CZ473099A3 - Reversible hydroxamate inhibitors of matrix metalloproteinases - Google Patents

Abstract

The compounds of formula I are inhibitors matrix metalloproteinases. They are further described preparations for inhibiting matrix metalloproteinases and methods for inhibiting matrix metalloproteinases in mammals.

Description

Technical field

The present invention relates to compounds having activity to inhibit matrix metalloproteinases, to pharmaceutical compositions containing these compounds, and to medical treatments. More particularly, the present invention relates to a reverse hydroxamate comprising compounds that inhibit matrix metalloproteinases, pharmaceutical compositions containing these compounds, and a method of inhibiting matrix metalloproteinases.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) are a group of extracellular enzymes including collagenases, stromelysin and gelatinases, which we believe are involved in tissue destruction that accompanies a large number of stages of disease from arthritis to cancer.

Typical connective tissue cells are deposited within the extracellular matrix of high molecular weight proteins and glycoproteins. In healthy tissue, there is a continuous and finely balanced series of processes that include cell division, matrix synthesis, and matrix degradation. In certain pathological conditions, the imbalance of the three carpets may lead to inappropriate tissue restructuring. In arthritis, eg mobility of the ground joint can be lost if there is an improper conversion of the load carrying cartilage. In cancer, a lack of coordination of cell division and two matrix synthesis and degradation processes may result in the conversion of transformed cells into invasive phenotypes in which increased matrix conversion allows tumor cells to penetrate the base of adjacent capillary membranes, resulting in the following metastases:. / ^ / 1 & /

There has been considerable interest in the appearance of therapeutic agents that bind to MMPs and inhibit MMPs. The discovery of new therapeutic agents possessing tutdactivity will lead to new drugs having new mechanisms of action to combat diseases related to degenerative tissue processes including, for example, rheumatoid arthritis, osteoarthritis, osteopenia such as osteoporosis, periodontitis, gingivitis, comeal, epidermal or gastric ulceration and metastasis or invasion.

Summary of the Invention ^and s

In its basic embodiment, the present invention relates to a compound which inhibits ratrix metalloproteinase of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein A is hydrogen; index n is zero;

R 1 and R 3 are independently selected from the group consisting of (1) hydrogen (2) alkyl having from 1 to 6 carbon atoms;

R 2 and R 4 are independently selected from the group consisting of (1) hydrogen;

(2) alkyl having from 1 to 6 carbon atoms;

(3) alkenyl having from 1 to 6 carbon atoms;

(4) alkynyl having from 1 to 6 carbon atoms;

(5) alkoxyalkyl;

(6) alkoxycarbonylalkyl, wherein the alkylene and alkyl groups independently have from 1 to 6 carbon atoms;

(7) haloalkyl having from 1 to 6 carbon atoms;

(8) hydroxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms;

(9) - (alkylene) -S (O) _p -alkyl wherein the alkylene has from 1 to 6 carbon atoms and the alkyl has from 1 to 6 carbon atoms;

(10) phenyl;

(11) phenylalkoxyalkyl, wherein the alkylene and alkyl groups independently have from 1 to 6 carbon atoms;

(12) phenylalkyl, wherein the alkylene group has from 1 to 6 carbon atoms;

(13) phenoxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms;

(14) - (alkylene) -N (R ₅ ) SO 2 -phenyl, wherein the alkylene group has from 1 to 6 carbon atoms and the substituent R 5 is selected from the group consisting of (a) hydrogen and (b) an alkyl having from 1 to 6 6 carbon atoms;

(15) (heterocycle) oxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms;

(16) - (alkylene) -S (O) _p -heterocycle, wherein the alkylene group has from 1 to 6 carbon atoms;

(17) - (alkylene) -heterocycle, wherein the alkylene group has from 1 to 6 carbon atoms; and (18) - (alkylene) -NR 6 R 7, wherein the alkylene group has from 1 to 6 carbon atoms; wherein for (15) - (17) the heterocycle is selected from the group consisting of (a) pyridyl, (b) pyrazinyl, (c) pyridazinyl, (d) furyl, (e) thienyl, (f) isoxazolyl, (g) oxazolyl, (h) thiazolyl, (i) isothiazolyl and wherein for (10) - (17) are phenyl, phenyl portions of phenylalkoxyalkyl, phenylalkyl, (alkylene) -N (R 5) SO 2 -phenyl, phenoxyalkyl, and - (alkylene) -S (O) _p -phenyl, and heterocycle, heterocyclic moieties (heterocycle) oxyalkyl, - (alkylene) -heterocycle and - (alkylene) -S (O) _p heterocycle optionally substituted with one, two or three substituents independently selected from the group consisting of (a) alkyl having from 1 to 6 carbon atoms;

(b) alkoxy groups having from 1 to 6 carbon atoms;

(c) alkoxyalkyl, wherein the alkyl group and the alkylene group independently have from 1 to 6 carbon atoms;

(d) halogen;

(e) haloalkyl having from 1 to 6 carbon atoms;

(i) hydroxy groups;

(g) hydroxyalkyl having from 1 to 6 carbon atoms;

(h) - (alkylene) -heterocycle;

(i) - (alkylene) -phenyl, (j) -N (R ₅ ) SO ₂ -alkyl, (k) phenyl, wherein the phenyl is optionally substituted with 1,2, 3,4 or 5 substituents independently selected from the group consisting of from (i) a cyano group (ii) a nitro group and (iii) a halogen, (1) -C (O) OR ₅ ; and (m) -C (O) NR _x R _y , wherein R _x and R _y are independently selected from the group consisting of (i) alkyl having 1 to 6 carbon atoms, (ii) phenyl and (iii) phenylalkyl wherein for (ii) and (iii) the phenyl and phenyl portion of the phenylalkyl are optionally substituted with substituents independently selected from the group consisting of halo and alkoxy of from 1 to 6 carbon atoms; wherein for (18), R 8 and R 7 are independently selected from the group consisting of (a) hydrogen;

(b) alkyl having from 1 to 6 carbon atoms;

(c) cycloalkyl having from 3 to 8 carbon atoms;

(d) cycloalkylalkyl, wherein the cycloalkyl group has from 3 to 8 carbon atoms and the alkylene group has from 1 to 10 carbon atoms;

(e) an alkanoyl having from 1 to 10 carbon atoms;

(f) phenyl and (g) phenylalkyl, wherein the alkylene group has from 3 to 10 carbon atoms, wherein for (1) and (g) the phenyl and phenyl portion of the phenylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of ( i) alkyl having from 1 to 6 carbon atoms;

(ii) alkoxy groups having from 1 to 6 carbon atoms;

(iii) perfluoroalkyl having from 1 to 6 carbon atoms;

(iv) halogen;

(v) haloalkyl having from 1 to 6 carbon atoms and (vi) alkanoyl having from 1 to 6 carbon atoms; or R ₆ and R ₇ are joined together with the nitrogen atom to which they are attached to form a defined group selected from the group consisting of

(1) m-folinyl (2) thiomorpholinyl; (3) thiomorpholinylsulfone; (4) pyrrolidinyl; (5) piperazinyl; (6) piperidinyl; (7) succinimidyl; (8) maleimidyl; Italy (9) glutarimidyl; (10) phthalimidyl; Italy (11) naphthalimidyl;

.0 (12)

N

CH ₃

NN (13) ^H - ^{C - CH} 3

o- ^ ch ₃

CH, (14)

(19)

N

N ^ O

CH,

O

I N-

(22) • ·

wherein for (1) - (23) the groups defined by R ₆ and R ₇ are joined together with the nitrogen atom to which they are attached, optionally substituted by one or two substituents independently selected from the group consisting of (a) halogen, (b) alkyl (c) alkoxy, (d) phenoxy, (e) phenylalkyl, and (f) benzyloxy; or R 1 and R 2 are taken together with the carbon atom to which they are attached to form a ring selected from the group consisting of (1) a spiroalkyl having from 3 to 8 carbon atoms of (2) tetrahydropyranyl; or R ₃ and R 4 are linked to the carbon atom to which they are attached to form a spiroalkyl group having from 3 to 8 carbon atoms; or R 1 and R ₃ are taken together with the carbon atom to which they are attached to form a 5-, 6-, or 7-membered ring;

X is selected from the group consisting of (1) -O-;

(2) NR 5 SO 2 -;

(3) -S (O) _p -; and (4) -C (O) -;

wherein each group is drawn with its left-hand end that is attached to the alkylene group and its right-hand end that is attached to Ar 1;

Ar 1 is phenyl, which is optionally substituted with one or two substituents independently selected from the group consisting of

(and) alkyl having from 1 to 6 carbon atoms; (b) perfluoroalkyl having from 1 to 6 carbon atoms; (C) halogen; (d) haloalkyl having from 1 to 6 carbon atoms; (E) alkoxy groups having from 1 to 6 carbon atoms; (0 hydroxy groups; (G) hydroxyalkyl having from 1 to 6 carbon atoms; (h) alkoxyalkyl wherein the alkyl and alkylene group independently have from 1 to 6 carbon atoms; (and) nitro groups; the substituent Y is selected from the group consisting of (1) covalent bonds; (2) -O-; (3) alkylene having from 2 to 4 carbon atoms; (4) piperidinyl, (5) alkenylene having 2 carbon atoms; (6) alkynylene having 2 carbon atoms; (7) ^ S (O) _P -α (8) -WHAT)-; and Ar ₂ is an aryl group selected from the group consisting of (1) phenyl; (2) pyridyl; ^F (3) pyrazinyl;

(9) pyridazinyl; (4) pyridazinyl;

(5) furyl;

(6) thienyl;

(7) isoxaloyl;

(8) oxazolyl;

(9) thiazolyl and (10) isothiazolyl, wherein the aryl group is optionally substituted with one, two or three substituents independently selected from the group consisting of (a) alkyl having from 1 to 6 carbon atoms;

(b) alkoxy groups having from 1 to 6 carbon atoms;

(c) alkoxy groups having from 1 to 6 carbon atoms substituted with alkoxy groups having from 1 to 6 carbon atoms;

(d) -alkyl-CO ₂ R ₅ ;

(e) -alkyl-NR _x R _y ;

(f) alkoxyalkyl wherein the alkyl group has from 1 to 6 carbon atoms and the alkylene group has from 1 to 6 carbon atoms;

(g) cyano groups;

(h) cyanoalkyl groups having from 1 to 6 carbon atoms;

(i) halogen;

(j) haloalkyl having from 1 to 6 carbon atoms;

(k) hydroxy groups;

(1) hydroxyalkyl groups having from 1 to 6 carbon atoms;

(m) hydroxyalkyl groups wherein the alkyl group has from 1 to 6 carbon atoms;

(n) thioalkoxy groups having from 1 to 6 carbon atoms;

(o) thioalkoxyalkyl wherein the alkyl group has from 1 to 6 carbon atoms and the alkylene group has from 1 to 6 carbon atoms;

(p) phenylalkoxy groups wherein the alkylene group has from 1 to 6 carbon atoms;

(q) phenoxy groups;

(r) phenoxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms;

(s) (heterocyclic) oxy groups;

(t) (heterocycle) oxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms;

(u) perfluoroalkyl having from 1 to 6 carbon atoms;

(v) perfluoroalkoxy groups, wherein the perfluoroalkyl moiety has from 1 to 6 carbon atoms;

(w) sulfinylalkyl, wherein the alkyl moiety has from 1 to 6 carbon atoms;

(x) sulfonylalkyl, wherein the alkyl moiety has from 1 to 6 carbon atoms;

TO

Y 1 -ο (y), wherein X is selected from -CH 2 -, -CH 2 O- and -O- and Y is selected from -C (O) - and - (C (R ") 2) v- wherein the substituent

R is hydrogen or alkyl having from 1 to 4 carbon atoms and the index v is

1-3;

(z) -N (R ₅ (SO 2) R 5, wherein R 5 is as defined above and R ₅ - is selected from the group consisting of (i) hydrogen and (ii) alkyl having from 1 to 6 carbon atoms, and ( aa) -SO ₂ N (R ₅ ) (R ₅ ), wherein for (s) and (t) the heterocyclic moieties of (heterocycle) oxy and (heterocycle) oxyalkyl are selected from the group consisting of (i) pyridyl;

(ii) pyrazinyl;

(iii) pyridazinyl;

(iv) furyl;

(v) thienyl;

(vi) isoxazolyl;

(vii) oxazolyl;

(viii) thiaolyl and (ix) isothiazolyl; and (ix) isothiazolyl and (ix) isothiazolyl; and (ix) isothiazolyl; and (ix) isothiazolyl; Wherein for (s) and (t) the heterocyclic moieties of the (heterocyclic) oxy group and the (heterocyclic) oxyalkyl are optionally substituted with one or two substituents independently selected from the group consisting of z (i) an alkyl having from 1 to 6 carbon atoms;

(ii) alkoxy groups having from 1 to 6 carbon atoms;

(iii) perfluoroalkyl having from 1 to 6 carbon atoms;

(iv) halogen;

(v) cyano groups;

(vi) cyanoalkyl;

(vii) haloalkyl having from 1 to 6 carbon atoms;

(viii) alkanoyl having from 1 to 6 carbon atoms;

wherein for (q) and (r) the phenyl portion of the phenoxy group and the phenoxyalkyl are optionally substituted with one or two substituents independently selected from the group consisting of (i) alkyl having from 1 to 6 carbon atoms;

(ii) alkoxy groups of 1 to 6 carbon atoms;

(iii) perfluoroalkyl having from 1 to 6 carbon atoms;

(iv) halogen;

(v) cyano groups;

(vi) cyanoalkyl;

(vii) haloalkyl having from 1 to 6 carbon atoms;

(viii) alkanoyl having from 1 to 6 carbon atoms;

In another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a method of inhibiting matrix metalloproteinase in a host mammal in need of such treatment comprising, in need of such treatment, administering to the mammal a therapeutically effective amount of a compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms

The following terms, which are used in these specifications and the appended claims, have the following meanings:

The term "alkyl" as used herein refers to a monovalent group derived from a branched or unbranched saturated hydrocarbon chain by removal of a single hydrogen atom. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl and tert-butyl, neopentyl, and the like.

The term "alkanoyl" as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group. Examples of alkanoyl include formyl, acetyl, propionyl, butanoyl, and the like.

The term "alkenyl," as used herein, refers to a monovalent branched or unbranched chain of groups containing a carbon-carbon double bond derived from an alkene by removal of one hydrogen atom. Examples of alkenyl include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and the like.

The term "alkoxy" as used herein refers to an alkyl group attached to the parent molecular moiety through an oxygen atom. Examples of the alkoxy group include a methoxy group, an isopropoxy group, a tert-butoxy group, and the like.

The term "alkoxyalkyl," as used herein, refers to an alkyl group to which an alkoxy group is attached.

The term "alkoxycarbonyl", as used herein, refers to an ester group, namely an alkoxy group attached to the parent molecule group via a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, and the like.

The term "alkoxycarbonylalkyl" as used herein refers to the above alkyl group substituted with an alkoxycarbonyl group.

The term "alkylene" as used herein refers to a saturated divalent hydrocarbon group derived from a branched or unbranched saturated hydrocarbon chain by removal of two hydrogen atoms. Examples of alkylene include methylene, ethylene, isopropylene, and the like.

The term "alkynyl," as used herein, refers to a monovalent unbranched or branched chain of groups having from 2 to 6 carbon atoms that contain a carbon-carbon triple bond derived from an alkyne by removal of one hydrogen atom. Examples of alkynyl include ethynyl, 1-propynyl, and the like.

The term "benzyloxy," as used herein, refers to - (CH ₂ ) -O-.

The term "cyano group" as used herein refers to a -CN group.

The term "cyanoalkyl" as used herein refers to a cyano group attached to the parent molecular moiety through an alkyl group.

The term "cycloalkyl" as used herein refers to a monovalent saturated cyclic hydrocarbon group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl, and the like.

The term "cycloalkylalkyl," as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through an alkylene group.

The term "halogen" as used herein refers to F, Cl, Br and I.

The term "haloalkyl" as used herein refers to an alkyl group substituted with one, two, three, or four halogen atoms. Examples of haloalkyl include chloromethyl, bromoethyl, chlorodifluoromethyl, and the like.

The term "heterocycle" as used herein refers to a five, six, or seven membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. A five-membered ring has 0 to 2 double bonds and a six-membered ring and a seven-membered ring has 0 to 3 double bonds. Heterocycles include indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, oxo, oxo, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfone, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thiolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, succinimidyl, maleimidyl, glutarimidyl, phthalimidyl, naphthalimidyl, and the like.

Heterocycles also include

The term "(heterocyclic) oxy", as used herein, refers to a heterocyclic group attached to the parent molecular moiety through an oxygen atom.

The term "(heterocycle) oxyalkyl" as used herein refers to a (heterocycle) oxy group attached to the parent molecular moiety through an alkyl group.

The term "hydroxy" as used herein refers to a -OH group.

The term "hydroxyalkyl" as used herein refers to an alkyl group as defined above substituted with from 1 to 3 hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group. Examples of hydroxyalkyl include hydroxymethyl, dihydroxypropyl, and the like.

The term "nitro group" as used herein refers to -NO ₂ .

The term "perfluoroalkyl" as used herein refers to an alkyl group as defined above, wherein each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. Perfluoroalkyl groups are such as trifluoromethyl, pentafluoroethyl, and the like.

The term "perfluoroalkoxy" as used herein refers to the above perfluoroalkyl group attached to the parent molecular moiety through an oxygen atom.

The term "pharmaceutically acceptable salt," as used herein, refers to those salts that are fit for use in contact with human or lower animal tissues without toxic action, irritation, allergic reactions, and the like, and in good medical judgment. they represent a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. Describes in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately, by reacting the free base with a suitable organic acid. Representative examples of acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, glucose, fumarate, fumarate, fumarate, fumarate, fumarate heptanoate, hexanoate, hydrogen bromide, hydrogen chloride, hydrogen iodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, oxalate, oxalate, oxalate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, etc. Representative alkali or alkaline earth metal salts include the following cations sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and cation amine including, but not limited to, ammonia, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

The term "phenoxy group" as used herein refers to a phenyl group attached to the parent molecular moiety through an oxygen atom.

The term "phenoxyalkyl," as used herein, refers to a phenoxy group attached to the parent molecular moiety through an alkyl group.

The term "phenyl" as used herein refers to a six-membered monocyclic aromatic carbocyclic ring.

The term "phenylalkyl" as used herein refers to a phenyl group attached to the parent molecular moiety through an alkylene group. Examples of phenylalkyl include benzyl, phenethyl, and the like.

The term "phenylalkoxy" as used herein refers to a phenyl group attached to the parent molecular moiety through an alkoxy group.

The term "phenylalkoxyalkyl," as used herein, refers to a phenylalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group.

The term "prodrug," as used herein, refers to a compound that rapidly transforms in vivo to the parent compound of the above formula, e.g., by hydrolysis in blood. A thorough analysis of this issue can be found in T. Higuchi and V. Stella, Prodrugs as Novel Delivory Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, E.,

Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. The prodrugs of the compounds of the present invention, to the extent of sound medical judgment suitable for use in contact with human and lower animal tissues, are those which do not cause toxicity, irritation, allergic reactions, etc. proportional to a reasonable benefit / risk ratio and effective for their intended use. as well as possible forms of zwitterion.

The term "spiroalkyl," as used herein, refers to an alkylene radical, both ends, which are attached to the same carbon atom of the parent group, form a spirocyclic group.

The term "sulfinyl," as used herein, refers to the group -S (O) -.

The term "sulfinylalkyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group.

The term "sulfonyl," as used herein, refers to a -SO ₂ - group.

The term "sulfonylalkyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group.

The term "thioalkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfur atom.

The compounds of the present invention may exist as sterioisomers, with asymmetric or chiral centers present. These compounds are designated by the symbols "R" and "S" depending on the configuration of the substituents on the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers are indicated by (±). The individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers, or by preparing a racemic mixture followed by resolution into enantiomers - these techniques are well known in the art. Such methods of resolution into enantiomers are such as (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing the optically pure product from the auxiliary group, or (2) directly separating the mixture of optical enantiomers on chiral chromatography columns.

Preferred embodiments

Preferred compounds of the present invention have formula (I) wherein A is hydrogen;

R 1, R 3 and R 4 are hydrogen;

the X moiety is selected from the group consisting of (1) -O-;

(2) -C (O) -;

(3) -S (O) _P , wherein the index p is 2 and (4) -NR 5 SO 2 -; the Ar 1 moiety is phenyl;

the Y moiety is selected from the group consisting of (1) a covalent bond and (2) -O-, and the index n is 0;

More preferred compounds of the present invention having formula (I), wherein A is hydrogen, R 1, R ₃ and R 4 are hydrogen; X is -O-; the Ar 1 moiety is phenyl; the Y moiety is a covalent bond; and index n is 0.

