz) (+) API-ES MS m/z: 345, 347 and 349 (M++Na) 15 Preparation 4-2) A solution of sodium borohydride (2.16 g) in water (59 ml) was added dropwise to a stirred suspension of 4-(5 chlorovaleryl)-4'-chlorodiphenyl ether (30.8 g) and sodium bicarbonate (9.61 g) in ethanol (480 ml) under a nitrogen 20 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 25 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 (br), 1242 cm'1 30 NMR (CDCl 3 , 8): 1.43-1.89 (7H, m), 3.53 (2H, t, J=6.6Hz), 4.67 (1H, m), 6.89-7.01 (4H, m), 7.24 7.34 (4H, m) (+) API-ES MS m/z: 347, 349 and 351 (M++Na), 311 and 313 (M+-HC+Na) 35 WO 00/40576 PCT/JPOO/00018 84 Preparation 4-3) Thionyl chloride (31.2 g) was added dropwise to a stirred solution of 4-(5-chloro-1-hydroxypentyl)-4' chlorodiphenyl ether (31.0 g) in chloroform (383 ml) under 5 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 10 sodium bicarbonate (twice) and brine, dried over sodium sulfate, and evaporated in vacuo to afford 4-chloro-4'-(1,5 dichloropentyl)diphenyl ether (33.7 g) as a pale brown oil. IR (Film): 1242 cm- 1 NMR (CDCl 3 , 8): 1.47-1.85 (4H, m), 2.02-2.19 (2H, m), 15 3.53 (2H, t, J=6.5Hz), 4.85 (1H, dd, J=7.9, 6.6Hz), 6.91-7.00 (4H, m), 7.27-7.38 (4H, m) Preparation 4-4) Sodium sulfide nonahydrate (21.8 g) was added gradually 20 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 25 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 30 toluene) over silica gel to afford 2-[4-(4 chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H thiopyran (13.8 g) as a colorless powder. mp: 69.5-70.5'C 35 Preparation 5-1) WO 00/40576 PCT/JPOO/00018 85 5-( 4 -Chlorophenyl)-2-(5-chlorovaleryl)thiophene (3.75 g) was obtained in a similar manner to that of Preparation 4-1). NMR (CDCl 3 , 8): 1.86-1.95 (4H, m), 2.95 (2H, dd, 5 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) 10 Ethyl 7-chloro-3-[5-( 4 -chlorophenyl)-2-thienyl]hept-2 enoate (4.2 g) was obtained in a similar manner to that of Preparation 8-2). NMR (CDCl 3 , 8): 1.21-1.34 (3H, m), 1.61-1.93 (4H, m), 2.53-2.57 (1H, m), 3.06-3.11 (1H, m), 3.52-3.60 15 (2H, m), 4.12-4.23 (2H, m), 5.88 (0.5H, s), 6.23 (0.5H, s), 7.21-7.34 (4H, m), 7.51-7.53 (2H, m) Preparation 6-1) Potassium tert-butoxide (1.34 g) was gradually added to 20 a stirred solution of 4-chloro-4'-(1,5-dichloropentyl) 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 25 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. 30 The oily residue (4.63 g) was chromatographed (eluent: n hexane - toluene) over silica gel to afford 4-(1 benzoylthio-5-chloropentyl)-4'-chlorodiphenyl ether (1.16 g) as a pink oil. IR (Film): 1660, 1242 cm-1 35 NMR (CDCl 3 , 6): 1.36-1.65 (2H, m), 1.75-1.90 (2H, WO 00/40576 PCT/JPOO/00018 86 m), 1.99-2.12 (2H, m), 3.52 (2H, t, J=6.6Hz), 4.77 (1H, t, J=7.8Hz), 6.90-6.98 (4H, m), 7.25-7.57 (7H, m), 7.90-7.96 (2H, m) (+) API-ES MS m/z: 467, 469 and 471 (M++Na) 5 Preparation 6-2) 28% Solution of sodium methoxide in methanol (96.5 mg) was added dropwise to a stirred solution of 4-(1 benzoylthio-5-chloropentyl)-4'-chlorodiphenyl ether (223 mg) 10 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 15 mixture was stirred at room temperature for 15 hours. The reaction mixture was acidified with 3N hydrochloric acid (0.5 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 20 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 25 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 30 of Preparation 4-1). IR (Film): 1680, 1250 cm-1 NMR (CDCl 3 , 8): 2.22 (2H, m), 3.14 (2H, t, J=7.0Hz), 3.68 (2H, t, J=6.2Hz), 6.96-7.05 (4H, m), 7.31 7.40 (2H, m), 7.93-8.01 (2H, m) 35 WO 00/40576 PCT/JPOO/00018 87 Preparation 7-2) 4-(4-Chloro-1-hydroxybutyl)-4'-chlorodiphenyl ether (6.14 g) was prepared in a similar manner to that of Preparation 4-2). 5 NMR (CDCl 3 , 6): 1.76-2.01 (4H, m), 3.51-3.64 (2H, m), 4.70 (1H, m), 6.90-7.00 (4H, m), 7.24-7.34 (4H, m) (+) API-ES MS m/z: 333, 335 and 337 (M++Na) Preparation 7-3) 10 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 (4H, m), 3.57 (2H, t, J=6.4Hz), 4.88 (1H, t, J=7.2Hz), 6.89-7.00 (4H, m), 15 7.24-7.39 (4H, m) (+) API-ES MS m/z: 293 and 295 (M+-C1) Preparation 7-4) 2-[4-(4-Chlorophenoxy)phenyl]-2,3,4,5 20 tetrahydrothiophene (3.63 g) was prepared in a similar manner to that of Preparation 4-4). IR (Film): 1238 cm-1 NMR (CDCl 3 , 8): 1.87-2.02 (2H, m), 2.23-2.44 (2H, m), 2.99-3.17 (2H, m), 4.50 (1H, dd, J=8.4, 6.0Hz), 25 6.88-6.97 (4H, m), 7.23-7.31 (2H, m), 7.38 (2H, d, J=8.5Hz) Preparation 7-5) 2-[4-(4-Chlorophenoxy)phenyll-2,3,4,5 30 tetrahydrothiophene 1,1-dioxide (3.05 g) was prepared in a similar manner to that of Preparation 1-4). mp: 74.5-78.5'C IR (Film): 1315, 1234, 1169, 1126 cm-1 NMR (CDCl 3 , 8): 2.18-2.55 (4H, m), 3.12-3.36 (2H, m), 35 4.14 (1H, dd, J=11.7, 7.3Hz), 6.92-7.05 (4H, m), WO 00/40576 PCT/JPOO/0001 8 88 7.28-7.39 (4H, m) (+) APCI MS m/z: 323 and 325 (M++H) Preparation 8-1) 5 To a suspension of aluminum chloride (3.58 g) in methylene chloride (20 ml) was added a solution of 5-chlorovaleryl chloride (4.17 g) in methylene chloride (5 ml) dropwise at 0 0 C. After being stirred for 30 minutes at the same temperature, a solution of 4-chlorodiphenyl ether 10 (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 15 2). The combined organic layer was washed with water and brine, and concentrated under reduced pressure. The resulting residue was washed with hexane to give 4-(5 chlorovaleryl)-4'-chlorodiphenyl ether (6.89 g) as a slightly yellow solid. 20 NMR (DMSO-d 6 , 8): 1.84-1.95 (4H, m), 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) 25 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 (20 ml) at 0 0 C. After being stirred 30 minutes at the same 30 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. 35 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)phenyl]hept-2-enoate (E:Z = 1:1 mixture) (67.4 g) as a yellow oil. 5 NMR (CDCl 3 , 6): 1.14 (1.5H, t, J=7Hz), 1.26 (1.5H, t, J=7Hz), 1.29-1.40 (2H, m), 1.50-1.67 (2H, m), 1.74-1.89 (2H, m), 2.45 (1.5H, t, J=7Hz), 3.09 (1.5H, t, J=7Hz), 3.51 (1H, t, J=7Hz), 3.53 (1H, t, J=7Hz), 4.03 (lH, q, J=7Hz), 4.14 (lH, q, J=7Hz), 10 5.89 (0.5H, s), 6.04 (0.5H, s), 6.90-7.01 (4H, m), 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) 15 A solution of sodium iodide (128 g) and ethyl 7-chloro 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 2). The combined organic layer was 20 washed with water and brine, and dried over magnesium sulfate to give ethyl 3-[4-(4-chlorophenoxy)phenyll-7-iodo hept-2-enoate (67.8 g) (E:Z = 1:1 mixture) as a yellow oil. NMR (CDCl 3 , 6): 1.14 (1.5H, t, J=7Hz), 1.26 (1.5H, t, J=7Hz), 1.29-1.37 (2H, m), 1.46-1.62 (2H, m), 25 1.78-1.94 (2H, m), 2.44 (1.5H, t, J=7Hz), 3.12 (1.5H, t, J=7Hz), 3.18 (3H, t, J=7Hz), 4.04 (1H, q, J=7Hz), 4.20 (1H, q, J=7Hz), 5.88 (0.5H, s), 6.04 (0.5H, s), 6.89-7.00 (4H, m), 7.14 (2H, d, J=8Hz), 7.26-7.36 (3H, m), 7.42 (2H, d, J=8Hz) 30 Preparation 8-4) A mixture of ethyl 3-[4-(4-chlorophenoxy)phenyl)-7 iodo-hept-2-enoate (59.8 g) and thiourea (9.39 g) in ethanol (123 ml) was refluxed for 24 hours. The resulting mixture 35 was cooled and evaporated to give ethyl 7-amidinothio-3-[4- WO 00/40576 PCT/JPOO/00018 90 (4-chlorophenoxy)phenyl]hept-2-enoate hydroiodide (70.2 g) (E:Z = 1:1 mixture) as slightly yellow oil. NMR (DMSO-d 6 , 6): 1.05 (1.5H, t, J=7Hz), 1.24 (1.5H, t, J=7Hz), 1.33-1.68 (4H, m), 2.48 (1H, t, J=7Hz), 5 3.05-3.16 (3H, m), 3.96 (1H, q, J=7Hz), 4.12 (1H, q, J=7Hz), 5.93 (0.5H, s), 6.07 (0.5H, s), 6.96 7.13 (4H, m), 7.20 (1H, d, J=8Hz), 7.46 (1H, d, J=8Hz), 7.48 (1H, d, J=8Hz), 7.60 (1H, d, J=8Hz) MS (ES-) m/z: 433 (M-H) 10 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 (CDCl 3 , 8): 1.81-1.92 (4H, m), 2.97 (2H, dd, J=7, 15 7Hz), 3.53-3.6 (2H, m), 6.94-7.12 (6H, m), 7.92 7.95 (2H, m) Preparation 9-2) Ethyl 7-chloro-3-[4-(4-fluorophenoxy)phenyllhept-2 20 enoate (1.90 g) was obtained in a similar manner to that of Preparation 8-2). NMR (CDCl 3 , 8): 1.31 (3H, dd, J=7, 7Hz), 1.54-1.64 (2H, m), 1.78-1.88 (2H, m), 3.12 (2H, dd, J=7.5, 7.5Hz), 3.53 (2H, dd, J=7, 7Hz), 4.20 (2H, ddd, 25 J=7, 7, 7Hz), 6.03 (lH, s), 6.93-7.09 (6H, m), 7.39-7.42 (2H, m) Preparation 10-1) 4-(5-Chlorovaleryl)-4'-bromodiphenyl ether (6.71 g) was 30 obtained in a similar manner to that of Preparation 4-1). NMR (CDCl 3 , 6): 1.82-1.94 (4H, m), 2.99 (2H, t, J=6.5Hz), 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) 35 WO 00/40576 PCT/JPOO/00018 91 Preparation 10-2 Ethyl 3-[4-(4-bromophenoxy)phenyl]-7-chlorohept-2 enoate (7.55 g) was obtained in a similar manner to that of Preparation 8-2). 5 NMR (CDCl 3 , 8): 1.14 (1.5H, t, J=7Hz), 1.21-1.39 (1.5H, m), 1.49-1.65 (2H, m), 1.74-1.88 (2H, m), 2.47 (1H, t, J=7Hz), 3.12 (1H, t, J=7Hz), 3.47 3.56 (2H, m), 4.03 (1H, q, J=7Hz), 4.20 (1H, q, J=7Hz), 5.89 (0.5H, s), 6.04 (0.5H, s), 6.86-6.99 10 (4H, m), 7.39-7.50 (4H, m) Preparation 10-3) Ethyl 3-[4-(4-bromophenoxy)phenyll-7-iodohept-2-enoate (7.85 g) was obtained in a similar manner to that of 15 Preparation 8-3). NMR (CDC1 3 , 8): 1.14 (1.5H, t, J=7Hz), 1.21-1.39 (1.5H, m), 1.49-1.65 (2H, m), 1.74-1.88 (2H, m), 2.47 (1H, t, J=7Hz), 3.12 (1H, t, J=7Hz), 3.47 3.56 (2H, m), 4.03 (1H, q, J=7Hz), 4.20 (1H, q, 20 J=7Hz), 5.89 (0.5H, s), 6.04 (0.5H, s), 6.86-6.99 (4H, m), 7.39-7.50 (4H, m) Preparation 10-4) Ethyl 7-amidinothio-3-[4-(4-bromophenoxy)phenyl]hept-2 25 enoate hydroiodide (10.4 g) was obtained in a similar manner to that of Preparation 8-4). NMR (DMSO-d 6 , 6): 1.06 (1.5H, t, J=7Hz), 1.24 (1.5H, t, J=7Hz), 1.35-1.52 (2H, m), 1.54-1.75 (2H, m), 3.06-3.17 (2H, m), 3.39-3.49 (2H, m), 3.94 (1H, q, 30 J=7Hz), 4.15 (1H, q, J=7Hz), 5.94 (0.5H, s), 6.07 (0.5H, s), 6.96-7.11 (4H, m), 7.56-7.64 (4H, m), 9.01-9.15 (4H, m) MS (ESI+) m/z: 479, 563 (+TFA) 35 Preparation 11-1) WO 00/40576 PCT/JP0O/00018 92 Methyl 4-(5-chlorovaleryl)phenyl ether (8.77 g) was obtained in a similar manner to that of Preparation 4-1). NMR (CDCl 3 , 8): 1.84-1.94 (4H, m), 2.97 (2H, t, J=7Hz), 3.59 (2H, t, J=6.5Hz), 3.88 (3H, s), 6.94 5 (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 10 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'C on a dry-ice acetone bath. The mixture was stirred for 1 hour at -60'C and quenched by addition of saturated aqueous ammonium chloride. The 15 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 20 acetate in n-hexane) to give ethyl 7-chloro-3-hydroxy-3-(4 methoxyphenyl)-heptanoate (3.56 g) as an oil. NMR (CDCl 3 , 8): 1.12 (3H, t, J=7.5Hz), 1.16-1.30 (1H, m), 1.39-1.56 (lH, m), 1.62-1.82 (4H, m), 2.77 (1H, d, J=16Hz), 2.94 (1H, d, J=16Hz), 3.45 (2H, t, 25 J=6.5Hz), 3.80 (3H, s), 4.04 (2H, q, J=7.5Hz), 4.38 (lH, s), 6.86 (2H, d, J=9Hz), 7.31 (2H, d, J=9Hz) Preparation 11-3) 30 A mixture of ethyl 7-chloro-3-hydroxy-3-(4 methoxyphenyl)heptanoate (3.55 g), 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 35 poured into saturated aqueous ammonium chloride and WO 00/40576 PCT/JPOO/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-(4 5 methoxyphenyl)heptanoate (3.61 g) as an oil. NMR (CDCl 3 , 8): 1.12 (3H, t, J=7Hz), 1.33-1.55 (4H, m), 1.66-1.80 (2H, m), 2.30 (3H, s), 2.72-2.81 (3H, m), 2.93 (1H, d, J=15.5Hz), 3.80 (3H, s), 4.03 (2H, q, J=7Hz), 4.36 (1H, s), 6.85 (2H, d, J=9Hz), 7.30 10 (2H, d, J=9Hz) Preparation 11-4) A mixture of ethyl 7-acetylthio-3-hydroxy-3-(4 methoxyphenyl)heptanoate (3.60 g) and potassium carbonate 15 (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 3 20 hydroxy-3-(4-methoxyphenyl)-7-mercaptoheptanoate (3.01 g) as an oil. NMR (CDCl3, 8): 1.12 (3H, t, J=7.5Hz), 1.26 (1H, t, J=7.5Hz), 1.35-1.60 (4H, m), 1.65-1.82 (2H, m), 2.40-2.57 (2H, m), 2.77 (1H, d, J=16Hz), 2.94 (1H, 25 d, J=16Hz), 3.80 (3H, s), 4.04 (2H, q, J=7.5Hz), 4.36 (1H, s), 6.86 (2H, d, J=9Hz), 7.30 (2H, d, J=9Hz) Preparation 12-1) 30 5-(4-Fluorophenyl)-2-(5-chlorovaleryl)thiophene (2.03 g) was obtained in a similar manner to that of Preparation 4-1). NMR (CDCl 3 , 8): 1.79-1.99 (4H, m), 2.95 (2H, t, J=7Hz), 3.59 (2H, t, J=7Hz), 7.12 (2H, dd, J=8, 35 8Hz), 7.59-7.68 (4H, m) WO 00/40576 PCT/JPOO/00018 94 Preparation 12-2) Ethyl 7-chloro-3-[5-( 4 -fluorophenyl)-2-thienyl]hept-2 enoate (1.71 g) (E:Z = 1:1 mixture) was obtained in a 5 similar manner to that of Preparation 8-2). NMR (CDCl 3 , 8): 1.24 (1.5H, t), 1.37 (1.5H, t), 1.63-1.98 (4H, m), 2.56 (0.5H, t, J=7Hz), 2.87 3.00 (1H, m), 3.08 (0.5H, t, J=7Hz), 3.53 (1H, t, J=7Hz), 3.61 (1H, t, J=7Hz), 4.10-4.24 (2H, m), 10 5.87 (0.5H, s), 6.22 (0.5H, s), 7.04-7.31 (3H, m), 7.55-7.69 (3H, m) Preparation 12-3) Ethyl 3 -[5-(4-fluorophenyl)-2-thienyl]-7-iodohept-2 15 enoate (1.94 g) was obtained in a similar manner to that of Preparation 8-3). NMR (CDCl 3 , 6): 1.06 (1.5H, t, J=7Hz), 1.32 (1.5H, t, J=7Hz), 1.67-2.08 (4H, m), 3.24 (2H, t, J=7Hz), 4.18 (2H, q, J=7Hz), 6.22 (1H, s), 6.92-7.30 (4H, 20 m), 7.48-7.60 (2H, m) Preparation 12-4) Ethyl 7-amidinothio-3-[5-(4-fluorophenyl)-2 thienyl]hept-2-enoate hydroiodide (1.57 g) was obtained in a 25 similar manner to that of Preparation 8-4). NMR (CDCl 3 , 8): 1.05 (3H, t, J=7Hz), 1.57-1.82 (4H, m), 3.18 (2H, t, J=7Hz), 4.14 (2H, q, J=7Hz), 4.36 (2H, t, J=7Hz), 6.19 (1H, s), 7.24-7.69 (6H, m) MS (ESI+) m/z = 407 (M+H) 30 Preparation 13-1) 4 -(5-Chlorovaleryl)biphenyl (1.35 g) was obtained in a similar manner to that of Preparation 4-1). NMR (CDCl 3 , 6): 1.90-1.93 (4H, m), 3.06 (2H, dd, J=6, 35 6Hz), 3.61 (2H, dd, J=7, 7Hz), 7.40-7.50 (3H, m), WO 00/40576 PCT/JPOO/00018 95 7.63 (2H, d, J=8Hz), 7.69 (2H, d, J=8Hz), 8.03 (2H, d, J=8Hz) Preparation 13-2) 5 Ethyl 3

-(

4 -biphenylyl)-7-chlorohept-2-enoate (1 g) was obtained in a similar manner to that of Preparation 8-2). NMR (CDC1 3 , 6): 1.10 (1.5H, dd, J=7, 7Hz), 1.33 (1.5H, dd, J=7, 7Hz), 1.55-1.68 (1H, m), 1.76-1.90 (1H, m), 2.51 (1H, dd, J=7.5, 7.5Hz), 3.18 (1H, dd, 10 J=7.5, 7.5Hz), 3.52 (1H, dd, J=6.5, 6.5Hz), 3.54 (1H, dd, J=6.5, 6.5Hz), 4.02 (1H, ddd, J=7, 7, 7Hz), 4.22 (1H, ddd, J=7, 7, 7Hz), 5.92 (0.5H, s), 6.13 (0.5H, s), 7.24-7.65 (9H, m) 15 Preparation 14-1) 4'-Chloro- 4 -(5-chlorovaleryl)biphenylyl (3.29 g) was obtained in a similar manner to that of Preparation 4-1). NMR (CDCl 3 , 8): 1.90-1.93 (4H, m), 3.05 (2H, dd, J=6, 6Hz), 3.60 (2H, dd, J=6, 6Hz), 7.44 (2H, d, J=8Hz), 20 7.56 (2H, d, J=8Hz), 7.65 (2H, d, J=8Hz), 8.03 (2H, d, J=8Hz) Preparation 14-2) Ethyl 7-chloro-3- (4'-chloro-4-biphenylyl)hept-2-enoate 25 (0.70 g) was obtained in a similar manner to that of Preparation 8-2). NMR (CDCl 3 , 6): 1.11 (1.5H, dd, J=7, 7Hz), 1.32 (1.5H, dd, J=7, 7Hz), 1.50-1.58 (1H, m), 1.58-1.65 (1H, m), 2.49 (1H, dd, J=7, 7Hz), 3.17 (1H, dd, J=7, 30 7Hz), 3.50 (1H, dd, J=6, 6Hz), 3.54 (1H, dd, J=6, 6Hz), 4.01 (1H, ddd, J=7, 7, 7Hz), 4.22 (1H, ddd, J=7, 7, 7Hz), 5.93 (0.5H, s), 6.12 (0.5H, s), 7.40-7.58 (8H, m) 35 Preparation 15-1) WO 00/40576 PCT/JP0O/00018 96 4'-Bromo-4-(5-chlorovaleryl)biphenyl (1.97 g) was obtained in a similar manner to that of Preparation 4-1). NMR (CDCl 3 , 8): 1.90-1.93 (4H, m), 3.05 (2H, dd, J=7, 7Hz), 3.60 (2H, dd, J=6, 6Hz), 7.49 (2H, d, J=8Hz), 5 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-2-enoate 10 (0.64 g) was obtained in a similar manner to that of Preparation 8-2). NMR (CDCl 3 , 6): 1-11 (1.5H, dd, J=7, 7Hz), 1.33 (1.5H, dd, J=7, 7Hz), 1.52-1.67 (2H, m), 1.75-1.89 (2H, m), 2.50 (1H, dd, J=7, 7Hz), 3.17 (1H, dd, J=8, 15 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, s), 6.11 (0.5H, s), 7.24-7.60 (8H, m) 20 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 , 6): 1.89-1.95 (4H, m), 3.05 (2H, dd, J=7, 7Hz), 3.60 (2H, dd, J=6, 6Hz), 7.13-7.19 (2H, m), 25 7.57-7.65 (2H, m), 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 30 Preparation 8-2). NMR (CDCl 3 , 6): 1.33 (3H, dd, J=7, 7Hz), 1.59-1.67 (2H, m), 1.81-1.90 (2H, m), 3.17 (2H, dd, J=7.5, 7.5Hz), 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, 35 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 5 that of Preparation 1-4). mp: 78-82'C NMR (CDCl 3 , 6): 1.44-1.80 (3H, m), 1.83-1.96 (1H, m), 2.10-2.42 (2H, m), 2.72-2.85 (1H, m), 3.14-3.78 (1H, m), 5.57 (1H, dd, J=3, 8Hz), 3.82 (3H, s) 10 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 15 magnesium chloride (11.1 g) at 0 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 20 reaction mixture was stirred at ambient temperature for 5 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*C. The organic layer was washed with 13% aqueous hydrochloric 25 acid and concentrated in vacuo to give ethyl 3-oxo-3-(4 phenoxyphenyl)propanoate as a yellow oil (14 g). NMR (CDCl 3 , 8): 1.27 (3H, t, J=7.0Hz), 3.95 (2H, s), 4.24 (2H, q, J=7.OHz), 6.99 (2H, d, J=8.OHz), 7.07 (2H, d, J=8.OHz), 7.18 (1H, dd, J=8.0, 30 8.0Hz), 7.41 (2H, dd, J=8.0, 8.0Hz), 7.92 (2H, d, J=8.0Hz) MS (ESI-) m/z: 283.1 (M-H) Preparation 19-1) 35 5-Bromo-2-(5-chlorovaleryl)thiophene (13.4 g) was WO 00/40576 PCT/JP0O/00018 98 obtained in a similar manner to that of Preparation 4-1). NMR (CDCl 3 , 8): 1.86-1.91 (4H, m), 2.88 (2H, dd, J=6.9, 6.9Hz), 3.55 (2H, dd, J=6.6, 6.6Hz), 7.11 (1H, d, J=4.2Hz), 7.45 (1H, d, J=4.2Hz) 5 Preparation 19-2) Ethyl 7 -chloro- 3 -(5-bromo-2-thienyl)hept-2-enoate (12.5 g) was obtained in a similar manner to that of Preparation 8-2). 10 NMR (CDCl 3 , 8): 1.22-1.59 (3H, m), 1.65-1.92 (4H, m), 3.01-3.06 (1H, m), 3.50-3.59 (2H, m), 4.10-4.23 (2H, m), 5.85 (0.5H, s), 6.09 (0.5Hz, s), 6.98 7.07 (2H, m) 15 Preparation 20-1) tert-Butyl 7 -chloro-3-hydroxy-3-(5-bromo-2 thienyl)heptanoate (244 g) was obtained in substantially the same manner as that of Preparation 11-2). NMR (CDCl 3 , 6): 1.36 (9H, s), 1.38-1.57 (2H, m), 1.68 20 1.80 (4H, m), 2.70 (1H, d, J=15.6Hz), 2.79 (1H, d, J=15.6Hz), 3.49 (2H, t, J=6.9Hz), 5.00 (1H, s), 6.59 (1H, d, J=3.9Hz), 6.89 (1H, d, J=3.9Hz) Preparation 20-2) 25 tert-Butyl 7 -acetylthio-3-hydroxy-3-(5-bromo-2 thienyl)heptanoate (267 g) was obtained in substantially the same manner as that of Preparation 11-3). NMR (CDCl 3 , 8): 1.35 (9H, s), 1.39-1.57 (4H, m), 1.66 1.80 (2H, m), 2.31 (3H, s), 2.67 (1H, d, J=15.9Hz), 30 2.76 (1H, d, J=15.9Hz), 2.82 (2H, t, J=7.5Hz), 4.96 (1H, s), 6.58 (1H, d, J=3.9Hz), 6.88 (1H, d, J=3.9Hz) Preparation 20-3) 35 tert-Butyl 3-hydroxy-3-(5-bromo-2-thienyl)-7- WO 00/40576 PCT/JPOO/00018 99 mercaptoheptanoate (277 g) was obtained in substantially the same manner as that of Preparation 11-4). NMR (CDCl 3 , 6): 1.30 (1H, t, J=7.8Hz), 1.31-1.39 (9H, m), 1.40-1.65 (4H, m), 1.67-1.83 (2H, m), 2.49 (2H, 5 dd, J=7.8, 15Hz), 2.70 (1H, d, J=16H), 2.79 (1H, d, J=16Hz), 4.98 (1H, s), 6.59 (1H, d, J=4.2Hz), 6.89 (1H, d, J=4.2Hz) Preparation 21-1) 10 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 15 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 , 6): 1.42 (9H, s), 4.66 (2H, s), 6.88 (2H, 20 d, J=4.5Hz), 7.45 (2H, d, J=4.5Hz) Preparation 21-2) To a solution of 4-bromophenoxyacetic acid t-butyl ester (4 g) in dichloromethane (10 ml) was added 25 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 30 vacuo to give 4-bromophenoxy acetic acid (2.1 g) as a power. NMR (DMSO-d 6 , 6): 4.67 (2H, s), 6.89 (2H, d, J=9Hz), 7.45 (2H, d, J=9Hz) MS (ESI-): 230 (M-H) 35 Preparation 21-3) WO 00/40576 PCT/JPOO/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 , 8): 1.03 (3H, t, J=7.2Hz), 3.10-3.19 (2H, 5 m), 4.45 (2H, s), 6.93 (2H, d, J=9Hz), 7.47 (2H, d, J=9Hz), 8.11 (1H, br) Preparation 21-4) 4-(Ethylaminocarbonylmethoxy)benzeneboronic acid 10 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. 15 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 , 8): 1.42 (9H, s), 4.65 (2H, s), 6.84 (2H, 20 d, J=9.OHz), 7.71 (2H, d, J=9.OHz), 7.88 (2H, s) Preparation 23-1) 4-Chloro-1-(5-bromo-2-thienyl)butan-l-one (8.0 g) was obtained in substantially the same manner as that of 25 Preparation 8-1). NMR (CDCl 3 , 8): 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) 30 Preparation 23-2) tert-Butyl 6-chloro-3-hydroxy-3-(5-bromo-2 thienyl)hexanoate (4.46 g) was obtained in substantially the same manner as that of Preparation 11-2). NMR (CDCl 3 , 5): 1.37 (9H, s), 1.64-1.80 (1H, m), WO 00/40576 PCT/JPO0/00018 101 1.82-1.98 (3H, m), 2.70 (1H, d, J=16Hz), 2.80 (1H, d, J=16Hz), 3.48-3.55 (2H, m), 5.02 (1H, s), 6.61 (1H, d, J=4Hz), 6.90 (1H, d, J=4Hz) 5 Preparation 23-3) tert-Butyl 6-acetylthio-3-hydroxy-3-(5-bromo-2 thienyl)hexanoate (4.77 g) was obtained in substantially the same manner as that of Preparation 11-3). NMR (CDCl 3 , 6): 1.36 (9H, s), 1.45-1.60 (1H, m), 10 1.62-1.94 (3H, m), 2.31 (3H, s), 2.68 (1H, d, J=16Hz), 2.77 (1H, d, J=16Hz), 2.85 (2H, t, J=7Hz), 4.98 (1H, s), 6.59 (1H, d, J=4Hz), 6.88 (1H, d, J=4Hz) 15 Preparation 23-4) tert-Butyl 3-hydroxy-3- (5-bromo-2-thienyl) -6 mercaptohexanoate (4.0 g) was obtained in substantially the same manner as that of Preparation 11-4). NMR (CDCl 3 , 8): 1.30 (1H, t, J=8Hz), 1.36 (9H, s), 1.44 20 1. 62 (1H, m) , 1. 66-1. 93 (3H, m) , 2. 44-2. 55 (2H, m) , 2.70 (1H, d, J=16Hz), 2.79 (1H, d, J=16Hz), 4.99 (1H, s), 6.60 (1H, d, J=4Hz), 6.89 (1H, d, J=4Hz) Preparation 24-1) 25 A mixture of 4-bromobenzaldehyde (5.00 g), 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 30 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 5

(

4 -bromophenyl)oxazole (4.06 g) as a solid. NMR (CDCl 3 , 8): 7.37 (1H, s), 7.51-7.58 (4H, m), 35 7.93 (1H, s) WO 00/40576 PCT/JPOO/00018 102 MS (ESI+): 224 (M+H) Preparation 24-2) A mixture of 5-( 4 -bromophenyl)oxazole (672 mg), 5 bis(pinacolato)diborane (762 mg) dichlorobis(triphenyl phosphine)palladium(II) (42.1 mg) and potassium acetate (883 mg) in dioxane (15 ml) was stirred for 14 hours at 80'C to form 4 -(S-oxazolyl)benzeneboronic acid pinacol cyclic ester. After cooling to room temperature, the mixture was used to 10 next reaction without further purification. Preparation 25 (4-(Methoxycarbonylaminomethyl)phenyl)boronic acid (70 mg) was obtained from ( 4 -aminomethylphenyl)boronic acid 15 hydrochloride in a similar manner to that of Example 130. NMR (DMSO-d 6 , 8): 3.53 (3H, s), 4.18 (2H, d, J=7.5Hz), 7.20 (2H, d, J=8.5Hz), 7.66-7.75 (3H, m), 8.00 (2H, s) 20 Preparation 26

(

4 -(Cyclopropylcarbonyloxy)phenyl)boronic acid (77 mg) was obtained from ( 4 -hydroxyphenyl)boronic acid in a similar manner to that of Preparation 21-1). NMR (DMSO-d 6 , 8): 1.00-1.07 (4H, m), 1.85-1.94 (1H, m), 25 7.08 (2H, d, J=8.5Hz), 7.81 (2H, d, J=8.5Hz), 8.09 (2H, s) Preparation 27

(

4 -(Ethoxycarbonylmethoxy)phenyl)boronic acid (100 mg) 30 was obtained in a similar manner to that of Preparation 21 1). NMR (DMSO-d 6 , 6): 1.21 (3H, dd, J=7.2, 7.2Hz), 4.17 (2H, ddd, J=7.2, 7.2, 7.2Hz), 4.78 (2H, s), 6.87 (2H, d, J=8.5Hz), 7.72 (2H, d, J=8.5Hz), 7.88 (2H, s) 35 WO 00/40576 PCT/JPOO/00018 103 Preparation 28 (4-(Ethylcarbonylmethoxy)phenyl)boronic acid (95 mg) was obtained in a similar manner to that of Preparation 21 1). 5 NMR (DMSO-d 6 , 8): 0.97 (3H, dd, J=7.2, 7.2Hz), 2.49-2.54 (2H, m), 4.82 (2H, s), 6.84 (2H, d, J=8.5Hz), 7.71 (2H, d, J=8.5Hz), 7.87 (2H, s) Preparation 29 10 ( 4 -Cyclopropylaminocarbonylmethoxyphenyl)boronic acid (160 mg) was obtained in a similar manner to that of Example 32. NMR (DMSO-d 6 , 6): 0.46-0.50 (2H, m), 0.61-0.64 (2H, m), 2.65-2.72 (1H, m), 4.43 (2H, s), 6.88 (2H, d, 15 J=8.5Hz), 7.72 (2H, d, J=8.5Hz), 7.88 (2H, s), 8.13 (1H, br) Preparation 30 20 0 Br S HN 25 - 0 / ' HN

H

2 N-O 0 / 0 H 30 (a) (b) To a solution of (2S)-2-(5-bromo-2-thienyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (4.24 g) 35 in N,N-dimethylformamide (60 ml) was added 1-hydroxy- WO 00/40576 PCT/JP0O/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 5 temperature. The crowns were washed with N,N-dimethyl formamide, methanol and dichloromethane, successively and air dried to give (2S)-N-[2-[2-(5-bromo-2-thienyl)-1,1 dioxo-3,4,5,6-tetrahydro-2H-thiopyran-2-yl]acetyll hydroxylamine trityl crowns (b) (10.0 pmol/crown x 100). 10 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 15 of sodium carbonate (8.5 g) in degassed water (20 ml) and (2S)-N-[2-[2-(5-bromo-2-thienyl)-1,1-dioxo-3,4,5,6 tetrahydro-2H-thiopyran-2-yl]acetyljhydroxylamine trityl crowns (202 pmol, 10.1 pmol/crown x 20) in an atmosphere of nitrogen. After the resulting mixture was heated for 48 20 hours at 60'C, the crowns were washed with degassed N,N dimethylformamide, a solution of sodium diethylditiocarbamate (1.0 g) and diisopropylethylamine (1.0 ml) in N,N-dimethylformamide (200 ml), N,N-dimethylformamide, methyl sulfoxide, water, methanol and dichloromethane, 25 successively to give (2S)-N-[2-[2-(5-(3-nitrophenyl)-2 thienyl)-1,1-dioxo-3,4,5,6-tetrahydro-2H-thiopyran-2 yllacetyllhydroxylamine trityl crowns (202 pmol, 10.1 pmol/crown x 20). 30 Preparation 31-2) To a solution of 2M tin (II) chloride dihydrate (7.67 g) in N,N-dimethylformamide (17 ml) was added (2S)-N-[2-[2 (5-(3-nitrophenyl)-2-thienyl)-1,1,-dioxo-3,4,5,6-tetrahydro 2H-thiopyran-2-yl]acetyllhydroxylamine trityl crowns (304 35 tmol, 13.2 tmol/crown x 23). The reaction mixture was left WO 00/40576 PCT/JPO/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-3,4,5,6 5 tetrahydro-2H-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 10 that of Preparation 24-2). Preparation 32 6-Methylpyridine-3-boronic acid pinacol cyclic ester 15 Preparation 33 6 -Methoxypyridine-3-boronic acid pinacol cyclic ester Preparation 34 4 -(5-Methyl-1,2,4-oxadiazol-3-yl)benzeneboronic acid 20 pinacol cyclic ester Preparation 35 5-(Methoxycarbonylamino)pyridine-3-boronic acid pinacol cyclic ester 25 Preparation 36 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(pinacolatoboryl) 2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide 30 Preparation 37 4-(Methylaminocarbonylmethyl)benzeneboronic acid pinacol cyclic ester 35 Preparation 38 WO 00/40576 PCT/JPOO/00018 106 2-(Methylaminocarbonyl)benzofuran-5-boronic acid pinacol cyclic ester Example 1 5 1.5M Lithium diisopropylamide mono tetrahydrofuran in cyclohexane (0.28 ml) was added dropwise to a stirred suspension of 2 -[4-(4-chlorophenoxy)phenyl]-3,4,5,6 tetrahydro-2H-thiopyran 1,1-dioxide (117 mg) in tetrahydrofuran (2.4 ml) under dry ice - acetone cooling and 10 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 15 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 20 acetate) over silica gel to afford a mixture (86 mg) of t-butyl 2-[4-(4-chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-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 25 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 30 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-2H thiopyran-2-acetic acid 1,1-dioxide (44 mg) as a colorless powder. 35 mp: 191-193'C WO 00/40576 PCT/JPOO/00018 107 IR (KBr): 1711, 1290, 1244, 1124 cm-1 NMR (CDCl 3 , 8): 1.75-2.05 (2H, m), 2.15 (2H, m), 2.6 2.85 (2H, m), 3.08-3.15 (2H, m), 3.21 (1H, d, J=15.6Hz), 3.60 (1H, d, J=15.6Hz), 6.94-7.01 (4H, 5 m), 7.31 (2H, dd, J=6.7, 2.1Hz), 7.59 (2H, d, J=9.0Hz) (-) API-ES MS m/z: 393 (M+-H) Anal. Calcd. for C 1 gH 1 gC105S: C 57.79, H 4.85 Found: C 57.88, H 4.83 10 Example 2 A mixture of ethyl 2 -(4-methoxyphenyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-acetate (100 mg) and lithium hydroxide monohydrate (42.8 mg) in a mixture of methanol and 15 water was stirred for 4 hours at 60*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 20 sodium sulfate and evaporated in vacuo to give 2-(4 methoxyphenyl)-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetic acid (93 mg) as a crystalline solid. NMR (DMSO-d 6 , 8): 1.44-1.80 (4H, m), 2.26-2.54 (3H, m), 2.62-2.79 (2H, m), 3.00 (1H, d, J=14.5Hz), 25 3.75 (3H, s), 6.89 (2H, d, J=9Hz), 7.48 (2H, d, J=9Hz) MS (ESI-) m/z: 265 (M-H) Example 3 30 To a solution of ethyl 2 -[5-(4-fluorophenyl)-2 thienyl]-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 00C and the mixture was stirred for 5 hours at room temperature. The resulting mixture was 35 evaporated to remove methanol. The residue was acidified WO 00/40576 PCT/JPOO/00018 108 with 1N hydrochloric acid (HCl) and extracted with ethyl acetate (x3). 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-2H 5 thiopyran-2-acetic acid (296 mg) as white solid. NMR (CDCl 3 , 6): 1.58-1.92 (4H, m), 2.20-2.32 (1H, m), 2.57-2.68 (2H, m), 2.70-2.81 (1H, m), 2.89 (1H, d, J=14Hz), 2.97 (1H, d, J=14Hz), 6.97-7.08 (4H, m), 7.48-7.56 (2H, m) 10 MS (ESI-) m/z: 335 (M-H) Example 4 To a solution of methyl 2 -(4-phenoxybenzyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-carboxylate 1,1-dioxide in 15 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 60'C for 2 hours, the mixture was concentrated in vacuo to remove MeOH. The residual solution was acidified by 1M hydrochloric acid and 20 extracted with ethyl acetate (AcOEt) (20 ml x 2). The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give 2-(4 phenoxybenzyl)-3,4,5, 6 -tetrahydro-2H-thiopyran-2-carboxylic acid 1,1-dioxide (320 mg) as an amorphous powder. 25 NMR (CDCl 3 , 8): 1.70-1.84 (2H, m), 1.95-2.20 (3H, m), 2.25-2.37 (1H, m), 3.11-3.25 (3H, m), 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) 30 MS (ESI-) m/z: 359 (M-H) Example 5 2-(4-Phenoxybenzyl)-3,4,5, 6 -tetrahydro-2H-thiopyran-2 carboxylic acid (280 mg) was obtained in a similar manner to 35 that of Example 4.

WO 00/40576 PCT/JPOO/00018 109 NMR (CDC1 3 , 8): 1.45-2.02 (5H, m), 2.35-2.46 (1H, m), 2.52-2.65 (1H, m), 2.68-2.85 (1H, m), 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), 5 7.32 (2H, t, J=8Hz) MS (ESI-) m/z: 327 (M-H) Example 6 To a solution of ethyl 2-(4-phenoxyphenyl)-1,3 10 dithiane-2-acetate (370 mg) in ethanol (4 ml) was added 1N sodium hydroxide aqueous solution (2 ml) and the mixture was stirred at 50'C for 3 hours. The resulting mixture was evaporated to remove ethanol. The residue was acidified with 1N HCl and extracted with diethyl ether. The organic 15 layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated to give 2-(4 phenoxyphenyl)-1,3-dithiane-2-acetic acid (280 mg) as white crystal. NMR (CDCl 3 , 6): 2.03 (2H, br), 2.83 (4H, br), 3.22 20 (2H, br), 6.93-7.05 (4H, m), 7.13 (1H, d, J=7.0Hz), 7.41-7.48 (2H, m), 7.82-7.86 (2H, m) MS (ESI-) m/z: 345.1 (M-H) Example 7 25 1.5M Solution of lithium diisopropylamide mono tetrahydrofuran 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 30 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. 35 After addition of a saturated aqueous solution of ammonium WO 00/40576 PCT/JPOO/00018 110 chloride (10 ml) under the same conditions, the reaction mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, dried over 5 magnesium sulfate, and evaporated in vacuo to afford an oil (0.68 g). Potassium permanganate (259 mg), sodium periodate (1.75 g), and potassium carbonate (618 mg) was successively added to a stirred emulsion of the obtained oil in tert-butyl 10 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 15 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 20 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 2-[4-(4 25 chlorophenoxy)phenyl]-2,3,4,5-tetrahydrothiophene-2-acetic acid 1,1-dioxide (306 mg) as a colorless amorphous powder. mp: 45-50'C IR (KBr): 2750-2400, 1734, 1716, 1300, 1244, 1126 cm- 1 NMR (DMSO-d 6 , 6): 2.16-2.25 (2H, m), 2.65-2.77 (2H, 30 m), 3.08-3.41 (4H, m), 7.00-7.10 (4H, m), 7.41 7.51 (4H, m), 12.38 (1H, br) (-) API-ES MS m/z: 379 and 381 (M+-H) Anal. Calcd. for C 18

H

1 7 ClO5S: C 56.76, H 4.50 Found: C 57.32, H 5.04 35 WO 00/40576 PCT/JPOO/00018 111 Example 8 Potassium permanganate (172 mg), sodium periodate (1.28 g), and potassium carbonate (409 mg) was successively added to a stirred emulsion of 2-allyl-2-[4-(4-chlorophenoxy) 5 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 10 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 15 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 2-[4-(4 chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetic acid 1,1-dioxide (250 mg) as a colorless powder. 20 mp: 191-193*C Example 9 2-[4-(4-Chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-6 methyl-2H-thiopyran-2-acetic acid 1,1-dioxide (59 mg) was 25 prepared in a similar manner to that of Example 8. IR (KBr): 3442, 1735, 1714, 1284, 1245, 1124 cm-1 NMR (DMSO-d 6 , 8): 1.16 (3H, d, J=6.6Hz), 1.62-1.98 (4H, m), 2.47-2.63 (2H, m), 3.2-3.59 (3H, m), 6.98-7.10 (4H, m), 7.46 (2H, d, J=9.OHz), 7.55 (2H, 30 d, J=9.0Hz) (-) API-ES MS m/z: 407 and 409 (M+-H) Example 10 A suspension of (2R or 2S)-2-[4-(4-chlorophenoxy) 35 phenyl]-3,4,5,6-tetrahydro-N-((lR)-l-phenylethyl)-2H- WO 00/40576 PCT/JPOO/00018 112 thiopyran-2-acetamide 1,1-dioxide (diastereomer A, 149 mg) obtained in Example 31 in a mixture of 14N sulfuric acid (7.0 ml) and 1,4-dioxane (4.2 ml) was stirred under reflux for 21 hours and cooled to room temperature. The reaction 5 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 2S)-(-)-2-[4-(4 10 chlorophenoxy)-phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetic 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 (CDCl 3 , 6): 1.93 (2H, m), 2.14 (2H, m), 2.6-2.85 15 (2H, m), 3.08-3.16 (2H, m), 3.22 (1H, d, J=15.6Hz), 3.62 (1H, d, J=15.6Hz), 6.95-7.04 (4H, m), 7.28 7.35 (2H, m), 7.60 (2H, d, J=9.0Hz) (-) API-ES MS m/z: 393 and 395 (M+-H) 25 [a]D : _32.30 (C=1.0, MeOH) 20 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 25 detection: 220 nm retention time: 50.0 minutes Example 11 (2R or 2S)-2-[4-(4-Chlorophenoxy)phenyl]-3,4,5,6 30 tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (an optical isomer B, 77 mg) was prepared from (2R or 2S)-(+)-2 [4-(4-chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-N-((1R)-1 phenylethyl)-2H-thiopyran-2-acetamide 1,1-dioxide (diastereomer B, 133 mg) obtained in Example 31 in a similar 35 manner to that of Example 10.

WO 00/40576 PCT/JPOO/00018 113 IR (KBr): 1711, 1290, 1242, 1122 cm-1 NMR (CDCl 3 , 6): 1.82-1.95 (2H, m), 2.10-2.15 (2H, m), 2.62-2.80 (2H, m), 3.03-3.11 (2H, m), 3.21 (1H, d, J=15.6Hz), 3.60 (1H, d, J=15.6Hz), 6.92-7.01 (4H, 5 m), 7.28-7.34 (2H, m), 7.59 (2H, d, J=9.0Hz) (-) API-ES MS m/z: 393 (M+-H) Analytical chiral HPLC: column: Chiralpak AS (4.6 x 250 mm, Daicel Chemical Industries, Ltd.) 10 eluent: n-hexane-ethanol-TFA (700:300:1) flow rate: 1.0 ml/minute detection: 220 nm retention time: 8.96 minutes 15 Example 12 To a solution of 2

-[

4 -(4-chlorophenoxy)phenyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (16.8 g) in ethyl acetate (420 ml) was added (R)-(+)-a methylbenzylamine (2.84 g) at room temperature. After being 20 stirred overnight at the same temperature, the resulting crystal was filtrated and washed with ethyl acetate to give (2R or 2

S)-

2

-[

4 -(4-chlorophenoxy)phenyl]-3,4,5,6-tetrahydro 2 H-thiopyran-2-acetic acid 1,1-dioxide (R)-(+)-a methylbenzylamine salt (9.43 g). A suspension of resulting 25 salt in ethyl acetate (200 ml) was washed with 1N hydrochloric acid (100 ml x 2), 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 2S)-(-)-2-[4-(4 30 chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid (an optical isomer A) (4.75 g) as a white solid. [a]D : 32.3* (C=1.0, MeOH) Optical purity: 91% ee 35 Analytical chiral HPLC: WO 00/40576 PCT/JPO0/00018 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 5 detection: 220 nm retention time: 50.0 minutes Example 13 To a solution of 2-(5-bromo-2-thienyl)-3,4,5,6 10 tetrahydro-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) 15 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (R)-(+)-c-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 20 resoluted (2R or 2 S)-2-(5-bromo-2-thienyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (300 mg) as a white solid. NMR (DMSO-d 6 , 6): 1.74-1.87 (4H, m), 2.30-2.37 (lH, m), 3.07-3.56 (5H, m), 7.02 (1H, d, J=4.2Hz), 7.21 25 (1H, d, J=4.2Hz) MS (ESI-) m/z: 351 (M-H) 25. D 5 25.3- (C=1.0, MeOH) Optical purity: 95% ee Analytical chiral HPLC: 30 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 35 detection: 220 nm WO 00/40576 PCT/JPOO/00018 115 retention time: 20.2 minutes Example 14 A mixture of 2 -[4-(4-chlorophenoxy)phenyl]-3,4,5,6 5 tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (98.7 mg), ammonium formate (78.8 mg), and 10% palladium - carbon (50% 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 10 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-(4 phenoxyphenyl)-2H-thiopyran-2-acetic acid 1,1-dioxide (87 15 mg) as a colorless powder. mp: 208.5-209.5'C IR (KBr): 2750-2550, 1707, 1290, 1246, 1124 cm'1 NMR (CDCl 3 , 6): 1.75-2.25 (4H, m), 2.74 (2H, m), 3.11 (2H, m), 3.21 (1H, d, J=15.6Hz), 3.61 (1H, d, 20 J=15.6Hz), 6.97-7.07 (4H, m), 7.14 (1H, t, J=7.4Hz), 7.36 (2H, t, J=7.7Hz), 7.59 (2H, d, J=9.0Hz) (-) API-ES MS m/z: 359 (M+-H) 25 Example 15 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]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (118 mg) 30 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 35 the solution was added dropwise to a stirred mixture of WO 00/40576 PCT/JPOO/00018 116 hydroxylammonium chloride (125 mg), 1N 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 5 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 10 afford a colorless powder, which was washed with diisopropyl ether to afford 2-[4-(4-chlorophenoxy)phenyl]-3,4,5,6 tetrahydro-N-hydroxy-2H-thiopyran-2-acetamide 1,1-dioxide (88 mg) as a colorless powder. mp: 179-180'C (dec.) 15 IR (KBr): 3421, 3315, 3220, 1652, 1284, 1248, 1119 cm-1 NMR (DMSO-d 6 , 8): 1.74-1.99 (4H, m), 2.5 (1H, m), 2.87 (1H, br d, J=13.8Hz), 3.01-3.55 (4H, m), 6.87-7.12 (4H, m), 7.42-7.59 (4H, m), 8.73 (1H, s), 10.48 20 (1H, s) (+) API-ES MS m/z: 432 (M++Na) Anal. Calcd. for C 19

H

20 ClNO5S: C 55.68, H 4.92, N 3.42 Found: C 55.67, H 5.28, N 3.23 25 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 2S)-[4-(4-chlorophenoxy)phenyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide 30 (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 35 evaporated in vacuo. The residue was dissolved in WO 00/40576 PCT/JPOO/00018 117 dichloromethane (0.9 ml) and the solution was added dropwise to a stirred mixture of hydroxylammonium chloride (91.7 mg), 1N aqueous solution of sodium hydroxide (1.3 ml), tetrahydrofuran (2.6 ml), and tert-butyl alcohol (1.3 ml) at 5 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 10 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]-3,4,5,6 tetrahydro-N-hydroxy-2H-thiopyran-2-acetamide 1,1-dioxide 15 (optical isomer A, 55 mg) as a colorless powder. mp: 183.5-187'C (dec.) ]8 _9.30 (C=0.71, MeOH) IR (KBr): 3446, 3423, 1653, 1284, 1250, 1119 cm 1 NMR (DMSO-d 6 , 8): 1.75-2.05 (4H, m), 2.5 (1H, m), 20 2.87 (1H, br d, J=12.9Hz), 3.01-3.5 (4H, m), 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) 25 (-) API-ES MS m/z: 408 and 410 (M+-H) Analytical chiral HPLC: column: Chiralpak AS (4.6 x 250 mm, Daicel Chemical Industries, Ltd.) eluent: n-hexane-ethanol-TFA (700:300:1) 30 flow rate: 1.0 ml/minute detection: 220 nm retention time: 18.2 minutes Example 17 35 (R or S)-(+)-2-[4-(4-Chlorophenoxy)phenyl]-3,4,5,6- WO 00/40576 PCT/JP0O/00018 118 tetrahydro-N-hydroxy-2H-thiopyran-2-acetamide 1,1-dioxide (41 mg) was prepared from crude (2R or 2S)-2-[4-(4 chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetic acid 1,1-dioxide (an optical isomer B, 87 mg) 5 obtained in Example 11 in a similar manner to that of Example 16. mp: 187-188'C (dec.) 28: 10.5 (C=0.56, MeOH) IR (KBr): 3444, 3423, 3317, 3224, 1655, 1284, 1250, 10 1122 cm 1 NMR (DMSO-d 6 , 8): 1.75-2.05 (4H, m), 2.5 (1H, m), 2.87 (1H, br d, J=13.6Hz), 3.01-3.52 (4H, m), 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), 15 10.48 (1H, s) (+) API-ES MS m/z: 432 and 434 (M++Na) (-) API-ES MS m/z: 408 and 410 (M+-H) Analytical chiral HPLC: column: Chiralpak AS (4.6 x 250 mm, 20 Daicel Chemical Industries, Ltd.) eluent: n-hexane-ethanol-TFA (700:300:1) flow rate: 1.0 ml/minute detection: 220 nm retention time: 27.9 minutes 25 Example 18 2-[4-(4-Chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-N hydroxy-6-methyl-2H-thiopyran-2-acetamide 1,1-dioxide (30 mg) was prepared from 2-[4-(4-chlorophenoxy)phenyl]-3, 4 ,5, 6 30 tetrahydro-6-methyl-2H-thiopyran-2-acetic acid 1,1-dioxide (55 mg) in a similar manner to that of Example 15. mp: 102'C (dec.) IR (KBr): 3446 and 3421 (br), 1668, 1282, 1246, 1124 cm 1 35 NMR (DMSO-d 6 , 6): 1.17 (3H, d, J=6.6Hz), 1.5-2.05 (4H, WO 00/40576 PCT/JPOO/00018 119 m), 2.4 (1H, m), 2.8-2.95 (1H, br d), 3.09 (1H, d, J=15.0Hz), 3.23 (1H, d, J=15.0Hz), 3.54 (1H, m), 7.00 (2H, d, J=8.8Hz), 7.08 (2H, d, J=8.9Hz), 7.42-7.49 (2H, m), 7.56 (2H, d, J=8.9Hz), 8.73 (1H, 5 s), 10.49 (1H, s) (+) API-ES MS m/z: 446 and 448 (M++Na) Example 19 3,4,5,6-Tetrahydro-N-hydroxy-2-(4-phenoxyphenyl)-2H 10 thiopyran-2-acetamide 1,1-dioxide (41 mg) 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 15. mp: 182-183'C (dec.) 15 IR (KBr): 3446 and 3423 (br), 1655, 1288, 1246, 1115 cm- 1 NMR (DMSO-d 6 , 8): 1.75-2.05 (4H, m), 2.4 (1H, m), 2.87 (1H, br d, J=13.OHz), 3.04-3.55 (4H, m), 6.96 (2H, d, J=8.9Hz), 7.06 (2H, d, J=7.5Hz), 7.19 (1H, t, 20 J=7.3Hz), 7.43 (2H, t, J=7.4Hz), 7.54 (2H, d, J=8.9Hz), 8.74 (1H, s), 10.48 (1H, s) (+) APCI MS m/z: 376 (M++H), 343 (M+-NHOH) (-) API-ES MS m/z: 374 (M+-H) 25 Example 20 2-[4-(4-Chlorophenoxy)phenyl]-2,3,4,5-tetrahydro-N hydroxy-2-thiophene-2-acetamide 1,1-dioxide (88 mg) was prepared from 2-[4-(4-chlorophenoxy)phenyl]-2,3,4,5 tetrahydrothiophene-2-acetic acid 1,1-dioxide (122 mg) in a 30 similar manner to that of Example 15. mp: 63-68'C (dec.) IR (KBr): 3423 (br), 1662, 1296, 1244, 1126 cm-1 NMR (DMSO-d 6 , 6): 2.19-2.23 (2H, m), 2.56-3.28 (6H, m), 6.99-7.10 (4H, m), 7.38-7.48 (4H, m), 8.73 (1H, 35 s), 10.40 (1H, s) WO 00/40576 PCT/JPOO/00018 120 (+) APCI MS m/z: 396 and 398 (M++H), 363 and 365 (M+-NHOH) Anal. Calcd. for C 18

