US2003008901A1PendingUtilityA1

Hydroxy pipecolate hydroxamic acid derivatives

47
Priority: Aug 12, 1998Filed: Dec 3, 2001Published: Jan 9, 2003
Est. expiryAug 12, 2018(expired)· nominal 20-yr term from priority
Inventors:Kim F. McclureMark C. NoeMichael A. LetavicLouis S. Chupak
A61P 3/10A61P 37/08A61P 37/06A61P 9/08A61P 43/00A61P 25/28A61P 25/00A61P 35/00A61P 31/04A61P 31/18A61P 27/02A61P 1/02A61P 11/00A61P 11/06A61P 19/10A61P 17/00A61P 19/02A61P 1/04C07D 211/96C07D 409/12C07D 401/12C07D 405/12C07D 413/12C07D 261/06C07D 317/54C07D 333/28C07D 213/30
47
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Claims

Abstract

A compound of the formula wherein R 1 , R 2 R 3 , R 4 R 5 , R 6 , R 7 , R 8 , R 9 and Ar are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, and other diseases characterized by matrix metalloproteinase or mammalian reprolysin activity. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID'S), COX-2 inhibitors and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.

Claims

exact text as granted — not AI-modified
1 . A compound of the formula  
       
         
           
           
               
               
           
         
         wherein R 1 -R 8  are selected from the group consisting of hydroxy, hydrogen, NH 2 , halogen, —CN, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 6 -C 10 )aryl(C 2 -C 6 )alkenyl, (C 2 -C 9 )heteroaryl(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl(C 2 -C 6 )alkynyl, (C 2 -C 9 )heteroaryl(C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 amino, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 6 )alkyl, perfluoro(C 1 -C 6 )alkoxy, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, (C 6 -C 10 )arylamino, (C 6 -C 10 )arylthio, (C6-C 10 )aryloxy, (C 2 -C 9 )heteroarylamino, (C 2 -C 9 )heteroarylthio, (C 2 -C 9 )heteroaryloxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl(hydroxymethylene), piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 1 -C 6 )acyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylthio, (C 1 -C 6 )acyloxy, (C 1 -C 6 )alkoxy-(C═O)—, —CO 2 H, (C 1 -C 6 )alkyl-NH—(C═O)—, and [(C 1 -C 6 )aIky] 2 —N—(C═O)—;  
         wherein said (C 1 -C 6 )alkyl is optionally substituted by one or two groups selected from (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy, trifluoromethyl, halo, —CN, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, (C 6 -C 10 )arylamino, (C 6 -C 10 )arylthio, (C 6 -C 10 )aryloxy, (C 2 -C 9 )heteroarylamino, (C 2 -C 9 )heteroarylthio, (C 2 -C 9 )heteroaryloxy, (C 6 -C 10 )aryl(C 6 -C 10 )aryl, (C 3 -C 6 )cycloalkyl, hydroxy, piperazinyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy, (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkoxy, (C 1 -C 6 )acylamino, (C 1 -C 6 )acylthio, (C 1 -C 10 )acyloxy, (C 1 -C 6 )alkylsulfinyl, (C 6 -C 10 )arylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 6 -C 10 )aryisulfonyl, amino, (C 1 -C 6 )alkylamino or ((C 1 -C 6 )alkyl) 2 amino;  
         or R 1  and R 2 , or R 3  and R 4 , or R 5  and R 6  may be taken together to form a carbonyl;  
         or R 1  and R 2 , or R 3  and R 4 , or R 5  and R 6 , or R 7  and R 8  may be taken together to form a (C 3 -C 6 )cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula  
         
           
             
             
                 
                 
             
           
         