Preferred compounds within the scope of formula (I) include, but are not limited to: (±) -N- [1 - [[(4'-cyano- [1,1-biphenyl] -4-yl) oxy] methyl] - 2-phenoxyethyl) -N-hydroxyformamide, (±) -N- [l - ^[[(4-cyano- [l, r-biphenyl] -4-yl) oxy] methyl] -2- (phenylthio) ethyl) -N-Hydroxyformamide, (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,3-dihydro-1) , 3-dioxo-1H-isoindol-2-yl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] (methyl) -2- (3,4,4-trimethyl-2,5-dioxo-1H-imidazobdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1]) , 1'-biphenyl] -4-yl) oxy] methyl] -3- (3,4,4-trimethyl-2,5-dioxo-limidazobdinyl) propyl] -N-hydroxyformamide, (±) -N- [1 - [[ [3 '- (cyanomethyl) - [1,1'-biphenyl] -4-yl) oxy] methyl] pentyl) -N-hydroxyformamide, (±) -N- [1 - [((4'-cyano- [1']) , 1'-biphenyl] -4-yl) oxy] methyl] -3-methylbutyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl] -4] -yl) oxy] methyl] -2-methylbutyl] -N-hydroxyformamide;

(±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] pentyl] -N-hydroxyformamide, (±) -N- [1- [[(4'-cyano - [[1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4-methylphenyl) ethyl] -N-hydroxyformamide, (±) -N- [2 - [( 4'-cyano- [1,1'-biphenyl] -4-yl) oxy] -1- (4-fluorophenyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano) - [1,1-biphenyl] -4-yl) oxy] methyl] -2- (4-fluorophenyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1, 2'-cyano- (1-Biphenyl) -4-yl) oxy] methyl] ethyl] -N-hydroxyformamide;

N- [2 - [(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyacetamide,

N- [2 - [(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide, (±) -N- [1- [4 - [(2E-phenylethenyl)] (phenoxy) methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[4- (2-furanyl)] phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl) N-hydroxyformamide, (±) -N- [1 - [[(4'-butoxy [1] (1'-biphenyl) -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1- [[(4'-fluoro [1,1'-biphenyl) -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl) -N-hydroxyformamide, (±) -N- [1 - [(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethyl) [Ι, if-biphenyl] -4- yl] oxy] ethyl] -N-hydroxyformamide, (±) - N - [1 - [[(4'-methoxy [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4) (4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl) -N-hydroxyfoimamide, (±) -N- [1 - [[(4'-methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-butoxy [1,1'-butoxy] -biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimime) ethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2- [(4'-ethoxy [1,1'-biphenyl] -4yl) oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[4- (1,3-benzodioxol-5-yl) phenoxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl) -N-hydroxyformamide, (±) -N- [1 - [[(4'-butoxy [1,1- biphenyl] -4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide,

(±) -N- [1 - [[4- (3-thienyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, ( ±) -N- [1 - [[([1,1-Biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] - N-hydroxyformamide, (±) -N- [1 - [[(3'-chloro-4'-fluoro- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4, 4-Trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide ₅ (±) -N- [1 - [[(2'-methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2+ (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) - N - [1 - [[(4'-cyano [1,1'-cyano] -biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano (1, 2'-cyano) 1'-Biphenyl] -4-yl) oxy] methyl] -2- (1,1-dioxido-3-oxo-1,2-benzisothiazol-2 (3H) -yl) ethyl] -N-hydroxyformamide, (± -N - [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1' biphenyl] -4-yl] oxy) ethyl -N-hydroxyformamide (±) -N- [1 - [[4- (4-phenyl-1-piperidinyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1) imidazohdinyl) ethyl] -N-hydroxyformamide, (±) -N - [1 - ((4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] · 4-yl] oxy] ethyl] - N-hydroxyformamide, (±) -N- [1 - [[(3'-cyano (1,1'-biphenyl] -4-yl) oxy] methyl] -2- [methyl [(4-methylphenyl) sulfonyl] amino] ethyl] -N-hydroxyformamide, (±) - N - [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- [4,4-dimethyl-2] , 5-dioxo-3- (3-pyridinylmethyl) -1-imidazolidinyl] ethyl] -N-hydroxyformamide, (±) -N- [2 - [(4'-cyano [1,1'-biphenyl] -4-yl) (oxy) -1-methylpropyl] -N-hydroxyformamide, (±) -N- [1 - [[(3'-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3) 4,4-trimethyl-2,5-dioxo-1-imidazotidinyl) ethyl] -N-hydroxyformamide;

(±) -N- [1 - [[[4 '- (methylthio) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5- dioxo-1 imidazohdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1- [4 - [[4- (trifluoromethyl) phenoxy] phenoxy] methyl] -2- (3,4,4-trimethyl- 2,5-dioxo-1-imidazohdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -2-N-hydroxyformamide, (±) -N- [1 - [([4 '- (methylsulfonyl)] [ 1,1'-biphenyl] -4-yl] oxy] methyl) -2- (3,4,4-trimethyl-2,5-dioxo-limidazobdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1] - [[[3 '- (cyanomethyl) -4'-methoxy [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazobdinyl) (ethyl) -N-hydroxyformamide, (±) -N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -3- (4,4- dimethyl-2,5-dioxo-limidazobdinyl) propyl]] - N -hydroxyforniamide, (±) -N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] - 2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4] -yl) oxy] methyl] -3- (4, 4-Dimethyl-2,5-dioxo-1-imidazobdinyl) propyl] -N-hydroxyformamide, (±) -N- [1 - [[[4 '- (methylsulfonyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazolinyl) ethyl) -N-hydroxyformamide, (±) -N- [1 - [[(3'-cyano [1,1'-biphenyl]] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrobdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1 '- biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,6-dioxo-1-piperidinyl) ethyl] -N-hydroxyformamide,

N - [1S - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide,

N - [1 R - [[(4'-Cyano [1,1'-biphenyl) -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide, (± ) -N- [1 - [[(4'-Cyano [[1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-ethyl-3-methyl-2,5-dioxo) (Pyrrolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [4- [4 - [[(4-chlorophenoxy) phenyl] sulfonyl] methyl] tetrahydro-2H-pyran-4-yl] -N-hydroxyformamide, (± ) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [[(2-methoxycarbonyl) phenyl) thio] ethyl] -Nhydroxyformamide, ( ±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl) -4-yl) oxy] methyl] -5 - [(4-methyl-2-oxo-2H-1-benzopyran) 6-yl) oxy] pentyl] -N-hydroxyformamide, (±) -N- [1 - [[(4-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -4 - [(4- methyl-2-oxo-2H-1-benzopyran-6-yloxy] butyl] -N-hydroxyformamide, (±) -N- [1 - ([(4'-cyano [1,1'-biphenyl] -4-yl) (oxy) methyl] -4 - [(4-methyl-2-oxo-2H-1-benzopyran-7-yl) oxy] butyl) -N-hydroxyformamide;

2i ...............

(±) - N - [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -5 - [(4-methyl-2-oxo-2H-1-benzopyran) -7yl) oxy] pentyl] -N-hydroxyphonamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (5 , 5-dimethyl-2,4-dioxo-3-oxazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [U'-biphenyl]] (4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano ( 1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1] - [[(4'-chloro- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] - N-hydroxyformamide, (±) -N- [1 - [[(3'-cyanomethyl- [1,1-biphenyl] -4-yloxy) methyl] -2- (3,5,5-trimethyl-2) (4-dioxo-1-imidazolidinyl) propyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2-isopropylthioethyl] -N-hydroxyformamide, (± ) -N- [1 - [[(3'-Cyanomethyl- [1,1-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1) imidazolidinyl) ethyl] -N-hydroxyformamide, (±) - N - [1 - [[(4'-cyano- [Ι,--biphenyl] -4-yl) oxy] methyl] -2- (3-ethyl- 4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) - N - [1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) (oxy) methyl] -2- (3-benzyl-4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyfortamide, (±) -N- [1 - [[(4'-cyano- [ 1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,5,5-trimethyl-2,4-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N - [1 - [[4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide;

(±) -N- [1 - [[(4'-Chloro (1,1'-biphenyl] -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide (±) -N- [1 - [[[ 4- (1,3-benzodioxol-5-yl) phenyl] sulfonyl] methyl] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl [ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-methoxy [1,1-biphenyl] -4-yl) sulfonyl) methyl] propyl] -N-hydroxyformamide, (±) -N- [1- [1,1-dimethyl-2 - [(4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide,

Ί ·?

(±) -N- [1 - [(phenylmethoxy) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide, (±) -N - [1- (hydroxymethyl) -2 - [[(4 '- (trifluoromethyl) [1,1-biphenyl] -4-yl] sulfonyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [(4 4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] 4-yl] thio] ethyl] -N-hydroxyformamide; ±) -N- [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazobdinyl) methyl] -2 - [[4 '- (trifluoromethyl) [1,1' biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide, (±) -N- [1 - [(2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1-biphenyl] (4-yl) oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxol-imidazoidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-butyl [1,1-biphenyl] -4- yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-1-imidazobdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [(3-methyl-2,5-dioxo) -1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] oxy] ethyl] -N -hydroxyformamide, (±) -N- [4- [4 - [(4'-chloro [1,1'-biphenyl] -4-yl) sulfonyl] methyl] tetrahydro-2H-pyran-4-yl) N-hydroxyformamide, ( ±) -N- [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazobdinyl) ethyl] -N- hydroxyformamide, (±) -N- [1 - [[(4-butyl [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo) -limidazobdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [((4'-butyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4- dimethyl-2,5-dioxo-1-imidazobdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1'-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1- [4- (2-thienyl) phenoxy] methyl) -2 - [1- (3,4,4-trimethyl-2,5-dioxo-1-imidazohdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(3-nitro [1,1 '- biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1 imidazobdinyl) ethyl] -N-hydroxyformamide,

• · • · • · • · • · • e • · • · • · • • • • • · • . · • · ·· · • · · • · • · · • • • ·

(±) -N- [1 - [[(4'-Methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [[3- (methylsulfonyl) amino] phenyl] ethyl] N -hydroxyformamide, (±) -N- [1 - [[[3- (diethylamino) carbonyl] phenyl] methyl] -2 - [(4'-methyl- [1,1'-biphenyl] -4-yl) oxy] ethyl N-hydroxyformamide,

N- [1 - [[(4'-cyano [1,1-biphenyl] -4-yl) oxy] methyl] -2 - [(4'-cyano [1,1-biphenyl] -4-yl) oxy] ethyl ] -N-Hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5 - dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- ( 2-methoxyethoxy) [1,1-biphenyl) -4-yl] oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)] methyl] -2 - [(4'-propoxy [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [(4,4-dimethyl-2, 5-dioxo-1-imidazolidinyl) methyl] -2 - [(4'-pentyloxy [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[ 3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl] sulfonyl) methyl] -3- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) propyl] -N-hydroxyformamide, (±) N- [l - [[[4 ^'- (trifluoromethoxy) [l, ^l-biphenyl] -4-yl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-l- imidazobdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (3-methyl- 2,5-d ioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxol-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4] -yl) oxyl] methyl] -2- (1,6-dihydro-3-methyl-6-oxo-1 pyridazinyl) ethyl] - N -hydroxyformamide, (±) -N- [1 - [[(4'- cyano [1,1-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazobdinyl) ethyl] -N-hydroxyformamide, (±) -N- [ 1 - [[[4- (4-fluorophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazobdinyl) ethyl] -N-hydroxyformamide, (±) -N - [1 - [[4- (4-pyridinyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] N-hydroxyformamide, (S) -N - [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] oxy] ethyl] - N-hydroxyformamide, (R) -N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1' biphenyl] -4-yl] oxy] ethyl] -N-hydroxyformamide;

N- [1 - [[[4 '- (trifluoromethoxy)] [1,1'-biphenyl] -4-yl] oxy] methyl] -3- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) propyl 1-N-hydroxyformamide;

N- [1- [4 - [(4-pyridinylthio) phenoxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide;

N- [1 - [[[(4-chlorophenoxy) phenyl] sulfonyl] methyl] -3- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) propyl] -N-hydroxyformamide;

N- [1 - [[(4'-Cyano [1,1-biphenyl] -4-yl) oxy] methyl] -2- (1,6-dihydro-6-oxo-1-pyridazinyl) ethyl] -N-hydroxyformamide ;

N- [1 - [[[4 '- (aminosulfonyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1) imidazolidinyl) ethyl] -N-hydroxyformamide;

N- [1 - [[[4 '- (trifluoromethoxy) [1,1-biphenyl] -4-yl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl 1-N-hydroxyformamide;

N- [1- [4 - [(4-pyridinyloxy) phenyl] sulfonyl]] ethyl] -N-hydroxyformamide;

N- [1 - [[[(4-cyanophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazohinyl) ethyl] -N-hydroxyformamide;

N- [1 - [[4 - [[4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] methyl] -3- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) propyl] -N-hydroxyformamide; and

N- [1 - [[4 - [[4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide.

Pharmaceutical preparations

The present invention also provides pharmaceutical compositions comprising the compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.

The pharmaceutical compositions of the invention may be administered to humans or animals only orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally or topically (such as dusting, ointments, drops), buccally, or as an oral or nasal spray. The term "parenteral" application, as used herein, refers to modes of administration that

include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.

Pharmaceutical compositions of the invention for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile dusting powders for reconstitution into sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of coating agents such as lecithin, by the maintenance of the desired particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents such as sugar, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form may be due to agent inclusion. (such as aluminum monostearate and gelatin) that delay absorption.

In some cases, in order to prolong the effect of the drug, it is desired to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The rate of absorption of a drug then depends on its solubility, which may depend on crystalline size and crystalline form.

Alternatively, delayed absorption of the parenterally administered drug may be achieved by dissolving or suspending the drug in an oil carrier.

Injectable depot forms are made by molding microencapsulated drug matrices into biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the amount of drug polymer and the origin of the polymer particles used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body formulations. tissues.

«« * ·· * ·

Injectable formulations may be sterilized, eg, by filtration through a bacterial retention filter, or by incorporating a sterilizing agent into a sterile solid preparation, which may be dissolved or dispersed in sterile water or other sterile injectable medium before use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and orthosilicic acid, b binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) wetting agents such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and calcium carbonate, e) solution inhibitors such as paraffin, 1) absorption accelerators such as quaternary ammonium compounds, g) detergents such as cetyl alcohol and glycerol monostearate, h) adsorbents such as for example, kaolin and bentonite kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain a buffering agent.

Solid compositions of a similar type may also be employed as fillers in lightly filled and densely filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulations. Solid dosage forms may contain a opacifying agent and may also be free of such formulations that release only or preferably the active ingredients in a particular portion of the intestinal tract, possibly delayed to some extent. Examples of embedding compositions that can be used include polymeric substances and waxes.

The active compounds may also be in microencapsulated form with one or more of the above carriers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid forms may be liquid.

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0 0

0 0

0 0 • 0 · • 0 00 doses containing inert diluents commonly used in the art such as water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,

1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, groundnuts, corn, germs, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof.

Compared to inert diluents, oral preparations may also include adjuvants such as detergents, emulsifiers and suspending agents, sweetening agents, flavoring agents, and fragrance release agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitols and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and traganth, and mixtures thereof.

Formulations for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or wax suppositories that are solid at room temperature but liquid inside the body and therefore thaw in the rectum. or vaginal cavity to release the active compound.

The compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolamellar or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present liposome formulations may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., (1976), page 33 et seq.

Dosage forms for topical administration of a compound of this invention include dusting powders, sprays, inhalants and creams. The active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative buffer or propellant as desired. Ophthalmic formulations, eye ointments, dusting powders and solutions are also contemplated within the scope of the present invention.

²⁸

The actual dosage level of the active compound component in the pharmaceutical compositions of the invention may be as varied as necessary to obtain the amount of active compound (s), which is efficacy to achieve the desired therapeutic response for a particular patient, formulations and route of administration. The selected dosage level will depend upon the activity of the individual compound, the mode of administration, the strength of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill in the art that to achieve the desired therapeutic effect, dosages of the compound are started at lower levels than desired and the doses are gradually increased until the desired effect is achieved.

Generally, dosage levels are from about 1 to about 50, more preferably from about 5 to about 20 mg of active compound per kilogram of body weight per day when administered orally to a patient (mammal). If desired, the effective daily dose may be divided into multiple doses for purposes of administration of, for example, from 2 to 4 separate doses per day.

Determination of inhibition of Stromelysin

The effect of the compounds of this invention as matrix metalloproteinase inhibitors was determined by measuring the inhibition of stromelysin. Inhibition of stromelysin by the compounds of the invention was determined as follows: recombinant engineered stromelysin (human sequence) produced by E.coli was prepared by expression and purification of the protein as described in Ye et al. (Biochemistry, 1992, 31, 11231-11235, incorporated herein by reference). The enzyme is determined by cleavage of the substrate of the thiopeptide ester Ac-Pro-Leu-Gly- [2-mercapto-4-methyl-pentanoyl] -Leu-Gly-OEt substrate as described in Weingarten and Feder (Anal. Biochem., 1985, 147, 437-440 (1985), incorporated herein by reference) as a vertebrate collagenase substrate. The published conditions were modified to allow the assay to be performed in a microtiter plate. In the hydrolysis of the thioester bond, the rapidly released thiol group reacts with 5,5'-thio-bis (2-nitrobenzoic acid) (DNTB) to produce a yellow color, which is measured on a microtiter plate reader. The rates of substrate cleavage by stromelysin in the presence or absence of inhibitors were measured in a 30-minute assay at room temperature. Compounds solutions in DMSO were prepared and diluted at various concentrations for assay and buffer (50 mM MES / NaOH pH 6.5 with 10 mM CaCl 2 and 0.2% Pluronic F-68), which was also used to dilute the enzyme and substrate . Compound potency [IC 50] was calculated from the inhibition / inhibitor concentration data. The compounds of the invention inhibited stromelysin as shown in Table 1 in representative examples.

• · • · • · • · • · • '· • · • • • • • · • • • • • · · • 9 • • • • · • • • • · · • · · • · • · · • * • ·

Table 1

Example IC ₅₀ (nM) 1 130 2 36 3 21 4 9.1 5 17 6 30 7 120 8 170 9 100 ALIGN! 10 1,500 11 300 12 180 13 310 14 4,000 15 Dec 620

Preparation of compounds of the invention

The compounds and processes of the present invention will be better understood in conjunction with the following synthetic schemes, which are here only to illustrate the methods by which the compounds of the invention may be prepared and are not intended to limit the scope of the invention, which is fully defined in the appended claims. Representative procedures are outlined in the following Schemes 1-5.

Abbreviations

The abbreviations used in the descriptions of the schemes and examples that follow are: THF for tetrahydrofuran and DMF for Ν, Ν-dimethylformamide.

As shown in Scheme 1, deprotonation of the phenol portion of compound 1 with a base, preferably sodium hydride or potassium hydride, and alkylation of the resulting anion with an excess, preferably 2 to 4

• · • · • · • · • · • • • · • • • • • • • • • • • • · · • · · • • • · • · · • • fc · • • · •

an excess of the electrophile, preferably epibromohydrin or epichlorohydrin, obtains alkylated epoxide 2. The excess of the second nucleophile, preferably 2-4 excess, is deprotonated with a base such as sodium hydride or potassium hydride and condensed with 2 to obtain alcohol 3 which is reacted with bis-Boc -hydroxylamine under Mitsunobu reaction conditions to afford the protected hydroxylamine 6 with the bis-Boc group. Removal of the Boc protecting groups with an acid, preferably HCl in dioxane or trifluoroacetic acid in methylene chloride, and neutralization of the amine salt with bases, preferably sodium bicarbonate, affords the exposed hydroxylamine moiety which is reacted with a formulating agent, preferably formiacetyl anhydride, in a solvent such as THF or dichloromethane. to obtain hydroxamic acids 7.

Alternatively, compound 2 is converted to the corresponding iodo ketone 4 by a two step process comprising (a) reacting the epoxide with triphenylphosphine and an iodonizing agent, preferably iodine, in an inert solvent such as dichloromethane to give the corresponding iodo alcohol followed by (b) oxidation to the corresponding iodo ketone 4 using a mild oxidizing agent, preferably Dess-Martin periodinane (Dess, DB; Martin, JC, J. Am. Chem. Soc. 1991, 113, 7277-7287, incorporated herein by reference). Introduction of R 1 is achieved by alkylating the desired phenol or benzenethiol derivative of compound 4 in the presence of a base, preferably sodium carbonate, in a polar solvent such as DMF. The resulting ketone is converted to the corresponding oxime 5 by reaction with hydroxylamine hydrochloride in a hydroxyl solvent, preferably ethanol, with a catalytic amount of a base, preferably pyridine. When R 1 contains sulfur, the alcohol is oxidized to the corresponding ketone using Dess-Martin periodinane in an inert solvent such as dichloromethane and then converted to compound 5 as described above. Reaction of compound 5 with a reducing agent, preferably boranopyridine complex, in a hydroxyl solvent, preferably ethanol, and excess aqueous hydrochloric acid is added to give the corresponding hydroxylamine which is formulated as described above. Depending on the R 1 substituent group, protection and sequential removal of the protecting group of other reactive groups is required to successfully complete the described synthetic sequences. Commonly used protecting groups are disclosed in Green, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)), incorporated herein by reference.

Scheme 1

HO-Art-Y-Ar ₂ + ^< J> _x ^ Br 1 '' ArrY-Ara

I ¹

Λζ ».

Boc-N '' - 'Ar _r Y-Ar ₂ O-Boc

1 ’

ΗΟ ^ - 'θ'Ατ, .Υ-ΑΓ:

78 ° ·

Αγ, -Υ-Αγ,

S? ' _H '* k _N Jx ^ O.

'Ar _r Y-Ar ₂

OH i

OH • Ar ₂ -Y-Ar

Scheme 2 shows an alternative preparation of intermediate 5. Alkylation of compound 1 with ethyl bromoacetate is achieved in the presence of a base, preferably potassium carbonate, in a polar solvent, preferably DMF, to obtain compound 8, which is subsequently hydrolyzed to compound 9 by reaction with an aqueous base, preferably lithium hydroxide. solvent mixtures, preferably water and dioxane. Amide 10 is prepared by coupling of Ν, Ο-dimethylhydroxylamine hydrochloride to compound 9 with a coupling agent, preferably bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (BOP-C1). Reaction of compound 10 with R 1 -MgX, wherein X is Br or Cl, at a reduced temperature, preferably -78 ° C in an inert solvent, preferably THF, affords ketone 11, which is converted to compound 5 and finally to compound 7 as is described in Scheme 1.

• ·

• · • 9 9 · 9 9 9 · 9 9 * · «· 9 9 • · 9 9 • · • 9 · • 9 9 9 9 9 9 9 • 9 • ·

ArrY - Arr - OH + Br ^x ' ^v | f ^c O

Scheme 2

ArrY-Arf

O

N @ 2 -Y-Ar @ 2 ^O 2 OH

Ar ₂ -Y-Ar <o ^'x ^ ^x N' ^Me

About me

Ar ₂ -Y-Arf ° ' ^x - ^' R,

Arg-Y-Arf ^H %;

R,

Scheme 3 shows the synthesis of compounds where the fouling of the phenol group and the substituent group R 1 is reversed. This path crosses the path described in Scheme 1 for epoxide 14, and the path described in Scheme 1 can be used to convert compound 14 to hydroxamic acid using HO-Ari-Y-Ar ₂ instead of R 1 -H. Heterocyclic R 1 -H derivatives, preferably those having appropriate pKa values, such as hydantoin in this scheme, are condensed with the desired olefin alcohols under Mitsunobu reaction conditions to yield the corresponding N-alkenylheterocycle 12. Reaction of compound 12 with an alkylating agent, preferably methyl iodide, in the presence of a base, preferably sodium hydride, gives N-methyl (alkenylheterocycle) 13 which is epoxidized with meta-chloroperbenzoic acid (MCPBA) in dichloromethane to give compound 14. The reaction sequence described in Scheme 1 is then used to convert to hydroxamic acid 5. .

·· ··

^{CH 2} (alkylene) - NH ₆ R ₇ 13 - (alkylene) - OH ⁺

alkylene) -NR ₆ R ₇

O

Even though the alkylene group has 1 to 6 carbon atoms, the index n is 1 and the substituents R 6 and R 6 are substituted by R 1 and R 2. are linked together with the nitrogen atom to which they are attached to form a ring of formula

NMe

Scheme 4 shows an alternative method of synthesizing substituted hydantoin compounds 22 and 23. Alkylating compound 16 with substituted hydantoin 17 in the presence of a base, preferably potassium carbonate, affords enolether 18. Reaction of compound 18 with a brominating agent such as NBS in acetone affords bromoketone 19. alkylated with either arylthiol (20, X = S) or substituted phenol (20, X = O) to give ketones 21. Ketones 21, wherein Y is a covalent bond, can also be prepared from compound 19 in a two step synthesis, which means first alkylate either the bromothiophenols (20a, X = S) or the bromophenols (20a, H = O) and then coupling the aryl bromides 10a with the appropriate boronic acid aryls followed by the Suzuki protocol or the appropriate arylstannane. The reaction sequence described in Scheme 1 can then be used to convert compound 21 to hydroxamic acids 22. Compounds where X = S can be converted to sulfones 23 via oxidation with suitable oxidants such as m-chloroperbenzoic acid or oxone.