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 5 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)phenyl]hept-2-enoate hydroiodide (70.1 g) 10 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 15 reduced pressure to give 2

-[

4 -(4-chlorophenoxy)phenyl] 3

,

4 ,5, 6 -tetrahydro-2H-thiopyran-2-acetic acid (60 g) as an yellow oil. NMR (CDCl 3 , 8): 1.51-1.90 (4H, m), 2.26-2.38 (1H, m), 2.48-2.68 (3H, m), 2.90 (2H, d, J=14Hz), 2.98 (2H, 20 d, J=14Hz), 6.94 (4H, d, J=8Hz), 7.27 (2H, d, J=8Hz), 7.57 (2H, d, J=8Hz) MS (ES-) m/z: 361 (M-H) Example 22 25 2

-[

4

-(

4 -Bromophenoxy)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid (3.99 g) was obtained in a similar manner to that of Example 21. NMR (CDCl 3 , 6): 1.50-1.87 (4H, m), 2.27-2.49 (1H, m), 2.47-2.70 (3H, m), 2.90 (1H, d, J=15Hz), 3.00 (1H, 30 d, J=15Hz), 6.96 (4H, d, J=9Hz), 7.44 (4H, d, J=9Hz) MS (ESI-) m/z: 407 (M-H) Example 23 35 Ethyl 2 -[5-( 4 -fluorophenyl)-2-thienyl]-3,4,5,6- WO 00/40576 PCT/JP0O/00018 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 (CDCl 3 , 8): 1.12 (3H, t, J=7Hz), 1.49-1.92 (4H, 5 m), 2.18-2.30 (1H, m), 2.55-2.68 (2H, m), 2.73 2.82 (lH, m), 2.81 (lH, 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) 10 Example 24 To a solution of ethyl 3-(4-biphenylyl)-7-chlorohept-2 enoate (0.90 g) in acetone (15 ml) was added NaI (1.55 g) at 60'C. After being stirred overnight, the reaction mixture was cooled, concentrated in vacuo, diluted with water, and 15 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 20 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 0 C and was quenched by cautions dropwise addition of a solution 25 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: 5% 30 methanol (MeOH) in chloroform (CHCl 3 ) to give 2-(4 biphenylyl)-3,4,5,6-tetrahydro-2H-thiopyran-2-acetic acid (335 mg) as an amorphous. NMR (CDCl 3 , 6): 1.60-1.85 (4H, m), 2.30-2.39 (1H, m), 2.50-2.70 (3H, m), 2.94 (lH, d, J=14.7Hz), 3.01 35 (1H, d, J=14.7Hz), 7.34 (lH, dd, J=7, 7Hz), 7.56- WO 00/40576 PCT/JPOO/00018 122 7.61 (4H, m), 7.68-7.71 (2H, m) MS (ESI-) m/z: 311 (M-H) Example 25 5 2-[4-(4-Fluorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid (200 mg) was obtained in a similar manner to that of Example 24. NMR (CDCl 3 , 8): 1.60-1.84 (4H, m), 2.27-2.36 (1H, m), 2.50-2.67 (3H, m), 2.88 (1H, d, J=15Hz), 2.97 (1H, 10 d, J=16Hz), 6.91 (2H, d, J=9Hz), 6.99-7.06 (4H, m), 7.56 (2H, d, J=9Hz) MS (ESI-) m/z: 345 (M-H) Example 26 15 2-[4-(4-Chlorophenyl)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid (310 mg) was obtained in a similar manner to that of Example 24. NMR (CDC1 3 , 6): 1.60-1.85 (4H, m), 2.29-2.38 (1H, m), 2.52-2.69 (3H, m), 2.94 (1H, d, J=14.7Hz), 3.01 20 (1H, d, J=14.7Hz), 7.39 (2H, d, J=8Hz), 7.50-7.54 (4H, m), 7.69 (2H, d, J=8Hz) MS (ESI-) m/z: 345 (M-H) Example 27 25 2-[4-(4-Bromophenyl)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid (120 mg) was obtained in a similar manner to that of Example 24. NMR (CDCl 3 , 8): 1.61-1.85 (4H, m), 2.29-2.36 (1H, m), 2.51-2.69 (3H, m), 2.94 (1H, d, J=14.7Hz), 3.01 30 (1H, d, J=14.7Hz), 7.45 (2H, d, J=9Hz), 7.51-7.57 (4H, m), 7.69 (2H, d, J=9Hz) MS (ESI-) m/z: 389 (M-H) Example 28 35 2

-[

4 -(4-Fluorophenyl)phenyl]-3,4,5,6-tetrahydro-2H- WO 00/40576 PCT/JPOO/00018 123 thiopyran-2-acetic acid (200 mg) was obtained in a similar manner to that of Example 24. NMR (CDCl 3 , 6): 1.60-1.85 (4H, m), 2.29-2.38 (1H, m), 2.53-2.67 (2H, m), 2.94 (1H, d, J=l5Hz), 3.01 (1H, 5 d, J=16Hz), 7.07-7.12 (2H, m), 7.51-7.56 (4H, m), 7.69 (2H, d, J=8.SHz) MS (ESI-) m/z: 329 (M-H) Example 29 10 2 -[S-(4-Chlorophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-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, m), 2.25-2.32 (1H, m), 2.45-2.63 (3H, m), 2.74 (1H, d, J=14Hz), 3.97 15 (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-) m/z: 351 (M-H) 20 Example 30 2-(5-Bromo-2-thienyl)-3,4,5,6-tetrahydro-2H-thiopyran 2-acetic acid (8.5 g) was obtained in a similar manner to that of Example 24. NMR (DMSO-d 6 , 8): 1.45-1.73 (4H, m), 2.12-2.20 (1H, 25 m), 2.45-2.70 (4H, m), 2.87 (1H, d, J=14.4Hz), 6.84 (1H, d, J=4.2Hz), 7.08 (1H, d, J=4.2Hz) Example 31 1-Ethyl-3-( 3 -dimethylaminopropyl)carbodiimide (WSCD) 30 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 mg), (R)-(+)-ca-methylbenzyl amine (105 mg), and 1-hydroxybenzotriazole (123 mg) in dichloromethane (8 ml) under ice cooling, and then the 35 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 dichloromethane. The extract was washed successively with water, 0.1N hydrochloric acid, water, and a saturated aqueous solution of sodium bicarbonate, dried over magnesium 5 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-[(1R)-1 10 phenylethyllacetamide 1,1-dioxide as a colorless solid and colorless crystals, respectively. Diastereomer A: mp: 138-160.5'C [a]2 7 : 31.00 (C=0.52, MeOH) 15 IR (KBr): 3421 (br), 1651, 1288, 1244, 1124 cm'1 NMR (CDCl 3 , 8): 1.06 (3H, d, J=6.8Hz), 1.94-2.15 (4H, m), 2.68-2.74 (2H, m), 2.99-3.26 (4H, m), 4.72 4.87 (1H, m), 5.21 (1H, br d, J=8.OHz), 6.97 (2H, d, J=9.OHz), 7.00-7.11 (4H, m), 7.19-7.37 (5H, m), 20 7.70 (2H, d, J=9.0Hz) (+) APCI MS m/z: 498 and 500 (M++H) Diastereomer B: mp: 82.5-89'C 25 [a] 7 : 53.40 (C=0.50, MeOH) IR (KBr): 3365 (br), 1651, 1288, 1246, 1122 cm-1 NMR (CDCl 3 , 8): 1.32 (3H, d, J=6.9Hz), 1.91 (2H, m), 2.13 (2H, m), 2.62 (2H, m), 2.99-3.30 (4H, m), 4.85 (1H, m), 5.31 (1H, br d, J=8.OHz), 6.74-6.80 30 (2H, m), 6.90-6.99 (4H, m), 7.15-7.36 (5H, m), 7.58 (2H, d, J=9.OHz) (+) APCI MS m/z: 498 and 500 (M++H) Example 32 35 To a solution of (2R or 2

S)-

2

-[

4 -(4-chlorophenoxy)- WO 00/40576 PCT/JPOO/00018 125 phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (4.75 g) obtained in Example 10, O-(2 tetrahydropyranyl)hydroxylamine (2.11 g), and 1-hydroxybenzotriazole (1.95 g) in N,N-dimethylformamide (60 5 ml) was added WSCD hydrochloride (2.77 g). 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 5% aqueous citric acid solution, saturated sodium bicarbonate 10 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 1,1 dioxide (6.52 g) as a slightly yellow oil. 15 NMR (CDCl 3 , 6): 1.46-2.22 (10H, m), 2.77 (1H, br), 3.02-3.28 (4H, m), 3.38-3.55 (1H, m), 3.65-3.78 (1H, m), 4.37 (0.5H, s), 4.77 (0.5H, s), 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) 20 MS (ESI-) m/z: 493 (M-H) The following compounds were obtained in a similar manner to that of Example 32. 25 Example 33 2-[4-(4-Chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide (140 mg) NMR (CDCl 3 , 8): 1.42-1.91 (10H, m), 2.23-2.36 (1H, m), 2.49-2.72 (4H, m), 2.74-2.83 (1H, m), 3.45 30 3.58 (1H, m), 3.71-3.83 (1H, m), 4.55 (1H, s), 4.79 (0.5H, s), 6.89-7.03 (4H, m), 7.27 (2H, d, J=8Hz), 7.60 (2H, d, J=8Hz), 7.96 (0.5H, s), 8.16 (0.5H, s) MS (ESI-) m/z: 460 (M-H) 35 WO 00/40576 PCT/JP0O/00018 126 Example 34 N-(2-Tetrahydropyranyloxy)-2-[4-(4-fluorophenoxy) phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (307 mg) 5 NMR (CDCl 3 , 8): 1.53-1.70 (10H, m), 2.08-2.17 (2H, m), 2.73-2.76 (2H, m), 3.02-3.23 (4H, m), 3.42-3.52 (1H, m), 6.98-7.05 (6H, m), 7.64 (2H, d, J=9Hz) MS (ESI-) m/z: 476 (M-H) 10 Example 35

N-(

2 -Tetrahydropyranyloxy)-2-[4-(4-fluorophenoxy) phenyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide (250 mg) NMR (CDC1 3 , 8): 1.50-1.64 (6H, m), 1.74-1.78 (4H, m), 2.25-2.34 (2H, m), 2.52-2.70 (4H, m), 2.76-2.82 15 (1H, m), 3.49-3.57 (1H, m), 3.72-3.83 (1H, m), 6.95-7.04 (6H, m), 7.59 (2H, d, J=9Hz) MS (ESI-) m/z: 444 (M-H) Example 36 20 N-( 2 -Tetrahydropyranyloxy)-2-[4-(4-fluorophenoxy) phenyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1-oxide (152 mg) NMR (CDCl 3 , 8): 1.54-1.81 (10H, m), 2.45-2.56 (2H, m), 2.75-2.96 (5H, m), 3.53-3.59 (1H, m), 3.81-3.87 25 (1H, m), 6.95-7.04 (6H, m), 7.39 (2H, d, J=9Hz) MS (ESI-) m/z: 460 (M-H) Example 37 N-(2-Tetrahydropyranyloxy)-2-[4-(4-fluorophenoxy) 30 phenyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (173 mg) NMR (CDC1 3 , 8): 1.45-1.75 (6H, m), 1.89-2.01 (2H, m), 2.06-2.20 (2H, m), 2.68-2.80 (2H, m), 3.00-3.24 (4H, m), 3.40-3.55 (1H, m), 3.64-3.75 (1H, m), 35 4.49 (0.5H, br s), 4.75 (0.5H, br s), 6.93 (2H, d, WO 00/40576 PCT/JP00/00018 127 J=9Hz), 7.04 (2H, d, J=9Hz), 7.45 (2H, d, J=9Hz), 7.67 (2H, d, J=9Hz), 7.77 (2H, d, J=9Hz), 7.77 (0.5H, br s), 7.90 (0.5H, br s) MS (ESI-) m/z: 536 (M-H) 5 Example 38 N-(2-Tetrahydropyranyloxy)-2-[4-[4-(4-fluorophenyl) phenoxy]phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (122 mg) 10 NMR (CDC1 3 , 8): 1.45-1.79 (6H, m), 1.88-2.02 (2H, m), 2.06-2.24 (2H, m), 2.66-2.82 (2H, m), 3.00-3.25 (4H, m), 3.40-3.56 (1H, m), 3.64-3.77 (1H, m), 4.41 (0.5H, br s), 4.75 (0.5H, br s), 7.00-7.18 (6H, m), 7.42-7.56 (4H, m), 7.67 (2H, d, J=9Hz), 15 7.75 (0.5H, br s), 7.89 (0.5H, br s) MS (ESI-) m/z: 552 (M-H) Example 39 N-(2-Tetrahydropyranyloxy)-2-(4-methoxyphenyl)-3,4,5,6 20 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (113 mg) NMR (CDCl 3 , 8): 1.41-1.72 (6H, m), 1.87-2.01 (2H, m), 2.06-2.21 (2H, m), 2.59-2.81 (2H, m), 3.00-3.25 (4H, m), 3.32-3.73 (2H, m), 3.81 (3H, s), 4.37 4.44 (0.5H, m), 4.69-4.79 (0.5H, m), 6.91-7.03 (2H, 25 m), 7.53-7.69 (2H, m), 7.70-7.91 (1H, m) MS (ESI-) m/z: 396 (M-H) Example 40 N-(2-Tetrahydropyranyloxy)-2-[5-(4-fluorophenyl)-2 30 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide (145 mg) NMR (CDC1 3 , 8): 1.45-1.99 (10H, m), 2.17-2.32 (1H, m), 2.50-2.97 (3H, m), 3.40-3.51 (1H, m), 3.71-3.86 (1H, m), 4.70 (0.5H, s), 4.86 (0.5H, s), 6.93-7.19 35 (4H, m), 7.52-7.67 (2H, m), 8.09 (0.5H, s), 8.22 WO 00/40576 PCT/JPOO/00018 128 (0.5H, s) MS (ESI-) m/z: 434 (M-H) Example 41 5 N-( 2 -Tetrahydropyranyloxy)-2-[5-(4-fluorophenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (345 mg) NMR (CDCl 3 , 6): 1.39-1.79 (6H, m), 1.89-2.00 (2H, m), 2.05-2.27 (2H, m), 2.64-2.92 (2H, m), 3.06 (lH, s), 10 3.09-3.16 (1H, m), 3.27-3.50 (1H, m), 3.61-3.73 (1H, m), 4.53 (0.5H, br s), 4.82 (1H, br s), 7.02 7.11 (2H, m), 7.16-7.27 (2H, m), 7.55 (1H, d, J=8Hz), 7.57 (1H, d, J=8Hz), 7.97 (0.5H, s), 8.13 (1H, br s) 15 Example 42

N-(

2 -Tetrahydropyranyloxy)-2-(4-biphenylyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide (330 mg) NMR (CDCl 3 , 8): 1.45-1.81 (10H, m), 2.29-2.38 (lH, m), 20 2.52-2.96 (7H, m), 3.58-3.75 (1H, m), 7.35-7.37 (1H, m), 7.42-7.47 (2H, m), 7.56-7.64 (4H, m), 7.71-7.75 (2H, m) MS (ESI-) m/z: 410 (M-H) 25 Example 43

N-(

2 -Tetrahydropyranyloxy)-2-(4-biphenylyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (390 mg) NMR (CDC1 3 , 6): 1.38-1.66 (6H, m), 1.95-2.03 (2H, m), 2.12-2.21 (2H, m), 2.73-2.84 (2H, m), 2.89 (1H, s), 30 2.96 (1H, s), 3.04-3.31 (4H, m), 3.50-3.62 (1H, m), 7.35-7.47 (3H, m), 7.58-7.60 (2H, m), 7.65-7.70 (2H, m), 7.77-7.81 (2H, m) MS (ESI-) m/z: 442 (M-H) 35 Example 44 WO 00/40576 PCT/JPOO/00018 129 N-(2-Tetrahydropyranyloxy)-2-[4-(4 chlorophenyl)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (300 mg) NMR (CDC1 3 , 8): 1.60-1.66 (6H, m), 1.94-2.03 (2H, m), 5 2.13-2.21 (2H, m), 2.76-2.84 (2H, m), 2.89-2.96 (2H, m), 3.07-3.27 (4H, m), 3.53-3.65 (1H, m), 7.41 (2H, d, J=8.5Hz), 7.51 (2H, d, J=8.5Hz), 7.60-7.64 (2H, m), 7.76-7.80 (2H, m) MS (ESI-) m/z: 476 (M-H) 10 Example 45 N-(2-Tetrahydropyranyloxy)-2-[4-(4-bromophenyl)phenyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (100 mg) 15 NMR (CDCl 3 , 8): 1.44-1.62 (10H, m), 2.10-2.20 (2H, m), 2.76-2.84 (2H, m), 3.05-3.31 (4H, m), 3.53-3.65 (1H, m), 7.45 (2H, d, J=9Hz), 7.56-7.64 (4H, m), 7.70-7.77 (2H, m) MS (ESI-) m/z: 520 (M-H) 20 Example 46 N-(2-Tetrahydropyranyloxy)-2-[4-(4 fluorophenyl)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (230 mg) 25 NMR (CDCl 3 , 6): 1.45-1.70 (10H, m), 2.12-2.19 (2H, m), 2.79-2.81 (2H, m), 3.05-3.32 (4H, m), 3.55-3.64 (1H, m), 7.13 (2H, dd, J=9, 9Hz), 7.52-7.61 (4H, m), 7.73-7.78 (2H, m) MS (ESI-) m/z: 460 (M-H) 30 Example 47 N-(2-Tetrahydropyranyloxy)-2-(4-phenoxybenzyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-carboxamide 1,1-dioxide (360 mg) NMR (CDC1 3 , 8): 1.45-2.31 (12H, m), 2.42-2.63 (1H, m), 35 3.03-3.20 (3H, m), 3.43 (1H, d, J=14Hz), 3.57-3.70 WO 00/40576 PCT/JPO0/00018 130 (1H, m), 3.84-4.02 (1H, m), 4.91, 5.11 (1H, s), 6.91 (2H, d, J=8Hz), 6.97-7.14 (3H, m), 7.19 (2H, t, J=8Hz), 7.28-7.48 (2H, m), 9.99, 10.07 (1H, s) MS (ESI-) m/z: 458 (M-H) 5 Example 48 N-(2-Tetrahydropyranyloxy)-2-(4-phenoxybenzyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-carboxamide (320 mg) NMR (CDC1 3 , 8): 1.33-2.00 (12H, m), 2.47-2.59 (1H, m), 10 2.64-2.90 (3H, m), 3.08-3.22 (1H, m), 3.50-3.65 (1H, m), 3.75-4.00 (1H, m), 4.70, 4.98 (1H, s), 6.87-7.20 (7H, m), 7.32 (2H, t, J=8Hz), 9.70 (1H, s) MS (ESI-) m/z: 426 (M-H) 15 Example 49 N-(2-Tetrahydropyranyloxy)-2-(4-biphenylylmethyl) 3,4,5,6-tetrahydro-2H-thiopyran-2-carboxamide 1,1-dioxide (152 mg) 20 NMR (CDC1 3 , 8): 1.54-2.35 (12H, m), 2.45-2.66 (1H, m), 3.08-3.25 (3H, m), 3.33-3.55 (1H, m), 3.56-3.70 (1H, m), 3.82-4.08 (1H, m), 4.95, 5.14 (1H, s), 7.23-7.36 (3H, m), 7.42 (2H, t, J=8Hz), 7.47-7.67 (4H, m), 10.01, 10.08 (1H, s) 25 MS (ESI-) m/z: 442 (M-H) Example 50 N-(2-Tetrahydropyranyloxy)-2-(4-phenoxyphenyl)-1,3 dithiane-2-acetamide (150 mg) 30 NMR (DMSO-d 6 , 8): 1.47-1.62 (6H, m), 1.85-1.90 (2H, m), 2.73 (2H, s), 2.89 (4H, br), 3.33 (2H, m), 4.57 (1H, s), 6.98 (2H, d, J=8.OHz), 7.03 (2H, d, J=8.0Hz), 7.16 (1H, dd, J=8.0, 8.OHz), 7.40 (2H, dd, J=8.0, 8.OHz), 7.83 (2H, d, J=8.OHz) 35 MS (ESI-) m/z: 444.1 (M-H) WO 00/40576 PCT/JPO0/00018 131 Example 51 N-(2-Tetrahydropyranyloxy)-2-[5-(4-chlorophenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 5 dioxide (250 mg) NMR (CDCl 3 , 8): 1.45-1.67 (10H, m), 1.90-1.97 (2H, m), 2.67-3.12 (6H, m), 3.62-3.68 (1H, m), 7.24-7.26 (2H, m), 7.35 (2H, d, J=8.7Hz), 7.52 (2H, d, J=8.7Hz) MS (ESI-) m/z: 482 (M-H) 10 Example 52 N-(2-Tetrahydropyranyloxy)-2-(5-bromo-2-thienyl) 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (190 mg) 15 NMR (CDCl 3 , 8): 1.50-2.17 (11H, m), 2.65-3.10 (6H, m), 3.47-3.58 (1H, m), 3.72-3.81 (1H, m), 7.00-7.05 (2H, m) MS (ESI-) m/z: 450 (M-H) 20 Example 53 (2R or 2S)-N-( 2 -Tetrahydropyranyloxy)-2-(5-bromo-2 thienyl)-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (80 mg) from (2R or 2S) 2-(5-bromo-2-thienyl) 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide 25 (63 mg) obtained in Example 13 NMR (CDCl 3 , 8): 1.50-2.17 (11H, m), 2.65-3.10 (6H, m), 3.47-3.58 (1H, m), 3.72-3.81 (1H, m), 7.00-7.05 (2H, m) MS (ESI-) m/z: 450 (M-H) 30 Example 54 To a mixture of (2R or 2 S)-N-(2-tetrahydropyranyloxy) 2-[4-(4-chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (6.51 g) obtained in 35 Example 32 in methanol (40 ml) was added 10% hydrogen WO 00/40576 PCT/JPOO/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 5 2 S)-(-)-N-hydroxy-2-[4-(4-chlorophenoxy)phenyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (optical isomer A, 4.72 g) as white crystalline. [a]25 -13.7 0 C (C=0.98, MeOH) Analytical chiral HPLC: 10 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 15 retention time: 18.2 minutes The following compounds were obtained in a similar manner to that of Example 54. 20 Example 55 N-Hydroxy-2-[4-( 4 -chlorophenoxy)phenyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide (61 mg) NMR (DMSO-d 6 , 6): 1.32-1.78 (4H, m), 2.30-2.58 (4H, m), 2.60-2.73 (2H, m), 6.96-7.08 (4H, m), 7.43 (2H, 25 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]-3,4,5,6 30 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (220 mg) NMR (DMSO-d 6 , 8): 1.75-2.03 (4H, m), 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, m), 7.23-7.29 (2H, m), 7.53 (2H, d, J=9Hz), 8.74 (1H, s) 35 MS (ESI-) m/z: 392 (M-H) WO 00/40576 PCT/JP00/00018 133 Example 57 N-Hydroxy-2-[4-(4-fluorophenoxy)phenyll-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide (143 mg) 5 NMR (DMSO-d 6 , 6): 1.46-1.73 (4H, m), 2.35-2.49 (4H, m), 2.64-2.71 (2H, m), 6.93 (2H, d, J=9Hz), 7.05 7.09 (2H, m), 7.20-7.26 (2H, m), 7.53 (2H, d, J=9Hz), 8.62 (1H, s), 10.18 (1H, s) MS (ESI-) m/z: 360 (M-H) 10 Example 58 N-Hydroxy-2-[4-(4-fluorophenoxy)phenyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1-oxide (80 mg) NMR (DMSO-d 6 , 8): 1.47-1.65 (4H, m), 1.95-2.02 (1H, 15 m), 2.25-2.44 (3H, m), 2.57 (1H, d, J=14Hz), 2.70 (1H, d, J=14Hz), 6.96 (2H, d, J=9Hz), 7.07-7.12 (2H, m), 7.22-7.28 (2H, m), 7.40 (2H, d, J=9Hz), 8.64 (1H, s), 10.31 (1H, s) MS (ESI-) m/z: 376 (M-H) 20 Example 59 N-Hydroxy-2-[4-(4-bromophenoxy)phenyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (104 mg) NMR (CDC1 3 , 8): 1.86-1.97 (2H, m), 2.02-2.23 (2H, m), 25 2.60-2.80 (2H, m), 3.01-3.24 (4H, m), 6.93 (2H, d, J=9Hz), 7.01 (2H, d, J=9Hz), 7.46 (2H, d, J=9Hz), 7.64 (2H, d, J=9Hz) MS (ESI-) m/z: 452 (M-H) 30 Example 60 N-Hydroxy-2-[4-[4[(4-fluorophenyl)phenoxy]phenyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (63 mg) NMR (CDCl 3 , 8): 1.87-2.00 (2H, m), 2.04-2.25 (2H, m), 35 2.60-2.82 (2H, m), 3.01-3.25 (4H, m), 7.00-7.19 WO 00/40576 PCT/JPO0/00018 134 (6H, m), 7.47-7.57 (4H, m), 7.64 (2H, d, J=9Hz) MS (ESI-) m/z: 468 (M-H) Example 61 5 N-Hydroxy-2-(4-methoxyphenyl)-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (21 mg) NMR (DMSO-d 6 , 8): 1.70-2.05 (4H, m), 2.39-2.52 (1H, m), 2.81-2.91 (1H, m), 2.95-3.22 (4H, m), 3.26 (3H, s), 6.91 (2H, d, J=9Hz), 7.45 (2H, d, J=9Hz), 8.70 10 (1H, s), 10.46 (1H, s) MS (ESI-) m/z: 312 (M-H) Example 62 N-Hydroxy-2-[5-(4-fluorophenyl)-2-thienyl]-3,4,5,6 15 tetrahydro-2H-thiopyran-2-acetamide (87 mg) NMR (CDC1 3 , 8): 1.45-1.85 (4H, m), 2.35-2.74 (4H, m), 2.46 (1H, d, J=14Hz), 2.66 (1H, d, J=14Hz), 7.17 7.33 (3H, m), 7.45 (1H, d, J=3Hz), 7.64-7.77 (2H, m)', 8.74 (1H, s) 20 MS (ESI-) m/z: 350 (M-H) Example 63 N-Hydroxy-2-[5-(4-fluorophenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (286 mg) 25 NMR (CDC1 3 , 6): 1.69-2.07 (4H, m), 2.35-2.48 (2H, m), 2.94-3.54 (4H, m), 7.17-7.33 (3H, m), 7.45 (1H, d, J=3Hz), 7.64-7.77 (2H, m), 8.74 (1H, s) MS (ESI-) m/z: 382 (M-H) 30 Example 64 N-Hydroxy-2-(4-biphenylyl)-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide (230 mg) NMR (DMSO-d 6 , 6): 1.61-1.79 (4H, m), 2.39-2.56 (2H, m), 2.65-2.75 (3H, m), 2.89 (1H, s), 7.36 (1H, dd, 35 J=7, 7Hz), 7.47 (2H, dd, J=7, 7Hz), 7.64-7.69 (6H, WO 00/40576 PCT/JPOO/00018 135 m), 8.63 (1H, s) MS (ESI-) m/z: 326 (M-H) Example 65 5 N-Hydroxy-2-(4-biphenylyl)-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (230 mg) NMR (DMSO-d 6 , 8): 1.77-2.05 (4H, m), 2.49-2.51 (2H, m), 3.19-3.41 (4H, m), 7.41 (1H, dd, J=7.5, 7.5Hz), 7.49 (2H, dd, J=7.5, 7.5Hz), 7.65-7.71 (6H, m), 10 8.74 (1H, s) MS (ESI-) m/z: 358 (M-H) Example 66 N-Hydroxy-2-[4-(4-chlorophenyl)phenyl]-3,4,5,6 15 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (150 mg) NMR (DMSO-d 6 , 8): 1.78-2.04 (4H, m), 2.91-3.10 (2H, m), 3.17-3.36 (4H, m), 7.54 (2H, d, J=9Hz), 7.61 7.69 (4H, m), 7.73 (2H, d, J=9Hz), 8.72 (1H, s) 20 Example 67 N-Hydroxy-2-[4-(4-bromophenyl)phenyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (70 mg) NMR (DMSO-d 6 , 6): 1.77-2.06 (4H, m), 2.93-3.08 (2H, m), 3.19-3.36 (4H, m), 7.61-7.70 (8H, m), 8.74 (1H, 25 s) MS (ESI-) m/z: 436 (M-H) Example 68 N-Hydroxy-2-[4-(4-fluorophenyl)phenyl]-3,4,5,6 30 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (160 mg) NMR (DMSO-d 6 , 8): 1.77-2.05 (4H, m), 2.93-3.54 (6H, m), 7.31 (2H, dd, J=9, 9Hz), 7.63-7.77 (6H, m), 8.73 (1H, s), 10.53 (1H, s) MS (ESI-) m/z: 376 (M-H) 35 WO 00/40576 PCT/JPOO/00018 136 Example 69 N-Hydroxy-2-(4-phenoxybenzyl)-3,4,5,6-tetrahydro-2H thiopyran-2-carboxamide 1,1-dioxide (199 mg) NMR (CDC1 3 , 8): 1.47-2.20 (5H, m), 2.46-2.62 (1H, m), 5 2.96-3.20 (3H, m), 3.43 (1H, d, J=14Hz), 6.89 (2H, d, J=8Hz), 6.98 (2H, d, J=8Hz), 7.05-7.18 (3H, m), 7.33 (2H, d, J=8Hz), 7.96 (1H, br s), 9.98 (1H, br s) MS (ESI-) m/z: 374 (M-H) 10 Example 70 N-Hydroxy-2-(4-phenoxybenzyl)-3,4,5,6-tetrahydro-2H thiopyran-2-carboxamide (203 mg) mp: 124-126'C 15 NMR (CDC1 3 , 8): 1.22-1.38 (1H, m), 1.45-1.66 (2H, m), 1.70-1.83 (1H, m), 1.88-1.98 (1H, m), 2.43-2.55 (1H, m), 2.60-2.75 (2H, m), 2.80 (1H, d, J=14Hz), 3.15 (1H, d, J=14Hz), 6.90 (2H, d, J=8Hz), 7.00 (2H, d, J=8Hz), 7.05-7.15 (3H, m), 7.33 (2H, t, 20 J=8Hz), 9.47 (1H, s) MS (ESI-) m/z: 342 (M-H) Example 71 N-Hydroxy-2-(4-biphenylylmethyl)-3,4,5,6 25 tetrahydro-2H-thiopyran-2-carboxamide 1,1-dioxide (78 mg) mp: 101-104'C NMR (DMSO-d 6 , 6): 1.58-2.18 (6H, m), 3.06-3.17 (1H, m), 3.39 (1H, d, J=14Hz), 3.49-3.64 (1H, m), 3.65 (1H, d, J=14Hz), 7.31 (2H, d, J=8Hz), 7.37 (1H, d, 30 J=8Hz), 7.46 (2H, t, J=8Hz), 7.59 (2H, d, J=8Hz), 7.65 (2H, d, J=8Hz), 9.20 (1H, s) MS (ESI-) m/z: 358 (M-H) Example 72 35 N-Hydroxy-2-(4-phenoxyphenyl)-1,3-dithian-2-acetamide WO 00/40576 PCT/JPOO/00018 137 (88 mg) NMR (DMSO-d 6 , 8): 2.27-2.38 (2H, m), 3.43 (2H, s), 3.60-3.67 (2H, m), 3.80-3.88 (2H, m), 7.00 (2H, d, J=8.OHz), 7.10 (2H, d, J=8.OHz), 7.22 (1H, dd, 5 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) m/z: 360.1 (M-H) Example 73 10 N-Hydroxy-2-[5-(4-chlorophenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (200 mg) NMR (DMSO-d 6 , 6): 1.74-2.02 (4H, m), 2.96-3.52 (6H, m), 7.22 (1H, d, J=3.6Hz), 7.47-7.53 (3H, m), 7.67 (2H, d, J=8.7Hz), 8.85 (1H, s), 10.59 (1H, s) 15 MS (ESI-) m/z: 398 (M-H) Example 74 N-Hydroxy-2-(5-bromo-2-thienyl)-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (140 mg) 20 NMR (DMSO-d 6 , 6): 1.73-2.00 (4H, m), 2.26-2.33 (1H, m), 2.86-2.96 (2H, m), 3.11-3.23 (2H, m), 3.40 3.45 (1H, m), 7.03 (1H, d, J=3.9Hz), 7.22 (1H, d, J=3.9Hz), 8.86 (1H, s), 10.57 (lH, s) MS (ESI-) m/z: 366 (M-H) 25 Example 75 (2R or 2S)-N-Hydroxy-2-(5-bromo-2-thienyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (65 mg) from (2R or 2 S)-N-(2-tetrahydropyranyloxy)-2-(5-bromo-2-thienyl) 30 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (80 mg) obtained in Example 53 [a]2 5 -17.1 0 C (C=0.485, DMF) NMR (DMSO-d 6 , 6): 1.73-2.00 (4H, m), 2.26-2.33 (1H, m), 2.86-2.96 (2H, m), 3.11-3.23 (2H, m), 3.40 35 3.45 (1H, m), 7.03 (1H, d, J=3.9Hz), 7.22 (1H, d, WO 00/40576 PCT/JPOO/00018 138 J=3.9Hz), 8.86 (1H, s), 10.57 (1H, s) MS (ESI-) m/z: 366 (M-H) Optical purity: 95% ee Analytical chiral HPLC: 5 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 10 The following compounds were obtained in a similar manner to that of Preparation 1-4). Example 76 15 2-[4-(4-Fluorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid 1,1-dioxide (450 mg) NMR (CDCl 3 , 8): 1.87-2.21 (4H, m), 2.67-2.85 (2H, m), 3.03-3.15 (2H, m), 3.21 (1H, d, J=16Hz), 3.62 (1H, d, J=16Hz), 6.94-7.04 (6H, m), 7.59 (2H, d, J=9Hz) 20 MS (ESI-) m/z: 377 (M-H) Example 77 2-[4-(4-Bromophenoxy)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid 1,1-dioxide 25 NMR (CDCl 3 , 6): 1.75-2.02 (4H, m), 2.08-2.21 (2H, m), 2.63-2.85 (2H, m), 3.02-3.16 (2H, m), 3.21 (1H, d, J=16Hz), 3.60 (1H, d, J=16Hz), 6.92 (2H, d, J=9Hz), 7.00 (2H, d, J=9Hz), 7.46 (2H, d, J=9Hz), 7.60 (2H, d, J=9Hz) 30 MS (ESI-) m/z: 439 (M-H) Example 78 2-(4-Methoxyphenyl)-3,4,5,6-tetrahydro-2H-thiopyran-2 acetic acid 35 NMR (CDCl 3 , 6): 1.71-2.00 (4H, m), 2.07-2.20 (2H, m), WO 00/40576 PCT/JPOO/00018 139 2.60-2.86 (2H, m), 2.99-3.14 (2H, m), 3.19 (1H, d, J=15.5Hz), 3.60 (1H, d, J=15.5Hz), 3.81 (3H, s), 6.82 (2H, d, J=9Hz), 7.56 (2H, d, J=9Hz) MS (ESI-) m/z: 297 (M-H) 5 Example 79 2-[5-(4-Fluorophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid NMR (CDCl 3 , 8): 1.70-2.02 (2H, m), 2.09-2.24 (2H, m), 10 2.67-2.86 (2H, m), 3.02-3.20 (2H, m), 3.19 (1H, d, J=15Hz), 3.46 (1H, d, J=15Hz), 7.06 (2H, dd, 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) 15 Example 80 2-(4-Biphenylyl)-3,4,5,6-tetrahydro-2H-thiopyran-2 acetic acid 1,1-dioxide (0.33 g) NMR (CDC1 3 , 6): 1.80-2.01 (2H, m), 2.11-2.19 (2H, m), 20 2.69-2.76 (1H, m), 2.82-2.92 (1H, m), 3.02-3.16 (2H, m), 3.24 (1H, d, J=15.6Hz), 3.67 (1H, d, J=15.6Hz), 7.37-7.46 (2H, m), 7.58-7.63 (4H, m), 7.71 (2H, d, J=9Hz) MS (ESI-) m/z: 343 (M-H) 25 Example 81 2-[4-(4-Chlorophenyl)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid 1,1-dioxide (275 mg) NMR (CDCl 3 , 6): 1.79-2.00 (2H, m), 2.10-2.18 (2H, m), 30 2.66-2.89 (2H, m), 3.02-3.14 (2H, m), 3.23 (1H, d, J=16Hz), 3.65 (1H, d, J=16Hz), 7.40 (2H, d, J=9Hz), 7.50 (2H, d, J=8.5Hz), 7.57 (2H, d, J=8.5Hz), 7.70 (2H, d, J=9Hz) MS (ESI-) m/z: 377 (M-H) 35 WO 00/40576 PCT/JPOO/00018 140 Example 82 2-[4-(4-Bromophenyl)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid 1,1-dioxide (105 mg) NMR (CDC1 3 , 8): 1.70-2.20 (4H, m), 2.72-2.92 (2H, m), 5 3.05-3.16 (2H, m), 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) 10 Example 83 2-[4-(4-Fluorophenyl)phenyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid 1,1-dioxide (220 mg) NMR (CDCl 3 , 8): 1.80-2.18 (4H, m), 2.69-2.91 (1H, m), 3.04-3.16 (3H, m), 3.24 (1H, d, J=16Hz), 3.66 (1H, 15 d, J=16Hz), 7.12 (2H, dd, J=9, 9Hz), 7.52-7.58 (4H, m), 7.70 (2H, d, J=8.5Hz) MS (ESI-) m/z: 361 (M-H) Example 84 20 A mixture of 2-[4-(4-chlorophenoxy)phenyll-3,4,5,6 tetrahydro-2H-thiopyran-2-acetic acid (56 g), potassium permanganate (48.8 g) and benzyltrimethylammonium chloride (2.87 g) in water-methylene chloride (2:1, 1.5 V) was stirred for 3 hours at room temperature. After the reaction mixture 25 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 2). The combined organic layer was washed with brine, dried over magnesium 30 sulfate and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography (eluent: chloroform-methanol 10:1) to give 2-[4-(4 chlorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetic acid 1,1-dioxide (17.2 g) as colorless crystal. 35 mp: 191-193'C WO 00/40576 PCT/JPOO/00018 141 Example 85 N-Hydroxy-2-(4-phenoxyphenyl)-1,3-dithiane-2-acetamide 1,1,3,3-tetraoxide (56 mg) was obtained in a similar manner 5 to that of Preparation 1-4). NMR (DMSO-d 6 , 8): 2.27-2.38 (2H, m), 3.43 (2H, s), 3.60-3.67 (2H, m), 3.80-3.88 (2H, m), 7.00 (2H, d, J=8.OHz), 7.10 (2H, d, J=8.OHz), 7.22 (1H, dd, J=8.0, 8.0Hz), 7.45 (2H, dd, J=8.0, 8.0Hz), 8.04 10 (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]-3,4,5,6 15 tetrahydro-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 20 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 2-[4-(4-fluorophenoxy)phenyl]-3,4,5,6-tetrahydro-2H 25 thiopyran-2-acetic acid 1-oxide (150 mg) as an amorphous. NMR (CDCl 3 , 8): 1.55-1.76 (4H, m), 2.45-2.62 (4H, m), 3.05-3.07 (2H, m), 6.95-7.07 (6H, m), 7.39 (2H, d, J=9Hz) MS (ESI-) m/z: 361 (M-H) 30 Example 87 2-[5-(4-Chlorophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetic acid 1,1-dioxide (1.95 g) was obtained in a similar manner to that of Preparation 1-4). 35 NMR (DMSO-d 6 , 8): 1.76-1.90 (4H, m), 3.16-3.55 (6H, WO 00/40576 PCT/JPO0/00018 142 m), 7.19 (1H, d, J=3.6Hz), 7.47-7.52 (3H, m), 7.68 (2H, d, J=8.4Hz) Example 88 5 2-(5-Bromo-2-thienyl)-3,4,5,6-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 , 8): 1.74-1.87 (4H, m), 2.30-2.37 (1H, m), 3.07-3.56 (5H, m), 7.02 (1H, d, J=4.2Hz), 7.21 10 (1H, d, J=4.2Hz) MS (EST-) m/z: 351 (M-H) Example 89 A mixture of 2 -[4-(4-bromophenoxy)phenyl]-3,4,5,6 15 tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (130 mg), 4-fluorobenzeneboronic acid (49.7 mg) and tetrakis(triphenylphosphine)palladium(0) (3.4 mg) in a mixture of 1,2-dimethoxyethane (0.5 ml) and 2M aqueous sodium carbonate (0.5 ml) was refluxed for 6 hours. The 20 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-[4-(4 fluorophenyl)phenoxy]phenyl]-3,4,5,6 25 tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (116 mg) as an oil. NMR (CDCl 3 , 8): 1.75-2.02 (4H, m), 2.08-2.21 (2H, m), 2.64-2.84 (2H, m), 3.01-3.17 (2H, m), 3.23 (1H, d, J=15Hz), 3.62 (1H, d, J=15Hz), 7.04 (2H, d, J=9Hz), 30 7.07-7.16 (4H, m), 7.41-7.56 (4H, m), 7.61 (2H, d, J=9Hz) MS (ESI-) m/z: 453 (M-H) Example 90 35 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 (10 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-2 5 carboxylate 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 10 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 15 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 20 (745 mg) as an oil. NMR (CDCl 3 , 8): 1.68-1.92 (2H, m), 2.02-2.34 (4H, m), 3.10-3.30 (2H, m), 3.17 (1H, d, J=14Hz), 3.74 (1H, d, J=14Hz), 3.83 (3H, s), 6.91 (2H, d, J=8Hz), 7.00 (2H, d, J=8Hz), 7.06-7.18 (3H, m), 7.34 (2H, 25 t, J=8Hz) Example 91 Methyl 2-(4-phenoxybenzyl)-3,4,5,6-tetrahydro-2H thiopyran-2-carboxylate (605 mg) was obtained in a similar 30 manner to that of Example 90. NMR (CDCl 3 , 6): 1.46-1.82 (4H, m), 1.86-1.96 (1H, m), 2.28-2.40 (1H, m), 2.52-2.62 (1H, m), 2.69-2.80 (1H, m), 3.07 (2H, s), 3.71 (3H, s), 6.89 (2H, d, J=8Hz), 7.00 (2H, d, J=8Hz), 7.06-7.14 (3H, m), 35 7.33 (2H, t, J=8Hz) WO 00/40576 PCT/JPOO/00018 144 Example 92 Methyl 2-(4-biphenylylmethyl)-3,4,5,6-tetrahydro-2H thiopyran-2-carboxylate 1,1-dioxide (250 mg) was obtained in 5 a similar manner to that of Preparation 90. NMR (CDCl 3 , 8): 1.72-1.93 (2H, m), 2.06-2.20 (3H, m), 2.25-2.37 (1H, m), 3.12-3.30 (2H, m), 3.24 (1H, d, J=14Hz), 3.81 (1H, d, J=14Hz), 3.86 (3H, s), 7.23 (2H, d, J=8Hz), 7.30-7.38 (1H, m), 7.43 (2H, t, 10 J=8Hz), 7.49-7.58 (4H, m) Example 93 To a stirred solution of ethyl 3-hydroxy-3-(4 methoxyphenyl)- 7 -mercaptoheptanoate (3.00 g) in 15 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 20 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) 25 3

,

4 ,5,6-tetrahydro-2H-thiopyran-2-acetate (2.216 g) as an oil. NMR (CDCl 3 , 8): 1.05 (3H, t, J=7Hz), 1.50-1.84 (5H, m), 2.25-2.36 (1H, m), 2.45-2.71 (2H, m), 2.79 (1H, d, J=14Hz), 2.91 (1H, d, J=14Hz), 3.81 (3H, s), 30 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) 35 propanoate (500 mg) and 1,3-propanedithiol (2 ml) was added WO 00/40576 PCT/JPOO/00018 145 boron trifluoride diethyl etherate (2 ml) at 0 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 5 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 (1:10)) to give ethyl 2-(4 phenoxyphenyl)-1,3-dithian-2-acetate (370 mg) as a yellow 10 oil. NMR (CDCl 3 , 6): 1.12 (3H, t, J=7.OHz), 1.94-2.01 (2H, m), 2.75-2.81 (4H, m), 3.13 (2H, s), 4.00 (2H, q, J=7.OHz), 6.98 (2H, d, J=8.5Hz), 7.03 (2H, d, J=7.OHz), 7.12 (lH, dd, J=7.0, 7.0Hz), 7.34 (2H, 15 dd, J=7.0, 7.0Hz), 7.88 (2H, d, J=8.5Hz) MS (ESI-) m/z: 374 (M-H) Example 95 A mixture of tert-Butyl 2-(5-bromo-2-thienyl)-3,4,5,6 20 tetrahydro-2H-thiopyran-2-acetate (199 g) and aqueous 90% 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 2-(5 25 bromo-2-thienyl)-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetic acid (166.2 g). NMR (DMSO-d 6 , 8): 1.45-1.73 (4H, m), 2.12-2.20 (1H, m), 2.45-2.70 (5H, m), 2.87 (1H, d, J=14.4Hz), 6.84 (1H, d, J=4.2Hz), 7.08 (1H, d, J=4.2Hz) 30 MS (ESI-): 319 (M-H) Example 96 To a solution of ( 2 S)-N-(2-tetrahydropyranyloxy)-2-[5

(

3

-(

2 -(tert-butyl) (diphenyl)sillyloxy)ethylaminocarbonyl 35 amino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2- WO 00/40576 PCT/JPOO/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 0 C and the reaction mixture was stirred at ambient temperature for 3 hours. The resulting 5 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 10 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-2H thiopyran-2-acetamide 1,1-dioxide (70 mg) as a white amorphous. 15 NMR (CDCl 3 , 6): 1.46 (2H, br), 1.52-1.68 (4H, m), 1.94 (2H, br), 2.04-2.24 (2H, m), 2.67-2.88 (2H, m), 3.00-3.06 (2H, m), 3.11 (2H, m), 3.30-3.47 (2H, m), 3.72 (2H, td, J=7.0, 7.0Hz), 4.24 (2H, td, J=7.0, 7.0Hz), 4.52 (1/2H, br), 4.82 (1/2H, br), 6.80 (1H, 20 s), 7.18-7.46 (6H, m), 7.60 (1H, s), 8.32 (1/2H, s), 8.46 (1/2H, s) MS (ESI-): 550.5 (M-H) Example 97 25 To a solution of 2-(5-bromo-2-thienyl)-3,4,5,6 tetrahydro-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'C. After been allowed to cool to 30 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 (2S)-2-(5-bromo-2-thienyl)-3,4,5,6-tetrahydro-2H-thiopyran 35 2-N-[(R)-1-phenylethyllacetamide 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, m), 2.18-2.32 (1H, m), 2.86-3.10 (3H, m), 3.24 (1H, 5 d, J=15.6Hz), 3.36-3.52 (2H, m), 4.15 (1H, q, J=6.6Hz), 6.96 (1H, d, J=4.2Hz), 7.14 (1H, d, J=4.2Hz), 7.24-7.43 (5H, m) The following compounds were obtained in substantially 10 the same manner as that of Example 54. Example 98 (2S)-N-Hydroxy-2-[5-(3-methylphenyl)-2-thienyll 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (120 15 mg) NMR (DMSO-d 6 , 8): 1.75-2.06 (4H, m), 2.35 (3H, s), 2.95-3.52 (6H, m), 7.13 (1H, d, J=7.SHz), 7.20 (1H, d, J=5Hz), 7.30 (1H, dd, J=7.5, 7.5Hz), 7.42-7.45 (3H, m), 8.84 (1H, s) 20 MS (ESI-): 378 (M-H) Example 99 (2S)-N-Hydroxy-2-[5-(4-methylphenyl)-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (82 25 mg) NMR (DMSO-d 6 , 6): 1.74-2.04 (4H, m), 2.32 (3H, s), 2.47-2.53 (1H, m), 2.95-3.25 (4H, m), 3.43-3.53 (1H, m), 7.16 (1H, d, J=3.OHz), 7.23 (2H, d, J=7.OHz), 7.40 (1H, d, J=3.OHz), 7.53 (2H, d, 30 J=7.OHz), 8.85 (1H, s) MS (ESI-): 378.0 (M-H) Example 100 (2S)-N-Hydroxy-2-[5-(4-ethylphenyl)-2-thienyll-3,4,5,6 35 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (115 mg) WO 00/40576 PCT/JPOO/00018 148 NMR (CDC1 3 , 6): 1.24 (3H, t, J=7Hz), 1.74-1.93 (2H, m), 1.96-2.16 (2H, m), 2.57-2.73 (2H, m), 2.65 (2H, q, J=7Hz), 2.94-3.15 (4H, m), 7.14-7.24 (4H, m), 7.50 (2H, d, J=8Hz), 8.52 (1H, s) 5 MS (ESI-) : 392 (M-H) Example 101 (2S)-N-Hydroxy-2-[5-(4-methoxyphenyl)-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (970 10 mg) NMR (DMSO-d 6 , 6): 1.72-2.06 (4H, m), 2.34-2.45 (1H, m), 2.94-3.26 (4H, m), 3.39-3.56 (1H, m), 3.78 (3H, s), 6.98 (2H, d, J=7Hz), 7.16 (1H, d, J=3Hz), 7.34 (1H, d, J=3Hz), 7.57 (2H, d, J=7Hz), 8.85 (1H, s), 15 10.58 (1H, s) MS (ESI-): 394 (M-H) Example 102 (2S)-N-Hydroxy-2-[5-(4-hydroxymethylphenyl)-2-thienyl] 20 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (75 mg) NMR (DMSO-d 6 , 6): 1.67-2.08 (4H, m), 2.33-2.48 (1H, m), 2.92-3.28 (4H, m), 3.39-3.54 (1H, m), 4.50 (2H, d, J=6Hz), 5.24 (1H, t, J=6Hz), 7.20 (1H, d, J=3Hz), 25 7.36 (2H, d, J=7Hz), 7.44 (1H, d, J=3Hz), 7.60 (2H, d, J=7Hz), 8.86 (1H, s) MS (ESI-): 394 (M-H) Example 103 30 (2S)-N-Hydroxy-2-[5-(2-thienyl)-2-thienyl]-3,4,5, 6 tetrahydlro-2H-thiopyran-2-acetamide 1,1-dioxide (130 mg) NMR (DMSO-d 6 , 6): 1.72-2.04 (4H, m), 2.93-3.51 (6H, m), 7.10 (1H, dd, J=4.5, 4.5Hz), 7.15 (1H, d, J=4.OHz), 7.26 (1H, d, J=4.OHz), 7.29 (1H, d, J=4.5Hz), 7.53 35 (1H, d, J=4.5Hz), 8.32 (1H, s) WO 00/40576 PCT/JPOO/00018 149 MS (ESI-): 370 (M-H) Example 104 (2S)-N-Hydroxy-2-[5-(2-furyl)-2-thienyl]-3,4,5,6 5 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (12 mg) NMR (CDC1 3 , 8): 1.80-1.97 (2H, m), 2.00-2.25 (2H, m), 2.56-2.69 (1H, m), 2.74-2.89 (1H, m), 2.96-3.20 (4H, m), 6.43-6.47 (1H, m), 6.52-6.56 (1H, m), 7.15-7.22 (2H, m), 7.39-7.44 (1H, m), 8.12 (1H, br 10 s) MS (ESI-): 354 (M-H) Example 105 (2S)-N-Hydroxy-2-[5-(4-methylcarbamoylphenyl)-2 15 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (46 mg) NMR (DMSO-d 6 , 8): 1.68-2.10 (4H, m), 2.33-2.48 (1H, m), 2.79 (3H, d, J=4Hz), 2.92-3.32 (4H, m), 3.40-3.57 (1H, m), 7.26 (1H, d, J=3Hz), 7.60 (1H, d, J=3Hz), 20 7.74 (2H, d, J=8Hz), 7.88 (2H, d, J=8Hz), 8.50 (lH, m) MS (ESI-): 421 (M-H) Example 106 25 ( 2 S)-N-Hydroxy-2-[5-(4-ethylcarbamoylphenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (740 mg) NMR (DMSO-d 6 , 8): 1.13 (3H, t, J=7.5Hz), 1.75-2.05 (4H, m), 2.36-2.45 (1H, m), 2.95-3.03 (2H, m), 3.13 30 3.47 (5H, m), 7.24 (1H, d, J=5.OHz), 7.60 (1H, d, J=5.OHz), 7.73 (2H, d, J=9.OHz), 7.87 (2H, d, J=9.0Hz), 8.51 (1H, t, J=3.OHz) MS (ESI-): 435.2 (M-H) 35 Example 107 WO 00/40576 PCT/JPOO/00018 150 (2S)-N-Hydroxy-2-[5-(3-acetylaminophenyl)-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide, 1,1-dioxide (2 g) NMR (DMSO-d 6 , 8): 1.74-2.01 (4H, m), 2.06 (3H, s), 5 2.35-2.46 (1H, m), 2.94-3.50 (5H, m), 7.20 (1H, d, J=3.0Hz), 7.33 (2H, d, J=5.OHz), 7.39 (1H, d, J=3.OHz), 7.44-7.49 (1H, m), 7.94 (1H, s) MS (ESI-): 421.1 (M-H) 10 Example 108 (2S)-N-Hydroxy-2-[5-(3-aminophenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide hydrochloride (87 mg) NMR (DMSO-d 6 , 8): 1.69-2.09 (4H, m), 2.34-2.56 (1H, m), 15 2.95-3.07 (2H, m), 3.11-3.32 (2H, m), 3.40-3.57 (1H, m), 7.17 (1H, d, J=8Hz), 7.24 (1H, d, J=3Hz), 7.42-7.60 (4H, m), 10.63 (1H, s) MS (ESI-): 379 (M-H) 20 Example 109 (2S)-N-Hydroxy-2-[5-(3-ethylcarbamoylaminophenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide NMR (DMSO-d 6 , 8): 1.06 (3H, t, J=7.2Hz), 1.69-2.09 (4H, 25 m), 2.31-2.53 (1H, m), 2.93-3.55 (7H, m), 6.14 (1H, t, J=4.5Hz), 7.12-7.30 (4H, m), 7.38 (1H, d, J=4.5Hz), 7.84 (1H, s), 8.56 (1H, s), 8.72-8.95 (1H, m), 10.60 (1H, s) MS (ESI-): 450 (M-H) 30 Example 110 (2S)-N-Hydroxy-2-[5-(3-methoxycarbonylaminophenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (82 mg) 35 NMR (DMSO-d 6 , 6): 1.70-2.07 (4H, m), 2.34-2.53 (1H, m), WO 00/40576 PCT/JPOO/00018 151 2.94-3.08 (2H, m), 3.10-3.27 (2H, m), 3.30-3.55 (1H, m), 3.69 (3H, s), 7.20 (1H, d, J=3.5Hz), 7.27-7.41 (4H, m), 7.83 (1H, s), 9.76 (1H, s) MS (ESI+): 456 (M+H+NH 3 ) 5 Example 111 (2S)-N-Hydroxy-2-[5-(3-carbamoylaminophenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (45 mg) 10 NMR (DMSO-d 6 , 6): 1.70-2.08 (4H, m), 2.32-2.55 (1H, m), 2.93-3.07 (2H, m), 3.09-3.30 (2H, m), 3.39-3.55 (1H, m), 5.90 (2H, s), 7.16-7.23 (2H, m), 7.24 7.39 (2H, m), 7.37 (1H, d, J=3.SHz), 7.78 (1H, s), 8.66 (1H, s), 8.84 (1H, s) 15 MS (ESI-): 422 (M-H) Example 112 (2S)-N-Hydroxy-2-[5-( 3 -methylcarbamoylaminophenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 20 dioxide (77 mg) NMR (DMSO-d 6 , 6): 1.74-2.05 (4H, m), 2.38-2.46 (1H, m), 2.66 (3H, d, J=4.OHz), 2.95-3.26 (4H, m), 3.42 3.52 (1H, m), 6.06 (1H, q, J=4.OHz), 7.17-7.20 (2H, m), 7.22-7.26 (2H, m), 7.36 (1H, d, J=3.5Hz), 7.82 25 (1H, s), 8.65 (1H, s), 8.83 (1H, s) MS (ESI-): 436.2 (M-H) Example 113 30 35 WO 00/40576 PCT/JPOO/00018 152 o 0 Br 50 \ O 0 HN \\S/ \ 0S N 0 NH 10 H (b) (d) To a solution of pyridine-3-boronic acid 1,3 propanediol cyclic ester (130 mg) in degassed N,N 15 dimethylformamide (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 (2S)-N-[2 [2-(5-bromo-2-thienyl)-1,1-dioxo-3,4,5,6-tetrahydro-2H 20 thiopyran-2-yl]acetyl]hydroxylamine trityl crowns (b) (4 mmol, 10.0 [tmol/crown) in an atmosphere of nitrogen. After resulting mixture was heated for 48 hours at 60'C, the crowns were washed with degassed N,N-dimethylformamide, a solution of sodium diethyldithiocarbamate (500 mg) and 25 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. 30 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 ( 2 S)-N-hydroxy-2-[5-(3-pyridyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (10 mg) as a 35 powder.