         Ar is (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 2 -C 9 )heteroaryl optionally substituted by one or more substituents, independently selected from halo, —CN, (C 1 -C 6 )alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy optionally substituted with one or more fluorine atoms, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, HO—(C═O)—, (C 1 -C 6 )alkyl-O—(C═O)—, HO—(C═O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C═O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-(C═O)—O—, (C 1 -C 6 )alkyl-(C═O)-O—(C 1 -C 6 )alkyl, H(O═C)—, H(O═C)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(O═C)—, (C 1 -C 6 )alkyl(O═C)—(C 1 -C 6 )alkyl, NO 2 , amino, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkyl] 2 amino(C 1 -C 6 )alkyl, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-NH—(C═O)—, [(C 1 -C 6 )alkyl] 2 N—(C═O)—, H 2 N(C═O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-HN(C═O)—(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkyl] 2 N—(C═O)—(C 1 -C 6 )alkyl, H(O═C)—NH—, (C 1 -C 6 )alkyl(C═O)—NH—, (C 1 -C 6 )alkyl(C═O)-[NH](C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C═O)-[N(C 1 -C 6 )alkyl](C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—, (C 1 -C 6 )alkyl-(S═O)—, (C 1 -C 6 )alkyl-SO 2 —, (C 1 -C 6 )alkyl-SO 2 —NH—, H 2 N—SO 2 —, H 2 N—SO 2 —(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylHN—SO 2 —(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkyl] 2 N—SO 2 —(C 1 -C 6 )alkyl, CF 3 SO 3 —, (C 1 -C 6 )alkyl-SO 3 —, phenyl, phenyl(C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, and (C 2 -C 9 )heteroaryl;  
         with the proviso that at least one of R 1 -R 8  is hydroxy;  
         with the additiional proviso that the compounds of formula I can not be (2R,4S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-3-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R, 3S)-3-Hydroxy-1-[4-(pyridin4-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R,3 S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-1{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-3-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-1-[4-(2-pyridin4-yl-ethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-1-[4-(Benzothiazol-2-ylmethoxy)-benzenesulfonyl]-3-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-1-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-1-[4-(2-Chloro-thiazol-5-ylmethoxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1-[4-(thiazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1-[4-(pyridin-4-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-1{4-[2-(4-Fluorophenyl)-ethoxy]-benzenesulfonyl}-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1-[4-(2-pyridin-4-yl-ethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-1-[4-(Benzoth iazol-2-ylmethoxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-3-Hydroxy-3-methyl-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R, 3S)-3-Hydroxy-3-methyl-1-[4-(1H-tetrazol-5-ylmethoxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide; (2R,4S)--(4-Benzyloxy-benzenesulfonyl)-4-butylaminomethyl-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,4S)4-Butylaminomethyl-1-[4-(4-fluorobenzyloxy)-benzenesulfony]4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,4R)-1-(4-Benzyloxy-benzenesulfonyl)-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,4R)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,5S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,5S)-1-(4-Benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxyic acid hydroxyamide; (2R,5R)-1-(4-Benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,5R)-1-[4-(4-F luorobenzyIoxy)-benzenesufonyl-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,3S)-1-(4-Benzyloxy-benzenesulfonyl)-3-hydroxy-piperidine-2-carboxylic acid hydroxyamide; (2R,4S)-1-(4-Benzyloxy-benzenesulfonyl)-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide; and (2R,4S)-1-[4-(4-Fluorobenzyloxy)-benzenesulfonyl]4-hydroxy-piperidine-2-carboxylic acid hydroxyamide;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . A compound according to  claim 1 , wherein at least one of R 1 -R 6  is (C 1 -C 6 )alkyl.  
     
     
         3 . A compound according to  claim 1 , wherein at least one of R 1 -R 6  is hydroxy and each of the other of R 1 -R 8  is hydrogen.  
     
     
         4 . A compound according to  claim 1 , wherein at least one of R 1 -R 6  is hydroxy and at least one of the other of R 1 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         5 . A compound according to  claim 1 , wherein at least one of R 1 -R 6  is hydroxy and each of R 7 -R 8  is hydrogen.  
     
     
         6 . A compound according to  claim 1 , wherein at least one of R 1 -R 6  is hydroxy and each of R 7 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         7 . A compound according to  claim 1 , wherein R 1  is hydroxy.  
     
     
         8 . A compound according to  claim 1 , wherein R 1  is hydroxy and each of the other of R 2 -R 8  is hydrogen.  
     
     
         9 . A compound according to  claim 1 , wherein R 1  is hydroxy and at least one of the other of R 2 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         10 . A compound according to  claim 1 , wherein R 1  is hydroxy and each of R 7 -R 8  is hydrogen.  
     
     
         11 . A compound according to  claim 1 , wherein R 1  is hydroxy and each of R 7 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         12 . A compound according to  claim 1 , wherein R 1  is hydroxy and R 2  is (C 1 -C 6 )alkyl.  
     
     
         13 . A compound according to  claim 1 , wherein R 1  is hydroxy and R 2  is (C 1 -C 6 )alkyl and each of the other of R 3 -R 5  is hydrogen.  
     
     
         14 . A compound according to  claim 1 , wherein R 1  is hydroxy and R 2  is (C 1 -C 6 )alkyl and at least one of the other of R 3 -R 1  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         15 . A compound according to  claim 1 , wherein R 1  is hydroxy and R 2  is (C 1 -C 6 )alkyl and each of R 7 -R 8  is hydrogen.  
     
     
         18 . A compound according to  claim 1 , wherein R 1  is hydroxy and R 2  is (C 1 -C 6 )alkyl and each of R 7 -R 3  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         19 . A compound according to  claim 1 , wherein R 1  is hydroxy and R 2  is methyl.  
     
     
         20 . A compound according to  claim 1 , wherein R 1  is hydroxy and R 2  is methyl and each of the other of R 3 -R 3  is hydrogen.  
     
