ACETYLENIC $g(a)-AMINO ACID-BASED SULFONAMIDE HYDROXAMIC ACID TACE INHIBITORS

Title:

ACETYLENIC $g(a)-AMINO ACID-BASED SULFONAMIDE HYDROXAMIC ACID TACE INHIBITORS

Document Type and Number:

WIPO Patent Application WO/2000/044709

Kind Code:

A2

Abstract:

Compound of the formula (B) are useful in treating disease conditions mediated by TNF-$g(a), such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss.

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Inventors:

LEVIN JEREMY IAN
CHEN JAMES MING
COLE DEREK CECIL

Application Number:

PCT/US2000/001981

Publication Date:

August 03, 2000

Filing Date:

January 27, 2000

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Assignee:

AMERICAN CYANAMID CO (US)

International Classes:

A61K31/18; A61K31/381; A61K31/40; A61K31/401; A61K31/4164; A61K31/4184; A61K31/42; A61K31/426; A61K31/44; A61K31/4406; A61K31/4468; A61K31/472; A61K31/495; A61K31/496; A61K31/5375; A61K31/54; A61K31/55; A61K31/551; A61K31/5513; A61K31/554; A61P1/00; A61P3/10; A61P7/00; A61P9/04; A61P25/28; A61P29/00; A61P31/04; A61P31/18; A61P37/06; A61P43/00; C07C303/40; C07C309/42; C07C309/87; C07C311/29; C07C311/39; C07C311/44; C07C311/47; C07C311/64; C07C319/20; C07C323/60; C07D207/12; C07D207/16; C07D207/27; C07D209/20; C07D211/66; C07D213/32; C07D213/42; C07D213/70; C07D213/71; C07D213/76; C07D213/81; C07D213/82; C07D213/89; C07D215/48; C07D217/26; C07D233/60; C07D235/06; C07D235/08; C07D241/04; C07D243/08; C07D261/10; C07D261/18; C07D265/30; C07D277/06; C07D277/24; C07D279/12; C07D279/14; C07D279/16; C07D281/06; C07D295/08; C07D295/092; C07D295/125; C07D295/13; C07D333/40; C07D401/06; C07D409/06; C07D513/10; C07D521/00; C07D207/26; (IPC1-7): C07C311/00

Domestic Patent References:

WO1998008815A1	1998-03-05
WO1998008825A1	1998-03-05
WO1996033172A1	1996-10-24
WO1998008853A1	1998-03-05

Other References:

DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; STN, CAPLUS accession no. 1975:467728, XP002142178 & G. SVILPIENE ET AL: LIET. TSR MOKSLU AKAD. DARB., SER B, no. 3, 1974, pages 63-68,

Attorney, Agent or Firm:

Barrett, Rebecca R. (Patent Law Department -2B One Campus Driv, Parsippany NJ, US)
Wileman, David Francis (Huntercombe Lane South Taplo, Maidenhead Berkshire SL6 0PH, GB)

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Claims:

CLAIMS

1.

A compound having having the formula: wherein: X is SO2 orP (O)Rlo; Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y; Z is O, NH, CH2 or S; RI is hydrogen, aryl, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms; R2 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl of 36 carbon atoms, C4Cg cycloheteroalkyl, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms; or Ri and R2, together with the atom to which they are attached, may form a ring wherein R, and R2 represent a divalent moiety of the formula: wherein Q = a carboncarbon single or double bond, O, S, SO, SO2,NR,, or CO1V114 m = 13; r = 1 or 2, with the proviso that when Q is a bond, r is equal to 2; R3 is hydrogen, alkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, C4C8 cycloheteroalkyl, aralkyl, or heteroaralkyl; or Ri and R3, together with the atoms to which they are attached, may form a 5 to 8 membered ring wherein R, and R3 represent divalent moieties of the formulae: wherein Q and m are as defined above; A is aryl or heteroaryl; s is 03; u is 14; R, and Rs are each, independently, hydrogen or alkyl of 16 carbon atoms, CN, orCCH; R6 is hydrogen, aryl, heteroaryl, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cycloalkyl of 36 carbon atoms, orCsCgcycloheteroalkyl; R8 and R are each, independently, hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cycloalkyl of 36 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl, orC4 Cgcycloheteroalkyl; Rlo is alkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, aryl or heteroaryl; Rl, is hydrogen, alkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, aryl, heteroaryl,S (O) nR8,COOR8,CONR8Rg,SO2NR8Rg orCOR8; R, 2and R, 3are independently selected from H,OR,,NRR,, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cycloalkyl of 36 carbon atoms, aryl, heteroaryl,COOR,; CONR8Rg; or R, 2and R, 3together form aC3C6cycloalkyl of 36 carbon atoms or aC5C8cycloheteroalkyl ring; or Rl2 and R, 3 together with the carbon to which they are attached, form a carbonyl group; with the proviso that Rto and Rl2 or R, l and R, 2 may form a cycloheteroalkyl ring when they are attached to adjacent atoms; 263 Rl4 is hydrogen, aryl, heteroaryl, alkyl of 16 carbon atoms or cycloalkyl of 3 6 carbon atoms; and n is 02; or a pharmaceutically acceptable salt thereof.

2.	A compound according to Claim 1 wherein Y is a phenyl ring substituted at the 1and 4positions by X and Z, respectively, or a pharmaceutically acceptable salt thereof.

3.	A compound according to Claim 1 or Claim 2 wherein X is SO2, or a pharmaceutically acceptable salt thereof.

4.	A compound according to any one of Claims 1 to 3 wherein Z is oxygen, or a pharmaceutically acceptable salt thereof.

5.	A compound according to any one of Claims 1 to 4 wherein R4 and Rs are hydrogen, or a pharmaceutically acceptable salt thereof.

6.	A compound according to any one of Claims 1 to 5 wherein R6 is CH2OH or methyl, or a pharmaceutically acceptable salt thereof.

7.	A compound according to any one of Claims 1 to 6 wherein R, and R3, together with the atoms to which they are attached, form a piperazine, piperidine, tetrahydroisoquinoline, morpholine, thiomorpholine, or diazepine ring.

8.	A compound according to any one of Claims 1 to 7 wherein R2 is hydrogen.

9.	A compound according to Claim 8 wherein R, is hydrogen such that structure B has the absolute stereochemistry shown below, or a pharmaceutically acceptable salt thereof.

10.	A compound according to any one of Claims 1 to 6 wherein Ri is hydrogen, such that this compound has the Dconfiguration, as shown below:.

11.	A compound according to Claim 10 wherein R3 is hydrogen, or a pharmaceutically acceptable salt thereof.

12.	A compound according to Claim 10 wherein R3 is hydrogen, Y is a phenyl ring substituted at the 1and 4positions by X and Z, respectively, X is SO2, and Z is oxygen, or a pharmaceutically acceptable salt thereof.

13.