WO 00/40576 PCT/JP00/00018 153 NMR (DMSO-d 6 , 6): 1.25-2.05 (4H, m), 2.87-2.93 (1H, m), 2.97-3.50 (5H, m), 7.28 (1H, d, J=4.OHz), 7.53 7.58 (1H, m), 7.65 (1H, d, J=4.OHz), 8.16 (1H, d, J=7.5Hz), 8.56 (1H, br), 8.95 (1H, br) 5 MS (ESI-): 365.0(M-H) Example 114 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 methylcarbamoylaminophenyl)-2-thienyl]-3,4,5,6-tetrahydro 10 2H-thiopyran-2-acetamide 1,1-dioxide (132 mg) NMR (CDC1 3 , 8): 1.45 (4H, br), 1.62-1.66 (2H, m), 1.93 (2H, br), 2.07-2.17 (2H, m), 2.77-2.81 (5H, m), 2.98-3.03 (1H, m), 3.10-3.15 (3H, m), 3.32-3.50 (1H, m), 3.70-3.78 (1H, m), 4.59 (1Hxl/2, s), 4.83 15 (lHxl/2, s), 7.00 (1H, d, J=3.5Hz), 7.07-7.08 (1H, m), 7.12-7.21 (4H, m), 7.30-7.40 (2H, m), 9.16 (lHxl/2, s), 9.35 (lHxl/2, s) MS (ESI-): 520.2 (M-H) 20 The following compounds were obtained in substantially the same manner as that of Example 89. Example 115 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-methylphenyl) 25 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (200 mg) NMR (CDCl 3 , 8): 1.40-1.73 (10H, m), 2.37 (3H, s), 2.69 2.88 (2H, m), 3.06-3.16 (4H, m), 3.30-3.45 (1H, m), 3.61-3.75 (2H, m), 7.11 (1H, d, J=7.5Hz), 7.24 30 7.28 (3H, m), 7.38-7.41 (2H, m) Example 116 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-methylphenyl) 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 35 dioxide (142 mg) WO 00/40576 PCT/JPOO/00018 154 NMR (CDC1 3 , 6): 1.43 (2H, br), 1.65-1.69 (2H, m), 1.95 (2H, br), 2.07-2.18 (2H, m), 2.37 (3H, s), 2.63 2.80 (2H, m), 3.06 (2H, br s), 3.10-3.16 (2H, m), 3.40-3.50 (2H, m), 3.58-3.76 (2H, m), 4.53 (lHxl/2, 5 s), 4.80 (lHxl/2, s), 7.15-7.24 (4H, m), 7.46 (2H, d, J=8.OHz), 7.39 (lHxl/2, s), 8.06 (lHx1/2, s) MS (ESI-): 462.1 (M-H) Example 117 10 (2S)-N-(2-Tetrahydropyranyloxy)-2 -[5-(4-ethylphenyl)-2 thienyl)-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide NMR (CDCl 3 , 6): 1.25 (3H, t, J=8Hz), 1.35-1.76 (6H, m), 1.87-2.00 (2H, m), 2.04-2.23 (2H, m), 2.60-2.91 15 (4H, m), 3.00-3.19 (4H, m), 3.27-3.50 (1H, m), 3.60-3.77 (1H, m), 4.53, 4.71 (1H, s), 7.15-7.28 (4H, m), 7.51 (2H, d, J=8Hz), 8.10, 8.25 (1H, s) MS (ESI+): 478 (M+H) 20 Example 118 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-methoxyphenyl) 2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (1.85 g) NMR (CDC1 3 , 6): 1.36-1.82 (6H, m), 1.98-2.02 (2H, m), 25 2.10-2.25 (2H, m), 2.62-2.88 (2H, m), 2.98-3.20 (4H, m), 3.26-3.50 (1H, m), 3.57-3.72 (1H, m), 3.83 (3H, s), 6.90 (2H, d, J=8Hz), 7.13, 7.15 (1H, d, J=3Hz), 7.22, 7.24 (1H, d, J=3Hz), 7.52 (2H, d, J=8Hz), 8.11, 8.25 (1H, s) 30 MS (ESI-): 478 (M-H) Example 119 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 hydroxymethylphenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H 35 thiopyran-2-acetamide 1,1-dioxide (181 mg) WO 00/40576 PCT/JPOO/00018 155 NMR (CDCl 3 , 6): 1.36-1.78 (6H, m), 1.85-2.03 (2H, m), 2.06-2.55 (2H, m), 2.66-2.93 (2H, m), 2.98-3.21 (4H, m), 3.26-3.50 (1H, m), 3.62-3.73 (1H, m), 4.52, 4.82 (1H, m), 4.70 (1H, s), 7.22-7.30 (1H, 5 m), 7.35 (2H, d, J=8Hz), 7.42-7.62 (1H, m), 7.57 (2H, d, J=8Hz), 8.25, 8.35 (1H, s) MS (ESI-): 478 (M-H) Example 120 10 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(2-thienyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (200 mg) NMR (CDCl 3 , 6): 1.41-1.75 (10H, m), 2.65-2.82 (2H, m), 3.04-3.17 (4H, m), 3.30-3.74 (3H, m), 7.00-7.02 15 (1H, m), 7.11-7.13 (1H, m), 7.17-7.19 (3H, m) MS (ESI-): 454 (M-H) Example 121 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(2-furyl)-2 20 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (95 mg) NMR (CDC1 3 , 6): 1.41-1.77 (6H, m), 1.85-2.00 (2H, m), 2.03-2.25 (2H, m), 2.61-2.91 (2H, m), 3.00-3.06 (2H, m), 3.07-3.16 (2H, m), 3.28-3.53 (1H, m), 25 3.61-3.75 (1H, m), 4.51 (0.5H, s), 4.80 (0.5H, s), 6.42-6.47 (1H, m), 6.50-6.56 (1H, m), 7.17-7.24 (2H, m), 7.38-7.42 (1H, m), 7.93 (0.5H, s), 8.09 (0.5H, s) MS (ESI-): 438 (M-H) 30 Example 122 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-carboxyphenyl) 2 -thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (910 mg) 35 NMR (CDCl 3 , 6): 1.36-1.73 (6H, m), 1.85-2.25 (4H, m), WO 00/40576 PCT/JPOO/00018 156 2.76-2.88 (2H, m), 3.02-3.25 (4H, m), 3.28-3.53 (1H, m), 3.69-3.81 (1H, m), 4.56, 4.87 (1H, s), 7.57 (1H, d, J=8Hz), 7.36-7.44 (1H, m), 7.72-7.83 (2H, m), 8.00 (2H, d, J=8Hz) 5 MS (ESI-): 492 (M-H) Example 123 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 ethylcarbamoylphenyl)-2-thienyl)-3,4,5,6-tetrahydro-2H 10 thiopyran-2-acetamide 1,1-dioxide (984 mg) NMR (CDC1 3 , 8): 1.28 (3H, t, J=7.0Hz), 1.44-1.55 (4H, m), 1.64-1.68 (2H, m), 1.95 (2H, br), 2.06-2.23 (2H, m), 2.67-2.91 (2H, m), 3.01-3.16 (4H, m), 3.27-3.33 (1H, m), 3.46-3.55 (2H, m), 3.62-3.65 15 (1H, m), 4.50 (1Hxl/2, s), 4.82 (lHxl/2, s), 7.28 (1H, d, J=4.OHz), 7.33 (1H, d, J=4.OHz), 7.62 (2H, d, J=8.0Hz), 7.75 (2H, d, J=8.OHz), 8.19 (lHx1/2, s), 8.27 (lHxl/2, s) MS (ESI-): 519.2 (M-H) 20 Example 124 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 acetylaminophenyl)-2-thienyll-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (2.63 g) 25 NMR (CDCl 3 , 6): 1.43 (2H, br), 1.55-1.64 (4H, m), 1.93 (2H, br), 2.04-2.15 (2H, m), 2.19 (3H, s), 2.80 2.85 (2H, m), 3.02-3.16 (4H, m), 3.44-3.48 (1H, m), 3.66-3.73 (1H, m), 4.55 (lHxl/3, s), 4.85 (lHx2/3, s), 7.08-7.11 (1H, m), 7.16-7.23 (3H, m), 7.38 (1H, 30 br s), 7.57 (1H, d, J=7.OHz), 7.94 (1H, s), 8.93 (lHxl/3, s), 9.02 (lHx2/3, s) MS (ESI-): 505.4 (M-H) Example 125 35 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-aminophenyl)-2- WO 00/40576 PCT/JPOO/00018 157 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (214 mg) NMR (CDCl 3 , 8): 1.36-1.80 (6H, m), 1.84-2.25 (4H, m), 2.61-2.92 (2H, m), 2.98-3.20 (4H, m), 3.27-3.89 5 (4H, m), 4.54 (0.5H, s), 4.81 (0.5H, s), 6.62 (1H, dd, J=2.3, 8Hz), 6.91 (1H, s), 6.99 (1H, d, J=8Hz), 7.15 (1H, t, J=8Hz), 7.20-7.29 (2H, m), 7.98 (0.5H, s), 8.15 (0.5H, s) MS (ESI-): 463 (M-H) 10 Example 126 tert-Butyl-2-(5-bromo-2-thienyl)-3,4,5,6-tetrahydro-2H thiopyran-2-acetate (199 g) was obtained in substantially the same manner as that of Example 93. 15 NMR (CDCl 3 , 8): 1,34 (9H, s), 1.46-1.91 (5H, m), 2.10 2.22 (1H, m), 2.49-2.62 (2H, m), 2.66 (1H, d, J=13.2Hz), 2.75 (1H, d, J=13.2Hz), 6.74 (1H, d, J=3.9Hz), 7.45 (1H, d, J=3.9Hz) 20 Example 127 (2S)-2-(5-Bromo-2-thienyl)-3,4,5,6-tetrahydro-2H thiopyran-2-N-[(R)-1-phenylethyl]acetamide 1,1-dioxide (78 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 (100 ml) and brine (100 ml), dried over sodium sulfate and concentrated in vacuo to give (2S)-2-(5-bromo-2-thienyl) 3,4,5,6-tetrahydro-2H-thiopyran-2-acetic acid 1,1-dioxide (57.5 g) as an solid. 30 mp: 189'C (dec.) NMR (DMSO-d 6 , 6): 1.74-1.87 (4H, m), 2.30-2.37 (1H, m), 3.07-3.56 (5H, m), 7.02 (1H, d, J=4.2Hz), 7.21 (1H, d, J=4.2Hz) 35 Example 128 WO 00/40576 PCT/JPOO/00018 158 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 methylcarbamoylphenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (68 mg) was obtained in substantially the same manner as that of Example 32. 5 NMR (DMSO-d 6 , 8): 1.35-1.64 (6H, m), 1.71-2.08 (4H, m), 2.36-2.53 (1H, m), 2.79 (3H, d, J=4Hz), 2.88-3.32 (4H, m), 3.40-3.53 (2H, m), 3.74-3.92 (1H, m), 4.45, 4.75 (1H, s), 7.22-7.30 (1H, m), 7.55-7.64 (1H, m), 7.74 (2H, d, J=8Hz), 7.88 (2H, d, J=8Hz), 10 8.50 (1H, d, J=4Hz), 11.25 (1H, s) MS (ESI-): 505 (M-H) Example 129 To a mixture of (2S)-N-(2-tetrahydropyranyloxy)-2-[5 15 (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. 20 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-(3 ethylcarbamoylaminophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (100 mg) as an amorphous 25 solid. NMR (CDCl 3 , 8): 1.08-1.18 (3H, m), 1.38-1.75 (6H, m), 1.86-2.00 (2H, m), 2.02-2.24 (2H, m), 2.76-2.90 (2H, m), 2.96-3.17 (4H, m), 3.20-3.55 (3H, m), 3.70-3.85 (1H, m), 4.61 (0.5H, s), 4.84 (0.5H, s), 30 5.25-5.40 (1H, m), 6.95-7.34 (5H, m), 7.36-7.50 (1H, m), 9.13 (0.5H, s), 9.35 (0.5H, s) MS (ESI-): 534 (M-H) Example 130 35 To a mixture of (2S)-N-(2-tetrahydropyranyloxy)-2-[5- WO 00/40576 PCT/JPOO/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 5 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 10 (methanol in chloroform, 0.5 to 3% gradient) to give (2S)-N-( 2 -tetrahydropyranyloxy)-2-[5-(3 methoxycarbonylaminophenyl) -2-thienyl] -3,4,5, 6-tetrahydro 2 H-thiopyran-2-acetamide 1,1-dioxide (101 mg) as an amorphous solid. 15 NMR (CDCl 3 , 6): 1.35-1.56 (4H, m), 1.59-1.75 (2H, m), 1.86-2.00 (2H, m), 2.05-2.26 (2H, m), 2.63-2.93 (2H, m), 3.01-3.17 (4H, m), 3.27-3.51 (1H, m), 3.58-3.74 (1H, m), 3.79 (3H, s), 4.54 (0.5H, s), 4.82 (0.5H, s), 6.74 (1H, br s), 7.15-7.21 (1H, m), 20 7.23-7.37 (4H, m), 7.62 (1H, br s), 8.10 (0.5H, s), 8.24 (0.5H, s) MS (ESI-): 521 (M-H) The following compound was obtained in substantially 25 the same manner as that of Example 129. Example 131 (2S)-N-( 2 -Tetrahydropyranyloxy)-2-[5-(3 aminocarbamoylphenyl) -2-thienyl] -3,4,5, 6-tetrahydro-2H 30 thiopyran-2-acetamide 1,1-dioxide (170 mg) NMR (DMSO-d 6 , 8): 1.36-1.65 (6H, m), 1.69-2.10 (4H, m), 2.34-2.48 (1H, m), 2.89-3.32 (4H, m), 3.39-3.54 (2H, m), 3.72-3.91 (1H, m), 4.43 (0.SH, s), 4.75 (0.5H, s), 5.90 (2H, s), 7.16-7.30 (4H, m), 7.32 35 7.49 (1H, m), 7.79 (1H, s), 8.66 (1H, s) WO 00/40576 PCT/JPOO/00018 160 MS (ESI-): 506 (M-H) Example 132 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-fluorophenyl) 5 2-thienyl]-2,3,4,5-tetrahydrothiophene-2-acetamide 1,1 dioxide (272 mg) was obtained in a similar manner to that of Example 32. NMR (CDC1 3 , 8): 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 10 (1H, m), 3.68-3.80 (1H, m), 4.55-4.64 (0.5H, m), 4.81-4.89 (0.5H, m), 7.03-7.11 (2H, m), 7.13-7.40 (2H, m), 7.49-7.58 (2H, m), 8.20 (0.5H, s), 8.30 (0.5H, s) MS (ESI-): 452 (M-H) 15 The following compounds were obtained in substantially the same manner as that of Example 54. Example 133 20 (2S)-N-Hydroxy-2-[5-(3-ethoxyacetylaminophenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (4.62 g) NMR (DMSO-d 6 , 8): 1.20 (3H, t, J=7Hz), 2.35-2.48 (1H, m), 2.94-3.28 (4H, m), 3.42-3.53 (1H, m), 3.58 (2H, 25 q, J=7Hz), 4.04 (2H, s), 7.21 (1H, d, J=3Hz), 7.32-7.44 (3H, m), 7.57-7.63 (1H, m), 8.03 (1H, s), 8.85 (1H, br), 9.81 (1H, s) MS (ESI-): 465 (M-H) 30 Example 134 (2S)-N-Hydroxy-2-[5-(3-propionylaminophenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (76 mg) NMR (DMSO-d 6 , 6): 1.09 (3H, t, J=7Hz), 2.35 (2H, q, 35 J=7Hz), 2.37-2.48 (1H, m), 2.90-3.52 (5H, m), 7.21 WO 00/40576 PCT/JPOO/00018 161 (1H, d, J=3Hz), 7.28-7.53 (5H, m), 8.00 (1H, s), 9.98 (1H, s), 10.61 (1H, s) MS (ESI-): 435 (M-H) 5 Example 135 (2S)-N-Hydroxy-2-[5-( 3 -propylaminocarbonylaminophenyl) 2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (75 mg) NMR (DMSO-d 6 , 8): 0.88 (3H, t, J=7Hz), 1.44 (2H, q, 10 J=7Hz), 1.68-2.10 (4H, m), 2.34-2.48 (1H, m), 2.90-3.58 (7H, m), 6.22 (1H, br), 7.11-7.30 (4H, m), 7.48 (1H, d, J=3Hz), 7.84 (1H, s), 8.60 (1H, s), 10.61 (1H, s) MS (ESI-) : 464 (M-H) 15 Example 136 (2S)-N-Hydroxy-2-[5-( 3 -butyrylaminophenyl)-2-thienyl] 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (79 mg) 20 NMR (DMSO-d 6 , 6): 0.92 (3H, t, J=7Hz), 1.55-1.68 (2H, m), 1.69-2.10 (4H, m), 2.30 (2H, t, J=7Hz), 2.35 2.48 (1H, m), 2.92-3.65 (5H, m), 7.20 (1H, d, J=3Hz), 7.34 (2H, d, J=3Hz), 7.40 (1H, d, J=3Hz), 7.44-7.53 (1H, m), 8.00 (1H, s) 25 MS (ESI-): 449 (M-H) Example 137 (2S)-N-Hydroxy-2-[5-(3-( 2 -methoxyethoxycarbonylamino) phenyl)-2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2 30 acetamide 1,1-dioxide (64 mg) NMR (DMSO-d 6 , 6): 1.70-2.11 (4H, m), 2.34-2.50 (1H, m), 2.92-3.26 (4H, m), 3.29 (3H, s), 3.40-3.66 (3H, m), 4.15-4.28 (2H, m), 7.20 (1H, d, J=3Hz), 7.26-7.42 (4H, m), 7.85 (1H, s), 8.84 (1H, s), 9.87 (1H, s), 35 10.60 (1H, s) WO 00/40576 PCT/JP00/00018 162 MS (ESI-): 481 (M-H) Example 138 (2S)-N-Hydroxy-2-[5-(3-(2 5 methoxycarbonylaminoacetylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (58 mg) NMR (DMSO-d 6 , 8): 1.69-2.07 (4H, m), 2.32-2.48 (1H, m), 2.92-3.50 (5H, m), 3.56 (3H, s), 3.80 (2H, d, J=8Hz), 7.19 (1H, d, J=3Hz), 7.30-7.52 (5H, m), 10 7.97 (1H, s), 8.82 (1H, s) MS (ESI-): 494 (M-H) Example 139 (2S)-N-Hydroxy-2-[5-(3-(phenoxyacetylamino)phenyl)-2 15 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (3.8 g) NMR (DMSO-d 6 , 6): 1.70-2.09 (4H, m), 2.35-2.50 (1H, m), 2.92-3.55 (5H, m), 4.72 (2H, s), 6.94-7.05 (3H, m), 7.21 (1H, d, J=3Hz), 7.28-7.44 (5H, m), 7.52-7.60 20 (1H, m), 8.03 (1H, s), 8.84 (1H, s), 10.21 (IH, s), 10.60 (1H, s) MS (ESI-): 513 (M-H) Example 140 25 (2S)-N-Hydroxy-2-[5-(3-(propoxyacetylamino)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (2.28 g) NMR (DMSO-d 6 , ): 0.91 (3H, t, J=8Hz) , 1.54-1.67 (2H, m), 1.70-2.11 (4H, m), 2.36-2.49 (1H, m), 2.94 30 3.29 (4H, m), 3.43-3.58 (1H, m), 3.48 (2H, t, J=8Hz), 4.05 (2H, s), 7.21 (1H, d, J=3Hz), 7.32 7.45 (3H, m), 7.54-7.62 (1H, m), 8.03 (1H, s), 8.85 (1H, s), 9.81 (1H, s), 10.60 (1H, s) MS (ESI-): 479 (M-H) 35 WO 00/40576 PCT/JPOO/00018 163 Example 141 (2S)-N-Hydroxy-2-[5-[3-(2-propen-1 yloxy)acetylamino]phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (9.32 g) 5 NMR (DMSO-d 6 , 6): 1.70-2.09 (4H, m), 2.35-2.56 (1H, m), 2.94-3.08 (2H, m), 3.10-3.29 (2H, m), 3.30-3.55 (1H, m), 4.07 (2H, s), 4.10 (2H, d, J=6Hz), 5.22 (1H, d, J=9Hz), 5.34 (1H, d, J=15Hz), 5.89-6.04 (1H, m), 7.21 (1H, d, J=3.5Hz), 7.31-7.44 (3H, m), 10 7.55-7.61 (1H, m), 8.03 (1H, s), 8.85 (1H, br s), 9.86 (1H, s), 10.6 (1H, br s) MS (ESI-): 477 (M-H) Example 142 15 ( 2 S)-N-Hydroxy-2-[5-[4-(5-oxazolyl)phenyl]-2-thienyl] 3

,

4 ,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (331 mg) NMR (DMSO-d 6 , 6): 1.72-2.10 (4H, m), 2.36-2.49 (1H, m), 2.95-3.09 (2H, m), 3.11-3.30 (2H, m), 3.42-3.56 20 (1H, m), 7.24 (1H, d, J=3.9Hz), 7.57 (1H, d, J=3.9Hz), 7.76 (1H, s), 7.77 (4H, s), 8.48 (1H, s) MS (ESI-): 431 (M-H) Example 143 25 (2S)-N-Hydroxy-2-[5-{3-(n-butyloxyacetylamino)phenyl} 2 -thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (90 mg) NMR (DMSO-d 6 , 6): 0.92 (3H, t, J=7.OHz), 1.47 (2H, tq, J=7.0, 7.0Hz), 1.60 (2H, dd, J=7.0, 7.0Hz), 1.74 30 2.06 (4H, m), 2.37-2.47 (1H, m), 2.96-3.30 (4H, m), 3.38-3.45 (1H, m), 3.52 (2H, t, J=7.OHz), 4.05 (2H, s), 7.22 (1H, d, J=4.0Hz), 7.32-7.37 (2H, m), 7.41 (1H, d, J=4.OHz), 7.55-7.60 (1H, m), 8.02 (1H, s), 8.84 (1H, s), 9.80 (1H, s), 10.59 (1H, s) 35 MS (ESI-): 493.2 (M-H) WO 00/40576 PCT/JPOO/00018 164 Example 144 (2S)-N-Hydroxy-2-[5-{3 ethoxycarbonylaminoacetylamino)phenyl}-2-thienyl]-3,4,5,6 5 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (2.3 g) NMR (DMSO-d 6 , 8): 1.18 (3H, t, J=7.0Hz), 1.74-2.05 (4H, m), 2.36-2.46 (1H, m), 2.95-3.26 (4H, m), 3.40 3.53 (1H, m), 3.79 (2H, d, J=6.OHz), 4.02 (2H, q, J=7.0Hz), 7.21 (1H, d, J=4.0Hz), 7.35-7.40 (3H, m), 10 7.40 (1H, d, J=4.OHz), 7.45-7.49 (1H, m), 7.97 (1H, s), 8.84 (lH, s), 10.08 (1H, s) MS (ESI-): 508.3 (M-H) Example 145 15 (2S)-N-Hydroxy-2-[5-{3-(2 chloroethylaminocarbonylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (72 mg) NMR (DMSO-d 6 , 8): 1.72-2.04 (4H, m), 2.36-2.45 (1H, m), 2.93-3.23 (4H, m), 3.39-3.46 (3H, m), 3.67 (2H, t, 20 J=6.OHz), 6.44 (1H, t, J=6.OHz), 7.17-7.30 (4H, m), 7.38 (1H, d, J=4.OHz), 7.84 (1H, s), 8.81 (1H, s), 8.84 (1H, s) MS (ESI-): 484.3 (M-H) 25 Example 146 (2S)-N-Hydroxy-2-[5-{3-(3-methoxypropionylamino) phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (3.4 g) NMR (DMSO-d 6 , 6): 1.72-2.05 (4H, m), 2.38-2.47 (1H, m), 30 2.56 (2H, t, J=6.OHz), 2.95-3.21 (4H, m), 3.27 (3H, s), 3.36-3.52 (1H, m), 3.64 (2H, t, J=6.OHz), 7.20 (1H, d, J=4.OHz), 7.31-7.36 (2H, m), 7.40 (1H, d, J=4.OHz), 7.45-7.49 (1H, m), 8.01 (1H, s), 10.07 (1H, s), 10.60 (1H, s) 35 MS (ESI-): 479.2 (M-H+Na) WO 00/40576 PCT/JPOO/00018 165 Example 147 (2S)-N-Hydroxy-2-[5-{3-(methoxyacetylamino)phenyl}-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 5 dioxide (2.5 g) NMR (DMSO-d 6 , 6): 1.74-2.06 (4H, m), 2.37-2.48 (1H, m), 2.95-3.26 (4H, m), 3.41 (3H, s), 3.43-3.53 (1H, m), 4.02 (2H, s), 7.20 (1H, d, J=4.OHz), 7.32-7.38 (2H, m), 7.42 (1H, d, J=4.0Hz), 7.58-7.63 (1H, m), 8.04 10 (1H, s), 8.84 (1H, s), 9.87 (1H, s), 10.60 (1H, s) MS (ESI-): 451.2 (M-H) Example 148 (2S)-N-Hydroxy-2-[5-(3-hydroxymethylphenyl)-2-thienyl] 15 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (60 mg) NMR (DMSO-d 6 , 6): 1.71-2.08 (4H, m), 2.37-2.46 (1H, m), 2.95-3.54 (5H, m), 4.54 (2H, d, J=5.5Hz), 5.29 (1H, dd, J=5.5, 5.5Hz), 7.21 (1H, d, J=4.OHz), 7.25 (1H, 20 d, J=8.0Hz), 7.38 (1H, dd, J=8.0, 8.0Hz), 7.46 (1H, d, J=4.OHz), 7.53 (iH, d, J=8.0Hz), 7.59 (1H, s), 8.85 (1H, s), 10.6 (1H, s) MS (ESI-): 394 (M-H) 25 Example 149 (2S)-N-Hydroxy-2-[5-(4-(cis-1,2-dihydroxyethyl) phenyl)-2-thienyll-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (100 mg) NMR (DMSO-d 6 , 8): 1.73-2.07 (4H, m), 2.35-2.46 (1H, m), 30 2.95-3.50 (SH, m), 4.51-4.56 (1H, m), 4.70-4.80 (1H, br), 5.24-5.35 (1H, br), 7.20 (1H, 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) 35 MS (ESI-): 424 (M-H) WO 00/40576 PCT/JPOO/00018 166 Example 150 (2S)-N-Hydroxy-2-[5-(3-(methylaminocarbonyloxymethyl) phenyl)-2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2 5 acetamide 1,1-dioxide (100 mg) NMR (DMSO-d 6 , 8): 1.70-2.06 (4H, m), 2.35-2.46 (1H, m), 2.59 (3H, d, J=5.OHz), 2.96-3.54 (5H, m), 5.05 (2H, m), 7.22 (1H, d, J=4.OHz), 7.29 (1H, d, J=8.OHz), 7.42 (1H, dd, J=8.0, 8.0Hz), 7.49 (1H, d, J=4.0Hz), 10 7.59-7.61 (2H, m), 8.84 (1H, br), 10.59 (1H, br) MS (ESI-): 451 (M-H) Example 151 (2S)-N-Hydroxy-2-[5-(4-( 2 -methylaminocarbonyl 15 ethenyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran 2-acetamiide 1,1-dioxide (170 mg) NMR (DMSO-d 6 , 8): 1.72-2.09 (4H, m), 2.38-2.48 (1H, m), 2.71 (3H, d, J=5Hz), 2.98-3.51 (5H, m), 6.63 (1H, d, J=15Hz), 7.23 (1H, d, J=4Hz), 7.42 (1H, d, 20 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, J=5Hz), 10.60 (1H, s) MS (ESI-): 447 (M-H) 25 Example 152 (2S)-N-Hydroxy-2-[5-(4-( 2 -ethylaminocarbonylethyl) phenyl)-2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (200 mg) NMR (DMSO-d 6 , 8): 1.08 (3H, t, J=7.2Hz), 1.73-2.12 (4H, 30 m), 2.39-2.48 (1H, m), 2.96-3.05 (2H, m), 3.11 3.54 (5H, m), 6.63 (1H, d, J=15Hz), 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 (lH, dd, J=7.2, 7.2Hz), 10.6 (1H, s) 35 MS (ESI-): 461 (M-H) WO 00/40576 PCT/JPOO/00018 167 Example 153 (2S)-N-Hydroxy-2-[5-(3-(isopropylaminocarbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 5 acetamide 1,1-dioxide (82 mg) NMR (DMSO-d 6 , 8): 1.10 (6H, d, J=8Hz), 1.65-2.11 (4H, m), 2.30-2.45 (1H, m), 2.85-3.26 (4H, m), 3.36 3.56 (1H, m), 3.65-3.88 (1H, m), 6.08 (1H, br s), 7.07-7.45 (6H, m), 7.84 (1H, s), 8.50 (1H, s), 10 10.62 (1H, s) MS (ESI-): 464 (M-H) Example 154 (2S)-N-Hydroxy-2-[5-[3-[(2-hydroxyethylamino) 15 acetylamino]phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide hydrochloride (82 mg) NMR (DMSO-d 6 , 6): 1.70-2.10 (4H, m), 2.32-2.53 (1H, m), 2.94-3.06 (2H, m), 3.09-3.20 (2H, m), 3.21-3.30 (2H, m), 3.40-3.88 (3H, m), 3.98-4.05 (2H, m), 20 7.23 (1H, d, J=3.5Hz), 7.37-7.53 (4H, m), 7.93 8.00 (2H, m), 8.93-9.07 (2H, s) MS (ESI+): 482 (M+H) Example 155 25 (2S)-N-Hydroxy-2-[5-[3-[(4-morpholino)acetylamino] phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide hydrochloride (75 mg) NMR (DMSO-d 6 , 6): 1.70-2.10 (4H, m), 2.32-2.52 (1H, m), 2.90-3.06 (2H, m), 3.09-3.37 (4H, m), 3.41-3.58 30 (5H, m), 3.62-4.03 (2H, m), 4.25 (2H, s), 7.23 (1H, d, J=3.5Hz), 7.40-7.54 (5H, m), 8.03 (1H, s) MS (ESI+): 508 (M+H) Example 156 35 ( 2 S)-N-Hydroxy- 2 -[5-(3-(4-methoxyphenyl)acetylamino)- WO 00/40576 PCT/JPOO/00018 168 phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (105 mg) NMR (DMSO-d 6 , 8): 1.70-2.08 (4H, m), 2.34-2.48 (1H, m), 2.92-3.30 (4H, m), 3.42-3.54 (1H, m), 3.58 (2H, s), 5 3.73 (3H, s), 6.90 (2H, d, J=9Hz), 7.20 (1H, d, J=3Hz), 7.26 (2H, d, J=9Hz), 7.32-7.38 (2H, m), 7.40 (1H, d, J=3Hz), 7.44-7.53 (1H, m), 7.99 (1H, s), 8.84 (1H, br s), 10.24 (1H, s), 10.60 (1H, s) MS (ESI-): 527 (M-H) 10 Example 157 (2S)-N-Hydroxy-2-[5-(3-(3-methoxyphenoxy)acetylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (110 mg) 15 NMR (DMSO-d 6 , 6): 1.68-2.11 (4H, m), 2.32-2.50 (1H, m), 2.90-3.66 (5H, m), 4.71 (2H, s), 6.49-6.66 (2H, m), 7.13-7.26 (2H, m), 7.31-7.47 (2H, m), 7.52-7.72 (2H, m), 7.94-8.14 (1H, m), 8.70 (2H, br s), 10.23 (1H, s), 10.62 (1H, s) 20 MS (ESI-): 543 (M-H) Example 158 (2S)-N-Hydroxy-2-[5-(3-(3-phenoxypropionylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 25 acetamide 1,1-dioxide (78 mg) NMR (DMSO-d 6 , 8): 1.69-2.12 (4H, m), 2.35-2.50 (1H, m), 2.82 (2H, t, J=7Hz), 2.92-3.56 (5H, m), 4.28 (2H, t, J=7Hz), 6.95 (3H, d, J=9Hz), 7.21 (1H, d, J=3Hz), 7.29 (2H, t, J=8Hz), 7.34-7.55 (4H, m), 30 8.03 (1H, s), 8.84 (1H, s), 10.21 (1H, s), 10.60 (1H, s) MS (ESI-): 527 (M-H) Example 159 35 ( 2 S)-N-Hydroxy-2-[5-(3-(4-fluorophenoxy)acetylamino)- WO 00/40576 PCT/JPOO/00018 169 phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (75 mg) NMR (DMSO-d 6 , 8): 1.69-2.11 (4H, m), 2.34-2.49 (1H, m), 2.92-3.56 (5H, m), 4.71 (2H, s), 6.97-7.36 (SH, m), 5 7.83-7.46 (3H, m), 7.52-7.62 (1H, m), 8.02 (1H, s), 8.84 (1H, s), 10.20 (1H, s), 10.60 (1H, s) MS (ESI-): 531 (M-H) Example 160 10 (2S)-N-Hydroxy-2-[5-(3-(4-methoxyphenoxy)acetylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (89 mg) NMR (DMSO-d 6 , 6): 1.68-2.08 (4H, m), 2.35-2.50 (1H, m), 2.94-3.30 (4H, m), 3.41-3.54 (1H, m), 3.70 (3H, s), 15 4.65 (2H, s), 6.90 (2H, d, J=1OHz), 6.98 (2H, d, J=lOHz), 7.21 (1H, d, J=3Hz), 7.33-7.45 (3H, m), 7.54-7.62 (1H, m), 8.03 (1H, s), 8.84 (1H, s), 10.17 (1H, s), 10.60 (1H, s) MS (ESI-): 543 (M-H) 20 Example 161 (2S)-N-Hydroxy-2-[5-(3-(2-(methylaminocarbonyloxy) acetylamino)phenyl)-2-thienyll-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (68 mg) 25 NMR (DMSO-d 6 , 8): 1.64-2.08 (4H, m), 2.32-2.51 (1H, m), 2.61 (3H, s), 2.92-3.56 (5H, m), 4.57 (2H, s), 7.12-7.54 (7H, m), 7.98 (1H, s), 10.14 (1H, s), 10.61 (1H, s) MS (ESI-): 494 (M-H) 30 Example 162 (2S)-N-Hydroxy-2-(5-phenyl-2-thienyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (51 mg) NMR (DMSO-d 6 , 6): 1.70-2.07 (4H, m), 2.34-2.52 (1H, m), WO 00/40576 PCT/JPOO/00018 170 2.94-3.07 (2H, m), 3.10-3.27 (2H, m), 3.30-3.50 (1H, m), 7.21 (1H, d, J=3.5Hz), 7.29-7.36 (1H, m), 7.43 (2H, t, J=8Hz), 7.48 (1H, d, J=3.5Hz), 7.65 (2H, d, J=8Hz), 8.85 (1H, br s) 5 MS (ESI-): 364 (M-H) Example 163 (2S)-N-Hydroxy-2-[5-( 4 -ethylaminocarbonylmethoxy) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 10 acetamide 1,1-dioxide (35 mg) NMR (DMSO-d 6 , 8): 1.04 (3H, t, J=7.2Hz), 1.71-2.08 (4H, m), 1.35-1.45 (1H, m), 2.95-3.50 (7H, m), 4.89 (2H, s), 7.00 (2H, d, J=9.0Hz), 7.17 (1H, d, J=4.OHz), 7.35 (1H, d, J=4.0Hz), 7.58 (2H, d, J=9.OHz), 8.12 15 (1H, br), 8.84 (1H, s), 10.59 (1H, s) Example 164 (2S)-N-Hydroxy-2-[5-(4-(methylaminocarbonylmethoxy) phenyl)-2-thienyl]-3,4,5,6-tetrarahydro-2H-thiopyran-2 20 acetamide 1,1-dioxide (450 mg) NMR (DMSO-d 6 , 8): 1.70-2.07 (4H, m), 2.35-2.45 (1H, m), 2.65 (3H, d, J=4.5Hz), 2.95-3.50 (5H, m), 4.50 (2H, s), 7.01 (2H, d, J=9.OHz), 7.16 (1H, d, J=4.OHz), 7.35 (1H, d, J=4.OHz), 7.57 (2H, d, J=9.OHz), 8.06 25 (1H, br), 8.84 (1H, s), 10.57 (1H, s) MS (ESI-): 451 (M-H) Example 165 (2S)-N-Hydroxy-2-[5-(4-fluorophenyl)-2-thienyl] 30 2, 3

,

4 ,5-tetrahydrothiophene-2-acetamide 1,1-dioxide (200 mg) NMR (DMSO-d 6 , b): 2.14-2.35 (2H, m), 2.55-2.68 (1H, m), 2.80 (1H, d, J=15Hz), 2.90 (1H, d, J=15Hz), 3.05 3.40 (3H, m), 7.17 (1H, d, J=4Hz), 7.26 (2H, d, J=9Hz), 7.45 (1H, d, J=4Hz), 7.70 (2H, dd, J=5, 35 9Hz), 8.88 (1H, s), 10.60 (1H, s) WO 00/40576 PCT/JPOO/00018 171 MS (ESI-): 368 (M-H) Example 166 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 5 (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 dichloromethane (10 ml) and the reaction mixture was stirred at room temperature for 1 hour. After the mixture was concentrated in vacuo, the 10 residue was purified by SiO 2 column chromatography (eluent: 2% MeOH in CHCl 3 ) to afford (2S)-N-hydroxy-2-[5-(3 (acetoxyacetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (65 mg) as a powder. NMR (DMSO-d 6 , 6): 1.69-2.07 (4H, m), 2.14 (3H, s), 15 2.32-2.47 (lH, m), 2.92-3.55 (5H, m), 4.67 (2H, s), 7.22 (lH, d, J=3Hz), 7.32-7.52 (3H, m), 7.97 (lH, s) MS (ESI-): 479 (M-H) 20 Example 167 (2S)-N-Hydroxy-2-[5-(3-((2S)-2 acetoxypropionylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (50 mg) NMR (DMSO-d 6 , 6): 1.44 (3H, d, J=8Hz), 1.72-2.08 (4H, 25 m), 2.33-2.49 (1H, m), 2.93-3.32 (4H, m), 3.40 3.56 (1H, m), 5.04 (1H, q, J=8Hz), 7.22 (lH, d, J=3Hz), 7.32-7.53 (4H, m), 7.97 (lH, s), 8.84 (lH, s), 10.19 (1H, s), 10.59 (lH, s) MS (ESI-): 493 (M-H) 30 Example 168 35 WO 00/40576 PCT/JPOO/00018 172 Br s 5\ H OH 10 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) 15 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)-1,1-dioxo-3,4,5,6-tetrahydro-2H thiopyran-2-yl]acetyl]hydroxylamine trityl crowns (59.2 pmol, 14.8 pmol/crown) in an atmosphere of nitrogen. After 20 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, 25 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 (0.1% trifluoroacetic acid 30 in 30% ethanol-hexane) to give (2S)-N-hydroxy-2-[5-(3 chlorophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (4.5 mg) as a powder. MS (ESI+): 400.2 (M+H) WO 00/40576 PCT/JPOO/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. 5 Reaction Scheme: (Examples 169 to 190) 10 0 0 Br Br

R-B(OH)

2 00 0 R, S Starting Compounds 2 15 / \ | O NH H Object Compounds 20 Starting Compounds 1 25 30 35 WO 00/40576 PCT/JPOO/00018 174 Table Example Object Compounds Nos. R Physicochemical Data F 169 / MS (ESI+): 384.3 (M+H) F 170 MS (ESI+): 384.3 (M+H) 171 Cl MS (ESI+): 434.2 (M+H) C1 F 172 MS (ESI+): 402.2 (M+H) F X 173 MS (ESI+): 422.4 (M+H) CH3 CH3 174 MS (ESI+): 408.2 (M+H) CH3

CH/

WO 00/40576 PCT/JPOO/00018 175 Example Object Compounds Nos. R Physicochemical Data 175 MS (ESI+): 394.2 (M+H) CH3 CH3-/b\ 176 S MS (ESI+) 372.2 (M+H) / 177 -s MS (ESI+): 422.2 (M+H) 178 0 MS (ESI-): 568.4 (M-H) 179 MS (ESI+): 434.3 (M+H) F3C/\ 180 F3C-O MS (ESI+): 450.2 (M+H) 181 MS (ESI+): 408.3 (M+H) CH3CO (2R or 2S) WO 00/40576 PCT/JPOO/00018 176 Example Object Compounds Nos. R Physicochemical Data 182 MS (ESI+): 412.3 (M+H) CH3S / \ 183 MS (ESI+): 426.2 (M+H) CH3CH2S 184 MS (ESI+): 442.3 (M+H) F 185 MS (ESI+): 501.2 (M+H) 186 CH2 MS (ESI-): 568.4 (M-H) 187 / 20 / MS (ESI+): 513.3 CH20

(M+H+CH

3 CN) 188 MS (ESI+): 382.3 (M+H) HO /(2R or 2S) WO 00/40576 PCT/JPO0/00018 177 Example Object Compounds Nos. R Physicochemical Data 189 MS (ESI+): 416.3 (M+H) 190 MS (ESI+): 410.3 (M+H) The following compounds were obtained in a similar manner to that of Example 54. 5 Example 191 (2S)-N-Hydroxy-2-[5-(3-aminoacetylamino)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide hydrochloride (3.0 g) from (2S)-N-(2 tetrahydropyranyloxy)-2-[5-(3-(2-(t-butoxycarbonylamino) 10 acetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 6): 1.68-2.10 (4H, m), 2.34-2.48 (1H, m), 2.92-3.62 (5H, m), 3.76-3.88 (2H, m), 7.23 (1H, d, J=3Hz), 7.36-7.46 (3H, m), 7.49-7.56 (1H, m), 7.99 15 (1H, s), 10.69 (lH, s), 10.92 (lH, s) MS (ESI+): 438 (M+H) Example 192 (2S)-N-Hydroxy-2-[5-(3-(3-(N-methylamino) 20 propionylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide hydrochloride (112 mg) from (2S)-N-(2-tetrahydropyranyloxy)-2-[5-(3-(3-(N-t butoxycarbonyl-N-methylamino)propionylamino)phenyl)-2- WO 00/40576 PCT/JPOO/00018 178 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide NMR (DMSO-d 6 , 8): 1.68-2.11 (4H, m), 2.32-2.47 (1H, m), 2.61 (3H, t, J=4Hz), 2.78 (2H, t, J=7Hz), 2.90 5 3.30 (6H, m), 3.38-3.62 (1H, m), 7.22 (1H, d, J=3Hz), 7.32-7.50 (4H, m), 8.04 (lH, s), 8.36-8.58 (2H, m), 10.33 (1H, s), 10.61 (1H, s) MS (ESI+): 466 (M+H) 10 Example 193 (2S)-N-Hydroxy-2-[5-{3-(((2S)-2-amino-3-(3 pyridyl)propionyl)amino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide hydrochloride (500 mg) from (2S)-N-(2-tetrahydropyranyloxy) 15 2 -[5-{ 3

-((

2 S)-2-(t-butoxycarbonylamino)-3-(3 pyridyl)propionylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 6): 1.74-2.06 (4H, m), 2.35-2.46 (1H, m), 2.97-3.34 (4H, m), 3.46-3.55 (3H, m), 4.24 (1H, 20 br), 7.23 (1H, d, J=4.0Hz), 7.41-7.44 (3H, m), 7.56 (1H, d, J=7.0Hz), 7.88 (1H, dd, J=7.0, 7.0Hz), 7.95 (1H, s), 8.38 (1H, d, J=7.OHz), 8.48 (2H, br), 8.77 (1H, br), 8.87 (lH, br s) MS (ESI+) : 529.1 (M+H) 25 Example 194 (2S)-N-Hydroxy-2-[5-(3-(2-(N-methylamino)acetylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide hydrochloride (78 mg) from (2S)-N-(2 30 tetrahydropyranyloxy)-2-[5-(3-(2-(N-t-butoxycarbonylamino) acetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 6): 1.65-2.08 (4H, m), 2.31-2.49 (1H, m), 2.63 (2H, t, J=7Hz), 2.92-3.52 (5H, m), 3.92 35 4.00 (2H, m), 7.23 (1H, d, J=3Hz), 7.34-7.45 (3H, WO 00/40576 PCT/JPOO/00018 179 m), 7.49-7.57 (1H, m), 7.98 (1H, s), 8.97-9.14 (2H, m), 10.67 (1H, s), 10.94 (1H, s) MS (ESI+): 454 (M+H) 5 Example 195 (2S)-N-Hydroxy-2-[5-(3-(3-aminopropionylamino)phenyl) 2-thienyl)-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide hydrochloride (78 mg) from (2S)-N-(2 tetrahydropyranyloxy)-2-[5-(3-(3-(t-butoxycarbonylamino) 10 propionylamino)phenyl)-2-thienyl]- 3

,

4 ,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 8): 1.68-2.09 (4H, m), 2.32-2.50 (1H, m), 2.78 (2H, d, J=8Hz), 2.92-3.62 (7H, m), 7.23 (1H, d, J=3Hz), 7.32-7.57 (4H, m), 7.92-8.16 (4H, 15 m), 10.45 (1H, s), 10.67 (1H, s) MS (ESI+): 454 (M+H) Example 196 (2S)-N-Hydroxy-2-[5-[3-(((2S)-2-amino-3 20 methoxypropionyl)amino)phenyl]-2-thienyl]- 3

,

4 ,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide hydrochloride (1.64 g) from (2S)-N-(2-tetrahydropyranyloxy) 2-[5-[3-(((2S)-2-(t-butoxycarbonylamino)-3 methoxypropionyl)amino)phenyl]-2-thienyl]-3,4,5,6 25 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 6): 1.70-2.10 (4H, m), 2.34-2.53 (1H, m), 2.94-3.06 (2H, m), 3.10-3.56 (6H, m), 3.74-3.86 (2H, m), 4.17-4.29 (1H, m), 7.22 (1H, d, J=3.5Hz), 7.38-7.46 (3H, m), 7.53-7.59 (1H, m), 7.95 (1H, s), 30 8.30-8.44 (2H, m), 8.84 (1H, br s), 10.63 (1H, s), 10.85 (1H, br s) MS (ESI+): 482 (M+H) Example 197 WO 00/40576 PCT/JPOO/00018 180 (2S)-N-Hydroxy-2-[5-(3-(2-hydroxyacetylamino)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (58 mg) from (2S)-N-(2-tetrahydropyranyloxy)-2-[5 (3-(2-methoxycarbonyloxyacetylamino)phenyl)-2-thienyl] 5 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 8): 1.70-2.12 (4H, m), 2.32-2.49 (1H, m), 2.91-3.28 (4H, m), 3.39-3.55 (1H, m), 4.01 (2H, d, J=7Hz), 5.71 (1H, t, J=7Hz), 7.22 (1H, d, J=3Hz), 7.38-7.40 (2H, m), 7.40 (1H, d, J=3Hz), 7.60-7.72 10 (1H, m), 8.08 (1H, s), 8.85 (1H, s), 9.79 (1H, s), 10.61 (1H, s) MS (ESI-): 437 (M-H) Example 198 15 (2S)-N-Hydroxy-2-[5-(3-(((2S)-2-hydroxypropionyl) amino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (65 mg) from (2S)-N-(2 tetrahydropyranyloxy)-2-[5-(3-(((2S)-2 acetoxypropionyl)amino)phenyl)-2-thienyl]- 3

,

4 ,5,6 20 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 8): 1.33 (3H, br s), 1.67-2.12 (4H, m), 2.30-2.48 (1H, m), 2.90-3.71 (5H, m), 4.09-4.24 (1H, m), 7.21 (1H, br s), 7.38-7.48 (3H, m), 7.68 7.75 (1H, m), 8.11 (1H, s), 9.26 (1H, s), 10.60 25 (1H, s) MS (ESI-): 451 (M-H) Example 199 To a solution of (2S)-N-2-(tetrahydropyranyloxy)- 2

