ARYLSULFONYLAMINO HYDROXAMIC ACID DERIVATIVES

Abstract: A compound of formula (I), wherein n, X, R<3>, R<4> and Ar are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF.

Description: ARYLSULFONYLAMINO HYDROXAMIC ACID DERIVATIVES Background of the Invention The present invention relates to arylsulfonylamino hydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or the production of tumor necrosis factor (hereinafter also referred to as TNF) and as such are useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritiβ and other diseases characterized by matrix metalloproteinaβe activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF. This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefor. There are a number of enzymes which effect the breakdown of structural proteins and which are structurally related etalloproteases. Matrix- degrading metalloproteinases, such as gelatinase, stromelysin and collagenase, are involved in tissue matrix degradation (e.g. collagen collapse) and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis) , tissue ulceration (e.g. corneal, epidermal and gastric ulceration) , abnormal wound healing, periodontal disease, bone disease (e.g. Paget's disease and osteoporosis) , tumor metastasis or invasion, as well as HIV-infection (J. Leuk. Biol.. 52 (2) :244-248, 1992) . Tumor necrosis factor is recognized to be involved in many infectious and auto-immune diseases ( . Friers, FEBS Letters. 1991, 285, 199) . Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (CE. Spooner et al., Clinical Immunology and Immunopatholoσv, 1992, 62. Sll) . fintnm»rv of the Invention The present invention relates to a compound of the formula or the pharmaceutically acceptable salts thereof, wherein n is 1 to 6; X is hydroxy, (C 1 -Cg)alkoxy or NR-'-R 2 wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, (C-^-Cg)alkyl, piperidyl, (C χ -C 6 )alkylpiperidyl, (Cg-C 10 )arylpiperidyl, (C 5 - C 9 )heteroarylpiperidyl, (Cg-C 10 )aryl (C χ - C 6 )alkylpiρeridyl, (C 5 -C 9 )heteroaryl {C - C 6 )alkylpiρeridyl, (C^Cg)acylpiperidyl, (Cg-C 10 )aryl, (C 5 -C 9 )heteroaryl, (Cg-C 10 )aryl (C^Cg)alkyl, (C 5 - C 9 )heteroaryl(C 1 -C 6 )alkyl, (Cg-C 10 )aryl (Cg-C 10 )aryl, (Cg-C 10 )aryl (Cg-C 10 )aryl (Ci-Cg)alkyl, (C 3 - C 6 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C^ ^ -Cg)alkyl, R 5 (C 2 - C 6 )alkyl, (C 1 -C 5 )alkyl (CHR 5 ) (C^ ^ -Cg)alkyl wherein R 5 is hydroxy, (C-^-Cg)acyloxy, (C 1 -C 8 )alkoxy, piperazino, (C- j ^CgJalkylamino, (C-^-CgJalkylthio, (Cg-C 10 )arylthio, (C-L-Cg)alkylsulfinyl, (Cg-C 10 )arylsulfinyl, < c ι~ Cg)alkylsulfoxyl, (Cg-C 1Q )arylsulfoxyl, amino, (C^ Cg)alkylamino, ( (C^-Cg)alkyl) 2 mino, (C^- Cg)acylpiperazino, (C^Cg)alkylpiperazino, (Cg- C 10 )aryl (C-^-Cg)alkylpiperazino, (Cg-Cg)heteroaryl(C 1 - Cg)alkylpiperazino, orpholino, thiomorpholino, piperidino or pyrrolidino; R 6 (C 1 -C 8 )alkyl, (C 1 - C 5 )alkyl(CHR 6 ) (C j^ -Cg)alkyl wherein R 6 is piperidyl, (C^C )alkylpiperidyl, (Cg-C 10 )arylpiperidyl, (C 8 - C 10 )aryl(C 1 -Cg)alkylpiperidyl, (C 5 - C 9 )heteroarylpiperidyl or (Cg-C 9 )heteroaryl (C-^- Cg)alkylpiperidyl; and CH(R 7 )COR 8 wherein R 7 is hydrogen, (C 1 -C 8 )alkyl, (Cg-C 10 )aryl(C^Cg)alkyl, (Cg- C 9 )heteroaryl(C^Cg)alkyl, (C 1 -Cg)alkylthio(C 1 - Cg)alkyl, (Cg-C 10 )arylthio(C^Cg)alkyl, (C χ - Cg)alkylsulfinyl(^-Cg)alkyl, (Cg-C 10 )arylsulfinyl (C - Cg)alkyl, (C^Cg)alkylsulfonyl (C^Cg)alkyl, (C 8 - C^ Q )arylsulfonyl(C^-Cg)alkyl, hydroxy(C^-Cg)alkyl, amino(C^-Cg)alkyl, (C^-Cgjalkylamino(C^-Cg)alkyl, ((C*,- O(C 1 -C 8 )alkyl or are each independently selected from the group consisting of hydrogen, d (Cg-C 9 )het R X R" L *N wherein R and R are each independently selected from the group consisting of hydrogen, (C^- C 6 )alkyl, (Cg-C 10 )aryl(C^Cg)alkyl and (Cg- C 9 )heteroaryl (C 1 -Cg)alkyl; or R 1 and R 2 , or R 9 and R 10 , or R 11 and R 12 may be taken together to form an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (C^C )acylpiperazinyl, (C^- Cg)alkylpiperazinyl, (Cg-C 10 )arylpiperazinyl, (C 5 - C 9 ) heteroarylpiperazinyl or a bridged diazabicycloalkyl ring selected from the group consisting of ( <( CCCJHHH 222 ))) rrr d e wherein r is 1, 2 or 3; m is 1 or 2; p is 0 or 1; and Q is hydrogen, (C-^-C*-,) alkyl or (C^-Cgjacyl; R 3 and 4 are each independently selected from the group consisting of hydrogen, (C-^-Cg) alkyl, trifluoromethyl, trifluoromethyl (C^-Cg)alkyl, < c ι _ Cg) alkyl (difluoromethylene) , (C-^- C 3 )alkyl (difluoromethylene) (C* j _-C 3 )alkyl, (Cg-C 10 ) aryl, (C 5 -C 9 )heteroaryl, (Cg-C 10 ) aryl (C ] _-Cg) alkyl, (Cg- C 9 )heteroaryl (C 1 -Cg) alkyl, (C 8 -C 10 )aryl (Cg-C 10 ) aryl, (C 6 -C 10 ) aryl (Cg-C 10 )aryl (C 1 -C 6 )alkyl, (C 3 - Cg)cycloalkyl, (C 3 -Cg) cycloalkyl (C- j^ -Cg) alkyl, hydroxy(C 1 -Cg) alkyl, (C 1 -Cg) acyloxy(C 1 -Cg)alkyl, (C χ - Cg) alkoxy(C 1 -C 8 ) alkyl, piperazinyl (C 1 -Cg)alkyl, (C χ - Cg) acylamino(C-^-Cg)alkyl, piperidyl, (C^ Cg) alkylpiperidyl, (Cg-C 10 )aryl (C^Cg)alkoxy(C^ Cg) alkyl, (Cg-C 9 )heteroaryl (^-Cg)alkoxy(C 1 -Cg)alkyl, ( -C 6 )alkylthio^-Cg)alkyl, (C 8 -C 10 ) arylthio{C 1 - Cg)alkyl, (C 1 -Cg) alkylsulfinyl (C^Cg) alkyl, (Cg- C 10 )arylsulfinyl (^-Cg) alkyl, (C 1 -Cg) alkylsulfonyl (C χ - Cg) alkyl, (Cg-C 10 ) arylsulfonyl (C 1 -Cg)alkyl, amino(C^ C 6 ) alkyl, (C 1 -Cg)alkyla ino(C 1 -Cg) alkyl, ( (C^ Cg)alkylamino) 2 (C^Cg) alkyl, R 13 CO(C^Cg)alkyl wherein R 13 is R 20 O or R 20 R 21 N wherein R 20 and R 21 are each independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (Cg-C 10 )aryl (C- j^ -Cg)alkyl or (Cg-C 9 )heteroaryl (C 1 -C 6 ) alkyl; or R 14 (C 1 -C 8 )alkyl wherein R" is (C 1 -C 8 )acylpiperazino, (Cg- C 10 )arylpiperazino, (Cg-C 9 )heteroarylpiperazino, ( -^- Cg ) alkylpiperazino, i c s ~ c 10 ^ ar l rl (Ci-Cg- 1 alkylpiperazino, (Cg-C 9 )heteroaryl (C*-_-Cg)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C^-Cg) alkylpiperidyl, (Cg-C 1Q )arylpiperidyl, (Cg- C 9 )heteroarylpiperidyl, (Cg-C 10 )aryl (C^- Cg) alkylpiperidyl, (Cg-C 9 )heteroaryl (C-^- Cg) alkylpiperidyl or (C*-_-Cg) acylpiperidyl; or R 3 and R4, or R20 and R21 may be taken together to form a (C -Cg) cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula ,15 wherein P. 15 is hydrogen, (C^ gJacyl, (C-^Cg) alkyl, (Cg-C 10 ) aryl (C^ ^ -Cg) alkyl, (Cg-C 9 )heteroaryl (C^Cg) alkyl or (C- j^ -Cg) alkylsulfonyl; and Ar is (Cg-C 10 )aryl, (Cg-C 9 )heteroaryl, (C*^ Cg) alkyl (C 6 -C 10 )aryl, (C^Cg)alkoxy(Cg-C 10 )aryl, ( ( - C ) alkoxy) 2 (Cg-C 10 )aryl, (Cg-C 10 )aryloxy(Cg-C 10 )aryl, (Cg-C 9 )heteroaryloxy(Cg-C 10 )aryl, (C- Cg)alkyl(Cg- C 9 )heteroaryl, (C^Cg)alkoxy(Cg-C 9 )heteroaryl, ( (C- j^ - Cg) alkoxy) 2 (Cg-C 9 )heteroaryl, (Cg-C 1Q )aryloxy(Cg- C 9 )heteroaryl, (Cg-C 9 )heteroaryloxy(Cg-C 9 )heteroaryl; with the proviso that when either R 1 or R 2 is CH(R 7')COR8 u wherein R7' and R8° are as defined above, the other of R 1 or R2* is hydrogen, (C-^-Cg)alkyl or benzyl. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituentβ selected from the group consisting of fluoro, chloro, trifluoromethyl, (C^-Cg)alkoxy, (Cg-C^ø)aryloxy, trifluoromethoxy, difluoromethoxy and (C-^-Cg)alkyl. The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, terazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C-^- Cg)alkoxy, (Cg-C 10 )aryloxy, trifluoromethoxy, difluoromethoxy and (C^Cg)alkyl. The term "acyl", as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or aryalkyloxy and the terms "alkyl" or "aryl" are as defined above. The term "acyloxy", as used herein, includes O-acyl groups wherein "acyl" is defined above. The compound of formula I may have chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof. Preferred compounds of formula I include those wherein n is 2. Other preferred compounds of formula I include those wherein λr is 4-methoxyphenyl or 4- phenoxyphenyl. Other preferred compounds of formula I include those wherein either R 3 or R4 is not hydrogen. Other preferred compounds of formula I include those wherein n is 1 and either R 1 or R2 is hydrogen. Other preferred compounds of formula I include those wherein X is hydroxy, Ar is 4- methoxyphenyl or 4-phenoxyphenyl and either R or R is not hydrogen. Other preferred compounds of formula I include those wherein X is alkoxy, Ar is 4- methoxyphenyl or 4-phenoxyphenyl and either R 3 or R 4 is not hydrogen. Other preferred compounds of formula I include those wherein Ar is 4-methoxyphenyl or 4- phenoxyphenyl and R 3 and R 4 are taken together to form (C 3 -Cg) cycloalkanyl, oxacyclohexanyl, thiocyclohexanyl, indanyl or a group of the formula wherein R 15 is (C 1 -C 8 )acyl, (C^Cg)alkyl, (Cg- C 10 )aryl(C 1 -Cg).alkyl, (Cg-C 9 )heteroaryl (C 1 -Cg)alkyl or (C-, -Cg)alkylsulfonyl. More preferred compounds of formula I are those wherein n is 2, Ar is 4-methoxyphenyl or 4- phenoxyphenyl, R 1 and R 2 are taken together to form piperazinyl, (C-^Cg)alkylpiperazinyl, (Cg-C 10 )aryl piperazinyl or (Cg-C 9 )heteroaryl (C-^- Cg)alkylpiperazinyl, and either R 3 or R 4 is not hydrogen or both R 3 and R 4 are not hydrogen. More preferred compounds of formula I are those wherein n is 2, Ar is 4-methoxyphenyl or 4- phenoxyphenyl, R 1 is hydrogen or (C-^-Cg)alkyl, R 2 is 2- pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R or R is not hydrogen or both R 3 and are not hydrogen. More preferred compounds of formula I are those wherein n is 1, Ar iβ 4-methoxyphenyl or 4- phenoxyphenyl, R 1 is hydrogen, R2 is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R 3 or R is not hydrogen or both and R are not hydrogen. More preferred compounds of formula I are those wherein n is 2, Ar is 4-methoxyphenyl, R is hydrogen or (C 1 -C 8 )alkyl and R 2 iβ R 5 (C 2 -C 8 )alkyl wherein R is morpholino, thiomorpholino, piperidino, pyrrolidino, (C-^-CgJacylpiperazino, (C-^- Cg)alkylpiperazino, (Cg-C 10 )arylpiperazino, (Cg- C 9 )heteroarylpiperazino, (Cg-C 10 )aryl {C 1 - Cg)alkylpiperazino or (Cg-C 9 )heteroaryl (C^ Cg)alkylpiperazino and either R 3 or R 4 is not hydrogen or both R and R are not hydrogen. More preferred compounds of formula I are those wherein n is 1, Ar is 4-methoxyphenyl or 4- phenoxyphenyl, R 1 is hydrogen, R 2 is R 5 (C 2 -C 8 )alkyl wherein R 5 iβ morpholino, thiomorpholino, piperidino, pyrrolidino (C^-Cg)acylpiperazino, (C- j - Cg) alkylpiperazino, (Cg-C 10 )arylpiperazino, (Cg- C 9 )heteroarylpiperazino, (Cg-C 10 )aryl (C^- Cg)alkylpiperazino or (Cg-C 9 )heteroaryl (Ci - Cg)alkylpiperazino and either R or R 4 is not hydrogen or both R 3 and R 4 are not hydrogen. Specific preferred compounds of formula I include the following: 2- (R) -N-Hydroxy-2- [ (4- methoxybenzenesulfonyl) (3-morpholin-4-yl-3- oxopropyl)amino] -3-methylbutyra ide; 2- (R) -2- [ (2-Benzylcarbamoylethyl) (4- methoxybenzenesulfonyl)amino] -N-hydroxy-3- methylbutyramide; 2- (R) -N-Hydroxy-2- ( (4- methoxybenzenesulfonyl) (2- [ (pyridin-3-ylmethyl) - carbamoyl] ethyl)amino) -3-methylbutyramide; 2- (R) -N-Hydroxy-2- ( [4- ethoxybenzenesulfonyl] [2- (methylpyridin-3- ylmethylcarbamoyl)ethyl]amino) -3-methylbutyramide; 4- (3- [1- (R) -1-Hydroxycarbamoy1-2- methylpropyl) (4- methoxybenzenesulfonyl)amino]propionyl)piperazine-l- carboxylic acid, tert-butyl ester; 2- (R)-N-Hydroxy-2- [(4- methoxybenzenesulfonyl) (3-oxo-3-piperazin-1- ylpropyl)amino) -3-methylbutyramide hydrochloride; 2- (R) -2- [ (Benzylcarbamoylmethyl) (4- methoxybenzenesulfonyl)amino]N-hydroxy-3- methylbutyramide; 2- (R) -N-Hydroxy-2- ( [4- methoxybenzenesulfonyl] - [ (2-morpholin-4- ylethylcarbamoyl)methyl]amino) -3-methylbutyramide; and 2- (R) -N-Hydroxy-2- ( (4- methoxybenzenesulfonyl) ( [ (pyridin-3- ylmethyl)carbamoyl]methyl)amino) -3-methylbutyramide. Other specific compounds of formula I include the foilowing: 2- (R) -3,3,3-Trifluoro-N-hydroxy-2- [ (methoxybenzenesulfonyl) (3-morpholin-4-yl-3- oxopropyl)amino]propionamide; 2- (R) -N-Hydroxy-2- ( (4- phenoxybenzenesulfonyl) [2- (methylpyridin-4- ylmethylcarbamoyl)ether]amino) -3-methylbutyramide; 4- [4-Methoxybenzenesulfonyl) (3-morpholin-4- yl-3-oxopropyl)amino] -l-methylpiperidene-4-carboxylic acid hydroxyamide; 2- (R) -N-Hydroxy-2- ( (4- methoxybenzenesulfonyl) - [3- (4-methylpiperazin-l-yl) -3- oxopropyl] amino) -3-methylbutyramide; 2- (R) -2- [(2-Carboxyethyl) (4- methoxybenzenesulfonyl)amino] -N-hydroxy-3- methylbutyramide; [(2-Carboxyethyl) (3,4- dimethoxybenzenesulfonyl)amino] -N-hydroxy-acetamide; 2- (R) -2- [ (2-Carbamoylethyl) (4- methoxybenzenesulfonyl) amino] -N-hydroxy-3- ethylbutyramide; 2- (R) ,3- (R) -3,N-Dihydroxy-2- [ (4- methoxybenzenesulfonyl) (3-oxo-3-piperidin-l- ylpropyl)amino] -butyramide; 2- (R) -N-Hydroxy-2- ( (4- methoxybenzenesul onyl) [3- (methylpyridin-3- ylmethylcarbamoyDpropyl]amino) -3-methylbutyramide; 