• • • · • • · «· • · • · • • • · • • • • • • • • • Φ 4 • ♦ • • • · · • • · · • • • · « «· · • 4 • • • ·

OMOM 'KxU ⁺ r ₂ p

R ₂ 1 Ν ^ Χ, γ ₊ HX-Ar _r Y-Ar ₂

R ₂ o

4 ⁵

R ₂ b _R ^^ Ν '^ Α ^Χ-ΑΓίΥ-ΑΓ ₂ \ HX — Ar _r Br

20a

Rr _R ^ L ^ ^N - ^ A ^ ^X ~ ^Ar 1 ~ ^Br

K r ₂ o

19a

JY «

r ₂ ó

Scheme 5 shows an alternative synthesis of sulfones 29. Deprotonation of sulfones 25 with bases such as LDA followed by addition to a ketone or aldehyde 24 provides an alcohol that can be dehydrated either by reaction with an acid such as toluenesulfonic acid or by a two step procedure: first converting the alcohol to a leaving group such as methanesulfonate via reaction with mesyl chloride and triethylamine, then by elimination of bases, preferably 1,8-diazabicyclo [5.4.0] undec-7-ene. Reaction of the olefin with hydroxylamine by O-protection, preferably O-benzyl, provides adduct 28. Formylation as described above in Scheme 1, followed by deprotection, preferably under hydrogenation conditions for compounds in which P is benzyl, yields sulfone 29. Sulfone 28 can also be prepared directly via deprotonation of sulfone 25 with a base such as n-BuLi and subsequent addition, preferably in the presence of boron trifluoride etherate, to the O-protected oxime 30.

Scheme 5 O A * In ^x '' Arf Y — Ar ₂ / W> ff Y — Ar ₂ 24 25 26 IV op Λ ^H χ - '' Aff Y — Ar ₂ —— RR h _R V 27 Mar: 28 29

ζΟΡ

Ar _r Y — Αγ ₂

The following will be better understood in conjunction with the following examples which illustrate the methods by which the compounds of the invention may be prepared and are not intended to limit the scope of the invention, which is fully defined in the appended claims.

Examples

Example 1 (±) -N- [1 - [[(4'-Cyano- [1,1-biphenyl] -4-yl) oxy] methyl] -2-phenoxyethyl] -N-hydroxyformamide

Example IA (±) -3-Phenoxypropane- [1,2] oxirane

A suspension of sodium hydride (0.47 g, 11.7 mmol) in THF (20 mL) was treated successively with a solution of phenol (1.00 g, 10.6 mmol) in THF (20 mL) followed by epibromohydrin (2 mL). 73 ml, 31.8 mmol) in a single portion, reflux for 2 hours, cool, react with

20% aqueous potassium bisulfate was then partitioned between ethyl acetate and brine. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried

was (Na 2 SO ₄ ) and concentrated to give 1.65 g of a golden oil, which was purified on a silica gel column eluting with 10% ethyl acetate / hexanes (500 mL) and 20% ethyl acetate / hexanes to afford 1.19 g (75%). ) the desired compound.

MS (DCI / NH ₃ ) m / e 168 (? +? 0 + and 185 (M + NH 4 + NH ₃ ) ⁺ ).

Example IB (±) -1- (4- (4'-Carbnitrilophenyl) phenoxy) -3-phenoxy-2-propanol

A suspension of sodium hydrides (0.18 g, 4.39 mmol) in THF (4 mL) was sequentially treated with a solution of 4'-hydroxy-4-biphenyl carbonitrile (0.78 g, 3.99 mmol) in THF (4 mL), Example 1A (0.60 g, 3.99 mmol) in THF (2 mL) then DMF (6 mL), refluxed for 1 hour boiled, cooled, mixed with 20% aqueous hydrogen sulfate solution and partitioned into ethyl acetate and brine. The organic layer was washed with saturated aqueous sodium bicarbonate, 15% sodium hydroxide solution and brine, dried (Na ₂ SO ₄ ) and concentrated to 1.04 g of a yellow oil which was purified on a silica gel column eluting with 25-30% ethyl acetate hexanes to give 0.42g (22%) of the title compound.

MS (DCI / NH ₃ ) m / e 363 (M + NH 3) ⁺ and 380 (M + NH + NH ₃ ) ⁺ .

Example IC (±) - N, O-Bis (t-butyloxycarbonyl) -1- (4- (4'-carbonitrilephenyl) phenoxy) -3-phenoxy-prop-2-yl-N-hydroxylamine

A solution of Example IB (0.41 g, 1.19 mmol), triphenylphosphane (0.40 g, 1.54 mmol), and di-Bochydroxylamine (0.33 g, 1.42 mmol) in THF (5 mL) was added. was added dropwise with diethyl azodicarboxylate (0.24ml, 1.54mmol), stirred at ambient temperature for 1 hour and concentrated. The resulting oil was redissolved in dichloromethane (30 mL) and concentrated in vacuo (2x) until all excess THF had disappeared. Purify on a silica gel column eluting with 15% ethyl acetate / hexanes to afford 0.50 g (75%) of the title compound as a colorless foam.

Example ID of (±) -1- (4- (4'-Carbonitrilphenyl) phenoxy) -3-phenoxy-prop-2-yl-N-hydroxylamine

A solution of Example 1C (0.45 g, 0.80 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (6 mL), stirred for 15 minutes at room temperature, poured into excess saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The resulting organic phases were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to the resulting brown oil 0.70 g, which was purified on a silica gel column eluting with 50% ethyl acetate / hexanes to give 0.23 g (81%). ) of unprotected hydroxylamine in the form of a slightly yellow foam.

Example IE (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2-phenoxyethyl] -N-hydroxyformamide

A solution of Example 1D (0.15 g, 0.41 mmol) in dichloromethane (2 mL) was cooled to -10 ° C and treated with a solution of formacetylanhydride (38 mg, 0.43 mmol) in dichloromethane (1 mL) at rt. stirring for 15 minutes. Dilute with ether and wash successively with saturated aqueous sodium bicarbonate, 10% hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, dry (Na ₂ SO ₄ ) and concentrate to 0.17 g of brown glassy oil which is purified on a column Silica gel eluting with 97.5% (40% ethyl acetate / hexanes) / 2.5% methanol to give 67 mg (42%) of a light brown foam. After recrystallization from ethyl acetate / hexane / acetone, pinkish clump crystals formed, mp 133-135 ° C

1 H NMR (300 MHz, CDCl ₃ ) d 8.15 (br s; 1H), 8.07 (s; 1H), 7.69 (AB; 1H; J = 9 Hz), 7.62 (AB; 1H) > 9 Hz), 7.54 (d; 1H;> 9 Hz), 7.32 (dd; 1H;> 6.5, 8.0 Hz), 6.97-7.06 (m; 3H) 6.92 (d; 2H; J = 7.5 Hz); 4.24-4.47 (m; 5H);

MS (DCI / NH 3) m / e 345 (M + NHt-HCONHOH) +;

Calculated for C ₂ 3H ₂ oN ₂ 0 _4: C, 71.12; H, 5.19; N, 7.21. Found: C, 71.04; H, 5.16; N, 7.01.

Example 2 (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (phenylthio) ethyl] -N-hydroxyformamide

Example 2A (±) -3- (4- (4'-Carbonitrilphenyl) phenoxy) propane [1,2] oxirane

Said compound was prepared by the procedure of Example 1A, but using instead of phenol

4'-hydroxy-4-biphenylcarbonitrile (10.0 g, 51.2 mmol). Purification by trituration in ether gave 9.13 g (71%) of the product as a Cretaceous solid, m.p. 115-116 [deg.] C

MS (DCI / NH 3) m / e 269 (M + NH 3) ⁺ and 286 (Μ + ΝΗ 4 + ΝΗ 3)

Example 2B (±) -1- (4- (4'-Carbonitrilphenyl) phenoxy) -3-thiophenoxy-2-propanol

A solution of Example 2A (0.90 g), triethylamine (1.75 mL) and benzethiol (1.10 mL) in absolute ethanol (14 mL) was heated at reflux for 1 hour, cooled and partitioned between ethyl acetate and 10% aq. sodium hydroxide solution. The organic layer was washed successively with 10% aqueous HCl, saturated bicarbonate solution and brine, dried (Na ₂ SO ₄ ) and concentrated to 1.27 g of a thick golden oil. Purification by recrystallization from ethyl acetate / hexane / methanol gave clusters of colorless crystals of the product, mp 105-106 ° C

MS (DCI / NH 3) m / e 379 (M + NH 3).

Example 2C (±) -1- (4- (4'-Carbonitrilephenyl) phenoxy) -3-thiophenoxy-2-propanone

A suspension of the Dess-Martin periodical in dichloromethane (25ml) was treated with the product of Example 2B (2.02g) in dichloromethane (15ml), stirred at room temperature for 0.5 hours and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. . The organic phase was washed successively in saturated sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and brine, dried (Na ₂ SO 4) and concentrated to 2.27 g of an orange amorphous solid which, after purification on a silica gel column, eluted with 30% ethyl acetate / hexanes gave 1.90 g of a chalky yellowish product.

MS (DCI / NH 3) m / e 377 (M + NH 4) ⁺ .

Example 2D (±) -1- (4- (4'-Carbonitrilephenyl) phenoxy) -3-thiophenoxy-2-propanone oxime

A solution of Example 2C (2.02 g) in methanol (20 mL) and THF (10 mL) was treated successively with 10 drops of pyridine followed by hydroxylamine hydrochloride (0.78 g), heated at reflux for 1 hour. . It was then cooled and partitioned between ethyl acetate and saturated aqueous solution

sodium bicarbonate. The organic layer was washed successively with water and brine, dried (Na ₂ SO ₄ ), and concentrated to 1.90 g of the title compound as a chalky yellow solid, which was used without further purification.

MS (DCI / NH ₃ ) m / e 375 (M + H) ^&lt; ^{+ &gt};, m / e 392 (M + NH &lt; + &gt;) ⁺ .

Example 2E (±) -N- (4- (4'-Carbonitrilphenyl) phenoxy) -3- (thiophenoxyprop-2-yl) hydroxylamine

A solution of Example 2D (1.90 g) in THF (10 mL) was treated sequentially with absolute ethanol (20 mL), borane-pyridine (1.5 mL) and then dropwise with 6N aqueous HCl, with stirring. at room temperature for 1 hour. Pour into an excess of saturated aqueous sodium bicarbonate solution and extract into ethyl acetate. The combined organic extracts were washed with brine, dried (Na ₂ SO 4) and concentrated to 2.25 g of an orange oil which, after purification on a silica gel column eluting with 30% ethyl acetate / hexanes gave 1.26 g of the product as a golden oil.

MS (DCI / NH 3) m / e 377 (M + H) ⁺ , m / e 394 (M + NH 3) +.

Example 2F (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (phenylthio) ethyl] -N-hydroxyformamide Compound solution from 2E (1.24 g) in THF (10 mL) was cooled to -23 ° C and treated with a solution of methacetic anhydride (280 μhydr) in THF (2 mL), stirred for 15 minutes. Dilute with ether and wash successively in saturated aqueous sodium bicarbonate, 10% aqueous HCl, saturated sodium bicarbonate, and brine. After drying (Na ₂ SO ₄ ) and concentrating to 1.27 g of glassy orange oil, it was purified on a silica gel column eluting with 97.5% (40% ethyl acetate / hexanes) / 2.5% methanol to give 300 mg. mg of the title compound as a slightly orange foam.

1 H NMR (300 MHz, CDCl ₃ ) d 7.95 (br s; 1H), 7.90 (s; 1H), 7.70 (AB; 1H; J = 7.5 Hz), 7.62 ( AB (1H;> 7.5 Hz), 7.51 (d; 1H;> 9 Hz)), 7.20-7.43 (m; 5H), 6.95 (d; 2H;> 9 Hz) 4.33 (dd; 1H; > 8.5, 10.5 Hz), 4.17 (dd; 1H; > 4.5, 10.5 Hz), 4.0 (m; 1H), 3, 36 (dd; 1H; > 8.5.14 Hz), 3.28 (dd; 1H; > 6.14 Hz);

MS (DCI / NH ₃₎ m / e 422 (M + NH) ^+;

Calcd for C ₂₃ H ₂₀ N ₂ O ₃ S: C, 68.30; H, 4.98; N, 6.73. Found: C, 68.19; H, 4.86; N, 6.73.

• · ·· > · ·· • '' · ·· • · · ·· ·· * l *. · • · · • · · · • · · • · » ·· * ·· · '· ··

Example 3 (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,3-dihydro-1,3- dioxo-1H-isoindol-2-yl) ethyl] -N-hydroxyformamide

Example 3A (±) -3- (4- (4'-Carbonitrilphenyl) phenoxy) -3-iodo-2-propanol

A solution of iodine (1.54 g, 6.0 mmol) in dichloromethane (20 mL) was treated with triphenylphosphane (1.58 g, 6.0 mmol) for 5 min, stirred for 5 min, then added 3 times at a time. - (4'-Carbonitrilphenyl) phenoxy) propane- [1,2] oxirane (1.0 g, 4.0 mmol) and stirred at room temperature for 30 minutes. Water was added and the solution was partitioned between ethyl acetate and brine. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to 3 g of crude product, which was purified on a silica gel column eluting with 30% ethyl acetate / hexane to 1.38 g (91%) pure product.

MS (DCI / NH ₃ ) m / e 397 (M + NH 4) ⁺ and 414 (Μ + ΝΗ4 + ΝΗ3Λ)

Example 3B

3- (4- (4'-Carbonitrilephenyl) phenoxy) -1-iodopropan-2-one

The title compound was prepared as in Example 2C but substituting Example 3A (1.0 g, 2.63 mmol) instead of 3- (4- (4-carbonitrile-phenyl) -phenoxy) -1-thiophenoxy-propan-2-ol. Purification on a silica gel column eluting with 20% ethyl acetate / hexane gave 0.65 g (66%) of the title compound.

MS (DCI / NH 3) m / e 395 (M + NH 4) ⁺ and 412 (M + NH 4 + NH ₃ ) ⁺ .

Example 3C

- (4- (4'-Carbonitrilephenyl) phenoxy) -3-phthaloylpropan-2-one

A solution of Example 3B (1.38 g, 3.66 mmol) in DMF (20 mL) was treated with potassium phthalimide (1.02 g, 5.50 mmol), stirred for 10 minutes at room temperature. Water was then added and the solution was partitioned between ethyl acetate and brine. The organic layer was dried (Na ₂ SO 4) and concentrated to 1.1 g of crude product. Purification on a silica gel column eluting with ethyl acetate gave 0.98 g (67%) of the product.

MS (DCI / NH 3) m / e 414 (M + NH 4) ⁺

Example 3D (±) - N - [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,3-dihydro-1,3- dioxo-1H-isoindol-2-yl) ethyl] -N-hydroxyformamide

The title compound was prepared according to Example 2D, but instead of 1- (4- (4-carbonitrilophenyl) phenoxy) -3-thiophenoxypropan-2-one, the product of Example 3C was used to obtain the corresponding oxime which was reduced according to Example 2E using 1- (4- (4'-carbonitrile-phenyl) phenoxy) -3-phthaloylpropan-2-one oxime instead of 1- (4- (4'-carbonitrile-phenyl) phenoxy) -3-thiophenoxypropan-2-one oxime. The resulting hydroxylamine is formulated according to Example 2F, but using 1- (4- (4'-carbonitrilphenyl) phenoxy) -3-phthaloyl-2-propylhydroxylamine instead of 1- (4- (4-carbonitrilphenyl) phenoxy) -3-thiophenoxy-2. -propylhydroxylamine. Purification on a silica gel column eluting with 60% ethyl acetate / hexane gave 0.185 g (30%) of the title product.

m.p. 199-202;

1 H NMR (300 MHz, CDCl 3) d 10.06 (s; 0.5H), 9.67 (s; 0.5H), 8.32 (s; 0.5H), 7.99 (s; 0) 5H), 7.88 (m; 8H), 7.72 (m; 2H), 7.02 (m; 3H), 4.96 (m; 0.5H), 4.52 (m; 5H), 4.25 (m, 2H), 3.78-4.00 (m, 2H);

MS (DCI / NH 3) m / e 459 (M + H +) ⁺ ;

Calcd for C25H19N3O5: C, 67.96; H, 4.304; N, 9.51. Found: C, 67.43; H, 4.34; N, 9.04.

Example 4 (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2, 5-dioxoimidazolidin-1-yl) ethyl] -N-hydroxyformamide

Example 4A (±) -1- (4- (4'-Carbonitrilphenyl) phenoxy) -3 - ((5,5-dimethyl) hydantion-3-yl) -2-propanol

A solution of 5,5-dimethylhydanedione (0.26 g, 1.99 mmol) in THF (20 mL) was treated with potassium tert-butoxide (1.99 mL, 1.99 mmol) with stirring for 5 minutes. Adds at once

3- (4'-Carbonitrile-phenyl) -phenoxy) - [1,2] oxirane (0.50 g, 1.99 mmol) was stirred at 70 ° C for 6 hours. An excess of saturated aqueous ammonium chloride solution was added and the mixture was partitioned between ethyl acetate and brine. The organic layer was dried (Na 2 SO 4) and concentrated to a yellow solid

substance. Purification on a silica gel column eluting with ethyl acetate gave 0.70 g (93%) of the product.

MS (DCI / NH ₃ ) m / e 397 (M + NH 3) ⁺ .

Example 4B (±) -1- (4- (4'-Carbonitrilphenyl) phenoxy) -3- (3- (5,5-dimethyl) hydantione) -2- (t-butyldimethylsilyloxy) propane

A solution of the product of Example 4A (0.40 g, 1.06 mmol) in dichloromethane (20 mL) was treated with tert-butyldimethylsilyl chloride (0.24 g, 1.60 mmol) and imidazole (0.1 g, 1.6). mmol) with stirring at room temperature for 30 minutes. It was then mixed with water and partitioned between ethyl acetate and water. The organic layer was dried (Na 2 SO 4) and concentrated to a solid which was purified on a silica gel column eluting with 50% ethyl acetate / hexane to give 0.50 g (95%) of the product.

MS (DCI / NH 3) m / e 511 (M + NH 3) ⁺ .

Example 4C (±) -1- (4'-Cyano- [1,1'-biphenyl] -4-yl) oxy) -3- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidine) (1-yl) -2-butyldimethylsilyloxypropane

A solution of product 4B (0.60 g, 1.20 mmol) in THF (20 mL) was treated with sodium hydride (0.035 g, 1.40 mmol) and then in one portion with iodomethane (0.26 g, 1 mL). 8 mmol), stirred for 30 minutes at 70 ° C. An excess of saturated aqueous ammonium chloride solution was added and the mixture was partitioned between ethyl acetate and aqueous. The organic layer was dried (Na 2 SO 4) and concentrated to give the white crystals of the product.

Example 4D (±) -1- (4'-Cyano- [1,1'-biphenyl] -4-yl) oxy) -3- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidine) -1-yl) -2-propanol

A solution of Example 4C in THF (30 mL) was treated with tetrabutylammonium fluoride (1M in THF, 2.0 mL, 2.0 mmol) with stirring at ambient temperature for 30 minutes. It is then mixed with water and partitioned into ethyl acetate and aqueous portions. The organic layer was dried (Na 2 SO 4) and concentrated to a crude product which was purified on a silica gel column eluting with ethyl acetate to give 0.47 g (100%) of the product.

• 0 0 * 00 00 00 0 · 0 · • 0 0 0 0 0 • 0 0 0 • 0 0 0 0 0 0 0 0 • · · 0 00 00 00 0 00 00

MS (DCI / NH 3) m / e 411 (M + NH) ⁺ .

Example 4E (±) -1- (4'-Cyano- [1,1'-biphenyl] -4-yl) oxy) -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) ) -2-propanone

The product of Example 4D (0.59 g, 1.50 mmol) was reacted according to the procedures of Example 2C. Purification on a silica gel column eluting with 50% ethyl acetate / hexane gave 0.58 g (98%) of the title compound.

MS (DCI / NH 3) m / e 409 (M + NH) ⁺ .

Example 4F (±) - [1- (4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1 -) yl) -prop-2-yl] hydroxylamine

The product of Example 4E (0.57 g, 1.46 mmol) was treated according to the procedures of Examples 2D and 2E. Purification on a silica gel column eluting with 60% ethyl acetate / hexanes gave 0.31 g (52%) of the product.

MS (DCI / NH 3) m / e 409 (M + NH) ⁺ .

Example 4G (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2, 5-dioxoimidazolidin-1-yl) ethyl] -N-hydroxyformamide

The product of Example 4F was processed according to the procedures of Example 2F. Purification of the crude product on a silica gel column eluting with 60% ethyl acetate / hexane gave 0.19 g (60%) of the title compound.

m.p. 65-67 [deg.] C

MS (DCI / NH 3) m / e 437 (M + H) ⁺ and 454 (M + NH) ⁺ .

1 H NMR (300 MHz, CDCl ₃ ) d 9.90 (s; 0.5H), 9.58 (s; 0.5H), 8.32 (s; 0.5H), 7.92 (s; 0.5H), 7.85 (m; 4H), 7.72 (d; 2H; J = 5.6 Hz), 7.02 (dd; 2H; J = 5.5, 2.5 Hz), 4.86 (m; 0.5H), 4.42 (m; 0.5H), 4.05-4.02 (m; 2H), 3.82-3.70 (m; 1H), 3, 55-4.05 (m; 1H), 2.8 (s; 1.5H), 2.78 (s; 1.5H), 1.5 (s; 3H), 1.48 (s; 3H) ;

Calcd for C23H24N4O5: C, 63.23; H, 5.50; N, 12.83. Found: C, 62.96; H, 5.55; N, 12.45.

Example 5 (+ -) - [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -3- (3,4,4-trimethyl-2; 5-dioxoimidazolidin-1-yl) propyl] -N-hydroxyformamide

Example 5A 1- (Prop-2-enyl) -4,4-dimethyl-2,5-dioxoimidazolidine

A solution of 3-buten-1-ol (1 g, 13.9 mmol), triphenylphosphane (4.73 g, 18 mmol) and 5,5-dimethylhydantoin (2.1 g, 16.7 mmol) in THF (50 mL) was added. was treated dropwise with diethyl azodicarboxylate (3.13 g, 18.0 mmol) with stirring at ambient temperature for 1 hour. It is then mixed with water and partitioned into ethyl acetate and aqueous portions. The organic layer was dried (Na ₂ SO 4) and concentrated to a crude product which was purified on a silica gel column eluting with 50% ethyl acetate / hexanes to give 2.5 g (100%) of the desired compound.

Example 5B

- (Prop-2-enyl) -3,4,4-trimethyl-2,5-dioxoimidazolidine

The product of Example 5A (2.3 g, 18.9 mmol) in THF (50 mL) was treated with sodium hydride (0.45 g, 18.9 mmol) and then all at once with iodomethane (2.7 g, 18, 9 mmol), refluxed for 2 hours. It was then cooled, water was added and partitioned between ethyl acetate and aqueous. The organic layer was dried (Na ₂ SO 4) and concentrated to 3.5 g of a yellow solid, which was purified on a silica gel column eluting with 50% ethyl acetate / hexane to give 2.4 g (98%) of the title compound.