-[S

30 (3-(3-aminopropionylamino)phenyl)-2-thienyl]- 3 ,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (180 mg) 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 35 mixture was concentrated in vacuo. The residue was WO 00/40576 PCT/JPOO/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 5 residue was dissolved in 1% hydrogen chloride in methanol (5 ml), the mixture was stirred at room temperature for 15 minutes and concentrated in vacuo. The residue was purified by SiO 2 column chromatography (eluent: 2% MeOH in CHCl 3 ) to afford (2S)-N-hydroxy-2-[5-(3-(3 10 (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 , 8): 1.22-2.11 (4H, m), 2.35-2.56 (3H, m), 2.94-3.33 (6H, m), 3.42-3.58 (1H, m), 7.20 (1H, d, 15 J=3Hz), 7.21-7.38 (1H, m), 7.32-7.38 (2H, m), 7.40 (1H, d, J=3Hz), 7.42-7.50 (1H, m), 8.01 (1H, s), 8.85 (1H, m) MS (ESI-): 508 (M-H) 20 Example 200 To a solution of (2S)-N-(2-tetrahydropyranyloxy)-2-[5 (4-(t-butyloxycarbonylmethoxy)phenyl)-2-thienyll-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (220 mg) in tetrahydrofuran (THF):H 2 0= 2:1 (3 ml) was added lithium 25 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 30 and concentrateed in vacuo to give (2S)-N-(2 tetrahydropyranyloxy)-2-[5-(4-carboxymethoxyphenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (190 mg) as an amorphous solid. NMR (DMSO-d 6 , 8): 1.35-1.60 (6H, m), 1.66-1.71 (2H, m), WO 00/40576 PCT/JPOO/00018 182 1.73-2.05 (2H, m), 2.34-2.46 (1H, m), 2.90-3.50 (6H, m), 3.72-3.90 (1H, m), 4.45, 4.75 (1H, s), 4.72 (2H, s), 6.96 (2H, d, J=9.0Hz), 7.16 (1H, d, J=4.OHz), 7.32 (1H, d, J=4.OHz), 7.56 (2H, d, 5 J=9.0Hz), 11.2 (1H, s) MS (ESI-): 522 (M-H) Example 201 To the reaction mixture of 4-(5-oxazolyl) 10 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-2 acetamide 1,1-dioxide (679 mg), tetrakis(triphenylphosphine)palladium(O) (8.67 mg) and 15 aqueous 2M sodium carbonate (7.5 ml) at room temperature. The mixture was stirred for 3 hours at 80 0 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 20 was purified by chromatography on silica gel (eluted with 0.5 to 3% methanol in chloroform) to give (2S)-N-(2 tetrahydropyranyloxy)-2-[5-[4-(5-oxazolyl)phenyl]-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (795 mg) as an amorphous solid. 25 NMR (CDCl 3 , 8): 1.40-1.55 (4H, m), 1.61-1.75 (2H, m), 1.91-2.02 (2H, m), 2.05-2.25 (2H, m), 2.70-2.94 (2H, m), 3.01-3.17 (4H, m), 3.29-3.51 (1H, m), 3.64-3.74 (1H, m), 4.53 (0.5Hz, s), 4.82 (0.5H, s), 7.26-7.34 (2H, m), 7.39 (1H, s), 7.65 (4H, s), 30 7.94 (1H, s), 8.25 (0.5H, s), 8.37 (0.5H, s) MS (ESI-): 515 (M-H) The following compounds were obtained in a similar manner to that of Example 89. 35 WO 00/40576 PCT/JPOO/00018 183 Example 202 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-formylphenyl) 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (0.9 g) 5 NMR (CDCl 3 , 6): 1.40-1.75 (6H, m), 1.90-2.02 (2H, m), 2.05-2.26 (2H, m), 2.70-2.93 (2H, m), 3.01-3.19 (2H, m), 3.28-3.53 (1H, m), 3.62-3.75 (1H, m), 4.53, 4.83 (1H, s), 7.26-7.37 (2H, m), 7.56 (1H, dd, J=8.0, 8.0Hz), 7.80-7.85 (2H, m), 8.09 (1H, s), 10 10.05 (1H, s) MS (ESI-): 476 (M-H) Example 203 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-ethenylphenyl) 15 2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (2.1 g) NMR (CDCl 3 , 8): 1.37-1.75 (6H, m), 1.86-2.00 (2H, m), 2.05-2.25 (2H, m), 2.65-2.91 (2H, m), 3.00-3.17 (4H, m), 3.26-3.49 (1H, m), 3.59-3.70 (1H, m), 20 4.51, 4.81 (1H, s), 5.28 (1H, d, J=l1Hz), 5.78 (1H, d, J=17.7Hz), 6.66-6.75 (1H, m), 7.41 (2H, d, J=8.OHz), 7.55 (2H, d, J=8.OHz) MS (ESI-): 474 (M-H) 25 Example 204 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-(2 carboxyethenyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (1.1 g) NMR (CDCl 3 , 6): 1.41-1.71 (6H, m), 1.92-2.25 (4H, m), 30 2.76-2.88 (2H, m), 3.05-3.19 (4H, m), 3.30-3.51 (1H, m), 3.69-3.76 (1H, m), 4.54, 4.84 (1H, s), 6.40 (1H, d, J=15Hz), 7.45-7.74 (7H, m) MS (ESI-): 518 (M-H) 35 Example 205 WO 00/40576 PCT/JPOO/00018 184 (2S)-N-(2-Tetrahydropyranyloxy)-2-(5-phenyl-2-thienyl) 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (93 mg) NMR (CDCl 3 , 8): 1.39-1.75 (6H, m), 1.90-2.00 (2H, m), 5 2.04-2.24 (2H, m), 2.63-2.91 (2H, m), 3.03-3.18 (4H, m), 3.27-3.50 (1H, m), 3.59-3.70 (1H, m), 4.53 (0.5H, s), 4.80 (0.5H, s), 7.24-7.41 (5H, m), 7.56-7.63 (2H, m), 7.95 (0.5H, s), 8.12 (0.5H, s) MS (ESI-): 448 (M-H) 10 Example 206 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-(t butyloxycarbonylmethoxy)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (3.8 g) 15 NMR (DMSO-d 6 , 6): 1.35-1.60 (15H, m), 1.65-1.71 (2H, m), 1.73-2.04 (2H, m), 2.34-2.45 (1H, m), 2.90 3.50 (6H, m), 3.72-3.90 (1H, m), 4.45, 4.75 (1H, s), 4.73 (2H, s), 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, 20 J=9.OHz) Example 207 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 (ethylaminocarbonylmethoxy)phenyl)-2-thienyl]-3,4,5,6 25 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (65 mg) 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, m), 1.69-1.81 (2H, m), 1.83-2.04 (2H, m), 2.35 2.47 (1H, m), 2.87-3.51 (8H, m), 3.74-3.90 (1H, m), 30 3.95, 4.75 (1H, s), 4.49 (2H, s), 7.00 (2H, d, J=9.OHz), 7.15-7.20 (1H, m), 7.33-7.36 (1H, m), 7.58 (2H, d, J=9.OHz), 8.13 (1H, br) Example 208 35 ( 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3- WO 00/40576 PCT/JPOO/00018 185 (propylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (140 mg) NMR (DMSO-d 6 , 8): 0.88 (3H, t, J=7Hz), 1.26-2.09 (12H, m), 2.43-2.46 (1H, m), 2.78-3.56 (6H, m), 5 3.72-3.92 (1H, m), 4.44, 4.75 (1H, s), 6.11-6.24 (1H, m), 7.09-7.42 (6H, m), 7.85 (1H, s), 8.55 (1H, s) MS (ESI-): 548 (M-H) 10 The following compounds were obtained in a similar manner to that of Example 129. Example 209 (2S)-N-( 2 -Tetrahydropyranyloxy)-2-[5-(3 15 (isopropylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (160 mg) NMR (DMSO-d 6 , 8): 1.10 (6H, m), 1.30-2.10 (10H, m), 2.34-2.47 (1H, m), 2.83-3.30 (5H, m), 3.40-3.53 (1H, m), 3.18-3.90 (2H, m), 4.36, 4.44 (1H, s), 20 6.04 (1H, d, J=8Hz), 7.09-7.40 (6H, m), 7.85 (1H, s), 8.44 (1H, s) MS (ESI-): 548 (M-H) Example 210 25 ( 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2 chloroethylaminocarbonylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (335 mg) NMR (CDC1 3 , 8): 1.46 (2H, br), 1.62-1.67 (4H, m), 1.84-1.96 (2H, m), 2.74-2.88 (2H, m), 2.96-3.06 30 (2H, m), 3.08-3.14 (2H, m), 3.31-3.41 (2H, m), 3.49-3.54 (1H, m), 3.55-3.60 (2H, m), 3.66 (2H, t, J=6.OHz), 3.70-3.80 (1H, m), 4.48 (1/2H, br), 4.84 (1/2H, br), 7.17-7.24 (4H, m), 7.30-7.50 (5H, m) MS (ESI-): 568.4 (M-H) 35 WO 00/40576 PCT/JPOO/00018 186 Example 211 To a solution of ( 2 S)-N-(2-tetrahydropyranyloxy)-2-[5

(

3 -aminophenyl)-2-thienyll-3,4,5,6-tetrahydro-2H-thiopyran 2-acetamide 1,1-dioxide (7.00 g), ethoxyacetic acid (2.04 g) 5 and 1-hydroxybenzotriazole (2.65 g) in N,N-dimethylformamide (80 ml) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD HCl) (3.75 g) at room temperature. After being stirred at the same temperature overnight, the mixture was concentrated in vacuo. The 10 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 15 chromatography (eluent 1% MeOH in CHC1 3 ) to afford (2S)-N

(

2 -tetrahydropyranyloxy)-2-[5-(3-(2 ethoxyacetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (7.00 g). NMR (DMSO-d 6 , 8): 1.20 (3H, t, J=7Hz), 1.33-1.62 (6H, 20 m), 1.70-2.12 (4H, m), 2.35-2.50 (1H, m), 2.88 3.22 (5H, m), 3.38-3.52 (1H, m), 3.58 (2H, q, J=7Hz), 3.75-3.92 (1H, m), 4.44, 4.75 (1H, s), 7.18-7.25 (1H, m), 7.34-7.45 (3H, m), 7.55-7.64 (1H, m), 8.03 (1H, s), 9.81 (1H, s), 11.24 (1H, s) 25 MS (ESI-): 549 (M-H) The following compounds were obtained in substantially the same manner as that of Example 211. 30 Example 212 (2S)-N-( 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) 35 NMR (DMSO-d 6 , 6): 1.36-2.10 (10H, m), 2.36-2.51 (1H, WO 00/40576 PCT/JPOO/00018 187 m), 2.60 (3H, d, J=6Hz), 2.87-3.30 (5H, m), 3.40 3.54 (1H, m), 3.72-3.90 (1H, m), 4.43, 4.76 (1H, m), 4.57 (2H, s), 7.18-7.30 (2H, m), 7.35-7.52 (4H, m), 7.99 (1H, s), 10.14 (1H, s), 11.25 (1H, s) 5 MS (ESI-): 578 (M-H) Example 213 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-[3-((2S)-2-(tert butoxycarbonylamino)-3-methoxypropionylamino)phenyl]-2 10 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (2.90 g) NMR (CDC1 3 , 8): 1.37-1.51 (11H, m), 1.59-2.01 (6H, m), 2.04-2.25 (2H, m), 2.64-2.91 (2H, m), 3.00 3.17 (4H, m), 3.26-3.50 (4H, m), 3.53-3.72 (2H, m), 15 3.80-3.94 (1H, m), 4.34-4.45 (1H, m), 4.53 (0.5H, s), 4.82 (0.5H, s), 5.45-5.59 (lH, m), 7.20-7.36 (5H, m), 7.43-7.51 (1H, m), 7.75-7.83 (1H, m), 8.18 (0.5H, s), 8.31 (0.5H, s), 8.49 (1H, br s) MS (ESI+): 683 (M+H+NH 3 ) 20 Example 214 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(4 methoxyphenyl)acetylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (160 mg) 25 NMR (CDCl 3 , 8): 1.36-1.76 (8H, m), 1.86-1.98 (2H, m), 2.04-2.22 (2H, m), 2.69-2.92 (2H, m), 3.02-3.17 (2H, m), 3.26-3.51 (1H, m), 3.62-3.73 (1H, m), 3.68 (2H, s), 3.82 (3H, s), 4.52, 4.72 (1H, s), 6.87-6.95 (2H, m), 7.13-7.32 (6H, m), 7.45-7.56 30 (3H, m), 8.56, 8.59 (1H, s) MS (ESI-): 611 (M-H) Example 215 (2S)-N-(2-Tetrahydropyranyloxy)-2-[S-(3-(2-(tert 35 butoxycarbonylamino)acetyl)amino)phenyl)-2-thienyl]-3,4,5,6- WO 00/40576 PCT/JPOO/00018 188 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (246 mg) NMR (DMSO-d 6 , 6): 1.26-1.63 (6H, m), 1.40 (9H, s), 1.68-2.06 (4H, m), 2.35-2.48 (1H, m), 2.88-3.30 (5H, m), 3.36-3.53 (1H, m), 3.74 (2H, d, J=7Hz), 5 3.72-3.92 (1H, m), 4.43, 4.75 (1H, s), 7.03-7.12 (1H, m), 7.18-7.24 (1H, m), 7.40-7.53 (4H, m), 7.98 (1H, s), 10.05 (1H, s), 11.25 (1H, s) MS (ESI-): 620 (M-H) 10 Example 216 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 propoxyacetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (3.68 g) NMR (CDC1 3 , 8): 1.01 (3H, t, J=7Hz), 1.36-1.78 (10H, m), 15 1.88-1.99 (2H, m), 2.03-2.25 (2H, m), 2.65-2.93 (2H, m), 2.98-3.18 (2H, m), 3.28-3.52 (1H, m), 3.58 (2H, t, J=7Hz), 3.62-3.74 (1H, m), 4.07 (2H, s), 4.52, 4.82 (1H, s), 7.23-7.38 (4H, m), 7.52 7.59 (1H, m), 7.80 (1H, s), 8.19, 8.32 (1H, s), 20 8.56 (1H, s) MS (ESI-): 563 (M-H) Example 217 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(n 25 butyloxyacetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (140 mg) NMR (CDC1 3 , 8): 1.95 (2H, br), 2.08-2.23 (2H, m), 2.64 2.88 (2H, m), 3.06 (2H, s), 3.16 (2H, br), 3.39 3.50 (2H, m), 3.62 (2H, t, J=7.5Hz), 4.06 (2H, s), 30 4.54 (1/2H, br), 4.80 (1/2H, br), 7.21-7.30 (2H, m), 7.34-7.36 (2H, m), 7.52-7.56 (1H, m), 7.80 (1H, s), 7.94 (1/2H, s), 8.12 (1/2H, s), 8.34 (1H, s) MS (ESI-): 577.3 (M-H) 35 Example 218 WO 00/40576 PCT/JPOO/00018 189 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(3 methoxypropionylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (4.34 g) NMR (CDCl 3 , 8): 1.46 (2H, br), 1.57-1.70 (2H, m), 1.95 5 (2H, br), 2.07-2.20 (2H, m), 2.66 (2H, t, J=6.OHz), 2.70-2.89 (2H, m), 3.06 (2H, s), 3.10-3.16 (2H, m), 3.26-3.44 (1H, m), 3.47 (3H, s), 3.62-3.70 (2H, m), 3.75 (2H, t, J=6.0Hz), 4.52 (1/2H, br), 4.82 (1/2H, br), 7.20-7.25 (2H, m), 7.28-7.31 (2H, m), 7.46 10 7.51 (1H, m), 7.70-7.73 (1H, m), 8.18 (1/2H, s), 8.31 (1/2H, s), 8.31 (1H, s) MS (ESI-): 549.4 (M-H) Example 219 15 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3 (methoxyacetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (3.24 g) NMR (CDCl 3 , 8): 1.46 (4H, br), 1.55-1.58 (2H, m), 1.94 (2H, br), 2.07-2.20 (2H, m), 2.66-2.88 (2H, m), 20 3.05 (2H, s), 3.09-3.14 (2H, m), 3.27-3.48 (1H, m), 3.53 (3H, s), 3.60-3.72 (1H, m), 4.04 (2H, s), 4.52 (1/2H, br), 4.81 (1/2H, br), 7.23-7.30 (2H, m), 7.43-7.46 (2H, m), 7.55-7.59 (1H, m), 7.80 (1H, s), 8.04 (1/2H, s), 8.20 (1/2H, s), 8.30 (1H, s) 25 MS (ESI-): 535.3 (M-H) Example 220 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(3-(9 fluorenylmethoxycarbonylamino)propionylamino)phenyl)-2 30 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (2.70 g) NMR (CDCl 3 , 6): 1.31-1.81 (8H, m), 1.84-2.28 (4H, m), 2.58-2.76 (2H, m), 2.92-3.22 (4H, m), 3.30-3.84 (4H, m), 4.02-4.22 (2H, m), 4.37-4.49 (1H, m), 35 4.62, 4.94 (lH, s), 6.89-7.90 (13H, m), 7.99-8.14 WO 00/40576 PCT/JPOO/00018 190 (2H, m), 8.66, 8.78 (1H, s), 10.00, 10.46 (1H, s) MS (ESI-): 756 (M-H) Example 221 5 ( 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 phenoxyacetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (4.90 g) NMR (CDC1 3 , 8): 1.37-1.76 (8H, m), 1.88-1.99 (2H, m), 2.05-2.26 (2H, m), 2.67-2.92 (2H, m), 2.98-3.18 10 (2H, m), 3.28-3.51 (1H, m), 3.62-3.75 (1H, m), 4.62 (2H, s), 4.52, 4.82 (1H, s), 6.98-7.11 (3H, m), 7.23-7.30 (2H, m), 7.32-7.40 (4H,i m), 7.58 7.62 (1H, m), 7.79 (1H, s), 8.24, 8.35 (1H, s), 8.36 (1H, s) 15 MS (ESI-): 597 (M-H) Example 222 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(3 methoxyphenoxy)acetylamino)phenyl)-2-thienyl]-3,4,5,6 20 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (140 mg) NMR (DMSO-d 6 , 8): 1.34-1.77 (8H, m), 1.86-1.99 (2H, m), 2.05-2.24 (2H, m), 2.66-2.90 (2H, m), 3.03-3.17 (2H, m), 3.28-3.52 (1H, m), 3.62-3.74 (1H, m), 3.82 (3H, s), 4.52, 4.82 (1H, s), 4.61 (2H, s), 25 6.52-6.65 (3H, m), 7.22-7.30 (3H, m), 7.33-7.42 (2H, m), 7.55-7.62 (1H, m), 7.72-7.82 (1H, m), 8.26-8.42 (2H, m) MS (ESI-): 627 (M-H) 30 Example 223 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(3 phenoxypropionylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (135 mg) NMR (CDCl 3 , 8): 1.32-1.78 (8H, m), 1.86-1.98 (2H, m), 35 2.06-2.25 (2H, m), 2.71-2.92 (2H, m), 2.86 (2H, t, WO 00/40576 PCT/JPOO/00018 191 J=7Hz), 3.01-3.20 (2H, m), 3.28-3.52 (1H, m), 3.63-3.77 (1H, m), 4.35 (2H, t, J=7Hz), 4.54, 4.84 (1H, s), 6.78-7.03 (4H, m), 7.12-7.36 (5H, m), 7.47-7.65 (2H, m), 8.13 (1H, s), 8.73 (1H, s) 5 MS (ESI-): 644 (M-H) Example 224 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(4 fluorophenoxy)acetylamino)phenyl)-2-thienyl]-3,4,5,6 10 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (158 mg) NMR (CDC1 3 , 8): 1.35-2.01 (10H, m), 2.05-2.23 (2H, m), 2.66-2.94 (2H, m), 3.01-3.19 (2H, m), 3.29-3.53 (1H, m), 3.62-3.26 (1H, m), 4.53, 4.82 (1H, s), 4.58 (2H, s), 6.92-7.10 (5H, m), 7.24-7.39 (3H, m), 15 7.56-7.62 (1H, m), 7.73-7.77 (1H, m), 8.34 (1H, s), 8.39, 8.49 (1H, s) MS (ESI-): 615 (M-H) Example 225 20 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(4 methoxyphenoxy)acetylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (150 mg) NMR (CDC1 3 , 8): 1.36-1.78 (8H, m), 1.87-2.01 (2H, m), 2.06-2.26 (2H, m), 2.65-2.94 (2H, m), 3.02-3.23 25 (2H, m), 3.27-3.56 (1H, m), 3.62-3.36 (1H, m), 3.80 (3H, s), 4.52, 4.83 (1H, s), 4.57 (2H, s), 6.84-7.03 (4H, m), 7.24-7.43 (4H, m), 7.54-7.67 (1H, m), 7.80 (1H, s), 8.28-8.49 (2H, m) MS (ESI-): 627 (M-H) 30 Example 226 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(3-(N-tert butoxycarbonyl-N-methylamino)propionylamino)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 35 dioxide (160 mg) WO 00/40576 PCT/JPOO/00018 192 NMR (CDC1 3 , 6): 1.38-1.75 (8H, m), 1.48 (9H, s), 1.88 2.01 (2H, m), 2.06-2.24 (2H, m), 2.62-2.88 (4H, m), 2.91 (3H, s), 3.02-3.17 (2H, m), 3.27-3.50 (1H, m), 3.58-3.75 (3H, m), 4.53, 4.32 (1H, s), 7.18-7.31 5 (6H, m), 7.52-7.59 (1H, m), 7.70-7.83 (1H, m) MS (ESI-): 648 (M-H) Example 227 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-((2S)-2-(tert 10 butoxycarbonylamino)-3-(3-pyridyl)propionylamino)phenyl}-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (1.54 g) NMR (DMSO-d 6 , 8): 1.22-1.27 (2H, m), 1.43 (9H, s), 1.63-1.68 (4H, m), 1.98 (2H, br), 2.07-2.25 (2H, m), 15 2.74-2.98 (2H, m), 3.04-3.20 (6H, m), 3.41-3.48 (1H, m), 3.66-3.76 (1H, m), 4.45 (1/2H, br), 4.54 4.63 (1H, br), 4.86 (1/2H, br), 5.31-5.45 (1H, m), 6.82-7.00 (2H, m), 7.04-7.20 (3H, m), 7.22-7.27 (2H, m), 7.52-7.65 (2H, m), 8.43-8.59 (3H, m) 20 MS (ESI+): 713.1 (M+H) Example 228 (2S)-N-(2-Tetrahydropyranyloxy-2-[5-[3-[2-(2-propen-1 yloxy)acetyl]aminophenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H 25 thiopyran-2-acetamide 1,1-dioxide (14.6 g) NMR (CDCl 3 , 6): 1.37-1.76 (6H, m), 1.88-2.01 (2H, m), 2.04-2.26 (2H, m), 2.64-2.92 (2H, m), 3.00-3.17 (4H, m), 3.27-3.51 (1H, m), 3.61-3.72 (1H, m), 4.08 (2H, s), 4.16 (2H, d, J=6Hz), 4.52 (0.5H, s), 30 4.81 (0.5H, s), 5.33 (1H, d, J=9Hz), 5.37 (1H, d, J=16.5Hz), 5.90-6.04 (1H, m), 7.23-7.39 (5H, m), 7.53-7.60 (1H, m), 7.80 (1H, s), 8.16 (0.5H, s), 8.22 (0.5H, s), 8.35 (1H, s) MS (ESI-): 561 (M-H) 35 WO 00/40576 PCT/JPOO/0001 8 193 Example 229 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2 (ethoxycarbonylamino)acetylamino)phenyl}-2-thienyl]-3-4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (4 g) 5 NMR (CDC1 3 , 8): 1.28 (3H, t, J=7.5Hz), 1.41 (2H, br), 1.92 (2H, br), 2.04-2.17 (2H, m), 2.55 (4H, br), 2.73-2.91 (2H, m), 3.02-3.13 (4H, m), 3.28-3.49 (1H, m), 3.64-3.74 (1H, m), 4.03-4.05 (2H, m), 4.20 (2H, q, J=7.5Hz), 4.52 (1/2H, br), 4.83 (1/2H, 10 br), 7.11-7.21 (3H, m), 7.37-7.43 (1H, m), 7.48 7.56 (2H, m), 7.74-7.80 (1H, m), 8.46 (1H, br) MS (ESI-): 628.2 (M-H+Cl) Example 230 15 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(N-tert butoxycaronyl-N-methylamino)acetylamino)phenyl)-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (119 mg) NMR (CDC1 3 , 8): 1.35-1.74 (8H, m), 1.51 (9H, s), 20 1.88-2.00 (2H, m), 2.05-2.55 (2H, m), 2.18-2.92 (2H, m), 3.03 (3H, s), 3.05-3.16 (2H, m), 3.28 3.50 (1H, m), 3.62-3.76 (1H, m), 3.99 (2H, s), 4.53, 4.83 (1H, s), 7.22-7.34 (4H, m), 7.43 (1H, br s), 7.67-7.85 (1H, m), 8.42, 8.50 (1H, s) 25 MS (ESI-): 634 (M-H) Example 231 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(3-(tert butoxycaronylamino)propionylamino)phenyl)-2-thienyl] 30 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (150 mg) NMR (CDC1 3 , 8): 1.35-1.72 (8H, m), 1.44 (9H, s), 1.88-2.01 (2H, m), 2.05-2.23 (2H, m), 2.57-2.67 (2H, m), 2.75-2.89 (2H, m), 3.00-3.17 (4H, m), 35 3.28-3.56 (3H, m), 3.65-3.76 (1H, m), 4.54, 4.84 WO 00/40576 PCT/JPOO/00018 194 (1H, s), 5.28 (1H, br s), 7.13-7.28 (4H, m), 7.48 7.66 (2H, m), 8.14 (1H, br s), 8.75, 8.78 (1H, s) MS (ESI-): 634 (M-H) 5 The following compounds were obtained in a similar manner to that of Example 130. Example 232 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 10 (propionylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (160 mg) NMR (DMSO-d 6 , 6): 1-09 (3H, t, J=7Hz), 1.32-2.07 (10H, m), 2.36 (2H, q, J=7Hz), 2.37-2.47 (1H, m), 2.88 3.22 (5H, m), 3.35-3.54 (1H, m), 3.74-3.92 (1H, m), 15 4.44, 4.75 (1H, s), 7.17-7.25 (1H, m), 7.30-7.42 (3H, m), 7.43-7.52 (1H, m), 8.00 (1H, s), 9.98 (1H, s), 11.36 (1H, s) MS (ESI-): 519 (M-H) 20 Example 233 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (butyrylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (166 mg) NMR (CDCl 3 , 6): 1.01 (3H, t, J=7Hz), 1.35-1.84 (10H, 25 m), 2.05-2.25 (2H, m), 2.37 (2H, t, J=7Hz), 2.66 2.92 (2H, m), 2.97-3.17 (2H, m), 3.27-3.52 (1H, m), 3.60-3.77 (1H, m), 4.54, 4.74 (1H, s), 7.08-7.32 (5H, m), 7.48-7.66 (2H, m), 8.64 (1H, br) MS (ESI-): 533 (M-H) 30 Example 234 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2 methoxyethoxycarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (120 mg) 35 NMR (CDC1 3 , 6): 1.37-1.78 (8H, m), 1.89-2.00 (2H, m), WO 00/40576 PCT/JPOO/00018 195 2.05-2.25 (2H, m), 2.67-2.94 (2H, m), 3.02-3.18 (3H, m), 3.26-3.52 (1H, m), 3.58-3.69 (2H, m), 3.66 (3H, s), 4.25-4.32 (2H, m), 4.52, 4.83 (1H, s), 6.90-7.00 (1H, m), 7.20-7.32 (5H, m), 7.63 (1H, 5 s), 8.34, 8.46 (1H, s) MS (ESI-): 565 (M-H) Example 235 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(9 10 fluorenylmethoxycarbonylamino)acetylamino)phenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (486 mg) NMR (DMSO-d 6 , 6): 1.34-1.62 (6H, m), 1.71-2.08 (4H, m), 2.36-2.47 (1H, m), 2.88-3.34 (5H, m), 3.39 15 3.52 (2H, m), 3.74-3.92 (3H, m), 4.19-4.37 (3H, m), 4.42, 4.77 (1H, s), 7.18-7.27 (1H, m), 7.32-7.52 (7H, m), 7.62-7.70 (1H, m), 7.75 (2H, d, J=7Hz), 7.92 (2H, d, J=7Hz), 8.02 (1H, s) 20 Example 236 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (acetoxyacetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 2 H-thiopyran-2-acetamide 1,1-dioxide (260 mg) NMR (CDC1 3 , 8): 1.35-1.77 (8H, m), 1.86-2.00 (2H, m), 25 2.03-2.24 (2H, m), 2.71-2.92 (2H, m), 3.00-3.20 (2H, m), 3.38-3.54 (1H, m), 3.65-3.78 (1H, m), 4.52, 4.72 (1H, s), 4.72 (2H, s), 7.14-7.35 (4H, m), 7.52, 7.59 (1H, s), 7.56-7.67 (1H, m), 8.06-8.15 (1H, m), 8.59-8.70 (1H, m) 30 MS (ESI-): 563 (M-H) Example 237

(

2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-((2S)-2 acetoxypropionylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 35 2 H-thiopyran-2-acetamide 1,1-dioxide (313 mg) WO 00/40576 PCT/JPOO/00018 196 NMR (CDCl 3 , 8): 1.38-1.78 (8H, m), 1.49, 1.57 (3H, d, J=8Hz), 1.88-2.00 (2H, m), 2.07-2.22 (2H, m), 2.72-2.92 (2H, m), 3.03-3.19 (2H, m), 3.29-3.56 (1H, m), 3.64-3.78 (1H, m), 4.53, 4.82 (1H, s), 5 5.06, 5.34 (1H, q, J=8Hz), 7.18-7.36 (4H, m), 7.53-7.68 (2H, m), 8.10 (lH, br s), 8.55, 8.59 (1H, s) MS (ESI-): 577 (M-H) 10 Example 238 (2S)-N-( 2 -Tetrahydropyranyloxy)-2-[5-(3 (chloroacetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (201 mg) NMR (CDCl 3 , 6): 1.40-1.54 (4H, m), 1.60-1.73 (2H, m), 15 1.88-2.00 (2H, m), 2.06-2.25 (2H, m), 2.67-2.91 (2H, m), 3.02-3.18 (4H, m), 3.29-3.51 (1H, m), 3.62-3.75 (1H, m), 4.21 (2H, s), 4.53 (0.5H, s), 4.82 (0.5H, s), 7.23-7.29 (2H, m), 7.32-7.41 (2H, m), 7.51-7.59 (1H, m), 7.70-7.76 (1H, m), 8.22 20 (0.5H, s), 8.28-8.36 (1.5H, s) MS (ESI-): 539 (M-H) Example 239 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(9 25 (fluorenylmethoxycarbonylamino)acetylamino)phenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (478 mg) was dissolved in a solution of 20% piperidine in N,N-dimethylformamide (8 ml) at room temperature. After being stirred at the same temperature 30 for 1 hour, the reaction mixture was concentrated in vacuo. The residue was purified by SiO 2 column chromatography (eluent: 1-5% MeOH in CHCl 3 ) to give (2S)-N-(2 tetrahydropyranyloxy)-2-[5-(3-( 2 -aminoacetylamino)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 35 dioxide (335 mg).

WO 00/40576 PCT/JPOO/00018 197 NMR (DMSO-d 6 , 8): 1.37-1.65 (6H, m), 1.70-2.08 (4H, m), 2.34-2.50 (1H, m), 2.87-3.52 (8H, m), 3.72-3.90 (1H, m), 4.44, 4.75 (1H, s), 7.18-7.25 (1H, m), 7.32-7.44 (3H, m), 7.52-7.60 (1H, m), 8.02 (1H, s) 5 MS (ESI+): 522 (M+H) Example 240 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(3 aminopropionylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 10 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 , 6): 1.32-2.09 (10H, m), 2.32-2.48 (3H, m), 2.72-3.56 (8H, m), 3.72-3.90 (1H, m), 4.45, 4.75 (1H, s), 7.17-7.24 (1H, m), 7.28-7.51 (3H, m), 15 7.43-7.54 (1H, m), 8.01 (1H, s), 12.4 (1H, br s) MS (ESI-): 534 (M-H) Example 241 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2 20 (methoxycarbonylamino)acetylamino)phenyl)-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 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, m), 1.87-1.99 (2H, m), 2.07-2.27 (2H, m), 2.79-2.92 (2H, m), 3.00 25 3.23 (2H, m), 3.28-3.52 (1H, m), 3.68-3.76 (lH, m), 3.75 (3H, s), 3.96-4.12 (2H, m), 4.53, 4.84 (1H, s), 5.76-5.88 (1H, m), 7.05-7.22 (5H, m), 7.36 7.55 (2H, m), 8.40 (1H, s) MS (ESI-): 578 (M-H) 30 Example 242 To a solution of (2S)-N-(2-tetrahydropyranyloxy)-2-[5 (3-formylphenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran 2-acetamide 1,1-dioxide (100 mg) in tetrahydrofuran (1.5 ml) 35 was added dropwise sodium borohydride (8.71 mg) in water WO 00/40576 PCT/JPOO/00018 198 (0.7 ml) at room temperature. After being stirred for 30 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 5 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 (2S)-N-(2 tetrahydropyranyloxy)-2-[5-(3-hydroxymethylphenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 10 dioxide (96 mg) as an amorphous solid. NMR (CDC1 3 , 8): 1.38-1.72 (6H, m), 1.81-2.00 (2H, m), 2.03-2.25 (2H, m), 2.67-3.17 (6H, m), 3.29-3.51 (1H, m), 3.61-3.72 (1H, m), 4.52, 4.81 (1H, s), 4.72 (2H, d, J=6.OHz), 7.25-7.41 (4H, m), 7.52 (1H, 15 d, J=8.5Hz), 7.60 (1H, s) MS (ESI-): 478 (M-H) Example 243 A solution of (2S)-N-(2-tetrahydropyranyloxy)- 2

-[

5 -(4 20 ethenylphenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 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 (1:1:1) (3.0 ml) was stirred at room temperature for 12 hours. After the 25 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 (2S)-N-(2 30 tetrahydropyranyloxy)-2-[5-(4-(cis-1,2 dihydroxyethyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide as an amorphous solid (200 mg). NMR (CDCl 3 , 6): 1.38-1.75 (6H, m), 1.90-2.00 (2H, m), 35 2.07-2.23 (2H, m), 2.60-2.89 (2H, m), 3.09-3.17 WO 00/40576 PCT/JPOO/00018 199 (4H, m), 3.25-3.50 (1H, m), 3.59-3.71 (1H, m), 3.73-3.82 (1H, m), 4.52, 4.80 (1H, s), 4.80-4.88 (1H, m), 7.34-7.40 (3H, m), 7.54-7.59 (3H, m) MS (ESI-): 508 (M-H) 5 Example 244 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (phenoxycarbonyloxymethyl)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (620 mg) was 10 obtained from (2S)-N-(2-tetrahydropyranyloxy)-2-[5-( 3 hydroxymethylphenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (500 mg) in a similar manner to that of Example 130. NMR (CDCl 3 , 6): 1.38-1.75 (6H, m), 1.90-2.01 (2H, m), 15 2.06-2.23 (2H, m), 2.65-2.90 (2H, m), 3.04-3.17 (4H, m), 3.30-3.50 (1H, m), 3.62-3.70 (1H, m), 4.53, 4.81 (1H, s), 5.28 (2H, s), 7.19 (2H, d, J=8.5Hz), 7.25-7.31 (4H, m), 7.37-7.42 (4H, m), 7.59-7.61 (1H, m), 7.66 (1H, s) 20 MS (ESI-): 598 (M-H) Example 245 To a solution of (2S)-N-(2-tetrahydropyranyloxy)- 2 -[5 (3-(phenoxycarbonyloxymethyl)phenyl)-2-thienyll-3,4,5,6 25 tetrahydro-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% 30 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: CHCl 3 ) to give (2S)-N-(2-tetrahydropyranyloxy)-2 [5-(3-(methylaminocarbonyloxy 35 methyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2- WO 00/40576 PCT/JPO0/00018 200 acetamide 1,1-dioxide (150 mg) as an amorphous solid. NMR (CDC1 3 , 6): 1.37-1.75 (6H, m), 1.90-2.00 (2H, m), 2.05-2.23 (2H, m), 2.83 (3H, d, J=5.OHz), 2.89 3.17 (6H, m), 3.29-3.50 (1H, m), 3.61-3.71 (1H, m), 5 4.53, 4.81 (1H, s), 5.11 (2H, s), 7.25-7.31 (2H, m), 7.36 (1H, dd, J=8.0, 8.0Hz), 7.51-7.59 (3H, m) MS (ESI-): 535 (M-H) Example 246 10 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-(2 (methylaminocarbonyl)ethenyl)phenyl)-2-thienyl.]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (270 mg) was obtained from (2S)-N-(2-tetrahydropyranyloxy)-2-[5-(4-(2 carboxyethenyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H 15 thiopyran-2-acetamide 1,1-dioxide (300 mg) in a similar manner to that of Example 32. NMR (CDCl 3 , 8): 1.38-1.73 (6H, m), 1.88-2.02 (2H, m), 2.09-2.25 (2H, m), 2.78-2.89 (2H, m), 2.96 (3H, d, J=5Hz), 3.05-3.19 (4H, m), 3.29-3.51 (1H, m), 20 3.65-3.75 (1H, m), 4.54, 4.84 (1H, s), 6.40 (1H, d, J=15Hz), 7.20-7.59 (7H, m), 8.78 (1H, d, J=5Hz) Example 247 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-(2 25 (ethylaminocarbonyl)ethenyl)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (280 mg) was obtained in a similar manner to that of Example 32. NMR (DMSO-d 6 , 8): 1.23 (3H, t, J=7.2Hz), 1.38-1.73 (6H, m), 1.90-2.01 (2H, m), 2.07-2.23 (2H, m), 2.78 30 2.88 (2H, m), 3.02-3.20 (4H, m), 3.38-3.48 (3H, m), 3.67-3.76 (1H, m), 4.54, 4.84 (1H, s), 6.41 (1H, d, J=15Hz), 7.21-7.59 (7H, m), 8.78 (1H, br) Example 248 35 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4- WO 00/40576 PCT/JPOO/00018 201 (methylaminocarbonylmethoxy)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (720 mg) was obtained in a similar manner to that of Example 247. NMR (DMSO-d 6 , 6): 1.37-1.62 (6H, m), 1.67-1.81 (2H, m), 5 1.82-2.05 (2H, m), 2.33-2.45 (lH, m), 2.66 (3H, d, J=4.5Hz), 2.90-3.50 (6H, m), 3.73-3.91 (1H, m), 4.45, 4.75 (1H, s), 4.50 (2H, s), 7.01 (2H, d, J=9.0Hz), 7.16 (1H, d, J=4.0Hz), 7.32 (1H, d, J=4.0Hz), 7.59 (2H, d, J=9.OHz), 8.07 (lH, br), 10 11.23 (1H, s) Example 249 A mixture of ( 2

S)-N-(

2 -tetrahydropyranyloxy)-2-[5-[3 (chloroacetylamino)phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H 15 thiopyran-2-acetamide 1,1-dioxide (98 mg), n-tetrabutylammonium 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 20 aqueous sodium bicarbonate. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo to give ( 2