     
         21 . A compound according to  claim 1 , wherein R 1  is hydroxy and R 2  is methyl and at least one of the other of R 3 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         22 . A compound according to  claim 1 , wherein R 1  is hydroxy and R 2  is methyl and each of R 7 -R 8  is hydrogen.  
     
     
         23 . A compound according to  claim 1 , wherein R 1  is hydroxy and R 2  is methyl and each of R 7 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         24 . A compound according to  claim 1 , wherein R 2  is hydroxy.  
     
     
         25 . A compound according to  claim 1 , wherein R 2  is hydroxy and each of the other of R 1  and R 3 -R 8  is hydrogen.  
     
     
         26 . A compound according to  claim 1 , wherein R 2  is hydroxy and at least one of the other of R 1  and R 3 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         27 . A compound according to  claim 1 , wherein R 2  is hydroxy and each of R 7 -R 8  is hydrogen.  
     
     
         28 . A compound according to  claim 1 , wherein R 2  is hydroxy and each of R 7 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         29 . A compound according to  claim 1 , wherein R 3  is hydroxy.  
     
     
         30 . A compound according to  claim 1 , wherein R 3  is hydroxy and each of the other of R 1  -R 2  and R 4 -R 8  is hydrogen.  
     
     
         31 . A compound according to  claim 1 , wherein R 3  is hydroxy and at least one of the other of R 1  -R 2  and R 4 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         32 . A compound according to  claim 1 , wherein R 3  is hydroxy and each of R 7 -R 8  is hydrogen.  
     
     
         33 . A compound according to  claim 1 , wherein R 3  is hydroxy and each of R 7 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         34 . A compound according to  claim 1 , wherein R 4 is hydroxy.  
     
     
         35 . A compound according to  claim 1 , wherein R 4  is hydroxy and each of the other of R 1  -R 3  and R 5 -R 8  is hydrogen.  
     
     
         36 . A compound according to  claim 1 , wherein R 4  is hydroxy and at least one of the other of R 1  -R 3  and R 5 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         37 . A compound according to  claim 1 , wherein R 4  is hydroxy and each of R 7 -R 8  is hydrogen.  
     
     
         38 . A compound according to  claim 1 , R 4  is hydroxy and each of R 7 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         39 . A compound according to  claim 1 , wherein R 5  is hydroxy.  
     
     
         40 . A compound according to  claim 1 , wherein R 1  is hydroxy and each of the other of R 1  -R 4  and R 6 -R 8  is hydrogen.  
     
     
         41 . A compound according to  claim 1 , wherein R 1  is hydroxy and at least one of the other of R 1  -R 4  and R 6 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         42 . A compound according to  claim 1 , wherein R 1  is hydroxy and each of R 7 -R 8  is hydrogen.  
     
     
         43 . A compound according to  claim 1 , wherein R 1  is hydroxy and each of R 7 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         44 . A compound according to  claim 1 , wherein R 6  is hydroxy.  
     
     
         45 . A compound according to  claim 1 , wherein R 6  is hydroxy and each of the other of R 1  -R 5  and R 7 -R 8  is hydrogen.  
     
     
         46 . A compound according to  claim 1 , wherein R 6  is hydroxy and at least one of the other of R 1  -R 5  and R 7 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         47 . A compound according to  claim 1 , wherein R 6  is hydroxy and each of R 7 -R 8  is hydrogen.  
     
     
         48 . A compound according to  claim 1 , wherein R 6  is hydroxy and each of R 7 -R 8  is optionally substituted (C 1 -C 6 )alkyl.  
     
     
         49 . A compound according to  claim 1 , wherein Ar is (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroary](C 1 -C 6 )alkoxy(C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 2 -C 9 )heteroaryl, optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         50 . A compound according to  claim 2 , wherein Ar is (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 2 -C 9 )heteroaryl, optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         51 . A compound according to  claim 3 , wherein Ar is (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C6-C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 2 -C 9 )heteroaryl, optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         52 . A compound according to  claim 4 , wherein Ar is (C 6 -C 10 )aryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, (C 6 -C 1 )aryl(C 1 -C 6 )alkoxy(C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkoxy(C 2 -C 9 )heteroaryl, optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         53 . A compound according to  claim 1 , wherein Ar is (C 6 -C 10 )arylmethoxy(C 6 -C 10 )aryl, (C 6 -C 10 )arylmethoxy(C 2 -C 9 )heteroaryl, (C 2 -C 9 )heteroarylmethoxy(C 6 -C 10 )aryl or (C 2 -C 10 )heteroarylmethoxy(C 2 -C 9 )heteroaryl, optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         54 . A compound according to  claim 1 , wherein Ar is optionally substituted(C 6 -C 10 )arylmethoxyphenyl, pyridylmethoxyphenyl, thienylmethoxyphenyl, pyrazinylmethoxyphenyl, pyrimidylmethoxyphenyl, pyridazinylmethoxyphenyl, thiazolyl methoxyphenyl, or oxazolylmethoxyphenyl.  
     