2- (R) -N-Hydroxy-2- ( (4- methoxybenzenesulfonyl) [2- (methylcarboxymethylcarbamoyl)ethyl] amino) -3- methylbutyramide; 2- (R)-N-Hydroxy-2- ((4- methoxybenzenesulfonyl) - [ (l-methylpiperidin-4- ylcarbamoyl)methyl] amino) -3-methylbutyramide; 2- (R) -2-Cyclohexyl-N-hydroxy-2- ( (4- methoxybenzenesulfonyl) - [3- (4-methylpiperazin-l-yl) -3- oxopropyl] amino) -acetamide; 2- (R) -N-Hydroxy-2- [(methoxybenzenesulfonyl) (3-morpholin-4-yl-3- oxopropyl)amino] -4- (morpholin-4-yl)butyramide. The present invention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) 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 and a pharmaceutically acceptable carrier. The present invention also relates to a method for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) 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. The present invention also relates to a method for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) 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. Detailed Description of the Invention The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated R 1, R2, R3, R4, n and Ar in the reaction Schemes and the discussion that follow are defined as above. Sehftwi 1 VII VI IV V III SC-VIOTIO l cont'd III II r VIII 25 1 Scheme 3 20 Scheme 4 IV VI XIII XIV Scheme 4 cont'd XIV 15 XV 30 XVI In reaction 1 of Scheme 1, the amino acid compound of formula VII, wherein R 16 is (C ^ -Cg)alkyl, benzyl, allyl or tert-butyl, is converted to the corresponding compound of formula VI by reacting VII with a reactive functional derivative of an arylsulfonic acid compound, such as an arylsulfonyl chloride, in the presence of a base, such as triethylamine, and a polar solvent, such as tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water. The reaction mixture is stirred, at room temperature, for time period between about 10 minutes to about 24 hours, preferably about 60 minutes. In reaction 2 of Scheme 1, the arylsulfonyl amino compound of formula VI, wherein R is (C*.- Cg)alkyl, benzyl, allyl or tert-butyl, iβ converted to the corresponding compound of formula V, wherein n is 1, 3, 4, 5 or 6, by reacting VI with a reactive derivative of an alcohol of the formula O R 1 j -7'-O-C!•- (CH 2 ) n -0H such as the chloride, bromide or iodide derivative, preferably the bromide derivative, wherein the R protecting group is (C^-Cg)alkyl, benzyl, allyl or tert-butyl, in the presence of a base such as potassium carbonate or sodium hydride, preferably sodium hydride, and a polar solvent, such as dimethylformamide. The reaction mixture iβ stirred, at room temperature, for a time period between about 60 minutes to about 48 hours, preferably about 18 hours. The R 17 protecting group is chosen such that it may be selectively removed in the preβence of and without loss of the R protecting group, therefore, R 4 "7 cannot be the same as R1 A 6. Removal of the R protecting group from the compound of formula V to give the correβponding carboxylic acid of formula IV, in reaction 3 of Scheme 1, iβ carried out under conditionβ appropriate for that particular R17 protecting group m use which will not affect the R protecting group. Such conditions include; (a) βaponification where R is (C,-Cg)alkyl and R is tert-butyl, (b) hydrogenolysiβ where R 17' iβ benzyl and R 16 is tert-butyl or (C^Cg)alkyl, (c) treatment with a strong acid such aβ trifluoroacetic acid or hydrochloric acid where R iβ tert-butyl and R iβ (C^-Cg)alkyl, benzyl or allyl, or (d) treatment with tributyltinhydride and acetic acid in the presence of catalytic bis (triphenylphoβphine) palladium (II) chloride where R x 7 iβ allyl and RIK iβ (C-i-Cg)alkyl, benzyl or tert-butyl. In reaction 4 of Scheme 1, the carboxylic acid of formula IV iβ condensed with an amine, R 1 R NH, or the salt thereof, to give the correβponding amide compound of formula III. The formation of amides from primary or secondary amines or ammonia and carboxylic acidβ iβ achieved by converβion of the carboxylic acid to an activated functional derivative which subsequently undergoes reaction with a primary or secondary amine or ammonia to form the amide. The activated functional derivative may be isolated prior to reaction with the primary or secondary amine or ammonia. Alternatively, the carboxylic acid may be treated with oxalyl chloride or thionyl chloride, neat or in an inert solvent, such aβ chloroform, at a temperature between about 25°C. to about 80°C, preferably about 50°C, to give the correβponding acid chloride functional derivative. The inert solvent and any remaining oxalyl chloride or thionyl chloride iβ then removed by evaporation under vacuum. The remaining acid chloride functional derivative is then reacted with the primary or βecondary amine or ammonia in an inert βolvent, βuch aβ methylene chloride, to form the amide. The preferred method for the condenβation of the carboxylic acid of formula IV with an amine to provide the correβponding amide compound of formula III iβ the treatment of IV with (benzotriazol- 1-yloxy) trie(dimethylamino) phoβphonium . hexafluorophoβphate in the presence of a base, such aβ triethylamine, to provide the benzotriazol-1-oxy ester in βitu which, in turn, reacts with the amine, R 1 R 2 N, in an inert solvent, such as methylene chloride, at room temperature to give the amide compound of formula III. Removal of the R 16 protecting group from the compound of formula III to give the corresponding carboxylic acid of formula II, in reaction 5 of Scheme 1 , iβ carried out under conditions appropriate for the particular protecting group in use. Such conditionβ include; (a) βaponification where R iε lower alkyl, (b) hydrogenolyβis where R iβ benzyl, (c) treatment with a βtrong acid, βuch aβ trifluoroacetic acid or hydrochloric acid, where R iβ tert-butyl, or (d) treatment with tributyltinhydride and acetic acid in the preβence of catalytic bis (triphenylphoβphine) palladium (II) chloride where R 16 iβ allyl. In reaction 6 of Scheme 1 , the carboxylic acid compound of formula II iβ converted to the hydroxamic acid compound of formula I by treating II with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenztriazole in a polar solvent, βuch aβ dimethylformamide, followed by the addition of hydroxylamine to the reaction mixture after a time period between about 15 minutes to about 1 hour, preferably about 30 minutes. The hydroxylamine iβ preferably generated in βitu from a βalt form, βuch aβ hydroxylamine hydrochloride, in the preβence of a baβe, βuch aβ N-methylmorpholine. Alternatively, a protected derivative of hydroxylamine or itβ βalt form, where the hydroxyl group iβ protected aβ a tert-butyl, benzyl or allyl ether, may be uβed in the preβence of (benzotriazol-1-yloxy) trie(dimethylamino) phoβphonium hexafluorophoβphate and a base, such as N- methylmorpholine. Removal of the hydroxylamine protecting group is carried out by hydrogenolyβiβ for a benzyl protecting group or treatment with a βtrong acid, βuch aβ trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyltinhydride and acetic acid in the preβence of catalytic bis(triphenylphosphine) palladium (II) chloride. N,0- bis (4-methoxybenzyl)hydroxylamine may also be uβed aβ the protected hydroxylamine derivative where deprotection iβ achieved using a mixture of methanesulfonic acid and trifluoroacetic acid. In reaction 1 of Scheme 2 , the aryleulfonylami.no compound of formula VI, wherein R 16 iβ (C- j^ -C )alkyl, benzyl or tert-butyl, iβ converted to the correβponding compound of formula VIII, wherein K. ° iβ 2-propenyl or 3-butenyl, by reacting IX with a reactive functional derivative, βuch aβ the halide, preferably the iodide derivative, of 2-propen-l-ol when I B 16 R i0 iβ 2-propenyl or 3-buten-l-ol when xo is 3- butenyl, in the preβence of a base, such as potassium carbonate, cesium carbonate or sodium hydride, preferably Bodium hydride when R 18 is 2-propenyl or cesium carbonate when R 18 is 3-butenyl. The reaction is stirred in a polar solvent, such aβ dimethylformamide, at room temperature, for a time period between about 2 hours to about 48 hours, preferably about 18 hours. In reaction 2 of Scheme 2 , the compound of formula VIII iβ converted to the carboxylic acid compound of formula IV, wherein n iβ 2. The compound of formula VIII, wherein R 18 iβ 2-propenyl, iβ converted to the compound of formula IV, wherein n iβ 2, by reacting VIII with borane-dimethylβulfide complex, followed by immediate oxidation using chromium trioxide in aqueous acetic acid. The oxidative cleavage of terminal olefins to carboxylic acidβ can be achieved by βeveral methods known in the art. The preferred method for the oxidative cleavage of the compound of formula VIII, wherein R 18 iβ 3-butenyl, to obtain the carboxylic acid contpound of formula IV is to react VIII with sodium periodate in the presence of a catalytic amount of ruthenium (III) chloride in a mixture of carbon tetrachloride, acetonitrile and water. The compound of formula IV, wherein n iβ 2, iβ further reacted to provide the hydroxamic acid compound of formula I, wherein n iβ 2, according to the procedure deβcribed above in reactions 4, 5 and 6 of Scheme 1. An alternative method for the βynthesis of the hydroxamic acid compound of formula I, wherein n iβ 1 and R 3 and R4 are both hydrogen, iβ shown in reaction 1 of Scheme 3., beginning with reacting iminoacetic acid or a metal or ammonium salt of iminoacetic acid of formula X with a functional derivative of an arylsulfonic acid compound, βuch aβ an arylsulfonyl chloride, at room temperature, in the preβence of a βuitable baβe, βuch aβ triethylamine, and a polar solvent βuch aβ tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water, to give the correβponding dicarboxylic acid compound of formula XI. In reaction 2 of Scheme 3., the dicarboxylic acid compound of formula XI iβ dehydrated to give a cyclic anhydride compound of formula XII. The formation of cyclic anhydrides by dehydration of dicarboxylic acidβ may be achieved by a variety of means. The preferred method for the dehydration of the dicarboxylic acid compound of formula XI to give a cyclic anhydride compound of formula XII iβ to treat XI with an excess of acetic anhydride at a temperature between about 25°C. to about 80°C, preferably about 60°C. Exceββ acetic anhydride and acetic acid, a by¬ product of the reaction, are removed by evaporation under reduced pressure leaving the cyclic anhydride compound of formula XII. In reaction 3 of Scheme 3_, the cyclic anhydride compound of formula XII is reacted, at room temperature, with an amine, NR 1R2, or a βalt of the amine, βuch aβ the hydrochloride, in the preβence of a base, βuch aβ triethylamine, to give the carboxylic acid of formula II, wherein n iβ 1 and R and R are both hydrogen. Suitable βolventβ for the reaction are thoβe that will not react with the starting materials, which include chloroform, methylene chloride and dimethylformamide, preferably methylene chloride. The compound of formula II is further reacted to give the hydroxamic acid compound of formula I, wherein n is 1 and R 3 and R4 are both hydrogen, according to the procedure deβcribed above in reaction 6 of Scheme 1. In reaction 1 of Scheme 4, the carboxylic acid compound of formula IV, wherein n iβ 2, iβ converted to the correβponding compound of formula V, wherein R 19 iβ (C^-Cg)alkyl or tert-butyl, by reacting IV with a compound of the formula (R 19 0) 2 CHN(CH 3 ) 2 wherein R 19 iβ (C-^-Cg)alkyl or tert-butyl, in an inert solvent, such as toluene, at a temperature between about 60°C. to about 100°C, preferably about 100°C, for a time period between about 1 hour to about 3 hourβ, preferably 2 hourβ. In reaction 2 of Scheme 4., the arylβulfonyl amino compound of formula VI wherein n iβ 1, 3, 4, 5 or 6 and R 16 iβ (C^Cg)alkyl, benzyl, allyl or tert-butyl, iβ converted to the correβponding compound of formula XIII, wherein R 19 iβ (C-^-Cg)alkyl or tert-butyl, by reacting VI with a reactive derivative of an alcohol of the formula 0 R 1 l 9 b -0-IC'-(CH 2 ) n -OH βuch aβ the chloride, bromide or iodide derivative, preferably the bromide derivative, wherein R 19 iβ (C * ,- Cg) lkyl or tert-butyl, in the preβence of a baβe such aβ potaββium carbonate or βodium hydride, preferably sodium hydride, and a polar solvent, βuch aβ dimethylformamide. The reaction iβ βtirred, at room temperature, for a time period between about 60 minutes to about 48 hourβ, preferably about 18 hourβ. The R 16 protecting group, of the compounds of formulae IV and VI, iβ chosen βuch that it may be selectively removed in the preβence of and without lose of the R 19 ( c l"C )alkyl or tert-butyl group, therefore, R 16 cannot be the same as R 19. Removal of the R1 x fi o protecting group from the compound of formula XIII to give the correβponding carboxylic acid of formula XIV, wherein