A compound according to Claim 1 which is selected from the group consisting of: 2[ (4But2ynyloxybenzenesulfonyl)methylamino]Nhydroxy3methyl butyramide; 2 [ (4But2ynyloxybenzenesulfonyl)methylamino]Nhydroxyacetamide; NHydroxy2 [ (4methoxybenzenesulfonyl)methylamino]3methyl butyramide; 2 [ (4But2ynyloxybenzenesulfonyl)pyridin3ylmethylamino]Nhydroxy acetamide hydrochloride; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxyacetamide; 265 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxy3methylbutyramide; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxypropionamide; 2 [ (4But2ynyloxybenzenesulfonyl)pyridin3ylmethylamino]Nhydroxy propionamide hydrochloride; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxy2methyl propionamide; 4(4But2ynyloxybenzenesulfonyl)2,2dimethylthiomorpholine3 carboxylic acid hydroxyamide; 4 (4Hept2ynyloxybenzenesulfonyl)2,2dimethylthiomorpholine3 carboxylic acid hydroxyamide; 2(4But2ynyloxybenzenesulfonyl)1,2,3,4tetrahydroisoquinoline3 carboxylic acid hydroxyamide; 4Benzoyl1 (4but2ynyloxybenzenesulfonyl) [ 1,4] diazepane2carboxylic acid hydroxyamide; 1 (4But2ynyloxybenzenesulfonyl)4methylpiperazine2carboxylic acid hydroxyamidehydrochloride; 4 [4 (4Hydroxybut2ynyloxy)benzenesulfonyl]2,2dimethyl thiomorpholine3carboxylic acid hydroxyamide; 4 (4But2ynyloxybenzenesulfonyl)3hydroxycarbamoylpiperazine1 carboxylic acid tertbutyl ester; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxy2methyl propionamide; 2 (4But2ynyloxybenzenesulfonylamino)5guanidinopentanoic acid hydroxyamide; 2 (4But2ynyloxybenzenesulfonylamino)5 (4methylbenzenesulfonyl guanidino)pentanoic acid hydroxyamide; 3 (4But2ynyloxybenzenesulfonylamino)Nhydroxysuccinamic acid cyclohexyl ester; 2 (4But2ynyloxybenzenesulfonylamino)3cyclohexylNhydroxy propionamide; 2 (4But2ynyloxybenzenesulfonylamino)2cyclohexylNhydroxy acetamide; 3tertButylsulfanyl2 (4but2ynyloxybenzenesulfonylamino)Nhydroxy propionamide; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxy3 (4methoxy benzylsulfanyl)propionamide; 2 (4But2ynyloxybenzenesulfonylamino)N1hydroxysuccinamide; 2 (4But2ynyloxybenzenesulfonylamino)3cyclohexylNhydroxy propionamide; 2 (4But2ynyloxybenzenesulfonylamino)2cyclohexylNhydroxy acetamide; 2 (4But2ynyloxybenzenesulfonylamino)4methylpentanoic acid hydroxyamide; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxy4methylsulfanyl butyramide; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxy3phenylpropionamide 1 (4But2ynyloxybenzenesulfonyl)pyrrolidine2carboxylic acid hydroxyamide; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxy3 ( 1 Hindol3yl) propionamide; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxy3 (4hydroxyphenyl) propionamide; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxy3methylbutyramide; 2 (4But2ynyloxybenzenesulfonylamino)4methylpentanoic acid hydroxyamide; 2 (4But2ynyloxybenzenesulfonylamino)6 (2chlorobenzylamino) hexanoic acid hydroxyamide; 2 (4But2ynyloxybenzenesulfonylamino)hexanoic acid hydroxyamide; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxy2phenylacetamide; 3Benzyloxy2 (4but2ynyloxybenzenesulfonylamino)Nhydroxy propionamide; 2 (4But2ynyloxybenzenesulfonylamino)Nhydroxyacetamide; (2R, 3 S)2 ({ [4(2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy3 methylpentanamide; (2R)2({ [4(2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy3,3 dimethylbutanamide ; (2S)2 [ (4But2ynyloxybenzenesulfonyl)methylamino]Nhydroxy propionamide; 2 [ (4But2ynyloxybenzenesulfonyl)ethylamino]Nhydroxy3methyl butyramide ; 2[{ [4(2Butynyloxy) phenyl] sulfonyl}[{ [4(2Butynyloxy) phenyl] sulfonyl} (2propynyl) amino]Nhydroxy3 methylbutanamide ; 2 [ (4But2ynyloxybenzenesulfonyl)propylamino]Nhydroxy3methyl butyramide ; 2 [ (4But2ynyloxybenzenesulfonyl) (3phenylpropyl)amino]Nhydroxy3 methylbutyramide; 2 [ (4But2ynyloxybenzenesulfonyl)cyclopropylmethylamino]Nhydroxy3 methylbutyramide; 2 [ (4But2ynyloxybenzenesulfonyl)isobutylamino]Nhydroxy3methyl butyramide; 2 [ (4But2ynyloxybenzenesulfonyl)pyridin3ylmethylamino]Nhydroxy3 methylbutyramide; 2 [ (4But2ynyloxybenzenesulfonyl)methylamino]2cyclohexylNhydroxy acetamide ; 2 [ (4But2ynyloxybenzenesulfonyl)pyridin3ylmethylamino]2cyclohexyl Nhydroxyacetamide ; 2 { (4But2ynyloxybenzenesulfonyl) [4 (2piperidin1ylethoxy)benzyl] amino}2cyclohexylNhydroxyacetamide ; 2 { { [4(2Butynyloxy) phenyl] sulfonyl} [3(diethylamino) propyl] amino}N hydroxy3methylbutanamide; 2 { { [4 (2Butynyloxy) phenyl] sulfonyl} [3 (4morpholinyl) propyl] amino}N hydroxy3methylbutanamide; 2 { { [4(2Butynyloxy) phenyl] sulfonyl} [3 (4methyllpiperazinyl) propyl] amino}Nhydroxy3methylbutanamide hydrochloride; 2 { { [4 (2Butynyloxy) phenyl] sulfonyl) [4 (diethylamino) butyl] amino}N hydroxy3methylbutanamide; 2 { { [4 (2Butynyloxy) phenyl] sulfonyl} [4 (4methyl1piperazinyl) butyl] amino} Nhydroxy3methylbutanamide ; 2 [ [ [4 (2Butynyloxy) phenyl] sulfonyl] [2 (4morpholinyl) ethyl] amino]N hydroxy3methylbutanamide ; 2[{[4(But2ynyloxy)phenyl] sulfonyl} (2morpholin4ylethyl) amino]N hydroxyacetamide hydrochloride; 2 { { [4 (2Butynyloxy) phenyl] sulfonyl} [4 (4methyllpiperazinyl)2 butynyl] amino}Nhydroxy3methylbutanamide; 2 { [4(2Butynyloxy) phenyl] sulfonyl} [4(diethylamino)2butynyl] amino}N hydroxy3methylbutanamide; 2 { { [4 (2Butynyloxy) phenyl] sulfonyl} [4 (methylamino)2butynyl] amino}N hydroxy3methylbutanamide; ( (2R) { [4 (2Butynyloxy) phenyl] sulfonyl} (methyl) amino) [ (4diethylamino) cyclohexyl]Nhydroxyethamide; (2R){[4(2Butynyloxy)phenyl] sulfonyl} aminoNhydroxy2 (4hydroxy cyclohexyl) ethanamide; (2R){ [4(2Butynyloxy) phenyl] sulfonyl} (methyl) amino)Nhydroxy2 (4 hydroxycyclohexyl)ethanamide; 2[(6But2ynyloxypyridine3sulfonyl)methylamino]Nhydroxyacetamide ; 2 [ [ (4 { [3 (4Chlorophenyl)2propynyl] oxy} phenyl) sulfonyl] (methyl) amino]N hydroxyacetamide ; NHydroxy2(methyl{[4(prop2ynylamino)phenyl] sulfonyl} amino) acetamide ; 2 [ (4But2ynylthiophenylsulfonyl)methylamino]Nhydroxyacetamide; 2 { { [4 (2Butynyloxy) phenyl] sulfonyl} [4 (4methyl1piperazinyl)2yl} [4 (4 methyl1piperazinyl)2butynyl] amino}Nhydroxypropanamide; 1[{ [4(2Butynyloxy) phenyl] sulfonyl}[{ [4(2Butynyloxy) phenyl] sulfonyl} (methyl) amino]Nsulfonyl} (methyl) amino]Nhydroxycyclohexanecarboxamide; 1 [ { [4(2Butynyloxy) phenyl] sulfonyl} (3pyridinylmethyl) amino] Nhydroxy cyclohexanecarboxamide ; 1 ( { [4(2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxycyclo hexanecarboxamide; 1 ( { [4 (2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxycyclo pentanecarboxamide; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl) (methyl) amino]Nhydroxy3methyl3 [(2(4morpholinylethyl) sulfanyl]butanamide hydrochloride ; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl) (methyl) amino]Nhydroxy3methyl3 { [2 (4methyl1ethyl1piperazinyl) ethyl] sulfanyl} butanamide; 2({[4(2Butynyloxy)phenyl] sulfonyl) (methyl) amino]Nhydroxy3methyl3 { [2 (diethylamino) ethyl] sulfanyl} butanamide ; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl) (methyl) amino]Nhydroxy3methyl3 { [2 (lpyrrolidinyl) ethyl] sulfanyl} butanamide; 2({ [4(2Butynyloxy)({ [4(2Butynyloxy) phenyl] sulfonyl) (methyl) amino]Nhydroxy3methyl3 { [2(lHimidazol1yl) ethyl] sulfanyl} butanamide; Methyl 1 [2 ( {2 [ { [4 (2butynyloxy) phenyl] sulfonyl} (methyl)] amino]3 (hydroxyamino)1,1dimethyl3oxopropyl} sulfanyl) ethyl]2 pyrrolidinecarboxylate; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl) (methyl) amino]Nhydroxy3methyl3 [ (2 (4morpholinylpropyl) sulfanyl]butanamide; 2({ [4(2Butynyloxy)({ [4(2Butynyloxy) phenyl] sulfonyl) (methyl) amino]Nhydroxy3methyl3 { [2 (4methyl1ethyl1piperazinyl) propyl] sulfanyl} butanamide ; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl) (methyl) amino]Nhydroxy3methyl3 { [2 (diethylamino) propyl] sulfanyl} butanamide; 2 [ (4But2ynyloxybenenesulfonyl)methylamino]Nhydroxy3methyl3 methylsulfanylbutyramide; 2 [ (4But2ynyloxybenenesulfonyl)methylamino]Nhydroxy3methyl3 ethylsulfanylbutyramide; 2 [ (4But2ynyloxybenenesulfonyl)methylamino]Nhydroxy3methyl3 propylsulfanylbutyramide ; 2 [ (4But2ynyloxybenenesulfonyl)methylamino]Nhydroxy3methyl3 (pyridin3ylmethylsulfanyl)butyramide; 2 [ (4But2ynyloxybenenesulfonyl)methylamino]Nhydroxy3methyl3 benzylsulfanylbutyramide; 2 [ (4But2ynyloxybenenesulfonyl)methylamino]Nhydroxy3 (methylsulfanyl)butyramide; 2 [ (4But2ynyloxybenenesulfonyl)methylamino]Nhydroxy3 (pyridin3 ylmethylsulfanyl)butyramide; 3(Benzylthio)2[[[4(2butynyloxy)phenyl] sulfonyl] methylamino]N hydroxypropanamide; 3 (Benzylthio)2 [ [ [4 (2butynyloxy) phenyl] sulfonyl] pyridin3ylmethylamino] Nhydroxypropanamide; 2 [ [ [4 (2Butynyloxyphenyl] sulfonyl] amino]Nhydroxy3methyl (3 methylthio)butyramide; 2 [ (4But2ynyloxybenenesulfonyl)amino]Nhydroxy3methyl3 ethylsulfanylbutyramide; 2 [ (4But2ynyloxybenenesulfonyl)amino]Nhydroxy3methyl3 propylsulfanylbutyramide ; 2 [ (4Butynyloxyphenylsulfonyl)amino]Nhydroxy3methyl [ (3 pyridinylmethyl) thio] butyramide; 2 [ (4Butynyloxyphenyl) sulfonyl)amino]Nhydroxy3methyl (3 benzylsulfanyl) butyramide; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl} aminoNhydroxy3 { [ (methyl1 H imidazol2yl] methylsulfanyl} butanamide; 2({ [4(2butynyloxy) phenyl] sulfonyl} aminoNhydroxy3methyl3{ [2(4 morpholinyl) ethyl] sulfanyl} butanamide; tertButyl { [2( { [42butynyloxy) phenyl] sulfonyl} amino)3 (hydroxyamino)1,1 dimethyl3oxopropyl] sulfanyl} acetate; tertButyl { [2 ( { [42butynyloxy) phenyl] sulfonyl} amino)3 (hydroxyamino)1,1 dimethyl3oxopropyl] sulfanyl acetic acid, sodium salt; 2[ (4Butynyloxyphenylsulfonyl)amino]Nhydroxy3 (methylthio) propanamide; 2 [ [4Butynyloxyphenylsulfonyl]amino]Nhydroxy3 (benzylthio) propanamide; 2[[4Butynyloxyphenylsulfonyl]amino]Nhydroxy3 (pyridinylthio) propanamide ; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy3 [ (Z)11 tetradecenylsulfanyl] propanamide ; (2S)2({ [4(2Butynyloxy) phenyl]sulfonyl}amino)Nhydroxy3 [ (3 hydroxypropyl) sulfanyl]3methylbutanamide; (2S)2({ [4(2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy3[(3 hydroxypropyl) sulfanyl]3propanamide ; (3S)4 ( { [4 (2Butynyloxy) phenyl] sulfonyl}Nhydroxy2,2dimethyl1,4 thiazepane3carboxamide; (3 S)4({ [4(2Butynyloxy) phenyl] sulfonyl}Nhydroxy1,4thiazepane3 carboxamide; (3 S)4({ [4(2Butynyloxy) phenyl] sulfonyl}Nhydroxy1,4thiazepane3 carboxamide 1, ldioxide ; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy2 (4 hydroxyphenyl)acetamide ; 2({[4(2Butynyloxy)phenyl] sulfonyl} amino)Nhydroxy2 [4 (2 propynyloxy) phenyl] acetamide ; 2 [ { [4 (2Butynyloxy) phenyl] sulfonyl} (methyl) amino]Nhydroxy2 (4 methoxyphenyl)acetamide; 2 [ { [4 (2Butynyloxy) phenyl] sulfonyl} (methyl) amino]Nhydroxy2 {4 [2 (4 morpholinyl) ethoxy] phenyl} acetamide; tertButyl 2f4 [I [f [4 (2butynyloxy) phenyl] sulfonyl) (methyl) amino]2 (hydroxyamino)2oxoethyl] phenoxy} ethylcarbamate ; 2 [4 (2Aminoethoxy) phenyl]2 [ { [4 (2butynyloxy) phenyl] sulfonyl} (methyl) amino]Nhydroxyacetamide; 2 [ { [4 (2Butynyloxy) phenyl] sulfonyl} (methyl) amino]2 {4 [2 (dimethylamino) ethoxy] phenyl}Nhydroxyacetamide; 2[{[4(2Butynyloxy)phenyl]sulfonyl}(methyl) amino]Nhydroxy2{4[2(1 pyrrolidinyl) ethoxy] phenyl} acetamide ; 2 [f [4 (2Butynyloxy) phenyl] sulfonyl} (methyl) amino]Nhydroxy2 {4 [2 (2 oxo1pyrrolidinyl) ethoxy] phenyl} acetamide; tertButyl 4 (214 [I [ { [4 (2butynyloxy) phenyl] sulfonyl} (methyl) amino]2 (hydroxyamino)2oxoethyl] phenoxy} ethyl)1piperazinecarboxylate ; 2[{ [4(2Butynyloxy) phenyl] sulfonyl} (methyl) amino]Nhydroxy2{4[2(1 piperazinyl) ethoxy] phenyl} acetamide; tertButyl 3{4[1[ { [4 (2butynyloxy) phenyl] sulfonyl} (methyl) amino]2 (hydroxyamino)2oxoethyl] phenoxy} propylcarbamate; 2[4(3Aminopropoxy)phenyl]2[{[4(2butynyloxy)phenyl] sulfonyl} (methyl) amino]Nhydroxyacetamide; tertButyl (3 S)3{4[(1R)1[{ [4(2butynyloxy) phenyl] sulfonyl} (methyl) amino]2 (hydroxyamino)2oxoethyl] phenoxy}1 pyrrolidinecarboxylate; (2R)2 [ { [4 (2Butynyloxy) phenyl] sulfonyl} (methyl) amino]Nhydroxy2 {4 [ (3 S)pyrrolidinyloxy] phenyl} ethanamide ; tertButyl (2 {4 [1( { [4 (2butynyloxy) phenyl] sulfonyl} (methyl) amino)2 (hydroxyamino)2oxoethyl) phenoxy] ethyl) (methyl) carbamate ; 2({ [4(2Butynyloxy)({ [4(2Butynyloxy) phenyl] sulfonyl} (methyl) amino)Nhydroxy2 {4 [2 (methylamino) ethoxy] acetamide; Ethyl 3f 4 [1 [ { [4 (2butynyloxy) phenyl] sulfonyl} (methyl) amino]2 (hydroxyamino)2oxoethyl] phenoxy} propylcarbamate ; 2 {4 [3 (Acetylamino) propoxy] phenyl}2 [ { [4 (2 butynyloxy) phenyl] sulfonyl} (methyl) amino]Nhydroxyacetamide; Butyl 3 {4 [I [ { [4 (2butynyloxy) phenyl] sulfonyl} (methyl) amino]2 (hydroxyamino)2oxoethyl] phenoxy} propylcarbamate; Benzyl 3 {4 [I [ { [4 (2butynyloxy) phenyl] sulfonyl} (methyl) amino]2 (hydroxyamino)2oxoethyl] phenoxy} propylcarbamate; 2[{ [4(2Butynyloxy)[{ [4(2Butynyloxy) phenyl] sulfonyl} (methyl) amino]Nhydroxy2 (4 {3 [(methylsulfonyl) amino] propoxy} phenyl) acetamide ; 2 (4 {3 [ (Anilinocarbonyl) amino] propoxy} phenyl)2 [ { [4 (2 butynyloxy) phenyl] sulfonyl} (methyl) amino]Nhydroxyacetamide; tertButyl 