MS (DCI / NH ₃₎ m / e 214 (M + NH ₄₎ +.

Example 5C (±) -1 - ((1 ', 2'-Oxiranyl) propyl) -3,4,4-trimethyl-2,5-dioxoimidazolidine

A solution of 5B (3.0 g, 15.3 mmol) in dichloromethane (50 mL) was treated with m-chlorobenzoic acid (4.4 g) at ambient temperature for 2 h. An excess of saturated aqueous sodium carbonate solution was added and the mixture was partitioned between ethyl acetate and aqueous. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to a solid which was purified on a silica gel column eluting with 70% ethyl acetate / hexane to give 1.5 g (46%) of the title compound.

MS (DCI / NH ₃ ) m / e 213 (M + 1) ⁺ and 230 (M + NH 3) ⁺ .

Example 5D (±) -1- (2-hydroxy-3-iodopropyl) -3,4,4-trimethyl-2,5-dioxoimidazolidine

A solution of iodine (0.29 g, 1.88 mmol) in dichloromethane (20 mL) was stirred with triphenylphosphane (0.3 g, 1.88 mmol) for 5 min then added to one product from Example 5C (0.2 mL). g, 0.94 mmol). After stirring at room temperature for 30 minutes, water was added and the mixture was partitioned between ethyl acetate and aqueous layers. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to a yellow solid which was purified on a silica gel column eluting with 75% ethyl acetate / hexanes to afford 0.26 g (80%) of the title compound.

MS (DCI / NH ₃₎ m / e 342 (M + H) ⁺ 358 (M + NH) ^+.

Example 5E 1- (3-iodo-propan-2-onyl) -3,4,4-trimethyl-2,5-dioxoimidazolidine

The product of Example 5D was processed as in Example 2C. Purification of the crude product on a silica gel column eluting with 60% ethyl acetate / hexanes gave 0.3 g (96%) of the title compound.

MS (DCI / NH ₃ ) m / e 339 (M + H) ⁺ and 356 (M + NH 3) ⁺ .

Example 5F (±) -1- (3 - [(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] propan-2-one-1-yl) -3,4,4 -trimethyl-2,5-dioxoimidazolidine

A solution of 4'-hydroxy-4-biphenylcarbonitrile (0.38 g, 1.9 mmol) in THF (50 mL) was treated with potassium carbonate (0.5 g) and then with the product of Example 5E (0.44 g, 1 mL). (30 mmol), refluxed for 7 hours. After cooling, a 10% aqueous HCl solution was added and the mixture was partitioned between ethyl acetate and aqueous layers. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to a yellow solid, which was purified on a silica gel column eluting with 75% ethyl acetate / hexanes to give 0.52 g (99%) of the title compound.

MS (DCI / NH ₃₎ m / e 423 (M + NH) ^+.

Example 5G (±) -1- (3 - [(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] propan-2-oximo-1-yl) -3,4,4 -trimethyl-2,5-dioxoimidazolidine ·· · 00 0 «

9 · 9 9 9 9 9 • · 0 · 0 0 0 0 0 0

0 «« 00 00 «0

Example 5F was processed according to the procedures of Examples 2E and 2F. Purification of the crude product on a silica gel column eluting with 75% ethyl acetate / hexanes gave 0.68 g (1.60 mmol, 100%) of the title compound.

MS (DCI / NH) <RTIgt; m / e </RTI> 439 (M + NH) ⁺ .

Example 5H /

(±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -3- (3,4,4-trimethyl-2,5- dioxo-1-imidazolidinyl) propyl] -N-hydroxyformamide

Example 5G was processed according to the procedures of Examples 2E and 2F. Purification of the crude product on a silica gel column eluting with 75% ethyl acetate / hexanes gave 0.408 g (56%) of the product.

m.p. 68-70 [deg.] C .;

MS (DCI / NH 3) m / e 468 (M + NH) + ·

1 H NMR (300 MHz, CDCl ₃ ) d 9.99 (s; 0.5H), 9.46 (s; 0.5H), 8.35 (s; 0.5H), 7.92 (s; 0) 5H), 7.92 (d; 2H; J = 5.6 Hz), 7.85 (d; 2H; J = 5.6 Hz), 7.72 (d; 2H; J = 5.6 Hz) 7.05 (d; 2H; J = 5.6 Hz), 4.52 (m; 0.5H), 4.18-3.95 (m; 3.5H), 3.46 (m; 2H), 2.82 (s; 1.5H), 2.79 (s; 1.5H), 2.021.72 (m; 1H), 1.32 (s; 6H);

Calcd for C24H26N4O5: C, 63.93; H, 5.77; N, 12.43. Found: C, 63.38; H, 5.99; N, 11.97.

Example 6 (±) -N- [1 - [[[3 '- (cyanomethyl) - [1,1'-biphenyl] -4-yl) oxy] methyl] pentyl] -N-hydroxyformamide

Example 6A

4 - ((t-butyldimethyl) silyloxy) phenylboronic acid

A solution of (4-bromophenoxy) trimethylsilane (69 g, 20.9 mmol) in THF (60 mL) was stirred with n-butyllithium at -78 ° C for 15 min. Then 10 min at -78 ° C with triisopropylborate. The mixture was warmed to room temperature and stirred for an additional 30 minutes. Water was added and the mixture was partitioned between ethyl acetate and aqueous layers. The organic layer was dried (MgSO 4) and concentrated to 7.79 g (91%) of the product.

Example 6B ' -hydroxy-3-biphenylcarbonitrilomethane

0 «000

00 0 0

0 0

0 0

A mixture of Example 6A (4.8 g, 19.0 mmol), 3-bromophenylacetonitrile (3.1 g, 16.0 mmol), cesium carbonate (7.8 g, 24.0 mmol) and tetrakis (triphenylphosphane) complex. palladium (0.55 g, 0.48 mmol) was mixed and allowed to react with DMF (30 mL) at 100 ° C for 10 h via a syringe under nitrogen ammonium. Water was then added and the mixture was partitioned between ethyl acetate and aqueous. layer. The organic layer was dried (MgSO ₄ ) and concentrated to a brown oil which was purified on a silica gel column eluting with 50% ethyl acetate / hexanes to give 3.3 g (82%) of the product.

MS (DCI / NH 3) m / e 227 (M + NH 3) ⁺ .

Example 6C Ethyl [2- (4- (3'-carbonitrilmethylphenyl) phenoxy) acetate]

A solution of Example 6B (0.5 g, 2.4 mmol) in THF (20 mL) was treated with potassium carbonate (0.5 g) and ethyl bromoacetate (0.6 g, 3.6 mmol), refluxed after for 3 hours. After cooling, add 10% aqueous HCl and separate the mixture into ethyl acetate and brine. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to a yellow solid which was purified on a silica gel column eluting with 50% ethyl acetate / hexanes to give 0.48 g (68%) of the product.

1 H NMR (300 MHz, CDCl ₃ ) d 7.52 (m; 4H), 7.40 (m; 1H), 7.36 (m; 1H), 7.00 (m; 2H), 4.65 ( s; 2H), 4.30 (q; 2H; J = 4.8Hz), 3.80 (q; 2H; J = 4.8Hz), 3.80 (s; 2H), 1.32 (s) t: 3H; J = 4.8 Hz).

Example 6D

2- (4- (3'-Carbonitrilmethylphenyl) phenoxy) acetic acid

A solution of Example 6C (0.47 g, 1.6 mmol) in 1,4-dioxane (20 mL) and water (10 mL) was treated with lithium hydroxide (0.5 g) at room temperature for 30 min. Then add 10% aqueous HCl and separate the mixture into ethyl acetate and aqueous layers. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to a yellow solid which was purified on a silica gel column eluting with 50% ethyl acetate / hexanes to give 0.37 g (83%) of the title compound.

1 H NMR (300 MHz, CDCl ₃ ) d 7.60 (m; 4H), 7.46 (m; 1H), 7.32 (m; 1H), 7.02 (m; 2H), 4.72 (s; 2H), 4.08 (s; 2H).

Example 6E

N, O-dimethyl-2- (4- (3'-carbonitrilomethylphenyl) phenoxy) acetyl hydroxylamine

• ·· • ·· ·· • ·· • • 4) • · • · ·· • • * • • • • • • • • • • · • ··· ··· · « ··· ·· ··

A solution of Example 6D (0.35 g, 1.3 mmol), triethylamine (0.5 mL), and bis (2-oxo-3-oxazolidinyl) -phosphonic acid chloride (0.78 g, 2.6 mmol) in dichloromethane ( 20 ml) was treated with Ν, Ο-dimethyl-hydroxylamine hydrochloride (0.25 g, 2.6 mmol) at ambient temperature for 2 hours. Water was then added and the mixture was partitioned between ethyl acetate and aqueous layers. The organic layer was dried (Na 2 SO ₄ ) and concentrated to a yellow solid which was purified on a silica gel column eluting with 50% ethyl acetate / hexanes to afford 0.28 g (69%) of the title compound.

1 H NMR (300 MHz, CDCl ₃ ) d 7.59 (m; 4H), 7.46 (m; 1H), 7.32 (m; 1H), 7.02 (m; 2H), 4.96; 1 (s; 2H), 4.08 (s; 2H), 3.78 (s; 3H), 3.15 (s; 3H).

Example 6F

- (4- (3'-Carbonitrilmethylphenyl) phenoxy) -2-hexanone

A solution of Example 6E (0.27 g, 0.85 mmol) in THF (10 mL) was cooled to -78 ° C and treated with equally cold n-butylmagnesium bromide (1 mL, 2.0 mmol) for 1 h. Water was then added and the mixture was partitioned between ethyl acetate and brine. The organic layer was dried (Na 2 SO ₄ ) and concentrated to a yellow solid which was purified on a silica gel column eluting with 25% ethyl acetate / hexanes to give 0.15 g (59%) of the title compound.

1 H NMR (300 MHz, CDCl ₃ ) d 7.52 (m; 4H), 7.42 (m; 1H), 7.28 (m; 1H), 6.98 (m; 2H), 4.60 (s; 2H), 3.82 (s; 2H), 2.62 (t; 2H; &gt; 5.5 Hz), 1.64 (m; 2H), 1.38 (m; 2H), O, 92 (t; 3H; > 4.8 Hz).

Example 6G (±) -N- [1 - [[[3 '- (cyanomethyl) - [1,1'-biphenyl] -4-yl) oxy] methyl] pentyl] -N-hydroxyformamide »

The product of Example 6F (0.15 g, 0.50 mmol) was processed according to the procedures described in Example 2D-F (inclusive). Purification on a silica gel column eluting with 40% ethyl acetate / hexanes gave 0.07 g (41%) of the title compound, m.p. 99-101 [deg.] C .;

MS (DCI / NH ₃₎ m / e 352 (M + NH /.

1 H NMR (300 MHz, CDCl ₃ ) d 8.58 (brs; 0.5H), 8.04 (brs; 0.5H), 8.0 (s; 1H), 7.48 (m; 4H) 7.42 (m; 1H); 7.26 (m; 1H); 6.98 (m; 2H); 4.05 (t; 1H;> 5.6 Hz); 3.8-4.0 (m; 2H), 3.80 (s; 2H), 1.92 (m; 1H), 1.60 (m; 2H), 1.38 (m; 3H), 0.98 (t; 3H; > 4.8 Hz);

Calcd for C21H24N2O3: C, 71.50; H, 6.81; N, 7.94. Found: C, 71.44; H, 6.90; N, 7.80.

Example 7 (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -3-methylbutyl] -N-hydroxyformamide

4'-Hydroxy-4-biphenylcarbonitrile (1.0 g, 5.12 mmol) was treated according to the procedures described in Examples 6C-G (inclusive), but isobutylmagnesium bromide was used instead of n-butyl magnesium bromide in Example 6F. Purification on a silica gel column eluting with 30% ethyl acetate / hexanes gave 0.036 g of the title compound.

m.p. 112-113 [deg.] C .;

MS (DC1 / _NH3) m / e 356 (M + NH) ^+;

1 H NMR (300 MHz, CDCl ₃ ) d 7.95 (s; 1H), 7.70 (d; 2H; J = 5.6 Hz), 7.62 (d; 2H; J = 5.8) 7.52 (d; 2H; J = 5.8 Hz), 6.98 (d; 2H; J = 5.8), 4.25 (m; 1H), 3.92-4.05 (m) 2H), 1.95 (m; 1H), 1.75 (m; 1H), 1.35 (m; 1H), 1.00 (d; 3H; J = 4.8 Hz), 0.98 (d; 3H; J = 4.8Hz);

Calcd for C 20 H ₂ N ₂ O ₃ : C, 70.92; H, 6.50; N, 8.27. Found: C, 70.91; H, 6.68; N, 8.13.

Example 8 (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2-methylbutyl] -N-hydroxyformamide

The title compound was prepared according to the procedures described in Example 7, but secbutylmagnesium chloride was used in place of isobutylmagnesium bromide. Purification on a silica gel column eluting with 30% ethyl acetate / hexanes gave 0.10 g of the title compound, m.p. 96-98 [deg.] C .;

MS (DC1 / _NH3) m / e 356 (M + NH) ^{+; 1}

1 H NMR (300 MHz, CDCl ₃ ) d 7.95 (s; 1H), 7.70 (d; 2H; J = 5.6 Hz), 7.62 (d; 2H; J = 5.8), 7.52 (d; 2H; J = 5.8 Hz); 6.98 (d; 2H; J = 5.8); 4.32 (m; 1H); 4.15 (m; 2H); 65 (m; 1H); 1.98 (m; 1H); 1.62 (m; 1H); 1.02 (m; 3H); 0.98 (m; 3H);

Anal. Calcd for 0.8 H ₂ O ₂ O ₂ 2Ν ₂ 0 ₃ : N, 68.03; H, 6.69; N, 7.90. Found: C, 68.60; H, 6.58; N, 7.23.

Example 9 (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] pentyl] -N-hydroxyformamide

The title compound was prepared according to the procedures described in Example 7, but using n-butyl magnesium bromide instead of isobutyl magnesium bromide. Purification on a silica gel column eluting with 30% ethyl acetate / hexane gave 0.210 g of product, m.p. 105-108 [deg.] C .;

MS (DCI / NH 3) m / e 356 (Μ + ΝΗ,) ⁺ ;

1 H NMR (300 MHz, CDCl ₃ ) d 7.95 (s; 1H), 7.70 (d; 2H; J = 5.6 Hz), 7.62 (d; 2H; J = 5.8) 7.52 (d; 2H; J = 5.8 Hz), 6.98 (d; 2H; J-5.8), 4.25 (m; 1H), 3.99-3.82 (m 2H), 1.92 (m, 1H), 1.60 (m; 2H), 1.40 (m; 3H), 0.98 (t; 3H; J = 4.23 Hz);

Calcd for 0.5 Cefl + C20H22N2O3: C, 73.13; H, 6.62; N, 7.42. Found: C, 73.18; H, 6.65; N, 7.39.

Example 10 (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4-methylphenyl) ethyl] -Nhydroxyformamide

The title compound was prepared as described in Example 7, but using 4-methylbenzyl magnesium bromide instead of isobutyl magnesium bromide. Purification on a silica gel column eluting with 30% ethyl acetate / hexane gave 0.24 g of product, m.p. 173-175 [deg.] C .;

MS (DCI / NH 3) m / e 404 (M + NH ₄ ) ⁺ ;

1 H NMR (300 MHz, CDCl 3) d 7.70 (d; 2H; J = 5.6 Hz), 7.68 (s; 1H), 7.62 (d; 2H; J = 5.8), 7.52 (d; 2H; J = 5.8 Hz); 7.12 (s; 4H); 6.98 (d; 2H; J = 5.8); 4.35 (m; 1H); 12-3.98 (m; 2H); 3.15 (m; 1H); 2.94 (m; 1H); 1.35 (s; 3H);

Calcd for C24H22N2O3: C, 74.52; H, 5.69; N, 7.24. Found: C, 73.95; H, 5.79; N, 7.06.

Example 11 (±) -N- [2 - [(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] -1- (4-fluorophenyl) ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures described in Example 7, but using 4-fluorophenyl magnesium bromide instead of isobutyl magnesium bromide. Purification on a silica gel column eluting with 30% ethyl acetate / hexanes gave 0.285 g of product, m.p. Mp 194-196 ° C;

MS (DCI / NH 3) m / e 394 (M + H +) ⁺ ;

1 H NMR (300 MHz, CDCl ₃ ) d 9.70 (brs; 1H), 8.42 (s; 0.5H), 8.28 (s, 0.5H), 7.86 (m, 4H),

7.72 (d; 2H; J = 5.6 Hz), 7.55 (m; 2H), 7.25 (m; 2H), 7.12 (d; 2H; J = 5.8 Hz), 5.72 (brs; 0.5H),

5.35 (brs; 0.5H), 4.60 (m, 1H), 4.36 (m, 1H);

Calcd for C22H17N2O3F: C, 70.14; H, 4.45; N, 7.44. Found: C, 70.19; H,

4.25; N, 7.30.

Example 12 (±) -N- [2 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4-fluorophenyl) ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures described in Example 7 and using 4-fluorobenzyl magnesium bromide in place of isobutylmagnesium bromide. Purification on a silica gel column eluting with 30% ethyl acetate / hexane gave 0.22 g of product.

MS (DCI / NH 3) m / e 408 (M + NH 3) ⁺ ;

1 H NMR (300 MHz, CDCl 3) d 8.35 (brs; 1H), 7.65 (m; 5H), 7.52 (d; 2H; J = 5.6 Hz), 7.20 (m; 2H) 1.98 (m; 4H), 4.35 (m; 1H), 4.15-3.98 (m; 2H), 3.18 (dd; 1H; J = 6.0, 9.0) Hz), 2.95 (dd; 1H; J = 3.0, 9.0 Hz);

Calcd for C23H19N2O3F: C, 70.69; H, 4.87; N, 7.17. Found: C, 70.38; H, 4.96; N, 6.98.

Example 13 (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] ethyl] -N-hydroxyformamide

Example 13A (4- (4'-Carbonitrilphenyl) phenoxy) propan-2-one

A solution of 4- (4'-carbonitrile-phenyl) -phenol (4.86 g, 24.9 mmol) in DMF (100 mL) was first reacted at 50 ° C for 10 minutes with potassium carbonate (13.8 g, 99.6). mmol) and then with stirring at room temperature for 4 hours with one portion of chloroacetone (2.48 mL, 30 mmol). The mixture was partitioned between an organic layer (ether: hexane 3: 1) and an aqueous layer saturated with sodium carbonate. The organic layer was dried (MgSO 4) and concentrated under vacuum to 1/3 of the original volume until the product started to precipitate out of solution. The solution was diluted with excess ether and cooled to -20 ° C and allowed to stand for 17 hours. The title compound (2.01 g, 32%) was collected by filtration and dried in vacuo.

MS (DCI / NH 3) m / e 251 (M) ⁺ , 269 (M + NH 3) ⁺ , 286 (M + NH 4 + NH 3) ⁺ .

Example 13B (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures described in Examples 2D-F, but replaced by Example 13A (2.00 g, 7.96 mmol) for Example 2C. Purification of the final crude product on a silica gel column eluting with 5% methanol / dichloromethane gave 325 mg of the title compound.

m.p. 141-144 [deg.] C .;

MS (DCI / NH ₃ ) m / e 314 (M + NH 3) ⁺ ;

1 H NMR (300 MHz, d ₆ -DMSO) d 9.88 and 9.45 (br s; 1H), 8.02 and 8.33 (s; 1H), 7.90 (AB; 2H; J = 7) 5 Hz), 7.84 (AB; 2H; J = 7.5 Hz), 7.61 (d; 2H; J = 9 Hz), 7.06 (d; 2H; J = 9 Hz), 4 67 (m; 0.32H), 3.92-4.25 (m; 2.68H), 1.23 and 1.18 (d; 3H; J = 6 Hz);

Calcd for C17H16N2O3: C, 68.90; H, 5.44; N, 9.45. Found: C, 68.61; H, 5.55; N, 9.21.

Example 14

N- [2 - [(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyacetamide

Example 14 A

2- (4- (4'-Carbonitrilephenyl) phenoxy) bromoethane

A solution of 4- (4'-carbonitrilphenyl) phenol (3.00 g, 24.8 mmol) in DMF (20 mL) was allowed to react at 50 ° C for 19 hours with potassium carbonate (8.24 g, 99.4 mmol) and 1,2-dibromoethane (6.42 mL, 124 mmol). The mixture was partitioned between an organic layer (ether: hexane 3: 1) and an aqueous layer. The organic layer was isolated from aqueous, which was then extracted with 3: 1 etherrhexane. The combined organic layers were combined and dried (MgSO 4) and concentrated. Purification of the crude product on a silica gel column eluting with 50% dichloromethane / hexanes gave a solid which, after recrystallization from ether / pentane, gave 1.25 g (17%) of the title compound as colorless needles.

MS (DCI / NH 3) m / e 301/303 (M) ⁺ , 319/321 (M + NH) ⁺ , 336/338 (M + NH 4 + NH 3) ⁺ .

Example 14B

N, O-bis (t-butyloxycarbonyl) 2- (4- (4'-carbonitrilephenyl) phenoxy) ethyl-N-hydroxylamine 9 · · · · · · · · · · · · · · · · · ·

A solution of N, O-bis (t-butyloxycarbonyl) -N-hydroxylamine (443 mg, 1.9 mmol) in DMF (15 mL) was treated with 60% sodium hydride (76 mg, 1.9 mmol) at ambient temperature for 15 min. ) dispersed in oil. The product of Example 13A (0.54 g, 1.79 mmol) was added and the mixture was allowed to react at room temperature for 4 hours. The mixture was partitioned into an organic 1: 1 ether: hexane layer and an aqueous layer saturated with ammonium chloride. The organic layer was separated and the aqueous extracted with 1: 1 ether: hexane. The mixture of the two organic layers was dried (MgSO ₄ ) and concentrated. Purification on a silica gel column with 10% ethyl acetate / hexanes afforded 0.65 g (80%) of the compound as a colorless viscous oil.

Example 14C

2- (4- (4'-Carbonitrilphenyl) phenoxy) ethyl-N-hydroxylamine hydrochloride

The product of Example 14B (0.64 g, 1.41 mmol) was treated with 4N hydrochloric acid in dioxane (10 mL) at ambient temperature for 2.5 hours. A colorless deposit is formed during the reaction. This was filtered, washed with dioxane and dried to give a colorless HCl salt (0.22 g, 56%).

Example 14D

N, O-bis (acetyl) -2- (4- (4'-carbonitrilphenyl) phenoxy) ethyl-N-hydroxylamine

A solution of Example 14C (27 mg, 0.093 mmol) in THF at 0 ° C was treated with triethylamine (32 mL, 0.23 mmol) for 1 hour. Acetyl chloride (16 μΐ) was added dropwise and allowed to react at 0 ° C for 1 hour and then at ambient temperature for an additional 18 hours. The solution was partitioned into 1N aqueous HCl and ether. The organic phase was separated and the aqueous extracted into ethyl acetate. The combined organic phases were dried (MgSO ₄ ) and concentrated. Purification on a silica gel column eluting with 2% acetone / dichloromethane gave 29 mg (83%) of the title compound.