n iβ 1 to 6, in reaction 3 of Scheme 4 , iβ carried out under conditionβ appropriate for that particular R protecting group in uβe which will not affect the R 19 (C^-C )alkyl or tert-butyl group. Such conditionβ include; (a) βaponification where R iβ (C^-Cg)alkyl and R 19 iβ tert-butyl, (b) hydrogenolyβiβ where R fi iβ benzyl and R 19 iβ tert-butyl or (C 1 -Cg)alkyl, (c) treatment with a βtrong acid βuch aβ trifluoroacetic acid or hydrochloric acid where R iβ tert-butyl and R 19 iβ (C 1 -Cg)alkyl, or (d) treatment with tributyltinhydride and acetic acid in the preβence of catalytic bis(triphenylphoβphine) palladium (II) chloride where R 16 is allyl and R 19 iβ (C-^-Cg)alkyl or tert-butyl. In reaction 4 of Scheme 4 , the carboxylic acid of formula XIV iβ converted to the hydroxamic acid compound of formula XV, wherein n iβ 1 to 6, by treating XIV with 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide and 1-hydroxybenztriazole in a polar βolvent, βuch aβ dimethylformamide, followed by the addition of hydroxylamine to the reaction mixture after a time period between about 15 minuteβ to about 1 hour, preferably about 30 minuteβ. The hydroxylamine iβ preferably generated in βitu from a βalt form, βuch aβ hydroxylamine hydrochloride, in the preβence of a baβe, βuch aβ N-methylmorpholine. Alternatively, a protected derivative of hydroxylamine or itβ βalt form, where the hydroxyl group iβ protected aβ a tert-butyl, benzyl or allyl ether, may be uβed in the preβence of (benzotriazol-1-yloxy) trie (dimethylami.no) phoβphonium hexafluorophoβphate and a baβe, βuch aβ N- methylmorpholine. Removal of the hydroxylamine protecting groups iβ carried out by hydrogenolyβiβ for a benzyl protecting group or treatment with a βtrong acid, βuch aβ trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyltinhydride and acetic acid in the preβence of catalytic bis (triphenylphosphine) palladium (II) chloride. N,0- bis(4-methoxybenzyl)hydroxylamine may also be uβed, when R1 iβ (C^-Cg)alkyl, aβ the protected hydroxylamine derivative where deprotection iβ achieved using a mixture of methanesulfonic acid and trifluoroacetic acid. In reaction 5 of Scheme 4, the amide formula of formula XV iβ, if desired, converted to the correβponding carboxylic acid compound of formula XVI by (a) βaponification where R 9 iβ lower alkyl or (b) treatment with a βtrong acid, βuch aβ trifluoroacetic acid or hydrochloric acid, where R 19 iβ tert-butyl. Pharmaceutically acceptable salts of the acidic compounds of the invention are βaltβ formed with baβes, namely cationic βaltβ βuch aβ alkali and alkaline earth metal βaltβ, βuch aβ sodium, lithium, potaββium, calcium, magnesium, aβ well aβ ammonium βaltβ, βuch aβ ammonium, trimethyl-ammonium, diethylammonium, and trie- (hydroxymethyl) - methylammonium βaltβ. Similarly acid addition βaltβ, such aβ of mineral acidβ, organic carboxylic and organic βulfonic acidβ e.g. hydrochloric acid, methaneβulfonic acid, maleic acid, are alβo poββible provided a baβic group, βuch aβ pyridyl, constituted part of the structure. The ability of the compounds of formula I or their pharmaceutically acceptable saltβ (hereinafter alβo referred to aβ the compounds of the present invention) to inhibit matrix metalloproteinaβeβ or the production of tumor necrosis factor (TNF) and, consequently, demonstrate their effectiveneββ for treating diseases characterized by matrix metalloproteinaβe or the production of tumor necroβiβ factor iβ βhown by the following in vitro aββay testβ. Biological Aββav Inhibition of Human Collagenaβe (MMP-1) Human recombinant collagenaβe iβ activated with trypβin using the following ratio: 10 μg trypsin per 100 μg of collagenase. The trypβin and collagenaβe are incubated at room temperature for 10 minuteβ then a five fold excess (50 μg/10 μg trypβin) of soybean trypβin inhibitor iβ added. 10 mM stock solutions of inhibitors are made up in dimethyl βulfoxide and then diluted using the following Scheme: 10 mM > 120 μM > 12 μM > 1.2 μM > 0.12 μM Twenty-five microliters of each concentration iβ then added in triplicate to appropriate wells of a 96 well microfluor plate. The final concentration of inhibitor will be a 1:4 dilution after addition of enzyme and substrate. Positive controls (enzyme, no inhibitor) are set up in wells D1-D6 and blankβ (no enzyme, no inhibitorβ) are βet in wells D7-D12. Collagenaβe iβ diluted to 400 ng/ml and 25 μl iβ then added to appropriate wells of the microfluor plate. Final concentration of collagenaβe in the aββay Subβtrate (DNP-Pro-Cha-Gly-Cyβ (Me) -Hiβ-Ala- Lyβ(NMA) -NH 2 ) iβ made aβ a 5 mM βtock in dimethyl βulfoxide and then diluted to 20 μM in aββay buffer. The aββay iβ initiated by the addition of 50 μl substrate per well of the microfluor plate to give a final concentration of 10 μM. Fluorescence readingβ (360 nM excitation, 460 nm emiββion) were taken at time 0 and then at 20 minute intervale. The aββay iβ conducted at room temperature with a typical aββay time of 3 hourβ. Fluorescence vs time iβ then plotted for both the blank and collagenaβe containing samples (data from triplicate determinations is averaged) . A time point that provideβ a good signal (the blank) and that is on a linear part of the curve (usually around 120 minutes) iβ chosen to determine ICg values. The zero time iβ uβed aβ a blank for each compound at each concentration and theβe values are subtracted from the 120 minute data. Data is plotted aβ inhibitor concentration vβ % control (inhibitor fluorescence divided by fluorescence of collagenaβe alone x 100) . IC 50 's are determined from the concentration of inhibitor that gives a signal that iβ 50% of the control. If ICgg's are reported to be <0.03 μM then the inhibitorβ are assayed at concentrations of 0.3 μM, 0.03 μM, 0.03 μM and 0.003 μM. Inhibition of Gelatinaβe (MMP-2) Inhibition of gelatinaβe activity iβ assayed using the Dnp-Pro-Cha-Gly-Cyβ (Me) -Hiβ-Ala-Lyβ(NMA) -NH 2 substrate (10 μM) under the same conditionβ aβ inhibition of human collagenaβe (MMP-1) . 72kD gelatinaβe is activated with 1 mM APMA (p-aminophenyl mercuric acetate) for 15 hours at 4°C. and is diluted to give a final concentration in the aββay of 100 mg/ml. Inhibitorβ are diluted aβ for inhibition of human collagenaβe (MMP-1) to give final concentrationβ in the aββay of 30 μM, 3 μM, 0.3 μM and 0.03 μM. Each concentration iβ done in triplicate. Fluorescence readings (360 nm excitation, 460 emisβion) are taken at time zero and then at 20 minuteβ intervale for 4 hourβ. ICgø's are determined aβ per inhibition of human collagenaβe (MMP-1) . If ICgg'β are reported to be less than 0.03 μM, then the inhibitors are aβsayed at final concentrationβ of 0.3 μM, 0.03 μM, 0.003 μM and 0.003 μM. Inhibition of Stromelvβin Activity (MMP-3) Inhibition of βtromelyβin activity iβ based on a modified spectrophotometric asβay deβcribed by Weingarten and Feder ( eingarten, H. and Feder, J. , Spectrophotometric Aββay for Vertebrate Collagenaβe, Anal. Biochem. 147. 437-440 (1985)). Hydrolyβiβ of the thio peptolide βubβtrate [Ac-Pro-Leu-Gly- SCH[CH 2 CH(CH 3 ) 2 ]CO-Leu-Gly-OC 2 Hg] yieldβ a mercaptan fragment that can be monitored in the preβence of Ellman's reagent. Human recombinant proβtromelyβin is activated with trypβin uβing a ratio of 1 μl of a 10 mg/ml trypβin βtock per 26 μg of βtromelyβin. The trypβin and βtromelyβin are incubated at 37°C. for 15 minuteβ followed by 10 μl of 10 mg/ml βoybean trypβin inhibitor for 10 minuteβ at 37°C. to quench trypβin activity. Aββays are conducted in a total volume of 250 μl of aβsay buffer (200 mM sodium chloride, 50 mM MES, and 10 mM calcium chloride, pH 6.0) in 96-well microliter plates. Activated βtromelyβin iβ diluted in aβsay buffer to 25 μg/ml. Ellman's reagent (3-Carboxy- 4-nitrophenyl disulfide) iβ made aβ a 1M βtock in dimethyl formamide and diluted to 5 mM in aββay buffer with 50 μl per well yielding at 1 mM final concentration. 10 mM βtock βolutionβ of inhibitorβ are made in dimethyl βulfoxide and diluted βerially in aββay buffer βuch that addition of 50 μL to the appropriate wells yields final concentrations of 3 μM, 0.3 μM, 0.003 μM, and 0.0003 μM. All conditionβ are completed in triplicate. A 300 mM dimethyl βulfoxide βtock solution of the peptide substrate iβ diluted to 15 mM in aββay buffer and the aββay iβ initiated by addition of 50 μl to each well to give a final concentration of 3 mM substrate. Blanks conβiβt of the peptide substrate and Ellman's reagent without the enzyme. Product formation was monitored at 405 nm with a Molecular Devices UVmax plate reader. ICg values were determined in the same manner aβ for collagenase. Inhibition of MMP-13 Human recombinant MMP-13 iβ activated with 2mM APMA (p-aminophenyl mercuric acetate) for 1.5 hours, at 37°C. and iβ diluted to 400 mg/ml in aββay buffer (50 mM Trie, pH 7.5, 200 mM βodium chloride, 5mM calcium chloride, 20μM zinc chloride, 0.02% brij) . Twenty-five microliterβ of diluted enzyme iβ added per well of a 96 well microfluor plate. The enzyme iβ then diluted in a 1:4 ratio in the aββay by the addition of inhibitor and βubβtrate to give a final concentration in the aββay of 100 mg/ml. 10 mM βtock solutions of inhibitors are made up in dimethyl βulfoxide and then diluted in aβsay buffer aβ per the inhibitor dilution scheme for inhibition of human collagenaβe (MMP-1) : Twenty-five microliterβ of each concentration iβ added in triplicate to the microfluor plate. The final concentrationβ in the aββay are 30 μM, 3 μM, 0.3 μM and 0.03 μM. Subβtrate (Dnp-Pro-Cha-Gly-Cyβ(Me) -Hiβ-Ala- Lye (NMA) -NH ) iβ prepared aβ for inhibition of human collagenaβe (MMP-1) and 50 μl iβ added to each well to give a final aββay concentration of 10 μM. Fluoreβcence readingβ (360 nM excitation; 450 emission) are taken at time 0 and every 5 minutes for 1 hour. Poβitive controlβ conβiβt of enzyme and substrate with no inhibitor and blanks conβiβt of βubβtrate only. ICgo'β are determined aβ per inhibition of human collagenaβe (MMP-1) . If ICg 0 's are reported to be lees than 0.03 μM, inhibitorβ are then aββayed at final concentrationβ of 0.3 μM, 0.03 μM, 0.003 μM and 0.0003 μM. Inhibition of TNF Production The ability of the compounds or the pharmaceutically acceptable βaltβ thereof to inhibit the production of TNF and, conβequently, demonstrate their effectiveness for treating diseaβeβ involving the production of TNF iβ βhown by the following in vitro aββay: Human mononuclear cellβ were isolated from anti-coagulated human blood using a one-step Ficoll- hypaque separation technique. The mononuclear cells were washed three times in Hanks balanced salt solution (HBSS) with divalent cations and reβuβpended to a density of 2 x 10°/ml in HBSS containing 1% BSA. Differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that monocyteβ ranged from 17 to 24% of the total cellβ in theβe preparations. lβOμ of the cell βuβpenβion was aliquoted into flate bottom 96 well plates (Costar) . Additions of compoundβ and LPS (lOOng/ml final concentration) gave a final volume of 200μl. All conditionβ were performed in triplicate. After a four hour incubation at 37°C. in an humidified C0 2 incubator, plates were removed and centrifuged (10 minuteβ at approximately 250 x g) and the βupernatants removed and aββayed for TNFα using the R&D ELISA Kit. For administration to humane for the inhibition of matrix metalloproteinaβeβ or the production of tumor necroβiβ factor (TNF) , a variety of conventional routes may be uβed including orally, parenterally and topically. In general, the active compound will be adminiβtered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will neceββarily occur depending on the condition of the βubject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. The compounds of the present invention can be administered in a wide variety of different dosage forme, in general, the therapeutically effective compounds of this invention are preβent in βuch doβage forme at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients such as macrocrystalline cellulose, βodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants βuch aβ βtarch (and preferably corn, potato or tapioca βtarch) , alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating agents βuch as magneβium stearate, sodium lauryl sulfate and talc are often very uβeful for tabletting purpoβeβ. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection alβo include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueouβ βuβpenβionβ and/or elixirβ are deβired for oral adminiβtration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if βo deβired, emulβifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention in either βeβame or peanut oil or in aqueouβ propylene glycol may be employed. The aqueouβ βolutionβ βhould be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent firβt rendered iβotonic. Theβe aqueous βolutionβ are βuitable intravenous injection purpoβeβ. The oily βolutionβ are βuitable for intraarticular, intramuβcular and subcutaneous injection purpoβeβ. The preparation of all theβe βolutionβ under βterile conditionβ iβ readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. The present invention iβ illustrated by the following examples, but it iβ not limited to the detailβ thereof. EXAMPLE 1 2- (R) -N-Hvdroxy-2- [ (-methoxybenzeneβulfonyl) (2-morpholin-4-yl-2-oxoethyl)amino] -3-methylbutyramide To a βolution of D-valine benzyl eβter hydrochloride (2.4 grams, 10 mmol) and triethylamine (2.5 gramβ, 3.5 mL, 25 mmol) in water (50 mL) and 1,4- dioxane (50 mL) iβ added 4-methoxybenzeneβulfonyl chloride (2.3 gramβ, 11 mmol). The mixture was stirred at room temperature for 1 hour and then most of the solvent was removed by evaporation under vacuum. The mixture was diluted with ethyl acetate and was washed succeββively with dilute hydrochloric acid βolution, water and brine. The organic βolution waβ dried over magneβium βulfate and concentrated to leave N- (4- methoxybenzeneβulfonyl) -D-valine benzyl eβter aβ a white βolid, 3.6 gramβ (97%); m.p. 92-94°C. N- (4-Methoxybenzeneβulfonyl) -D-valine benzyl eβter (1.50 gramβ, 4.0 mmol) waβ added to a βuβpenβion of βodium hydride (0.1 gramβ, 4.2 mmol) in dry dimethylformamide (20 mL) and, after 30 minuteβ, tert- butyl bromoacetate (0.8 mL, 4.2 mmol) waβ added. The reβulting mixture waβ βtirred overnight at room temperature and waβ then quenched by addition of βaturated ammonium chloride βolution (3 mL) . The dimethylformamide waβ removed by evaporation under vacuum. The reβidue waβ taken up in ethyl acetate and washed with water and brine. After drying over magneβium sulfate, ethyl acetate waβ evaporated to leave an oil from which 2- (R) -2- [tert- butoxycarbonylmethyl(4-methoxybenzeneβulfonyl)amino] -3- methylbutyric acid benzyl eβter, a clear oil (1.92 gramβ, 98%) , waβ iβolated uβing flaβh chromatography on βilica gel eluting with 15% ethyl acetate in hexane. To a cold (0°C.) βolution of 2- (R) -2- [tert- butoxycarbonylmethyl (4-methoxybenzeneβulfonyl)amino] -3- methylbutyric acid benzyl eβter (1.92 gramβ, 3.9 mmol) in methylene chloride (28 mL) waβ added trifluoroacetic acid (7 mL) . The reβulting βolution waβ allowed to warm to room temperature and waβ βtirred overnight. The methylene chloride and trifluoroacetic acid were evaporated under vacuum leaving 2-(R)-2- [carboxymethyl (4-methoxybenzeneβulfonyl)amino) ] -3- methylbutyric acid benzyl eβter aβ a clear oil, 1.70 gramβ (100%) . To a βolution of 2- (R) -2- [carboxymethyl (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl eβter (573 mg, 1.32 mmol) in methylene chloride (12 mL) were added βequentially triethylamine (0.46 mL, 3.28 mmol), morpholine (0.127 mL, 1.46 mmol) and (benzotriazol-1-yloxy) trie(dimethy1amino)phoβphonium hexafluorophoβphate (646 mg, 1.46 mmol) . The mixture waβ βtirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N hydrochloric acid solution and brine, dried over magnesium sulfate and concentrated under vacuum. The reβidue waβ chromatographed on βilica gel uβing 40% ethyl acetate in hexane affording 2-(R)-2-[(4- methoxybenzenesulfonyl) (2-morpholin-4-yl- oxoethy1)amino] -3-methylbutyric acid benzyl ester as a clear oil, 590 mg (89%) . To a βolution of 2-(R)-2-[(4- methoxybenzeneβulfonyl) (2-morpholin-4-yl-2- oxoethyl)amino] -3-met;hylbutyric acid benzyl eβter (590 mg, 1.17 mmol) in ethanol (50 mL) waβ added 10% palladium on activated carbon (200 mg) . The mixture was agitated under 3 atmosphereβ hydrogen in a Parr βhaker for 2 hourβ. The catalyst waβ removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving 2-(R)-2-[(4- methoxybenzeneβulfonyl) (2-morpholin-4-yl-2- oxoethyl)amino] -3-methylbutyric acid aβ a white foam, 485 mg (100%) . To a βolution of 2-(R)-2-[(4- methoxybenzeneβulfonyl) (2-morpholin-4-yl-2- oxoethyl)amino] -3-methylbutyric acid (485 mg, 1.17 mmol) in methylene chloride (12 mL) were added βequentially triethylamine (0.52 mL, 3.71 mmol), O- benzylhydroxylamine hydrochloride (205 mg, 1.28 mmol) and (benzotriazol-1- yloxy) trie (dimethylamino)phoβphonium hexafluorophoβphate (570 mg, 1.29 mmol) . The mixture was βtirred at room temperature overnight and then diluted with ethyl acetate. The βolution waβ washed βequentially with 0.5 N hydrochloric acid βolution, water, βaturated βodium hydrogen carbonate βolution and brine, dried over magneβium βulfate and concentrated under vacuum. The reβidue waβ chromatographed on βilica gel uβing 20% hexane in ethyl acetate to afford 2- (R) -N-benzyloxy-2- [ (4-methoxybenzeneβulfonyl) (2- morpholin-4-yl-2-oxoethyl) mino] -3-methylbutyramide aβ a white foam, 510 mg (84%) . To a βolution of 2- (R) -N-benzyloxy-2- [ (4- methoxybenzenesulfonyl) (2-morpholin-4-yl-2- oxoethyl)amino] -3-methylbutyramide (510 mg, 0.98 mmol) in methanol (50 mL) waβ added 5% palladium on activated carbon (120 mg) . The mixture waβ agitated under 2 atmospheres hydrogen in a Parr βhaker for 2 hourβ. The catalyst waβ removed by filtration through nylon (pore size 0.45 μm) and the solvent waβ evaporated leaving 2- (R) -N-hydroxy-2- [ (-methoxybenzeneβulfonyl) (2- morpholin-4-yl-2-oxoethyl)amino] -3-methylbutyramide aβ a white βolid, 418 mg (99%); 1 H NMR (CDC1 3 ) : δ 10.3 (br β, 1H) , 7.90 (br β, 1H, overlapped), 7.86 (d, J = 8.8 Hz, 2H, overlapped), 6.94 (d, J = 8.8 Hz, 2H) , 4.39 (d, J = 17.1 Hz, 1H) , 4.09 (d, J = 17.1, 1H) , 3.84 (β, 3H) , 3.80-3.48 (m, 9H) , 2.20-1.95 (m, 1H) , 0.82 (d, J = 6.5 Hz, 3H) , 0.45 (d, J = 6.5 Hz, 3H) ; MS (LSIMS) : m/z 430 (M+H) . EXAMPLE 2 2- (R) -N-Hvdroxy-2- [ (4-methoxybenzeneβulfonyl) (3-morpholin-4-yl-3-oxopropyl)amino] -3-methylbutyramide To a βolution of N-(4- methoxybenzeneβulfonyl) -D-valine benzyl eβter (2.2 gramβ, 5.83 mmol) in dry dimethylformamide (40 mL) were added cesium carbonate (2.3 grams, 7.1 mmol) and 1- iodo-3-butene (1.3 gramβ, 7.1 mmol) . The mixture waβ stirred at room temperature overnight and waβ then poured into water. The mixture waβ extracted twice with ether and the combined ether extracts were washed with brine, dried over magneβium βulfate and concentrated under reduced preββure. The reβidue waβ taken up in 20% ethyl acetate/hexane; βtarting material N- (4-methoxybenzeneβulfonyl) -D-valine benzyl eβter (1.5 g) cryβtallized from the mixture and waβ recovered by filtration. The filtrate waβ concentrated under vacuum and the reβidue waβ chromatographed on βilica gel uβing 20% ethyl acetate/hexane aβ eluent to provide 2- (R) -2- [but-3-enyl (4-methoxybenzeneβulfonyl)amino] -3- methylbutyric acid benzyl eβter aβ a clear oil, 404 mg (16%) . To a mixture of 2- (R) -2- [but-3-enyl(4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl eβter (780 mg, 1.81 mmol) and ruthenium (III) chloride hydrate (10 mg, 0.048 mmol) in acetonitrile (6 mL) , carbon tetrachloride (6 mL) and water (8 mL) waβ added βodium periodate (1.7 gramβ, 7.9 mmol) . After βtirring at room temperature for 2 hourβ, the mixture waβ diluted with methylene chloride and filtered through diatomaceous earth. The organic layer waβ βeparated, washed with dilute hydrochloric acid βolution and brine, dried over magnesium sulfate and concentrated to leave 2- (R) -2- [2-carboxyethyl (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl eβter aβ an oil, 710 mg (87%) . Alternatively, the intermediate 2-(R)-2-[2- carboxyethyl (4-methoxybenzenesulfonyl)amino] -3- methylbutyric acid benzyl eβter waβ prepared by the following higher yielding procedure: N- (4-Methoxybenzeneβulfonyl) -D-valine benzyl eβter (18.8 gramβ, 49.8 mmol) waβ added to a βuβpenβion of βodium hydride (1.3 gramβ, 54 mmol) in dry dimethylformamide (200 mL) and, after 1.5 hourβ, a βolution of allyl bromide (4.7 mL, 54 mmol) waβ added. The resulting mixture was βtirred overnight at room temperature and waβ then quenched by addition of βaturated ammonium chloride βolution. The dimethylformamide waβ removed by evaporation under vacuum. The reβidue waβ taken up in ether and washed with water and brine. After drying over magneβium βuifate, ether waβ evaporated to leave an oil from which 2- (R) -2- [ (4-methoxybenzeneβulfonyl)prop-2- enylamino] -3-methylbutyric acid benzyl eβter, a clear oil (18.1 gramβ, 87%), waβ iβolated uβing flaβh chromatography on βilica gel eluting with 10% ethyl acetate in hexane and then 20% ethyl acetate in hexane. To a 1 M βolution of borane/disulfide complex in methylene chloride (1.45 mL, 2.9 mmol) waβ added a βolution of 2- (R) -2- [(4-methoxybenzeneβulfonyl)prop-2- enylamino] -3-methylbutyric acid benzyl eβter (3.6 gramβ, 8.6 mmol) in methylene chloride (8 mL) . The βolution waβ βtirred at room temperature for 4 hourβ at which time more 1 M βolution of borane/disulfide complex in methylene chloride (2.0 mL, 4.0 mmol) was added. The mixture waβ βtirred at room temperature overnight and waβ then added dropwiβe to a mechanically βtirred βolution of chromium trioxide (5.1 gramβ, 51.6 mole) in acetic acid (31 mL) and water (3.5 mL) while keeping the internal temperature between -5°C. and 10°C. After βtirring at room temperature overnight, the mixture waβ diluted with water and extracted with methylene chloride. The extract waβ washed with brine, dried (magnesium βulfate) and concentrated. The reβidue waβ chromatographed on βilica gel eluting βucceββively with chloroform and 2% methanol in chloroform to afford 2- (R) -2- [2-carboxyethyl (4- methoxybenzeneβulfonyl) amino] -3-methylbutyric acid benzyl aβ an oil (2.42 gramβ, 63%). To a βolution of 2- (R) -2- [2-carboxyethyl(4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl eβter (710 mg, 1.58 mmol) in methylene chloride (15 mL) were added βequentially triethylamine (0.47 mL, 3.35 mmol), morpholine (0.15 mL, 1.72 mmol) and (benzotriazol-1-yloxy) trie(dimethylamino)phoβphonium hexafluorophoβphate (769 mg, 1.74 mmol) . The mixture waβ βtirred at room temperature overnight and then diluted with methylene chloride. The βolution waβ waβhed with 0.5 N hydrochloric acid βolution and brine, dried over magneβium βuifate and concentrated under vacuum. The βolid reβidue waβ chromatographed on βilica gel uβing 20% hexane in ethyl acetate affording 2- (R) -2- [ (4-methoxybenzenesulfonyl) (3-morpholin-4-yl-3- oxopropyl)amino] -3-methylbutyric acid benzyl eβter aβ a clear oil, 725 mg (88%) . To a βolution of 2-(R)-2-[(4- methoxybenzeneβulfonyl) (3-morpholin-4-yl-3- oxopropyl) amino] -3-methylbutyric acid benzyl eβter (725 mg, 1.40 mmol) in ethanol (35 mL) waβ added 10% palladium on activated carbon (50 mg) . The mixture waβ agitated under 3 atmoβphereβ hydrogen in a Parr shaker for 3 hourβ. The catalyβt waβ removed by filtration through nylon (pore size 0.45 μm) and the βolvent waβ evaporated leaving 2- (R) - (2) - [ (4- methoxybenzeneβulfonyl) (3-morpholin-4-yl-3- oxopropyl)amino] -3-methyl-butyric acid aβ a white solid, 540 mg (90%) . To a βolution of 2-(R)-2-[(4- methoxybenzenesulfonyl) (3-morpholin-4-yl-3- oxopropyl)amino] -3-methylbutyric acid (540 mg, 1.26 mmol) and 1-hydroxybenztriazole hydrate (205 mg, 1.33 mmol) in dry dimethylformamide (12 mL) was added 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (289 mg, 1.51 mmol) . After stirring for 30 minuteβ, hydroxylamine hydrochloride (350 mg, 5.04 mmol) and then triethylamine (1.0 mL, 7.17 mmol) were added. The mixture waβ βtirred at room temperature overnight and then diluted with ethyl acetate. The βolution was waβhed βequentially with water, 0.5 N hydrochloric acid βolution and brine. The βolution waβ then dried over magneβium βulfate and concentrated under vacuum to leave a white foam. The material waβ diββolved in toluene, filtered and concentrated. The reβidue waβ triturated with ether to afford 2- (R) -N-hydroxy-2 [ (4- methoxybenzeneβulfonyl) (3-morpholin-4-yl-3- oxopropyl)amino] -3-methylbutyramide aβ a βolid, 200 mg (36%); 1 H NMR (CDC1 3 ) : δ 9.35 (br β, 1H) , 7.73 (d, J = 8.9 Hz, 2H) , 6.95 (d, J = 8.9 Hz, 2H) , 3.86 (β, 3H) , 3.83-3.73 (m, 1H) , 3.70-3.52 (m, 7H) , 3.46-3.43 (m, 2H) , 3.41-3.29 (m, IH) , 2.92-2.69 (m, 2H) , 2.30-2.17 (m, IH) , 0.84 (d, J = 6.5 Hz, 3H) , 0.41 (d, J « 6.5 Hz, 3H) ; MS (particle beam) : m/z 444 (M+H) , 428, 383, 329; HRMS calculated for C 19 H 30 N 3 O 7 S (M+H) : 444.1804, Found: 464.1818. The title compounds of Examples 3-6 were prepared by a method analogous to that deβcribed in Example 2 uβing 2- (R) -2- [2-carboxyethyl (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl eβter aβ the βtarting material which is coupled with the amine indicated. EXAMPLE 3 2- (R) -2- [ (2-Benzylcarbamoylethyl) (4- methoxybenzeneβulfonyl)amino] -N-hvdroxy-3- methylbutyramide