2 {4 [(1 R)1( { [4 (2butynyloxy) phenyl] sulfonyl} amino)2 (hydroxyamino)2oxoethyl] phenoxy} ethylcarbamate ; (2R)2[4(2Aminoethoxy) phenyl]2({ [4(2butynyloxy) phenyl] sulfonyl} amino)Nhydroxyethanamide; (2R)2{4[2(Acetylamino) ethoxy] phenyl}2({ [4(2butynyloxy) phenyl] sulfonyl} amino)Nhydroxyethanamide; tertButyl 4(2 {4 [1( { [4 (2butynyloxy) phenyl] sulfonyl} amino)2 (hydroxyamino)2oxoethyl) phenoxy] ethyl)lpiperazinecarboxylate ; tertButyl 4(2{4[1({ [4(2butynyloxy) phenyl] sulfonyl}(2{4[1({ [4(2butynyloxy) phenyl] sulfonyl} amino)2 (hydroxyamino)2oxoethyl) phenoxy] ethyl) (methyl) carbamate; 2 { [4 (2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy2 {4 [2 (methylamino) ethoxy] phenyl}) acetamide ; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy2 {4 [2 (I pyrrolidinyl) ethoxy] phenyl} acetamide; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy2 {4 [2 (4 morpholinyl) ethoxy] phenyl} acetamide; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl} amino) {4 [2 (dimethylamino) ethoxy] phenyl}Nhydroxyacetamide; 2({[4(2Butynyloxy)phenyl] sulfonyl} amino)Nhydroxy2 {4 [2 (4methyl 1,3thiazol5yl) ethoxy] phenyl} acetamide; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy2 (4 {2 [2 (2 thoxyethoxy) ethoxy] ethoxy} phenyl) acetamide; 2 ( { [4 (2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy2 {4 [2 (2 methoxyethoxy) ethoxy] phenyl) acetamide ; 2[{[4(2Butynyloxy)phenyl] sulfonyl} (methyl) amino]Nhydroxy2 phenylacetamide; 2 [ { [4 (2Butynyloxy) phenyl] sulfonyl} (methyl) amino]2 (4chlorophenyl)N hydroxyacetamide; 2[{ [4(2Butynyloxy)[{ [4(2Butynyloxy) phenyl] sulfonyl} (methyl) amino]5 [ (4chlorophenyl) sulfanyl]Nhydroxypentanamide; 1 (4But2ynyloxybenzenesulfonyl)piperazine2carboxylic acid hydroxyamide ; 1 (4But2ynyloxybenzenesulfonyl)4 (morpholine4carbonyl)piperazine2 carboxylic acid hydroxyamide; 4 (4But2ynyloxybenzenesulfonyl)piperazine1, 3dicarboxylic acid 1 diethylamide 3hydroxyamide; 1 (4But2ynyloxybenzenesulfonyl)4 (pyrrolidine1carbonyl)piperazine2 carboxylic acid hydroxyamide; 4 (4But2ynyloxybenzenesulfonyl)piperazine1,3dicarboxylic acid 1 diisopropylamide 3hydroxyamide ; Benzyl 4 { [4 (2butynyloxy) phenyl] sulfonyl}3[(hydroxyamino) carbonyl]1 piperazinecarboxylate; 4 (4But2ynyloxybenzenesulfonyl)piperazine1,3dicarboxylic acid 3 hydroxyamide 1 (methylphenylamide); 4 { [4 (2Butynyloxy) phenyl] sulfonyl}N3hydroxyN1 (4methoxyphenyl) 1,3 piperazinedicarboxamide; 4{[4(2Butynyloxy)phenyl] sulfonyl)NI (4fluorophenyl)N3hydroxy1,3 piperazinedicarboxamide ; 4{[4(2Butynyloxy)phenyl] sulfonyl}N1 (3, 5dichlorophenyl)N3hydroxy 1,3 piperazinedicarboxamide; 4Acetyl1 (4but2ynyloxybenzenesulfonyl)piperazine2carboxylic acid hydroxyamide ; 1 (4But2ynyloxybenzenesulfonyl)4propionylpiperazine2carboxylic acid hydroxyamide; 1 (4But2ynyloxybenzenesulfonyl)4 (thiophene2carbonyl)piperazine2 carboxylic acid hydroxyamide; 1 (4But2ynyloxybenzenesulfonyl)4methanesulfonylpiperazine2carboxylic acid hydroxyamide; 4(4But2ynyloxybenzenesulfonyl)3hydroxycarbamoylpiperazine1 carboxylic acid methyl ester ; 2 [4 (4But2ynyloxybenzenesulfonyl)3hydroxycarbamoylpiperazin1yl] 2oxoethyl}carbamic acid tertbutyl ester; 4Aminoacetyl1 (4but2ynyloxybenzenesulfonyl)piperazine2carboxylic acid hydroxyamide; 1 { [4 (2Butynyloxy) phenyl] sulfonyl}Nhydroxy4 [ (2,2,5trimethyl1,3 dioxan5yl)carbonyl]2piperazinecarboxamide ; 1{[4(2Butynyloxy)phenyl]sulfbnyi}Nhydroxy4 [3hydroxy2 (hydroxymethyl)2methylpropanoyl2piperazinecarboxamide; 4(4Bromobenzyl)1(4but2ynyloxybenzenesulfonyl)piperazine2 carboxylic acid hydroxyamide; 1 (4But2ynyloxybenzenesulfonyl)4pyridin3ylmethylpiperazine2 carboxylic acid hydroxyamide; (3 S)4 ( { [4 (2Butynyloxy) phenyl] sulfonyl)2, 2dimethylthiomorpholine3 carboxylic acid hydroxyamide ; 9 ( { [4 (2Butynyloxy) phenyl] sulfonyl}Nhydroxy6thia9 azaspiro [4,5] decane10carboxamide; 9({[4(2Butynyloxy)phenyl]sulfonyl}Nhydroxy1thia4 azaspiro [5,5] undecane5carboxamide ; 4 (f [4 (2Butynyloxy) phenyl] sulfonyl)2, 2diethylthiomorpholine3carboxylic acid hydroxyamide; 4 ( { [4 (2Butynyloxy) phenyl] sulfonyl)Nhydroxythiomorpholine3 carboxamide; 4 ( [4 (2Butynyloxy) phenyl] sulfonyl}Nhydroxy3morpholinecarboxamide; 276 9Benzyl4 { [4 (2butynyloxy) phenyl] sulfonyl}Nhydroxy1thia4,9 diazaspiro [5.5] undecane5carboxamide ; 9Methyl4 { [4 (2butynyloxy) phenyl]sulfonyl}Nhydroxy1thia4,9 diazaspiro [5.5] undecane5carboxamide ; NHydroxy2,2dimethyl4[(4{[5(tetrahydro2Hpyran2yloxy)2 pentynyl] oxy} phenyl) sulfonyl]3thiomorpholine carboxamide; NHydroxy4({4[(5hydroxy2pentynyl)oxy]phenyl}sulfonyl)2,2dimethyl3 thiomorpholine carboxamide; tertButyl 5 [4 ( {3 [ (hydroxyamino) carbonyl]2,2dimethyl4thiomorpholinyl} sulfonyl) phenoxy]3pentynylcarbamate; 4({4[(5Amino2pentynyl)oxy]phenyl}sulfonyl)Nhydroxy2,2dimethyl3 thiomorpholine carboxamide; 4[(4{ [4(Benzyloxy)2butynyl] oxy} phenyl) sulfonyl]Nhydroxy2, 2dimethyl 3thiomorpholine carboxamide; NHydroxy2,2dimethyl4 [ (4 { [6 (tetrahydro2Hpyran2yloxy)2 hexynyl] oxy} phenyl) sulfonyl]3thiomorpholine carboxamide; NHydroxy4({4[(6hydroxy2hexynyl)oxy] phenyl} sulfonyl)2,2dimethyl3 thiomorpholine carboxamide; tertButyl 6 [4 ( { (3 S)3 [ (hydroxyamino) carbonyl]2,2 dimethylthiomorpholinyl} sulfonyl) phenoxy]4hexynylcarbamate ; (3 S)4({4[(6Amino2hexynyl) oxy] phenyl} sulfonyl)Nhydroxy2,2dimethyl 3thiomorpholine carboxamide; tertButyl 7 [4 ( { (3S)3 [ (hydroxyamino)carbonyl]2,2 dimethylthiomorpholinyl} sulfonyl) phenoxy]5heptynylcarbamate; (3S)4({4[(7Amino2heptynyl)oxy] phenyl} sulfonyl)Nhydroxy2,2 dimethyl3thiomorpholine carboxamide; (3 S)NHydroxy2, 2dimethyl4({4[(3phenyl2propynyl) oxy] phenyl} sulfonyl)3 thiomorpholine carboxamide; (3 S)4 { [4 (2Butynyloxy) phenyl]sulfonyl}Nhydroxy2,2dimethyl3 thiomorpholine carboxamide (1S)oxide; (3 S)4 { [4 (2Butynyloxy) phenyl] sulfonyl}Nhydroxy2,2dimethyl3 thiomorpholine carboxamide (lR)oxide; (3 S)4{ [4(2Butynyloxy) phenyl] sulfonyl}Nhydroxy2,2dimethyl3 thiomorpholine carboxamide 1,1dioxide; (3 S)NHydroxy2, 2dimethyl4{ [4(2propynyloxy) phenyl] sulfonyl}3 thiomorpholine carboxamide; (3 S)NHydroxy2,2dimethyl4 { [4 (2pentynyloxy) phenyl] sulfonyl}3 thiomorpholine carboxamide; (3 S)NHydroxy4({4[(4hydroxy2butynyl) oxy] phenyl} sulfonyl)2,2 dimethyl3thiomorpholine carboxamide; 4[4({(3S)3[(Hydroxyamino)carbonyl]2, 2dimethylthiomorpholinyl} sulfonyl) phenoxy]2butynyl acetate; (3 S)NHydroxy4({4[(6hydroxy2,4hexadiynyl) oxy] phenyl} sulfonyl)2,2 dimethyl3thiomorpholine carboxamide; (3 S)NHydroxy2, 2dimethyl4{ [4(2,4pentadiynyloxy) phenyl] sulfonyl}3 thiomorpholine carboxamide; (3 S)4 ( {4 [ (4Fluoro2butynyl) oxy] phenyl} sulfonyl)Nhydroxy2,2dimethyl 3thiomorpholine carboxamide; 4({4[(4Amino2butynyl) oxy] phenyl} sulfonyl)Nhydroxy2,({4[(4Amino2butynyl) oxy] phenyl} sulfonyl)Nhydroxy2, 2dimethyl3 thiomorpholine carboxamide; tertButyl 4 [4 ( {3 [ (hydroxyamino)carbonyl]2,2dimethyl4 thiomorpholinyl} sulfonyl) phenoxy]2butynylcarbamate ; tertButyl 4 [4 ( {3 [ (hydroamino)carbonyl]2,2dimethyl4 thiomorpholinyl} sulfonyl) phenoxy]2butynyl (methyl) carbamate; 7[4({(3S)3[(Hydroxyamino)carbonyl]2,2dimethylthiomorpholinyl} sulfonyl) phenoxy]5heptynyl acetate ; (3 S)NHydroxy4 ( {4 [ (7hydroxy2heptynyl) oxy] phenyl} sulfonyl)2,2 dimethyl3thiomorpholinecarboxamide; (3 S, 5 S)4 { [4 (2Butynyloxy) phenyl] sulfonyl}Nhydroxy2,2,5trimethyl3 thiomorpholinecarboxamide; (3 S, 5R)4 { [4 (2Butynyloxy) phenyl] sulfonyl}Nhydroxy2,2,5trimethyl3 thiomorpholinecarboxamide ; (3 S, 6S)4f [4 (2Butynyloxy) phenyl] sulfonyl}Nhydroxy2,2,6trimethyl3 thiomorpholinecarboxamide; tertButyl { (2R,5S)4{[4(2butynyloxy)phenyl] sulfonyl}5 [ (hydroxyamino) carbonyl]6,6dimethylthiomorpholinyl} methylcarbamate; tertButyl { (2S, 5 S)4 { [4 (2butynyloxy) phenyl] sulfonyl}5 [ (hydroxyamino) carbonyl]6, 6dimethylthiomorpholinyl) methylcarbamate; (3 S, 6R)Trans6(aminomethyl)4 { [4(2butynyloxy) phenyl] sulfonyl}N hydroxy2,2dimethyl3thiomorpholinecarboxamide hydrochloride; (3S, 6S)Cis6 (aminomethyl)4 { [4 (2butynyloxy) phenyl] sulfonyl}Nhydroxy 2,2dimethyl3thiomorpholinecarboxamide hydrochloride ; tertButyl { (2S, 5 S)4{ [4(2butynyloxy) phenyl] sulfonyl}5 [(hydroxyamino) carbonyl]6, 6dimethylthiomorpholinyl} acetate; {(2S,5S)4{[4(2Butynyloxy)phenyl] sulfonyl}5[(hydroxyamino) carbonyl] 6,6dimethylthiomorpholinyl} acetic acid; (3 S, 6S)4{ [4(2Butynyloxy) phenyl] sulfonyl}Nhydroxy6[2(hydroxyamino) 2oxoethyl]2,2dimethyl3thiomorpholinecarboxamide; (3 S, 6 S)6(2Amino2oxoethyl)4 { [4 (2butynyloxy) phenyl] sulfonyl}N hydroxy2,2dimethyl3thiomorpholinecarboxamide; (3 S, 6S)4{ [4(2Butynyloxy) phenyl] sulfonyl}6[2(dimethylamino)2 oxoethyl]Nhydroxy2,2dimethyl3thiomorpholinecarboxamide ; (3S,6S)4{[4(2Butynyloxy)phenyl] sulfonyl}Nhydroxy2,2dimethyl6 [2 (4 morpholinyl)2oxoethyl]3thiomorpholinecarboxamide; (3 S, 6S)4{ [4(2Butynyloxy) phenyl] sulfonyl}Nhydroxy2, 2dimethyl6[2(4 methyl1piperazinyl)2oxoethyl]3thiomorpholinecarboxamide hydrochloride; (3 S, 6 S)4 { [4(2Butynyloxy) phenyl] sulfonyl}6(2 { [2(dimethylamino) ethyl] amino}2oxoethyl)Nhydroxy2, 2dimethyl3thiomorpholinecarboxamide ; Methyl (3 S, 6S)6{ [(tertbutoxycarbonyl) amino]methyl}4{[4(2 butynyloxy) phenyl] sulfonyl}2,2dimethyl3thiomorpholinecarboxylate; (4S)3 { [4 (2Butynyloxy) phenyl] sulfonyl}Nhydroxy5, 5dimethyl1,3 thiazolidine4carboxamide; tertButyl 4 ( { [4 (2butynyloxy) phenyl] sulfonyl} amino)4 [(hydroxyamino) carbonyl]1piperidinecarboxylate; 4 ( { [4 (2Butynyloxy) phenyl] sulfonyl} amino)Nhydroxy4 piperidinecarboxamide; 1Benzoyl4{ [4(2butynyloxy){ [4(2butynyloxy) phenyl] sulfonyl}Nhydroxy1,4diazepane5 carboxamide; 1Benzyl4{[4(2butynyloxy)phenyl] sulfonyl}Nhydroxy1,4diazepane5 carboxamide; tertButyl 4 { [4 (2butynyloxy) phenyl] sulfonyl}5[(hydroxyamino) carbonyl] 1,4diazepane1carboxylate; 4{ [4(2Butynyloxy) phenyl] sulfonyl}Nhydroxy1,{ [4(2Butynyloxy) phenyl] sulfonyl}Nhydroxy1, 4diazepane5carboxamide; 4{[4(2Butynyloxy)phenyl] sulfonyl}Nhydroxy1methyl1, 4diazepane5 carboxamide ; 4 { [4 (2Butynyloxy) phenyl] sulfonyl}Nhydroxy1,4thiazepine5carboxamide; (2R)5(Acetylamino)2({ [4(but2ynyloxy) phenyl] sulfonyl} amino)N hydroxypentanamide; N[(4R)4({[4(But2ynyloxy)phenyl]sulfonyl}amino)5(hydroxyamino)5 oxopentyl] thiophene2carboxamide ; (2R)2({ [4(But2ynyloxy) phenyl] sulfonyl} amino)5 { [(ethylamino) carbonyl] amino}Nhydroxypentanamide ; (2R)5[(Anilinocarbonyl) amino]2({ [4(but2ynyloxy) phenyl] sulfonyl} amino)Nhydroxypentanamide; Octyl (4R)4 ( { [4 (but2ynyloxy) phenyl] sulfonyl} amino)5 (hydroxyamino)5 oxopentylcarbamate; 4Methoxyphenyl (4R)4 ( { [4 (but2ynyloxy) phenyl] sulfonyl} amino)5 (hydroxyamino)5oxopentylcarbamate; (2R)2({ [4(But2ynyloxy) phenyl] sulfonyl} amino)5{ [(diethylamino) carbonyl] amino}Nhydroxypentanamide; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy5 {[(methylanilino) carbonyl] amino} pentanamide ; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy5 { [ (1methyl lHimidazol4yl) sulfonyl] amino} pentanamide; (2R)2({ [4(But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy5[(2 morpholin4ylacetyl) amino] pentanamide; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy5 { [2 (4 methylpiperazin1yl) acetyl] amino} pentanamide; (2R)5 { [2(Benzylamino) acetyl] amino}2({ [4(but2ynyloxy) phenyl] sulfonyl} amino)Nhydroxypentanamide; (3S)4{[4(2Butynyloxy)phenyl] sulfonyl}Nhydroxy2,2dimethyl3,4 dihydro2H1,4thiazine3carboxamide; (2R)2 ( { [4 (2Butynyloxy) phenyl] sulfonyl} amino)NhydroxyS [ (imino { [ (4 { [ (4methoxy2,3,6trimethylphenyl) sulfonyl] amino} methyl) amino] pentanamide; (2R)2 (4But2ynyloxybenzenesulfonylamino)5guanidinopentanoic acid hydroxyamide; (2R)2({[4(2Butynyloxy)phenyl]sulfonyl}amino)Nhydroxy5[(imino{[(4 methylphenyl) sulfonyl] amino} methyl) amino] pentanamide ; (3R)3({[4(But2ynyloxy)phenyl] sulfonyl} amino)4 (hydroxyamino)4 oxobutanoic acid; (2S)3(tertButylthio)2({ [4(but2ynyloxy) phenyl] sulfonyl} amino)N hydroxypropanamide; (2S)3{[(Acetylamino)methyl] thio}2 ( { [4 (but2 ynyloxy) phenyl] sulfonyl} amino)Nhydroxypropanamide; (2S)2({ [4(But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy3 [ (4 methylbenzyl) thio] propanamide ; (2S)2({[4(But2ynyloxy)phenyl] sulfonyl} amino)Nhydroxy3 [ (4 methoxybenzyl) thio] propanamide; (2R)2 ( { [4(But2ynyloxy) phenyl] sulfonyl} amino)N hydroxypentanediamide; (4R)4({[4(But2ynyloxy)phenyl] sulfonyl} amino)5 (hydroxyamino)5 oxopentanoic acid ; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy4 phenylbutanamide; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy3 (1 H imidazol5yl) propanamide; (2R, 4S)1 { [4(But2ynyloxy) phenyl] sulfonyl}N, 4dihydroxypyrrolidine2 carboxamide; (2R)6Amino2({ [4(but2ynyloxy) phenyl] sulfonyl} amino)N hydroxyhexanamide; Benzyl (5R)5({ [4(but2ynyloxy) phenyl] sulfonyl} amino)6(hydroxyamino) 6oxohexylcarbamate; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy3 (1 naphthyl) propanamide; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy3 (2 naphthyl) propanamide; (2R)2 ( { [4(But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxyhexanamide; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxypentanamide; (2R)5Amino2({ [4(but2ynyloxy) phenyl] sulfonyl} amino)N hydroxypentanamide; (2R)2({[4(But2ynyloxy)phenyl] sulfonyl} amino)3 (3,4difluorophenyl)N hydroxypropanamide ; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)3 (4fluorophenyl)N hydroxypropanamide; (2R)2 (f [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy3 (4 nitrophenyl) propanamide; (2R)1{ [4(But2ynyloxy) phenyl] sulfonyl}Nhydroxypiperidine2 carboxamide ; (2R)2({[4(But2ynyloxy)phenyl] sulfonyl} amino)N, 3 dihydroxypropanamide; (2R)3(B enzyloxy)2( { [4(but2ynyloxy) phenyl] sulfonyl} amino)N hydroxypropanamide; (2R)2 ( {[4(But2ynyloxy)phenyl] sulfonyl} amino)Nhydroxy3thien2 ylpropanamide; (2R, 3 S)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)N, 3 dihydroxybutanamide; (2R, 3 S)3 (Benzyloxy)2({ [4(but2ynyloxy) phenyl] sulfonyl) amino)N hydroxybutanamide; (4S)3 {[4(But2ynyloxy)phenyl] sulfonyl}Nhydroxy1,3thiazolidine4 carboxamide; (3R)2 {[4(But2ynyloxy)phenyl] sulfonyl}Nhydroxyl, 2,3,4 tetrahydroisoquinoline3carboxamide; (2R)3 [4 (Benzyloxy) phenyl]2 ( { [4 (but2ynyloxy) phenyl] sulfonyl} amino) Nhydroxypropanamide; (2R)2 ( { [4(But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy2 phenylethanamide; (2R)5(Acetylamino)2({ [4(but2ynyloxy) phenyl] sulfonyl} amino)N hydroxypentanamide; N[(4R)4({ [4(But2ynyloxy) phenyl] sulfonyl} amino)5(hydroxyamino)5 oxopentyl]lHbenzimidazole5carboxamide ; N[(4R)4({ [4(But2ynyloxy) phenyl] sulfonyl} amino)5(hydroxyamino)5 oxopentyl] benzamide; 4BromoN[(4R)4({[4(but2ynyloxy)phenyl] sulfonyl} amino)5 (hydroxyamino)5oxopentyl] benzamide; (2R)2({[4(But2ynyloxy)phenyl] sulfonyl} amino)5 (butyrylamino)N hydroxypentanamide; N[(4R)4({[4(But2ynyloxy)phenyl] sulfonyl} amino)5 (hydroxyamino)5 oxopentyl]3chlorothiophene2carboxamide; N[(4R)4({[4(But2ynyloxy)phenyl] sulfonyl}amino)5(hydroxyamino)5 oxopentyl]4chlorobenzamide; N [ (4R)4 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)5 (hydroxyamino) 5 oxopentyl] cyclohexanecarboxamide; (2R)2({ [4 (But2ynyloxy) phenyl] sulfonyl} amino)5 { [2 (3,4 dichlorophenyl) acetyl] amino}Nhydroxypentanamide ; N [ (4R)4 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)5 (hydroxyamino)5 oxopentyl]2,5dimethyl3furamide; N [ (4R)4 ( { [4 (But2ynyloxy) phenyl]sulfonyl}amino)5 (hydroxyamino)5 oxopentyl]3,5dimethylisoxazole4carboxamide ; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy5 [ (3 phenylpropanoyl) amino] pentanamide; N[(4R)4({[4(But2ynyloxy)phenyl] sulfonyl} amino)5 (hydroxyamino)5 oxopentyl] isonicotinamide; N[(4R)4({ [4(But2ynyloxy) phenyl] sulfonyl} amino)5(hydroxyamino)5 oxopentyl] nicotinamide; N[(4R)4({[4(But2ynyloxy)phenyl] sulfonyl} amino)5 (hydroxyamino)5 oxopentyl]2methoxybenzamide; N [ (4R)4 ( { [4 (But2ynyloxy) phenyl] sulfonyl}amino)5(hydroxyamino)5 oxopentyl]4methoxybenzamide; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy5 { [2 (4 nitrophenyl) acetyl] amino} pentanamide; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfbnyl} amino)Nhydroxy5 [ (2 phenylacetyl) amino] pentanamide; N[(4R)4({[4(But2ynyloxy)phenyl] sulfonyl}amino)5(hydroxyamino)5 oxopentyl] quinoline3carboxamide; N[(4R)4({[4(But2ynyloxy)phenyl] sulfonyl} amino)5 (hydroxyamino)5 oxopentyl] thiophene3carboxamide; (E)N[(4R)4({[4(But2ynyloxy)phenyl] sulfonyl} amino)5 (hydroxyamino) 5oxopentyl]3phenylprop2enamide; N [ (5R)5 (f [4 (But2ynyloxy) phenyl] sulfonyl} amino)6 (hydroxyamino)6 oxohexyl]1Hbenzimidazole5carboxamide; N [ (5R)5 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)6 (hydroxyamino)6 oxohexyl] benzamide; 4BromoN[(5R)5({[4(but2ynyloxy)phenyl]sulfonyl}amino)6 (hydroxyamino)6oxohexyl]benzamide ; N[(5R)5({ [4(But2ynyloxy) phenyl] sulfonyl} amino)6(hydroxyamino)6 oxohexyl]3chlorothiophene2carboxamide; N[(5R)5({ [4(But2ynyloxy) phenyl] sulfonyl} amino)6(hydroxyamino)6 oxohexyl]4chlorobenzamide; N[(5R)5({[4(But2ynyloxy)phenyl] sulfonyl} amino)6 (hydroxyamino)6 oxohexyl] cyclohexanecarboxamide; (2R)2({[4(But2ynyloxy)phenyl] sulfonyl} amino)6 { [2 (3,4 dichlorophenyl) acetyl] amino}Nhydroxyhexanamide; N[(5R)5({[4(But2ynyloxy)phenyl] sulfonyl} amino)6 (hydroxyamino)6 oxohexyl]2,5dimethyl3furamide; N[(5R)5({[4(But2ynyloxy)phenyl] sulfonyl} amino)6 (hydroxyamino)6 oxohexyl]3,5dimethylisoxazole4carboxamide; (2R)2({[4(But2ynyloxy)phenyl] sulfonyl} amino)Nhydroxy6 [ (3 phenylpropanoyl) amino] hexanamide; N[(5R)5({ [4(But2ynyloxy) phenyl] sulfonyl} amino)6(hydroxyamino)6 oxohexyl]isonicotinamide; N [ (5R)5 ( { [4 (But2ynyloxy) phenyl]sulfonyl}amino)6(hydroxyamino)6 oxohexyl]2methoxybenzamide ; N[(5R)5({[4(But2ynyloxy)phenyl]sulfonyl}amino)6(hydroxyamino)6 oxohexyl]4methoxybenzamide; (2R)2 ( {[4(But2ynyloxy)phenyl]sulfonyl}amino)Nhydroxy6{[2(4 nitrophenyl) acetyl] amino} hexanamide; (2R)2({[4(But2ynyloxy)phenyl] sulfonyl}amino)Nhydroxy6[(2 phenylacetyl) amino] hexanamide; N[(5R)5({ [4(But2ynyloxy) phenyl] sulfonyl} amino)6(hydroxyamino)6 oxohexyl] quinoline3carboxamide; N [ (5R)5 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)6 (hydroxyamino)6 oxohexyl] thiophene3carboxamide; (E)N[(5R)5({ [4(But2ynyloxy) phenyl] sulfonyl} amino)6(hydroxyamino) 6oxohexyl]3phenylprop2enamide; (Z)N[(4R)4({ [4(But2ynyloxy) phenyl] sulfonyl} amino)5(hydroxyamino) 5oxopentyl] octadec9enamide; N[(4R)4({[4(But2ynyloxy)phenyl] sulfonyl} amino)5 (hydroxyamino)5 oxopentyl]thiophene2carboxamide; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)5 { [ (ethylamino) carbonyl] amino}Nhydroxypentanamide; (2R)5[(Anilinocarbonyl) amino]2({ [4(but2 ynyloxy) phenyl] sulfonyl) amino)Nhydroxypentanamide; Octyl (4R)4 ( { [4 (but2ynyloxy) phenyl] sulfonyl} amino)5 (hydroxyamino)5 oxopentylcarbamate; 4Methoxyphenyl (4R)4 ( { [4 (but2ynyloxy) phenyl] sulfonyl} amino)5 (hydroxyamino)5oxopentylcarbamate; (2R)2({ [4(But2ynyloxy) phenyl] sulfonyl} amino)5 { [ (diethylamino) carbonyl] amino}Nhydroxypentanamide; (2R)2 ( { [4 (But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy5 { [(methylanilino) carbonyl] amino} pentanamide; (2R)2({ [4(But2ynyloxy) phenyl] sulfonyl}amino)Nhydroxy5{[(1methyl 1 Himidazol4yl) sulfonyl] amino} pentanamide; (2R)2({ [4(But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy5[(2 morpholin4ylacetyl) amino] pentanamide; (2R)2({ [4(But2ynyloxy) phenyl] sulfonyl} amino)Nhydroxy5 { [2 (4 methylpiperazin1yl) acetyl] amino} pentanamide; and (2R)5{[2(Benzylamino)acetyl] amino}2({ [4(but2 ynyloxy) phenyl] sulfonyl} amino)Nhydroxypentanamide; or a pharmaceutical salt thereof.