S)-N-(

2 -tetrahydropyranyloxy)-2-[5-[3

[(

2 -hydroxyethylamino)acetylamino]phenyl]-2-thienyl] 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (100 25 mg) as an amorphous solid. NMR (CDCl 3 , 8): 1.38-1.77 (6H, m), 1.89-2.00 (2H, m), 2.05-2.24 (2H, m), 2.68-2.91 (4H, m), 3.00-3.18 (4H, m), 3.29-3.52 (3H, m), 3.62-3.80 (3H, m), 4.53 (0.5H, s), 4.82 (0.5H, s), 7.22-7.32 (4H, m), 30 7.59-7.67 (1H, m), 7.69-7.75 (1H, m), 8.01 (1H, s), 9.48 (1H, s) MS (ESI-): 564 (M-H) Example 250 35 ( 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-[3-[(4- WO 00/40576 PCT/JPOO/00018 202 morpholino)acetylamino]phenyl]-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (96 mg) was obtained in a similar manner to that of Example 249. NMR (CDC1 3 , 8): 1.40-1.56 (4H, m), 1.61-1.73 (2H, m), 5 1.89-2.01 (2H, m), 2.06-2.32 (2H, m), 2.61-2.87 (6H, m), 3.05-3.19 (4H, m), 3.31-3.51 (1H, m), 3.62-3.74 (1H, m), 3.77-3.85 (4H, m), 4.53 (0.5H, s), 4.81 (0.5H, s), 7.25-7.31 (2H, m), 7.33-7.38 (2H, m), 7.52-7.61 (1H, m), 7.74-7.80 (1H, m), 10 8.00-8.23 (1H, m), 9.10 (1H, s) MS (ESI-): 590 (M-H) The following compounds were obtained in a similar manner to that of Example 54. 15 Example 251 (2S)-N-Hydroxy-2-[5-( 4 -aminocarbonylphenyl)-2-thienyl] 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (40 mg) 20 NMR (DMSO-d 6 , 8): 1.74-2.04 (4H, m), 2.37-2.46 (1H, m), 2.96-3.27 (4H, m), 3.4-3.54 (1H, m), 7.25 (1H, d, J=4.OHz), 7.48 (1H, br), 7.59 (1H, d, J=4.OHz), 7.74 (2H, d, J=7.5Hz), 7.92 (2H, d, J=7.5Hz), 8.02 (1H, br), 8.85 (1H, br) 25 MS (ESI-): 407.1 (M-H) Example 252 (2S)-N-Hydroxy-2-[5-( 4 -benzylaminocarbonyl)phenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 30 dioxide (20 mg) NMR (DMSO-d 6 , 8): 1.74-2.08 (4H, m), 2.37-2.45 (1H, m), 2.95-3.26 (4H, m), 3.43-3.52 (1H, m), 4.49 (2H, d, J=6.OHz), 7.24 (2H, m), 7.31-7.34 (4H, m), 7.61 (1H, d, J=3.0Hz), 7.75 (2H, d, J=7.5Hz), 7.95 (2H, 35 d, J=7.5Hz), 8.84 (1H, s), 9.10 (1H, t, J=6.OHz) WO 00/40576 PCT/JPOO/00018 203 MS (ESI+): 523.1(M+H+Na) Example 253 (2S)-N-Hydroxy-2-[5-(3-(ethoxycarbonylamino)phenyl)-2 5 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (115 mg) NMR (DMSO-d 6 , 6): 1.28 (3H, t, J=7.OHz), 1.73-2.05 (4H, m), 2.37-2.45 (1H, m), 2.96-3.25 (4H, m), 3.42 3.53 (1H, m), 4.15 (2H, q, J=7.0Hz), 7.20 (1H, d, 10 J=4.0Hz), 7.28-7.34 (3H, m), 7.48 (1H, d, J=4.0Hz), 7.82 (1H, s), 8.84 (1H, br), 9.85 (1H, s), 10.60 (1H, br) MS (ESI-): 451.2 (M-H) 15 Example 254 (2S)-N-Hydroxy-2-[5-(3-(benzylaminocarbonyl)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (50 mg) NMR (DMSO-d 6 , 8): 1.73-2.05 (4H, m), 2.36-2.47 (1H, m), 20 2.95-3.25 (4H, m), 3.41-3.52 (1H, m), 4.31 (2H, d, J=7.OHz), 6.68 (1H, t, J=7.OHz), 7.18-7.38 (10H, m), 7.86 (1H, s), 8.72 (1H, s), 8.84 (1H, s) MS (ESI-): 512.3 (M-H) 25 Example 255 (2S)-N-Hydroxy-2-[5-(3-(n-propyloxycarbonylamino) phenyl)-2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (120 mg) NMR (DMSO-d 6 , 6): 0.95 (3H, t, J=7.0Hz), 1.66 (2H, qt, 30 J=7.0, 7.0Hz), 1.72-2.05 (4H, m), 2.35-2.46 (1H, m), 2.94-3.29 (4H, m), 3.40-3.53 (1H, m), 4.05 (2H, t, J=7.OHz), 7.20 (1H, d, J=4.OHz), 7.29-7.34 (3H, m), 7.38 (1H, d, J=4.OHz), 7.83 (1H, s), 8.83 (1H, s), 9.73 (1H, s), 10.59 (1H, s) 35 MS (ESI-): 465.3 (M-H) WO 00/40576 PCT/JPOO/00018 204 Example 256 (2S)-N-Hydroxy-2-[5-(3-(isopropoxycarbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 5 acetamide 1,1-dioxide (90 mg) NMR (DMSO-d 6 , 8): 1.26 (6H, d, J=6.OHz), 1.74-2.04 (4H, m), 2.35-2.55 (1H, m), 2.94-3.25 (4H, m), 3.40 3.51 (1H, m), 4.40 (1H, qq, J=6.0, 6.0Hz), 7.20 (1H, d, J=4.0Hz), 7.29-7.33 (3H, m), 7.36 (1H, d, 10 J=4.0Hz), 7.85 (1H, s), 8.83 (1H, s), 9.67 (1H, s), 10.59 (1H, s) MS (ESI-): 465.3 (M-H) Example 257 15 (2S)-N-Hydroxy-2-[5-{3-(2-chloroethoxycarbonylamino) phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (100 mg) NMR (DMSO-d 6 , 6): 1.75-2.05 (4H, m), 2.36-2.47 (1H, m), 2.94-3.29 (4H, m), 3.42-3.52 (1H, m), 3.88 (2H, d, 20 J=6.OHz), 4.35 (2H, d, J=6.OHz), 7.21 (1H, d, J=4.OHz), 7.32-7.36 (2H, m), 7.40 (1H, d, J=4.OHz), 7.84 (1H, s), 8.83 (1H, s), 9.94 (1H, s), 10.08 (1H, s) MS (ESI-): 485.2 (M-H) 25 Example 258 (2S)-N-Hydroxy-2-[5-(3-valerylaminophenyl)-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (102 mg) 30 NMR (DMSO-d 6 , 8): 0.91 (3H, t, J=8Hz), 1.24-1.41 (2H, m), 1.52-1.66 (2H, m), 1.69-2.08 (4H, m), 2.33 (2H, t, J=8Hz), 2.32-2.48 (1H, m), 2.92-3.28 (4H, m), 3.37-3.54 (1H, m), 7.20 (1H, d, J=3Hz), 7.34 (2H, d, J=3Hz), 7.40 (1H, d, J=3Hz), 7.42-7.52 (1H, m), 35 7.99 (1H, s), 10.00 (1H, s), 10.60 (1H, s) WO 00/40576 PCT/JP0O/00018 205 MS (ESI-): 463 (M-H) Example 259 (2S)-N-Hydroxy-2-[5-(3-(ethylthiocarbonylamino) 5 phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (92 mg) NMR (DMSO-d 6 , 8): 1.26 (3H, t, J=8Hz), 1.72-2.08 (4H, m), 2.36-2.49 (1H, m), 2.89 (2H, q, J=8Hz), 2.94 3.30 (4H, m), 3.39-3.55 (1H, m), 7.21 (1H, d, 10 J=3Hz), 7.32-7.44 (4H, m), 7.90 (1H, s), 8.85 (1H, s), 10.39 (1H, s), 10.60 (1H, s) MS (ESI+): 469 (M+H) Example 260 15 (2S)-N-Hydroxy-2-[5-( 3 -(methylthiocarbonylamino) phenyl)-2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (130 mg) NMR (DMSO-d 6 , 6): 1.68-2.08 (4H, m), 2.33 (3H, s), 2.35 2.46 (1H, m), 2.92-3.38 (4H, m), 3.39-3.53 (1H, m), 20 7.21 (1H, d, J=3Hz), 7.29-7.46 (4H, m), 7.90 (1H, s) MS (ESI-): 453 (M-H) Example 261 25 (2S)-N-Hydroxy-2-[5-(3-(benzyloxycarbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (60.2 mg) NMR (DMSO-d 6 , 6): 1.68-2.07 (4H, m), 2.32-2.48 (1H, m), 2.92-3.34 (4H, m), 3.52-3.65 (1H, m), 5.18 (2H, s), 30 7.21 (1H, d, J=3Hz), 7.26-7.50 (10H, m), 7.85 (1H, s), 9.91 (1H, s), 10.60 (1H, s) MS (ESI-): 513 (M-H) Example 262 35 ( 2 S)-N-Hydroxy-2-[5-(3-(2-(t-butoxycarbonylamino)- WO 00/40576 PCT/JP0O/00018 206 acetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (40 mg) NMR (DMSO-d 6 , 8): 1.40 (9H, s), 1.66-2.08 (4H, m), 2.35 2.48 (1H, m), 2.92-3.32 (4H, m), 3.45-3.53 (1H, m), 5 3.73 (2H, d, J=7Hz), 7.07 (1H, t, J=7Hz), 7.22 (1H, d, J=3Hz), 7.32-7.54 (4H, m), 7.97 (1H, s), 10.05 (1H, s), 10.61 (4H, s) MS (ESI-): 536 (M-H) 10 Example 263 (2S)-N-Hydroxy-2-[5-(3-(2-(4-chlorophenoxy) acetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (90 mg) NMR (DMSO-d 6 , 6): 1.71-2.09 (4H, m), 2.35-2.49 (1H, 15 m), 2.94-3.29 (4H, m), 3.42-3.55 (1H, m), 4.74 (2H, s), 7.00-7.12 (2H, m), 7.22 (1H, br s), 7.32-7.47 (5H, m), 7.51-7.62 (1H, m), 8.02 (1H, s), 8.84 (1H, s), 10.22 (iH, s), 10.60 (1H, s) MS (ESI-): 547 (M-H) 20 Example 264 (2S)-N-Hydroxy-2-[5-(3-(phenoxycarbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (88 mg) 25 NMR (DMSO-d 6 , 8): 1.68-2.09 (4H, m), 2.32-2.48 (1H, m), 2.92-3.30 (4H, m), 3.56-3.72 (1H, m), 7.17-7.30 (4H, m), 7.31-7.51 (6H, m), 7.89 (1H, s), 10.37 (1H, s), 10.61 (1H, s) MS (ESI-): 499 (M-H) 30 Example 265 (2S)-N-Hydroxy-2-[5-(3-(2-(4-chlorophenyl)acetylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (95 mg) 35 NMR (DMSO-d 6 , 8): 1.68-2.09 (4H, m), 2.35-2.48 (1H, m), WO 00/40576 PCT/JPOO/00018 207 2.92-3.32 (4H, m), 3.54-3.66 (1H, m), 3.68 (2H, s), 7.20 (1H, d, J=3Hz), 7.28-7.52 (8H, m), 7.99 (1H, s), 10.33 (1H, s), 10.60 (1H, s) MS (ESI-): 531 (M-H) 5 Example 266 (2S)-N-Hydroxy-2-[5-(3-(2-(4-morpholinocarbonylamino) acetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (50 mg) 10 NMR (DMSO-d 6 , 8): 1.71-2.08 (4H, m), 2.36-2.48 (1H, m), 2.94-3.62 (13H, m), 3.82 (2H, d, J=7Hz), 6.96 (1H, t, J=7Hz), 7.21 (1H, d, J=3Hz), 7.31-7.49 (4H, m), 8.02 (1H, s), 8.84 (1H, br s) MS (ESI-): 549 (M-H) 15 Example 267 (2S)-N-Hydroxy-2-[5-(3-(2-(N-ethyl-N-methylamino carbonyloxy)acetylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (133 mg) 20 NMR (DMSO-d 6 , 8): 1.05, 1.12 (3H, t, J=8Hz), 1.68-2.07 (4H, m), 2.35-2.48 (1H, m), 2.76-3.36 (9H, m), 3.39-3.54 (1H, m), 4.63 (2H, s), 7.21 (1H, d, J=3Hz), 7.32-7.47 (4H, m), 8.00 (1H, s), 8.85 (1H, s), 10.18 (1H, s), 10.61 (1H, s) 25 MS (ESI-): 522 (M-H) Example 268 (2S)-N-Hydroxy-2-[5-(3-(isopropoxyacetylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 30 acetamide 1,1-dioxide (204 mg) NMR (DMSO-d 6 , 8): 1.78 (6H, d, J=8Hz), 1.72-2.08 (4H, m), 2.35-2.49 (1H, m), 2.94-3.31 (4H, m), 3.42 3.56 (1H, m), 3.63-3.77 (1H, m), 4.04 (2H, s), 7.22 (1H, d, J=3Hz), 7.32-7.43 (2H, m), 7.40 (1H, 35 d, J=3Hz), 7.56-7.64 (1H, m), 8.02 (1H, s), 8.85 WO 00/40576 PCT/JPOO/00018 208 (1H, s), 9.68 (1H, s), 10.60 (1H, s) MS (ESI+): 482 (M+H) Example 269 5 ( 2 S)-N-Hydroxy-2-[5-(3-(2-(2-oxo-1,3-oxazolidinyl-3 yl)acetylamino)phenyl)-2-thienyl)-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (480 mg) NMR (DMSO-d 6 , 8): 1.65-2.09 (4H, m), 2.32-2.51 (1H, m), 2.88-3.53 (5H, m), 3.66 (2H, t, J=8Hz), 4.04 (2H, 10 s), 4.34 (2H, t, J=8Hz), 7.21 (1H, d, J=3Hz), 7.30-7.51 (4H, m), 8.03 (1H, s), 10.37 (1H, s), 10.62 (1H, s) MS (ESI-): 506 (M-H) 15 Example 270 (2S)-N-Hydroxy-2-[5-(3-( 4 -methoxyphenylaminocarbonyl amino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (140 mg) NMR (DMSO-d 6 , 8): 1.73-2.04 (4H, m), 2.38-2.45 (1H, m), 20 2.95-3.26 (4H, m), 3.39-3.54 (lH, m), 3.72 (3H, s), 6.86 (2H, d, J=7.5Hz), 7.20 (1H, d, J=4.OHz), 7.23-7.32 (3H, m), 7.37 (2H, d, J=7.5Hz), 7.50 (1H, d, J=4.0Hz), 7.87 (1H, s), 8.50 (1H, s), 8.72 (1H, s), 8.84 (1H, s), 10.59 (1H, s) 25 MS (ESI-): 528.3 (M-H) Example 271 (2S)-N-Hydroxy-2-[5-(3-( 3 -pyridylaminocarbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 30 acetamide 1,1-dioxide (70 mg) NMR (DMSO-d 6 , 6): 1.75-2.05 (4H, m), 2.37-2.48 (1H, m), 2.96-3.25 (4H, m), 3.58-3.69 (1H, m), 7.21 (1H, d, J=4.0Hz), 7.30-7.36 (3H, m), 7.42 (1H, d, J=4.OHz), 7.82 (1H, dd, J=7.5, 5.0Hz), 7.90 (1H, s), 8.29 35 (12H, d, J=7.SHz), 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 (ESI-): 499.2 (M-H) Example 272 5 (2S)-N-Hydroxy-2-[5-{3-(((2S)-2-aminopropionyl)amino) phenyl}-2-thienyl)-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide hydrochloride (120 mg) from (2S)-N-(2 tetrahydropyranyloxy)-2-[5-{3-(((2S)-2-tert butoxycarbonylaminopropionyl)amino)phenyl}-2-thienyl] 10 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 8): 1.50 (3H, d, J=7.OHz), 1.72-2.03 (4H, m), 2.35-2.46 (1H, m), 2.95-3.27 (4H, m), 3.43 3.54 (1H, m), 4.05 (1H, br t, J=7.0Hz), 7.21 (1H, d, J=4.0Hz), 7.37-7.43 (3H, m), 7.55 (1H, d, 15 J=7.5Hz), 7.95 (1H, s), 8.28-8.32 (3H, m), 10.63 (1H, s), 10.81 (1H, s) MS (ESI-): 450.7 (M-H) Example 273 20 (2S)-N-Hydroxy-2-[5-{3-(((2R)-2-(tert-butoxycarbonyl amino)propionyl)amino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (30 mg) NMR (DMSO-d 6 , 8): 1.27 (3H, d, J=6.OHz), 1.38 (9H, s), 1.74-2.04 (4H, m), 2.37-2.42 (1H, m), 2.95-3.25 25 (4H, m), 3.38-3.51 (1H, m), 4.08-4.15 (1H, m), 7.10 (1H, d, J=7.OHz), 7.20 (1H, d, J=4.OHz), 7.31-7.36 (2H, m), 7.40 (1H, d, J=4.OHz), 7.50 (1H, br), 7.96 (1H, s), 8.83 (1H, s), 10.04 (1H, s), 10.60 (1H, s) 30 MS (ESI-): 550.3 (M-H) Example 274 (2S)-N-Hydroxy-2-[5-{3-(((2R)-2-aminopropionyl)amino) phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 35 acetamide 1,1-dioxide (130 mg) from (2S)-N-(2- WO 00/40576 PCT/JPO0/00018 210 tetrahydropyranyloxy)-2-[5-{3-(((2R)-2-tert butoxycarbonylaminopropionyl)amino)phenyl}-2-thienyl] 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 8): 1.50 (3H, d, J=7.0Hz), 1.72-2.03 (4H, 5 m), 2.35-2.46 (1H, m), 2.95-3.27 (4H, m), 3.43 3.54 (1H, m), 4.05 (1H, br t, J=7.OHz), 7.21 (1H, d, J=4.OHz), 7.37-7.43 (3H, m), 7.55 (1H, d, J=7.5Hz), 7.95 (1H, s), 8.28-8.32 (3H, m), 10.63 (1H, s), 10.81 (1H, s) 10 MS (ESI-): 452.1 (M-H) Example 275 (2S)-N-Hydroxy-2-[5-{3-(2-(4-methylphenoxy) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H 15 thiopyran-2-acetamide 1,1-dioxide (150 mg) NMR (DMSO-d 6 , 6): 1.74-2.04 (4H, m), 2.24 (3H, s), 2.37 2.45 (1H, m), 2.95-3.26 (4H, m), 3.44-3.53 (1H, m), 4.67 (2H, s), 6.90 (2H, d, J=7.5Hz), 7.11 (2H, d, J=7.5Hz), 7.21 (1H, d, J=4.OHz), 7.34-7.37 (2H, m), 20 7.42 (1H, d, J=4.OHz), 7.56 (1H, d, J=6.OHz), 8.01 (1H, s), 8.82 (1H, s), 10.17 (1H, s), 10.59 (1H, s) MS (ESI-): 528.1 (M-H) 25 Example 276 (2S)-N-Hydroxy-2-[5-{3-(2-N,N-dimethylamino) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (65 mg) NMR (DMSO-d 6 , 6): 1.74-2.05 (4H, m), 2.36-2.45 (1H, m), 30 2.89 (6H, s), 2.96-3.27 (4H, m), 3.44-3.54 (1H, m), 4.17 (2H, s), 7.22 (lH, d, J=4.OHz), 7.38-7.42 (2H, m), 7.50 (1H, d, J=5.OHz), 7.95 (1H, s), 8.84 (1H, br), 9.88 (1H, br), 10.60 (1H, s), 10.82 (1H, s) MS (ESI-): 464.3 (M-H) 35 WO 00/40576 PCT/JPOO/00018 211 Example 277 (2S)-N-Hydroxy-2-[5-(3-(allyloxycarbonylamino) phenyl)-2-thienyl)-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (50 mg) 5 NMR (DMSO-d 6 , 6): 1.73-2.04 (4H, m), 2.36-2.45 (1H, m), 2.95-3.25 (4H, m), 3.41-3.49 (1H, m), 4.63 (2H, d, J=5.0Hz), 5.25 (1H, d, J=8.0Hz), 5.38 (1H, d, J=8.OHz), 5.93-6.06 (1H, m), 7.20 (1H, d, J=4.OHz), 7.30-7.35 (3H, m), 7.49 (1H, d, J=4.OHz), 7.84 (1H, 10 s), 8.83 (1H, s), 9.85 (1H, s) MS (ESI-): 463.3 (M-H) Example 278 (2S)-N-Hydroxy-2-[5-(3-ethoxycarbonylmethylamino 15 carbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (40 mg) NMR (DMSO-d 6 , 6): 1.23 (3H, t, J=7.5Hz), 1.73-2.05 (4H, m), 2.36-2.47 (1H, m), 2.94-3.25 (4H, m), 3.42 3.54 (1H, m), 3.87 (2H, d, J=7.OHz), 4.13 (2H, q, 20 J=7.5Hz), 6.50 (1H, t, J=7.OHz), 7.18 (1H, d, J=4.0Hz), 7.21-7.30 (3H, m), 7.37 (1H, d, J=4.OHz), 7.83 (1H, s), 8.83 (1H, s), 8.96 (1H, s) MS (ESI-): 508.3 (M-H) 25 Example 279 (2S)-N-Hydroxy-2-[5-(3-(benzyloxyacetylamino)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (55 mg) NMR (DMSO-d 6 , 8): 1.75-2.06 (4H, m), 2.36-2.46 (1H, m), 30 2.95-3.25 (4H, m), 3.42-3.53 (1H, m), 4.11 (2H, s), 4.64 (2H, s), 7.21 (1H, d, J=4.OHz), 7.28-7.43 (8H, m), 7.54-7.57 (1H, m), 8.01 (1H, s), 8.82 (1H, s), 9.90 (1H, s), 10.60 (1H, s) MS (ESI-): 527.3 (M-H) 35 WO 00/40576 PCT/JPO0/00018 212 Example 280 (2S)-N-Hydroxy-2-[5-(3-(cyclopentylcarbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (120 mg) 5 .NMR (DMSO-d 6 , 6): 1.52-2.06 (12H, m), 2.36-2.47 (1H, m), 2.78 (1H, tt, J=7.0, 7.0Hz), 2.95-3.25 (4H, m), 3.40-3.54 (1H, m), 7.20 (1H, d, J=4.0Hz), 7.32 7.34 (2H, m), 7.40 (1H, d, J=4.0Hz), 7.45-7.49 (1H, m), 8.03 (1H, s), 8.84 (1H, s), 9.98 (1H, s), 10 10.61 (1H, s) MS (ESI-): 475.3 (M-H) Example 281 (2S)-N-Hydroxy-2-[5-(3-((2-hydroxyethyl) 15 aminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (20 mg) NMR (DMSO-d 6 , 6): 1.72-2.04 (4H, m), 2.40-2.45 (1H, m), 2.93-3.25 (6H, m), 3.41-3.50 (3H, m), 4.75 (1H, t, J=5.OHz), 6.22 (1H, t, J=5.OHz), 7.16-7.25 (3H, m), 20 7.35 (1H, d, J=4.OHz), 7.82 (1H, s), 8.71 (1H, s), 8.83 (1H, s) MS (ESI-): 466.4 (M-H) Example 282 25 (2S)-N-Hydroxy-2-[5-(3-((2-aminoethoxy)carbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide hydrochloride (20 mg) NMR (DMSO-d 6 , 8): 1.74-2.07 (4H, m), 2.35-2.44 (1H, m), 2.95-3.27 (4H, m), 3.48-3.66 (SH, m), 7.12-7.51 30 (4H, m), 7.86-7.90 (2H, m), 8.00-8.08 (2H, m), 9.10 (1H, s), 9.85 (1H, s), 10.62 (1H, s) MS (ESI+): 468.3 (M+H) Example 283 35 (2S)-N-Hydroxy-2-[5-(3-(3-chloropropionylamino)phenyl)- WO 00/40576 PCT/JPOO/00018 213 2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (95 mg) NMR (DMSO-d 6 , 6): 1.73-2.06 (4H, m), 2.37-2.46 (1H, m), 2.84 (2H, t, J=6.0Hz), 2.95-3.26 (4H, m), 3.43 5 3.56 (1H, m), 3.90 (2H, t, J=6.OHz), 7.21 (1H, d, J=4.OHz), 7.35-7.40 (2H, m), 7.42 (1H, d, J=4.0Hz), 7.47-7.52 (1H, m), 8.00 (1H, s), 8.85 (1H, s) MS (ESI-): 469.1 (M-H) 10 Example 284 (2S)-N-Hydroxy-2-[5-(4-(methanesulfonylamino)phenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (40 mg) NMR (DMSO-d 6 , 8): 1.72-2.05 (4H, m), 2.34-2.44 (1H, m), 15 2.89 (3H, s), 2.93-3.23 (4H, m), 3.41-3.51 (1H, m), 7.12 (2H, d, J=7.5Hz), 7.15 (1H, d, J=4.0Hz), 7.31 (1H, d, J=4.0Hz), 7.50 (2H, d, J=7.SHz) MS (ESI-): 457.3 (M-H) 20 Example 285 (2S)-N-Hydroxy-2-[5-(4-(2-(phenylaminocarbonyl) ethenyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran 2-acetamide 1,1-dioxide (40 mg) NMR (DMSO-d 6 , 8): 1.73-2.07 (4H, m), 2.38-2.48 (1H, m), 25 2.97-3.54 (5H, m), 6.86 (lH, d, J=16Hz), 7.06 (1H, dd, J=8.0, 8.0Hz), 7.24 (1H, d, J=4.0Hz), 7.34 (2H, dd, J=8.0, 8.0Hz), 7.56 (1H, d, J=4.OHz), 7.61 (1H, d, J=16Hz), 7.65-7.75 (6H, m), 8.85 (1H, s), 10.2 (1H, s), 10.6 (1H, s) 30 Example 286 (2S)-N-Hydroxy-2-[5-(4-(2-(4-methoxyphenylamino carbonyl)ethenyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (100 mg) 35 NMR (DMSO-d 6 , 8): 1.72-2.07 (4H, m), 2.37-2.46 (1H, m), WO 00/40576 PCT/JPO0/00018 214 2.97-3.52 (5H, m), 3.74 (3H, s), 6.83 (1H, d, J=l6Hz), 6.92 (2H, d, J=8.5Hz), 7.24 (1H, d, J=4.OHz), 7.54-7.75 (8H, m), 8.85 (1H, s), 10.08 (1H, s), 10.6 (1H, s) 5 Example 287 (2S)-N-Hydroxy-2-[5-(4-(2-(4-fluorophenylamino carbonyl)ethenyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (80 mg) 10 NMR (DMSO-d 6 , 8): 1.73-2.07 (4H, m), 2.37-2.46 (1H, m), 2.98-3.53 (5H, m), 6.83 (1H, d, J=16Hz), 17.18 (2H, dd, J=8.5, 8.5Hz), 7.24 (1H, d, J=4.OHz), 7.57 7.75 (8H, m), 8.85 (1H, s), 10.3 (1H, s), 10.6 (1H, s) 15 Example 288 (2S)-N-Hydroxy-2-[5-(4-(ethylcarbonyloxy)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (100 mg) 20 NMR (DMSO-d 6 , 8): 1.13 (3H, dd, J=7.5, 7.5Hz), 1.71-2.07 (4H, m), 2.36-2.46 (1H, m), 2.62 (2H, ddd, J=7.5, 7.5, 7.5Hz), 2.96-3.52 (5H, m), 7.20-7.21 (3H, m), 7.46 (1H, d, J=4.OHz), 7.68 (2H, d, J=8.5Hz), 8.85 (1H, s) 25 MS (ESI-): 436 (M-H) Example 289 (2S)-N-Hydroxy-2-[5-(4-(methoxycarbonylaminomethyl) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 30 acetamide 1,1-dioxide (45 mg) NMR (DMSO-d 6 , 6): 1.70-2.06 (4H, m), 2.35-2.45 (1H, m), 2.96-3.50 (5H, m), 3.56 (3H, s), 4.19 (2H, d, J=7.OHz), 7.20 (1H, d, J=4.OHz), 7.29 (2H, d, J=8.5Hz), 7.43 (1H, d, J=4.OHz), 7.60 (2H, d, 35 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 (M-H) Example 290 5 (2S)-N-Hydroxy-2-[5-(4-(ethylcarbonylmethoxy)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (120 mg) NMR (DMSO-d 6 , 6): 0.98 (3H, t, J=7.2Hz), 1.70-2.07 (4H, m), 2.33-2.45 (1H, m), 2.54 (2H, q, J=7.2Hz), 10 2.95-3.50 (5H, m), 4.86 (2H, s), 6.95 (2H, d, J=8.5Hz), 7.16 (1H, d, J=4.OHz), 7.34 (1H, d, J=4.OHz), 7.55 (2H, d, J=8.5Hz), 8.84 (1H, br) MS (ESI-): 450 (M-H) 15 Example 291 (2S)-N-Hydroxy-2-[5-(4-(cyclopropylaminocarbonyl methoxy)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran 2-acetamide 1,1-dioxide (70 mg) NMR (DMSO-d 6 , 8): 0.46-0.51 (2H, m), 0.60-0.66 (2H, m), 20 1.70-2.07 (4H, m), 2.34-2.45 (1H, m), 2.66-2.75 (1H, m), 2.95-3.50 (5H, m), 4.47 (2H, s), 6.99 (2H, d, J=8.5Hz), 7.16 (1H, d, J=4.OHz), 7.35 (1H, d, J=4.OHz), 7.57 (2H, d, J=8.SHz), 8.15 (1H, br), 8.84 (1H, s), 10.59 (1H, s) 25 Example 292 (2S)-N-Hydroxy-2-[5-(4-(n-propylaminocarbonyl methoxy)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran 2-acetamide 1,1-dioxide (70 mg) 30 NMR (DMSO-d 6 , 8): 0.82 (3H, t, J=7.5Hz), 1.39-1.50 (2H, m), 1.73-2.07 (4H, m), 2.35-2.45 (1H, m), 2.95 3.52 (7H, m), 4.50 (2H, s), 7.01 (2H, d, J=8.5Hz), 7.17 (1H, d, J=4.OHz), 7.35 (1H, d, J=4.OHz), 7.58 (2H, d, J=8.5Hz), 8.11 (1H, br), 8.85 (1H, s), 35 10.59 (1H, s) WO 00/40576 PCT/JPOO/00018 216 MS (ESI-): 479 (M-H) Example 293 (2S)-N-Hydroxy-2-[5-(3-hydroxyphenyl)-2-thienyl] 5 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (120 mg) NMR (DMSO-d 6 , 8): 1.70-2.05 (4H, m), 2.36-2.45 (1H, m), 2.95-3.50 (5H, m), 6.71-6.74 (1H, m), 7.00 (1H, s), 7.06 (1H, d, J=8.OHz), 7.17-7.25 (2H, m), 7.39 (1H, 10 d, J=4.0Hz), 8.85 (1H, s), 9.62 (1H, s), 10.60 (1H, s) MS (ESI-): 380 (M-H) Example 294 15 (2S)-N-Hydroxy-2-[5-(3-butylaminocarbonylamino)phenyl) 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (170 mg) NMR (DMSO-d 6 , 6): 0.90 (3H, dd, J=7.2, 7.2Hz), 1.27-1.37 (2H, m), 1.37-1.47 (2H, m), 1.70-2.05 (4H, m), 20 2.37-2.45 (1H, m), 2.95-3.50 (7H, m), 6.16 (1H, dd, J=7.0, 7.0Hz), 7.17-7.28 (4H, m), 7.37 (1H, d, J=4.OHz), 7.84 (1H, s), 8.55 (1H, s), 10.6 (1H, s) MS (ESI-): 478 (M-H) 25 Example 295 (2S)-N-Hydroxy-2-[5-(3-(1-naphtyl)aminocarbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (250 mg) NMR (DMSO-d 6 , 6): 1.72-2.07 (4H, m), 2.38-2.47 (1H, m), 30 2.95-3.31 (5H, m), 7.22 (1H, d, J=4.OHz), 7.29 7.37 (3H, m), 7.44 (1H, d, J=4.OHz), 7.47-7.68 (4H, m), 7.94-7.96 (2H, m), 8.02 (1H, d, J=8.3Hz), 8.15 (1H, d, J=8.3Hz), 8.85 (1H, s), 9.27 (1H, s), 10.6 (1H, s) 35 MS (ESI-): 548 (M-H) WO 00/40576 PCT/JPOO/00018 217 Example 296 (2S)-N-Hydroxy-2-[5-(3-(allylaminocarbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 5 acetamide 1,1-dioxide (200 mg) NMR (DMSO-d 6 , 8): 1.70-2.07 (4H, m), 2.36-2.45 (1H, m), 2.96-3.25 (5H, m), 3.72-3.76 (2H, m), 5.02-5.19 (2H, m), 5.80-5.94 (1H, m), 6.29-6.32 (1H, m), 7.18-7.26 (4H, m), 7.38 (1H, d, J=4.OHz), 7.84 (1H, 10 s), 8.68 (1H, s), 10.6 (1H, s) MS (ESI-): 462 (M-H) Example 297 (2S)-N-Hydroxy-2-[5-(3-(isobutylaminocarbonylamino) 15 phenyl)-2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (170 mg) NMR (DMSO-d 6 , 6): 0.88 (6H, d, J=6.6Hz), 1.65-2.07 (5H, m), 2.40-2.47 (1H, m), 2.94 (2H, dd, J=6.5, 6.5Hz), 3.00-3.50 (5H, m), 6.23 (1H, dd, J=6.5, 6.5Hz), 20 7.17-7.20 (3H, m), 7.37 (1H, d, J=4.OHz), 7.84 (1H, s), 8.54 (1H, s), 10.6 (1H, s) MS (ESI-): 478 (M-H) Example 298 25 (2S)-N-Hydroxy-2-[5-(3-(cyclohexylmethylaminocarbonyl amino)phenyl)-2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (110 mg) NMR (DMSO-d 6 , 6): 0.83-0.95 (2H, m), 1.11-1.25 (3H, m), 1.60-1.75 (6H, m), 1.83-2.07 (4H, m), 2.37-2.45 30 (1H, m), 2.93-3.07 (4H, m), 3.08-3.30 (3H, m), 6.22 (1H, br), 7.19-7.28 (4H, m), 7.37 (1H, d, J=4.OHz), 8.55 (1H, s), 10.6 (1H, s) MS (ESI-): 518 (M-H) 35 Example 299 WO 00/40576 PCT/JPOO/00018 218 (2S)-N-Hydroxy-2-[5-(3-( 2 -methoxyethylaminocarbonyl amino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (150 mg) NMR (DMSO-d 6 , 6): 1.71-2.06 (4H, m), 2.37-2.46 (1H, m), 5 2.95-3.01 (2H, m), 3.05-3.25 (3H, m), 3.28 (3H, s), 3.35-3.51 (4H, m), 6.21-6.25 (1H, m), 7.16-7.25 (4H, m), 7.37 (1H, d, J=4.OHz), 7.83 (1H, s), 8.68 (1H, s), 8.79-8.86 (1H, br), 10.6 (1H, s) MS (ESI-): 480 (M-H) 10 Example 300 (2S)-N-Hydroxy-2-[5-(3-(N-methyl-N-ethylaminocarbonyl) amino)phenyl)-2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (55 mg) 15 NMR (DMSO-d 6 , 8): 1.08 (3H, t, J=7.OHz), 1.70-2.08 (4H, m), 2.37-2.45 (1H, m), 2.94 (3H, s), 2.97-3.54 (7H, m), 7.20 (1H, d, J=4.0Hz), 7.25 (2H, d, J=8.0Hz), 7.37 (1H, d, J=4.0Hz), 7.45 (2H, d, J=8.OHz), 7.84 (1H, s), 8.84 (1H, s), 10.59 (1H, s) 20 MS (ESI-): 464 (M-H) Example 301 (2S)-N-Hydroxy-2-[5-(4-(2-(N,N-dimethylaminocarbonyl) ethenyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran 25 2-acetamide 1,1-dioxide (180 mg) NMR (DMSO-d 6 , 5): 1.70-2.08 (4H, m), 2.37-2.45 (1H, m), 2.93 (3H, s), 2.94-3.10 (2H, m), 3.17 (3H, s), 3.18-3.55 (3H, m), 7.20 (1H, d, J=4.OHz), 7.25 (1H, d, J=16Hz), 7.45 (1H, d, J=16Hz), 7.55 (1H, d, 30 J=4.OHz), 7.66 (2H, d, J=8.5Hz), 7.75 (2H, d, J=8.5Hz), 8.84 (1H, br), 10.60 (iH, s) MS (ESI-): 461 (M-H) Example 302 35 ( 2 S)-N-Hydroxy- 2 -[5-(4-(2-(isopropylaminocarbonyl)- WO 00/40576 PCT/JPOO/00018 219 ethenyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran 2-acetamide 1,1-dioxide (110 mg) NMR (DMSO-d 6 , 8): 1.11 (6H, d, J=6.5Hz), 1.70-2.07 (4H, m), 2.36-2.44 (1H, m), 2.97-3.55 (5H, m), 3.40 5 4.00 (1H, m), 6.62 (1H, d, J=16Hz), 7.23 (1H, d, J=4.OHz), 7.40 (1H, d, J=16Hz), 7.55 (1H, d, J=4.OHz), 7.58 (2H, d, J=8.5Hz), 7.69 (2H, d, J=8.5Hz), 7.99 (1H, d, J=7.5Hz), 10.6 (1H, s) MS (ESI-): 475 (M-H) 10 Example 303 (2S)-N-Hydroxy-2-[5-(4-(2-(propylaminocarbonyl) ethenyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran 2-acetamide 1,1-dioxide (120 mg) 15 NMR (DMSO-d 6 , 8): 0.88 (3H, t, J=7.5Hz), 1.47 (2H, q, J=7.5Hz), 1.70-2.07 (4H, m), 2.35-2.45 (1H, m), 2.96-3.55 (7H, m), 6.65 (1H, d, J=16Hz), 7.23 (1H, d, J=4.OHz), 7.40 (1H, d, J=16Hz), 7.55 (1H, d, J=4.OHz), 7.60 (2H, d, J=8.5Hz), 7.69 (2H, d, 20 J=8.5Hz), 8.10 (1H, t, J=7.OHz), 10.6 (1H, s) MS (ESI-): 475 (M-H) Example 304 (2S)-N-Hydroxy-2-[5-(4-(methylaminocarbonyloxy)phenyl) 25 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (150 mg) NMR (DMSO-d 6 , 6): 1.71-2.05 (4H, m), 2.35-2.45 (1H, m), 2.67 (3H, d, J=4.5Hz), 2.95-3.51 (5H, m), 7.15 (2H, d, J=8.7Hz), 7.21 (1H, d, J=4.OHz), 7.43 (1H, d, 30 J=4.OHz), 7.63 (2H, d, J=8.7Hz), 7.65-7.68 (lH, m), 8.85 (1H, s), 10.6 (1H, s) MS (ESI-): 437 (M-H) Example 305 35 ( 2 S)-N-Hydroxy-2-[5-(4-(ethylaminocarbonyloxy)phenyl)- WO 00/40576 PCT/JPOO/00018 220 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (130 mg) NMR (DMSO-d 6 , b): 1.08 (3H, dd, J=7.2, 7.2Hz), 1.71-2.05 (4H, m), 1.85-1.96 (1H, m), 2.95-3.30 (6H, m), 5 3.41-3.53 (1H, m), 7.15 (2H, d, J=8.7Hz), 7.20 (1H, d, J=4.0Hz), 7.43 (1H, d, J=4.0Hz), 7.63 (2H, d, J=8.7Hz), 7.80 (1H, dd, J=7.0, 7.0Hz), 8.85 (1H, s), 10.6 (1H, s) MS (ESI-): 451 (M-H) 10 Example 306 (2S)-N-Hydroxy-2-[5-(5-acetyl-2-thienyl)-2-thienyl) 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (20 mg) 15 NMR (DMSO-d 6 , 8): 1.68-2.07 (4H, m), 2.35-2.45 (1H, m), 2.53 (3H, s), 2.95-3.53 (5H, m), 7.21 (1H, d, J=4.OHz), 7.44 (1H, d, J=4.OHz), 7.51 (1H, d, J=4.OHz), 7.91 (1H, d, J=4.OHz), 8.85 (1H, s) MS (ESI-): 412 (M-H) 20 The following compounds were obtained in a similar manner to that of Example 166. Example 307 25 (2S) -N-Hydroxy-2-[5-(4-methoxyacetoxy)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (100 mg) NMR (DMSO-d 6 , 8): 1.71-2.05 (4H, m), 2.36-2.45 (1H, m), 2.97-3.28 (4H, m), 3.41 (3H, s), 3.42-3.51 (1H, m), 30 4.36 (2H, s), 7.21 (1H, d, J=4.OHz), 7.22 (2H, d, J=8.5Hz), 7.48 (1H, d, J=4.OHz), 7.70 (2H, d, J=8.5Hz), 8.84 (1H, s) MS (ESI-): 452 (M-H) 35 Example 308 WO 00/40576 PCT/JPOO/00018 221 (2S)-N-Hydroxy-2-[5-(4-(ethoxycarbonyloxy)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (80 mg) NMR (DMSO-d 6 , 8): 1.31 (3H, dd, J=7.5, 7.5Hz), 1.70-1.93 5 (4H, m), 2.36-2.47 (1H, m), 2.97-3.51 (5H, m), 4.27 (2H, ddd, J=7.5, 7.5, 7.5Hz), 7.21 (1H, d, J=4.OHz), 7.30 (2H, d, J=8.5Hz), 7.49 (1H, d, J=4.0Hz), 7.69 (2H, d, J=8.5Hz) MS (ESI-): 452 (M-H) 10 Example 309 (2S)-N-Hydroxy-2-[5-(4-(cyclopropylcarbonyloxy)phenyl) 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (100 mg) 15 NMR (DMSO-d 6 , 8): 1.03-1.06 (4H, m), 1.70-2.05 (5H, m), 2.36-2.47 (1H, m), 2.95-3.51 (5H, m), 7.17 7.21 (3H, m), 7.46 (1H, d, J=4.0Hz), 7.66 (2H, d, J=8.5Hz), 8.84 (1H, s), 10.58 (1H, s) MS (ESI-): 448 (M-H) 20 Example 310 (2S)-N-Hydroxy-2-[5-(4-(ethoxycarbonylmethoxy) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (150 mg) 25 NMR (DMSO-d 6 , 6): 1.22 (3H, t, J=7.2Hz), 1.70-2.07 (4H, m), 2.35-2.45 (1H, m), 2.95-3.52 (5H, m), 4.17 (2H, q, J=7.2Hz), 4.82 (2H, s), 6.97 (2H, d, J=8.SHz), 7.16 (1H, d, J=4.OHz), 7.34 (lH, d, J=4.OHz), 7.56 (2H, d, J=8.5Hz), 8.83 (1H, s), 10.6 (1H, s) 30 Example 311 To a solution of 0.5M 4-chlorophenylisocyanate (192 mg) in dichloromethane (2.5 ml) was added N-[2-[2-(5-(3 aminophenyl)-2-thienyl)-1,1-dioxo-3,4,5,6-tetrahydro-2H 35 thiopyran-2-yl]acetyl]hydroxylamine trityl crowns (26 lmol, WO 00/40576 PCT/JPOO/00018 222 13.2 imol/crown x 2). 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 5% 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, 10-40% gradient) to 10 give (2S)-N-hydroxy-2-[5-(3-(4-chlorophenylaminocarbonyl amino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (1.6 mg) as a white powder. MS (ESI+): 551.3 (M+H+NH 3 ) 15 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) 20 phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (1.2 mg) MS (ESI-): 492.3 (M-H) Example 313 25 (2S)-N-Hydroxy-2-[5-(3-(n-hexylaminocarbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (3.0 mg) MS (ESI-): 506.4 (M-H) 30 Example 314 (2S)-N-Hydroxy-2-[5-(3-(3-chlorophenylaminocarbonyl amino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (1.3 mg) MS (ESI+): 550.7

(M+H+NH

3 ) 35 WO 00/40576 PCT/JPOO/00018 223 Example 315 (2S)-N-Hydroxy-2-[5-(3-(((R)-2-amino-2-phenylacetyl) amino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide hydrochloride (76 mg) was obtained in 5 a similar manner to that of Example 54. NMR (DMSO-d 6 , 8): 1.64-2.11 (4H, m), 2.32-2.98 (1H, m), 2.87-3.62 (5H, m), 5.30 (1H, br s), 7.22 (1H, s), 7.34-7.82 (10H, m), 7.97 (1H, s), 8.91 (2H, br s), 10.66 (1H, br s), 11.27 (1H, s) 10 MS (ESI+): 514 (M+H) Example 316 (2S)-N-Hydroxy-2-[5-(3-(3-(benzoylamino) propionylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H 15 thiopyran-2-acetamide 1,1-dioxide (96 mg) was obtained in a similar manner to that of Example 199. NMR (DMSO-d 6 , 8): 1.64-2.10 (4H, m), 2.33-2.48 (1H, m), 2.58-2.76 (2H, m), 2.88-3.56 (9H, m), 7.21 (1H, br s), 7.30-7.64 (8H, m), 7.84 (2H, br s), 8.03 (1H, 20 br s), 8.64 (1H, br s) MS (ESI-): 554 (M-H) Example 317 (2S)-N-Hydroxy-2-[5-(3-(3-(ethylaminocarbonylamino) 25 propionylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (98 mg) was obtained in a similar manner to that of Example 199. NMR (DMSO-d 6 , 8): 0.96 (3H, t, J=7Hz), 1.69-2.10 (4H, m), 2.33-2.48 (1H, m), 2.90-3.64 (11H, m), 7.19 30 (1H, d, J=3Hz), 7.28-7.51 (5H, m), 8.04 (1H, s) MS (ESI-): 521 (M-H) Example 318 (2S)-N-Hydroxy-2-[5-(3-(3-(methanesulfonylamino) 35 propionylamino)phenyl)-2-thienyl]-3,4,5,6-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 , 8): 1.22-2.12 (4H, m), 2.35-2.49 (1H, m), 2.58 (2H, t, J=7Hz), 2.99 (3H, s), 2.94-3.62 (7H, 5 m), 7.06-7.16 (lH, m), 7.22 (1H, d, J=3Hz), 7.33 7.39 (2H, m), 7.40 (1H, d, J=3Hz), 7.43-7.52 (1H, m), 8.01 (1H, s) MS (ESI-): 528 (M-H) 10 Example 319 (2S)-N-Hydroxy-2-[5-(3-((4-piperidinyloxy)acetylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide hydrochloride (55 mg) was obtained from ( 2 S)-N-(2-tetrahydropyranyloxy)-2-[5-(3-((1-tert 15 butoxycarbonyl-4-piperidinyloxy)acetylamino)phenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide in a similar manner to that of Example 54. NMR (DMSO-d 6 , 8): 1.68-2.11 (8H, m), 2.34-2.98 (lH, m), 2.89-3.56 (8H, m), 3.66-3.80 (1H, m), 4.14 (2H, s), 20 7.11-7.62 (5H, m), 8.00 (lH, s), 8.85 (1H, s), 9.83 (1H, s), 10.60 (1H, s) MS (ESI+): 522 (M+H) The following compounds were obtained in a similar 25 manner to that of Example 89. Example 320 (2S)-N-( 2 -Tetrahydropyranyloxy)-2-[5-(4 (methanesulfonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 30 2 H-thiopyran-2-acetamide 1,1-dioxide (70 mg) NMR (CDCl 3 , 8): 1.32 (2H, br), 1.40-1.49 (2H, m), 1.64-1.68 (2H, m), 1.94 (2H, br), 2.10-2.20 (2H, m), 2.76-2.80 (2H, m), 3.00 (2H, s), 3.06-3.10 (2H, m), 3.15 (2H, br), 3.33-3.51 (1H, m), 3.65-3.74 (1H, m), 35 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, m), 7.45 (2H, d, J=7.5Hz), 8.25 (1/2H, s), 8.33 (1/2H, s) MS (ESI-): 541.4 (M-H) 5 Example 321 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 (methoxycarbonylaminomethyl)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (80 mg) NMR (DMSO-d 6 , 8): 1.37 (6H, m), 1.69-1.81 (2H, m), 10 1.82-2.07 (2H, m), 2.35-2.45 (1H, m), 2.90-3.50 (6H, m), 3.57 (3H, s), 3.72-3.88 (1H, m), 4.20 (2H, d, J=7.OHz), 4.45, 4.75 (1H, s), 7.20-7.22 (1H, m), 7.28 (2H, d, J=8.5Hz), 7.41-7.43 (1H, m), 7.61 (2H, d, J=8.5Hz), 7.72 (1H, t, J=7.OHz) 15 MS (ESI-): 535 (M-H) Example 322 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 (cyclopropylcarbonyloxy)phenyl)-2-thienyl-3,4,5,6 20 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (150 mg) NMR (DMSO-d 6 , 8): 1.03-1.07 (4H, m), 1.39-1.64 (6H, m), 1.70-2.05 (5H, m), 2.35-2.45 (1H, m), 2.90-3.51 (6H, m), 3.75-3.90 (1H, m), 4.45, 4.75 (1H, s), 7.02-7.05 (1H, m), 7.19 (2H, d, J=8.5Hz), 7.44 25 7.47 (1H, m), 7.76 (2H, d, J=8.5Hz) Example 323 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 (ethoxycarbonylmethoxy)phenyl)-2-thienyll-3,4,5,6 30 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (220 mg) NMR (DMSO-d 6 , 6): 1.22 (3H, t, J=7.OHz), 1.35-1.62 (6H, m), 1.66-2.05 (4H, m), 2.35-2.45 (1H, m), 2.90 3.50 (6H, m), 3.73-3.90 (1H, m), 4.18 (2H, q, J=7.OHz), 4.45, 4.75 (1H, s), 4.82 (2H, s), 6.98 35 (2H, d, J=8.5Hz), 7.16-7.21 (1H, m), 7.32-7.36 (1H, WO 00/40576 PCT/JPOO/00018 226 m), 7.57 (2H, d, J=8.5Hz) Example 324 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 5 (ethylcarbonylmethoxy)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (200 mg) NMR (DMSO-d 6 , 6): 0.98 (3H, t, J=7.2Hz), 1.35-1.65 (6H, m), 1.67-2.05 (4H, m), 2.32-2.45 (1H, m), 2.54 (2H, q, J=7.2Hz), 2.90-3.50 (6H, m), 3.74-3.89 (1H, m), 10 4.45, 4.75 (1H, s), 4.86 (2H, s), 6.95 (2H, d, J=8.5Hz), 7.16-7.20 (1H, m), 7.31-7.35 (1H, m), 7.55 (2H, d, J=8.5Hz) Example 325 15 ( 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 (cyclopropylaminocarbonylmethoxy)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (140 mg) NMR (DMSO-d 6 , 8): 0.45-0.50 (2H, m), 0.60-0.65 (2H, m), 1.35-1.65 (6H, m), 1.70-2.07 (4H, m), 2.35-2.45 20 (1H, m), 2.65-2.74 (1H, m), 2.90-3.50 (6H, m), 3.75-3.90 (1H, m), 4.47 (2H, s), 4.45, 4.75 (1H, s), 6.98 (2H, d, J=8.5Hz), 7.15-7.20 (1H, m), 7.30-7.35 (1H, m), 7.58 (2H, d, J=8.5Hz), 8.15 (1H, br), 11.20 (1H, s) 25 Example 326 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-hydroxyphenyl) 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (205 mg) 30 NMR (DMSO-d 6 , 6): 1.35-1.64 (6H, m), 1.66-2.05 (4H, m), 2.35-2.45 (1H, m), 2.90-3.50 (6H, m), 3.75-3.90 (1H, m), 4.45, 4.75 (1H, s), 6.70-6.73 (1H, m), 7.00-7.07 (2H, m), 7.16-7.21 (2H, m), 7.35-7.40 (1H, m), 9.61 (1H, s) 35 WO 00/40576 PCT/JPOO/00018 227 Example 327 (2S)-N-( 2 -Tetrahydropyranyloxy)-2-[5-(5-acetyl-2 thienyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (100 mg) 5 NMR (CDCl 3 , 8): 1.43-1.78 (6H, m), 1.85-1.98 (2H, m), 2.05-2.25 (2H, m), 2.58 (3H, s), 2.63-2.86 (2H, m), 2.95-3.17 (4H, m), 2.95-3.61 (1H, m), 3.65-3.82 (1H, m), 4.51, 4.83 (1H, s), 7.18 (1H, d, J=4.OHz), 7.57 (1H, d, J=4.OHz), 7.64 (1H, d, J=4.OHz), 7.70 10 (1H, d, J=4.OHz) Example 328 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 aminocarbonylphenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H 15 thiopyran-2-acetamide 1,1-dioxide (49 mg) was obtained from (2S)-N-( 2 -tetrahydropyranyloxy)-2-[5-(4-carboxyphenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (133 mg) in a similar manner to that of Example 32. NMR (CDCl 3 , 8): 1.45 (2H, br), 1.63-1.68 (2H, m), 1.94 20 (2H, br), 2.08-2.17 (2H, m), 2.30-2.36 (2H, m), 3.00-3.22 (4H, m), 3.26-3.47 (1H, m), 3.68-3.76 (1H, m), 4.55 (1/2H, br), 4.85 (1/2H, br), 7.43 7.57 (5H, m), 7.63-7.70 (3H, m), 7.75-7.80 (1H, m) MS (ESI+): 493.6 (M+H) 25 Example 329 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 (benzylaminocarbonyl)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 2 H-thiopyran-2-acetamide 1,1-dioxide (85 mg) was obtained in 30 a similar manner to that of Example 328. NMR (CDCl3, 8): 1.51-1.60 (2H, m), 1.70-1.79 (4H, m), 1.89-1.96 (2H, m), 2.08-2.18 (2H, m), 2.76-2.83 (2H, br), 2.97-3.14 (4H, m), 3.40-3.64 (1H, m), 3.72-3.92 (1H, m), 4.60-4.65 (2H, m), 4.68 (1/2H, 35 br), 4.84 (1/2H, br), 7.20-7.37 (7H, m), 7.56-7.83 WO 00/40576 PCT/JPOO/00018 228 (4H, m) MS (ESI-): 581.2 (M-H) The following compounds were obtained in a similar 5 manner to that of Example 130. Example 330 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (ethoxycarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 10 2H-thiopyran-2-acetamide 1,1-dioxide (190 mg) NMR (CDCl 3 , 8): 1.34 (1H, t, J=7.0Hz), 1.46 (2H, br), 1.6471.69 (4H, m), 1.94 (2H, br), 2.07-2.20 (2H, m), 2.67-2.88 (2H, m), 3.06 (2H, s), 3.11-3.16 (2H, m), 3.30-3.48 (1H, m), 3.60-3.70 (1H, m), 4.23 (2H, 15 q, J=7.OHz), 4.53 (1/2H, br), 4.81 (1/2H, br), 6.69 (1H, s), 7.27-7.32 (5H, m), 7.64 (1H, s), 8.05 (1/2H, s), 8.20 (1/2H, s) MS (ESI-): 535.2 (M-H) 20 Example 331 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(n propoxycarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (170 mg) NMR (CDCl 3 , 8): 0.99 (3H, t, J=6.OHz), 1.45 (2H, br), 25 1.63-1.75 (6H, m), 1.95 (2H, br), 2.06-2.21 (2H, m), 2.63-2.91 (2H, m), 3.05 (2H, s), 3.12 (2H, br), 3.28-3.50 (1H, m), 3.58-3.69 (1H, m), 4.07-4.15 (2H, m), 4.52 (1/2H, br), 4.80 (1/2H, br), 6.65 (1H, s), 7.20-7.30 (5H, m), 7.66 (1H, s), 7.96 30 (1/2H, s), 8.12 (1/2H, s) MS (ESI-): 549.4 (M-H) Example 332 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 35 (isopropoxycarbonylamino)phenyl)-2-thienyl]-3,4,5, 6

-

WO 00/40576 PCT/JPOO/00018 229 tetrahydro-2H-thiopyran-2-acetamide 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, m), 1.94 (2H, br), 2.05-2.21 (4H, m), 2.64-2.86 (2H, m), 3.05 (2H, s), 3.10-3.15 (2H, 5 m), 3.30-3.38 (1H, m), 3.60-3.70 (1H, m), 4.52 (1/2H, br), 4.80 (1/2H, br), 5.02 (1H, qq, J=7.5, 7.5Hz), 6.59 (1H, s), 7.24-7.28 (5H, m), 7.67 (1H, s), 7.94 (1/2H, s), 8.10 (1/2H, s) MS (ESI-): 549.4 (M-H) 10 Example 333 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2 chloroethoxycarbonylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (155 mg) 15 NMR (CDCl 3 , 6): 1.45 (2H, br), 1.62-1.68 (4H, m), 1.95 (2H, br), 2.07-2.22 (2H, m), 2.63-2.89 (2H, m), 3.05 (2H, s), 3.10-3.16 (2H, m), 3.28-3.48 (1H, m), 3.61-3.66 (1H, m), 3.75 (2H, t, J=5.OHz), 4.43 (2H, t, J=5.OHz), 4.52 (1/2H, br), 4.80 (1/2H, br), 20 6.80 (1H, s), 7.23-7.31 (5H, m), 7.65 (1H, s), 8.02 (1/2H, s), 8.17 (1/2H, s) MS (ESI-): 569.3 (M-H) Example 334 25 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (valerylaminophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (148 mg) NMR (CDCl 3 , 8): 0.96 (3H, t, J=7Hz), 1.32-1.78 (12H, m), 1.85-1.99 (2H, m), 2.03-2.25 (2H, m), 2.40 (2H, t, 30 J=7Hz), 2.69-2.93 (2H, m), 2.98-3.18 (2H, m), 3.28-3.51 (1H, m), 3.62-3.77 (1H, m), 4.55, 4.83 (1H, s), 7.10-7.32 (4H, m), 7.47-7.69 (3H, m), 8.66 (1H, s) MS (ESI-): 547 (M-H) 35 WO 00/40576 PCT/JPOO/00018 230 Example 335 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (ethylthiocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (130 mg) 5 NMR (CDC1 3 , 8): 1.26 (3H, t, J=8Hz), 1.39-1.77 (8H, m), 1.34-2.00 (2H, m), 2.06-2.75 (2H, m), 2.71-2.96 (2H, m), 2.99 (2H, q, J=8Hz), 3.04-3.17 (2H, m), 3.29-3.52 (2H, m), 3.64-3.76 (1H, m), 4.55, 4.84 (1H, s), 7.15-7.32 (4H, m), 7.38-7.54 (3H, m), 10 8.49, 8.58 (1H, s) MS (ESI-): 551 (M-H) Example 336 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 15 (methylthiocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (192 mg) NMR (CDCl 3 , 8): 1.36-1.78 (8H, m), 1.86-2.00 (2H, m), 2.07-2.75 (2H, m), 2.43, 2.45 (3H, s), 2.72-2.97 (2H, m), 3.03-3.22 (2H, m), 3.30-3.54 (1H, m), 20 3.64-3.76 (iH, m), 4.56, 4.74 (1H, br s), 7.12 7.32 (4H, m), 7.40-7.53 (2H, m), 7.62-7.71 (1H, m), 8.65, 8.72 (1H, s) MS (ESI-): 537 (M-H) 25 Example 337 (2S) -N- (2-Tetrahydropyranyloxy) -2- [5- (3 (benzyloxycarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (87 mg) NMR (CDCl3, 8): 1.35-1.72 (8H, m), 1.86-1.98 (2H, m), 30 2.02-2.22 (2H, m), 2.65-2.92 (2H, m), 2.98-3.16 (2H, m), 3.28-3.50 (1H, m), 3.62-3.73 (1H, m), 4.52, 4.71 (1H, s), 5.21 (2H, s), 6.88 (1H, br s), 7.19-7.46 (10H, m), 7.62 (1H, br s), 8.26, 8.38 (1H, s) 35 MS (ESI-): 597 (M-H) WO 00/40576 PCT/JPOO/00018 231 Example 338 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(4 chlorophenyl)acetylamino)phenyl)-2-thienyll-3,4,5,6 5 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (158 mg) NMR (CDC1 3 , 8): 1.35-1.79 (8H, m), 1.87-1.99 (2H, m), 2.04-2.24 (2H, m), 2.17-2.93 (1H, m), 3.02-3.17 (2H, m), 3.27-3.52 (1H, m), 3.63-3.74 (1H, m), 4.53, 4.82 (1H, s), 4.59 (2H, s), 6.83 (1H, d, 10 J=8Hz), 6.96 (2H, d, J=8Hz), 7.22-7.39 (5H, m), 7.56-7.62 (1H, m), 7.22-7.28 (1H, m), 8.30 (1H, s), 8.34, 8.45 (1H, s) MS (ESI+): 633, 634 (M+H) 15 Example 339 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (phenoxycarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (124 mg) NMR (CDC1 3 , 8): 1.34 (8H, m), 1.85-1.99 (2H, m), 20 2.03-2.24 (2H, m), 2.68-2.94 (2H, m), 3.00-3.20 (2H, m), 3.29-3.53 (1H, m), 3.62-3.77 (1H, m), 4.53, 4.82 (1H, s), 7.11-7.47 (11H, m), 7.63, 7.67 (1H, s), 8.49, 8.57 (1H, s) MS (ESI-): 583 (M-H) 25 Example 340 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(4 morpholinocarbonylamino)acetylamino)phenyl)-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (85 30 mg) NMR (DMSO-d 6 , 8): 1.32-2.09 (10H, m), 2.34-2.51 (1H, m), 2.87-3.62 (14H, m), 3.73-3.92 (1H, m), 3.80 (2H, d, J=7Hz), 4.43, 4.76 (1H, s), 6.96 (1H, t, J=7Hz), 7.17-7.26 (1H, m), 7.32-7.53 (4H, m), 8.02 (1H, s) 35 MS (ESI-): 633 (M-H) WO 00/40576 PCT/JPOO/00018 232 Example 341 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(N-ethyl-N methylaminocarbonyloxy)acetylamino)phenyl)-2-thienyl] 5 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (220 mg) was obtained in a similar manner to that of Example 211. NMR (CDCl 3 , 8): 1.18, 1.23 (3H, t, J=8Hz), 1.37-1.74 (8H, m), 1.89-2.01 (2H, m), 2.06-2.23 (2H, m), 2.72-2.88 (2H, m), 2.99, 3.03 (3H, s), 3.05-3.18 10 (2H, m), 3.15-3.28 (1H, m), 4.53, 4.83 (1H, s), 4.72, 4.74 (2H, s), 7.15-7.32 (4H, m), 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) 15 The following compounds were obtained in a similar manner to that of Example 129. Example 342 20 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (benzylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (80 mg) NMR (CDCl 3 , 8): 1.42 (2H, br), 1.60-1.66 (4H, m), 1.83-1.90 (2H, m), 2.00-2.18 (2H, m), 2.74 (2H, 25 br), 2.92-3.00 (2H, m), 3.04-3.10 (2H, m), 3.30 3.50 (1H, m), 3.68-3.78 (1H, m), 4.33-4.42 (2H, m), 4.57 (1/2H, br), 4.72 (1/2H, br), 6.93-7.12 (6H, m), 7.27-7.25 (2H, m), 7.28-7.32 (4H, m) MS (ESI-): 596.4 (M-H) 30 Example 343 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(4 methoxyphenylaminocarbonylamino)phenyl)-2-thieny1]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (224 mg) 35 NMR (CDCl 3 , 5): 1.43 (2H, br), 1.62-1.73 (4H, m), 1.90 WO 00/40576 PCT/JPOO/00018 233 (2H, br), 2.03-2.20 (2H, m), 2.77 (2H, br), 2.96 3.03 (2H, m), 3.08-3.14 (2H, m), 3.33-3.54 (1H, m), 3.68-3.75 (1H, m), 3.77 (3H, s), 4.61 (1/2H, br), 4.86 (1/2H, br), 6.80-6.93 (4H, m), 7.10-7.29 (6H, 5 m), 7.38-7.53 (2H, m), 9.04 (1/2H, s), 9.42 (1/2H, s) MS (ESI-): 611.5 (M-H) Example 344 10 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(ethoxy carbonylmethylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (490 mg) NMR (CDC1 3 , 6): 1.22-1.33 (5H, m), 1.42-1.47 (2H, m), 1.62-1.70 (2H, m), 1.94 (2H, br), 2.07-2.20 (2H, 15 m), 2.74-2.86 (2H, m), 3.08-3.20 (2H, m), 3.49 3.52 (2H, m), 3.68-3.78 (2H, m), 3.97-4.27 (4H, m), 4.58 (1/2H, br), 4.85 (1/2H, br), 5.68-5.80 (1H, m), 6.96-7.24 (5H, m), 7.28-7.34 (1H, m), 7.40 7.46 (1H, m), 9.12 (1/2H, s), 9.31 (1/2H, s) 20 MS (ESI-): 592.3 (M-H) Example 345 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (butylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 25 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (330 mg) NMR (CDCl 3 , 6): 0.90 (3H, dd, J=7.2, 7.2Hz), 1.26-1.74 (10H, m), 1.85-1.99 (2H, m), 2.02-2.21 (2H, m), 2.74-2.89 (2H, m), 2.97-3.26 (6H, m), 3.31-3.54 (1H, m), 3.71-3.80 (lH, m), 4.60, 4.83 (1H, s), 30 5.42-5.53 (1H, m), 6.95 (1H, d, J=4Hz), 7.01-7.30 (5H, m), 7.38-7.43 (1H, m), 9.3, 9.51 (1H, s) Example 346 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(1 35 naphtylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6- WO 00/40576 PCT/JP0O/00018 234 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (350 mg) NMR (CDCl 3 , 8): 1.30-1.65 (6H, m), 1.75-1.92 (2H, m), 1.93-2.19 (2H, m), 2.70-2.88 (2H, m), 2.92-3.20 (4H, m), 3.30-3.46 (1H, m), 3.70 (1H, br), 4.56, 5 4.83 (1H, s), 6.93-7.80 (12H, m), 7.95 (1H, dd, J=8.0, 8.0Hz) Example 347 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 10 (allylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (300 mg) NMR (CDCl 3 , 8): 1.35-1.70 (6H, m), 1.85-2.25 (4H, m), 2.75-2.88 (2H, m), 2.95-3.17 (4H, m), 3.30-3.52 (1H, m), 3.70-3.90 (3H, m), 4.59, 4.83 (1H, s), 15 5.10-5.23 (2H, m), 5.40-5.49 (1H, m), 5.80-5.94 (1H, m), 6.95-7.28 (6H, m) MS (ESI-): 546 (M-H) Example 348 20 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 25 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 30 residue was purified by flash column chromatography on silica gel 60 (eluent: 3% methanol-chloroform) to give (2S) N-(2-tetrahydropyranyloxy)-2-[5-(3-(3 pyridylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (150 mg) as 35 a white amorphous.