Coupled with benzylamine; 1 H NMR (DMSO-dg) : δ 10.72 (s, IH) , 8.89 (s, IH) , 8.39 ( , IH) , 7.74 (d, J •= 9.0 Hz, 2H) , 7.32-7.21 (m, 5H) , 7.05 (d, J = 9.0 Hz, 2H) , 4.21 (d, J = 5.9 Hz, 2H) , 4.02-3.87 (m, IH) , 3.82 (β, 3H) , 3.63 (d, J = 10.8 Hz, IH) , 3.29-3.17 ( , IH) , 2.71-2.57 (m, IH) , 2.52-2.40 (m, IH) , 2.06-1.94 ( , IH) , 0.77 (d, J = 6.6 Hz, 3H) , 0.74 (d, J • = 6.5 Hz, 3H) ; MS (LSIMS) : m/z 464 (M+H) ; HRMS calculated for C 22 H 30 N 3 O 6 S (M+H) : 464.1855. Found: 464.1832. EXAMPLE 4 2- (R) -N-Hvdroxy-2- ( (4-methoxybenzenesulfonyl) (2- [ (pyridin-3-ylmethyl)carbamoyl] ethyl) amino) -3- methylbutyramide Coupled with 3-pyridylmethylamine: H NMR (DMSO-dg) : δ 10.72 (β, IH) , 8.89 (β, IH) , 8.49-8.42 (m, 3H) , 7.73 (d, J = 8.9 Hz, 2H) , 7.63-7.60 (m, IH) , 7.32 (dd, J = 4.8, 7.8 Hz, IH) , 7.05 (d, J = 8.9 Hz, 2H) , 4.23 (d, J = 5.8 Hz, 2H) , 4.00-3.88 (m, IH) , 3.81 (ε, 3H) , 3.62 (d, J = 10.8 Hz, IH) , 3.27-3.17 (m, IH) , 2.69-2.58 (m, IH) , 2.52-2.41 (m, IH) , 2.07-1.94 (m, IH) , 0.76 (d, J β 6.5 Hz, 3H) , 0.72 (d, J = 6.4 Hz, 3H) ; MS (LSIMS) : m/z 465 (M+H) . EXAMPLE 5 2- (R) -N-Hvdroxy-2- ( r4-methoxybenzeneβulfonyll [2- (methylpyridin-3-ylmethylc»»-r>>Mnnyl)ethyl] amino) -3- methylbutyramide Coupled with 3- (N-methylaminomethyl)pyridine: ^ ■ H NMR (DMSO-dg) : 10.75 (br β, IH) , 8.92 (β, IH) , 8.52-8.29 (m, 2H) , 7.75 (d, J •= 8.8 Hz, 1.4 H) , 7.67 (d, J ■ 8.8 Hz, 0.6 H) , 7.62-7.58 (m, IH) , 7.42-7.32 (m, IH) , 7.06 (d, J - 8.8 Hz, 1.4 H) , 7.01 (d, J = 8.8 Hz, 0.6 H) , 4.55-4.41 (m, 2H) , 3.94-3.82 (m, IH) , 3.81 (β, 2.1 H) , 3.80 (β, 0.9 H) , 3.68-3.60 (m, IH) , 3.33- 3.19 (m, IH) , 2.90-2.50 (m, 2H) , 2.88 (β, 2.1 H overlapped), 2.79 (s, 0.9 H) , 2.05-1.80 (m, IH) , 0.79-0.63 (m, 6H) : MS (thermospray) : m/z 479 (M+H), 364. EXAMPLE 6 4- (3- I (1- (R) -l-Hvdroxycarbamoyl-2- methylpropyl) (4-methoxybenzeneβulfonyl) amino] ropionyl) piperazine-1-carboxylic acid, tert-butyl eβter Coupled with tert-butyl-1- piperazinecarboxylate: -^H NMR (DMSO-dg): δ 10.77 (br β, IH) , 8.93 (β, IH) , 7.74 (d, J = 8.9 Hz, 2H) , 7.06 (d, J = 8.9 Hz, 2H) , 3.90-3.80 (m, IH) , 3.82 (s, 3H, overlapped), 3.64 (d, J = 10.8 Hz, IH) , 3.60-3.16 (m, 9H) , 2.80-2.71 (m, IH) , 2.59-2.47 (m, IH) , 2.03-1.91 (m, IH) , 1.39 (β, 9H) , 0.77 (d, J = 6.5 Hz, 3H) , 0.71 (d, J = 6.5, 3H) ; MS (thermoβpray) : m/z 543 (M+H), 443, 382, 328. EXAMPLE 7 2- (R) -N-Hvdroxy-2- [ (4-methoxybenzeneβulfonyl) (3-oxo-3-piperazin-1-ylpropyl)amino] -3-methylbutyramide hvdrocholoride A βolution of 4- (3- [ (1- (R) -1- hydroxycarbamoyl-2-methylpropyl) (4- methoxybenzeneβulfonyl)amino]propionyl)piperazine-1- carboxylic acid, tert-butylester [Example 6] (430 mg, 0.79 mmol) in methylene chloride (11 mL) waβ cooled to 0°C. Hydrogen chloride gas was then bubbled through the solution for about 0.5 minute. The solution waβ allowed to warm to room temperature with βtirring over 1 hour. Volatileβ were removed by evaporation and the reβidue waβ filtered waβhing with methylene chloride to collect βolid 2- (R) -N-hydroxy-2- [ (4- methoxybenzenesulfonyl) (3-oxo-3-piperazin-1- ylpropyl)amino] -3-methylbutyramide hydrochloride, 375 mg (99%). E NMR (DMSO-dg): δ 10.78 (br s, IH) , 9.16 (br β, IH) , 7.74 (d, J = 8.8 Hz, 2H) , 7.07 (d, J = 8.9 Hz, 2H) , 3.82 (β, 3H) , 3.62 (br ε, 4H) , 3.38-3.18 (m, IH) , 3.16-3.07 (br s, 2H) , 3.07-2.98 (br β, 2H) , 2.83- 2.73 (m, IH) , 2.65-2.53 (m, IH) , 2.06-1.90 (m, IH) , 0.76 (d, J = 6.5 Hz, 3H) , 0.72 (d, J = 6.5 Hz, 3H) . A broad water peak between δ 4.0 and 3.5 obscured some βignalβ from this compound; MS (thermospray) : m/z 443 (M+H), 382, 328. EXAMPLE 8 2- (R) -2- T (Benzylcarbamoylmethyl) (4- methoxybenzenesulfonyl)amino] -N-hvdroxy-3-methyl¬ butyramide To a βolution of 2- (R) -2- [carboxymethyl (4- ethoxybenzenesulfonyl)amino] -3-methylbutyric acid benzyl ester (example 1) (905 mg, 2.08 mmol) in methylene chloride (18 mL) were added βequentially triethylamine (0.72 mL, 5.14 mmol), benzylamine (0.25 mL, 2.29 mmol) and (benzotriazol-1- yloxy) trie (dimethylamino)phosphonium hexafluoro¬ phoβphate (1.01 gramβ, 2.28 mmol) . The mixture waβ βtirred at room temperature overnight and then diluted with ethyl acetate. The βolution was waβhed with 0.5 N hydrochloric acid βolution and brine, dried over magneβium βulfate and concentrated under vacuum. The residue waβ chromatographed on βilica gel uβing a 2:5:16 ratio of methylene chloride/ethyl acetate/hexane affording 2- (R) -2- [(benzylcarbamoylmethy1) (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl ester as a clear oil, 933 mg (86%) . To a solution of 2-(R)-2- [ (benzylcarbamoylmethyl) (4-methoxybenzeneβulfonyl) - amino] -3-methylbutyric acid benzyl eβter (933 mg, 1.17 mmol) in ethanol (50 mL) waβ added 10% palladium on activated carbon (85 mg) . The mixture waβ agitated under 3 atmospheres hydrogen in a Parr shaker for 4 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving 2- (R) -2- [ (benzylcarbamoylmethyl) (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid aβ a white foam, 755 mg (98%) . To a βolution of 2-(R)-2- [ (benzylcarbamoylmethyl) (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid (655 mg, 1.51 mmol) and 1-hydroxybenztriazole hydrate (224 mg, 1.46 mmol) in dry dimethylformamide (15 mL) waβ added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (316 mg, 1.65 mmol). After stirring for 30 minutes, hydroxylamine hydrochloride (416 mg, 6.0 mmol) and then N-methylmorpholine (0.99 mL, 9.0 mmol) were added. The mixture waβ βtirred at room temperature overnight and then diluted with ethyl acetate. The βolution waβ waβhed βequentially with water, 0.5 N hydrochloric acid βolution and brine. The βolution waβ then dried over magneβium βuifate and concentrated under vacuum to leave a white foam which waβ chromatographed on βilica gel eluting with ethyl acetate to afford 2- (R) -2- [ (benzylcarbamoylmethyl) (4- methoxybenzene-βulfonyl)amino] -N-hydroxy-3- methylbutyramide aβ a white foam, 570 mg (84%) ; 1 H NMR (DMSO-dg) : δ 10.75 (br β, IH) , 8.90 (β, IH) , 8.47 (m, IH) , 7.85 (d, J - 8.9 Hz, 2H) , 7.83-7.19 (m, 5H) , 7.04 (d, J = 8.9 Hz, 2H) , 4.37 (d, J = 11.4 Hz, IH) , 4.28 (d, J = 5.9 Hz, 2H) , 3.89 (d, J = 11.4 Hz, IH) , 3.82 (s, 3H) , 3.45 (d, J •= 10.3 Hz, IH) , 1.90-1.79 (m, IH) , 0.73 (d, J = 6.3 Hz, 6H) ; MS (LSIMS) : m/z 450 (M+H) . EXAMPLE 9 2- (R) -2- [ (Benzylmethylcarbamoylmethyl) (4- methoxybenzeneβulfonyl)amino] -N-hvdroxy-3- methylbutyramide To a βolution of 2- (R) -2- [carboxymethyl (4- methoxybenzenesulfonyl)amino] -3-methylbutyric acid benzyl ester (Example 1) (1.05 grams, 2.41 mmol) in methylene chloride (20 mL) were added βequentially triethylamine (0.84 mL, 6.0 mmol), N-benzylmethy1amine (0.34 mL, 2.63 mmol) and (benzotriazol-1- yloxy) trie (dimethyla ino)phoβphonium hexafluorophoβphate (1.17 gramβ, 2.69 mmol) . The mixture waβ βtirred at room temperature overnight and then diluted with ethyl acetate. The βolution was waβhed with 0.5 N hydrochloric acid βolution and brine, dried over magneβium βulfate and concentrated under vacuum. The reβidue waβ chromatographed on βilica gel uβing 35% ethyl acetate in hexane (plus a email amount of methylene chloride to load the βample on the column) affording 2- (R) -2- [benzylmethylcarbamoylmethyl) (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl eβter aβ a clear oil, 1.14 gramβ (88%) . To a βolution of 2-(R)-2- [ (benzylmethylcarbamoylmethyl) (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl eβter (1.14 grams, 2.12 mmol) in ethanol (100 mi.) was added 10% palladium on activated carbon (400 mg) . The mixture was agitated under 3 atmosphereβ hydrogen in a Parr βhaker for 3 hourβ. The catalyβt waβ removed by filtration through nylon (pore βize 0.45 μm) and the βolvent waβ evaporated leaving 2-(R)-2- [ (benzylmethylcarbamoylmethyl) (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid as a white foam, 902 mg (95%) . To a βolution of 2-(R)-2- [ (benzylmethylcarbamoylmethyl) (4- methoxybenzenesulfonyl)amino] -3-methylbutyric acid (902 mg, 2.01 mmol) in methylene chloride (20 mL) were added βequentially triethylamine (0.90 mL, 6.42 mmol), O- allylhydroxylamine hydrochloride (242 mg, 2.21 mmol) and (benzotriazol-1-yloxy) tris- (dimethylamino)phoβphonium hexafluorophoβphate (978 mg, 2.21 mmol) . The mixture waβ βtirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N hydrochloric acid solution and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel using 40% hexane in ethyl acetate to afford 2- (R) -N-allyloxy-2- [ (benzylmethylcarbamoylmethyl) (4-methoxy¬ benzenesulfonyl)amino] -3-methylbutyramide as an oil, 1.008 gramβ (100%) . To a βolution of 2- (R) -N-allyloxy-2- [ (benzylmethyl-carbamoylmethyl) (4- methoxybenzenesulfonyl)amino] -3-methylbutyramide (500 mg, 0.99 mmol) in methylene chloride (40 mL) waβ added bis(triphenylphosphine)palladium (II) chloride (280 mg, 0.4 mmol) and then, dropwise, tributyltinhydride (0.43 mL, 2.2 mmol) . The solution waβ βtirred at room temperature for 1 hour, diluted with methylene chloride, waβhed with 1 N hydrochloric acid βolution, dried over magneβium βulfate and concentrated. The reβidue waβ taken up in ethyl acetate and filtered to remove a βolid. After concentration, the filtrate waβ chromatographed on βilica gel eluting with chloroform and then 2% methanol in chloroform to afford 2-(R)-2- [(benzylmethylcarbamoylmethyl) (4-methoxybenzene¬ βulfonyl)amino] -N-hydroxy-3-methylbutyramide aβ a white solid (340 mg, 74%). X H NMR (DMSO-dg) : δ 10.66 (br s, IH) , 8.87 (br β, 0.6 H) , 8.84 (β, 0.4 H) , 7.91 (d, J = 8.9 Hz, 1.2 H) , 7.78 (d, J - 8.9 Hz, 0.8 H) , 7.43-7.21 (m, 5H) , 7.05 (d, J « 8.9 Hz, 1.2 H) , 7.00 (d, J = 8.9 Hz, 0.8 H) 4.72 (d, J «* 17.7 Hz, 0.4 H) , 4.70 (d, J = 17.7 Hz, 0.6 H) , 4.59-4.42 ( , IH) , 4.25 (d, J = 17.8 Hz, 0.6H), 4.07 (d, J = 17.7 Hz, 0.4H), 3.82 (β, 3H) , 3.46-3.40 (m, IH) , 2.91 (s, 1.8H), 2.83 (β, 1.2 H) , 1.92-1.70 (m, IH) , 0.75-0.69 ( , 6H) ; MS (thermoβpray): m/z 464 (M+H), 307, 239. The title compounds of Examples 10-11 were prepared by a method analogous to that described in Example 9 using 2- (R) -2- [carboxy ethyl(4- methoxybenzenesulfonyl)amino] -3-methylbutyric acid benzyl ester (Example 1) as the βtarting material which iβ coupled with the amine indicated. EXAMPLE 10 2- (R) -N-Hvdroxy-2- ( f4- methoxybenzeneβulfonyl] - [ (2-morpholin-4- ylethylcarbamoyl)methyl1 amino) -3-methylbutyramide Coupled with 4- (2-aminoethyl)morpholine: -^H NMR (DMSO-dg) : δ 10.74 (br β, IH) , 8.90 (br β, IH) , 7.84 (br β, IH, overlapped), 7.84 (d, J = 8.8 Hz, 2H) , 7.06 (d, J = 8.8 Hz, 2H) , 4.33 (d, J = 17.5 Hz, IH) , 3.83 (β, 3H) , 3.78 (d, J = 17.5 Hz, IH) , 3.57-3.54 (m, 4H) , 3.49 (d, J = 10.2 Hz, IH) , 3.28-3.06 ( , 2H) , 2.34-2.30 (m, 6H) , 1.93-1.77 (m, IH) , 0.77-0.74 (m, 6H) . EXAMPLE 11 2- (R) -N-Hvdroxy-2- [(4- methoxybenzeneβulfonyl) (2-oxo-2-pyrrolidin-l- ylethyl)amino] -3-methylbutyramide Coupled with pyrrolidine: H NMR (CD 3 0D) : δ 7.90 (d, J ■ 8.9 Hz, 2H) , 7.04 (d, J = 8.9 Hz, 2H) , 4.50 (d, J = 17.6 Hz, IH) , 4.15 (d, J = 17.6 Hz, IH) , 3.87 (β, 3H) , 3.56-3.39 (m, 5H) , 2.07-1.82 (m, 5H) , 0.83 (d, J = 6.6 Hz, 3H) , 0.73 (d, J = 6.6 Hz, 3H) ; MS (thermoβpray) : m/z 414 (M+l) ; HRMS calculated for C 18 H 28 N 3 0gS (M+H) : 414.1699. Found 414.1703. EXAMPLE 12 2- [Dimethylcarbamoylmethyl (4- methoxybenzenesulfonγ * ι )« -ino] -N-hydroxy-3-methyl¬ butyramide A solution of 2- (R) -2- [carboxymethyl (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl eβter (Example 1) (1.89 grams, 4.34 mmol) in thionyl chloride (25 mL) was heated at reflux for 1 hour. After cooling, the excess thionyl chloride waβ evaporated. The reβidue waβ taken up in methylene chloride (50 mL) and the βolution waβ cooled in an ice bath. Dimethylamine gaβ waβ slowly bubbled through the βolution for 1 hour. After evaporation of the solvent, the residue was taken up in ethyl acetate, washed with I N hydrochloric acid solution, water and brine, dried over magnesium βulfate and concentrated to leave dimethylcarbamoylmethy1 (4-methoxybenzenesulfonyl)amino- 3-methylbutyric acid benzyl ester as an oil, 1.77 grams (88%) . To a βolution of dimethylcarbamoylmethyl (4- methoxybenzenesulfonyl)amino-3-methylbutyric acid benzyl ester (1.77 grams, 3.83 mmol) in ethanol (100 mL) waβ added 10% palladium on activated carbon (644 mg) . The mixture waβ agitated under 3 atmoβphereβ hydrogen in a Parr βhaker for 1.5 hourβ. The catalyβt waβ removed by filtration through nylon (pore βize 0.45 μm) and the βolvent waβ evaporated leaving dimethyl¬ carbamoylmethyl (4-methoxybenzeneβulfonyl)amino-3- methylbutyric acid aβ a white foam, 1.42 gramβ (100%) . To a βolution of dimethylcarbamoylmethyl (4- methoxybenzeneβulfonyl)amino-3-methylbutyric acid (1.42 gramβ, 3.81 mmol) and 1-hydroxybenztriazole hydrate (687 mg, 4.48 mmol) in dry dimethylformamide (7 mL) waβ added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (974 mg, 5.08 mmol) . After βtirring for 30 minuteβ, hydroxylamine hydrochloride (1.17 gramβ, 16.8 mmol) and then N-methylmorpholine (2.8 mL, 25.5 mmol) were added. The mixture was βtirred at room temperature overnight and then concentrated under vacuum. The reβidue waβ taken up in ethyl acetate and the reβulting βolution was waβhed βequentially with water, 0.5 N hydrochloric acid βolution and brine. The βolution waβ then dried over magneβium βulfate and concentrated under vacuum to leave an oil which waβ chromatographed on βilica gel eluting βucceββively with ethyl acetate, 5% methanol in chloroform and 10% methanol in chloroform to afford 2- [dimethyl¬ carbamoylmethyl (4-methoxybenzeneβulfonyl)amino] -N- hydroxy-3-methylbutyramide aβ a white solid, 390 mg (26%) . X H NMR (DMSO-dg): δ 10.70 (br s, IH) , 8.89 (β, IH) , 7.80 (d, J *= 8.9 Hz, 2H) , 7.10 (d, J = 8.9 Hz, 2H) , 4.62 (d, J - 17.7 Hz, IH) , 4.14 (d, J = 17.7 Hz, IH) , 3.84 (β, 3H) , 3.40 (d, J = 10.4 Hz, IH) , 2.97 (β, 3H) , 2.82 (β, 3H) , 1.88-1.72 (m, IH) , 0.72 (d, J = 6.5 Hz, 6H) ; MS (thermoβpray): m/z 388 (M+l) ; HRMS calculated for C 1 H 2 gN 3 0gS (M+H): 388.1542 Found: 388.1592. EXAMPLE 13 2- (R) -2-N-Hvdroxy-2- ( (4- methoxybenzeneβulfonyl) ( [(pyridin-3- ylmethyl)carbamoyl)methyl)amino) -3-methylbutyramide 2- (R) -N-Hydroxy-2- ( (4- methoxybenzenesulfonyl) ( [ (pyridin-3- ylmethyl) carbamoyl]methyl)amino) -3-methylbutyramide was prepared by a procedure βimilar to that of Example 12 βtarting with 2- (R) -2- [carboxymethyl (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl eβter (Example 1) and coupling this to 3- pyridylmethylamine via the acid chloride. 