Example 14E

N- [2 - [(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyacetamide

A solution of the product of Example 14D (29 mg, 0.077 mmol) in THF (5 mL) and ethanol (2 mL) was cooled to 0 ° C and treated with aqueous lithium hydroxide (0.31 mL 1, ON LiOH) for 10 min, then the reactants were warmed to ambient temperature and allowed to react for 1.5 hours. It was then separated into aqueous and ethyl acetate layers. The organic layer was separated and the aqueous extracted with ether. The combined organic phases were washed in 1N aqueous HCl, dried (MgSO4) and concentrated.

semi-solid, which was purified by trituration in ethyl acetate to give 19.7 mg (86%) of a colorless title compound, m.p. Mp 174-175 ° C

MS (DCI / NH 3) m / e 297 (M + H) ⁺ and 314 (Μ + ΝΗ) ⁺ ;

1 H NMR (300 MHz, d 1 -DMSO) d 9.90 (br s; 1H), 7.88 (AB; 2H; J = 7.5 Hz), 7.84 (AB; 2H; J = 7) 5 Hz), 7.71 (d; 2H; J = 8.5 Hz), 7.07 (d; 2H; J = 8.5 Hz), 4.20 (t; 2H; J = 7.5 7.5 Hz) 3.89 (t; 2H; J = 7.5, 7.5 Hz) 2.02 (s; 3H);

Calcd for C 17 H 16 N 2 O 3 (0.25H 2 O): C, 67.87; H, 5.52; N, 9.31. Found: C, 67.65; H, 5.55; N, 9.12.

Example 15

N- [2 - [(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide

A solution of Example 14C (78 mg, 0.27 mmol) in THF (2.0 mL) was first treated with triethylamine (75 mL, 0.54 mL) and then 2 hours at ambient temperature with formacetylanhydride (41 mg) added dropwise. , 0.30 mmol) in THF (0.5 mL). The mixture was partitioned between an ethyl acetate layer and an aqueous layer containing 1N hydrogen chloride. After separation, the aqueous layer was extracted with ethyl acetate. The two organic phases, after combination dried (MgSO ₄₎ and concentrated. Purification on a silica gel column eluting with 0.2% acetic acid / ethyl acetate followed by recrystallization from cold methanol gave 14.7 mg (19%) of the title compound.

m.p. M.p. 142-145 ° C

MS (DCI / NH 3) m / e 300 (M + H +) ⁺ ;

1 H NMR (300 MHz, d 6 -DMSO) d 10.18 and 9.74 (br s; 1H), 8.34 and 7.98 (br s, 1H), 7.88 (AB; 2H; J = 7) 5 Hz), 7.84 (AB; 2H; J = 7.5 Hz), 7.73 (d; 2H; J = 8.5 Hz), 7.07 (d; 2H; J = 8.5 Hz) Hz), 4.14-4.26 (m; 2H); 3.77-3.88 (m; 2H);

Calcd for C 16 H 14 N 2 O 3 (0.125H 2 O): C, 67.54; H, 5.05; N, 9.84. Found: C, 67.59; H, 5.32 N, 9.53.

Example 16

N- [1- [4 - [(2E-Phenylethenyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

Example 16A

3- (3,4,4, -trimethyl-2,5-dioxoimidazolidin-1-yl) -2-methoxymethyloxy-prop-1-ene

A mixture of 1,5,5-trimethylhydantoin (7.0 g, 49.2 mmol), powdered potassium carbonate (8.16 g, 59 mmol) and 2-methoxymethyloxy-allyl chloride (7.56 g, 56 mmol) in dry DMF (100 mL) was warmed to 100 ° C and stirred for 1.5 hours. The reaction mixture was cooled, filtered and concentrated, then partitioned between ethyl acetate and aqueous layers. The organic phase was washed twice with water and brine, then dried and concentrated. Purification on a silica gel column eluting with 50% ethyl acetate / hexanes gave 10.58 g (89%) of the title compound. MS (DCI / NH 3) m / e 260 (M + NH) ⁺ and 243 (M + H) ⁺ ;

Example 16B

-bromo-3- (3,4,4'-trimethyl-2,5-dioxoimidazolidin-1-yl) propan-2-one

A solution of Example 16A (10.58 g, 43.7 mmol) in acetone (200 mL) at 0 ° C was treated sequentially with aqueous (60 mL) potassium carbonate solution (0.58 g, 4.2 mmol) and N-bromosuccinimide (8.56 g, 48 mmol). The resulting mixture was stirred in an ice bath. After 1 and 2 hours respectively, two portions of 1.5 g of N-bromosuccinimide are added. The ice bath was removed and the reaction stirred for 10 minutes. It was further concentrated and extracted twice with ethyl acetate. The combined extracts were washed with water with 0.5M NaHSO ₄ , 1M NaHCO 3, water and brine. The solution was dried and concentrated. Purification on a silica gel column eluting with 50% ethyl acetate / hexane gave 7.39 g (61%) of the title compound.

MS (DCI / NH 3) m / e 294/296 (M + NH) ⁺ and 277/279 (M + H) ⁺ ;

Example 16C

- (4'-Bromophenyloxy) -3- (3,4,4'-trimethyl-2,5-dioxoimidazolidin-1-yl) propan-2-one

To a suspension of 4-bromophenol (3.99 g, 23.0 mmol) and cesium carbonate (7.45 g, 22.9 mmol) in DMF (150 mL) was added dropwise to a solution of bromoketone 16B (3 g,

11.5 mmol) in DMF (5 mL). The suspension is suspended at RT for 16 hours. Separate with ethyl acetate (500 mL), wash the organic phases with water and brine, dry (MgSO ₄ ) and concentrate under vacuum. Flash chromatography (hexane / ethyl acetate 1: 1) gave 2.55 g of the desired compound 16C as a white solid.

Example 16D

To a hot (100 ° C) solution of 16C (0.5 g, 1.25 mmol) and tributyl (phenylethenyl) tin (0.64 g, 1.62 mmol, Aldrich) in toluene (25 mL) was added a catalytic amount Pd (PPh 3) 4. The reaction was heated to reflux and maintained for 7 hours. The resulting black solution was diluted with ethyl acetate (125 mL). The organic phase was washed with aqueous 1 N NaOH and brine, dried (MgSO 4) and concentrated under vacuum. Flash chromatography (hexane / ethyl acetate gradient from 4: 1 to 1: 1) gave 0.24 g of the desired compound after trituration in diethyl ether.

Example 16E

N- [1- [4 - [(2E-Phenylethenyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide

The title compound was prepared as in Example 2D-F by substituting 16D for 2C.

MS (ESI) mlz 436 (M-H) and 438 (M + H);

1 H NMR (300 MHz, d 6 -DMSO) d 9.90 (s; 0.5H), 9.58 (s; 0.5H), 8.31 (s; 0.5H), 7.90 (s; 0.5H), 7.57-7.54 (m; 6H), 7.38-7.33 (m; 2H), 7.26-7.08 (m; 6H), 6.94-6, 90 (m; 2H), 4.804.60 (m; 0.5H), 4.55-4.40 (m; 0.5H), 4.16-4.04 (m; 4H), 3.76- 3.73 (m; 2H); 3.61-3.57 (m; 2H); 2.79 (s; 6H); 1.28 (s; 12H);

Anal. Calcd for (.delta.): C, 63.28; H, 6.41; N, 9.22. Found: C,

63.06; H, 5.97; N, 8.94.

Example 17

N- [1 - [[4- (2-furanyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

Prepared in the same manner as in Example 16 by substituting 2- (tributylstannyl) furan for tributyl (phenylethenyl) tin in Example 16D.

MS (ESI) mlz 402 (M-H) and 400 (M + H), 419 (M + NEU);

1 H NMR (300 MHz, d 6 -DMSO) d 9.86 (s; 0.5H), 9.53 (s; 0.5H), 8.30 (s; 0.5H), 7.91 (s) s; 0.5H), 7.67-7.61 (m; 6H), 6.96-6.94 (m; 4H), 6.79-6.74 (d; 2H; J = 3.4) Hz), 6.55-6.54 (m; 2H), 4.80-4.60 (m; 0.5H), 4.45-4.30 (m; 0.5H), 4.17- 3.98 (m; 6H), 3.76-3.70 (m; 2H), 3.62-3.56 (m; 2H), 2.79 (s; 6H), 1.28 (s; 12H);

Calcd for C ₂₀ H 23 N ₃ O ₆ : C, 59.84; H, 5.77; N, 10.46. Found: C, 59.83; H, 5.60; N, 10.12.

Example 18

N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1 imidazolidinyl) ethyl 1-N-hydroxyformamide

Example 18A 1- (4'-Butyloxy [1,1'-biphenyl] -4-yl) oxy) -3- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) -2-propanone

To a hot (75 ° C) solution of Example 16C (0.1 g, 0.27 mmol) and 4-butoxyphenylboronic acid (0.08 g, 0.41 mmol) in DME (2 mL) was added 1M Na ₂ solution. CO 3 (0.4 mL) followed by a catalytic amount of PdCl ₂ (dppf). The reaction was allowed to run at 100 ° C for 2 h. It was then diluted with ethyl acetate (25 mL), washed with saturated ammonium chloride, water and brine, dried (MgSO 4 and concentrated under vacuum. Flash chromatography (20% ethyl acetate in methylene chloride) gave 0.105 g of the desired compound 5 as a white solid.

Example 18B

N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazohdinyl) ethyl 1-N-hydroxyformamide

The preparation is identical to Example 2D-F, but 18A is used instead of 2C.

MS (ESI) mle 484 (M + H), 506 (M + NH 4);

1 H NMR (300 MHz, d 6 -DMSO) d 9.867 (s; 0.5H), 9.55 (s; 0.5H), 8.31 (s; 0.5H), 7.91 (s;

0.5H), 7.55-7.50 (m; 8H), 6.98-6.95 (m; 8H), 4.80-4.60 (m; 0.5H), 4.50- 4.35 (m; 0.5H), 4.164.06 (m; 4H), 4.01-3.96 (t; 4H; J = 7.0, 5.9 Hz), 3.76-3, 70 (m; 2H), 3.62-3.59 (m; 2H), 2.80 (s, 6H), 1.72-1.65 (m; 4H), 1.48-1.40 (m) m; 4H), 1.29 (s; 12H), 0.96-0.91 (t; 6H; J = 7.1, 7.5 Hz); Calcd for C 6 H 33 N 3 O 6 '. C, 64.57; H, 6.87; N, 8.68. Found: C, 64.70; H, 7.04; N, 8.50.

Example 19

N- [1 - [[(4'-Fluoro [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

Example 19A

3- (3,4,4-Trimethyl-2,5-dioxo-1-imidazolidinyl) -propane- [1,2] oxirane

The title compound was prepared according to the procedures described for Example 5A 5C, but using allyl alcohol instead of 3-buten-1-ol.

Example 19B

N- [1 - [[(4'-fluoro [1,1'-biphenyl) -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl) -N-hydroxyformamide

Prepared according to the reaction sequences described in Examples 5D through 5H, replacing 19A with 5C in Example 5D and 4- (4'-fluorophenyl) -phenol with 4'-hydroxy-4-biphenylcarbonitrile in Example 5F. Ή NMR (300 MHz, d ₆ -DMSO) δ 9.86 (S, 0.5H), 9.54 (S, 0.5H), 8.31 (S, 0.5H), 7.91 (S , 0.5H), 7.67-7.57 (Μ, 6H), 7.27-7.22 (Μ, 3H), 7.01-6.97 (Μ, 3H), 4.96-4 70 (M, 0.5H), 4.504.40 (M, 0.5H), 4.18-4.08 (Μ, 3H), 3.77-3.73 (Μ, 2H), 2.79 (S, 6H), 1.28 (S, 12H), MS (ESI), m / e 430 (M + H), 428 (MH),

Anal Calcd for C 22 H ₂ 4N3O5F * 0,5H2O: C, 60.26; H, 5.74; N, 9.58. Found: C, 60.48; H, 5.66; N, 8.72,

Example 20

N- [1 - [(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '(trifluoromethyl) [1,1'-biphenyl] 4-yl] oxy) ethyl] -N-hydroxyformamide

Prepared according to the reaction sequence described in Examples 5D through 5H, replacing 19A with 5C in Example 5D and replacing 4- (4'-trifluoromethylphenyl) phenol with 4'-hydroxy-4-biphenylcarbonitrile in Example 5F. ^! 1 H NMR (300 MHz, d 6 -DMSO), δ 9.80 (S, 0.5H), 9.58 (S, 0.5H), 8.32 (S, 0.5H), 7.92 ( S, 0.5H), 7.87-7.84 (D, 4H, J = 8.1 Hz), 7.79-7.76 (D, 4H, J = 8.8 Hz), 7.72 -7.69 (d, 4H, J = 8.4 Hz), 7.06-7.02 (m, 4H), 4.80-4.60 (m, 0.5H), 4.45-4 40 (m, 0.5H), 4.20-4.12 (m, 4H), 3.78-3.74 (m, 2H), 3.63-3.62 (m, 2H), 2 0.08 (s, 6H), 1.30 (s,

12H), MS (ESI) mlz M-H (478), M + H (480).

Anal Calcd for C23H24N3O ₅ F ₃ * 0,5H2O: C, 56.55; H, 5.15; N, 8.60. Found: C, 56.52; H, 5.07; N, 8.43.

Example 21 (±) -N- [1 - [[(4'-Methoxy [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5- dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 • · • 9 • · • · • 9 9 9 • 9 9 9 9 9 9 9 • 9 ··· 99 9 9

Prepared according to the reaction sequence described in Examples 5D through 5H, replacing 19A with 5C in Example 5D and 4- (4'-methoxyphenyl) phenol with 4'-hydroxy-4-biphenylcarbonitrile in Example 5F. 1 H NMR (300 MHz, d 6 -DMSO), δ 9.89 (s 0.5H), 9.57 (s, 0.5H), 8.31 (s, 0.5H), 7.91 (s) s, 0.5H), 7.56-7.53 (d, 8H, J = 8.8 Hz), 7.01-6.94 (m, 8H), 4.80-4.60 (m, 0.5H), 4.44-4.35 (m, 0.5H), 4.17-3.95 (m, 4H), 3.74-3.71 (m, 2H), 3.63- 3.58 (m, 2H), 2.79 (s, 6H), 1.28 (s, 12H), MS (ESI) m / e M + H (442),

Anal Calcd for C ₂ 3H ₂ 6N3O6 * 0.25H ₂ O: C, 62.08; H, 6.00; N, 9.44. Found: C, 62.25; H, 6.30; N, 8.94.

Example 22

N- [1 - [[(4'-Methyl [1,1-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl 1-N-hydroxyformamide

Prepared according to the reaction sequence described in Examples 5D through 5H, replacing 19A with 5C in Example 5D and 4- (4'-methoxyphenyl) phenol with 4'-hydroxy-4-biphenylcarbonitrile in Example 5F. Δ NMR (300 MHz, d 6 -DMSO) δ 9.89 (s; 0.5H), 9.57 (s, 0.5H), 8.31 (s, 0.5H), 7.92 (s, 0.5H), 7.59-7.56 (d, 4H, J = 8.8 Hz), 7.52-7.49 (d, 4H, J = 8.1 Hz), 7.24-7 22 (d, 4H, > 7.7 Hz), 7.00-6.97 (m, 4H), 4.80-4.60 (m, 0.5H), 4.40-4.35 ( m, 0.5H), 4.40-4.1 (m, 4H), 3.80-3.55 (m, 2H), 3.60-3.50 (m, 2H), 2.79 ( s, 6H), 2.32 (s, 6H), 1.28 (s, 12H),

MS (ESI) mlz 424 (M-H), 426 (M + H);

Calcd for C 3 H ₂₇ N3O _{2 5} * 0.25H ₂ O: C, 64.24; H, 6.44; N, 9.77. Detected; C, 64.30; H, 6.55; N, 9.36.

Example 23

N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazohdinyl) ethyl] - N-hydroxyformamide

Example 23A

-Bromo-3- (4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) propan-2-one

The title compound was prepared according to the procedure described in Examples 16A and 16B, except substituting 5,5-dimethylhydantoin for 1,5,5-trimethylhydantoin in Example 16A.

Example 23B

N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl) oxy] methyl) -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] - N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, substituting Example 23A for 16B and

Of 4- (4'-butyloxyphenyl) phenol to 4-bromophenol in Example 16C. 1 H NMR (300 MHz, d 6 -DMSO) δ 9.86 (s, 0.5H), 9.55 (s, 0.5H), 8.36 (s, 0.5H), 8.34 (s) s, 0.5H), 8.32 (s, 0.5H), 7.94 (s, 0.5H), 7.55-7.51 (m, 8H), 6.99-6.96 ( m, 8H), 4.85-4.80 (m, 0.5H), 4.40-4.36 (m, 0.5H), 4.20-4.06 (mm, 2H), 4, 01-3.97 (m, 4H), 3.78-3.71 (m, 2H), 3.60-3.51 (m, 2H), 1.73-1.66 (m, 6H), 1.451.38 (m, 4H), 1.25 (s, 12H), 0.96-0.86 (m, 6H).

MS (ESI) mlz (M-H) (468).

Calcd for C25H30N3O6: C, 63.95; H, 6.65; N, 8.94. Found: C, 63.89; H,

N, 8.63.

Example 24

N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [(4'-ethoxy [1,1'-biphenyl] -4yl) oxy] ethyl) - N-hydroxyformamide

Prepared according to the procedures of Example 23B, except substituting 4- (4'-ethoxyphenyl) phenol for 4- (4'-butyloxyphenyl) phenol. Ή NMR (300 MHz, d ₆ -DMSO) δ 9.84 (s, 0.5H), 9.52 (s, 0.5H), 8.37 (s, 0.5H), 8.32 (s 0.5H), 7.92 (s, 0.5H), 7.55-7.52 (m, 8H), 6.98-6.95 (d, 4H, J = 8.8 Hz), 4.90-4.80 (m, 0.5H), 4.45-4.30 (m, 0.5H), 4.19-3.98 (m, 8H), 3.74-3.67 (m, 2H), 3.59-3.53 (m, 2H), 1.36-1.25 (m, 18H).

MS (ESI) mlz (M-H) (440), M + H (442).

Anal Calcd for C ₂₃ H 7N3O6 ₂ * 0.5H ₂ O: C, 61.32; H, 6.26; N, 9.32. Found: C, 61.12; H, 6.35; N, 9.32.

Example 25

N- [1 - [[4- (1,3-benzodioxol-5-yl) phenoxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl) -N-hydroxyformamide

Prepared according to the procedures of Example 23B, except substituting 4- (3 ', 4'-methylenedioxyphenyl) -phenol for 4- (4'-butyloxyphenyl) phenol.

1 H NMR (300 MHz, d ₆ -DMSO) δ 9.84 (s; 0.5H), 9.52 (s, 0.5H), 8.37-8.31 (m, 3H), 7, 91 (s, 0.5H), 7.55-7.52 (d, 4H, J = 8.5 Hz), 7.19 (s, 2H), 7.09-7.06 (m, 2H) 6.97-6.93 (d, 6H, J = 10.2 Hz), 6.03 (s, 4H), 4.70-4.60 (m, 0.5H), 4.45-4 30 (m, 0.5H), 4.16-3.96 (s, 6H), 3.73-3.57 (m, 5H), 1.27 (s, 12H). .

MS (ESI) mlz (M-H) (440), M + H (442).

Calcd for C ₂₂ H ₂₃ N ₃ O 7 * 0.50H ₂ : C, 58.66; H, 5.37; N, 9.32. Found: C, 58.70; H, 5.80; N, 8.79.

Example 26 (±) -N- [1 - [[(4'-Butoxy [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-1) imidazolidinyl) ethyl] -N-hydroxyformamide

Example 26A

-Bromo-3- (3-methyl-2,5-dioxoimidazolidin-1-yl) propan-2-one

The title compound was prepared according to the procedure described in Examples 16A and 16B, except substituting 1-methylhydantoin for 1,5,5-trimethylhydantoin in Example 16A.

Example 26 B (±) -N- [1 - [[(4'-Butoxy [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo) 1-imidazolidinyl) ethyl] -N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, replacing 26A with 16B and 4- (4'-butyloxyphenyl) phenol with 4-bromophenol in Example 16C. 1 H NMR (300 MHz, d ₆ -DMSO) δ 9.97 (s, 0.5H), 9.60 (s, 0.5H), 8.34 (s, 0.5H), 7.97 (s) s, 0.5H), 7.55-7.50 (m, 8H), 6.99-6.91 (m, 8H), 4.86-4.82 (m, 0.5H), 4, 33-4.31 (m, 0.5H), 4.18-4.12 (m, 2H), 3.99-3.94 (m, 4H), 2.85 (s, 6H), 1, 82-1-68 (m, 4H), 1.50-1.38 (m, 6H), 0.96-0.91 (m, 6H).

MS (ESI) mlz (454) (M-H).

Calculated for C ₂ 4H _{2 6} * 0,25C4H5O 9N3O: C, 63.51; H, 6.44; N, 8.88. Found: C, 63.59; H, 6.46; N, 8.68.

Example 27

N- [1 - [[4- (3-thienyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, substituting 4- (4+ (3-thienyl) phenyl) phenol for 4-bromophenol in Example 16C.

Δ NMR (300 MHz, d 6 -DMSO) δ 9.90 (s, 0.5H), 9.57 (s, 0.5H), 8.31 (s, 0.5H), 7.91 (s , 0.5H), 7.75-7.74 (m, 2H), 7.77-7.60 (m, 6H), 7.52-7.49 (m, 2H), 6.96- 6.92 (m, 4H), 4.804.6 (m, 0.5H), 4.50-4.4 (m, 0.5H), 4.19-3.98 (m, 6H), 3, 81-3.70 (m, 2H), 3.61-3.56 (m, 2H), 2.79 (s, 6H), 1.29 (s, 12H).

Calcd for C20H23N3O5S: C, 57.54; H, 5.55; N, 10.06. Found: C, 57.72; H, 5.84; N, 9.76.

Example 28

N- [1 - [[([1,1-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] - Nhydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, substituting 4-phenylphenol for 4-bromophenol in Example 16C.

Δ NMR (300 MHz, cU-DMSO) δ 9.90 (S, 0.5H), 9.57 (S, 0.5H), 8.30 (s, 0.5H), 7.92 (S, 0.5H), 7.62-7.60 (D, 8H,> 8.1 Hz), 7.45-7.40 (t, 4H, J = 5.8, 7.8 Hz), 7, 33-7.28 (t, 2H, J = 7.1, 6.9 Hz), 7.02-6.97 (m, 4H), 4.80-4.60 (m, 0.5H), 4.45-4.40 (m, 0.5H), 4.18-4.01 (m, 4H), 3.77-3.70 (m, 2H), 3.63-3.6 (m 2H, 2.80 (s, 6H), 1.28 (s, 12H).

MS (ESI) mlz M-H (410), M + H (412).

Calcd for C22H25N3O5: C, 63.25; H, 6.17; N, 10.10. Found: C, 63.94; H, 6.41; N, 9.60.