14.

A process for preparing a compound of formula B, as defined in claim 1, which comprises one of the following: a) reacting a compound of formula V: wherein R, R2, R3, R4, R6, X, Y and Z are defined in claim 1, or a reactive derivative thereof, with hydroxylamine to give a corresponding compound of formula B; or b) deprotecting a compound of formula VI: wherein R, R2, R3, R4, R5, R6, X, Y and Z are defined in claim 1, and R30 is a suitable protecting group such as tbutyl, benzyl, and trialkylsilyl, to give a corresponding compound of formula B or c) cleaving a resin supported hydroxamate derivative containing the group: to give a compound of formula B as defined in claim 1; or d) resolving a mixture (e. g. racemate) of optically active isomers of a compound of formula B to isolate one enantiomer or diastereomer substantially free of the other enantiomer or diastereomers; or e) acidifying a basic compound of formula B with a pharmaceutically acceptable acid to give a pharmaceutically acceptable salt; or f) converting a compound of formula B having a reactive substituent group or site to give a compound of formula B having a different substituent group or site.

15.	A compound of formula II, with the proviso that R6 is not hydrogen and R4, R5 and R6 are as defined in Claim 1.

16.	A compound of formula m, with the proviso that R6 is not hydrogen wherein J is fluorine, bromine, chlorine, 1,2,4triazolyl, benzotriazolyl or imidazolyl, and R4, Rs and R6 are as defined in Claim 1.