1 H NMR (CD 3 OD) : δ 8.55-8.53 (m, IH) , 8.43-8.40 (m, IH) , 7.90- 7.82 (m, IH, overlapped), 7.86 (d, J = 8.9 Hz, 2H) , 7.40 (dd, J - 4.8, 7.8 Hz, IH) , 7.04 (d, J >= 8.9 Hz, 2H) , 4.50 (d, J = 17.5 Hz, IH) , 4.39 (d, J = 17.5 Hz, IH) , 4.32 (d, J = 17.7 Hz, IH) , 4.02 (d, J = 17.7 Hz, IH) , 3.87 (β, 3H) , 3.60 (d, J = 10.3 Hz, IH) , 2.08-1.93 (m, IH) , 0.85 (d, J = 6.5 Hz, 3H) , 0.70 (d, J = 6.5 Hz, 3H) ; MS (thermoβpray) : m/z 451 (M+H), 336, 320. EXAMPLE 14 N-Hvdroxy- [ (4-methoxybenzeneβulfonyl) (2- morpholin-4-yl-2-oxoethyl)amino] acetamide To a βolution of iminoacetic acid diβodium βalt monohydrate (5.0 gramβ, 25.6 mmol) in dioxane (50 ml) and water (50 ml) waβ added triethylamine (5.3 ml, 38 mmol) followed by 4-methoxybenzeneβulfonyl chloride (5.8 gramβ, 28.0 mmol). The mixture waβ βtirred overnight at room temperature and diluted with methylene chloride. The βolution was waβhed with 1 N hydrochloric acid βolution, water and brine, dried over magneβium βulfate and concentrated under vacuum leaving [carboxymethyl(4-methoxybenzeneβulfonyl) amino] acetic acid aβ a white solid, 3.83 grams (49%) . [Carboxymethyl(4- methoxybenzeneβulfonyl)amino] acetic acid (0.5 gramβ, 1.65 mmol) in acetic anhydride (15 mL) waβ diββolved in acetic anhydride by gentle warming. The reβulting βolution waβ βtirred at room temperature overnight. The acetic anhydride waβ removed by evaporation under vacuum; the reβidue waβ diββolved in methylene chloride and morpholine (0.16 mL, 1.82 mmol) waβ added. The mixture waβ βtirred overnight at room temperature and then concentrated under vacuum. The reβidue waβ diββolved in ethyl acetate, waβhed with 1 N hydrochloric acid βolution, water and brine, dried over magneβium sulfate and concentrated to afford [(4- methoxybenzenesulfonyl) (2-morpholin-4-yl-2- oxoethyl)amino] acetic acid as an oil, 0.33 grams (54%) . To a βolution of [(4- methoxybenzenesulfonyl) (2-morpholin-4-yl-2-oxoethyl) - amino] acetic acid (0.33 gramβ, 0.89 mmol) in methylene chloride (10 mL) were added βequentially triethylamine (0.43 mL, 3.1 mmol), O-benzylhydroxylamine hydrochloride (0.15 gramβ, 0.94 mmol) and (benzotriazol-1-yloxy) trie (dimethylajaino)phoβphonium hexafluorophoβphate (0.43 gramβ, 0.97 mmol) . The mixture waβ βtirred at room temperature overnight and then diluted with ethyl acetate. The βolution waβ waβhed βequentially with 0.5 N hydrochloric acid βolution, water and brine, dried over magneβium βulfate and concentrated under vacuum. The reβidue waβ chromatographed on βilica gel uβing ethyl acetate to afford N-benzyloxy- [ (4-methoxybenzeneβulfonyl) (2- morpholin-4-yl-2-oxoethyl)amino] acetamide aβ a white solid, 0.33 grams (78%) . To a βolution of N-benzyloxy- [ (4- methoxybenzenesulfonyl) (2-morpholin-4-yl-2- oxoethyl)amino] acetamide (0.33 gramβ, 0.69 mmol) in methanol (35 mL) waβ added 5% palladium on activated carbon (85 mg) . The mixture waβ agitated under 2 atmospheres hydrogen in a Parr shaker for 1.5 hourβ. The catalyst was removed by filtration through nylon (pore βize 0.45 μm) and the solvent waβ evaporated. The residue waβ chromatographed on βilica gel eluting with 5% methanol in methylene chloride to afford N- methoxy- [ (4-methoxybenzeneβulfonyl) (2-morpholin-4-yl-2- oxoethyl)amino]acetamide as a white βolid, 65 mg (24%); 1 H NMR (CD 3 OD) : δ 7.82 (d, J = 9.0 Hz, 2H) , 7.08 (d, J = 9.0 Hz, 2H) , 4.24 (β, 2H) , 3.88 (s, 3H) , 3.84 (ε, 2H) , 3.68-3.64 (m, 4H) , 3.58-3.50 (m, 4H) ; MS (thermoepray) : m/z 388 (M+l) , 387 (M) ; HRMS calculated for C 16 H 22 N 3 0 7 S (M+H) : 388.1178, Found 338.1180. The title compounds of Examples 15-16 were prepared by a method analogouβ to that deβcribed in Example 14 uβing [carboxymethyl (4- methoxybenzeneβulfonyl)amino] acetic acid aβ the starting material which, after treatment with acetic anhydride, is coupled with the amine indicated. EXAMPLE 15 N-Hvdroxy- [ (4-methoxybenzenesulfonyl) (2-oxo- 2-pyrrolidin-l-ylethyl)amino] acet--*-wid*» Coupled with pyrrolidine: H NMR (DMSO-dg) : δ 11.26 (br β, IH) , 8.89 (β, IH) , 7.81 (d, J = 8.9 Hz, 2H) , 7.10 (d, J = 8.9 Hz, 2H) , 4.09 (s, 2H) , 3.85 (β, 3H) , 3.74 (s, 2H) , 3.45-3.25 ( , 4H) , 1.93-1.72 (m, 4H) ; MS (thermoβpray) : m/z 372 (M+l) : Analysis calculated for C 15 H 21 N 3 0gS: C, 48.51; H, 5.70; N, 11.31. Found: C, 48.51; H, 5.82; N, 11.24. EXAMPLE 16 2- TDimethyT p a hampyinethyl (4- methoxybenzeneβulfory " * )*■ • " • 'no] -N-hvdroxyacetamide Coupled with dimethy1amine: mp: 170°C. (dec); 1 H NMR (DMSO-dg): δ 10.69 (br s, IH) , 8.88 (β, IH) , 7.91 (d, J * 8.9 Hz, 2H) , 7.06 (d, J = 8.9 Hz, 2H) , 4.19 (β, 2H) , 3.85 (β, 3H) , 3.73 (B, 2H) , 2.94 (β, 3H) , 2.84 (β, 3H) ; MS (thermoβpray) : m/z 346 (M+l); Analyβiβ calculated for C 13 H 19 N 3 0 S: C, 45.21; H, 5.55 N, 12.17. Found: C, 44.93, H, 5.61; N, 12.03. EXAMPLE 17 2- (R) -2- r (2-Carbamoylethyl) (4- methoxybenzeneβulfory * * )»"rno] -N-hvdroxy-3- methylbutyramide To a βolution of 2- (R) -2- [ (2-carboxyethyl (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid benzyl eβter (example 2) (900 mg., 2.0 mmol) in methylene chloride (10 mL) waβ added thionyl chloride (0.16 mL, 2.2 mmol) . The reaction mixture waβ βtirred for 1.5 hourβ at room temperature and then concentrated in vacuo. After diββolving the reβidue in methylene chloride (10 mL) , ammonia gaβ waβ bubbled through the βolution for 0.5 minuteβ. The βolution waβ βtirred at room temperature overnight and waβ concentrated under vacuum. Flaβh chromatography of the reβidue on βilica gel eluting with 2% methanol in chloroform provided 2- (R) -2- [ (2-carbamoylethyl) (4- methoxybenzeneβulfonyl)amino] -N-hydroxy-3-methylbutyric acid benzyl eβter aβ a clear oil (275 mg, 31%) . To a βolution of 2-(R)-2-[(2- carbamoylethyl) (4-methoxybenzeneβulfonyl)amino] -N- hydroxy-3-methylbutyric acid benzyl eβter (275 mg, 0.61 mmol) in ethanol (15 mL) waβ added 10% palladium on activated carbon (30 mg) . The mixture waβ agitated under 3 atmospheres hydrogen in a Parr shaker for 5 hours. The catalyst waβ removed by filtration through diatomaceous earth and the βolvent waβ evaporated leaving 2- (R) -2- [ (2-carbamoylethyl) (4- methoxybenzenesulfonyl)amino] -N-hydroxy-3-methylbutyric acid as a white foam, 211 mg (96%) . To a βolution of 2-(R)-2-[(2- carbamoylethyl) (4-methoxybenzeneβulfonyl)amino] -N- hydroxy-3-methylbutyric acid (205 mg, 0.57 mmol) and 1- hydroxybenztriazole hydrate (85 mg, 0.55 mmol) in dry dimethylformamide (5 mL) waβ added 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (120 mg, 0.63 mmol) . After βtirring for 30 minuteβ, hydroxylamine hydrochloride (158 mg, 2.3 mmol) and then N-methylmorpholint (0.37 mL, 3.4 mmol) were added. The mixture waβ βtirred at room temperature overnight and then diluted with ethyl acetate. The βolution waβ waβhed with water and brine. The βolution was then dried over magneβium βulfate and concentrated under vacuum to leave an oil which waβ chromatographed on βilica gel eluting with 2% methanol in chloroform to afford 2- (R) -2- [ (2-carbamoylethyl) (4- methoxybenzeneβulfonyl)amino] -N-hydroxy-3- methylbutyramide aβ a white βolid, 45 mg (21%) ; 1 H NMR (DMSO-dg) : δ 10.74 (br β, IH) , 8.91 (br β, IH) , 7.74 (d, J = 8.8 Hz, 2H) , 7.33 (br β, IH) , 7.07 (d, J = 8.8 Hz, 2H) , 6.79 (br β, IH) , 3.93-3.82 (m, IH, overlapped), 3.83 (β, 3H) , 3.64 (d, J « 10.7 Hz, IH) , 3.25-3.12 (m, IH) , 2.62-2.48 (m, IH) , 2.42-2.30 (m, IH) , 2.06-1.94 (m, IH) , 0.79 (d, J ■ 6.6 Hz, 3H) , 0.76 (d, J - 6 . 6 Hz , 3H) ; MS ( thermoβpray) : m/z 374 (M+H) . EXAMPLE 18 2- (R) -2- f (2-tert-Butoxycarbonylethyl) (4- methoxybenzeneβulforyT ) -»-m-i r>] -w-hvdroxy-3- methylbutyramide A solution of N,N-dimethylformamide di-tert- butyl acetal (1.9 mL, 7.9 mmol) in toluene (15 mL) was added dropwise to a solution of 2-(R)-2-[(2- carboxyethyl(4-methoxybenzenesulfonyl)amino] -3- methylbutyric acid benzyl eβter (example 2) 900 mg, 2.0 mmol) in toluene at 80°C. After heating for 2 hourβ at 80°C, the mixture waβ cooled and concentrated to leave an amber oil which waβ chromatographed on βilica gel eluting with chloroform to afford (2- (R) -2- [ (2-tert- butoxycarbonylethyl) (4-methoxybenzenesulfonyl)amino] -3- methylbutyric acid benzyl ester aβ an oil, 3.75 mg (37%) . To a βolution of 2- (R) -2- [ (2-tert- butoxycarbonylethyl) (4-methoxybenzeneβulfonyl)amino] -3- methylbutyric acid benzyl eβter (370 mg, 0.73 mmol) in ethanol (20 mL) waβ added 10% palladium on activated carbon (40 mg) . The mixture waβ agitated under 3 atmospheres hydrogen in a Parr shaker for 5 hours. The catalyst was removed by filtration through diatomaceouε earth and the solvent was evaporated leaving 2-(R)-2- [ (2-tert-butoxycarbonylethyl) (4- methoxybenzeneβulfonyl)amino] -3-methylbutyric acid aβ a white foam, 30 mg (100%) . To a βolution of 2- (R) -2- [ (2-tert- butoxycarbonylethyl) (4-methoxybenzenesulfonyl)amino] -3- methylbutyric acid (303 mg, 0.73 mmol) and 1- hydroxybenztriazole hydrate (108 xng, 0.70 mmol) in dry dimethylformamide (10 mL) waβ added 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (153 mg, 0.80 mmol) . After stirring for 45 minutes, hydroxylamine hydrochloride (203 mg, 2.9 mmol) and then N-methylmorpholine (0.48 mL, 4.4 mmol) were added. The mixture was stirred at room temperature overnight and then concentrated under vacuum. The residue was chromatographed on silica gel eluting with 2% methanol in chloroform and again with 10% ethyl acetate in hexane to afford 2- (R) -2- [ (2-tert- butoxycarbonylethyl) (4-methoxybenzeneβulfonyl)amino] -N- hydroxy-3-methylbutyramide aβ a white foam, 135 mg (43%); X H NMR (DMSO-dg) : δ 10.77 (br β IH) , 7.74 (d, J = 8.9 Hz, 2H) , 7.08 (d, J = 8.9 Hz, 2H) , 3.93-3.82 (m, IH, overlapped), 3.83 (β, 3H) , 3.64 (d, J = 10.8 Hz, IH) , 3.26-3.14 (m, IH) , 2.70-2.60 (m, IH) , 2.50- 2.38 (m, IH) , 2.04-1.91 (m, IH) , 1.38 (β, 9H) , 0.78 (d, J = 6.5 Hz, 3H) , 0.72 (d, J - 6.5 Hz, 3H) ; MS (thermoβpray) : m/z 431 (M+H), 375, 314. EXAMPLE 19 2- (R) -2- r2-Carboxyethyl) (4- methoxybenzenesulfonyl) amino] -N-hvdroxy-3- methylbutyramide To a βolution of 2- (R) -2- [2-tert- butoxycarbonylethyl) (4-methoxybenzenesulfonyl)amino] -N- hydroxy-3-methylbutyramide (example 18) (100 mg, 0.23 mmol) in methylene chloride (1 mL) at 0°C. waβ added trifluoroacetic acid (1 mL) . The mixture waβ allowed to warm to room temperature while βtirring overnight. After evaporation of the trifluoroacetic acid and methylene chloride, the reβidue waβ chromatographed on silica gel eluting with 5% methanol in chloroform. Concentration of the appropriate fractions afforded 2- (R) -2- [2-carboxyethyl(4-methoxybenzenesulfonyl)amino] - N-hydroxy-3-methylbutyramide aβ a white βolid, 35 mg (41%) . E NMR (DMSO-dg) : δ 10.79 (br S,1H), 8.97 (br β, IH) , 7.76 (d, J = 8.9 Hz, 2H) , 7.09 (d, J = 8.9 Hz, 2H) , 3.95-3.82 (m, IH, overlapped), 3.84 (β, 3H) , 3.66 (d, J = 10.8 Hz, IH) , 3.30-3.20 (m, IH) , 2.73-2.62 (m, IH) , 2.50-2.40 (m, IH) , 2.07-1.94 (m, IH) , 0.80 (d, J - 6.5 Hz, 3H) , 0.74 (d, J = 6.5 Hz, 3H) ; MS (thermoβpray) : m/z 375 (M+H), 314.