     
         55 . A compound according to  claim 1 , wherein Ar is (C 6 -C 10 )arylmethoxy(C 6 )aryl optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         56 . A compound according to  claim 2 , wherein Ar is (C 6 -C 10 )arylmethoxy(C 6 )aryl optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         57 . A compound according to  claim 3 , wherein Ar is (C 6 -C 10 )arylmethoxy(C 6 )aryl optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         58 . A compound according to  claim 4 , wherein Ar is (C 6 -C 10 )arylmethoxy(C 6 )aryl optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         59 . A compound according to  claim 5 , wherein Ar is (C 6 -C 10 )arylmethoxy(C6)aryl optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         60 . A compound according to  claim 6 , wherein Ar is (C 6 -C 10 )arylmethoxy(C 2 -C 10 )heteroaryl optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C0-C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         61 . A compound according to  claim 1 , wherein Ar is (C 2 -C 10 )heteroarylmethoxy(C 6 )aryl optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         62 . A compound according to  claim 1 , wherein Ar is (C 2 -C 9 )heteroarylmethoxy(C 2 -C 9 )heteroaryl optionally substituted by one or more, preferably one to three substituents per ring, most preferably one to three substituents on the terminal ring, wherein said substituents are independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl.  
     
     
         63 . A compound according to  claim 1 , wherein said compound is selected from the group consisting of: 
 (2R,5R)-1-[4-(2, 5-Dimethyl-benzyloxy)-benzenesulfonyl]-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide,    (2R,5R)-1-[4-(5-Fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide,    (2R,4R)-4-Hydroxy-1-[4-(2-methyl-benzyloxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide,    (2R,5R)-1-[4-(5-Fluoro-2-trifluoromethyl-benzyloxy)-benzenesulfonyl]-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide,    (2R,5R)-5-Hydroxy-1-[4-(2-isopropyl-benzyloxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide,    (2R,5R)-1-[4-(2-Ethyl-benzyloxy)-benzenesulfonyl]-5-hydroxy-piperidine-2-carboxylic acid hydroxyamide,    (2R,4R)-1-[4-(5-Fluoro-2-methyl-benzyloxy)-benzenesufonyl]-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide,    (2R,4R)-1-[4-(2, 5-Dimethyl-benzyloxy)-benzenesulfonyl]-4-hydroxy-piperidine-2-carboxylic acid hydroxyamide,    (2R,5R)-1-[4-(5-Fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-5-hydroxy-5-methyl-piperidine-2-carboxylic acid hydroxyamide,    (2R,5R)-1-[4-(5-Fluoro-2-trifluoromethyl-benzyloxy)-benzenesulfonyl]-5-hydroxy-5-methyl-piperidine-2-carboxylic acid hydroxyamide,    (2R,5R)-5-Hydroxy-1-[4-(2-isopropyl-benzyloxy)-benzenesulfonyl]-5-methyl-piperidine-2-carboxylic acid hydroxyamide,    (2R,5R)-5-Hydroxy-5-methyl-1-[4-(2-methyl-benzyloxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide,    (2R, 3R, 5R)-5-Hydroxy-3-methyl-1-[4-(2-methyl-benzyloxy)-benzenesulfonyl]-piperidine-2-carboxylic acid hydroxyamide,    (2R, 3R, 5R)-5-Hydroxy-1-[4-(2-isopropyl-benzyloxy)-benzenesulfonyl]-3-methyl-piperidine-2-carboxylic acid hydroxyamide, and    (2R,3S)-1-[4-(5-Fluoro-2-trifluoromethyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide.    
     
     
         64 . A pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of a matrix metalloproteinase in a mammal, including a human, comprising an amount of a compound of  claim 1  effective in such treatment and a pharmaceutically acceptable carrier.  
     
     
         65 . A pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of a mammalian reprolysin in a mammal, including a human, comprising an amount of a compound of  claim 1  effective in such treatment and a pharmaceutically acceptable carrier.  
     
     
         66 . A pharmaceutical composition for the treatment of arthritis, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scieritis, AIDS, sepsis and septic shock in a mammal, including a human, comprising an amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof, effective in such treatments or inhibition and a pharmaceutically acceptable carrier.  
     
     
         67 . A method for the inhibition of matrix metalloproteinases in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         68 . A method for the inhibition of a mammalian reprolysin in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         69 . A method for the inhibition of TACE in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         70 . A method for treating a condition selected from the group consisting of of arthritis, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis and septic shock in a mammal, including a human, comprising administering to said mammal an amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof, effective in treating such a condition.

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