WO 00/40576 PCT/JPOO/00018 235 NMR (CDC1 3 , 8): 1.38 (2H, br), 1.45-1.62 (4H, m), 1.94 (4H, br), 2.05-2.25 (2H, m), 2.92 (2H, br), 3.02 3.11 (4H, m), 3.32-3.50 (1H, m), 3.78 (1H, br), 4.20-4.23 (1H, m), 4.62 (1/2H, br), 4.94 (1/2H, 5 br), 6.89-7.27 (4H, m), 7.30-7.46 (1H, m), 7.51 7.72 (2H, m), 8.03-8.21 (1H, m), 8.40 (1/2H, s), 8.45 (1/2H, s) MS (ESI+): 585.4 (M+H) 10 The following compounds were obtained in a similar manner to that of Example 130. Example 349 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 15 (allyloxycarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (160 mg) NMR (CDC1 3 , 8): 1.45 (2H, br), 1.58-1.68 (4H, m), 1.94 (2H, br), 2.07-2.22 (2H, m), 2.66-2.90 (2H, m), 3.04-3.52 (2H, m), 3.09-3.15 (2H, m), 3.30-3.49 20 (1H, m), 3.63-3.72 (1H, m), 4.52 (1/2H, br), 4.67 (2H, d, J=7.0Hz), 4.80 (1/2H, br), 5.27 (1H, d, J=8.OHz), 5.38 (1H, d, J=8.OHz), 5.89-6.04 (1H, m), 6.83 (1H, s), 7.24-7.34 (5H, m), 7.63 (1H, s), 8.20 (1/2H, s), 8.35 (1/2H, s) 25 MS (ESI-): 547.3 (M-H) Example 350 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2 benzyloxyacetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 30 2H-thiopyran-2-acetamide 1,1-dioxide (410 mg) NMR (CDCl 3 , 6): 1.45 (2H, br), 1.61-1.68 (4H, m), 1.95 (2H, br), 2.06-2.22 (2H, m), 2.64-2.87 (2H, m), 3.03 (2H, br s), 3.08-3.13 (2H, m), 3.28-3.47 (1H, m), 3.61-3.67 (1H, m), 4.08 (2H, d, J=7.5Hz), 4.52 35 (1/2H, br), 4.63 (1H, s), 4.68 (1H, s), 4.67 (2H, WO 00/40576 PCT/JPOO/00018 236 d, J=15Hz), 4.82 (1/2H, br), 7.30-7.40 (9H, m), 7.53 (1H, d, J=5.OHz), 7.77 (1H, s), 8.01 (1H, s), 8.16 (lH, s), 8.34 (1H, s) MS (ESI-): 611.5 (M-H) 5 The following compounds were obtained in a similar manner to that of Example 211. Example 351 10 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(((2S)-2-(tert butoxycarbonylamino)propionyl)amino)phenyl}-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (310 mg) NMR (CDCl 3 , 6): 1.43-1.48 (14H, m), 1.65-1.68 (4H, m), 15 1.94 (42H, br), 2.04-2.20 (2H, m), 2.67-2.87 (2H, m), 3.04-3.07 (2H, m), 3.10-3.15 (2H, m), 3.28 3.62 (1H, m), 3.63-3.75 (1H, m), 4.32 (1H, br), 4.52 (1/2H, br), 4.82 (1/2H, br), 7.20-7.30 (4H, m), 7.40-7.50 (1H, m), 7.67 (1/2H, s), 7.77 (1/2H, 20 s), 8.36 (1/2H, s), 8.54 (1/2H, s) MS (ESI-): 634.3 (M-H) Example 352 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(((2R)-2-(tert 25 butoxycarbonylamino)propionyl)amino)phenyl}-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (475 mg) NMR (CDC1 3 , 6): 1.43-1.48 (14H, m), 1.65-1.68 (4H, m), 1.94 (42H, br), 2.04-2.20 (2H, m), 2.67-2.87 (2H, 30 m), 3.04-3.07 (2H, m), 3.10-3.15 (2H, m), 3.28 3.62 (1H, m), 3.63-3.75 (1H, m), 4.32 (1H, br), 4.52 (1/2H, br), 4.82 (1/2H, br), 7.20-7.30 (4H, m), 7.40-7.50 (1H, m), 7.67 (1/2H, s), 7.77 (1/2H, s), 8.36 (1/2H, s), 8.54 (1/2H, s) 35 MS (ESI-): 634.3 (M-H) WO 00/40576 PCT/JPOO/00018 237 Example 353 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(4 methylphenoxy)acetylamino)phenyl}-2-thienyl]- 3 ,4,5,6 5 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (230 mg) NMR (CDCl 3 , 8): 1.44 (2H, br), 1.56-1.68 (4H, m), 1.95 (2H, br), 2.07-2.21 (2H, m), 2.33 (3H, s), 2.63 2.90 (2H, m), 3.05 (2H, s), 3.11-3.13 (2H, br), 3.30-3.48 (1H, m), 3.60-3.70 (1H, m), 4.52 (1/2H, 10 br), 4.60 (2H, s), 4.80 (1/2H, br), 6.90 (2H, d, J=8.0Hz), 7.15 (2H, d, J=8.OHz), 7.22-7.29 (2H, m), 7.33-7.36 (2H, m), 7.55-7.59 (1H, m), 7.80 (1H, s), 8.00 (1/2H, s), 8.14 (1/2H, s), 8.32 (1H, s) MS (ESI-): 611.3 (M-H) 15 Example 354 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(N,N dimethylamino)acetylamino)phenyl}-2-thienyl)-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (90 mg) 20 NMR (CDCl 3 , 6): 1.46 (2H, br), 1.62-1.68 (4H, m), 1.95 (4H, br), 2.04-2.23 (2H, m), 2.41 (6H, s), 2.65 2.88 (1H, m), 3.05 (2H, s), 3.10 (2H, m), 3.12 3.15 (2H, m), 3.26-3.49 (1H, m), 3.62-3.72 (1H, m), 4.52 (1/2H, br), 4.80 (1/2H, br), 7.23-7.29 (2H, 25 m), 7.34 (2H, d, J=5.OHz), 7.60-7.66 (1H, m), 7.76 (1H, br), 8.00 (1/2H, br), 8.18 (1/2H, br), 9.19 (1H, s) MS (ESI+): 550.3 (M+H) 30 Example 355 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(4 chlorophenyl)acetylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (158 mg) NMR (CDC1 3 , 8): 1.34-1.98 (10H, m), 2.03-2.25 (2H, m), 35 2.69-2.88 (2H, m), 3.02-3.18 (2H, m), 3.27-3.51 WO 00/40576 PCT/JPOO/00018 238 (1H, m), 3.62-3.26 (1H, m), 3.68 (2H, s), 4.53, 4.83 (1H, br s), 7.00-7.66 (10H, m), 7.73, 7.76 (1H, s), 8.65-8.75 (1H, m) MS (ESI-): 616 (M-H) 5 Example 356 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(((R)-2-tert butoxycarbonylamino-2-phenylacetyl)amino)phenyl)-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (117 10 mg) NMR (DMSO-d 6 , 8): 1.20-1.62 (6H, m), 1.40 (9H, s), 1.68 2.06 (4H, m), 2.34-2.48 (1H, m), 2.86-3.32 (5H, m), 3.73-3.86 (1H, m), 4.40, 4.75 (1H, br s), 5.86 (1H, d, J=8Hz), 7.16-7.23 (1H, m), 7.28-7.61 (10H, m), 15 7.96 (1H, s), 10.37 (1H, s), 11.23 (1H, s) MS (ESI-): 696 (M-H) Example 357 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2 20 isopropoxyacetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (276 mg) NMR (CDC1 3 , 8): 1.29 (6H, d, J=7Hz), 1.36-1.77 (8H, m), 1.88-2.00 (2H, m), 2.65-2.92 (2H, m), 3.02-3.18 (2H, m), 3.28-3.51 (1H, m), 3.62-3.73 (1H, m), 25 3.77 (1H, q, J=7Hz), 4.07 (1H, s), 4.52, 4.82 (1H, br s), 7.23-7.48 (4H, m), 7.52-7.60 (1H, m), 7.78 (1H, s), 8.18, 8.32 (1H, br s), 8.40 (1H, s) MS (ESI+): 565 (M+H) 30 Example 358 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-((1-tert butoxycarbonyl-4-piperidinyloxy)acetylamino)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (360 mg) 35 NMR (CDC1 3 , 5): 1.40-1.77 (10H, m), 1.47 (9H, s), 1.89- WO 00/40576 PCT/JPOO/00018 239 2.01 (4H, m), 2.06-2.24 (2H, m), 2.68-2.92 (2H, m), 3.02-3.18 (4H, m), 3.28-3.52 (iH, m), 3.58-3.74 (2H, m), 3.79-3.92 (2H, m), 4.12 (2H, m), 4.53, 4.82 (1H, s), 7.22-7.38 (4H, m), 7.52-7.58 (1H, m), 5 7.76 (1H, s), 8.27, 8.84 (1H, s), 8.34, 8.38 (1H, S) MS (ESI+): 706 (M+H) Example 359 10 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(2-oxo-1,3 oxazolidin-3-yl)acetylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (600 mg) NMR (DMSO-d 6 , 8): 1.36-1.64 (6H, m), 1.69-2.06 (4H, m), 2.34-2.48 (1H, m), 2.88-3.32 (5H, m), 3.42-3.53 15 (1H, m), 3.66 (2H, t, J=8Hz), 3.73-3.90 (1H, m), 4.34 (2H, t, J=8Hz), 4.44, 4.75 (1H, s), 7.17-7.25 (1H, m), 7.33-7.48 (4H, m), 8.03 (1H, s) MS (ESI-): 590 (M-H) 20 Example 360 To a suspension of (2S)-N-(2-tetrahydropyranyloxy)-2 [5-(3-aminophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (300 mg) and triethylamine (392 mg) in chloroform (4 ml) was added triphosgene (192 mg) 25 at 0 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 0 C and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was poured into water and was 30 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 35 silica gel 60 (eluent: 2% methanol-chloroform) to give (2S)- WO 00/40576 PCT/JPOO/00018 240 N-(2-tetrahydropyranyloxy)-2-[5-(3-(2-((tert butyl) (diphenyl)sillyloxy)ethylaminocarbonylamino)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (350 mg) as a white amorphous. 5 NMR (CDCl 3 , 8): 1.04 (9H, s), 1.44 (2H, br), 1.62-1.68 (4H, m), 1.85-1.94 (2H, br), 2.05-2.19 (2H, m), 2.69-2.90 (2H, m), 2.98-3.10 (4H, m), 3.31-3.44 (3H, m), 3.62-3.80 (3H, m), 4.56 (1/2H, br), 4.80 (1/2H, br), 6.64 (1H, s), 7.09-7.30 (5H, m), 7.32 10 7.42 (7H, m), 7.56-7.64 (4H, m), 8.62 (1H, s) MS (ESI-): 788.5 (M-H) The following compounds were obtained in a similar manner to that of Example 130. 15 Example 361 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (cyclopentylcarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (205 mg) 20 NMR (CDCl 3 , 8): 1.46 (2H, br), 1.60-1.70 (6H, m), 1.77 1.84 (2H, m), 1.91-1.97 (6H, m), 2.07-2.21 (2H, m), 2.66-2.89 (2H, m), 2.71 (1H, tt, J=7.5, 7.5Hz), 3.05 (1H, s), 3.10-3.15 (2H, m), 3.30-3.49 (1H, m), 3.63-3.70 (1H, m), 4.54 (1/2H, br), 4.82 (1/2H, 25 br), 7.20-7.30 (4H, m), 7.41 (2H, br), 7.52 (1H, br), 7.71 (1H, br), 8.25 (1/2H, s), 8.37 (1/2H, s) MS (ESI-): 559.4 (M-H) Example 362 30 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(3 chloropropionylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (145 mg) NMR (CDCl 3 , 6): 1.45 (2H, br), 1.54-1.72 (4H, m), 1.95 (4H, br), 2.09-2.24 (2H, m), 2.72-2.82 (2H, m), 35 2.85 (2H, t, J=6.4Hz), 3.00-3.08 (2H, m), 3.11- WO 00/40576 PCT/JP0O/00018 241 3.16 (2H, m), 3.29-3.52 (1H, m), 3.63-3.73 (1H, m), 3.91 (2H, t, J=6.5Hz), 4.54 (1/2H, br), 4.83 (1/2H, br), 7.15-7.30 (4H, m), 7.54-7.72 (3H, m), 8.50 (1H, s) 5 MS (ESI-): 553.3 (M-H) The following compounds were obtained in a similar manner to that of Example 360. 10 Example 363 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (isobutylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (230 mg) NMR (CDCl 3 , 8): 0.90 (6H, d, J=6.6Hz), 1.40-1.70 (7H, 15 m), 1.88-1.97 (2H, m), 2.05-2.22 (2H, m), 2.99 3.18 (6H, m), 3.31-3.51 (1H, m), 6.96-7.29 (6H, m), 7.47-7.53 (1H, m), 9.25, 9.47 (1H, s) MS (ESI-): 562 (M-H) 20 Example 364 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(cyclohexyl methylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (200 mg) NMR (CDCl 3 , 8): 0.83-1.00 (2H, m), 1.10-1.25 (4H, m), 25 1.35-1.54 (5H, m), 1.55-1.79 (6H, m), 1.85-1.98 (2H, m), 2.01-2.22 (2H, m), 2.75-2.89 (2H, m), 3.00-3.22 (6H, m), 3.30-3.52 (1H, m), 3.66-3.82 (1H, m), 1.59, 4.84 (1H, s), 5.45-5.55 (1H, m), 6.95-7.30 (6H, m), 7.40 (1H, br) 30 Example 365 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2 methoxyethylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (220 mg) 35 NMR (CDCl 3 , 8): 1.38-1.68 (6H, m), 1.85-1.98 (2H, m), WO 00/40576 PCT/JPOO/00018 242 2.03-2.18 (2H, m), 2.75-2.90 (2H, m), 3.01-3.17 (4H, m), 3.30-3.35 (1H, m), 3.38 (3H, s), 3.42 3.55 (4H, m), 3.66-3.77 (1H, m), 4.55, 4.84 (1H, s), 5.51-5.60 (1H, m), 7.05-7.40 (6H, m), 9.10, 5 9.20 (1H, s) MS (ESI-):564 (M-H Example 366 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-((N-methyl-N 10 ethylaminocarbonyl)amino)phenyl)-2-thienyll-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (200 mg) NMR (CDC1 3 , 8): 1.33 (3H, t, J=7.OHz), 1.40-1.75 (6H, m), 1.85-1.98 (2H, m), 2.05-2.20 (2H, m), 2.60 2.90 (4H, m), 3.00-3.20 (5H, m), 3.29-3.50 (1H, m), 15 3.62-3.73 (1H, m), 4.23 (2H, q, J=7.0Hz), 4.53, 4.80 (1H, s), 7.15-7.35 (6H, m) MS (ESI-): 548 (M-H) Example 367 20 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-((2 phthalimidoethoxy)carbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (155 mg) from (2S)-N-(2-tetrahydropyranyloxy)-2-[5-(3-aminophenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 25 dioxide (300 mg) and 2-phthaloylethanol NMR (CDCl 3 , 8): 1.42-1.70 (6H, m), 1.81-1.96 (2H, m), 2.02-2.23 (2H, m), 2.87-3.27 (4H, m), 3.49 (2H, br), 3.52-3.75 (2H, m), 4.04 (2H, br), 4.16-4.48 (1H, m), 5.05-5.23 (1H, m), 6.76-7.36 (8H, m), 30 7.66-7.74 (2H, m), 7.79-7.87 (2H, m) MS (ESI-): 680.5 (M-H) The following compounds were obtained in a similar manner to that of Example 32. 35 WO 00/40576 PCT/JPOO/00018 243 Example 368 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-(2 phenylaminocarbonylethenyl)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (100 mg) 5 NMR (DMSO-d 6 , 8): 1.38-1.62 (6H, m), 1.72-2.06 (4H, m), 2.38-2.47 (1H, m), 2.90-3.52 (6H, m), 3.75-3.90 (1H, m), 4.45, 4.75 (1H, s), 6.86 (1H, d, J=16Hz), 7.06 (1H, dd, J=8.0, 8.0Hz), 7.24-7.27 (1H, m), 7.34 (2H, d, J=8.0, 8.0Hz), 7.55-7.58 (2H, m), 10 7.65-7.76 (6H, m) Example 369 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-(2-(4-methoxy phenylaminocarbonyl)ethenyl)phenyl)-2-thienyl]-3,4,5,6 15 tetrahydro-2H-thiopyran-2-acetamiide 1,1-dioxide (150 mg) NMR (DMSO-d 6 , 8): 1.37-1.64 (6H, m), 1.71-2.08 (4H, m), 2.36-2.47 (1H, m), 2.90-3.51 (6H, m), 3.74 (3H, s), 3.75-3.90 (1H, m), 4.45, 4.75 (1H, s), 6.82 (1H, d, J=16Hz), 6.92 (2H, d, J=8.5Hz), 7.24-7.27 (1H, m), 20 7.54-7.75 (8H, m) Example 370 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-(2-(4-fluoro phenylaminocarbonyl)ethenyl)phenyl)-2-thienyl]-3,4,5,6 25 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (150 mg) NMR (DMSO-d 6 , 6): 1.37-1.62 (6H, m), 1.70-2.08 (4H, m), 2.36-2.46 (1H, m), 2.91-3.54 (6H, m), 3.75-3.90 (1H, m), 4.45, 4.75 (1H, s), 6.83 (1H, d, J=16Hz), 7.18 (2H, dd, J=8.5, 8.5Hz), 7.24-7.27 (1H, m), 30 7.55-7.75 (8H, m), 10.3 (1H, s) Example 371 (2S)-N-( 2 -Tetrahydropyranyloxy)-2-[5-(4-(2-(N,N dimethylaminocarbonyl)ethenyl)phenyl)-2-thienyl]-3,4,5,6 35 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (250 mg) WO 00/40576 PCT/JPOO/00018 244 NMR (CDC1 3 , 8): 1.35-1.75 (6H, m), 1.88-2.01 (2H, m), 2.05-2.25 (2H, m), 2.65-3.18 (9H, m), 3.20 (3H, s), 3.26-3.49 (1H, m), 3.64-3.70 (1H, m), 4.54, 4.83 (1H, s), 6.91 (1H, d, J=16Hz), 7.29 (1H, d, 5 J=4.OHz), 7.47-7.69 (6H, m) Example 372 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-(2 (isopropylaminocarbonyl)ethenyl)phenyl)-2-thienyl]-3,4,5,6 10 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (220 mg) NMR (DMSO-d 6 , 6): 1.11 (6H, d, J=5Hz), 1.37-1.64 (6H, m), 1.70-2.07 (4H, m), 2.35-2.46 (1H, m), 2.90 3.37 (5H, m), 3.40-3.54 (1H, m), 3.74-3.90 (1H, m), 3.90-4.01 (1H, m), 4.45, 4.75 (1H, s), 6.62 (1H, d, 15 J=16Hz), 7.21-7.25 (1H, m), 7.40 (1H, d, J=16Hz), 7.51-7.55 (1H, m), 7.57 (2H, d, J=8.5Hz), 7.69 (2H, d, J=8.5Hz), 7.99 (1H, d, J=7.5Hz) Example 373 20 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-(2 (propylaminocarbonyl)ethenyl)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (210 mg) NMR (DMSO-d 6 , 6): 0.88 (3H, t, J=7.5Hz), 1.36-1.62 (8H, m), 1.70-2.06 (4H, m), 2.35-2.45 (1H, m), 2.40 25 3.30 (7H, m), 3.41-3.52 (1H, m), 3.74-3.90 (1H, m), 4.45, 4.75 (1H, s), 6.65 (1H, d, J=l6Hz), 7.22 7.25 (1H, m), 7.40 (1H, d, J=16Hz), 7.51-7.55 (1H, m), 7.60 (2H, d, J=8.5Hz), 7.70 (2H, d, J=8.5Hz), 8.10 (1H, t, J=7.OHz), 11.2 (1H, s) 30 Example 374 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-(n propylaminocarbonylmethoxy)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (140 mg) 35 NMR (DMSO-d 3 , 8): 0.82 (3H, t, J=7.SHz), 1.36-1.63 (8H, WO 00/40576 PCT/JPOO/00018 245 m), 1.70-2.05 (4H, m), 2.33-2.44 (1H, m), 2.93 3.50 (8H, m), 3.74-3.91 (lH, m), 4.45, 4.75 (1H, s), 4.50 (2H, s), 7.01 (2H, d, J=8.5Hz), 7.16-7.20 (1H, m), 7.33-7.37 (1H, m), 7.58 (2H, d, J=8.5Hz), 5 8.10 (1H, br) Example 375 To a suspension of (2S)-N-(2-tetrahydropyranyloxy)-2 [5-(3-((2-phthalimidoethoxy)carbonylamino)phenyl)-2 10 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (155 mg) in methanol (4 ml) was added hydrazine monohydrate (13.7 mg) and the reaction mixture was stirred at ambient temperature for 3 hours, the resulting mixture was filtrated and washed with methanol. The filtrate was 15 concentrated in vacuo to give (2S)-N-(2-tetrahydro pyranyloxy)-2-[5-(3-(2-aminoethylaminocarbonylamino)phenyl) 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (125 mg) as a white amorphous. NMR (CDCl 3 , 8): 1.24-1.35 (2H, m), 1.42-1.52 (2H, m), 20 1.62-1.73 (2H, m), 1.96 (2H, br), 2.08-2.25 (2H, m), 2.86 (2H, br), 3.01-3.05 (2H, m), 3.15 (2H, br), 3.44-3.50 (4H, m), 3.74-3.84 (1H, m), 4.22 4.25 (1H, m), 4.45 (1/2H, br), 4.83 (1/2H, br), 7.22-7.30 (4H, m), 7.37-7.44 (1H, m), 7.68 (1H, br 25 s), 7.83-7.86 (1H, m), 8.20-8.24 (1H, m) MS (ESI+): 552.3 (M+H) The following compounds were obtained in a similar manner to that of Example 130. 30 Example 376 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 (ethylcarbonyloxy)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (150 mg) 35 NMR (DMSO-d 6 , 8): 1.15 (3H, dd, J=7.5, 7.5Hz), 1.38-1.61 WO 00/40576 PCT/JPOO/00018 246 (6H, m), 1.70-2.07 (4H, m), 2.37-2.46 (1H, m), 2.58-2.66 (2H, m), 2.90-3.51 (6H, m), 3.75-3.88 (1H, m), 4.43, 4.75 (1H, s), 7.18-7.25 (3H, m), 7.43-7.48 (1H, m), 7.68 (2H, d, J=8.5Hz) 5 MS (ESI-): 520 (M-H) Example 377 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 (methoxyacetoxy)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H 10 thiopyran-2-acetamide 1,1-dioxide (150 mg) NMR (DMSO-d 6 , 6): 1.36-1.62 (6H, m), 1.69-2.05 (4H, m), 2.34-2.43 (1H, m), 2.87-3.29 (5H, m), 3.38 (3H, s), 3.40-3.51 (1H, m), 3.75-3.90 (1H, m), 4.37 (2H, s), 4.44, 4.75 (1H, s), 7.20-7.26 (3H, m), 7.42-7.48 15 (1H, m), 7.70 (2H, d, J=8.5Hz) MS (ESI-): 536 (M-H) Example 378 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 20 (ethoxycarbonyloxyphenyl)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (150 mg) NMR (DMSO-d 6 , 8): 1.30 (3H, dd, J=7.5, 7.5Hz), 1.38-1.65 (6H, m), 1.70-1.95 (4H, m), 2.36-2.45 (1H, m), 2.90-3.51 (6H, m), 3.72-3.90 (1H, m), 4.27 (2H, 25 ddd, J=7.5, 7.5, 7.5Hz), 7.43, 4.75 (1H, s), 7.20 7.26 (1H, m), 7.29 (2H, d, J=8.5Hz), 7.45-7.49 (1H, m), 7.69 (2H, d, J=8.5Hz) MS (ESI-): 536 (M-H) 30 The following compounds were obtained in a similar manner to that of Example 129. Example 379 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 35 (methylaminocarbonyloxy)phenyl)-2-thienyl]-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 , 8): 1.37-1.62 (4H, m), 1.70-2.05 (4H, m), 2.35-2.46 (1H, m), 2.67 (3H, d, J=4.5Hz), 2.90 3.30 (5H, m), 3.40-3.55 (1H, m), 3.75-3.88 (1H, m), 5 4.44, 4.75 (1H, s), 7.15 (2H, d, J=8.7Hz), 7.18 7.24 (1H, m), 740-7.45 (1H, m), 7.63 (2H, d, J=8.7Hz) MS (ESI-): 521 (M-H) 10 Example 380 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 (ethylaminocarbonyloxy)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (230 mg) NMR (CDCl 3 , 8): 1.23 (3H, dd, J=7.2, 7.2Hz), 1.36-1.75 15 (6H, m), 1.86-2.00 (2H, m), 2.03-2.25 (2H, m), 2.65-2.87 (2H, m), 3.01-3.18 (4H, m), 3.26-3.37 (2H, m), 3.60-3.69 (1H, m), 4.51, 4.80 (1H, s), 5.01-5.09 (1H, m), 7.14 (2H, d, J=8.7Hz), 7.16 7.25 (2H, m), 7.54 (2H, d, J=8.7Hz), 8.09, 8.24 20 (1H, s) MS (ESI-): 535 (M-H) Example 381 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-hydroxyphenyl) 25 2 -thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (1 g) was obtained in a similar manner to that of Example 201. NMR (CDCl 3 , 8): 1.38-1.66 (6H, m), 1.70-2.04 (4H, m), 1.84-1.94 (1H, m), 2.89-3.48 (6H, m), 3.75-3.90 30 (1H, m), 4.45, 4.75 (1H, s), 8.80 (2H, d, J=8.7Hz), 7.13-7.17 (1H, m), 7.21-7.25 (1H, m), 7.45 (2H, d, J=8.7Hz), 9.68 (1H, s) The following compounds were obtained in a similar 35 manner to that of Example 201.