Claims: C L A I M S A compound of the formula or the pharmaceutically acceptable βaltβ thereof, wherein n is 1 to 6; X is hydroxy, (C 1 -Cg)alkoxy or NR X R 2 wherein R 1 and R2* are each independently βelected from the group conβiβting of hydrogen, (C-^-Cg)alkyl, piperidyl, (C^Cg)alkylpiperidyl, (Cg-C 10 )arylpiperidyl, (Cg- C 9 )heteroarylpiperidyl, (Cg-C 10 )aryl (C^ Cg)alkylpiperidyl, (Cg-C 9 )heteroaryl (C j - Cg)alkylpiperidyl, (C- j ^CgJacylpiperidyl, (Cg-C 1£) )aryl, (Cg-C 9 )heteroaryl, (Cg-C 1Q )aryl (C j -Cg)alkyl, (Cg- C 9 )heteroaryl(C 1 -Cg)alkyl, (Cg-C 1£) )aryl (C 8 -C 10 )aryl, (C 6 -C 10 )aryl (Cg-C 1£) )aryl (Ci-Cg)alkyl, (C 3 - Cg)cycloalkyl, (C 3 -Cg)cycloalkyl (C^Cg)alkyl, R 5 (C 5 - C 6 )alkyl, (C 1 -Cg)alkyl (CHR 5 ) (C^Cg)alkyl wherein R 5 is hydroxy, (C-^-Cg)acyloxy, (C^-Cg)alkoxy, piperazino, (C j -Cg)acylamino, (C-^-Cg)alkylthio, (Cg-C 10 )arylthio, (C^ ^ -Cg)alkylsulfinyl, (Cg-C 1Q )arylsulfinyl, (C^ Cg)alkylsulfoxyl, (Cg-C 10 )arylsulfoxyl, amino, (C-^- Cg)alkylamino, ( (C^-Cg)alkyl) 2 amino, (C ] _- Cg)acylpiperazino, (C^-Cg)alkylpiperazino, (Cg- C 10 )aryl(C-^-Cg)alkylpiperazino, (Cg-C 9 )heteroaryl (C j - Cg)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R 6 (C^-Cg)alkyl, (C^- Cg)alkyl(CHR 6 ) (C- j^ -Cg)alkyl wherein R iβ piperidyl, (C- j^ -Cg)alkylpiperidyl, (Cg-C 10 )arylpiperidyl, (Cg- C 1Q )aryl(C-^-Cg)alkylpiperidyl, (Cg- C 9 )heteroarylpiperidyl or (Cg-C 9 )heteroaryl(C*,- Cg)alkylpiperidyl; and CH(R 7 )COR 8 wherein R 7 iβ hydrogen, (C^Cg)alkyl, (Cg-C 10 )aryl(C^Cg)alkyl, (Cg- C 9 )heteroaryl(C-^-Cg)alkyl, (C-^-Cg)alkylthio(C-^- Cg)alkyl, (Cg-C 10 )arylthio(C^Cg)alkyl, (C 1 - Cg) alkylsulfinyl (C-^-Cg)alkyl, (C 8 -C 10 )arylsulfinyl (C*. • Cg)alkyl, (C 1 -Cg)alkylβulfonyl(C 1 -Cg)alkyl, (Cg- C 10 )arylβulfonyl(C 1 -Cg)alkyl, hydroxy(C-^-Cg)alkyl, amino(C*-_-Cg)alkyl, i c ι~ c s ^ aJkylamino(C-^-Cg)alkyl, ((C, C 6 )alkylamino) 2 (C 1 -Cg)alkyl, R 9 R 10 NCO(C 1 -Cg)alkyl or R OCO(C 1 -Cg)alkyl wherein R 9 and R 1 are each independently selected from the group consisting of hydrogen, (C-^-Cg)alkyl, (Cg-C 10 )aryl(C 1 -C 8 )alkyl and (Cg-C 9 )heteroaryl (C-^-Cg)alkyl; and R B° iβ R1 x 1 x O or R 1:L R 12 N wherein R and R 1 are each independently selected from the group consisting of hydrogen, (C 1 - C 6 )alkyl, (Cg-C 1Q )aryl(C 1 -Cg)alkyl and (Cg- C 9 )heteroaryl(C^Cg)alkyl; or R 1 and R 2 , or R 9 and R 10 , or R 11 and R 12 may be taken together to form an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (C 1 ~C )acylpiperazinyl, (C 1 - Cg)alkylpiperazinyl, (Cg-C 10 )arylpiperazinyl, (Cg- C 9 )heteroarylpiperazinyl or a bridged diazabicycloalkyl ring βelected from t ting of d e wherein r is 1, 2 or 3; m is 1 or 2; p is 0 or 1; and Q is hydrogen, (C-^-C- j )alkyl or (C-^-CgJacyl; R3-" and R4 are each independently selected from the group consiβting of hydrogen, (C j -Cg)alkyl, trifluoromethyl, trifluoromethyl (C-^-Cg)alkyl, (C-^- Cg)alkyl (difluoromethylene) , (C-^- C 3 )alkyl (difluoromethylene) (C-^-C j )alkyl, (Cg-C 1Q )aryl, (Cg-C 9 )heteroaryl, (Cg-C 10 )aryl (C^Cg)alkyl, (Cg- C 9 )heteroaryl(C^Cg)alkyl, (Cg-C 10 )aryl (Cg-C 1Q )aryl, (C 6 -C 10 )aryl (Cg-C 10 )aryl (C^ ^ -Cg)alkyl, <C 3 - Cg)cycloalkyl, (C 3 -Cg)cycloalkyl (C 1 -Cg)alkyl, hydroxy(C 1 -Cg)alkyl, (C 1 -C 8 )acyloxy(C 1 -C 8 )alkyl, (C 1 - Cg)alkoxy(C-^-Cg)alkyl, piperazinyl (C-^-Cg)alkyl, (C-^- Cg)acylamino(C- j^ -Cg)alkyl, piperidyl, (C-^- Cg)alkylpiperidyl, (Cg-C 10 )aryl (C^-Cg)alkoxy(C-^- Cg)alkyl, (Cg-C 9 )heteroaryl (^-Cg)alkoxy(C- j^ -Cg)alkyl, (C- j^ -Cg)alkylthiotC-L-Cg)alkyl, (Cg-C 10 )arylthio(C χ - Cg)alkyl, (C^Cg)alkylβulfinyl (C^Cg)alkyl, (Cg- C 10 )arylβulfinyl(C^Cg)alkyl, (C^-Cg)alkylβulfonyl (C 1 - Cg)alkyl, (Cg-C 1Q )arylβulfonyl (C-^-Cg)alkyl, amino(C-^- Cg)alkyl, (C 1 -Cg)alkylamino(C^ ^ -Cg)alkyl, ( (C 1 - Cg)alkylamino) 2 (C-^-Cg)alkyl, R 13 J CO(C-^-Cg)alkyl wherein R 13 iβ R 20 O or R 20 R 21 N wherein R 20 and R 21 are each independently βelected from the group consisting of hydrogen, (C-^-Cg)alkyl, (Cg-C 1Q )aryl(C-^-Cg)alkyl or (Cg-C 9 )heteroaryKC-L-Cg)alkyl; or R 14 (C^Cg)alkyl wherein R 14 iβ (C-i -C fi )acylpiperazino, (Cg- C 10 )arylpiperazino, (Cg-C 9 )heteroarylpiperazino, (C^ Cg)alkylpiperazino, (Cg-C 10 )aryl (^-Cg)alkylpiperazino, (Cg-C 9 )heteroaryl(C-^-Cg)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -Cg)alkylpiperidyl, (Cg-C 10 )arylpiperidyl, (Cg- C 9 )heteroarylpiperidyl, (Cg-C 1Q )aryl(C*^- Cg)alkylpiperidyl, (Cg-C 9 )heteroaryl (C-^- Cg) alkylpiperidyl or (C-^-Cg)acylpiperidyl; or R 3 and R 4 , or R 20 and R 21 may be taken together to form a (C 3 -Cg) cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula wherein R 15 iβ hydrogen, (C-^-CgJacyl, (C -C )alkyl, (Cg-C 10 )aryl(C^ ^ -Cg)alkyl, (Cg-Cg)heteroaryl (C^Cg) alkyl or (C- j^ -Cg) alkylβulfonyl; and Ar iβ (Cg-C 10 )aryl, (Cg-Cg)heteroaryl, (C^- Cg) alkyl (Cg-C 10 )aryl, (C- j^ -Cg) alkoxy(Cg-C 10 )aryl, ( (C χ - Cg)alkoxy) 2 (Cg-C 10 )aryl, (Cg-C 10 )aryloxy(Cg-C 10 ) aryl, (Cg-C 9 )heteroaryloxy(Cg-C 10 )aryl, (C 1 -Cg)alkyl (Cg- C 9 )heteroaryl, (C-^-Cg)alkoxy(Cg-Cg)heteroaryl, ( (C 1 - Cg)alkoxy) 2 (Cg-Cg)heteroaryl, (Cg-C 10 )aryloxy(Cg- Cg)heteroaryl, (Cg-Cg)heteroaryloxy(Cg-Cg)heteroaryl; with the proviβo that when either R 1 or R2 iβ CH(R 7 )COR 8 wherein R and R are aβ defined above, the other of R 1 or R 2 iβ hydrogen, (C-^-Cg)alkyl or benzyl. 2. A compound according to claim 1, wherein n 3. Α compound according to claim 1, wherein Ar iβ 4-methoxyphenyl or 4-phenoxyphenyl. 4. A compound according to claim 1, 2 or 3, •a wherein either R or R ie not hydrogen. 5. A compound according to claim 1, wherein n iε 1 and either 1 or R2 is hydrogen. 6. A contpound according to claim 4, wherein X is hydroxy, Ar iβ 4-methoxyphenyl or 4-phenoxyphenyl. 7. A compound according to claim 4, wherein X iβ alkoxy, Ar iβ 4-methoxyphenyl or 4-phenoxyphenyl. 8. A compound according to claim 1, wherein Ar iβ 4-methoxyphenyl or 4-phenoxyphenyl and R 3 and R 4 are taken together to form (C 3 -C 8 )cycloalkanyl, oxacyclohexanyl, thiocyclohexanyl, indanyl or a group of the formula wherein R 15 iβ (C^-Cgjacyl, (C-^-Cg)alkyl, (Cg- C^ ^0 )aryl (C 1 -Cg)alkyl, (Cg-Cg)heteroaryl (C- j^ -Cg)alkyl or (C^-Cg)alkylβulfonyl. 9. A compound according to claim 1, wherein n iε 2, Ar iβ 4-methoxyphenyl or 4-phenoxyphenyl, and R are taken together to form piperazinyl, (C * - Cg)alkylpiperazinyl, (Cg-C^ø)aryl piperazinyl or (Cg- •a Cg)heteroaryl (C^-Cg)alkylpiperazinyl, and either or R 4' iβ not hydrogen or both R3 and R4 are not hydrogen. 10. A compound according to claim 1, wherein n iε 2, Ar iβ 4-methoxyphenyl or 4-phenoxyphenyl, R iβ hydrogen or (C-^-Cg)alkyl, R 2 iβ 2-pyridylmethyl, 3- pyridylmethyl or 4-pyridylmethyl, and either R 3 or R 4 iβ not hydrogen or both R 3 and are not hydrogen. 11. A compound according to claim 1, wherein n iβ 1, Ar iβ 4-methoxyphenyl or 4-phenoxyphenyl, R 1 iβ hydrogen, R 2 iβ 2-pyridylmethyl, 3-pyridylmethyl or 4- pyridylmethyl, and either R 3 or R4 iβ not hydrogen or both R 3 and R 4 are not hydrogen. 12. A compound according to claim 2, wherein Ar iβ 4-methoxyphenyl, R 1 is hydrogen or (C-^-Cg)alkyl and R 2 is R 5 (C 2 -Cg)alkyl wherein R is morpholino, thiomorpholino, piperidino, pyrrolidino, (C*ι- Cg)acylpiperazino, (C-^-Cg)alkylpiperazino, (Cg- C 10 )arylpiperazino, (Cg-Cg)heteroarylpiperazino, (Cg- C 1Q )aryl(C^Cg)alkylpiperazino or (Cg-Cg)heteroaryl(C 1 - Cg)alkylpiperazino and either R 3 or iβ not hydrogen or both R3 and R4 are not hydrogen. 13. A compound according to claim 1, wherein n is 1, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R 1 iβ hydrogen, R *1 is R J (C 2 -Cg)alkyl wherein R a iβ morpholino, thiomorpholino, piperidino, pyrrolidino, (C 1 -Cg)acylpiperazino, (C^Cg)alkylpiperazino, (Cg- C 1Q ) arylpiperazino, (Cg-Cg)heteroarylpiperazino, (Cg- C 10 )aryl(C- j^ -Cg)alkylpiperazino or (Cg-Cg)heteroaryl(C^- Cg)alkylpiperazino and either R or R is not hydrogen or both R3 and R4 are not hydrogen. 