Example 29

N- [1 - [[(3'-chloro-4'-fluoro- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo- limidazolidinyl) ethyl] -N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, substituting 4- (4'-fluoro (3-chlorophenyl) phenol) for 4-bromophenol in Example 16C.

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 000 0 000 0 * 0 000 00 00 00 00 00 1 H NMR (300 MHz, d 6 -DMSO) δ 9.90 (s, 0.5H), 9.57 (s, 0.5H), 8.31 (s, 0.5H), 7.92 (s,

0.5H), 7.84-7.82 (m, 2H), 7.65-7.61 (m, 6H), 7.49-7.43 (t, 2H, J = 9.2, 8) 8 Hz), 7.02-6.96 (m,

4H), 4.80-4.60 (m, 0.5H), 4.43-4.40 (m, 0.5H), 4.21-4.06 (m, 4H), 3.82- 3.70 (m, 2H), 3.623.59 (m, 2H), 2.79 (s, 6H), 1.28 (s, 12H).

MS (ESI) mlz M-H (462), M + H (464);

Calcd for C ₂ H 23 N ₃ O ₅ ClF * 0.25H ₂ O: C, 56.41; H, 5.05; N, 8.97. Found: C, 56.78; H, 5.24; N, 8.55.

Example 30 (±) -N- [1 - [[(2'-Methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5- dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, substituting 4- (3'-methylphenyl) phenol for 4-bromophenol in Example 16C.

Ή NMR (300 MHz, d ₆ -DMSO) δ 9.90 (s, 0.5H), 9.57 (s, 0.5H), 8.32 (s, 0.5H), 7.93 (s 0.58), 7.28-7.14 (mm, 12H), 6.99-6.64 (m, 4H), 4.90-4.80 (m, 0.5H), 4.42 -4.40 (m, 0.5H), 4.22-4.04 (m, 6H), 3.82-3.74 (m, 2H), 3.62-3.58 (m, 2H) 2.80 (s, 6H), 2.20 (s, 6H), 1.29 (s,

12H).

MS (ESI) mlz M-H (424), M + H (426).

Anal Calcd for C 3 H _{2 2 5} 7N3O * 0.25H2 O: C, 64.24; H, 6.44; N, 9.77. Found: C, 64.50; H, 6.69; N, 9.31.

Example 31

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

Example 31A

3- (4- (4'-Carbonitrilephenyl) phenoxy) -1-bromopropan-2-one 9 9 9 9 9 9 9

4 · 4 4 · · 4 4 • · 99 9 9

9,999,9994

444 944 94 ·· «44 44

The title compound was prepared according to the procedure described in Examples 16A and 16B, but substituting 4- (4'-cyanophenyl) -phenol for 1,5,5-trimethylhydantoin in Example 16A.

Example 31B

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, replacing Example 31A with 16B and hydantoin with 4-bromophenol in Example 16C.

1 H NMR (300 MHz, d 6 -DMSO) δ 3.6-3.8 (m, 2H), 3.92 (d, 2H, 1 = 8.4 Hz), 4.10-4.25 (m ,

2H), 4.3-4.4 (m, 0.5H), 4.8-4.9 (m, 0.5H), 7.0-7.1 (m, 2H), 7.74 ( d, 2H, J = 9.0 Hz), 7.84 (d, 2H, J = 8.4 Hz), 7.89 (d, 2H, J = 8.4 Hz), 7.98 (s, 0.5H), 8.1-8.2 (m, 1H), 8.35 (s, 0.5H), 9.57 (br s, 0.5H), 9.53 (br s, 0, 5H).

MS (ESI &lt; + &gt;) 395 (M + H).

Calculated for C ₂ OHI N405 * ₈ * 0,2H20 0,4EtOAc: C, 59.88; H, 5.03; N, 12.93. Found: C, 59.80; H, 4.81; N, 12.74.

Example 32

N- [1 - [[(4'-cyanol (1,1'-biphenyl] -4-yl) oxy] methyl] -2- (1,1-dioxido-3-oxo-1,2-benzisothiazole2 (3H) (1-yl) ethyl] -N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, replacing Example 31A with 16B and saccharin with 4-bromophenol in Example 16C.

Ή NMR (300 MHz, CDCl 3) δ 3.9-4.2 (m, 2H), 4.2-4.3 (m, 2H), 4.45-4.55 (m, 0.5H), 5.0-5.1 (m, 0.5H), 5.0-7.1 (m, 2H), 7.74 (d, 2H,> 8.4 Hz), 7.85 (d, 2H) > 8.7 Hz), 7.88 (d, 2H,> 8.4 Hz), 8.0-8.2 (m, 3.5H), 8.3-8.4 (m, 1, 5H), 9.78 (s, 0.5H), 10.14 (s, 0.5H),

MS (ESI -) 476 (M-H) -.

Calcd for C ₂₄ H ₁₉ N ₃ O ₆ S * 1.1 H ₂ O: C, 57.97; H, 4.30; N, 8.45. Found: C, 58.01; H, 3.96; N, 8.16.

Example 33

• • 0 0 00 0 « • · 0 · 0 0 00 • 0 V * <9 • 0 • • · • fl 0 0 0 0 0 0 0 « ··· 000 00 * 00 0 « 00

N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1'-biphenyl] 4-yl] oxy] ethyl] -N-hydroxyformamide

Prepared according to the procedures of Example 23B, except substituting 4- (4'-trifluoromethoxyphenyl) phenol for 4- (4'-butyloxyphenyl) phenol.

1 H NMR (300 MHz, d ₆ -DMSO) δ 1.27 (s, 6H), 3.5-3.8 (m, 2H), 4.0-4.3 (m, 2H), 4, 4-4.5 (na, 0.5H), 4.8-4.9 (m, 0.5H), 7.0-7.2 (m, 2H), 7.42 (d, 2H, J) = 7.8 Hz), 7.64 (d, 2H, J = 8.4 Hz), 7.75 (d, 2H,> 8.7 Hz), 7.93 (s, 0.5H), 8 33 (s, 0.5H), 8.35 (s, 0.5H), 8.40 (s, 0.5H), 9.56 (s, 0.5H), 9.87 (s, 0 , 5H).

MS (ESI &lt; + &gt;) 482 (M + H).

Calcd for C22H21N3O6F3: C, 54.88; H, 4.60; N, 8.72. Found: C, 55.22; H, 4.87; N, 8.36.

Example 34

N- [1 - [[4- (4-phenyl-1-piperidinyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide 1 H NMR (300 MHz, cF-DMSO) δ 1.27 (s, 3H), 1.28 (s, 3H), 1.7-1.9 (m, 4H), 2.55-2.75 (m, 3H), 2.78 (s, 1.5H), 2.79 (s, 1.5H), 3.5-3.8 (m, 4H), 3.9-4.1 (m 2H, 4.3-4.4 (m, 0.5H), 4.74.8 (na, 0.5H), 6.81 (d, 2H, J = 8.7 Hz), 6, 93 (d, 2H, > 9.0 Hz), 7.15-7.25 (m, 1H), 7.89 (s, 0.5H), 8.30 (s, 0.5H), 54 (s, 0.5H), 9.86 (s, 0.5H).

MS (ESI &lt; + &gt;) 495 (M + H).

Calcd for C27H34N4O5: C, 65.56; H, 6.92; Ν, 11.32. Found: C, 65.35; H, 7.24; N, 10.93.

Example 35

N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - ((4 '- (trifluoromethyl) [1,1'-biphenyl] -4yl) oxy] ethyl 1-N-hydroxyformamide

Prepared according to the procedures of Example 23B, except substituting 4- (4'-trifluoromethylphenyl) phenol for 4- (4'-butyloxyphenyl) phenol.

1 H NMR (300 MHz, d 6 -DMSO) δ 1.28 (s, 6H), 3.5-3.8 (m, 2H), 4.1-4.3 (m, 2H), 4.4 -4.5 (m, 0.5H), 4.8-4.9 (m, 0.5H), 7.0-7.2 (m, 2H), 7.72 (d, 2H, J = 8.4 Hz), 7.78 (d, 2H, J = 8.4 Hz), 7.86 (d, 2H, J = 8.4 Hz), 7.93 (s, 0.5H), 8 33 (s, 0.5H), 8.35 (s, 0.5H), 8.40 (s, 0.5H), 9.56 (s, 0.5H), 9.87 (s, 0 , 5H).

MS (ESI &lt; + &gt;) 466 (M + H).

Anal Calcd for C22H22N3O5F * 0,6H2O _3: C, 55.49; H, 4.91; N, 8.82. Found: C, 55.55; H, 4.66; N, 8.77.

Example 36

N- [1 - [[(3'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- [methyl [(4-methylphenyl) sulfonyl] amino] ethyl] -N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, replacing Example 31A with 16B and Nmethyl- (p-tolyl) sulfonamide with 4-bromophenol in Example 16C.

⁴ H NMR (300 MHz, d 6 -DMSO) δ 2.41 (s, 3H), 2.70 (s, 1.5H), 2.73 (s, 1.5H), 3.05-3.35 (m, 2H), 4.0-4.2 (m, 2H), 4.3-4.4 (m, 0.5H), 4.8-4.9 (m, 0.5H), 7 06 (d, 2H, J = 8.7 Hz), 7.46 (d, 2H, J = 8.1 Hz); 7.65-7.8 (m, 4H), 7.85 (d, 2H, J = 8.7 Hz), 7.89 (d, 2H, J = 8.7 Hz), 8.04 (s) 0.5H), 8.40 (s, OSH), 9.71 (s, 0.5H), 10.0 (s, 0.5H).

MS (ESI &lt; + &gt;) 480 (M + H).

Anal Calcd for C 25 H 5 N ₂ O ₅ S _3: C, 62.61; H, 5.25; N, 8.76. Found: C, 62.52; H, 5.27; N, 7.98.

Example 37

Ν- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-3- (3 pyridinylmethyl) -1-imidazolidinyl] ethyl] -N-hydroxyformamide

Example 37A

3- (3-pyridinylmethyl) -2,5-oxo-4,4-dimethylimidazolidine

The title compound was prepared according to the procedures described in Examples 68A, 68B, and

69B, except substituting 3-picolyl chloride for methyl iodide in Example 68B.

Example 37B

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-3- (3-pyridinylmethyl)) -1-imidazolidinyl] ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLES 16C and 16E, replacing Example 31A with 16B and 37A with 4-bromophenol in Example 16C.

1 H NMR (300 MHz, d ₆ -DMSO) δ d 1.25 (s, 6H), 3.6-3.7 (m, 1H), 3.8-3.9 (m, 1H), 4 , 1-4.3 (m, 2H), 4.4-4.5 (m, 0.5H), 4.56 (s, 2H), 4.85-4.95 (m, 0.5H) 7.0-7.1 (m, 2H), 7.35 (dd, 1H, > 8.1.4.8 Hz), 7.7-7.8 (m, 3H), 7.86 ( d, 2H, J = 8.4 Hz), 7.90 (d, 2H, J = 8.4 Hz), 7.96 (s,

0.5H), 8.34 (s, 0.5H), 8.45-8.50, (narrow m, 1H), 8.60 (s, 1H), 9.64 (s, 0, 5H), 9.97 (s, 0.5H). MS (ESI (+)), 514 (M + H);

Anal Calcd for C28H _{2 5} 7 N * 1,7H2O O5: C, 61.80; H, 5.63; N, 12.87. Found: C, 61.77; H, 5.08; N, 12.48.

Example 38

N- [2 - [(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] -1-methylpropyl] -N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLES 16C and 16E, substituting 3Bromo-2-butanone for 16B and 4- (4'-cyanophenyl) phenol for 4-bromophenol in Example 16C.

1 H NMR (300 MHz, c 1 -DMSO) δ 1.1-1.3 (m, 6H), 3.8-4.0 (m, 1H), 4.3-4.7 (m, 1H) 7.0-7.1 (m, 2H), 7.6-7.7 (m, 2H), 7.8-7.9 (m, 4H), 8.02 (s, 0.5H) 8.28 (s, 0.25H), 8.33 (s, 0.25H), 9.43 (s, 0.25H), 9.60 (s, 0.25H), 9.85 (s 0.25H), 9.95 (s, 0.25H).

MS (ESI &lt; + &gt;) 311 (M + H).

Calcd for C19H18Cl2O4H2O: C, 68.86; H, 5.91; N, 8.92. Found: C, 68.73; H, 5.79; N, 8.58.

Example 39

N- [1 - [[(3'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazotidinylethyl) -N -hydroxyformamide;

Example 39A '-cyano-4-hydroxybiphenyl

A 250 ml flask was charged with 2.21 g (2.7 mmol) of [1,1'-bis (diphenylphosphino) feroccen] dichloropalladium * CH ₂ Cl 2 and 6.26 g (2.73 mmol) 3-iodobenzonitrile, 6.0 g (3.95 mmol) of 4-methoxyphenylboronic acid and 12.45 g (8.20 mmol) of CsF in solid form are added followed by 180 mL of 1,2-dimethoxyethane. The flask is washed with N ₂ and the suspension is heated at reflux, which is maintained for the next 3 hours. The cooled reaction mixture was filtered through a column of 300 g of silica gel and the column was washed with ethyl acetate. The ethyl acetate solution was concentrated and the residue was purified by flash chromatography eluting with 10% hexanes / 90% ethyl acetate to give 3.3 g of the desired product (58% yield). This material was dissolved in 50 mL of anhydrous CH 2 Cl 2 and the solution was cooled in a dry ice-acetone bath and borontribromide solution (40 mL, mmol) was added dropwise under an inert atmosphere. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was cooled in an ice bath and 5 mL of H ₂ O was added dropwise followed by 20 mL of 1N HCl. The mixture was stirred for 1 hour and the resulting suspension was filtered and the filtrate was poured into a separator and the organic layer was separated and discarded. The filtered solid was washed with H ₂ O and ethyl acetate and filtered, the filtrate was poured into a separator and the organic layer was combined with the previous organic layer, dried over Na ₂ SO 4, filtered and the filtrate concentrated to 3.05 g of white solid (99% yield).

Example 39B

N- [1 - [[(3'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazotidinyl) ethyl] -N-hydroxyformamide;

Prepared according to the procedures of Examples 16C and 16E, substituting 3'-cyano-4-hydroxybiphenyl for 4-bromophenol in Example 16C.

m.p. NMR (300 MHz, tU-DMSO) δ 9.86 (s, 0.5H), 9.48-9.63 (c, 0.5H), 8.33 (s, 0.5H) ), 8.09 (s, 1H), 7.97 (d, 1H, J = 4.5 Hz), 7.93 (s, 0.5H), 7.75 (d, 1H,> 4.5) Hz), 7.70 (d, 2H,> 6.0 Hz), 7.63 (t, 1H,> 4.5 Hz), 7.00-7.07 (c, 2H), 4.83- 4.90 (c, 0.5H), 4.60-4.67 (c, 0.5H).

MS ESI (+): 409 (M-27), 437 (M + H), 454 (M + NH 4), 459 (M + Na)

Calcd for C23H24N * ₄ 0,25C4HgO2 O5: C, 62.87; H, 5.71; N, 12.21. Found: C, 62.68; H, 5.55; N, 12.27.

Example 40

Ν- [1 - [[[4 '- (methylthio) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E by substituting 4'-thiomethyl-4-hydroxy-biphenyl for 4-bromophenol in Example 16C. m.p. : 172-174.

1 H NMR (300 MHz, d 6 -DMSO) δ 9.48-9.86 (BS, 1H), 8.34 (S, 0.5H), 7.94 (S, 0.5H), 7.547, 63 (C, 4H), 7.29-7.34 (C, 2H), 6.97-7.03 (C, 2H), 74.82-4.92 (C, 0.5H), 4, 39-4.47 (C, 0.5H), 4,074.25 (C, 2H), 3.73-3.85 (C, 1H), 3.59-3.68 (C, 1H), 2, 80 (S, 1.5H); 2.79 (S,

1.5H).

MS (ESI (-)) 456 ((M-H)), 913 ((2M-H)), Theoretical: 458.175; Found: 458.1747 Anal. Calcd. For C 23 H 27 N 3 O 5 S: C, 60.37; H, 5.95; N, 9.19; S, 7.01. Found: C,

60.29; H, 5.82; N, 9.08; S, 6.98.

Example 41

N- [1- [4 - [[4- (trifluoromethyl) phenoxy] phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide,

Prepared according to the procedures of Examples 16C and 16E, substituting 4- (4'-trifluoromethylphenoxy) phenol for 4-bromophenol in Example 16C. mp: 121-123.

1 H NMR (300 MHz, c 1 -DMSO) δ 9.46-9.97 (C, 1H), 8.33 (S, 0.5H), 7.94 (S, 0.5H), 7.71 (S, 1H), 7.69 (S, 1H), 7.04-7.14 (C, 4H), 6.97-7.03 (C, 2H), 4.81-4.91 (C) , 0.5H), 4.39-4.47 (C, 0.5H), 4.14-4.22 (C, 1H), 4.04-4.13 (C, 1H), 2.81 (S, 1.5H), 2.80 (S, 1.5H), 1.30 (S, 1.5H). MS (ESI (-)) 494 ((M-H)), 530 (M + Cl), 989 (2M-H), 1011 (2M + Na 2 H) Theoretical: 496.169; Found: 496.1696

Calcd for C23H24N3O6 Theoretical: C, 55.75; H, 4.88; N, 8.48; F 11.50. Found: C, 55.68; H, 4.92; N, 8.40; F, 11.24.

Example 42

N- [1 - [[[4 '- (trifluoromethoxy) [1,1-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ) ethyl] -2-N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, substituting 4'-trifluoromethoxy-4-hydroxybiphenol for 4-bromophenol in Example 16C. mp: 129.3-130.

1 H NMR (300 MHz, d ₆ -DMSO) δ 9.46-9.84 (c, 1H), 8.26 (s, 0.5H), 7.87 (s, 0.5H), 7.67 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.34 (s, 1H), 7.32 (s, 1H) 6.94-6.97 (c, 2H), 4.78-4.82 (c, 0.5H), 4.34-4.38 (c, 0.5H), 4.02-4, 17 (c, 2H), 3.67-3.77 (c, 1H), 3.53-3.60 (c, 1H), 2.73 (s, 1.5H), 2.72 (s, 1.5H), 1.22 (s, 3H), 1.21 (s, 3H).

MS (ESI (-)) 494 ((M-H)), 530 (M + Cl), 989 (2M-H), 1011 (2M + Na-2H) Theoretical: 496.1695; Found: 496.1680

Calcd for C23H24F3N3O6 Theoretical: C, 55.75; H, 4.88; N, 8.48; F 11.50. Found: C, 55.69; H, 4.94; N, 8.23; F, 11.71.

Example 43

N- [1 - [[[4 '- (methylsulfonyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

Prepared according to the procedures of Examples 48A, 48B, and 48C by replacing 16B with 23A with 4-bromophenol in Example 48A. mp: 174-175.

1 H NMR (400 MHz, d 6 -DMSO) δ 9.47-9.98 (c, 1H), 8.35 (s, 0.5H), 7.92-8.00 (s, 4.5H) 7.77 (s, 1H); 7.75 (s, 1H); 7.07-7.10 (c, 2H); 4.85-4.94 (c, 0.5H); 4.42 -4.50 (0.5H), 4.13-4.30 (c, 2H), 3.76-3.86 (c, 1H), 3.63-3.69 (c, 1H), 3 39 (s, 3H), 2.83 (s, 1.5H), 2.82 (s, 1.5H), 1.32 (s, 3H), 1.31 (s, 3H).

MS (ESI (-)): 488 (M-H), 977 (2 M-H), 999 (2 M + Na-2H)

ESI (+): 490 (M + H), 507 (M + NH), 512 (M + Na).

Anal. Calcd for C 23 H 25 8.5 (M) 7.758: Theoretical: C, 54.91; H, 5.71; N, 8.35; S, 6.37.

Found: C, 54.85; H, 5.76; N, 8.00; S, 6.31.

Example 44

N- [l - [[[3 '- (cyanomethyl) ^-4, -methoxyl [l, r-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl) ethyl] -N-hydroxyformamide

Prepared according to the procedures of Examples 16C and 16E, substituting 4- (3-cyanomethyl-4'methoxyphenyl) phenol for 4-bromophenol in Example 16C.

H 1 H NMR (300 MHz, d 6 -DMSO) δ; 1,275,1,290 (6H), 2,788,2,800 (3H), 3,566-3,641 (m, 1H), 3,770-3,821 (m, 1H), 4,047-4,214 (m, 2H), 4,399-4,416 (m, 0,5H) ), 4.846 (m, 0.5H), 6.973-7.013 (2H), 7.110-7.140 (1H), 7.543-7.608 (m, 4H), 7.291 (s, 0.5H), 8.319 (s, 0.5H) ), 9.576 (s, 0.5H), 9.904 (s, 0.5H).

MS (ESI) mle 481 (M + H) ⁺ , 498 (M + NH 3) ⁺ , 479 (MH +).

Calcd for C25H18N6O * 0.5MeOH: C, 61:68; H, 6.08; Ν, 11.28. Found: C, 62.07; H, 6.21; N, 10.91.

Example 45

Ν- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -3- (4,4-dimethyl-2,5-dioxo-1-imidazobdinyl) propyl ]] - N-hydroxyphomiamide,

The title compound was prepared according to the procedures of Example 5, except avoiding methylation in Example 5B and substituting 4- (3'-cyanomethylphenyl) phenol for 4'-hydroxy-4-biphenylcarbonitrile in Example 5F.

H 1 H NMR (300 MHz, d 6 -DMSO) δ; 1.27 (s, 6H), 1.70-2.00 (m, 2H), 3.37-3.47 (m, 2H), 3,964.08 (s + m, 5H), 7.00- 7.03 (d, 2H, 8.4Hz), 7.28-7.31 (d, 1H, 8.7Hz), 7.426-7.477 (t, 1H, 7.5Hz), 7.56-7 61 (m, 4H), 7.915 (s, 0.73H), 8.28-8.34 (1.27H), 9.55 (s, 0.75H), 9.96 (s, 0.25H) )

MS (ESI) mle 451 (M + H) ⁺ , 468 (M + NH ⁺ ) ⁺ , 449 (MH) +,

Anal Calcd for C25H2sN OE * ₄ MeOH: C; 62.22; H, 6.26; 11, 11.61. Found: C, 62.25; H, 5.95; N, 11.57.

Example 46

N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl ] -N-hydroxyformamide,

Example 46A

- (4-bromophenylthio) -3- (4,4-methyl-2,5-dioxoimidazolidin-1-yl) -2-propanone

A solution of 4-bromothiophenol (2.15 g, 1.4 mmol) in DMF (50 mL) at room temperature was treated with cesium carbonate (5.57 g, 17.1 mmol) for 20 minutes, then allowed to react in one portion with the compound of Example 23A (2.5 g, 9.5 mmol), stirred for 1 hour at room temperature and diluted with water, extracted with ethyl acetate, the combined extracts washed with water and brine, dried (Na 2 SO 4). Concentrate and purify on a silica gel column eluting with 20-30 to 50% ethyl acetate / hexane to afford 3.17 g (90%) of the desired product as a white solid.