17.

A method of inhibiting pathological changes mediated by TNF a converting enzyme (TACE) in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound having the formula wherein: X is SO, orP (O)R, o; Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y; Z isO, NH, CH2orS; Rl is hydrogen, aryl, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms; R2 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl of 36 carbon atoms, C4Cg cycloheteroalkyl, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms; or R, and R2, together with the atom to which they are attached, may form a ring wherein R, and R2 represent a divalent moiety of the formula: wherein Q = a carboncarbon single or double bond, O, S, SO, S02,NR", or CONR, 4 ; m = 13; r = 1 or 2, with the proviso that when Q is a bond, r is equal to 2; R3 is hydrogen, alkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, C4C8 cycloheteroalkyl, aralkyl, or heteroaralkyl; or R, and R3, together with the atoms to which they are attached, may form a 5 to 8 membered ring wherein R, and R3 represent divalent moieties of the formulae: wherein Q and m are as defined above; A is aryl or heteroaryl; s is 03; u is 14; R4 and R5 are each, independently, hydrogen or alkyl of 16 carbon atoms, CN, orCCH; R6 is hydrogen, aryl, heteroaryl, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cycloalkyl of 36 carbon atoms, orC5Cgcycloheteroalkyl; R and R9 are each, independently, hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cycloalkyl of 36 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl, orC4 Cgcycloheteroalkyl; Rlo is alkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, aryl or heteroaryl; RI, is hydrogen, alkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, aryl, heteroaryl,S (O) nR,,COOR,,CONR$R,,SO,2NR8R9 orCOR,; R 12 and R13 are independently selected from H,OR8,NR8Rg, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cycloalkyl of 36 carbon atoms, aryl, heteroaryl,COOR8; CONR, R,; or R,, and R, 3 together form aC3C6cycloalkyl of 36 carbon atoms or aC5Cgcycloheteroalkyl ring; or R, 2and R, 3 together with the carbon to which they are attached, form a carbonyl group; with the proviso that R, o and R, 2 or R,, and R, 2 may form a cycloheteroalkyl ring when they are attached to adjacent atoms; R, 4is hydrogen, aryl, heteroaryl, alkyl of 16 carbon atoms or cycloalkyl of 3 6 carbon atoms; and n is 02; or a pharmaceutically acceptable salt thereof.

18.	The method according to Claim 17 wherein the condition treated is rheumatoid arthritis, graft rejection, cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease or HIV infection.

19.

A pharmaceutical composition comprising a compound having the formula wherein: X is SO2 orP (O)R10; Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y; Z isO, NH, CH2 or S; RI is hydrogen, aryl, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms; R2 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl of 36 carbon atoms, C4Cg cycloheteroalkyl, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms; or Ri and R2, together with the atom to which they are attached, may form a ring wherein R, and R2 represent a divalent moiety of the formula: wherein Q = a carboncarbon single or double bond, O, S, SO, S02,NRl,, or CONRt4; m = 13; r = 1 or 2, with the proviso that when Q is a bond, r is equal to 2; R3 is hydrogen, alkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, C4C8 cycloheteroalkyl, aralkyl, or heteroaralkyl; or Ri and R3, together with the atoms to which they are attached, may form a 5 to 8 membered ring wherein Ri and R3 represent divalent moieties of theformulae: wherein Q and m are as defined above; A is aryl or heteroaryl; s is 03; u is 14; R4 and Rs are each, independently, hydrogen or alkyl of 16 carbon atoms, CN, orCCH; R6 is hydrogen, aryl, heteroaryl, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cycloalkyl of 36 carbon atoms, orC5Cgcycloheteroalkyl; R8 and R, are each, independently, hydrogen, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cycloalkyl of 36 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl, orC4 Cgcycloheteroalkyl; Rlo is alkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, aryl or heteroaryl; R"is hydrogen, alkyl of 16 carbon atoms, cycloalkyl of 36 carbon atoms, aryl, heteroaryl,S (O) nR8,COOR8,CONR8R9,SO2NR8R9 orCOR8; R, 2 and R, 3 are independently selected from H,OR8,NR8R9, alkyl of 16 carbon atoms, alkenyl of 26 carbon atoms, alkynyl of 26 carbon atoms, cycloalkyl of 36 carbon atoms, aryl, heteroaryl,COOR8; CONR8R9; or Rl2and Rl3together form aC3C6cycloalkyl of 36 carbon atoms or aC5Cgcycloheteroalkyl ring; or R, 2 and Rl3 together with the carbon to which they are attached, form a carbonyl group; with the proviso that Rlo and R, 2 or R"and R, 2 may form a cycloheteroalkyl ring when they are attached to adjacent atoms; R, 4 is hydrogen, aryl, heteroaryl, alkyl of 16 carbon atoms or cycloalkyl of 3 6 carbon atoms; and n is 02; or a pharmaceutically acceptable salt thereof.

Description:

INTERNATIONALSEARCHREPORT Inte onal ApplicationNo PCT/US00/01981 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT CategoryCitationofdocument,withindication,whereappropnate,of therelevantpassagesRelevanttoclaimNo. AWO9808853A(THEPROCTER&GAMBLECO)1,17-19 5March1998(1998-03-05) citedintheapplication claims ADATABASECHEMABS'Online!15 CHEMICALABSTRACTSSERVICE,COLUMBUS, OHIO,US; STN,CAPLUSaccessionno.1975:467728, XP002142178 abstract;RN56136-19-7 &G.SVILPIENEETAL:LIET.TSRMOKSLU AKAD.DARB.,SERB, no.3,1974,pages63-68, 1 INTERNATIONALSEARCH REPORT Inter »nal ApplicationNo mformationon patent famiiymembers PCT/US 00/01981 PatentdocumentPublication Patent family Publication citedinsearchreportdate member(s)date WO9808815A05-03-1998AU 4074197 A 19-03-1998 CN 1232451 A 20-10-1999 CZ 9900631 A 11-08-1999 EP 0927161 A 07-07-1999 NO 990855 A 23-04-1999 PL 331802 A 02-08-1999 WO9808825A05-03-1998AU 4073997 A 19-03-1998 AU 4152997 A 19-03-1998 BR 9713185 A 03-11-1999 CN 1228773 A 15-09-1999 CN 1232457 A 20-10-1999 CZ 9900623 A 14-07-1999 CZ 9900627 A 14-07-1999 EP 0923563 A 23-06-1999 EP 0925287 A 30-06-1999 NO 990760 A 27-04-1999 NO 990839 A 28-04-1999 PL 331856 A 16-08-1999 PL 331900 A 16-08-1999 SK 25699 A 08-10-1999 WO 9808827 A 05-03-1998 WO9633172A24-10-1996CA 2218503 A 24-10-1996 AU 694635 B 23-07-1998 AU 5080296 A 31-10-1996 BR 9602001 A 07-04-1998 CN 1140165 A 15-01-1997 CZ 9601130 A 13-11-1996 EP 0821671 A 04-02-1998 FI 973974 A 16-10-1997 JP 10507466 T 21-07-1998 NO 961585 A 21-10-1996 NZ 286417 A 26-06-1998 SG 43350 A 17-10-1997 TR 960966 A 21-11-1996 US 5861510 A 19-01-1999 WO9808853A05-03-1998AU 4153197 A 19-03-1998 BR 9713182 A 03-11-1999 CN 1228780 A 15-09-1999 CZ 9900636 A 14-07-1999 EP 0925303 A 30-06-1999 NO 990857 A 28-04-1999 PL 331854 A 16-08-1999 US 5830915 A 03-11-1998

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