14. A compound according to claim 1, wherein said compound iβ selected from: 2- (R) -N-Hydroxy-2- [ (4- methoxybenzenesulfonyl) (3-morpholin-4-yl-3- oxopropyl)amino] -3-methylbutyramide; 2- (R) -2- [ (2-Benzylcarbamoylethyl) (4- methoxybenzeneβulfonyl)amino] -N-hydroxy-3- ethylbutyramide; 2- (R) -N-Hydroxy-2- ( (4- methoxybenzeneβulfonyl) (2- [ (pyridin-3- ylmethyl)carbamoyl) ethyl)amino) -3-methylbutyramide; 2- (R) -N-Hydroxy-2- ( [4- methoxybenzeneβulfonyl] [2- (methylpyridin-3- ylmethylcarbamoyl)ethyl] amino) -3-methylbutyramide; 4- (3- [1- (R) -l-Hydroxycarbamoyl-2- methylpropyl) (4- methoxybenzenesulfonyl)amino]propionyl)piperazine-1- carboxylic acid, tert-butyl ester; 2- (R) -N-Hydroxy-2- [ (4- methoxybenzenesulfonyl) (3-oxo-3-piperazin-l- ylpropyl)amino) -3-methylbutyramide hydrochloride; 2- (R) -2- [ (Benzylcarbamoylmethyl) (4- methoxybenzeneβulfonyl)amino]N-hydroxy-3- methylbutyramide; 2-(R)-N-Hydroxy-2- [(4- methoxybenzeneβulfonyl] - [ (2-morpholin-4- ylethylcarbamoyl)methyl]amino) -3-methylbutyramide; 2- (R) -N-Hydroxy-2- ( (4- methoxybenzeneβulfonyl) ( [(pyridin-3- ylmethyl) carbamoyl]methyl)amino) -3-methylbutyramide; 2- (R) -3,3,3-Trifluoro-N-hydroxy-2- [(methoxybenzeneβulfonyl) (3-morpholin-4-yl-3- oxopropyl)amino]propionamide; 2- (R) -N-Hydroxy-2- ( (4- phenoxybenzeneβulfonyl) [2- (methylpyridin-4- ylmethy1carbamoyl) ether] amino) -3-methylbutyramide; 4- [4-Methoxybenzeneβulfonyl) (3-morpholin-4- yl-3-oxopropyl)amino] -1-methylpiperidene-4-carboxylic acid hydroxyamide; 2- (R) -N-Hydroxy-2- ( (4- ethoxybenzeneβulfonyl) - [3- (4-methylpiperazin-l-yl) -3- oxopropyl]amino) -3-methylbutyramide; 2- (R) -2- [ (2-Carboxyethyl) (4- methoxybenzeneβulfonyl)amino] -N-hydroxy-3- methylbutyramide; [(2-Carboxyethyl) (3,4- dimethoxybenzeneβulfonyl)amino] -N-hydroxy-acetamide; 2- (R) -2- [ (2-Carbamoylethyl) (4- methoxybenzeneβulfonyl)amino] -N-hydroxy-3- methylbutyramide; 2- (R) ,3- (R)-3,N-Dihydroxy-2- [(4- methoxybenzeneβulfonyl) (3-oxo-3-piperidin-l- ylpropyl)amino] -butyramide; 2- (R) -N-Hydroxy-2- ( (4- methoxybenzenesulfonyl) [3- (methylpyridin-3- ylmethylcarbamoyDpropyl]amino) -3-methylbutyramide; 2- (R) -N-Hydroxy-2- ( (4- methoxybenzenesulfonyl) [2- (methylcarboxymethylcarbamoyl)ethyl] amino) -3- methylbutyramide; 2- (R) -N-Hydroxy-2- ( (4- methoxybenzenesulfonyl) - [ (l-methylpiperidin-4- ylcarbamoyl)methyl] amino) -3-methylbutyramide; 2- (R) -2-Clyclohexyl-N-hydroxy-2- ( (4- methoxybenzeneβulfonyl) - [3- (4-methylpiperazin-l-yl) -3- oxopropyl] amino) -acetamide; and 2- (R) -N-Hydroxy-2- [ (methoxybenzeneβulfonyl) (3-morpholin-4-yl-3- oxopropyl)amino] -4- (morpholin-4-yl)butyramide. 15. A pharmaceutical composition for (a) the treatment of a condition βelected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritiβ and other diβeaβeβ characterized by matrix metalloproteinaβe activity, AIDS, βepβiβ, βeptic βhock and other diseaβes involving the production of tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinaβeβ or the production of tumor necroβiβ factor (TNF) in a mammal, including a human, comprising an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in βuch treatments and a pharmaceutically acceptable carrier. 16. A method for the inhibition of (a) matrix metalloproteinaβeβ or (b) the production of tumor necroβiβ factor (TNF) in a mammal, including a human, comprising administering to said mamm l an effective amount of a compound of claim 1 or a pharmaceutically acceptable βalt thereof. 17. A method for treating a condition βelected from the group conβiβting of arthritiβ, cancer, tiββue ulceration, restenosis, periodontal diseaβe, epidermolyβiβ bulloβa, βcleritiβ and other diβeaβeε characterized by matrix metalloproteinaβe activity, AIDS, βepβiβ, βeptic βhock and other diεeaβes involving the production of tumor necroβiβ factor (TNF) in a mammal, including a human, compriβing adminiβtering to said mamm l an amount of a compound of claim 1 or a pharmaceutically acceptable βalt thereof, effective in treating βuch a condition. 18. A method of preparing a compound of the formula or the pharmaceutically acceptable βaltβ thereof, wherein X iβ hydroxy, (C^-Cg)alkoxy or NR A R 2 wherein R 1 and R2 are each independently βelected from the group conβiβting of hydrogen, (C^-Cg)alkyl, piperidyl, (C 1 -Cg)alkylpiperidyl, (Cg-C 10 )arylpiperidyl, (Cg- Cg)heteroarylpiperidyl, (Cg-C 10 )aryl (C-^- Cg) alkylpiperidyl, (Cg-Cg)heteroaryl (C^- Cg)alkylpiperidyl, (C 1 -Cg)acylpiperidyl, (C 8 -C 10 )aryl, (Cg-Cg)heteroaryl, (Cg-C 10 )aryl (C 1 -Cg)alkyl, (Cg- Cg)heteroaryl (C-^-Cg)alkyl, (Cg-C 10 )aryl (Cg-C 1Q )aryl, (C 6 -C 10 )aryl (C 8 -C 10 )aryl (C^Cg)alkyl, (C 3 - Cg)cycloalkyl, (C 3 -Cg)cycloalkyl (C-^Cg)alkyl, R 5 (C 2 - C 6 )alkyl, (C^Cg)alkyl (CHR 5 ) (C^Cg)alkyl wherein R 5 iβ hydroxy, (C^Cg)acyloxy, (C 1 -Cg)alkoxy, piperazino, (C 1 -Cg)acylamino, (C-^-Cg)alkylthio, (Cg-C 1Q )arylthio, (C 1 -Cg)alkylβulfinyl, (Cg-C 10 )arylβulfinyl, (C χ - Cg)alkylβulfoxyl, (Cg-C 10 )arylβulfoxyl, amino, (C 1 - Cg)alkylamino, ( (C^Cg)alkyl) amino, (C-^- Cg)acylpiperazino, (C- j^ -Cg)alkylpiperazino, (Cg- C 10 )aryl (C -Cg)alkylpiperazino, (Cg-Cg)heteroaryl (C-^- Cg)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R 6 (C-^-Cg)alkyl, (c*,- Cg) alkyl (CHR 6 ) (C j^ -Cg)alkyl wherein R 6 iβ piperidyl, (C-L-Cg)alkylpiperidyl, (Cg-C 10 )arylpiperidyl, (C 8 - C 10 )aryl(C 1 -Cg)alkylpiperidyl, (Cg- Cg)heteroarylpiperidyl or (Cg-Cg)heteroaryl (C-^- C 6 ) alkylpiperidyl; and CH(R 7 )COR 8 wherein R 7 iε hydrogen, (C-^Cg)alkyl, (Cg-C 1Q )aryl (^-Cg) alkyl, (Cg- Cg)heteroaryl (C 1 -Cg)alkyl, (C 1 -Cg)alkylthio(C 1 - Cg)alkyl, (Cg-C 10 )arylthio(C^Cg)alkyl, (C 1 - alkyl, (C 8 -C 10 )arylβulfinyl (C 1 - C 6 ) alkyl, (C^Cg)alkylβulfonyl (^-Cg)alkyl, (C 8 - C 10 ) arylβulfonyl (C^Cg)alkyl, hydroxy(C 1 -Cg) alkyl, amino(C- j^ -Cg)alkyl, (C 1 -C 8 )alkylamino(C 1 -C 8 ) alkyl, ( (C 1 - Cg)alkylamino) 2 (C^Cg)alkyl, R 9 R 10 NCO(C^Cg) alkyl or R 9 OCO(C 1 -Cg)alkyl wherein R 9 and R 10 are each independently βelected from the group consisting of hydrogen, (C-^-Cg)alkyl, (Cg-C 10 )aryl (C 1 -C 8 )alkyl and (Cg-Cg)heteroaryl (C j^ -Cg)alkyl; and R iε R l O or R 1 X 1 X R12 Λ N wherein R11 and R1 x 2* are each independently βelected from the group conβiβting of hydrogen, (C-,- C 6 )alkyl, (Cg-C 10 )aryl (C 1 -Cg) alkyl and (Cg- Cg)heteroaryl (C 1 -Cg)alkyl; or R 1 and R 2 , or R 9 and R 10 , or R 11 and R 12 may be taken together to form an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, iβoindolinyl, tetrahydroquinolinyl, tetrahydroiβoquinolinyl, (C^-Cg)acylpiperazinyl, (C 1 - Cg)alkylpiperazinyl, (Cg-C 1Q )arylpiperazinyl, (Cg- C g )heteroarylpiperazinyl or a bridged diazabicycloalkyl ring βelected from the group conεisting of d e wherein r iβ 1, 2 or 3; m iε 1 or 2; p iε 0 or 1; and Q iε hydrogen, (C-^-C*-.)alkyl or (C-^-CgJacvl; R 3 and R4 are each independently βelected from the group conβiβting of hydrogen, (C-^-Cg) alkyl, trifluoromethyl, trifluoromethyl (C-^-Cg)alkyl, (C^- Cg)alkyl (difluoromethylene) , iC±- C 3 )alkyl (difluoromethylene) (C*-_-C 3 )alkyl, (C -C^ )aryl (Cg-Cg)heteroaryl, (Cg-C 1Q )aryl (C 1 -Cg)alkyl, (Cg- Cg)heteroaryl (C 1 -C 8 ) alkyl, (Cg-C 10 )aryl (Cg-C 1Q )aryl, (Cg-C 10 )aryl (Cg-C 10 )aryl (C^Cg)alkyl, (C 3 - Cg) cycloalkyl, (C 3 ~Cg)cycloalkyl(C^Cg) alkyl, hydroxy(C j -Cg)alkyl, (C-^-Cg)acyloxy(C^-Cg)alkyl, « Cg)alkoxy(C 1 -Cg)alkyl, piperazinyl (C^C )alkyl, (<-*χ- Cg)acylamino(C- j^ -Cg)alkyl, piperidyl, (C^- Cg) alkylpiperidyl, (Cg-C 10 )aryl (C^C )alkoxy(C- j — Cg) alkyl, Cg-C 8 )heteroaryl (C-^-Cg)alkoxy(C-^-Cg)alkyl, (C 1 -Cg)alkylthio(C^Cg)alkyl, (Cg-C 1£) )arylthio(C χ - Cg) alkyl, (C-^Cg)alkylβulfinyl(C^Cg)alkyl, (Cg- 1Q )arylεulfinyl (C 1 -C 8 )alkyl, (C^Cg)alkylβulfonyl (C χ - Cg)alkyl, (Cg-C 1Q )arylβulfonyl (C^Cg)alkyl, amino(C 1 - C 6 ) alkyl, (C-^Cg)alkylamino(C^Cg)alkyl, ( (C^ C 6 )alkylamino) 2 (C 1 -C 6 )alkyl, R 13 CO(C 1 -C 8 )alkyl wherein R 13 i,β„ β R2 2 0 0 O or R 20 R 21 N wherein R 20 and R 21 are each independently βelected from the group conβiβting of hydrogen, (C^Cg)alkyl, (C 8 -C 10 )aryl (C^Cg)alkyl or (Cg-Cg)heteroaryl(C 1 -Cg)alkyl; or R 14 (C^Cg)alkyl wherein R 14 iβ (C j -Cg)acylpiperazino, (Cg- C 1Q ) arylpiperazino, (Cg-Cg)heteroarylpiperazino, (C*,- Cg) alkylpiperazino, (C 8 -C 10 )aryl (C-^-Cg)alkylpiperazino, (Cg-Cg)heteroaryl (C^-Cg)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C-^-Cg)alkylpiperidyl, (Cg-C 1Q )arylpiperidyl, (Cg- Cg ) heteroarylpiperidyl, (c 6" c ιo- 1 ar i ^ c ι~ Cg) alkylpiperidyl, (Cg-Cg)heteroaryl (C^- Cg) alkylpiperidyl or (C^-Cg)acylpiperidyl; or R and R , or R and R may be taken together to form a (C 3 -Cg)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula with the proviso that when either R 1 or R 2 is CH(R7' )CORB wherein R7 and RB are aβ defined above, the other of R 1 or R2* iβ hydrogen, (C-^-Cg)alkyl or benzyl; compriβing reacting a compound of the formula wherein n, X, R 3 , R4 and Ar are as defined above with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1- hydroxybenztriazole and hydroxylamine.

Inventors: RIZZI JAMES P, ROBINSON RALPH P, RIZZI, JAMES, P., ROBINSON, RALPH, P.
Applicants: PFIZER, RIZZI JAMES P, ROBINSON RALPH P, PFIZER INC., RIZZI, JAMES, P., ROBINSON, RALPH, P.
Application year: 1996
Main classification: C07C311
IPC codes: A61K31, A61P1, A61P9, A61P17, A61P29, A61P31, A61P35, A61P37, A61P43, C07C311, C07D207, C07D213, C07D241, C07D295