MS (APCI) m / e 371, 373 (M + H) ^&lt; ^{+ &gt};, 388, 390 (M + NH4), 369, 371 (MH), 405, 407 (M + Cl) &lt; + &gt;.

Example 46B 1 - [(4'-Butoxy [1,1'-biphenyl] -4-yl) thio] -3- (4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) -2-propanone Solution from Example 46A (700 mg, 1.89 mmol) in DME (20 mL) at room temperature was treated with 4-n-butoxybenzeneboronic acid (549 mg, 2.83 mmol), tetrakis (triphenylphosphine) palladium (218 mg) , 0.189 mmol) and 1M sodium carbonate (3.54 mL, 3.54 mmol), the reaction vessel was sealed and heated at 90 ° C for 6 hours, diluted with ethyl acetate, washed successively with saturated ammonium chloride, water and brine, dried (F 2 SCU), concentrated and purified on a silica gel column eluting with 30 to 50% ethyl acetate / dichloromethane to afford 650 mg (78%) of the title compound as a yellow solid.

MS (APCI) m / e 441 (M + H) &lt; + &gt;, 458 (M + NF &lt; + &gt;), 439 (MH), 475 (M + Cl) &lt; + &gt;.

Example 46C

N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl) thio] methyl] -2- (4,4-dimethyl-2,5-dioxo-imidazolidinyl) ethyl 1-N-hydroxyformamide

· · «......

The title compound is prepared from 46B followed by the procedures described in Example 2D,

2E, 2F.

Ή NMR (300 MHz, d ₆ -DMSO) δ; 0.919-0.967 (t, 3H, J = 7.2 Hz), 1.225-1.237 (s + s, 6H), 1.389-1.512 (m, 2H), 1.666-1.760 (m, 2H), 3.110- 3.192 (m, 2H), 3.528-3.735 (m, 2H), 3.9874.030 (t, 2H, J = 6.3 Hz), 4.030 (m, 0.5H), 4.750 (m, 0.5H) 6.991-7.020 (d, 2H, J = 9Hz), 7.3837.417 (dd, 2H, J = 1.8, 8.4Hz), 7561-7.601 (4H), (1.5H), 9.56 (s, 7.767 (s, 0.5H), 8.299 (s, 1H), 8.337 (s, 0.5H), 9.457 (br s, 0.5H), 9.695 (br s, 0.5H) ,

MS (ESI) mle 484 (M-H) -,

High Resolution MS (FAB). Calculated m / z for m + 485.1984, found m / z 485.1980.

Example 46D

N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide,

A solution of Example 46C (127 mg, 0.262 mmol) in methanol (2 mL) and a buffer (1 mL) at pH 7 at 0 ° C were treated with oxone (402 mg, 0.655 mmol) for 30 min then at room temperature for 1 hour, neutralized with saturated sodium bicarbonate, extracted with dichloromethane, the combined extracts washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude mixture was purified on a silica gel column eluting with ethyl acetate / hexane then 10% methanol / dichloromethane to give 82 mg (60%) of the title compound as a white solid.

1 H NMR (300 MHz, d 6 -DMSO) δ; 0.92-0.97 (t, 3H, 7.5Hz), 1.20-1.22 (s + s, 6H),

1.42-1.52 (m, 2H), 1.68-1.77 (m, 2H), 3.41-3.72 (m, 3.5H); 4.02-4.06 (t, 2H, 6.6 Hz), 4.52 (m, 0.5H), 4.89 (m, 0.5H), 7.05-7.08 (d, 2H) , 8.4Hz), 7.70-7.74 (2H), 7.91 (s, 3.5H), 8.10 (s, 0.5H), 8.32-8.35 (d, 1H) , 9.6Hz), 9.48 (s, 0.5H), 9.62 (s, 0.5H).

MS (ESI) mlz 518 (M + H) ⁺ , 535 (M + NH +) +, 516 (MH +), 552 (M + Cl) +.

Anal Calcd for 025 ^ 8 ^ 06 * 0.25H ₂ O: C, 57.51; H, 6.08; N, 8.04. Found: C, 57.78; H, 6.18; N, 7.84.

Example 47

......... .: .......... ..U .- ,. · «· 9 *« * * * * * * * * * * * 4 »· · · ·» »» »» »» »» »

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -3- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) propyl] - N-hydroxyformamide,

Example 47A

-Bromo-4- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) butan-2-one

To a suspension of CuBr ₂ (1.91 g, 8.5 mmol) and lithium bromide (1.48 g, 17 mmol) in THF (10 mL) was added a solution of 1.06 g (5.3 mmol) of 1- (( 12xiranyl) propyl-4,4-dimethyl-2,5-dioxoimidazolidine (prepared from Example 5A followed by the procedure of Example 5C) in 15 mL of THF The reaction mixture was stirred for 2 hours at room temperature, then partitioned between ethyl acetate and a buffer of pH 7. The organic extract was washed with brine, dried and concentrated, and the residue was filtered through a silica gel column eluting with ethyl acetate, and the filtrate was concentrated to give a white solid, which was dissolved in acetone (25 mL), cooled to 10 ° C. The reaction was quenched with 2 mL of isopropanol, then partitioned between ethyl acetate and water, and the organic extract was washed with brine, dried and concentrated. The residue was filtered through a silica gel column eluting with ethyl acetate and filtrate is concentrated to obtain the desired compound.

Example 47B

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -3- (4,4-dimethyl-2,5-dioxo-limidazohdinyl) propyl] -N -hydroxyformamide

The title compound was prepared according to the procedures in Examples 16C and 16E, except for substituting 47A for 16B and 4'-hydroxy-4-biphenylcarbonitrile for 4-bromophenol in Example 16C. mp 212-204 ° C

Ή NMR (300 MHz, d ₆ -DMSO) δ; 1.272 (6H), 1.70-2.00 (m, 2H), 338-3.46 (t, 2H, J = 6Hz), 3.92-4.18 (m, 2.5H), 4 -46-4.57 (m, 0.5H), 7.03-7.06 (d, 2H, J = 8.7 Hz), 7.695-7.724 (d, 2H, J = 8.7 Hz), 7.82-7.92 (m, 6.5H), 8.26-8.35 (1.5H), δ, 75 (s), 9.96 (s) (1H)

MS (ESI) mle 437 (M + H) ⁺ , 454 (M + NH 4) ⁺ , 459 (MH) +.

Anal Calcd for C ₂₅ H ₂ 8N4O6 * 0.25H ₂ O: C, 62.64; H, 5.60; N, 12.70. Found: C, 62.55; H, 5.47; N, 12.65.

 ♦ ·· «··

Example 48

N- [1 - [[[4 '- (methylsulfonyl) (1,1'-biphenyl] -4-yl] oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl) -N -hydroxyformamide,

Example 48A

- (4 '- (thiomethyl) [1,1'-biphenyl] -4-yl) oxy) -3- (4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) -2-propanone

A solution of 4'-hydroxy-4-biphenylmethylsulfide (1.18 g, 5.47 mmol) in DMF (25 mL) at room temperature was treated with cesium carbonate (2.23 g, 6.84 mmol) for 20 minutes , treated in a single portion with 23 A (1.2 g, 4.56 mmol), stirred for 2 hours at room temperature and diluted with water, extracted with ethyl acetate, the combined extracts washed with water and brine, dried (Na ₂ SO ₄ ), concentrated and purified on a silica gel column eluting with 50 to 80% ethyl acetate / hexane to afford 1.0 g (55%) of the desired compound as a white solid.

MS (APCI) m / e 399 (M + H) ^+, 416 (M + _NH4) ^+, 397 (MH) +, 433 (M + Cl).

Example 48B

N- [1 - [[[4 '- (thiomethyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl) -N-hydroxyformamide

The title compound was prepared from 48A according to the procedures described in Examples 2D,

2E, 2F.

MS (ESI) m / e 444 (M + H) ^+, 461 (M + NH) +, 466 (M + Na) ^+, 433 (M + Cl).

Example 48C

N- [1 - [[[4 '- (methylsulfonyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

A solution of Example 48B (440 mg, 0.993 mmol) in methanol (100 mL) and water (50 mL) at 0 ° C was treated with oxone (1.27 g, 2.06 mmol) and sodium bicarbonate (174 mL).

..,. -------------------- ..

«* ♦ · · · 4 4 4 4 · 4 4 4 4 4 4 4 4 4 4 4

9 99 9 9 (1 mg, 2.06 mmol) for 1 hour then at room temperature for 1.5 hours, dilute water, extracted with dichloromethane, the combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude mixture was purified on a silica gel column eluting with 80% ethyl acetate / hexane, then 10% methanol / dichloromethane, then recrystallized from dichloromethane / hexane to afford 375 mg (79%) of the title compound as a white solid. 1 H NMR (300 MHz, cU-DMSO) δ; 1.26-1.27 (s + s, 6H), 3.24 (s, 3H), 3.53-3.80 (m, 2H), 4.08-4.24 (m, 2H), 4.37-4.48 (m, 0.5H), 4.80-4.92 (m, 0.5H), 7.04-7.08 (dd, 2H, J = 3.4 Hz) 7.72-7.75 (d, 2H,> 8.7 Hz), 7.89-8.00 (4.5H), 8.33-8.40 (1.5H), 9.56 (s, 0.5H), 9.88 (s, 0.5H).

MS (ESI) m / e 476 (M + H) ⁺ , 493 (M + NH ₄ ) +, 474 (MH +), 510 (M + Cl) +.

Anal Calcd for C ₂₂ H ₂₅ N3O7 * 0.25H ₂ O:

Example 49

N- [1 - [[(3'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide

Example 49A

- (4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] -3- (2,5-dioxopyrrolidin-1-yl) -2-propanone

The title compound was prepared as in Example 3C except that potassium succinimide (0.10 g, 0.95 mmol) was used in place of potassium phthalimide. Purification by trituration with ethyl acetate gave 0.19 g (68%) of the title compound as a white solid.

MS (APCI) mlz 383 (M + Cl) ⁺ .

Example 49B

() - [1- (4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] -3- (2,5-dioxopyrrolidin-1-yl) -2-prop-2-yl] hydroxylamine The title compound is prepared from 49B using the procedure described in Example 2D a

2E.

Μ

Example 49C

N- [1 - [[(3'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide

The title compound was prepared from 49B using the procedure described in Example 2 1 H NMR (300 MHz, d ₆ -DMSO) d 10.01 (s, 0.5H), 9.63 (s, 0.5H), 8.34 (s, 0.5H), 7.98 (s, 0.5H), 7.90-7.82 (m, 4H), 7.73 (d, 2H,> 8.8 Hz), 7.06 -6.89 (m, 2H), 4.90-4.78 (m, 0.5H), 4.37-4.24 (m, 0.5H), 4.22-4.04 (m, 2H), 3.74-3.60 (m, 2H), 2.65-2.61 (m, 4H).

MS (ESI) mlz 394 (M + H) ⁺ , 411 (M + NH ₄ ) ⁺ , 392 (M-1) ⁺ .

Calcd for C ₂₁ H ₁₉ N ₃ O ₅ * H ₂ O: C, 61.30; H, 5.14; N, 10.21. Found: C, 61.20; H, 5.03; N, 10.03.

Example 50

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,6-dioxo-1-piperidinyl) ethyl] -N -hydroxyphocmamide

The title compound was prepared as in Example 49, except using potassium-3,3-dimethylglutarimide (0.16 g, 1.1 mmol) instead of potassium succinimide, m.p. 121 ° C 1 H NMR (d 6 -DMSO) d 9.88-9.78 (s, 0.5H), 9.60-9.52 (s, 0.5H), 8.31 (s, O, 5H), 7.95 (s, 0.5H), 7.90-7.82 (m, 4H), 7.73 (d, 2H, > 8.9 Hz), 7.02 (d, 2H, > 8.8 Hz), 4.88-4.77 (s, 1H), 4.303.78 (m, 4H), 2.56 (s, 4H), 0.98 (s, 6H).

MS (ESI) 436 (M + H) ^&lt; ^{+ &gt};, 458 (M + Na) ^&lt; ^{+ &gt};, 434 (MH) ^&lt; ^{+ &gt;} .

Examples 51 and 52

N- [1S - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide

N- [1R - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide

- · · · · · ·

Examples 51A and 52A

A solution of Example 49B (0.2 g, 0.55 mmol), D-Mannosadiacetonide (0.13 g, 0.5 mmol) and acetic acid (0.03 mL, 0.5 mmol) in CHCl ₃ (5 mL) ) were heated at reflux for 16 hours, cooled and partitioned between CH ₂ Cl ₂ and saturated aqueous sodium bicarbonate. The organic layer was washed successively with water and brine, dried (MgSO 4) and concentrated. Purification by HPLC afforded two enantiomers 51A (31%) and 52A (16%).

Example 51B

A solution of 51A in MeOH (1 mL) and HCl (conc.) (0.5 mL) was stirred at room temperature for 15 minutes, treated with saturated aqueous sodium bicarbonate, and partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated to give 0.014 g (79%) of the corresponding hydroxylamine, which was then formulated as in Example 2F. The title compound was prepared according to Example 51B but Example 52A was used instead of Example 51 A.

Example 52B

The title compound was prepared according to Example 51B, but Example 52A was used instead of Example 51A

Example 53

N- [1 - [[(4'-Cyano [[1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-ethyl-3-methyl-2,5-dioxo-1-pyrrolidinyl) ethyl 1-N-hydroxyformamide

The title compound was prepared as in Example 49, except using potassium-3-methyl-3-ethyl-succinimide (0.22 g, 1.53 mmol) instead of potassium succinimide.

1 H NMR (300 MHz, d 6 -DMSO) d 9.99-9.94 (br, 0.5H), 9.64-9.58 (br, 0.5H), 8.31 (d, O, 5H,> 1.8 Hz), 7.93 (d, 0.5H,> 2.9 Hz), 7.87 (q, 4H,> 4.1 Hz), 7.74 (d, 2H,> 8.9 Hz), 7.04 (dd, 2H, J = 8.8, 2.6 Hz), 4.93-4.81 (m, 0.5H), 4.44-4.33 (m , 0.5H), 4.24-4.05 (m, 2H), 3.85-3.71 (m, 1H), 3.62-3.53 (m, 1H), 2.69-2 38 (m, 2H), 1.64-1.46 (m, 2H), 1.18 (d, 3H, > 4.4 Hz), 0.85-0.75 (m, 3H).

MS (ESI) 436 (M + H) ^&lt; ^{+ &gt};, 434 (MH) ^&lt; ^{+ &gt};, 458 (M + Na) &lt; + &gt;, 453 (M + NH3).

• 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 «

9 9 99 «·» · *

Calcd for C24H25N3O5: C, 66.19; H, 5.78; N, 9.64. Found: C, 66.07; H, 5.85; N, 9.37

Example 54

N- [4- [4 - [[(4-chlorophenoxy) phenyl] sulfonyl] methyl] tetrahydro-2H-pyran-4-yl] -N-hydroxyformamide

Example 54A

The title compound was prepared as in Example 2d but using 5,6-dihydro-2H-pyran-2-one (4.3 g, 43 mmol) instead of 1- (4- (4'-carbonitrilphenyl) phenoxy) -3-thiophenoxypropane -2one and O-benzylhydroxylamine instead of hydroxylamine to give the corresponding oxime. Purification on a silica gel column eluting with 1% methanol / dichloromethane gave 8.5 g (96%) of the title compound as a clear liquid.

M + (ESI) 207 (M + H) ⁺ .

Example 54B

N- [4- [4 - [[(4-chlorophenoxy) phenyl] sulfonyl] methyl] tetrahydro-2H-pyran-4-yl] -N-hydroxyformamide

To a solution of phenoxyphenyl-4-chloro-4-methylsulfone (0.76 g, 2.7 mmol) (preparation described in J.Med. Chem. 29.427-433.1986) at -78 ° C was added n-BuLi ( 1.1 mL (2.7 mmol). After stirring at -78 ° C for 15 minutes, BF ₃ * OEt2 was added followed by Example 54A. After 1 h, the reaction mixture was partitioned between water and ethyl acetate, dried (MgSO ₄ ) and concentrated. Recrystallization with ethyl acetate gave 0.41 g (35%) of the title compound as a white solid.

MS (ESI) 488 (M + H) ^&lt; ^{+ &gt};, 510 (M + Na) &lt; + & gt ^; .

Example 54C · _'r .. .......... *

4 ♦ * * 4 4 44 • 9 99 9 4 · 9 9 9 9 9 · * 9 4 4 4

9 · ♦ · 9 4 9 49

N- [4- [4 - [[(4-chlorophenoxy) phenyl] sulfonyl] methyl] tetrahydro-2H-pyran-4-yl] -N-hydroxyformamide

A solution of 54B (0.05 g, 0.10 mmol) in CH ₂ C1 ₂ (2 mL) is reacted with an acid anhydride, p-methoxyphenyl-mold, stirred at room temperature for 16 hours, allowed to react with H ₂ 0 and partitioned between ethyl acetate and brine. The organic layer was dried (MgSO ₄ ) and concentrated. Purification on a silica gel column eluting with 10% ethyl acetate / dichloromethane gave 0.017 g (32%) of the title compound as a white solid.

MS (ESI) 516 (M + H) ^&lt; ^{+ &gt};, 533 (M + NH, 538 (M + Na) &lt; + &gt;).

Example 54D

N- [4- [4 - [[(4-chlorophenoxy) phenyl] sulfonyl] methyl] tetrahydro-2H-pyran-4-yl] -N-hydroxyformamide

A solution of 54C (0.017 g, 0.033 mmol) and black Pd (0.006 g) in dioxane (2 mL) and acetic acid (2 mL) was stirred under H for 20 min, treated with NaHCO ₃ , partitioned between ethyl acetate and water. The organic layers were dried (MgSO ₄ ) and concentrated. Purification on a silica gel column eluting with 2% MeOH / dichloromethane gave 0.002 (14%) of the title compound.

1 H NMR (300 MHz, d 6 -DMSO) d 9.50-9.45 (br, 1H), 8.19 (s, 1H), 7.90-7.86 (m, 2H), 7.537.50 ( m, 2H), 7.22-7.18 (m, 4H), 3.70-3.58 (m, 4H), 3.55-3.44 (m; 2H), 2.22-2, 07 (m, 2H); 2.07-1.91 (m, 2H).

MS (ESI) 424 (MH) ^&lt; ^{+ &gt};, 426 (M + H) ^&lt; ^{+ &gt};, 448 (M + Na) &lt; + & gt ^; .

Example 55

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [[(2-methoxycarbonyl) phenyl) thio] ethyl] -Nhydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 2B, C, D, E, F, but using methylthiosalicylate (600 mg, 2.39 mmol) instead of thiophenol in Example 2B. Mixture of two rotamers:

x * x «- ·, ν .... - · * - * £ ··

· Ti · «ti ti ti ti ti ti ti ti

1 H NMR (300 MHz, cb-DMSO) d 10.11 (s, 1H), 9.73 (s, 1H), 8.41 (s, 1H), 7.95 (s, 1H), 7.90 -7.83 (m, 10H), 7.75-7.71 (m, 4H), 7.59-7.55 (m, 4H), 7.31-7.26 (m, 2H), 7.09-7.05 (m, 4H), 4.75 (m, 1H), 4.280-4.24 (m, 4H0.4.18 (m, 1H), 3.83 (s, 3H), 3.82 (s, 3H); 3.31-3.18 (m, 4H);

MS (ESI) mle 463 (M + 1) ⁺ .

Calcd for C25H22N2O5S: C, 64.92; H, 4.79; N, 6.06. Found: C, 64.69; H, 4.63; N, 5.92.

Example 56

N- [1 - [[(4'-Cyano [1,1'-biphenyl) -4-yl) oxy] methyl] -5 - [(4-methyl-2-oxo-2H-1-benzopyran-6yl)] oxy) pentyl] -N-hydroxyformamide

Example 56A

6- (4-Methyl-2-oxo-2H-1-benzopyran-6-yl) oxy] -hex-1-ene

The title compound was prepared according to the procedure for EXAMPLE 5A, but using 6-hydroxy-4-methylcoumarin (500 mg, 2.84 mmol) instead of 5,5-dimethylhydantoin and 5-hexenol-1 instead of 3-buten-1-ol. Purification on a silica gel column eluting with 20% ethyl acetate / hexanes gave 560 mg (76%) of the title compound.

1 H NMR (300 MHz, d 6 -DMSO) d 7.34 (dd, 1H), 7.24-7.20 (m, 2H), 6.40 (d, 1H), 5.90-5, 77 (m, 1H); 5:04 (dq, 1H), 4.98 (dq, 1H), 4.06 (t, 2H), 2.43 (d, 3H), 2.10 (q, 2H) 1.75 (dt, 2H), 1.53 (dt, 2H).

Example 56B

N- [1 - [[(4'-Cyano [1,1'-biphenyl) -4-yl) oxy] methyl] -5 - [(4-methyl-2-oxo-2H-1-benzopyran-6-yl) oxy] oxy Pentyl] -N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLE 5C, IB, 2C, 2D, 2E and 2F, but using 56A (500 mg, 1.94 mmol) instead of 5B in Example 56B. Purification on a silica gel column eluting with 50% acetate / hexanes gave 400 mg (75%) of the title compound.

Mixture of two rotamers: 1 H NMR (300 MHz, d 6 -DMSO) d 9.89 (s, 1H), 9.51 (s, 1H), 8.42 (s, 1H), 8.03 (s, 1H) 7.86 (m, 8H), 7.73-7.70 (m, 4H), 7.34 (d, 2H), 7.24-7.21 (m, 4H), 7.08- 7.04 (m, 4H), 6.40 (s, 2H), 4.60 (s, 1H), 4.18-3.99 (m, 9H), 2.43 (s, 6H), 1 , 86-1.54 (m, 12H);

MS (ESI) mlz 513 (M + 1) ⁺ .

Calcd for C30H28N2O6: C, 70.30; H, 5.51; N, 5.47. Found: C, 70.52; H, 5.85; N, 5.20.

Example 57

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -4 - [(4-methyl-2-oxo-2H-1-benzopyran-6-yl)] oxy] butyl] -N-hydroxyformamide,

The title compound was prepared according to the procedure for EXAMPLE 56, but using 4-penten-1-ol instead of 5-hexen-1-ol in Example 56A.

Mixture of two rotamers: 1 H NMR (300 MHz, c 1 -DMSO) d 9.94 (s, 1H), 9.55 (s, 1H0, 8.44 (s, IH), 8.06 (s, IH) 7.86 (m, 8H), 7.73-7.70 (m, 4H), 7.35 (d, 2H), 7.26-7.22, (m, 4H), 7.087 / 05 ( m, 4H), 6.40 (s, 2H), 4.65 (m, 1H), 4.17-4.04 (m, 9H), 2.44 (s, 6H), 1.77 (m MS (ESI) m / e 499 (M + 1) &lt; ^{+ &gt;} .

Calculated for C29H26N ₂ O6 * 0.75H ₂ O: C, 68.03; H, 5.41; N, 5.47. Found: C, 68.21, H, 5.25; N, 5.28.