WO 00/40576 PCT/JPOO/00018 248 Example 382 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(6-methyl-3 pyridyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 5 acetamide 1,1-dioxide (99 mg) NMR (CDCl 3 , 8): 1.40-1.75 (6H, m), 1.90-2.00 (2H, m), 2.07-2.25 (2H, m), 2.59 (3H, s), 2.70-2.94 (2H, m), 3.05-3.17 (4H, m), 3.30-3.52 (1H, m), 3.63-3.74 (1H, m), 4.52 (0.5H, s), 4.81 (0.5H, s), 7.17 (2H, 10 d, J=8Hz), 7.26-7.33 (2H, m), 7.75 (1H, dd, J=1.5, 8Hz), 8.12 (0.5H, s), 8.24 (0.5, s), 8.74 (1H, d, J=1.5Hz) MS (ESI-): 463 (M-H) 15 Example 383 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(6-methyl-3 pyridyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (110 mg) NMR (CDCl 3 , 8): 1.40-1.74 (6H, m), 1.88-2.00 (2H, m), 20 2.07-2.20 (2H, m), 2.67-2.87 (2H, m), 3.04-3.08 (2H, m), 3.09-3.18 (2H, m), 3.30-3.52 (1H, m), 3.60-3.73 (1H, m), 3.96 (3H, s), 4.53 (0.5H, s), 4.81 (0.5H, s), 6.77 (1H, d, J=8Hz), 6.83 (1H, d, J=8Hz), 7.16-7.20 (1H, m), 7.64-7.79 (1H, m), 7.99 25 (0.5H, s), 8.13 (0.5H, s), 8.39-8.42 (1H, m) MS (ESI-): 479 (M-H) The following compounds were obtained in a similar manner to that of Example 130. 30 Example 384 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-acetylamino) phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (105 mg) 35 NMR (CDCl 3 , 5): 1.33-1.77 (8H, m), 1.87-2.00 (2H, m), WO 00/40576 PCT/JPOO/00018 249 2.11 (3H, m), 2.06-2.77 (2H, m), 2.85-3.36 (5H, m), 3.66-3.83 (2H, m), 4.36-4.48 (1H, m), 4.53 (1/2H, br), 4.88 (1/2H, br), 7.12-7.37 (5H, m), 7.59-7.67 (1H, m), 8.82 (1/2H, br s), 8.84 (1/2H, br s), 5 9.83 (1H, s), 10.04 (1H, s) MS (ESI-): 563.0 (M-H) Example 385 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(3 10 (methoxycarbonyl)propionylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (130 mg) NMR (CDCl 3 , 8): 1.44 (4H, br), 1.65-1.67 (2H, m), 1.95 (2H, br), 2.08-2.21 (2H, m), 2.67-2.77 (6H, m), 3.06-3.14 (4H, m), 3.29-3.48 (1H, m), 3.62-3.70 15 (1H, m), 3.72 (3H, s), 4.53 (1/2H, br), 4.81 (1/2H, br), 7.20-7.27 (3H, m), 7.51 (1H, br), 7.60 (1/2H, s), 7.66 (1/2H, s), 7.80 (1/2H, br), 7.84 (1/2H, br), 8.40 (1/2H, s), 8.44 (1/2H, s) MS (ESI-): 577.2 (M-H) 20 Example 386 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(N methoxycarbonyl-N-methylamino)acetylamino)phenyl}-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 25 dioxide (160 mg) NMR (CDCl 3 , 8): 1.46 (2H, br), 1.68 (4H, br), 1.96 (2H, br), 2.07-2.24 (2H, m), 2.70-2.94 (2H, m), 3.02 3.09 (2H, m), 3.10 (3H, s), 3.16 (2H, br), 3.31 3.53 (1H, m), 3.65-3.75 (1H, m), 3.80 (3H, s), 30 4.02-4.09 (2H, m), 4.54 (1/2H, br), 4.83 (1/2H, br), 7.24-7.31 (5H, m), 7.53 (1H, br), 7.63 (1/2H, s), 7.67 (1/2H, s), 8.44 (1/2H, s), 8.50 (1/2H, s) MS (ESI-): 592.1 (M-H) 35 Example 387 WO 00/40576 PCT/JPOO/00018 250 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-[4-(3-pyridyl-2 propenyloxy)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (270 mg) NMR (DMSOd 6 , 6): 1.36-1.65 (6H, m), 1.70-2.06 (4H, m), 5 2.36-2.47 (1H, m), 2.91-3.28 (5H, m), 3.41-3.52 (1H, m), 3.75-3.91 (1H, m), 4.45, 4.75 (1H, s), 7.07 (1H, d, J=16Hz), 7.21-7.26 (1H, m), 7.30 (2H, d, J=8.0Hz), 7.45-7.51 (2H, m), 7.72 (2H, d, J=8.0Hz), 7.94 (1H, d, J=16Hz), 8.28-8.32 (1H, m), 10 8.60-8.62 (1H, m), 8.99 (1H, s) MS (ESI-) : 595 (M-H) The following compounds were obtained in a similar manner to that of Example 211. 15 Example 388 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(2 methoxyethoxy)acetylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (175 mg) 20 NMR (CDCl 3 , 8): 1.35-1.74 (8H, m), 1.89-1.99 (2H, m), 2.06-2.25 (2H, m), 2.68-2.89 (2H, m), 3.02-3.17 (2H, m), 3.25-3.46 (1H, m), 3.52 (3H, s), 3.58 3.67 (2H, m), 3.74-3.81 (2H, m), 4.13 (2H, s), 4.52 (1/2H, br), 4.79 (1/2H, br), 7.22-7.38 (4H, 2.5 m), 7.55-7.62 (1H, m), 7.83 (1H, br s), 8.04 (1/2H, s), 8.19 (1/2H, s), 8.97 (1H, s) MS (ESI-): 579.9 (M-H) Example 389 30 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(N-9 fluorenylmethoxycarbonyl-N-methylamino)acetylamino)phenyl} 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (1.77 g) NMR (CDC1 3 , 8): 1.42 (2H, br), 1.64 (4H, br), 1.95 (2H, 35 br), 2.08-2.23 (2H, m), 2.70-2.90 (2H, m), 3.00- WO 00/40576 PCT/JPOO/00018 251 3.07 (5H, m), 3.10-3.16 (2H, m), 3.27-3.48 (1H, m), 3.60-3.70 (1H, m), 4.00-4.09 (lH, m), 4.28 (1H, br), 4.52 (2H, s), 4.56 (1/2H, br), 4.80 (1/2H, br), 7.21-7.48 (9H, m), 7.58-7.65 (3H, m), 7.75 5 (2H, br), 8.20 (1/2H, s), 8.32 (1/2H, s) MS (ESI-): 791.9 (M-H+Cl) Example 390 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(((2S)-2,6 10 bis(tert-butoxycarbonylamino)hexanoyl)amino)phenyl}-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (290 mg) NMR (CDC1 3 , 8): 1.45 (18H, s), 1.48-1.70 (14H, m), 1.95 (2H, br), 2.09-2.20 (2H, m), 2.68-2.92 (2H, m), 15 3.00-3.15 (4H, m), 3.25-3.49 (1H, m), 3.63-3.74 (1H, m), 4.16-4.28 (1H, m), 4.52 (1/2H, br), 4.65 (1/2H, br), 7.22-7.24 (2H, m), 7.27-7.30 (2H, m), 7.51 (1H, br), 7.62-7.82 (1H, m) MS (ESI-): 791.3 (M-H) 20 Example 391 (2S)-N-(2-Tetrahydropyranyloxy)-2-5-{3-(2-tert butoxycarbonylamino-3-(3-pyridyl)propionylamino)phenyl}-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 25 dioxide (1.54 g) NMR (DMSO-d 6 , 8): 1.22-1.27 (2H, m), 1.43 (9H, s), 1.63 1.68 (4H, m), 1.98 (2H, br), 2.07-2.25 (2H, m), 2.74-2.98 (2H, m), 3.04-3.20 (6H, m), 3.41-3.48 (1H, m), 3.66-3.76 (1H, m), 4.45 (1/2H, br), 4.54 30 4.63 (1H, br), 4.86 (1/2H, br), 5.31-5.45 (1H, m), 6.82-7.00 (2H, m), 7.04-7.20 (3H, m), 7.22-7.27 (2H, m), 7.52-7.65 (2H, m), 8.43-8.59 (3H, m) MS (ESI+): 713.1 (M+H) 35 Example 392 WO 00/40576 PCT/JPOO/00018 252 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(3 carboxypropionylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (50 mg) was obtained in a similar manner to that of Example 3. 5 NMR (DMSO-d 6 , 8): 1.36-2.06 (10H, m), 2.34-2.63 (5H, m), 2.88-3.52 (6H, m), 3.65-3.90 (1H, m), 4.43 (1/2H, br), 4.75 (1/2H, br), 7.17-7.32 (1H, m), 7.28-7.48 (4H, m), 8.00 (1H, s), 10.08 (1H, s), 10.59 (1H, s), 11.22 (1H, s), 12.13 (1H, br s) 10 MS (ESI-): 563.4 (M-H) Example 393 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(3 (methylaminocarbonyl)propionylamino)phenyl}-2-thienyl] 15 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (50 mg) was obtained in a similar manner to that of Example 32. NMR (CDCl 3 , 8): 1.48 (2H, br), 1.62 (4H, br), 1.96 (2H, br), 2.06-2.26 (2H, m), 2.62-2.66 (2H, m), 2.75 (3H, br s), 2.88 (2H, br), 3.05-3.22 (5H, m), 20 3.36-3.49 (1H, m), 3.73-3.99 (1H, m), 4.15-4.25 (1H, m), 4.70 (1/2H, s), 4.95 (1/2H, s), 6.97-7.12 (4H, m), 7.32-7.43 (2H, m), 9.12 (1/2H, br), 9.24 (1/2H, br) MS (ESI-): 576.3 (M-H) 25 Example 394 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(tert butoxycarbonylaminomethyl)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (200 mg) was 30 obtained in a similar manner to that of Example 89. NMR (CDCl 3 , 8): 1.47 (9H, s), 1.52-1.68 (6H, m), 1.81-1.95 (2H, m), 2.06-2.23 (2H, m), 2.63-2.89 (2H, m), 3.05 (2H, br s), 3.08-3.13 (2H, m), 3.27 3.50 (1H, m), 3.61-3.70 (1H, m), 4.24-4.39 (2H, m), 35 4.52 (1/2H, br), 4.80 (1/2H, br), 6.71-6.82 (1H, WO 00/40576 PCT/JPOO/00018 253 m), 7.14-7.70 (5H, m), 8.07 (1/2H, s), 8.24 (1/2H, s) MS (ESI-): 577.3 (M-H) 5 Example 395 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2 (methylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (915 mg) was obtained in a similar manner to that of Example 239. 10 NMR (DMSO-d 6 , 6): 1.42-1.59 (6H, m), 1.73-2.05 (4H, m), 2.32 (3H, s), 2.37-2.46 (1H, m), 2.89-3.20 (4H, m), 3.25 (2H, s), 3.42-3.48 (2H, m), 3.75-3.78 (1H, m), 4.44 (1/2H, br), 4.75 (1/2H, br), 7.20-7.24 (1H, m), 7.34-7.36 (2H, m), 7.38-7.42 (1H, m), 7.55 15 7.57 (1H, m), 8.02 (1H, s) MS (ESI+): 536.3 (M+H) The following compounds were obtained in a similar manner to that of Example 54. 20 Example 396 (2S)-N-Hydroxy-2-[5-(6-methyl-3-pyridyl)-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide hydrochloride (89 mg) 25 NMR (DMSO-d 6 , 8): 1.71-2.10 (4H, m), 2.35-2.54 (lH, m), 2.68 (3H, s), 2.96-3.08 (2H, m), 3.14-3.60 (3H, m), 7.32 (1H, d, J=3.5Hz), 7.74-7.81 (2H, m), 8.49 (1H, dd, J=1.5, 8Hz), 9.01 (1H, d, J=1.5Hz), 10.66 (1H, s) 30 MS (ESI-): 379 (M-H) Example 397 (2S)-N-Hydroxy-2-[5-(6-methoxy-3-pyridyl)-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide, 1,1-dioxide (50 35 mg) WO 00/40576 PCT/JPOO/00018 254 NMR (DMSO-d 6 , 8): 1.71-2.09 (4H, m), 2.33-2.52 (1H, m), 2.95-3.08 (2H, m), 3.10-3.29 (2H, m), 3.42-3.58 (1H, m), 3.89 (3H, s), 6.89 (1H, d, J=8Hz), 7.21 (1H, d, J=3.5Hz), 7.43 (1H, d, J=3.5Hz), 7.97 (1H, 5 dd, J=1.5, 8Hz), 8.47 (1H, d, J=1.5Hz) MS (ESI-): 395 (M-H) Example 398 (2S)-N-Hydroxy-2-[5-[4-(5-methyl-1,2,4-oxadiazol-3 10 yl)phenyll-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (67 mg) NMR (DMSO-d 6 , 8): 1.71-2.09 (4H, m), 2.20-2.52 (1H, m), 2.68 (3H, s), 2.94-3.08 (2H, m), 3.11-3.33 (2H, m), 3.36-3.56 (1H, m), 7.26 (1H, d, J=3.5), 7.63 (1H, 15 d, J=3.5Hz), 7.84 (2H, d, J=8Hz), 8.03 (2H, d, J=8Hz), 8.84 (1H, s) MS (ESI-): 446 (M-H) Example 399 20 ( 2 S)-N-Hydroxy-2-[5-{3-(2-(acetylamino)acetylamino) phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (75 mg) NMR (DMSO-d 6 , 6): 1.69-2.08 (4H, m), 1.89 (3H, s), 2.34-2.48 (1H, m), 2.94-3.30 (4H, m), 3.38-3.55 25 (1H, m), 3.88 (2H, d, J=8.OHz), 7.21 (1H, d, J=4.OHz), 7.32-7.40 (2H, m), 7.42 (1H, d, J=4.OHz), 7.44-7.51 (1H, m), 7.98 (1H, s), 8.22 (1H, t, J=8.OHz), 8.83 (1H, s), 10.08 (1H, s), 10.60 (1H, s) 30 MS (ESI-): 478.3 (M-H) Example 400 (2S)-N-Hydroxy-2-[5-{3-(3-methoxycarbonylpropionyl amino)phenyl)-2-thienyll-3,4,5,6-tetrahydro-2H-thiopyran-2 35 acetamide 1,1-dioxide (60 mg) WO 00/40576 PCT/JPOO/00018 255 NMR (DMSO-d 6 , 6): 1.72-2.09 (4H, m) , 2.33-2.48 (1H, m) 2.63 (3H, s), 2.77-3.40 (6H, m), 3.42-3.55 (1H, m), 7.21 (1H, d, J=4.OHz), 7.28-7.48 (4H, m), 7.98 (1H, s), 8.84 (1H, s), 10.12 (1H, s), 10.60 (1H, s) 5 MS (ESI-): 493.4 (M-H) Example 401 (2S)-N-Hydroxy-2-[5-{3-(3-(methylaminocarbonyl) propionylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H 10 thiopyran-2-acetamide 1,1-dioxide (30 mg) NMR (DMSO-d 6 , 6): 1.73-2.05 (4H, m), 2.40 (2H, t, J=6.0Hz), 2.45-2.49 (1H, m), 2.53-2.58 (3H, m), 2.95-3.26 (4H, m), 3.40-3.54 (3H, m), 7.20 (1H, d, J=4.OHz), 7.32 (2H, d, J=4.5Hz), 7.39 (1H, d, 15 J=4.OHz), 7.43-7.47 (2H, m), 7.82 (1H, br), 8.00 (1H, s), 10.08 (1H, s), 10.60 (1H, s) MS (ESI-): 492.1 (M-H) Example 402 20 ( 2 S)-N-Hydroxy-2-[5-{3-(2-(2-methoxyethoxy) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (120 mg) NMR (DMSO-d 6 , 6): 1.70-2.07 (4H, m), 2.36-2.46 (1H, m), 2.94-3.28 (4H, m), 3.31 (3H, s), 3.48-3.51 (1H, m), 25 3.52-3.58 (2H, m), 3.66-3.72 (2H, m), 4.10 (2H, s), 7.22 (1H, d, J=4.OHz), 7.33-7.40 (1H, m), 7.40 (1H, d, J=4.OHz), 7.52-7.62 (1H, m), 8.00 (1H, s), 8.84 (1H, s), 9.76 (1H, s), 10.60 (1H, s) MS (ESI-): 495.3 (M-H) 30 Example 403 (2S)-N-Hydroxy-2-[5-(3-aminomethylphenyl)-2-thienyll 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (132 mg) from ( 2 S)-N-(2-tetrahydropyranyloxy)-2-[5-(3-(tert 35 butoxycarbonylaminomethyl)phenyl)-2-thienyl]-3,4,5,6- WO 00/40576 PCT/JPOO/0001 8 256 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide NMR (DMS0 6 , 6): 1.73-2.08 (4H, m), 2.35-2.45 (1H, m). 2.95-3.26 (4H, m), 3.43-3.55 (1H, m), 4.08 (2H, br), 7.24 (1H, d, J=4.OHz), 7.37-7.39 (1H, m), 5 7.45-7.50 (2H, m), 7.68 (1H, d, J=7.5Hz), 7.75 (1H, s), 8.15 (2H, br), 8.83 (1H, s), 10.60 (1H, s) MS (ESI-): 435.2 (M-H+CH 3 CN) Example 404 10 (2S)-N-Hydroxy-2-[5-{3-(2-(N-methoxycarbonyl-N methylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (110 mg) NMR (DMSO-d 6 , 6): 1.75-2.06 (4H, m), 2.37-2.46 (1H, m), 2.90 (3/2H, s), 2.94 (3/2H, s), 2.95-3.26 (4H, m), 15 3.40-3.50 (1H, m), 3.56 (3/2H, s), 3.63 (3/2H, s), 4.05 (2H, s), 7.20 (1H, d, J=4.OHz), 7.32-7.39 (3H, m), 7.42 (1H, d, J=4.OHz), 8.02 (1H, s), 8.84 (1H, s) MS (ESI-): 508.4 (M-H) 20 Example 405 (2S)-N-Hydroxy-2-[5-{3-(((2S)-2,6-diaminohexanoyl) amino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (200 mg) from (2S)-N-(2 25 tetrahydropyranyloxy)-2-[5-{3-( ( (2S) -2,6-bis (tert butoxycarbonylamino)hexanoyl)amino)phenyl}-2-thienyl] 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 6): 1.33-1.44 (2H, m), 1.50-1.60 (2H, m), 1.73-1.93 (4H, m), 1.95-2.07 (1H, m), 2.35-2.45 30 (1H, m), 2.73-2.80 (2H, m), 2.95-3.28 (4H, m), 3.50-3.55 (1H, m), 3.94 (1H, br), 7.22 (1H, d, J=4.OHz), 7.42-7.45 (3H, m), 7.53 (1H, d, J=7.OHz), 7.94 (1H, s), 8.38 (1H, s) MS (ESI+): 509.3 (M+H) 35 WO 00/40576 PCT/JPOO/00018 257 Example 406 (2S)-N-Hydroxy-2-[5-{3-(2-amino-3-(3-pyridyl) propionylamino)phenyll-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (460 mg) from (2S)-N 5 (2-tetrahydropyranyloxy)-2-[5-{3-(2-tert butoxycarbonylamino-3-( 3 -pyridyl)propionylamino)phenyl}-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide NMR (DMSO-d 6 , 8): 1.74-2.07 (4H, m), 2.36-2.46 (1H, m), 10 2.96-3.32 (6H, m), 3.45-3.55 (1H, m), 4.24 (1H, br), 7.22 (1H, d, J=4.OHz), 7.39-7.48 (4H, m), 7.52-7.57 (1H, m), 7.83-7.88 (2H, m), 8.39 (2H, br), 8.56-8.60 (2H, m), 10.57 (1H, s), 10.60 (1H, s) 15 MS (ESI+): 529.1 (M+H) Example 407 (2S)-N-Hydroxy-2-[5-(4-( 3 -pyridyl-2-propenyloxy) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 20 acetamide 1,1-dioxide (180 mg) NMR (DMSO-d 6 , 8): 1.70-2.06 (4H, m), 2.36-2.47 (1H, m), 2.96-3.56 (5H, m), 7.16 (1H, d, J=16Hz), 7.23 (1H, d, J=4.OHz), 7.30 (2H, d, J=8.5Hz), 7.49 (1H, d, J=16Hz), 7.70-7.76 (3H, m), 7.97 (1H, d, J=8.5Hz), 25 8.53-8.57 (1H, m), 8.75 (1H, d, J=5Hz), 9.12 (1H, s), 10.6 (1H, s) MS (ESI-): 511 (M-H) Example 408 30 To a solution of ( 2 S)-2-tert-butoxycarbonylamino-3 hydroxypropionic acid (66 mg), 1-hydroxybenzotriazole (44 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (62 mg) in N,N-dimethylformamide (1.3 ml) was added a solution of (2S)-N-(2-tetrahydropyranyloxy)-2-[5-(3 35 aminophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2- WO 00/40576 PCT/JPOO/00018 258 acetamide 1,1-dioxide (100 mg) in N,N-dimethylformamide (0.5 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, 5 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. 10 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-3 15 hydroxypropionyl)amino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (30 mg) as a white powder. NMR (DMSO-d 6 , 6): 1.76-2.10 (4H, m), 2.38-2.46 (1H, m), 3.00 (2H, d, J=10Hz), 3.13-3.52 (4H, m), 3.82-3.93 20 (1H, m), 3.98-4.06 (1H, m), 7.23 (1H, d, J=4.OHz), 7.40-7.45 (3H, m), 7.50-7.54 (1H, m), 7.98 (1H, s), 8.32 (2H, br), 10.73 (1H, s) MS (ESI+): 468.3 (M+H) 25 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) 30 acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (30 mg) from (2S)-N-(2 tetrahydropyranyloxy)-2-[5-{3-((2-aminoacetyl)amino)phenyl} 2-thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (150 mg) and dimethylaminocarbonyl chloride. 35 NMR (DMSO-d 6 , 6): 1.74-2.04 (4H, m), 2.35-2.44 (1H, m), WO 00/40576 PCT/JPOO/00018 259 2.85 (6H, s), 2.95-3.25 (4H, m), 3.46-3.53 (1H, m), 3.78 (2H, d, J=4.OHz), 6.65 (1H, t, J=4.OHz), 7.20 (1H, d, J=4.OHz), 7.34-7.40 (2H, m), 7.40-7.48 (2H, m), 8.01 (1H, s), 8.08 (1H, br), 9.98 (1H, s), 5 10.60 (1H, s) MS (ESI+): 509.2 (M+H) Example 410 (2S)-N-Hydroxy-2-[5-{3-(2-(N-(dimethylaminocarbonyl)-N 10 methylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (30 mg) was obtained in a similar manner to that of Example 409. NMR (DMSO-d 6 , 8): 1.73-2.05 (4H, m), 2.37-2.48 (1H, m), 2.74 (6H, s), 2.87 (3H, s), 2.95-3.25 (4H, m), 15 3.44-3.52 (1H, m), 3.91 (2H, s), 7.20 (1H, d, J=4.OHz), 7.34-7.45 (3H, m), 7.42 (1H, d, J=4.OHz), 8.02 (1H, s), 10.06 (1H, s), 10.60 (1H, s) MS (ESI-): 521.2 (M-H) 20 Example 411 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-[4-(5-methyl 1,2,4-oxadiazol-3-yl)phenyl]-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (113 mg) was obtained in a similar manner to that of Example 201. 25 NMR (CDCl 3 , 8): 1.38-1.74 (6H, m), 1.90-2.01 (2H, m), 2.06-2.25 (2H, m), 2.67 (3H, s), 2.70-2.89 (2H, m), 3.03-3.08 (2H, m), 3.10-3.18 (2H, m), 3.28-3.50 (1H, m), 3.59-3.72 (1H, m), 4.53 (0.5H, s), 4.81 (0.SH, s), 7.28-7.32 (1H, m), 7.35-7.39 (1H, m), 30 7.71 (2H, d, J=8Hz), 7.99 (0.5H, s), 8.08 (2H, d, J=8Hz), 8.13 (0.5H, s) MS (ESI-) : 530 (M-H) 35 Example 412 WO 00/40576 PCT/JPOO/00018 260 tert-Butyl 2-(5-bromo-2-thienyl)-2,3,4,5 tetrahydrothiophene-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, m), 5 2.07-2.20 (2H, m), 2.26-2.36 (1H, m), 2.83 (1H, d, J=15Hz), 2.98-3.09 (2H, m), 3.12 (1H, d, J=15Hz), 6.70 (1H, d, J=4Hz), 6.87 (2H, d, J=4Hz) Example 413 10 tert-Butyl 2-[5-(4-fluorophenyl)-2-thienyl]-2,3,4,5 tetrahydrothiophene-2-acetate (479 mg) was obtained in substantially the same manner as that of Example 100. NMR (CDCl 3 , 8): 1.34 (9H, s), 2.02-2.29 (3H, m), 2.36 2.46 (1H, m), 3.00 (1H, d, J=16Hz), 3.01-3.14 (2H, 15 m), 3.17 (1H, d, J=16Hz), 6.92 (1H, d, J=4Hz), 7.00-7.08 (3H, m), 7.52 (2H, dd, J=4, 9Hz) Example 414 2-[5-(4-Fluorophenyl)-2-thienyl]-2,3,4,5 20 tetrahydrothiophene-2-acetic acid (298 mg) was obtained in a similar manner to that of Example 95. NMR (CDCl 3 , 6): 2.02-2.31 (3H, m), 2.39-2.50 (1H, m), 2.98-3.17 (3H, m), 3.30 (1H, d, J=16Hz), 6.93 (1H, d, J=4Hz), 6.99-7.08 (3H, m), 7.50 (2H, dd, J=5, 25 9Hz) MS (ESI-): 321 (M-H) Example 415 2-[5-(4-Fluorophenyl)-2-thienyl]-2,3,4,5 30 tetrahydrothiophene-2-acetic acid 1,1-dioxide (272 mg) was obtained in a similar manner to that of Preparation 1-4). NMR (CDCl 3 , 6): 2.18-2.43 (2H, m), 2.70-2.82 (1H, m), 2.89-3.01 (1H, m), 3.09 (1H, d, J=16Hz), 3.14-3.25 (2H, m), 3.36 (1H, d, J=16Hz), 7.07 (2H, t, J=9Hz), 35 7.13-7.18 (2H, m), 7.54 (2H, dd, J=5, 9Hz) WO 00/40576 PCT/JPOO/00018 261 The following compounds were obtained in a similar manner to that of Example 130. 5 Example 416 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2 (benzyloxycarbonylamino)acetylamino)phenyl}-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (230 mg) 10 NMR (CDC1 3 , 8): 1.43 (4H, br), 1.63-1.65 (2H, m), 1.94 (2H, br), 2.09-2.23 (2H, m), 2.82 (2H, br), 3.06 3.17 (4H, m), 3.27-3.50 (1H, m), 3.64-3.76 (1H, m), 4.03-4.05 (2H, m), 4.52 (1/2H, br), 4.83 (1/2H, br), 5.18 (2H, s), 7.10-7.22 (4H, m), 7.30-7.38 15 (6H, m), 7.45-7.55 (2H, m), 8.23 (1H, br), 8.77 (1/2H, br), 8.85 (1/2H, br) MS (ESI-): 654.2 (M-H) Example 417 20 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(4 methoxybenzenesulfonylamino)acetylamino)phenyl}-2-thienyl] 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (220 mg) NMR (CDCl 3 , 6): 1.43 (4H, br), 1.62-1.72 (2H, m), 1.95 25 (2H, br), 2.06-2.25 (2H, m), 2.75-2.90 (2H, m), 3.00-3.18 (4H, m), 3.28-3.50 (1H, m), 3.64-3.70 (1H, m), 3.75 (2H, d, J=6.OHz), 3.82 (3H, s), 4.54 (1/2H, br), 4.85 (1/2H, br), 5.72-5.86 (1H, m), 6.98 (2H, d, J=8.OHz), 7.14-7.23 (4H, m), 7.85 (2H, 30 d, J=8.OHz), 8.40 (1H, br), 8.78 (1/2H, s), 8.94 (1/2H, s) MS (ESI-): 690.1 (M-H) Example 418 35 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-[3-[2-(1,5,5- WO 00/40576 PCT/JPOO/00018 262 trimethylhydantoin-3-yl)acetylaminoiphenyl]-2-thienyl] 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (212 mg) was obtained in a similar manner to that of Example 211. NMR (CDCl 3 , 8): 1.38-1.75 (12H, m), 1.87-2.05 (2H, m), 5 2.07-2.28 (2H, m), 2.77-2.96 (5H, m), 3.00-3.25 (4H, m), 3.27-3.54 (1H, m), 3.68-3.81 (1H, m), 4.40 (2H, s), 4.53 (0.5H, s), 4.85 (0.5H, s), 6.93-7.06 (1H, m), 7.09-7.34 (4H, m), 7.54-7.66 (1H, m), 8.25-8.35 (1H, m), 9.05 (0.5H, s), 9.20 10 (0.5H, s) MS (ESI-): 645 (M-H) Example 419 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-[4 15 (phenoxycarbonyloxymethyl)phenyl]-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (120 mg) was obtained in a similar manner to that of Example 244. NMR (CDCl 3 , 6): 1.35-1.76 (6H, m), 1.87-2.00 (2H, m), 2.04-2.25 (2H, m), 2.65-2.91 (2H, m), 3.00-3.18 20 (4H, m), 3.25-3.51 (1H, m), 3.59-3.72 (1H, m), 4.53 (0.5H, s), 4.81 (0.5H, s), 5.27 (2H, s), 7.17 (2H, d, J=8Hz), 7.23-7.32 (1H, m), 7.35-7.49 (6H, m), 7.62 (2H, d, J=8Hz), 8.01 (0.5H, s), 8.15 (0.5H, s) 25 MS (ESI-): 598 (M-H) Example 420 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-[4 (methylaminocarbonyloxymethyl)phenyl]-2-thienyl]-3,4,5,6 30 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (70 mg) was obtained in a similar manner to that of Example 245. NMR (CDCl 3 , 8): 1.36-1.75 (6H, m), 1.86-2.01 (2H, m), 2.05-2.24 (2H, m), 2.64-2.85 (5H, m), 3.01-3.18 (4H, m), 3.27-3.50 (1H, m), 3.56-3.70 (1H, m), 35 4.53 (0.5H, s), 4.61-4.74 (1H, m), 4.80 (0.5H, s), WO 00/40576 PCT/JPOO/00018 263 5.11 (2H, s), 7.21-7.29 (2H, m), 7.36 (2H, d, J=8Hz), 7.56 (2H, d, J=8Hz), 7.96 (0.5H, s), 8.11 (0.5H, s) MS (ESI-): 535 (M-H) 5 Example 421 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-[5 (methoxycarbonylamino)-3-pyridyl]-2-thienyll-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (170 mg) was 10 obtained in a similar manner to that of Example 201. NMR (CDCl 3 , 6): 1.40-1.74 (6H, m), 1.89-2.01 (2H, m), 2.05-2.25 (2H, m), 2.70-2.95 (2H, m), 3.01-3.17 (4H, m), 3.30-3.56 (1H, m), 3.62-3.76 (1H, m), 3.83 (3H, s), 4.53 (0.5H, s), 4.84 (0.5H, s), 15 6.97-7.06 (1H, m), 7.25-7.33 (1H, m), 7.36-7.65 (1H, m), 8.10-8.19 (1H, m), 8.40-8.56 (3H, m) MS (ESI-): 522 (M-H) Example 422 20 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (methylaminocarbonylmethylaminocarbonylamino)phenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (45 mg) was obtained in a similar manner to that of Example 32. 25 NMR (CDCl 3 , 8): 1.40-1.47 (4H, m), 1.64-1.69 (2H, m), 2.15 (2H, br), 2.28 (2H, br), 2.80 (3H, br s), 2.81-2.88 (2H, m), 2.98-3.15 (4H, m), 3.25-3.52 (1H, m), 3.72-3.81 (1H, m), 3.85-3.94 (2H, m), 4.50 (1/2H, br), 4.85 (1/2H, br), 5.27-5.43 (1H, 30 m), 7.12-7.19 (6H, m), 7.48-7.55 (2H, m), 7.67 7.72 (1H, m) MS (ESI-): 577.2 (M-H) Example 423 35 ( 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3- WO 00/40576 PCT/JP00/00018 264 (carboxymethylaminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (130 mg) was obtained in a similar manner to that of Example 3. NMR (CDC1 3 , 8): 1.43-1.50 (2H, m), 1.64-1.68 (4H, m), 5 1.92 (2H, br), 2.08-2.21 (2H, m), 2.40-2.48 (2H, m), 2.95-3.14 (4H, m), 3.30-3.53 (1H, m), 3.75 3.81 (1H, m), 4.00 (2H, br s), 4.45 (1/2H, br), 4.82 (1/2H, br), 7.15-7.22 (5H, m), 7.53 (1/2H, s), 7.57 (1/2H, s) 10 MS (ESI-): 565.0 (M-H) The following compounds were obtained in a similar manner to that of Example 249. 15 Example 424 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2 (allylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (106 mg) NMR (CDCl 3 , 8): 1.45 (2H, br), 1.64-1.68 (4H, m), 1.95 20 (2H, br), 2.06-2.24 (2H, m), 2.64-2.86 (2H, m), 3.07 (2H, br s), 3.13-3.16 (2H, m), 3.30-3.49 (1H, m), 3.46 (3H, d, J=7.OHz), 3.45 (2H, s), 3.62-3.71 (1H, m), 4.52 (1/2H, s), 4.80 (1/2H, s), 5.20-5.30 (2H, m), 5.85-5.98 (1H, m), 7.23-7.32 (4H, m), 25 7.56 (1H, br), 7.80 (1H, s), 9.40 (1H, s) MS (ESI+): 562.2 (M+H) Example 425 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(2 30 ethoxyethylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (65 mg) NMR (CDCl 3 , 8): 1.23 (3H, t, J=7.5Hz), 1.46 (2H, br), 1.65-1.80 (4H, m), 1.95 (2H, br), 2.05-2.25 (2H, m), 2.65-2.85 (1H, m), 2.88 (2H, t, J=6.OHz), 35 3.30-3.49 (1H, m), 3.44 (2H, s), 3.51-3.58 (4H, m), WO 00/40576 PCT/JP0O/00018 265 3.62-3.70 (1H, m), 4.52 (1/2H, br), 4.80 (1/2H, br), 7.27-7.35 (5H, m), 7.57-7.61 (1H, m), 7.83 (1H, s), 8.03 (1/2H, br), 8.20 (1/2H, br s), 9.52 (1H, s) 5 MS (ESI+): 594.2 (M+H) Example 426 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2 (benzylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 10 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (95 mg) NMR (CDC1 3 , 6): 1.43 (2H, br), 1.52-1.68 (4H, m), 1.96 (2H, br), 2.10-2.22 (2H, m), 2.66-2.89 (2H, m), 3.06 (2H, br s), 3.10-3.16 (2H, m), 3.29-3.50 (1H, m), 3.45 (2H, br s), 3.60-3.70 (1H, m), 3.88 (2H, 15 s), 4.52 (1/2H, br), 4.80 (1/2H, br), 7.27-7.38 (10H, m), 7.52 (1H, br), 7.79 (1H, br), 8.05 (1/2H, br), 8.20 (1/2H, br), 9.33 (1H, s) MS (ESI+): 612.2 (M+H) 20 Example 427 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2 (pentylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (83 mg) NMR (CDC1 3 , 6): 0.87-0.94 (5H, m), 1.29-1.64 (6H, m), 25 1.42-1.64 (4H, m), 1.95 (2H, br), 2.08-2.22 (2H, m), 2.62-2.88 (2H, m), 2.69 (2H, t, J=7.OHz), 3.06 (2H, s), 3.10-3.14 (2H, m), 3.24-3.50 (1H, m), 3.39 (2H, s), 3.61-3.69 (1H, m), 4.54 (1/2H, br), 4.80 (1/2H, br), 7.25-7.33 (5H, m), 7.56 (1H, br), 30 7.80 (1H, s), 8.00 (1/2H, br), 8.16 (1/2H, s), 9.44 (1H, s) MS (ESI+): 592.3 (M+H) Example 428 35 ( 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-((2R)-2-tert- WO 00/40576 PCT/JPOO/00018 266 butoxycarbonylamino-3-benzyloxypropionyl)aminophenyl}-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (400 mg) NMR (CDC1 3 , 6): 1.40-1.48 (2H, br), 1.49 (9H, s), 5 1.60-1.68 (4H, m), 1.94 (2H, br), 2.06-2.24 (2H, m), 2.65-2.90 (2H, m), 3.06 (1H, br s), 3.11-3.16 (2H, br), 3.27-3.47 (1H, m), 3.63-3.70 (2H, m), 3.97-4.04 (1H, m)), 4.44 (1H, br), 4.52 (1/2H, br), 4.55 (1H, d, J=11.0Hz), 4.65 (1H, d, J=11.0Hz), 10 4.80 (1/2H, br), 5.50 (1H, br), 7.22-7.41 (11H, m), 7.72 (1H, br), 8.07 (1/2H, s), 8.20 (1/2H, s), 8.47 (1H, br) MS (ESI-): 776.2 (M-H+Cl) 15 The following compounds were obtained in a similar manner to that of Example 54. Example 429 (2S)-N-Hydroxy-2-[5-(3-cyclobutanecarbonylaminophenyl) 20 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (250 mg) NMR (DMSO-d 6 , 8): 1.75-2.30 (10H, m), 2.37-2.46 (1H, m), 2.95-3.52 (5H, m), 7.20 (1H, d, J=4.OHz), 7.33-7.35 (2H, m), 7.40 (1H, d, J=4.0Hz), 7.46 25 7.50 (lH, m), 8.02 (1H, s), 9.84 (1H, s), 10.60 (1H, s) MS (ESI-): 461 (M-H) Example 430 30 ( 2 S)-Hydroxy- 2 -[5-[3-[2-(1,5,5-trimethylhydantoin-3 yl)acetylamino]phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (117 mg) NMR (DMSO-d 6 , 8): 1.36 (6H, s), 1.70-2.09 (4H, m), 2.35-2.54 (1H, m), 2.84 (3H, s), 2.94-3.08 (2H, m), 35 3.10-3.29 (2H, m), 3.36-3.55 (1H, m), 4.23 (2H, s), WO 00/40576 PCT/JPOO/00018 267 7.21 (1H, d, J=3.5Hz), 7.35-7.43 (4H, m), 7.95 (1H, s), 8.83 (1H, s), 10.41 (1H, s), 10.60 (1H, s) MS (ESI-): 561 (M-H) 5 Example 431 (2S)-N-Hydroxy-2-[5-[4-(methylaminocarbonyloxymethyl) phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (46 mg) NMR (DMSO-d 6 , 6): 1.67-2.09 (4H, m), 2.34-2.53 (1H, m), 10 2.59 (3H, d, J=4.8Hz), 2.94-3.08 (2H, m), 3.10 3.30 (2H, m), 3.38-3.55 (1H, m), 5.02 (2H, s), 7.21 (1H, d, J=3.5Hz), 7.38 (2H, d, J=8Hz), 7.48 (1H, d, J=3.5Hz), 7.64 (2H, d, J=8Hz), 8.85 (1H, br s) 15 MS (ESI-): 451 (M-H) Example 432 (2S)-N-Hydroxy-2-[5-[5-(methoxycarbonylamino)-3 pyridyll-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 20 acetamide 1,1-dioxide (94 mg) NMR (DMSO-d 6 , 8,): 1.71-2.09 (4H, m), 2.35-2.56 (1H, m), 2.95-3.08 (2H, m), 3.11-3.32 (2H, m), 3.41-3.57 (1H, m), 3.74 (3H, s), 7.29 (1H, d, J=3.5Hz), 7.65 (1H, d, J=3.5Hz), 8.32 (1H, s), 8.63 (1H, d, 25 J=1.5Hz), 8.71 (1H, d, J=1.5Hz) MS (ESI+): 440 (M+H) Example 433 (2S)-N-Hydroxy-2-[5-[3-(2,2-dimethylpropionylamino) 30 phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (100 mg) NMR (DMSO-d 6 , 6): 1.24 (9H, s), 1.71-2.08 (4H, m), 2.35-2.53 (1H, m), 2.94-3.07 (2H, m), 3.10-3.28 (2H, m), 3.39-3.55 (1H, m), 7.20 (1H, d, J=3.5Hz), 35 7.30-7.39 (2H, m), 7.41 (1H, d, J=3.5Hz), 7.59- WO 00/40576 PCT/JPOO/00018 268 7.65 (1H, m), 8.01 (1H, s), 8.84 (1H, br s), 9.30 (1H, s) MS (ESI-): 463 (M-H) 5 Example 434 (2S)-N-Hydroxy-2-[5-[3-((E)-2-butenoylamino)phenyl]-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (104 mg) NMR (DMSO-d 6 , 8): 1.71-2.08 (7H, m), 2.36-2.55 (1H, m), 10 2.94-3.08 (2H, m), 3.10-3.29 (2H, m), 3.39-3.85 (1H, m), 6.14 (1H, dd, J=1.5, 14Hz), 6.75-6.88 (1H, m), 7.21 (1H, d, J=3.5Hz), 7.32-7.39 (2H, m), 7.41 (1H, d, J=3.5Hz), 7.50-7.56 (1H, m), 8.05 (1H, s), 10.08 (1H, s), 10.60 (1H, s) 15 MS (ESI-): 447 (M-H) Example 435 (2S)-N-Hydroxy-2-[5-{3-(2-(benzyloxycarbonylamino) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H 20 thiopyran-2-acetamide 1,1-dioxide (150 mg) NMR (DMSO-d 6 , 8): 1.75-2.06 (4H, m), 2.38-2.47 (1H, m), 2.96-3.27 (4H, m), 3.40-3.55 (1H, m), 3.83 (2H, d, J=6.5Hz), 5.06 (2H, s), 7.22 (1H, d, J=4.OHz), 7.29-7.40 (8H, m), 7.45-7.50 (1H,i m), 7.58 (1H, t, 25 J=6.5Hz), 8.00 (1H, s), 8.84 (lH, br), 10.10 (1H, s), 10.60 (1H, br) MS (ESI-): 570.1 (M-H) Example 436 30 (2S)-N-Hydroxy-2-[5-{3-(2-(4-methoxybenzenesulfonyl amino)acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (170 mg) NMR (DMSO-d 6 , 6): 1.73-2.05 (4H, m), 2.35-2.46 (1H, m), 2.95-3.26 (4H, m), 3.49-3.53 (1H, m), 3.62 (2H, s), 35 3.77 (3H, s), 7.08 (2H, d, J=8.OHz), 7.20 (1H, d, WO 00/40576 PCT/JPOO/0001 8 269 J=4.0Hz), 7.30-7.38 (4H, m), 7.75 (12H, d, J=8.OHz), 7.84 (1H, s), 8.84 (1H, br), 10.02 (1H, s) MS (ESI-): 606.2 (M-H) 5 Example 437 (2S)-N-Hydroxy-2-[5-(3-(methylaminocarbonylmethyl aminocarbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (25 mg) 10 NMR (DMSO-d 6 , 6): 1.72-2.08 (4H, m), 2.36-2.45 (1H, m), 2.61 (3H, d, J=4.5Hz), 2.95-3.25 (4H, m), 3.42 3.50 (1H, m), 3.70 (2H, d, J=6.5Hz), 6.45 (1H, t, J=6.5Hz), 7.17-7.27 (4H, m), 7.37 (1H, d, J=4.OHz), 7.84 (4H, s), 7.88 (1H, br), 8.84 (1H, br), 9.01 15 (1H, s), 10.63 (1H, s) MS (ESI-): 493.3 (M-H) Example 438 (2S)-N-Hydroxy-2-[5-{3-(((2R)-2-amino-3 20 benzyloxypropionyl)amino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide hydrochloride (125 mg) from (2S)-N-(2-tetrahydropyranyloxy) 2-[5-{3-(((2R)-2-tert-butoxycarbonylamino-3 benzyloxypropionyl)amino)phenyl}-2-thienyl]-3,4,5,6 25 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 6): 1.73-2.06 (4H, m), 2.36-2.46 (1H, m), 2.95-3.26 (4H, m), 3.40-3.55 (1H, m), 3.48 (2H, d, J=4.5Hz), 4.26 (1H, br t, J=4.5Hz), 4.58 (2H, d, J=5.OHz), 7.23 (1H, d, J=4.OHz), 7.27-7.35 (6H, m), 30 7.40-7.44 (2H, m), 7.53 (1H, d, J=6.OHz), 7.94 (1H, s), 8.41 (2H, br), 8.83 (1H, s), 10.62 (1H, s), 10.82 (1H, s) MS (ESI-): 558.3 (M-H) 35 Example 439 WO 00/40576 PCT/JPOO/00018 270 (2S)-N-Hydroxy-2-[5-{3-(2-(allylamino)acetylamino) phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (70 mg) NMR (DMSO-d 6 , 8): 1.75-2.06 (4H, m), 2.36-2.45 (1H, m), 5 2.96-3.27 (4H, m), 3.40-3.50 (1H, m), 3.69 (2H, d, J=6.OHz), 3.93 (2H, s), 5.42-5.54 (2H, m), 5.84 5.98 (1H, m), 7.22 (1H, d, J=4.0Hz), 7.38-7.45 (3H, m), 7.48-7.52 (1H, m), 7.95 (1H, s), 8.85 (1H, br), 10.63 (1H, s), 10.77 (1H, s) 10 MS (ESI-): 476.1 (M-H) Example 440 (2S)-N-Hydroxy-2-[5-{3-(2-(2-ethoxyethylamino) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H 15 thiopyran-2-acetamide 1,1-dioxide (45 mg) NMR (DMSO-d 6 , 6): 1.14 (3H, t, J=7.0Hz), 1.74-2.06 (4H, m), 2.35-2.45 (1H, m), 2.93-3.26 (4H, m), 3.41 3.47 (1H, m), 3.57 (2H, td, J=7.0, 7.0Hz), 3.55 (2H, t, J=4.5Hz), 3.65 (2H, s), 7.22 (1H, d, 20 J=4.OHz), 7.38-7.44 (3H, m), 7.50-7.54 (1H, m), 7.98 (1H, s), 8.84 (1H, s), 10.33 (1H, br), 10.62 (1H, s) MS (ESI-): 508.2 (M-H) 25 Example 441 (2S)-N-Hydroxy-2-[5-{3-(2-pentylamino)acetylamino) phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (55 mg) NMR (DMSO-d 6 , 6): 0.90 (3H, t, J=4.5Hz), 1.24-1.34 (4H, 30 m), 1.63 (2H, br), 1.73-2.05 (4H, m), 2.37-2.46 (1H, m), 2.92-3.28 (6H, m), 3.43-3.53 (1H, m), 3.92 (2H, s), 7.22 (1H, d, J=4.OHz), 7.38-7.44 (3H, m), 7.50-7.54 (1H, m), 7.96 (1H, s), 8.84 (2H, br s), 10.64 (1H, s), 10.75 (1H, s) 35 MS (ESI+): 508.1 (M+H) WO 00/40576 PCT/JPOO/00018 271 Example 442 (2S)-N-Hydroxy-2-[5-(3-isobutyrylaminophenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 5 dioxide (250 mg) NMR (DMSO-d 3 , 8): 1.11 (6H, d, J=7.0Hz), 1.70-2.08 (4H, m), 2.35-2.45 (1H, m), 2.55-2.64 (1H, m), 2.95 3.54 (5H, m), 7.20 (lH, c, J=4.OHz), 7.34-7.35 (2H, m), 7.40 (1H, d, J=4.OHz), 7.46-7.51 (1H, m), 8.01 10 (1H, s), 8.84 (1H, s), 9.94 (1H, s), 10.60 (1H, s) MS (ESI-): 449 (M-H) Example 443 (2S)-N-Hydroxy-2-[5-{3-(2-benzylamino)acetylamino) 15 phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (55 mg) NMR (DMSO-d 6 , 6): 1.74-2.06 (4H, m), 2.35-2.45 (1H, m), 2.95-3.28 (4H, m), 3.40-3.50 (3H, m), 3.89 (1H, s), 4.24 (1H, s), 7.22 (1H, d, J=4.OHz), 7.36-7.55 (9H, 20 m), 7.92 (1H, s), 8.84 (1H, s), 10.62 (1H, s), 10.68 (1H, s) MS (ESI-): 528.1 (M-H) The following compounds were obtained in a similar 25 manner to that of Example 408. Example 444 (2S)-N-Hydroxy-2-[5-{3-(((2S)-2-amino-3 benzyloxypropionyl)amino)phenyl}-2-thienyl]-3,4,5,6 30 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (40 mg) from L-Boc-Ser(bzl)-OH NMR (DMSO-d 6 , 8): 1.73-2.06 (4H, m), 2.36-2.46 (1H, m), 2.95-3.26 (4H, m), 3.40-3.55 (1H, m), 3.48 (2H, d, J=4.5Hz), 4.26 (1H, br t, J=4.5Hz), 4.58 (2H, d, 35 J=5.OHz), 7.23 (1H, d, J=4.OHz), 7.27-7.35 (6H, m), WO 00/40576 PCT/JPOO/00018 272 7.40-7.44 (2H, m), 7.53 (1H, d, J=6.OHz), 7.94 (1H, s), 8.41 (2H, br), 8.83 (1H, s), 10.62 (1H, s), 10.82 (lH, s) MS (ESI+): 558.3 (M+H) 5 Example 445 (2S)-N-Hydroxy-2-[5-{3-((2S)-2-pyrrolidinylcarbonyl amino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (40 mg) from L-Boc-Pro-OH 10 NMR (DMSO-d 6 , 8): 1.84-2.05 (7H, m), 2.35-2.45 (2H, m), 2.95-3.30 (4H, m), 3.44-3.53 (3H, m), 4.35 (1H, br), 7.22 (1H, d, J=4.OHz), 7.39-7.50 (4H, m), 7.96 (1H, s), 8.72 (1H, br), 8.83 (1H, s), 9.27 (1H, br) 15 MS (ESI+): 468.3 (M+H) Example 446 (2S)-N-Hydroxy-2-[5-{3-(((2S)-2-amino-3 cyclohexylpropionyl)amino)phenyl}-2-thienyl]-3,4,5,6 20 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (50 mg) from L-Boc-CHA-OH NMR (DMSO-d 6 , 6): 0.87-0.98 (2H, m), 1.10-1.25 (4H, m), 1.40 (1H, br), 1.60-1.77 (6H, m), 1.85-2.06 (4H, m), 2.35-2.47 (1H, m), 2.95-3.27 (4H, m), 3.44 25 3.53 (1H, m), 3.96 (1H, br), 7.22 (1H, d, J=4.OHz), 7.40-7.48 (3H, m), 7.60 (1H, d, J=7.OHz), 7.90 (1H, s), 8.23 (2H, br), 8.84 (1H, s), 10.55 (1H, s), 10.60 (1H, s) MS (ESI+): 534.8 (M+H) 30 Example 447 (2S)-N-Hydroxy-2-[5-{3-((2-amino-2-methylpropionyl) amino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (20 mg) from L-Boc-AiB-OH 35 NMR (DMSO-d 6 , 8): 1.62 (6H, s), 1.74-2.06 (4H, m), WO 00/40576 PCT/JP0O/00018 273 2.35-2.44 (1H, m), 2.95-3.27 (4H, m), 3.37-3.53 (1H, m), 7.22 (1H, d, J=4.0Hz), 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) 5 MS (ESI+): 466.3 (M+H) Example 448 (2S)-N-Hydroxy-2-[5-{3-(((2R)-2-methoxypropionyl) amino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 10 acetamide 1,1-dioxide (30 mg) NMR (DMSO-d 6 , 8): 1.32 (3H, d, J=6.OHz), 1.73-2.06 (4H, m), 2.36-2.43 (1H, m), 2.95-3.26 (4H, m), 3.34 (3H, s), 3.45-3.54 (1H, m), 3.87 (1H, q, J=6.0Hz), 7.20 (1H, d, J=4.OHz), 7.32-7.35 (2H, m), 7.40 (1H, d, 15 J=4.0Hz), 7.62 (1H, d, J=6.5Hz), 8.60 (1H, s), 9.93 (1H, s), 10.60 (1H, s) MS (ESI-): 465.2 (M-H) Example 449 20 (2S)-N-Hydroxy-2-[5-{3-(((2S)-2-amino-4 carboxybutyryl)amino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro 2H-thiopyran-2-acetamide 1,1-dioxide (33 mg) from L-Boc-Glu(tBu)-OH NMR (DMSO-d 6 , 6): 1.74-2.25 (6H, m), 2.37-2.46 (1H, m), 25 2.95-3.26 (4H, m), 3.45-3.62 (1H, m), 3.95-4.04 (3H, m), 7.23 (1H, d, J=4.OHz), 7.40-7.45 (3H, m), 7.52 (1H, d, J=7.0Hz), 7.90 (1H, s), 8.28 (2H, br), 8.84 (1H, br) MS (ESI+): 510.7 (M+H) 30 Example 450 (2S)-N-Hydroxy-2-[5-{3-(2-(benzoylamino)acetylamino) phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (42 mg) 35 NMR (DMSO-d 6 , 6): 1.72-2.04 (4H, m), 2.36-2.47 (1H, m), WO 00/40576 PCT/JPOO/00018 274 2.95-3.25 (4H, m), 3.43-3.53 (1H, m), 4.09 (2H, d, J=6.OHz), 7.20 (1H, d, J=4.0Hz), 7.36-7.39 (2H, m), 7.42 (lH, d, J=4.OHz), 7.47-7.57 (4H, m), 7.92 (2H, d, J=7.5Hz), 8.30 (1H, s), 8.88 (1H, t, J=6.OHz), 5 10.20 (1H, s), 10.60 (1H, s) MS (ESI-): 541.3 (M-H) Example 451 (2S)-N-Hydroxy-2-[5-{3-(2-(ethylamino)acetylamino) 10 phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (60 mg) from 2-(N-ethyl-N-tert butoxycarbonylamino)acetic acid NMR (DMSO-d 6 , 8): 1.22 (3H, t, J=7.OHz), 1.74-2.06 (4H, m), 2.35-2.45 (1H, m), 2.95-3.27 (6H, m), 3.51 15 3.57 (1H, m), 3.96 (2H, t, J=5.OHz), 7.22 (1H, d, J=4.OHz), 7.42-7.46 (3H, m), 7.48-7.51 (1H, m), 7.93 (1H, s), 8.87 (2H, br), 10.60 (1H, s), 10.54 (1H, s) MS (ESI+): 466.2 (M+H) 20 Example 452 (2S)-N-Hydroxy-2-[5-{3-(((2S)-2-(aminobutyryl)amino) phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (105 mg) from L-Boc-Abu-OH 25 NMR (DMSO-d 6 , 6): 0.98 (3H, t, J=6.5Hz), 1.74-2.06 (4H, m), 1.89 (2H, qt, J=6.5, 6.5Hz), 2.36-2.45 (1H, m), 2.96-3.27 (4H, m), 3.44-3.54 (1H, m), 3.90 (1H, br), 7.22 (1H, d, J=4.OHz), 7.39-7.46 (3H, m), 7.52-7.56 (1H, m), 7.91 (1H, s), 8.32 (2H, br), 30 8.85 (1H, s), 10.56 (1H, s), 10.60 (1H, s) MS (ESI+): 467.2 (M+H) Example 453 (2S)-N-Hydroxy-2-[5-{3-(2-(piperizinocarbonyloxy) 35 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 , 6): 1.48-1.58 (6H, m), 1.75-2.05 (4H, m), 2.37-2.46 (1H, m), 2.95-3.26 (4H, m), 3.46-3.55 (5H, m), 4.62 (2H, s), 7.20 (1H, d, J=4.OHz), 5 7.35-7.38 (3H, m), 7.62 (1H, d, J=4.OHz), 8.00 (1H, s), 10.17 (1H, s), 10.60 (1H, s) MS (ESI-): 548.2 (M-H) Example 454 10 (2S)-N-Hydroxy-2-[5-{3-(2-(benzylaminocarbonyloxy) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (55 mg) NMR (DMSO-d 6 , 6): 1.73-2.05 (4H, m), 2.37-2.46 (1H, m), 2.94-3.26 (4H, m), 3.42-3.53 (1H, m), 4.22 (2H, d, 15 J=5.OHz), 4.61 (2H, s), 7.20-7.48 (10H, m), 7.93 7.97 (2H, m), 8.84 (1H, br), 10.15 (1H, s), 10.60 (1H, s) MS (ESI-): 570.1 (M-H) 20 Example 455 (2S)-N-Hydroxy-2-[5-{3-(2-(3-methylphenoxy) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (30 mg) NMR (DMSO-d 6 , 6): 1.73-2.06 (4H, m), 2.30 (3H, s), 25 2.37-2.47 (1H, m), 2.95-3.26 (4H, m), 3.40-3.50 (1H, m), 4.70 (2H, s), 6.70-6.75 (3H, m), 7.20 7.22 (2H, m), 7.38-7.40 (2H, m), 7.43 (1H, d, J=4.OHz), 7.56 (1H, d, J=7.OHz), 8.03 (1H, s), 8.84 (1H, s), 10.17 (1H, s), 10.60 (1H, s) 30 MS (ESI+): 565.2 (M+H+Cl) Example 456 (2S)-N-Hydroxy-2-[5-{3-(2-(3-pyridyloxy) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H 35 thiopyran-2-acetamide 1,1-dioxide (50 mg) WO 00/40576 PCT/JP00/00018 276 NMR (DMSO-d 6 , 6):1.72-2.06 (4H, m), 2.37-2.48 (1H, m), 2.96-3.27 (4H, m), 3.40-3.50 (1H, m), 4.90 (2H, s), 7.20 (1H, d, J=4.OHz), 7.35-7.42 (3H, m), 7.52 7.56 (2H, m), 7.64-7.66 (1H, m), 8.00 (1H, s), 5 8.30 (1H, d, J=4.5Hz), 8.50 (1H, d, J=2.OHz), 10.30 (1H, s), 10.60 (1H, s) MS (ESI-): 514.1 (M-H) Example 457 10 (2S)-N-Hydroxy-2-[5-{3-(2-(4-pyridyloxy)acetylamino) phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (35 mg) NMR (DMSO-d 6 , 6): 1.72-2.05 (4H, m), 2.35-2.44 (1H, m), 2.95-3.25 (4H, m), 3.42-3.53 (1H, m), 5.26 (2H, s), 15 7.07 (2H, d, J=7.0Hz), 7.20 (1H, d, J=4.0Hz), 7.40-7.42 (4H, m), 8.03 (1H, s), 8.41 (2H, d, J=7.0Hz) MS (ESI+): 516.1 (M+H) 20 Example 458 (2S)-N-Hydroxy-2-[5-{3-(((2S)-2-amino-3-(4-pyridyl) propionyl)amino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (160 mg) L-Boc4-PyAla-OH NMR (DMSO-d 6 , 6): 1.72-2.06 (4H, m), 2.35-2.46 (lH, m), 25 2.96-3.39 (6H, m), 3.44-3.55 (lH, m), 4.30 (1H, br), 7.22 (lH, d, J=4.OHz), 7.42-7.48 (4H, m), 7.55 (1H, d, J=6.0Hz), 7.85 (1H, s), 8.39 (2H, br), 8.70 (2H, d,. J=5.5Hz), 10.60 (lH, s), 10.62 (1H, s) 30 MS (ESI+): 529.2 (M+H) Example 459 (2S)-N-Hydroxy-2-[5-{3-(((2S)-2-amino-3 phenylpropionyl)amino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro 35 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 , 8): 1.74-2.06 (4H, m), 2.35-2.44 (1H, m), 2.95-3.27 (6H, m), 3.43-3.53 (1H, m), 4.15 (1H, br), 7.22 (1H, d, J=4.0Hz), 7.25-7.35 (5H, m), 5 7.39-7.46 (4H, m), 7.80 (1H, s), 8.32 (2H, br), 8.85 (1H, br), 10.47 (1H, s), 10.73 (1H, s) MS (ESI+): 528.3 (M+H) The following compounds were obtained in a similar 10 manner to that of Example 130. Example 460 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2 (methanesulfonylamino)acetylamino)phenyl)-2-thienyl] 15 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (75 mg) NMR (DMSO-d 6 , 6): 1.46-1.72 (8H, m), 1.87-1.99 (2H, m), 2.06-2.24 (2H, m), 2.81-2.92 (2H, m), 3.02 (3H, s), 3.05-3.21 (2H, m), 3.28-3.52 (1H, m), 3.68-3.80 20 (1H, m), 3.98-4.06 (2H, m), 4.53, 4.87 (1H, br s), 5.94-6.08 (1H, m), 7.06-7.21 (4H, m), 7.42-7.52 (2H, m), 8.58, 8.59 (1H, br s) MS (ESI-): 598 (M-H) 25 Example 461 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (phenylacetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (132 mg) NMR (CDC1 3 , 6): 1.30-1.73 (8H, m), 1.84-1.97 (2H, m), 30 2.04-2.23 (2H, m), 2.70-2.90 (2H, m), 2.97-3.16 (2H, m), 3.26-3.51 (1H, m), 3.63-3.73 (1H, m), 3.73 (2H, s), 4.52, 4.72 (1H, br s), 7.08-7.62 (12H, m), 8.68 (1H, br s) MS (ESI-): 580 (M-H) 35 WO 00/40576 PCT/JPOO/00018 278 Example 462 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (cyclopropanecarbonylamino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (550 mg) 5 NMR (DMSO-d 6 , 6): 0.72-0.89 (4H, m), 1.32-1.64 (6H, m), 1.67-2.06 (5H, m), 2.34-2.49 (1H, m), 2.87-3.30 (5H, m), 3.41-3.53 (1H, m), 3.72-3.91 (1H, m), 4.44, 4.75 (1H, s), 7.16-7.26 (1H, m), 7.39-7.52 (4H, m), 8.02 (1H, s) 10 MS (ESI-): 531 (M-H) Example 463 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(propoxy carbonylamino)acetylamino)phenyl}-2-thienyll-3,4,5,6 15 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (93 mg) NMR (CDCl 3 , 8): 0.93-0.99 (3H, m), 1.44 (2H, br), 1.65-1.75 (6H, m), 1.95 (2H, br), 2.04-2.26 (2H, m), 2.72-2.92 (2H, m), 3.01-3.15 (4H, m), 3.28 3.48 (1H, m), 3.70 (1H, br), 3.95-4.12 (4H, m), 20 4.53 (1/2H, s), 4.84 (1/2H, s), 5.54-5.64 (1H, m), 7.12-7.23 (4H, m), 7.50 (1H, br s), 7.58 (1H, s), 8.28 (1H, br), 8.70-8.78 (1H, m) MS (ESI-): 606.1 (M-H) 25 Example 464 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2 (cyclopentyloxycarbonylamino)acetylamino)phenyl}-2-thienyl] 3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (53 mg) 30 NMR (CDCl 3 , 6): 1.44 (4H, br), 1.60-1.74 (4H, m), 1.86-1.96 (6H, m), 2.05-2.24 (2H, m), 2.70-2.89 (2H, m), 2.96-3.20 (4H, m), 3.29-3.52 (1H, m), 3.64-3.75 (1H, m), 3.94-4.02 (2H, m), 4.54 (1/2H, s), 4.83 (1/2H, s), 5.16 (1H, br), 5.45-5.54 (1H, 35 m), 7.16-7.25 (3H, m), 7.51-7.60 (2H, m), 8.30 (1H, WO 00/40576 PCT/JPOO/00018 279 br) MS (ESI-): 632.1 (M-H) The following compounds were obtained in a similar 5 manner to that of Example 211. Example 465 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2-(2 oxopyrrolidinyl)acetylamino)phenyl)-2-thienyl)-3,4,5,6 10 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (520 mg) NMR (DMSO-d 6 , 6): 1.32-1.63 (6H, m), 1.68-2.09 (6H, m), 2.28 (2H, t, J=7Hz), 2.35-2.48 (1H, m), 2.86-3.53 (6H, m), 3.46 (2H, t, J=7Hz), 3.22-3.40 (1H, m), 4.05 (2H, s), 4.44, 4.75 (1H, s), 7.16-7.25 (1H, 15 m), 7.32-7.46 (4H, m), 8.02 (1H, s), 10.20 (1H, s), 11.25 (1H, s) MS (ESI-): 588 (M-H) Example 466 20 ( 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(((3S)-N-tert butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3 carbonyl)amino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (135 mg) NMR (DMSO-d 6 , 8): 1.18-2.06 (10H, m), 1.31 (9H, s), 25 2.34-2.47 (1H, m), 2.88-3.31 (7H, m), 3.38-3.54 (1H, m), 3.72-3.88 (1H, m), 4.36-4.85 (4H, m), 7.14-7.50 (9H, m), 7.88-8.00 (1H, m), 10.16 (1H, s), 11.24 (1H, s) MS (ESI-): 722 (M-H) 30 Example 467 (2S)-N-(2-Tetrahydropyranyloxy)-2-[S-(3-(oxolane-2 carbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (670 mg) 35 NMR (DMSO-d 6 , 8): 1.38-1.62 (6H, m), 1.70-2.08 (7H, m), WO 00/40576 PCT/JPO0/00018 280 2.14-2.78 (1H, m), 2.36-2.50 (1H, m), 2.90-3.32 (5H, m), 3.40-3.53 (1H, m), 3.74-3.90 (1H, dd, J=7Hz), 4.02 (1H, dd, J=7Hz), 4.42 (1H, dd, J=7Hz), 4.45, 4.75 (1H, s), 7.19-7.25 (1H, m), 7.31-7.44 5 (3H, m), 7.65 (1H, d, J=8Hz), 8.07 (1H, s), 9.78 (1H, s), 11.25 (1H, s) MS (ESI-): 561 (M-H) Example 468 10 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(oxolane-3 carbonylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (700 mg) NMR (DMSO-d 6 , 6): 1.33-1.63 (6H, m), 1.69-2.15 (4H, m), 2.09 (2H, dd, J=8Hz), 2.35-2.48 (1H, m), 2.86-3.32 15 (4H, m), 3.39-3.56 (1H, m), 3.65-3.86 (4H, m), 3.88-4.00 (1H, m), 4.45, 4.75 (1H, s), 7.18-7.25 (1H, m), 7.30-7.52 (4H, m), 8.02 (1H, s), 10.15 (1H, s), 11.24, 11.25 (1H, s) MS (ESI-): 561 (M-H) 20 Example 469 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(ethyl aminocarbonylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (4.7 g) 25 NMR (CDC1 3 , 5): 0.85-0.93 (3H, M), 1.45 (4H, br), 1.55-1.68 (2H, m), 1.92 (2H, br), 2.01-2.25 (2H, m), 2.92-3.10 (7H, m), 3.26-3.75 (iH, m), 3.44 3.54 (2H, m), 3.68-4.02 (2H, M), 4.30-4.40 (1H, m), 4.65 (1/2H, br), 4.92 (1/2H, br), 6.02 (1H, br), 30 7.07-7.26 (7H, m), 7.54 (1/2H, s), 7.60 (1/2H, s), 9.27 (1/2H, s), 9.32 (1/2H, s) MS (ESI-): 591.2 (M-H) Example 470 35 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3- WO 00/40576 PCT/JPOO/00018 281 isovalerylaminophenyl)-2-thienyl)-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (200 mg) NMR (CDC1 3 , 6): 1.04 (6H, d, J=6.OHz), 1.16 (2H, d, J=7.5Hz), 1.45 (2H, br), 1.65-1.75 (2H, m), 1.92 5 1.95 (2H, m), 2.07-2.30 (2H, m), 2.28 (2H, br), 2.30-2.40 (1H, m), 2.71-2.90 (2H, m), 3.04-3.15 (4H, m), 3.30-3.50 (1H, m), 3.64-3.75 (1H, m), 4.52 (1/2H, br s), 4.82 (1/2H, br s), 7.20-7.30 (3H, m), 7.39-7.46 (1H, m), 7.50-7.57 (2H, m), 10 7.62-7.66 (1H, m), 8.37-8.47 (1H, m) MS (ESI-): 547.1 (M-H) Example 471 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2 15 (methoxyacetylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (195 mg) NMR (CDCl 3 , 8): 1.45 (2H, br), 1.67 (4H, br), 1.97 (2H, br), 2.07-2.24 (2H, m), 2.80-2.87 (2H, m), 3.01 3.06 (lH, m), 3.11-3.20 (3H, m), 3.30-3.44 (1H, m), 20 3.46 (3H, s), 3.68-3.78 (1H, m), 4.04 (2H, s), 4.09-4.13 (1H, m), 4.25-4.32 (1H, m), 4.53 (1/2H, s), 4.84 (1/2H, s), 7.08-7.24 (3H, m), 7.42 (2H, br), 7.48-7.54 (2H, m), 8.56 (1H, br), 9.08 (1/2H, s), 9.18 (1/2H, br s) 25 MS (ESI+): 591.1 (M+H) Example 472 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(3 pyridylcarbonylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 30 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (90 mg) NMR (CDCl 3 , 8): 1.36 (2H, br), 1.65 (4H, br), 1.94 (2H, br), 2.06-2.23 (2H, m), 2.80-3.20 (7H, m), 3.55 3.72 (1H, m), 4.36 (1/2H, br s), 4.37-4.65 (2H, m), 4.86 (1/2H, s), 7.13-7.30 (5H, m), 7.43-7.49 (1H, 35 m), 7.54 (1H, br s), 7.75-7.81 (1H, m), 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, m), 9.40 (1/2H, s) MS (ESI+): 625.1 (M+H) 5 Example 473 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3 (methoxymethylaminocarbonylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (100 mg) was obtained in a similar manner to that of Example 348. 10 NMR (CDC1 3 , 8): 1.25 (2H, br), 1.43 (2H, br), 1.64 (2H, br), 1.93 (2H, br), 2.05-2.22 (2H, m), 2.70-2.88 (2H, m), 3.00-3.13 (4H, m), 3.37 (3H, s), 3.45 3.52 (4H, m), 4.55 (1/2H, br), 4.81 (1/2H, br), 5.40-5.49 (1H, m), 7.08-7.20 (6H, m), 7.27-7.40 15 (1H, m), 8.91 (1/2H, br), 8.98 (1/2H, br) MS (ESI-): 567.1 (M-H+NH 3 ) Example 474 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(3 20 pyridylmethylamino)acetylamino)phenyl}-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (100 mg) was obtained in a similar manner to that of Example 249. NMR (CDC1 3 , 8): 1.42 (2H, br), 1.63-1.68 (4H, m), 1.95 (2H, br), 2.07-2.23 (2H, m), 2.68-2.95 (2H, m), 25 3.08 (2H, br s), 3.13 (2H, br), 3.27-3.44 (1H, m), 3.46 (2H, s), 3.62-3.70 (1H, m), 3.90 (2H, s), 4.52 (1/2H, br), 4.82 (1/2H, br), 7.24-7.34 (6H, m), 7.53-7.57 (1H, m), 7.65-7.70 (2H, m), 8.57 (1H, d, J=5.0Hz), 8.62 (1/2H, br), 8.65 (1H, s), 8.90 30 (1/2H, s), 9.17 (1H, d, J=6.OHz) MS (ESI+): 613.2 (M+H) Example 475 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-{3-(2-(tert 35 butylamino)acetylamino)phenyl}-2-thienyl]- 3

,

4 ,5, 6

-

WO 00/40576 PCT/JPOO/00018 283 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (95 mg) was obtained in a similar manner to that of Example 249. NMR (CDCl 3 , 6): 1.17 (9H, s), 1.46 (2H, br), 1.65-1.70 (4H, m), 1.96 (2H, br), 2.09-2.23 (2H, m), 2.64 5 2.86 (2H, m), 3.06 (2H, br s), 3.10-3.15 (2H, m), 3.36 (2H, br s), 3.43-3.70 (2H, m), 4.53 (1/2H, br), 4.80 (1/2H, br), 7.22-7.34 (5H, m), 7.56-7.60 (1H, m), 7.78 (1H, s), 9.53 (1H, s) MS (ESI-): 593.6 (M-H+NH 3 ) 10 The following compounds were obtained in a similar manner to that of Example 54. Example 476 15 ( 2 S)-N-Hydroxy-2-[5-(3-(2-(N-methanesulfonylamino) acetylamino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (32 mg) NMR (DMSO-d 6 , 8): 1.72-2.08 (4H, m), 2.33-2.48 (1H, m), 2.92-3.56 (7H, m), 3.00 (3H, s), 3.87 (1H, d, 20 J=7Hz), 7.21 (1H, d, J=3Hz), 7.34-7.52 (4H, m), 7.96 (1H, s), 8.84 (1H, s) MS (ESI-): 514 (M-H) Example 477 25 (2S)-N-Hydroxy-2-[5-(3-phenylacetylamino)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (92 mg) NMR (DMSO-d 6 , 8): 1.67-2.08 (4H, m), 2.32-2.51 (1H, m), 2.89-3.54 (5H, m), 3.66 (2H, s), 7.17-7.53 (11H, 30 m), 8.00 (1H, s), 10.30 (1H, s), 10.60 (1H, s) MS (ESI-): 497 (M-H) Example 478 (2S)-N-Hydroxy-2-[5-(3-(2-(2-oxopyrrolidinyl) 35 acetylamino)phenyl)-2-thienyll-3,4,5,6-tetrahydro-2H- WO 00/40576 PCT/JP0O/00018 284 thiopyran-2-acetamide 1,1-dioxide (420 mg) NMR (DMSO-d 6 , 8): 1.68-2.12 (6H, m), 2.19-2.48 (3H, m), 2.90-3.61 (7H, m), 4.06 (2H, s), 7.20 (1H, d, J=3Hz), 7.31-7.52 (5H, m), 8.02 (1H, s), 10.23 (1H, 5 s), 10.62 (1H, s) MS (ESI-): 504 (M-H) Example 479 (2S)-N-Hydroxy-2-[5-(3-(((3S)-1,2,3,4-tetrahydro 10 isolquinoline-3-carbonyl)amino)phenyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide hydrochloride (88 mg) from (2S)-N-(2-tetrahydropyranyloxy-2 [5-(3-(((3S)-N-tert-butoxycarbonyl-1,2,3,4 tetrahydroisoquinoline-3-carbonyl)amino)phenyl)-2-thienyl] 15 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide NMR (DMSO-d 6 , 8): 1.66-2.14 (4H, m), 2.32-2.48 (1H, m), 2.86-3.92 (7H, m), 4.26-4.51 (3H, m), 7.12-7.52 (8H, m), 7.56-7.68 (1H, m), 8.03 (1H, s), 9.55 (1H, br s), 9.96 (1H, br s), 10.67 (1H, s), 11.22 (1H, 20 s) MS (ESI+): 540 (M+H) Example 480 (2S)-N-Hydroxy-2-[5-(3-(cyclopropanecarbonylamino) 25 phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (410 mg) NMR (DMSO-d 6 , 6): 0.70-0.90 (4H, m), 1.66-2.10 (5H, m), 2.34-2.49 (1H, m), 3.42-3.55 (1H, m), 7.21 (1H, d, J=3Hz), 7.28-7.39 (2H, m), 7.40 (1H, d, J=3Hz), 30 7.42-7.52 (1H, m), 8.01 (1H, s), 10.33 (1H, s), 10.61 (1H, s) MS (ESI-): 447 (M-H) Example 481 35 (2S)-N-Hydroxy-2-[5-(3-(oxolane-2-carbonylamino)- WO 00/40576 PCT/JPOO/00018 285 phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (340 mg) NMR (DMSO-d 6 , 5): 1.71-2.07 (7H, m), 2.14-2.27 (1H, m), 2.93-3.27 (4H, m), 3.40-3.55 (1H, m), 3.84 (1H, dd, 5 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, m), 7.65 (1H, d, J=8Hz), 8.07 (1H, s), 8.85 (1H, s), 9.78 (1H, s), 10.60 (1H, s) MS (ESI-): 477 (M-H) 10 Example 482 (2S)-N-Hydroxy-2-[5-(3-(oxolane-3-carbonylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (541 mg) 15 NMR (DMSO-d 6 , 5): 1.68-2.20 (4H, m), 2.09 (2H, dd, J=8Hz), 2.24-2.49 (1H, m), 2.92-3.31 (4H, m), 3.43-3.54 (1H, m), 3.65-3.76 (4H, m), 3.95 (1H, t, J=8Hz), 7.21 (1H, d, J=3Hz), 7.30-7.54 (4H, m), 8.02 (1H, s), 10.17 (1H, s), 10.61 (1H, s) 20 MS (ESI-): 477 (M-H) Example 483 (2S)-N-Hydroxy-2-[5-{3-(2-(ethylaminocarbonylamino) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H 25 thiopyran-2-acetamide 1,1-dioxide (3.0 mg) NMR (DMSO-d 6 , 5): 1.00 (3H, t, J=7.5Hz), 1.73-2.05 (4H, m), 2.38-2.46 (1H, m), 2.95-3.25 (6H, m), 3.43 3.53 (1H, m), 3.83 (2H, d, J=6.OHz), 6.10-6.18 (2H, m), 7.20 (1H, d, J=4.OHz), 7.35-7.37 (2H, m), 7.40 30 (1H, d, J=4.0Hz), 7.46-7.50 (1H, m), 7.97 (1H, s), 8.84 (1H, s) MS (ESI-): 507.2 (M-H) Example 484 35 ( 2 S)-N-Hydroxy- 2 -[5-(3-isovalerylaminophenyl)-2- WO 00/40576 PCT/JPOO/00018 286 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (120 mg) NMR (DMSO-d 6 , 8): 0.95 (6H, d, J=7.5Hz), 1.74-2.15 (5H, m), 2.20 (2H, d, J=7.OHz), 2.38-2.45 (1H, m), 5 2.95-3.26 (4H, m), 3.40-3.53 (1H, m), 7.20 (1H, d, J=4.OHz), 7.32-7.37 (2H, m), 7.46-7.50 (1H, m), 8.00 (1H, s), 9.97 (1H, s), 10.60 (1H, s) MS (ESI-): 463.0 (M-H) 10 Example 485 (2S)-N-Hydroxy-2-[5-(3-(methoxymethylaminocarbonyl amino)phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (70 mg) NMR (DMSO-d 6 , 8): 1.73-2.04 (4H, m), 2.35-2.45 (1H, m), 15 2.95-3.28 (6H, m), 3.26 (3H, s), 3.37-3.42 (1H, m), 6.24 (1H, t, J=7.OHz), 7.16-7.27 (4H, m), 7.37 (1H, d, J=4.OHz), 7.83 (1H, s), 8.67 (1H, s) MS (ESI-): 466.4 (M-H) 20 Example 486 (2S)-N-Hydroxy-2-[5-{3-(2-(3-pyridylmethylamino) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (60 mg) NMR (DMSO-d 6 , 6): 1.72-2.06 (4H, m), 2.35-2.45 (1H, m), 25 2.97-3.28 (4H, m), 3.42-3.50 (1H, m), 3.98 (2H, br), 4.35 (2H, br), 7.22 (1H, d, J=4.OHz), 7.38 7.43 (2H, m), 7.48-7.52 (1H, m), 7.68-7.73 (1H, m), 7.93 (1H, s), 8.23 (1H, d, J=7.OHz), 8.74 (1H, d, J=6.OHz), 8.85 (1H, s), 9.68 (1H, br) 30 MS (ESI-): 527.1 (M-H) Example 487 (2S)-N-Hydroxy-2-[5-{3-(2-(propoxycarbonylamino) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H 35 thiopyran-2-acetamide 1,1-dioxide (70 mg) WO 00/40576 PCT/JP00/00018 287 NMR (DMSO-d 6 , 6): 0.91 (3H, t, J=7.0Hz), 1.58 (2H, qt, J=7.0, 7.0Hz), 1.73-2.05 (4H, m), 2.37-2.48 (1H, m), 2.94-3.27 (4H, m), 3.44-3.53 (1H, m), 3.79 (2H, d, J=6.0Hz), 3.93 (2H, t, J=7.0Hz), 7.21 (1H, d, 5 J=4.0Hz), 7.35-7.42 (4H, m), 7.45-7.48 (1H, m), 7.97 (1H, s), 8.84 (1H, s), 10.08 (1H, s), 10.61 (1H, s) MS (ESI-): 522.1 (M-H) 10 Example 488 (2S)-N-Hydroxy-2-[5-{3-(2-(cyclopentyloxycarbonyl amino)acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (30 mg) NMR (DMSO-d 6 , 8): 1.50-1.70 (6H, m), 1.75-2.05 (6H, m), 15 2.37-2.48 (1H, m), 2.95-3.25 (4H, m), 3.43-3.53 (1H, m), 3.77 (2H, d, J=5.OHz), 4.97 (1H, br), 7.20 (1H, d, J=4.OHz), 7.30 (1H, t, J=7.OHz), 7.35-7.38 (2H, m), 7.41 (1H, d, J=4.0Hz), 7.45 7.48 (1H, m), 7.98 (1H, s), 8.83 (1H, br), 10.07 20 (1H, s), 10.60 (1H, br) MS (ESI-): 548.1 (M-H) Example 489 (2S)-N-Hydroxy-2-[5-{3-(2-(methoxyacetylamino)phenyl} 25 2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (70 mg) NMR (DMSO-d 6 , 6): 1.74-2.05 (4H, m), 2.36-2.48 (1H, m), 2.95-3.26 (4H, m), 3.37 (3H, s), 3.43-3.54 (1H, m), 3.39 (2H, s), 3.45 (2H, d, J=6.OHz), 7.20 (1H, d, 30 J=4.OHz), 7.36-7.40 (2H, m), 7.42 (1H, d, J=4.OHz), 7.43-7.48 (1H, m), 7.94 (1H, s), 8.05 (1H, t, J=6.OHz), 8.84 (1H, s), 10.13 (1H, s), 10.60 (1H, s) MS (ESI-): 508.1 (M-H) 35 WO 00/40576 PCT/JPOO/00018 288 Example 490 (2S)-N-Hydroxy-2-[5-{3-(2-(tert-butylamino) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (50 mg) 5 NMR (DMSO-d 6 , 6): 1.32 (9H, s), 1.72-2.06 (4H, m), 2.35-2.46 (1H, m), 2.96-3.28 (4H, m), 3.38-3.52 (1H, m), 3.96 (2H, t, J=7.OHz), 7.22 (1H, d, J=4.0Hz), 7.41-7.44 (3H, m), 7.51-7.54 (1H, m), 7.97 (1H, s), 8.84 (1H, br), 8.95-8.98 (2H, br) 10 MS (ESI+): 494.1 (M+H) Example 491 (2S)-N-Hydroxy-2-[5-{3-(2-(3-pyridylcarbonylamino) acetylamino)phenyl}-2-thienyl]-3,4,5,6-tetrahydro-2H 15 thiopyran-2-acetamide 1,1-dioxide (60 mg) NMR (DMSO-d 6 , 8): 1.72-2.04 (4H, m), 2.37-2.45 (1H, m), 2.95-3.25 (4H, m), 3.40-3.52 (1H, m), 4.00 4.06 (2H, br), 4.13 (2H, d, J=7.OHz), 7.20 (1H, d, J=4.0Hz), 7.32-7.39 (2H, m), 7.42 (1H, d, J=4.0Hz), 20 7.46-7.50 (1H, m), 7.59-7.64 (1H, m), 8.02 (1H, s), 8.30-8.33 (1H, m), 8.77 (1H, d, J=6.OHz), 9.10 (1H, s), 9.15 (1H, t, J=7.SHz) MS (ESI-): 527.3 (M-H) 25 Example 492 (2S)-N-Hydroxy-2-[5-{3-(3,3-dimethylbutyrylamino) phenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (160 mg) was obtained from 3,3 dimethylbutyric acid in a similar manner to that of Example 30 408. NMR (DMSO-d 6 , 8): 1.03 (9H, s), 1.66-2.10 (4H, m), 2.21 (2H, s), 2.34-2.48 (1H, m), 2.92-3.29 (4H, m), 3.42-3.56 (1H, m), 7.20 (1H, d, J=3Hz), 7.28-7.38 (2H, m), 7.40 (1H, d, J=3Hz), 7.45-7.54 (1H, m), 35 7.99 (1H, s), 9.93 (1H, s), 10.61 (1H, s) WO 00/40576 PCT/JPOO/00018 289 MS (ESI-): 477 (M-H) Example 493 (2S)-N-Hydroxy-2-[5-(4-ethoxyphenyl)-2-thienyl] 5 3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (8.5 mg) was obtained in a similar manner to that of Example 168. NMR (DMSO-d 6 , 6): 1.35 (3H, t, J=7.OHz), 1.73-2.04 (4H, m), 2.34-2.44 (1H, m), 2.95-3.25 (4H, m), 3.62 3.68 (1H, m), 4.06 (2H, q, J=7.OHz), 6.97 (2H, d, 10 J=7.5Hz), 7.16 (1H, d, J=4.0Hz), 7.33 (1H, d, J=4.OHz), 7.56 (1H, d, J=7.5Hz) MS (ESI+): 410.2 (M+H) The following compounds were obtained in a similar 15 manner to that of Example 130. Example 494 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (cyclobutylcarbonylamino)phenyl)-2-thienyl]-3,4,5,6 20 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (340 mg) NMR (DMSO-d 6 , 6): 1.37-1.65 (6H, m), 1.70-2.30 (10H, m), 2.37-2.46 (1H, m), 2.90-3.55 (7H, m), 3.75-3.89 (1H, m), 4.44, 4.75 (1H, s), 7.19-7.22 (1H, m), 7.34-7.40 (3H, m), 7.45-7.51 (1H, m), 8.03 (1H, s), 25 9.83 (1H, s) Example 495 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3 (isobutyrylaminophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H 30 thiopyran-2-acetamide 1,1-dioxide (330 mg) NMR (DMSO-d 6 , 8): 1.11 (6H, d, J=7.OHz), 1.36-1.64 (6H, m), 1.70-2.05 (4H, m), 2.35-2.45 (1H, m), 2.55 2.64 (1H, m), 2.90-3.54 (6H, m), 3.75-3.90 (1H, m), 4.45, 4.75 (1H, s), 7.20-7.23 (1H, m), 7.33-7.41 35 (3H, m), 7.45-7.51 (1H, m), 8.03 (1H, s) WO 00/40576 PCT/JPOO/00018 290 Example 496 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-(2,2 dimethylpropionylamino)phenyl]-2-thienyl]-3,4,5,6 5 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (267 mg) NMR (DMSO-d 6 , 6): 1.24 (9H, s), 1.36-1.64 (6H, m), 1.69-2.09 (4H, m), 2.36-2.53 (1H, m), 2.88-3.29 (4H, m), 3.30-3.51 (2H, m), 3.74-3.91 (1H, m), 4.44 (0.5H, s), 4.76 (0.5H, s), 7.19-7.24 (1H, m), 10 7.30-7.42 (3H, m), 7.59-7.65 (1H, m), 8.01 (1H, s), 9.30 (1H, s) MS (ESI-): 547 (M-H) Example 497 15 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(3-((E)-2 butenoylamino)phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (160 mg) NMR (CDC1 3 , 8): 1.37-1.76 (6H, m), 1.86-2.02 (5H, m), 2.04-2.26 (2H, m), 2.68-2.94 (2H, m), 3.00-3.19 20 (4H, m), 3.30-3.51 (1H, m), 3.62-3.76 (lH, m), 4.55 (0.5H, s), 4.83 (0.5H, s), 6.00 (1H, dd, J=1.5, 15Hz), 6.94-7.09 (1H, m), 7.13-7.33 (4H, m), 7.49-7.67 (3H, m), 8.45-8.55 (1H, m) MS (ESI-): 531 (M-H) 25 The following compounds were obtained in a similar manner to that of Example 201. Example 498 30 35 WO 00/40576 PCT/JPOO/00018 291 5 Br 0', 0 0 0 B 3 S N N 0 ' -HCl NH oNH .0 0 20 ( 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4-pyridyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (60 mg) NMR (CDC1 3 , 8): 1.40-1.76 (6H, m), 1.86-2.00 (2H, m), 2.06-2.25 (2H, m), 2.71-2.93 (2H, m), 3.00-3.19 25 (4H, m), 3.25-3.55 (1H, m), 3.60-3.799 (1H, m), 4.50 (0.5H, s), 4.84 (0.5H, s), 7.16-7.35 (1H, m), 7.44-7.49 (3H, m), 8.21 (0.5H, s), 8.28 (0.5H, s), 8.59 (2H, d, J=8Hz) MS (ESI+): 451 (M+H) 30 Example 499 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 (methylaminocarbonylmethyl)phenyl]-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (67 mg) 35 MS (ESI-): 519 (M-H) Example 500 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(2 (methylaminocarbonyl)-5-benzofuranyl]-2-thienyl]-3,4,5,6 40 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (283 mg) NMR (CDCl3, )): 1.38-1.76 (6H, m), 1.88-2.02 (2H, m), 2.04-2.25 (2H, m), 2.65-2.93 (2H, m), 3.01-3.18 WO 00/40576 PCT/JPOO/00018 292 (7H, m), 3.26-3.51 (1H, m), 3.60-3.74 (1H, m), 4.55 (0.5H, s), 4.83 (0.5H, s), 6.61-6.71 (1H, m), 7.21-7.31 (2H, m), 7.43-7.50 (2H, m), 7.60-7.66 (1H, m), 7.83-7.88 (1H, m), 8.20 (0.5H, s), 8.27 5 (0.5H, s) Example 501 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 methylthiophenyl)-2-thienyl]-3,4,5,6-tetrahydro-2H 10 thiopyran-2-acetamide 1,1-dioxide (129 mg) was obtained in a similar manner to that of Example 89. NMR (CDCl 3 , 6): 1.38-1.76 (6H, m), 1.86-2.00 (2H, m), 2.05-2.24 (2H, m), 2.51 (3H, s), 2.61-2.90 (2H, m), 3.03-3.17 (4H, m), 3.26-3.50 (1H, m), 3.56-3.70 15 (1H, m), 4.52 (0.5H, s), 4.79 (0.5H, s), 7.20-7.36 (3H, m), 7.45-7.54 (2H, m), 7.62-7.68 (1H, m), 7.98 (0.5H, s), 8.09-8.15 (0.5H, m) Example 502 20 ( 2 S)-N-(2-Tetrahydropyranyloxy)-2-[5-(4 methanesulfonyl)phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (57 mg) was obtained from (2S)-N-(2-tetrahydropyranyloxy)-2-[5-(4-methylthiophenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 25 dioxide in a similar manner to that of Preparation 1-4). NMR (CDCl 3 , 6): 1.40-1.59 (4H, m), 1.62-1.74 (2H, m), 1.88-2.02 (2H, m), 2.05-2.25 (2H, m), 2.76-2.88 (2H, m), 3.04-3.20 (7H, m), 3.40-3.54 (1H, m), 3.60-3.77 (1H, m), 4.54 (0.5H, s), 4.82 (0.5H, s), 30 7.26-7.35 (1H, m), 7.37-7.43 (1H, m), 7.73-7.80 (2H, m), 7.90-7.97 (2H, m), 8.14 (0.5H, s), 8.20 (0.5H, s) The following compounds were obtained in a similar 35 manner to that of Example 54.

WO 00/40576 PCT/JPOO/00018 293 Example 503 (2S)-N-Hydroxy-2-[5-(4-methanesulfonyl)phenyl]-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 5 dioxide (27 mg) NMR (DMSO-d 6 , 6): 1.72-2.10 (4H, m), 2.36-2.55 (1H, m), 2.96-3.08 (2H, m), 3.12-3.36 (5H, m), 3.39-3.56 (1H, m), 7.28 (1H, d, J=3.9Hz), 7.70 (1H, d, J=3.9Hz), 7.91 (2H, d, J=8Hz), 7.96 (2H, d, J=8Hz), 10 8.86 (1H, s) MS (ESI-): 442 (M-H) Example 504 (2S)-N-Hydroxy-2-[5-(4-methylaminocarbonylmethyl) 15 phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide (25 mg) NMR (DMSO-d 6 , 8): 1.70-2.06 (4H, m), 2.34-2.52 (1H, m), 2.59 (3H, d, J=4.5Hz), 2.95-3.34 (4H, m), 3.36 3.54 (3H, m), 7.20 (1H, d, J=3.9Hz), 7.29 (2H, d, 20 J=8Hz), 7.43 (1H, d, J=3.9Hz), 7.56 (1H, d, J=8Hz), 7.94-8.02 (1H, m), 8.85 (1H, s) MS (ESI-): 435 (M-H) Example 505 25 (2S)-N-Hydroxy-2-[5-(4-pyridyl)-2-thienyl]-3,4,5,6 tetrahydro-2H-thiopyran-2-acetamide 1,1-dioxide (3.1 mg) MS (ESI+): 367 (M-H) Example 506 30 (2S)-N-Hydroxy-2-[5-(2-(methylaminocarbonyl)-5 benzofuranyl]-2-thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2 acetamide 1,1-dioxide hydrochloride (119 mg) NMR (DMSO-d 6 , 8): 1.72-2.10 (4H, m), 2.36-2.56 (1H, m), 2.81 (3H, d, J=4.8Hz), 2.95-3.31 (4H, m), 3.40 35 3.55 (1H, m), 7.22 (1H, d, J=3.9Hz), 7.49 (1H, d, WO 00/40576 PCT/JPOO/00018 294 J=3.9Hz), 7.53 (1H, s), 7.69 (1H, d, J=8Hz), 7.75 (lH, d, J=8Hz), 8.03 (1H, s), 8.73 (1H, q, J=4.8Hz0, 8.86 (1H, br s), 10.60 (1H, br s) MS (ESI-): 461 (M-H) 5 Example 507 (2S)-N-(2-Tetrahydropyranyloxy)-2-[5-[4 (methanesulfinyl)phenyl]-2-thienyl]-3,4,5,6-tetrahydro-2H thiopyran-2-acetamide 1,1-dioxide (45 mg) was obtained from 10 (2S)-N-(2-tetrahydropyranyloxy)-2-[5-(4-methylthiophenyl)-2 thienyl]-3,4,5, 6 -tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide in a similar manner to that of Preparation 1-4). NMR (CDCl 3 , 6): 1.38-1.76 (6H, m), 1.84-2.01 (2H, m),2.05-2.25 (2H, m), 2.77 (3H, s), 2.77-2.88 (2H, 15 m),3.00-3.18 (4H, m), 3.30-3.54 (1H, m), 3.64-3.79 (1H, m), 4.53 (0.5H, s), 4.83 (0.5H, s), 7.25-7.34 (2H, m), 7.65 (2H, d, J=8Hz), 7.70-7.78 (2H, m), 8.66 (0.5H, s), 8.71 (0.5H, s) MS (ESI-): 510 (M-H) 20 Example 508 (2S)-N-Hydroxy-2-[5-[4-(methanesulfinyl)phenyl)-2 thienyl]-3,4,5,6-tetrahydro-2H-thiopyran-2-acetamide 1,1 dioxide (11 mg) was obtained in a similar manner to that of 25 Example 54. NMR (DMSO-d 6 , 8): 1.71-2.10 (4H, m), 2.35-2.55 (1H, m), 2.78 (3H, s), 2.95-3.08 (2H, m), 3.11-3.38 (2H, m), 3.41-3.55 (1H, m), 7.25 (iH, d, J=3.9Hz), 7.61 (1H, d, J=3.9Hz), 7.72 (2H, d, J=8Hz), 7.85 (2H, d, 30 J=8Hz), 8.85 (1H, s) MS (ESI-): 426 (M-H) 35

Claims (17)

1. A compound of the formula: 5 A Y Z R1-X-Ar-(CH2)m (CH2)n-R 2 (I) 10 in which R 1 is lower alkyl, halogen, optionally substituted heterocyclic group or optionally substituted aryl, R2 is carboxy, protected carboxy or amidated carboxy, 15 Ar is optionally substituted aryl or optionally substituted heterocyclic group, A is lower alkylene, X is oxa or a single bond, 20 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 1 m+n 6, 25 and its salt.

2. The compound of claim 1, in which the heterocyclic group of R and Ar are selected from the group consisting of the following (1) to (14), 30 (1) unsaturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, (2) saturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, 35 (3) unsaturated

3- to 8-membered, WO 00/40576 PCT/JPOO/00018 296 heteromonocyclic group containing 1 or 2 sulfur atoms, (4) unsaturated condensed 7- to 13-membered, heterocyclic group containing 1 to 5 nitrogen 5 atoms, (5) unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, (6) saturated 3- to 8-merbered, heteromonocyclic 10 group containing 1 or 2 oxygen atoms, (7) unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, (8) unsaturated condensed 7- to 13-merbered, 15 heterocyclic group containing 1 or 2 oxygen atoms, (9) unsaturated condensed 7- to 13-membered, heterocyclic group containing 1 or 2 sulfur atoms, 20 (10) 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 25 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 30 group containing 1 or 2 sulfur atoms and I 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 35 WO 00/40576 PCT/JPOO/00018 297 the aryl group of RI and Ar is C 6 -C 10 aryl, and further, each of the above-mentioned heterocyclic group and aryl group are optionally substituted by the 5 group consisting of the following (Al) to (A35); (Al) halogen, (A2) lower alkyl, (A3) lower alkoxy, 10 (A4) halo(lower)alkyl, (A5) halo(lower)alkoxy, (A6) lower alkenyl, (A7) acyl, (A8) lower alkylthio, lower alkylsulfinyl, lower 15 alkylsulfonyl, (A9) C 6 -C 10 aryl, (AlO) halo(C 6 -C 10 )aryl, (All) hydroxy, (A12) hydroxy(lower)alkyl, protected 20 hydroxy(lower)alkyl, (A13) amino, (A14) carboxy, (A15) protected carboxy, (A16) nitro(lower)alkenyl, 25 (A17) lower alkylenedioxy, (A18) acylamino, (A19) nitro, (A20) (C 6 -C 10 )aryl(lower)alkoxy, (A21) carbamoyl(lower)alkenyl optionally N 30 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, 35 (A24) lower alkoxy(lower)alkanoyloxy, WO 00/40576 PCT/JP00/00018 298 (A25) lower alkoxycarbonyloxy, (A26) lower alkenoyloxy optionally substituted by heterocyclic group of the above (1) to (14), (A27) lower cycloalkanecarbonyloxy, 5 (A28) lower alkoxy substituted by the group consisting of carboxy, protected carboxy, lower alkanoyl, lower cycloalkanecarbamoyl, and lower alkylcarbamoyl, (A29) lower alkylcarbamoyloxy(lower)alkyl, 10 (A30) lower alkoxycarbonylamino(lower)alkyl, (A31) amino(lower)alkyl, (A32) lower alkylcarbamoyl(lower)alkyl, (A33) heterocyclic-carbonylamino, the heterocyclic group being selected from the above (1) to 15 (14) and optionally being substituted N protective group, (A34) the above heterocyclic groups (1) to (14) being optionally substituted by lower alkyl, and 20 (A35) oxo. 3. The compound of claim 2, in which R is lower alkyl; halogen; optionally substituted heterocyclic group consisting of the following 25 (1) to (10); or aryl consisting of phenyl and naphtyl; R2 is carboxy, lower alkoxycarbonyl, hydroxyaminocarbonyl, tetrahydropyranyloxyaminocarbonyl, or 30 phenyl(lower)alkylaminocarbonyl, Ar is phenyl or heterocyclic group of the following (3), and m and n are each an integer of 0 or 1, and m+n=1 or 2, wherein the above-mentioned heterocyclic group is; 35 (1) unsaturated 5- or 6-membered heteromonocyclic WO 00/40576 PCT/JPOO/00018 299 group containing 1 to 4 nitrogen atoms, (2) saturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, (3) unsaturated 5- or 6-membered heteromonocyclic 5 group containing 1 to 2 sulfur atoms, (4) unsaturated bicyclic 9- or lO-membered, heterocyclic group containing 1 to 5 nitrogen atoms, (5) unsaturated 5- or 6-membered heteromonocyclic 10 group containing 1 to 2 oxygen atoms, (6) saturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms, (7) unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 15 nitrogen atoms, (8) unsaturated bicyclic 9- or lO-membered, heterocyclic group containing 1 or 2 oxygen atoms, (9) unsaturated bicyclic 9- or lO-membered, heterocyclic group containing 1 or 2 sulfur .atoms, 20 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 25 optionally substituted by the group consisting of the following (B1) to (B5); (Bl) lower alkanoyl, (B2) lower aikyl, (B3) lower alkoxy, 30 (B4) lower alkoxycarbonylamino, (B ) carbamoyl or lower alkylcarbamoyl, (B6) lower alkoxycarbonyl, (B7) halo, and (B8) oxo; 3s and the above-mentioned aryl is optionally WO 00/40576 PCT/JPOO/00018 300 substituted by the group consisting of the (Al) to (A35) as defined in claim 2.

4. The compound of claim 3, in which 5 a group of the formula: 10 is one of the following formulae: S 02 15 CH 3 20 or 02 2 Ri is lower alkyl; halogen; optionally substituted heterocyclic group consisting of the following (1) 25 to (10); or aryl consisting of phenyl and naphtyl, R2 is carboxy, lower alkoxycarbonyl, hydroxyaminocarbonyl, or tetrahydropyranyloxyaminocarbonyl, Ar is phenyl or heterocyclic group of the following (3), 30 and m and n are each an integer of 0 or 1, and m+n=1 or 2, wherein the above-mentioned heterocyclic group is (1) pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, pyrimidyl, pyrazinyl, 35 pyridazinyl, triazolyl, tetrazolyl, WO 00/40576 PCT/JPOO/00018 301 dihydrotriazinyl, (2) azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperidino, pyrazolidinyl, piperazinyl, 5 (3) thienyl, (4) indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, 10 tetrazolopyridazinyl, dihydrotriazolopyridazinyl, (5) furyl, (6) oxolanyl, (7) oxazolyl, isoxazolyl, oxadiazolyl, 15 (8) benzofuranyl, benzodihydrofuranyl, benzodioxolenyl, (9) benzothienyl, dihydrobenzothienyl, (10) morpholinyl, morpholino, wherein the heterocyclic group being 20 optionally substituted by the group consisting of the (B1) to (B8) as defined in claim 3, and the above-mentioned aryl is optionally substituted by the group consisting of following (Al) to (A34), 25 (Al) halogen, (A2) lower alkyl, (A3) lower alkoxy, (A4) halo(lower)alkyl, (A5) halo(lower)alkoxy, 30 (A6) lower alkenyl, (A7) acyl, (A8) lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, (A9) C 6 -C 10 aryl 35 (AlO) halo(C6 C10)aryl, WO 00/40576 PCT/JPOO/00018 302 (All) hydroxy, (A12) hydroxy(lower)alkyl or protected hydroxy (lower) alkyl, (A13) amino, 5 (A14) carboxy, (A15) protected carboxy, (A16) nitro(lower)alkenyl, (A17) lower alkylenedioxy, (A18) acylamino, 10 (A19) nitro, (A20) 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 -0C 10 ) 15 aryl, and halo(C 6 -C 10 )aryl, (A22) lower alkylaminocarbonyloxy, (A23) lower alkanoyloxy, (A24) lower alkoxy(lower)alkanoyloxy, (A25) lower alkoxycarbonyloxy, 20 (A26) lower alkenoyloxy optionally substituted by the above heterocyclic group (1), (A27) lower cycloalkanecarbonyloxy, (A28) lower alkoxy substituted by the group consisting of carboxy, protected carboxy, 25 lower alkanoyl, lower cycloalkanecarbamoyl, and lower alkylcarbamoyl, (A29) lower alkylcarbamoyloxy(lower)alkyl, (A30) lower alkoxycarbonylamino(lower)alkyl, (A31) amino(lower)alkyl, 30 (A32) lower alkylcarbamoyl(lower)alkyl, (A33) heterocyclic-carbonylamino, the heterocyclic group being selected from the above (2), (4) and (5) and optionally substituted by N protective group, and 35 (A34) the heterocyclic group of the above (7) being WO 00/40576 PCT/JPOO/00018 303 optionally substituted by lower alkyl.

5. The compound of claim 4, having the following formula: 5 R1-X Y Z (CH 2 ) > (CH 2 )-R2 10 wherein a group of the formula: Y Z 15 is one of the following formulae: S 02 20 CH 3 25 or 02 2 Ri is lower alkyl, phenyl, halophenyl, or (halo) (phenyl)phenyl, 30 R2 is carboxy or hydroxyaminocarbonyl, and m and n are each an integer of 0 or 1, and m+n=l.

6. The compound of claim 4, having the following formula: 35 WO 00/40576 PCT/JPOO/00018 304 Y Z R1 (CH 2 ) m > (CH 2 ) n-R 2 S 5 wherein a group of the formula: Y Z 10 is one of the following formulae: 15 , 02 S CH 3 ' 0 1 02 ' 02 ' 20 or 2 n 02 R2 is carboxy or hydroxyaminocarbonyl, 25 m and n are each an integer of 0 or 1, and m+n=1, 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 30 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, 35 (C2) lower alkyl, WO 00/40576 PCT/JPOO/0001 8 305 (C3) lower alkoxy, (C4) halo(lower)alkyl, (C5) halo(lower)alkoxy, (C6) lower alkenyl, 5 (C7) lower alkylcarbamoyl, carbamoyl, phenyl(lower)alkylcarbamoyl, lower alkanoyl, (C8) lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, (C9) phenyl, naphthyl, 10 (C10) halophenyl, (C11) hydroxy, (C12)mono- or dihydroxy(lower)alkyl, phenoxycarbonyloxy(lower)alkyl (C13) amino, 15 (C14) carboxy, (C15) lower alkylenedioxy, (C16)lower alkanoylamino, phenyl(lower)alkanoylamino, halophenyl(lower)alkanoylamino, lower 20 alkoxy(lower)alkanoylamino, lower alkoxy(lower)alkanoylamino, phenoxy(lower)alkanoylamino, lower alkoxyphenoxy(lower)alkanoylamino, lower alkylphenoxy(lower)alkanoylamino, 25 halophenoxy(lower)alkanoylamino, carboxy(lower)alkanoylamino, lower alkoxycarbonyl(lower)alkanoylamino, lower alkylcarbamoyl(lower)alkanoylamino, halo(lower)alkanoylamino, 30 lower alkenyl(lower)alkanoylamino, lower alkoxy(lower)alkanoylamino, phenyl(lower)alkoxy(lower)alkanoylamino, piperidinyloxy(lower)alkanoylamino, N-lower alkoxycarbonylpiperidinyloxy 35 (lower)alkanoylamino, WO 00/40576 PCT/JPOO/00018 306 pyridyloxy(lower)alkanoylamino, hydroxy(lower)alkanoylamino, lower alkanoyloxy(lower)alkanoylamino, lower alkylcarbamoyloxy(lower)alkanoylamino, 5 N,N-di(lower alkyl)carbamoyloxy, piperidino-carbonyloxy(lower)alkanoylamino, phenyl(lower)alkylcarbamoyloxy(lower) alkanoylamino, lower alkoxycarbonylamino(lower)alkanoylamino, 10 amino(lower)alkanoylamino, lower alkoxycarbonylamino(lower)alkanoylamino, fluorenylmethoxycarbonylamino(lower) alkanoylamino, lower alkylamino(lower)alkanoylamino, [N,N 15 di(lower alkyl)amino](lower)alkanoylamino, [N-lower alkyl-N-(lower alkoxycarbonyl) amino](lower)alkanoylamino, [N-lower alkyl-N (fluorenylmethoxycarbonyl)amino] (lower)alkanoylamino, 20 [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 25 alkanoylamino(lower)alkanoylamino, lower alkanesulfonylamino(lower)alkanoylamino, lower alkoxy(lower)alkanoylamino (lower)alkanoylamino, cyclo(lower)alkyloxycarbonylamino 30 (lower)alkanoylamino, pyridylcarbonylamino(lower)alkanoylamino, morpholinocarbonylamino(lower)alkanoylamino, phenyl(lower)alkoxyoxycarbonylamino (lower)alkanoylamino, 35 lower alkoxyphenylsulfonylamino- WO 00/40576 PCT/JP0O/00018 307 (lower)alkanoylamino, hydroxy(lower)alkylamino(lower)alkanoylamino, morpholino(lower)alkanoylamino, oxooxazolidinyl(lower)alkanoylamino, 5 oxopyrrolidinyl(lower)alkanoylamino, trimethylhydantoinyl(lower)alkanoylamino, lower alkenylamino(lower)alkanoylamino, lower alkoxy(lower)alkylamino(lower) alkanoylamino, 10 phenyl(lower)alkylamino(lower)alkanoylamino, pyridyl(lower)alkylamino(lower)alkanoylamino, lower alkoxycarbonylamino, phenyl(lower)alkoxycarbonylamino, lower alkoxy(lower)alkoxycarbonylamino, 15 halo(lower)alkoxycarbonylamino, amino(lower)alkoxycarbonylamino, phthalimido(lower)alkoxycarbonylamino, carbamoylamino, (mono- or di(lower alkyl)carbamoylamino, 20 naphthylcarbamoylamino, halophenylcarbamoylamino, lower alkoxyphenylcarbamoylamino, lower alkenylcarbamoylamino, cyclo(lower)alkyl(lower)alkylcarbamoylamino, 25 phenyl(lower)alkylcarbamoylamino, halo(lower)alkylcarbamoylamino, lower alkoxy(lower)alkylcarbamoylamino, hydroxy(lower)alkylcarbamoylamino, (lower alkyl) (diphenyl)silyloxy(lower)alkyl 30 carbamoylamino, carboxy(lower)alkylcarbamoylamino, lower alkoxycarbonyl(lower)alkylcarbamoylamino, lower alkylcarbamoyl(lower)alkyl carbamoylamino, or 35 pyridylcarbamoylamino, WO 00/40576 PCT/JP0O/00018 308 lower alkylsulfonylamino, lower alkenoylamino, lower cycloalkanecarbonylamino, lower alkenyloxycarbonylamino, 5 phenoxycarbonylamino, lower alkylthiocarbonylamino, (C17) phenyl(lower)alkoxy, (C18) lower alkenyl, mono- or di(lower alkyl)carbamoyl(lower)alkenyl, (2 10 (methylcarbamoyl)ethenyl, 2 (ethylcarbamoyl)ethenyl, 2 (propylcarbamoyl)ethenyl, 2 (isopropylcarbamoyl)ethenyl, 2 (dimethylcarbamoyl)ethenyl,) 15 phenylcarbamoyl(lower)alkenyl, lower alkoxycarbamoyl(lower)alkenyl, halophenylcarbamoyl(lower)alkenyl, (C19) lower alkylaminocarbonyloxy, (C20) lower alkanoyloxy, 20 (C21) lower alkoxy(lower)alkanoyloxy, (C22) lower alkoxycarbonyloxy, (C23) pyridyl(lower)alkenoyloxy (C24) lower cycloalkanecarbonyloxy, (C25)carboxy(lower)alkoxy, 25 lower alkoxycarbonyl(lower)alkoxy, lower alkanoyl(lower)alkoxy, lower cycloalkanecarbamoyl(lower)alkoxy, lower alkylcarbamoyl(lower)alkoxy, (C26) lower alkylcarbamoyloxy(lower)alkyl, 30 (C27) lower alkoxycarbonylamino(lower)alkyl, (C28) amino(lower)alkyl, (C29) lower alkylcarbamoyl(lower)alkyl, (C30) furylcarbonylamino, teretahydroisoquinolylcarbonylamino, 35 N-lower alkoxycarbonyl- WO 00/40576 PCT/JPO0/00018 309 teretahydroisoquinolylcarbonylamino, pyrrolidinylcarbonylamino, (C31) oxazolyl, lower alkyloxadiazolyl. 5

7. The compound of claim 6, in which a group of the formula: Y Z 10 X, is one of the following formulae: S 02 ' 15 02 R2 is hydroxyaminocarbonyl, 20 m is 0 and n is 1, a group of the formula: R1 S is the group of the following formulae (a) to (e); 25 (a) Rl 30 wherein R is halo, naphtyl, phenyl, mono- or dihalophenyl, mono- or di(lower)alkylphenyl, lower alkoxyphenyl, trihalo(lower)alkylphenyl, trihalo(lower)alkoxyphenyl, lower alkenylphenyl, 35 lower alkylcarbamoylphenyl, carbamoylphenyl, WO 00/40576 PCT/JPOO/00018 310 phenyl(lower)alkylcarbamoylphenyl, lower alkanoylphenyl, lower alkylthiophenyl, lower alkylsulfinylphenyl, lower alkylsulfonylphenyl, phenylphenyl, (halo) (phenyl)phenyl, halophenylphenyl, 5 hydroxyphenyl, mono- or dihydroxy(lower)alkylphenyl, phenoxycarbonyloxy(lower)alkylphenyl, aminophenyl, carboxyphenyl, lower alkylendioxyphenyl, lower alkanesulfonylaminophenyl, lower alkenoylaminophenyl, lower cycloalkanecarbonylaminophenyl, 10 phenyl(lower)alkoxyphenyl, mono- or di(lower alkyl)carbamoyl(lower)alkenylphenyl, phenylcarbamoyl(lower)alkenylphenyl, lower alkoxycarbamoyl(lower)alkenylphenyl, halophenylcarbamoyl(lower)alkenylphenyl, lower 15 alkylcarbamoyloxyphenyl, lower alkanoyloxyphenyl, lower alkoxy(lower)alkanoyloxyphenyl, lower alkoxycarbonyloxyphenyl, pyridyl(lower)alkenoyloxyphenyl, cyclo(lower)alkylcarbonyloxyphenyl, 20 carboxy(lower)alkoxyphenyl, lower alkoxycarbonyl(lower)alkoxyphenyl, lower alkanoyl(lower)alkoxyphenyl, lower cycloalkanecarbamoyl(lower)alkoxyphenyl, lower alkylcarbamoyl(lower)alkoxyphenyl, lower 25 alkylcarbamoyloxy(lower)alkylphenyl, lower alkoxycarbonylamino(lower)alkylphenyl, amino(lower)alkylphenyl, lower alkylcarbamoyl(lower)alkylphenyl, furylcarbonylaminophenyl, 1,2,3,4 30 teretahydroisoquinolylcarbonylaminophenyl, N-t-butoxycarbonyl, 1,2,3,4 teretahydroisoquinolylcarbonylaminophenyl, pyrrolidinylcarbonylaminophenyl, oxazolylphenyl, lower alkyloxadiazolylphenyl. 35 WO 00/40576 PCT/JPOO/00018 311 (b) 0 5 R1 2 -C-HN S wherein R12 is lower alkyl optionally substituted by the group 10 consisting of phenyl, halophenyl, lower alkoxyphenyl, lower alkoxy, phenoxy, lower alkoxyphenoxy, halophenoxy, lower alkylphenoxy, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl, halo, lower alkenyloxy, lower alkoxy(lower)alkoxy, 15 phenyl(lower)alkoxy, piperidinyloxy, N-lower alkoxycarbonyl-piperidinyloxy, pyridyloxy, hydroxy, lower alkanoyloxy, mono- or di(lower)alkylcarbamoyloxy, piperidinylcarbonyloxy, pheny(lower)alkylcarbamoyloxy, lower 20 alkoxycarbonylamino, amino, lower alkoxycarbonylamino, fluorenylmethoxycarbonylamino, mono- or di(lower)alkylamino, N-lower alkyl-N (lower alkoxycarbonyl)amino, N-lower alkyl-N (fluorenylmethoxycarbonyl)amino, N-lower alkyl-N 25 (mono- or di(lower)alkylcarbamoyl)amino, N-(mono or di(lower alkyl)carbamoyl)amino, benzoylamino, lower alkanoylamino, lower alkanesulfonylamino, lower alkoxy(lower)alkanoylamino, cyclo(lower)alkyloxycarbonylamino, 30 pyridylcarbonylamino, morpholinocarbonylamino, phenyl(lower)alkoxyoxycarbonylamino, lower alkoxyphenylsulfonylamino, hydroxy(lower)alkylamino, morpholino, oxooxazolidinyl, oxopyrrolidinyl, trimethylhydantoinyl, pyridyl, lower alkenylamino, 35 lower alkoxy(lower)alkylamino, WO 00/40576 PCT/JPOO/00018 312 phenyl(lower)alkylamino, pyridyl(lower)alkylamino, and cyclo(lower)alkyl, (c) 5 o R1 3 -M--C-HN S wherein 10 M is oxygen or sulfur, R13 is lower alkyl, phenyl(lower)alkyl, lower alkoxy(lower)alkyl, halo(lower)alkyl, amino(lower)alkyl, or phthalimido(lower)alkoxycarbonylamino, 15 lower alkenyl, phenyl, (d) o R 14 -N-C-HN S 20 R15 wherein R15 is hydrogen or lower alkyl, R14 is hydrogen, lower alkyl, naphthyl, halophenyl, 25 lower alkoxyphenyl, lower alkenyl, lower cycloalyl(lower)alkyl, phenyl(lower)alkyl, halo(lower)alkyl, lower alkoxy(lower)alkyl, hydroxy(lower)alkyl, (lower alkyl) (diphenyl)silyloxy(lower)alkyl, 30 carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, lower alkylcarbamoyl(lower)alkyl, or pyridyl, (e) 35 WO 00/40576 PCT/JPOO/00018 313 RI 6 wherein 5 R 16 is benzothienyl, benzofuranyl, thienyl, furyl, lower alkylpyridyl, pyridyl, lower alkoxypyridyl, lower alkoxycarbonylaminopyridyl, lower alkanoylthienyl, lower alkylcarbamoylbenzofuranyl. 10

8. The compound of claim 7, wherein a group of the formula: R S is the same group as (a), (c), (d) and (e) of claim 7, 15 and the following formula (b): (b) 0 R1 2 -C-HN S 20 wherein R12 is lower alkyl, phenyl(lower)alkyl, halophenyl(lower)alkyl, lower alkoxyphenyl(lower)alkyl, 25 lower alkoxy(lower)alkyl, phenoxy(lower)alkyl, lower alkoxyphenoxy(lower)alkyl, halophenoxy(lower)alkyl, lower alkylphenoxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, 30 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, 35 N-t-butoxycarbonylpiperidinyloxy(lower)alkyl, WO 00/40576 PCT/JPOO/00018 314 pyridyloxy(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyloxy(lower)alkyl, mono- or di(lower) alkylcarbamoyloxy(lower)alkyl, piperidinylcarbonyloxy(lower)alkyl, 5 pheny(lower)alkylcarbamoyloxy(lower)alkyl, lower alkoxycarbonylamino(lower)alkyl, amino(lower)alkyl, lower alkoxycarbonylamino(lower)alkyl, fluorenylmethoxycarbonylamino(lower)alkyl, 10 mono- or di(lower)alkylamino(lower)alkyl, N-lower alkyl-N-(lower alkoxycarbonyl)amino(lower)alkyl, N-lower alkyl-N-(fluorenylmethoxycarbonyl)amino (lower)alkyl, N-lower alkyl-N-(mono- or di(lower) 15 alkylcarbamoyl)amino(lower)alkyl, N-(mono- or di(lower alkyl)carbamoyl)amino(lower)alkyl, benzoylamino(lower)alkyl, lower alkanoylamino(lower)alkyl, lower alkanesulfonylamino(lower)alkyl, 20 lower alkoxy(lower)alkanoylamino(lower)alkyl, cyclo(lower)alkyloxycarbonylamino(lower)alkyl, pyridylcarbonylamino(lower)alkyl, morpholinocarbonylamino(lower)alkyl, phenyl(lower)alkoxyoxycarbonylamino(lower)alkyl, 25 lower alkoxyphenylsulfonylamino(lower)alkyl, hydroxy(lower)alkylamino(lower)alkyl, morpholino(lower)alkyl, oxooxazolidinyl(lower)alkyl, oxopyrrolidinyl(lower)alkyl, trimethylhydantoinyl(lower)alkyl, 30 pyridyl(lower)alkyl, lower alkenylamino(lower)alkyl, lower alkoxy(lower)alkylamino(lower)alkyl, phenyl(lower)alkylamino(lower)alkyl, pyridyl(lower)alkylamino(lower)alkyl, cyclo(lower)alkyl, (amino) (phenyl) (lower)alkylamino, 35 (lower alkoxycarbonylamino) (phenyl) (lower)alkyl, WO 00/40576 PCT/JP0O/00018 315 (amino) (lower alkoxy) (lower)alkyl, (lower alkoxycarbonylamino) (lower alkoxy) (lower)alkyl, (amino) (carboxy) (lower)alkyl, (lower alkoxycarbonylamino) (carboxy) (lower)alkyl, 5 (amino) (lower alkoxycarbonyl) (lower)alkyl, (lower alkoxycarbonylamino) (lower alkoxycarbonyl) (lower)alkyl, (amino) (phenyl(lower)alkoxy) (lower)alkyl, (lower alkoxycarbonylamino) (phenyl(lower)alkoxy) (lower)alkyl, 10 (amino) (pyridyl) (lower)alkyl, (lower alkoxycarbonylamino) (pyridyl) (lower)alkyl, (amino) (hydroxy) (lower)alkyl, (lower alkoxycarbonylamino) (hydroxy) (lower)alkyl, (amino) (amino) (lower)alkyl, 15 (lower alkoxycarbonylamino) (amino) (lower)alkyl, (amino) (lower alkoxycarbonylamino) (lower)alkyl, (lower alkoxycarbonylamino) (lower alkoxycarbonylamino) (lower)alkyl, (amino) (lower cycloalkane) (lower)alkyl, 20 (lower alkoxycarbonylamino) (lower cycloalkane) (lower)alkyl.

9. The compound of claim 7, in which 25 a group of the formula: R S is the group of the following formula (a) to (e): (a) 30 35 wherein WO 00/40576 PCT/JPOO/00018 316 RP 1 is bromo, 2-naphthyl, phenyl, 3(or 4)-chlorophenyl, 2(or 3 or 4)-fluorophenyl, 3,4-dichloropheny, 3,5-difluorophenyl, 3(or 4)-methylphenyl, 4-ethylphenyl, 5 4-isopropylphenyl, 4-(t-butyl)phenyl, 3,4-dimethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-ethenylphenyl, 4-methylcarbamoylphenyl, 4-ethylcarbamoylphenyl, 4 10 carbamoylphenyl, 4-benzylcarbamoylphenyl, 4-acetylphenyl, 4-methylthiophenyl, 4-ethylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl, phenylphenyl, 4-phenyl-3 fluorophenyl, 4 -(4-fluorophenyl)phenyl, 3(or 4) 15 hydroxyphenyl, 3(or 4)-hydroxymethylphenyl, 4-(1,2-dihydroxyethyl)phenyl, 4-(phenoxycarbonyloxymethyl)phenyl, 3(or 4) aminophenyl, 4-carboxyphenyl, 3,4-methylendioxyphenyl, 20 4-(methanesulfonylamino)phenyl, 3-(2-butenoylamino)phenyl, 3-(cyclopropanecarbonylamino)phenyl, 3-(cyclobutanecarbonylamino)phenyl, 3-(cyclopentanecarbonylamino)phenyl, 25 4-benzyloxyphenyl, 4-(2-(methylcarbamoyl)ethenyl)phenyl, 4-(2-(ethylcarbamoyl)ethenyl)phenyl, 4-(2-(propylcarbamoyl)ethenyl)phenyl, 4-(2-(isopropylcarbamoyl)ethenyl)phenyl, 30 4-2-(dimethylcarbamoyl)ethenyl)phenyl, 4-(2-(phenylcarbamoyl)ethenyl)phenyl, 4-(2-(methoxyphenylcarbamoyl)ethenyl)phenyl, 4-(2-(4-fluorophenylcarbamoyl)ethenyl)phenyl, 4-(methylaminocarbonyloxy)phenyl, 35 4-(ethylaminocarbonyloxy)phenyl, WO 00/40576 PCT/JPOO/00018 317 4-propanoyloxyphenyl, 4- (methoxyacetyloxy) phenyl, 4-(ethoxycarbonyloxy)phenyl, 4-(3-(3-pyridyl)acryloyloxy)phenyl, 4-(cyclopropylcarbonyloxy)phenyl, 5 4-(carboxymethoxy)phenyl, 4-(ethoxycarbonylmethoxy)phenyl, 4-(t-butoxycarbonylmethoxy)phenyl, 4-(propanoylmethoxy)phenyl, 4-(cyclopropylcarbamoylmethoxy)phenyl, 10 3(or 4)-(methylcarbamoylmethoxy)phenyl, 4-(ethylcarbamoylmethoxy)phenyl, 4-(propylcarbamoylmethoxy)phenyl, 3(or 4)-(methylcarbamoyloxymethyl)phenyl, 4-(methoxycarbonylaminomethyl)phenyl, 15 4-(t-butoxycarbonylaminomethyl)phenyl, 4-aminomethylphenyl, 4-(methylcarbamoylmethyl)phenyl, 3-(2(or 3)-furylcarbonylamino)phenyl, 3-(1,2,3,4 teretahydroisoquinolylcarbonylamino)phenyl, 20 3-(N-(t-butoxycarbonyl)-1,2,3,4 teretahydroisoquinolylcarbonylamino)phenyl, 3-(pyrrolidinylcarbonylamino)phenyl, 4-(1,3-oxazolyl)phenyl, 4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenyl, 25 (b) 0 R1 2 -C--HN S 30 wherein R12 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, phenylmethyl, 35 4-chlorophenylmethyl, 4-methoxyphenylmethyl, WO 00/40576 PCT/JPOO/00018 318 methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, isopropyloxymethyl, 1-methoxyethyl, 2-methoxyethyl, phenoxymethyl, 2-phenoxyethyl, 3(or 4)-methoxyphenoxymethyl, 4-fluoro(or 5 chloro)phenoxymethyl, 3(or 4)-methylphenoxymethyl, 2-carboxyethyl, 2-methoxycarbonylethyl, 2-t butoxycarbonylethyl, 2-methylcarbamoylethyl, 2-chloroethyl, chloromethyl, allyloxymethyl, (2-ethoxyethoxy)methyl, benzyloxymethyl, 10 4-piperidinyloxymethyl, (N-t-butoxycarbonyl-4 piperidinyl)oxymethyl, 3(or 4)-pyridyloxymethyl, hydroxymethyl, 2-hydroxyethyl, acetoxymethyl, 1-acetoxyethyl, methylcarbamoyloxymethyl, 1-(N methyl-N-ethylcarbamoyloxy)methyl, (piperidino 15 carbonyloxy)methyl, (benzylcarbamoyloxy)methyl, (t-butoxycarbonylamino)methyl, aminomethyl, 1-aminoethyl, 1-(t-butoxycarbonylamino)ethyl, 2-aminoethyl, methoxycarbonylaminomethyl, 2-(methoxycarbonylamino)ethyl, 20 ethoxycarbonylaminomethyl, propoxycarbonylaminomethyl, 1-(fluorenylmethoxycarbonylamino)methyl, 2-(t-butoxycarbonylamino)ethyl, 2-(fluorenylmethoxycarbonylamino)ethyl, 25 1-aminoisopropyl, 1-aminopropyl, 1-(t-butoxycarbonylamino)propyl, 1-(t-butoxycarbonylamino)isopropyl, 1,5-diaminopentyl, 1,5-bis(t-butoxycarbonylamino) pentyl, methylaminomethyl, ethylaminomethyl, 30 3-(2-(N-methyl-N-ethylamino)methyl, 3-(dimethylaminomethyl, 3-(pentylaminomethyl, 3-(t-butylaminomethyl, 3-(3-methylaminoethyl, 3-(2-(N-methyl-N-methoxycarbonylamino)methyl, 1-(N-methyl-N-t-butoxycarbonylamino)methyl, 35 1-(N-ethyl-N-t-butoxycarbonylamino)methyl, WO 00/40576 PCT/JPOO/00018 319 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, 5 1-(N-(ethylcarbamoyl)amino)methyl, 2-(N-(ethylcarbamoyl)amino)ethyl, benzoylaminomethyl, 2-benzoylaminoethyl, acetylaminomethyl, isobutyrylaminomethyl, pivaloylaminomethyl, 10 1-(methanesulfonylamino)methyl, 2-(methanesulfonylamino)ethyl, methoxyacetylaminomethyl, cyclopentyloxycarbonylaminomethyl, pyridylcarbonylaminomethyl, 15 morpholinocarbonylaminomethyl, benzyloxycarbonylaminomethyl, 1-(4-methoxyphenylsulfonylamino)methyl, 1-(2-hydroxyethylamino)methyl, morpholinomethyl, 1-(2-oxo-1,3-oxazolidin-l 20 yl)methyl, 1-(2-oxopyrrolidin-1-yl)methyl, 1-(3,4,4-trimethylhydantoin-1-yl)methyl, allylaminomethyl, 1-(2-ethoxyethylamino)methyl, benzylaminomethyl, 1-(3-pyridylmethylamino)methyl, 2-phenyl-l-aminoethyl, 1-amino-l-phenylmethyl, 25 1-t-butoxycarbonylamino-1-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 30 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, 1-t 35 butoxycarbonylamino-2-(3-pyridyl)ethyl, 1-amino-2- WO 00/40576 PCT/JPOO/00018 320 (4-pyridyl)ethyl, 1-t-butoxycarbonylamino-2-(4 pyridyl)ethyl, 1-amino-2-hydroxyethyl, 1-t-butoxycarbonylamino-2-hydroxyethyl, (1,5-diaminopentyl, 1-t-butoxycarbonylamino-5 5 aminopentyl, 1,5-bis(t-butoxycarbonylamino)pentyl, 1-amino-5-(t-butoxycarbonylamino)pentyl, 1-amino-2 cyclohexylethyl, 1-t-butoxycarbonylamino-2 cyclohexylethyl, 10 (c) 0 R1 3 -M--HN S 15 wherein M=O and R13 is methyl, ethyl, propyl, isopropyl, benzyl, 2-methoxyethyl, 2-choloroethyl, 2-aminoethyl, 2 phthalimidoethyl, allyl, phenyl, or M=S and R13 is methyl, ethyl, 20 (d) 0 R1 4 -N-C -HN R15 S 25 wherein R15 is hydrogen and R14 is hydrogen, methyl, ethyl, propyl, isopropyl, 30 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, 35 carboxymethyl, ethoxycarbonylmethyl, WO 00/40576 PCT/JPOO/00018 321 methylcarbamoylmethyl, or 3-pyridyl, R14 is ethyl and R 15 is methyl, (e) R16 S 10 wherein R1 6 is 2-benzothienyl, 2-benzofuranyl, 2(or 3)-thienyl, 2-furyl, 3-pyridyl, 1-methyl-4-pyridyl, 6-methyl-3 pyridyl, 6-methoxy-3-pyridyl, 15 5-methoxycarbonylamino-3-pyridyl, 5-acetyl-2 thienyl, 2-methylcarbamoyl-5-benzofuranyl.

10. A process for the preparation of a compound of the formula: 20 A Y Z Rl-X-Ar-(CH2)m (CH2)n-R 2 (I) 25 in which R 1 , R 2 , Ar, A, X, Y, Z, m and n are each as defined in Claim 1, which comprises 30 (1) subjecting a compound of the formula: Y Z 35 Rl-X-Ar-(CH2)m (CH2)nRa (Ia) or a salt thereof to removal reaction of the carboxy- WO 00/40576 PCT/JPOO/00018 322 protective group, to give a compound of the formula: Y z 5 R1-X-Ar--(CH2)m (CH2)n-COOH (I-b) or a salt thereof; or (2) oxidating the vinyl group of a compound of the formula: 10 Y Z Rl-X-Ar-(CH2)m (CH2)n-CH=CH2 (II) 15 or a salt thereof, to give a compound of the above formula (I-b) or a salt thereof; or (3) reducing a compound of the formula: 20 Y Z Rl-X-Ar-(CH2)m (CH2)n-R 2 (I-c) or a salt thereof, to give a compound of the formula: 25 Y Z RI-X-Ar-(CH2)m (CH2)n-R 2 (I-d) 30 or a salt thereof; or (4) reacting a compound of the above formula (I-b) or its reactive derivative at the carboxy-group, or a salt thereof, with a compound of the formula: 35 WO 00/40576 PCT/JPOO/00018 323 NH 2 -OR 3 (IV) or its reactive derivative at the amino-group, or a salt thereof, to give a compound of the formula: 5 Y Z R1-X-Ar-(CH2) (CH2)n-CONH-OR 3 (-e) 10 or a salt thereof; or (5) cyclizing a compound of the formula: HN 15 H2N Y z R1-X-Ar- (CH2) -- CH~R2 nrl a or a salt thereof, to give a compound of the formula: 20 Y Z Rl-X-Ar-(CH2)m CH2-R 2 (1f) 25 or a salt thereof; or (6) reacting a compound of the above formula (I-b) or its reactive derivative at the carboxy-group, or a salt 30 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 35 R'-X-Ar-(CH2)m (CH2)n-R2 (I-g) WO 00/40576 PCT/JP0O/00018 324 or a salt thereof; or (7) subjecting a compound of the formula: 5 Y Z R1-X-Ar-(CH2)m (CH2)n-CONH-OR 3 (I-h) a 10 or a salt thereof to removal reaction of the hydroxy protective group, to give a compound of the formula: Y Z 15 Ri-X-Ar-(CH2)m (CH2)n-CONHOH or a salt thereof; or (8) oxidating a compound of the formula: 20 Ya Za R1-X-Ar-(CH2)m (CH2)n-R 2 (I-j) 25 or a salt thereof, to give a compound of the formula: Yb Zb R1-X-Ar-(CH2)m (CH2)n-R 2 (I-k) 30 or a salt thereof; or (9) reacting a compound of the above formula (I-c) or a salt thereof, with a compound of the formula: 35 WO 00/40576 PCT/JPOO/00018 325 R 5 R4-R6 5 to give a compound of the formula: Y Z R1-X-Ar-(CH2)m <(CH2)n-R2(-) 10 or a salt thereof; or (10) reacting a compound of the formula: 15 Y Z (VI) 2 c 20 or a salt thereof, with a compound of the formula: R'-X-Ar-(CH 2 )ml~L (VII) or a salt thereof, to give a compound of the formula: 25 Y Z Rl-X-Ar-(CH2)ml R2 (I-m) 30 or a salt thereof; or (11) cyclizing a compound of the formula: 35 WO 00/40576 PCT/JPOO/00018 326 H HO Z R1-X-Ar-(CH2)m (CH2)nR 2 (VIII) 5 or a salt thereof, to give a compound of the formula: Z 10 Rl-X-Ar-(CH2) m (CH2)n-R 2 (I-n) or a salt thereof; or (12) reacting a compound of the formula: 15 0 R--X-Ar-(CH2)m (CH2)n-R 2 (IX) 20 or a salt thereof, with a compound of the formula: HS-A-SH (X) to give a compound of the formula: 25 S S R1-X-Ar-(CH2)m (CH2)n-R 2 (1-0) 30 or a salt thereof; or (13) amidating a compound of the formula: 35 WO 00/40576 PCT/JPOO/00018 327 Y Z R -X-Ar-(CH2)m (CH2)n-R 2 (I-P) 5 or its reactive derivative at the carboxy group, or a salt thereof, to give a compound of the formula: Y Z 10 R--X-Ar-(CH2)m (CH2)n-R 2 (I-q) or a salt thereof; or (14) acylating a compound of the formula: 15 Y Z Rl-X-Ar-(CH2)m>K(CH 2 )n-R 2 (I-r) f 20 or its reactive derivative at the amino group, or a salt thereof, to give a compound of the formula: Y Z 25 Rl-X-Ar-(CH2)m (CH2)n-R 2 (I-s) g or a salt thereof; or (15) subjecting a compound of the formula: 30 Y Z Rl-X--Ar-(CH2)m (CH2)n-R 2 (I-t) 35 WO 00/40576 PCT/JP0O/00018 328 or a salt thereof to a removal reaction of the amino protective group, to give a compound of the formula: 5 Y z RI-X-Ar-(CH2)m><(CH 2 )n-R2 (I-r) or a salt thereof; or 10 (16) subjecting a compound of the formula: Y Z 15 R1-X-Ar-(CH2)m (CH2)n-R2 (I-u) or a salt thereof to a removal reaction of the hydroxy protective group, to give a compound of the formula: 20 y z R1-X-Ar-(CH2)m><(CH 2 )n-R2 (I-v) J 25 or a salt thereof; or (17) oxidating a compound of the formula: 30 Y Z R -X-Ar-(CH2)m><CH 2 )n-R 2 (I-w) or a salt thereof, to give a compound of the formula: 35 WO 00/40576 PCT/JPOO/00018 329 Y Z Rl-X-Ar-(CH2)m <(CH2)n,-R2 (I-x) 5 or a salt thereof; or (18) reducing a compound of the formula: 10 Y Z R1-X-Ar-(CH2)m><(CH 2 )n-R2 (I-y) m or a salt thereof, to give a compound of the formula: 15 Y Z Rl-X-Ar-(CH2)m <(CH2)n-R2 (I-z) 20 or a salt thereof; or (19) oxidating a compound of the formula: 25 Y Z Rl-X-Ar-(CH2)m><O(CH2)n-R 2 (I-aa) or a salt thereof, to give a compound of the formula: 30 Y Z R -X-Ar-(CH2)m (CH2)n-R 2 (I-ab) p or a salt thereof; or 35 WO 00/40576 PCT/JPOO/00018 330 (20) acylating a compound of the formula: Y Z 5 R1-X-Ar-(CH2)m><(CH 2 )n-R2 (I-v) J or a salt thereof, to give a compound of the formula: 10 Y z RI-X-Ar-(CH2)m><(CH 2 )n-R2 (I-ac) or a salt thereof; or 15 (21) reacting a compound of the formula: Y Z R5 B-Ar-(CH2) (CH2)n-R 2 (XI) R 6 20 or a salt thereof, with a compound of the formula: R 1 -L (XII) 25 or a salt thereof, to give a compound of the formula: Y Z 30 R1-Ar- (CH2) (CH2)n-R 2 (I-ad) or a salt thereof; or (22) subjecting a compound of the formula: 35 WO 00/40576 PCT/JPOO/00018 331 Y Z R1-X-Ar-(CH 2 ) (CH2)n-R 2 (I-ae) 5 or a salt thereof, to a removal reaction of the carboxy-protective group, to give a compound of the formula: 10 Y z Rl-X-Ar-(CH2)m (CH2)n-R 2 (I-p) or a salt thereof; or 15 (23) reacting a compound of the formula: Y Z 20 Rl-X-Ar-(CH 2 ) (CH2)n-R 2 (1-af) or a salt thereof, with a substituted amine, to give a compound of the formula: 25 Y Z Rl-X-Ar-(CH2)m (CH2)n-R 2 (I-ag) or a salt thereof, 30 in which R', R 2 , Ar, A, X, Y, Z, m and n are each as defined above, R is haloaryl or halo, 1 Rb is aryl, 35 R is aryl at least substituted by optionally WO 00/40576 PCT/JPOO/00018 332 substituted aryl, R4 is aryl at least having carboxy moiety, 4 is aryl at least having amid moiety, R is aryl at least having amino moiety, 5 R is aryl at least having acylamino moiety, g R is aryl at least having protected amino moiety, R is aryl at least having protected hydroxy moiety, RI is aryl at least having hydroxy moiety, R is aryl at least having thia moiety, 10 R is aryl at least having sulfinyl or sulfonyl moiety, R is aryl at least having formyl moiety, R is aryl at least having hydroxymethyl moiety, Rl is aryl at least having vinyl moiety, 15 R is aryl at least having 1,2-dihydroxyethyl moiety, p R is aryl at least having acyloxy moiety, R is aryl at least having protected carboxy moiety, R is aryl at least having halo(lower)alkanoyl. 20 moiety, R is aryl at least having substituted amino(lower)alkanoyl moiety, R2a is protected carboxy, Rb is optically active amide, 25 R2c is protected carboxy, R 3 is hydrogen or hydroxy-protective group, a is hydroxy-protective group, R4 is optionally substituted aryl, R 5 and R 6 are each hydrogen or combinedtogether to 30 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, 35 Yb is thia, sulfinyl or sulfonyl, WO 00/40576 PCT/JPOO/00018 333 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 5 ml is an integer of 1 to 6.

11. A pharmaceutical composition which comprises the compound of Claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier 10 or excipient.

12. A process for preparing a pharmaceutical composition which comprises admixing the compound of Claim 1 or a pharmaceutically acceptable salt thereof with a 15 pharmaceutically acceptable carrier or excipient.

13. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof as a medicament. 20

14. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof as an inhibitor of matrix metalloproteinases (MMP) or tumor necrosis factor a (TNF a). 25

15. Use of the compound of Claim 1 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating and/or preventing MMP- or TNF a-mediated diseases. 30

16. A method for treating and/or preventing MMP- or TNF a mediated diseases which comprises administering the compound of Claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal. 35

17. Use of the compound of Claim 1 or a pharmaceutically WO 00/40576 PCT/JPOO/00018 334 acceptable salt thereof for treating and/or preventing MMP- or TNF ax-mediated diseases. 5 10 15 20 25 30 35