Example 58

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -4 - [(4-methyl-2-oxo-2H-1-benzopyran-7yl) oxy] Butyl] -N-hydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 56 but substituting 7-hydroxy-4-methylcoumarin (500 mg, 2.8 mmol) instead of 6-hydroxy-4-methylcoumarin and 4-pentenl-ol instead of 5-hexen-1-ol in of Example 56A.

A mixture of two rotamers: Ή NMR (300 MHz, cU-DMSO) d 9.95 (s, 1H), 9.55 (s, 1H), 9.44 (s,

1H), 8.05 (s, 1H), 7.90-7.82 (m, 8H), 7.73-7.67 (m, 6H), 7.08-7.04 (m, 4H) 7.01-6.95 (m,

4H), 6.21 (s, 2H), 4.64 (m, 1H), 4.20-4.01 (m, 9H), 2.40 (s, 6H), 1.80-1.74 (m, 8H);

MS (ESI) mlz 499 (M + 1) ⁺ .

“- ·

Calcd for C29H26N2O6: C, 69.87; H, 5.26; N, 5.62. Found: C, 69.51; H, 5.33; N, 5.40.

Example 59

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -5 - [(4-methyl-2-oxo-2H-1-benzopyran-7yl)] oxy] pentyl] -N-hydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 56, but using Ί -hydroxy-4-methylcoumarin (500 mg, 2.8 mmol) instead of 6-hydroxy-4-methylcoumarin.

Mixture of two rotamers: 1 H NMR (300 MHz, c 1 -DMSO) d 9.89 (s, 1H), 9.50 (s, 1H), 8.42 (s, 1H), 8.03 (s, 1H) ), 7.90-7.82 (m, 8H), 7.73-7.66 (m; 6H), 7.08-7.03 (m, 4H), 6.98-6.94 (m) 2H, 6.21 (s, 2H), 4.60 (m, 1H), 4.15-3.98 (m, 9H), 2.40 (s, 6H), 1.84-1.40 (m, 12H);

MS (ESI) mlz 513 (M + 1) ⁺ .

Calcd for C30H28N2O6: C, 70.30: H, 5.51; N, 5.47. Found: C, 70.35; H, 5.52; N, 5.17.

Example 60

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (5,5-dimethyl-2,4-dioxo-3-oxazolidinyl) ethyl] -N -hydroxyformamide

The title compound was prepared as in Example 49, except using 5,5-dimethyl-oxazolidinin-2,4-dione (300 mg, 0.8 mmol) instead of succinimide.

Mixture of two rotamers: 1 H NMR (300 MHz, c 1 -DMSO) d 10.08 (s, 1H), 9.70 (s, 1H), 8.35 (s, 1H), 7.98 (s, 1H) 7.90-7.83 (m, 8H); 7.7.4 (d, 4H), 7.06 (d, 4H), 4.90 (m, 1H), 4:47 (m, 1H), 4.24-4.16 (m, 4H) 3.85 (d, 1H); 3.80 (d, 1H); 3.69-3.65 (m, 1H); 3.643.61 (m, 1H); 1.49 (s, 6H); 1.48 (s, 6H);

MS (ESI) mlz 441 (M + 18) ⁺ .

Example 61

N- [1 - [[(4'-Cyano [1,1-biphenyl] -4-yl) sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl -N-hydroxyformamide

»·· ···

Example 61A

- [(4'-Cyano [1,1-biphenyl] -4-yl) thio] -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) -2-propanone Solution 4 ' -thiol-4-biphenylcarbonitrile (150 mg, 0.71 mmol) in 6 mL of DMF at 5 ° C was treated with potassium carbonate (89 mg, 0.645 mmol) and 1-bromo-3- (3,4, 4-trimethyl-2,5-dioxo-1-imidazolidin-1-yl) -2-propanone (179 mg, 0.645 mmol), stirred for 1 hour at -5 ° C, quenched with saturated NH 4 Cl, extracted with ethyl acetate, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to a solid. Purification on a silica gel column eluting with 1: 1 ethyl acetate / hexanes gave 200 mg (75%) of the title compound.

1 H NMR (300 MHz, d 6 -DMSO) d 7.94-7.87 (m, 4H), 7.72 (d, 2H), 7.43 (d, 2H), 4.55 (s,

2H), 4.27 (s, 2H), 2.80 (s, 3H), 1.32 (s, 6H).

Example 61B

N- [1 - [[(4'-Cyano [1,1-biphenyl] -4-yl) thio] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl ] -N-hydroxyformamide,

The title compound was prepared from 61A according to the procedures of Example 2D, 2E, and 2F. A mixture of two rotamers: 1 H NMR (300 MHz, d 6 -DMSO) d 9.76 (s, 1H), 9.51 (s, 1H), 8.29 (s, 1H), 7.93-7.87 (m, 8H), 7.75-7.72 (m, SH), 7.50-7.44 (m, 4H), 4.60 (m, 1H), 4.10 (m, 1H), 3.80-3.60 (m, 4H), 3.25-3.15 (m, 4H), 2.77 (s, 6H), 1.25 (s, 12H).

Example 61C

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl -N-hydroxyformamide

A solution of 61B (81 mg, 0.18 mmol) in 4: 1 THF / H ₂ O at 0 ° C was treated with oxone (140 mg) and NaHCO ₃ (33 mg), stirred for 30 minutes at room temperature. 0 ° C, then at 23 ° C for 1 hour, quenched with H ₂ O, extracted with ethyl acetate, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to a white solid. Purification on a silica gel column eluting with 2% methanol / dichloromethane gave 43 mg (49%) of the title compound.

rassHsraasšaaaasaaaassa ^^ šSSSSSř ^ E

A mixture of two rotamers: 1 H NMR (300 MHz, c 1 -DMSO) d 9.71 (s, 1H), 9.54 (s, 1H), 8.09 (s, 1H), 8.07-7.96 (m, 16H), 7.74 (s, 1H), 4.90 (m, 1H), 4.54 (m, 1H), 3.74-3.60 (m, 4H), 3,553.44 ( m, 4H), 2.74 (s, 3H), 2.74 (s, 3H), 1.24-1.22 (m, 12H);

MS (ESI) mlz 485 (M + 1) ⁺ .

Calcd for C23H24N4O6S: C, 57.01; H; 4.99; Ν, 11.56. Found: C, 56.86; H, 5.21; NI 1.28.

Example 62

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] N- hydroxyformamide

The title compound was prepared as in Example 49, except that 1 methylhydantoin was used instead of succinimide. '*.

Rotamer mixture: 1 H NMR (300 MHz, d 6 -DMSO) d 9.97 (s, 1H), 9.61 (s, 1H), 8.35 (s, 1H), 7.98 (s, 1H) 7.90-7.83 (m, 8H), 7.73 (d, 4H), 7.03 (d, 2H), 7.01 (d, 2H), 4.88-4.84 (m , 1H), 4.39-4.35 (m, 1H), 4.22-4.08 (m, 4H), 3.97 (s, 2H), 3.94 (s, 2H), 3, 75-3.57 (m, 4H); 2.86 (s, 3H); 2.85 (s; 311);

MS (ESI) m / e 409 (M + 1) ’.

Calcd for C21H20N4O5: C, 61.76; H, 4.94; N, 13.72. Found: C, 61.47; H, 5.00; N, 13.39.

Example 63

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-imidazolidinyl) ethyl ] -N-hydroxyformamide,

The title compound was prepared according to the procedures for EXAMPLE 61, but using 1-bromo-3- (4,4-dimethyl-2,5-dioxo-1-imidazolidin-1-yl) -2-propanone in place of 1-bromo-3- ( 3,4,4-trimethyl-2,5-dioxo-1-imidazolin-1-yl) -2-propanone in Example 61 A.

Rotamer mixture: 1 H NMR (300 MHz, d 6 -DMSO) d 9.66 (s, 1H0, 9.51 (s, 1H), 8.38 (s, 1H),

8.34 (s, 1H), 8.10 (s, 1H), 8.07-7.96 (s, 16H), 7.74 (s, 1H), 4: 94-4.86 (m, 1H), 4.58-4.50 (m,

1H), 3.80-3.37 (m, 8H), 1.23-1.20 (m, 12H);

MS (ESI) m / e 488 (M + 18) ^&lt; ^{+ &gt};, ¹ &lt; tb &^gt;

Calcd for C22H22N4O6S: C, 56.16; H, 4.71; N, 11.91. Found: C, 56.12; H, 5.00; N, 11.59.

Example 64

() -N- [1 - [[(4'-Chloro- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo) (Imidazolidinyl) ethyl] -N-hydroxyphonamide

Example 64A

- [4''-chloro-Γ''-biphenyl] -4'-yl) oxy] -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) -propan-2-one

A solution of Example 16B (0.81 g, 2.93 mmol), 4-chloro-4'-hydroxybiphenyl (0.5 g, 2.44 mmol) and potassium carbonate (0.35 g, 2.57 mmol) in dry DMF (50 mL) was stirred at room temperature for 1.5 h and then partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (1x). The combined organic layers were diluted with an equivalent volume of hexanes and washed sequentially with water (3x), brine (2x), dried (Na 2 SO ₄ ) and concentrated to give 0.89 g of a waxy congealed solid which was purified on a silica gel column 40% ethyl acetate / dichloromethane to give 0.46 g (47%) of the title compound as a colorless solid.

m.p. Mp 165-166 ° C

MS (DCI / NH 3) m / e 379 (M + NH 3) ⁺ .

Example 64B

() -N- [1 - [[(4-Chloro- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl) ethyl] -N-hydroxyformamide

The ketone of Example 64B is sequentially converted to the corresponding oximes, hydroxylamine and end product as described in Examples 2D, 2E and 2F. The title compound was purified on a silica gel column (2.5% methanol / dichloromethane) to give the title compound as a colorless solid, which was recrystallized from ethyl acetate / hexanes.

m.p. 124-125 ocC

MS (DCI / NH 3) m / e 446 (M + H) ⁺ and 463 (M + NH) +

,. ^ χίίΒΐΜΡ «^ · ιι,

• 44 • 4 4 4 ·· • * • • • 4 4 • 4 4 • 4 « 4 4 4 4 4 • 444 ··· 4 44 4 «• 4 4 • 4 4 4 44 4

1 H NMR (300 MHz, CDCl ₃ ) d 9.90 (s; 0.5H), 9.58 (s; 0.5H), 8.32 (s; 0.5H), 7.92 (s; 0) , 5H),

7.65 (d; 2H; J = 9Hz); 7.61 (d; 2H; J = 9Hz); 7.47 (d; 2H; J = 9Hz); 6.99 (d; 1H; J = 9Hz); Hz), 6.97 (d; 1H; J = 9 Hz), 4.86 (m; 0.5H), 4.42 (m; 0.5H), 4.08-4.23 (m; 2H) ), 3.82-3.70 (m; 1H), 3.553.65 (m; 1H), 2.80 (s; 1.5H), 2.78 (s; 1.5H), 1.30 (s; 3H), 1.28 (s, 3H);

Calcd for C22H22N3O5Cl: C, 59.26; H, 5.42; N, 9.42. Found: C, 59.54; H, 5.61; N, 9.13.

Example 65 (+) - N- [1 - [[(3'-Cyanomethyl- [1,1'-biphenyl] -4-yloxy) methyl] -2- (3,5,5-trimethyl-2,4) (dioxo-limidazolidinyl) propyl] -N-hydroxyformamide

Example 65A

- (3 - [(3'-Cyano-methyl- [1,1'-biphenyl] -4-yl) oxy] -propan-2-one-1-yl) -3,4,4-trimethyl-2,5-dioxoimidazolidine

The title compound was prepared as in Example 5F, but using 4'-hydroxy-3-biphenylcarbonitrilomethane (0.95 g, 2.80 mmol) instead of 4'-hydroxy-4-biphenylcarbonitrile. Purification on a silica gel column eluting with 100% ethyl acetate gave 0.78 g of the title compound.

MS (DCI / NH 3) m / e 437 (M + H +).

Example 65B (+) - N- [1 - [[(3'-Cyanomethyl- [1,1'-biphenyl] -4-yloxy) methyl] -2- (3,5,5-trimethyl-2,4-dioxo-limidazolidinyl) propyl] -N-hydroxyformamide

Example 65 A (0.78 g, 1.87 mmol) was treated sequentially according to the procedure in Example 2D, 2E and 2F without purification of the intermediates. Purification on a silica gel column eluting with 100% ethyl acetate gave 500 mg (1.08 mmol) of the title compound.

1 H NMR (300 MHz, DMSO) 9.99 (s, 0.5H), 9.58 (s, 0.5H), 8.36 (s, 0.5H), 7.92 (s, 0.5H) d, 7:60 (m; 4H), 7.46 (t; 1H, J = 8 Hz), 7.30 (d; 1H;> 8 Hz), 7.02 (d; 2H; I = 8 Hz) ), 4.50 (m, · ··· ·············· · ··· ····················· 94 94

0.5H), 4.18 (m; 0.5H), 4.12 (s; 2H), 4.10 (m, 2H), 3.45 (m; 2H), 2.80 (s; 3H) 1.92 (m, 1H), 1.80 (m, 1H), 1.30 (s: 6H).

MS (DCI / NH ₃ ) m / e 482 (M + H ⁺⁾ .

Calcd for C18H18N2O4: C, 64.66; H, 6.03; N, 12.07. Detected

Example 66 (+) - N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yloxy) methyl] -2-isopropylthioethyl] -N-hydroxyformamide

Example 66A (+) - 1 - [(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] -3-isopropylthio-2-propanol

A solution of isopropyl thiol (0.48 g, 6.4 mmol) in THF (20 mL) was treated with K 2 CO 3 (0.5 g, 3.6 mmol). After 30 minutes, 3 - [(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] (1,2) oxirane (0.8 g, 3.19 mmol) was added in one portion. The resulting solution was stirred for 3 hours at 70 ° C, quenched by addition of excess aqueous sodium bicarbonate solution and partitioned between ethyl acetate and brine. The organic layer was dried (Na 2 SO 4), and the product was purified on a silica gel column eluting with 50% ethyl acetate / hexanes to afford 0.9 g (2.75 mmol, 86%) of the title compound.

MS (DCI / NH 3) m / e (M + NH 4) and 362 (M + NH 4 + NH 3).

Example 66B (+) - N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yloxy) methyl] -2-isopropylthioethyl] -N-hydroxyformamide Example 66A was processed according to procedures in Example 2C, 2D, 2E and 2F to give the title compound as a light orange foam.

1 H NMR (300 MHz, DMSO) 9.99 (s: 0.5H), 9.60 (s: 0.5H), 8.42 (s: 0.5H), 8.04 (s: 0, 5H), d

7.85 (m; 4H); 7.75 (d; 2H, J = 9 Hz); 7.05 (d; 2H; J = 9 Hz); 4.63 (m; 1H); 4.17 (m) 3H), 3.0 (m, 1H), 2.79 (m, 1H), 1.22 (dd, 6H, J = 7.50 Hz);

MS (DCI / NH 3) m / e 388 (M + NH 4) ⁺ .

Calcd for C20H22N2O3S: C, 64.86; H, 5.94; N, 7.57. Detected:

Example 67 (+) - N- [1 - [[(3'-Cyanomethyl- [1,1'-biphenyl] -4-yloxy) methyl] -2- (3,4,4-trimethyl-2,5-dioxo) (imidazobdinyl) ethyl] -N-hydroxyformamide,

Example 67A (+) - 1- [4- (3'-Cyanomethylphenyl) phenoxy] methyl] -3- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) 2-propanol

The title compound was prepared as in Example 4A, but using 4'-hydroxy-3-biphenylcarbonitrilomethane (170 mg, 0.64 mmol) and 3,5,5-trimethylhydantoin (37 mg, 0.96 mmol) instead of 4'-hydroxy- 4-biphenylcarbonitrile and 5,5-dimethylhydantoin. Purification on a silica gel column eluting with 100% ethyl acetate gave 130 g of the desired compound.

MS (DCI / NH ₃₎ m / e 415 (M + NH) ^+.

Example 67B (+) - N- [1 - [[(3'-Cyanomethyl- [1,1'-biphenyl] -4-yloxy) methyl] -2- (3,4,4-trimethyl-2,5-dioxo) (imidazolidinyl) ethyl] -N-hydroxyformamide

Example 67A was processed according to the procedures in Example 2C, 2D, 2E, and 2F to give the title compound.

1 H NMR (300 MHz, DMSO) 9.86 (s; 0.5H), 9.58 (s; 0.5H), 8.34 (s; 0.5H), 7.92 (s; 0.5H) δ 7.60 (m; 4H), 7.46 (t; 1H, 1 = 8 Hz), 7.30 (d; 1H, J = 8 Hz), 7.02 (d; 2H; J = 8Hz) 1.87 (m; 0.5H), 4.42 (m; 0.5H), 4.10 (m; 2H), 4.12 (s; 2H), 3.68 (m; 1H) 3.62 (m; 1H); 2.80 (s; 3H); 1.30 (s; 6H).

MS (DCI / NH 3) m / e 468 (M + NH 3).

Calcd for 62.85; H, 5.84; N, 11.85. Detected

Example 68 (+) - N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-ethyl-4,4-dimethyl-2) (5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide;

Example 68A

4,4-dimethyl-2,5-dioxo-N- (4-methoxoybenzyl) imidazolidine

A solution of 4,4-dimethyl-2,5-dioxoimidazolidine (17.0 g, 133 mmol), 4-methoxybenzyl chloride (30.0 g, 192 mmol) and potassium carbonate (27.5 g, 200 mmol) in dry DMF (600 mL) ) was heated at 80 ° C under nitrogen for 3 hours. The volume was reduced under high vacuum to about 1/4 of the original volume and the resulting solution was partitioned between ethyl acetate and water. The aqueous layer was separated, extracted with ethyl acetate (2x). The combined organic extracts were washed successively with water (2x) and brine (2x), dried (Na ₂ SO 4) and concentrated in vacuo to give 32.97 g of a solid. The pure title compound was obtained after recrystallization from ethyl acetate and hexanes in 24.5 g (74%) of a colorless solid.

m.p. 109-111 [deg.] C .;

MS (DCI / NH 3) m / e 249 (M + H) ⁺ and 266 (M + NH 4).

Example 68B

3-Ethyl-1- (4'-methoxybenzyl) -2,5-dioxo-4,4-dimethylimidazolidine

A solution of 4,4-dimethyl-2,5-dioxo-N- (4-methoxoybenzyl) imidazolidine (3.5 g, 14.1 mmol) in THF (100 mL) was treated with sodium hydride (0.5 g, 21.2 mmol), stirred for 10 minutes, treated with iodoethane (3.3 g, 21.2 mmol), stirred for 3 hours at 50 ° C, then treated with HCl solution ( 10%) and partitioned between ethyl acetate and brine. The organic layer was dried and concentrated to give 3.8 g (13.8 mmol, 98%) of the title compound as a white solid.

MS (DCI / NH 3) m / e 294 (M + NH 3) +.

Example 68C

3-Ethyl-2,5-dioxo-4,4-dimethylimidazolidine

A solution of 3-ethyl-1- (4'-methoxybenzyl) -2,5-dioxo-4,4-dimethylimidazolidine (3.86 g, 14.0 mmol) in methoxybenzene (100 mL) was treated with aluminum trichloride (5 mL). (5 g, 42 mmol), stirred for 30 min at 75 ° C, then poured into HCl solution (10%) and partitioned between ethyl acetate and brine. The organic layer was dried and concentrated. Purification by recrystallization with ethyl acetate gave 2.1 g (13.5 mmol, 96%) of the title compound as a white solid.

φ 't »

Example 68D

- [(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] -2- (3-ethyl-5,5-dimethyl-2,4-dioxo-1-imidazolidinyl) -2-propanone

A solution of 3-ethyl-2,5-dioxo-4,4-dimethylimidazolidine (0.7 g, 4.5 mmol) in DMF (100 mL) was treated with potassium carbonate (0.6 g, 4.5 mmol) and 1 - [(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] -3-bromo-2-propynon (1.0 g, 3.0 mmol), stirred for 20 hours at 25 ° C ° C, then poured into aqueous HCl (10%) and partition between ethyl acetate and brine. The organic layer was dried and concentrated. Purification on a silica gel column eluting with 50% ethyl acetate gave 0.8 g (1.97 mmol, 66%) of the title compound as a white solid. MS (DCI / NH ₃ ) m / e 424 (M + NH 4).

Example 68E (+) - N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-ethyl-4,4-dimethyl-2) (5-dioxo-limidazobdinyl) ethyl] -N-hydroxyformamide

Example 68B (0.72 g, 1.77 mmol) was treated sequentially according to the procedures in Example 2D, 2E and 2F without purification of the intermediates. Purification on a silica gel column eluting with 60% ethyl acetate / hexanes gave 158 mg (0.35 mmol) of the title compound.

1 H NMR (300 MHz, DMSO) 9.85 (s; 0.5H), 9.54 (s, 0.5H), 8.32 (s; 0.5H), 7.94 (s; 0.5H) ), d

7.86 (m; 4H), 7.72 (d; 2H, J = 9 Hz), 7.08 (d; 2H, J = 9 Hz), 4.85 (m; 0.5H), 4.42 (m; 0.5H), 4.18 (m; 2H), 3.78 (m; 1H), 3.62 (m; 1H), 1.32 (s; 6H), 1.12 (m; 3H).

MS (DCI / NH ₃ ) m / e 468 (M + NH 4) ⁺ .

Calcd for C24H26N4O5: C, 64.00; H, 5.78; N, 12.44. Detected

Example 69A

Example 69 (+) - N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-benzyl-4,4-dimethyl-2) , 5-dioxo-1-imidazobdinyl) ethyl] -N-hydroxyformamide,

• ·

3-Benzyl-1- (4'-methoxybenzyl) -2,5-dioxo-4,4-dimethylimidazolidine

The title compound was prepared as in Example 68B, but using benzyl iodine (3.9 g, 18 mmol) instead of iodoethane. Purification on a silica gel column eluting with 50% ethyl acetate gave 4.0 g of the desired compound.

MS (DCI / NH 3) m / e 356 (M + NH 3) +.

Example 69B

3-Benzyl-2,5-dioxo-4,4-dimethylimidazolidine

A solution of 3-benzyl-1- (4'-methoxybenzyl) -2,5-dioxo-4,4-dimethylimidazolidine (3.9 g,

11.54 mmol) in acetonitrile (100 mL) was treated with a solution of ammonium cerium nitrate (31 g, 57.7 mmol) in 65 mL water, stirred for 15 minutes at 25 ° C, then diluted. ethyl acetate and partitioned between ethyl acetate and brine. The organic layer was dried and concentrated. Purification by recrystallization from ethyl acetate / hexane gave 1.58 g (7.25 mmol, 63%) of the title compound as a white solid.

MS (DCI / NH) m / e 236 (M + NH) &lt; + &gt;.

Example 69C 1 - [(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] -3- (3-ethyl-4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) - 2propanon

The title compound was prepared as in Example 68D but using 3-benzyl-2,5-dioxo-4,4-dimethyl-imidazolidine (0.5 g, 2.28 mmol) instead of using 3-ethyl-2,5-dioxo-4, 4-dimethylimidazolidine. Purification on a silica gel column eluting with ethyl acetate / chloroform gave 634 mg of the title compound.

MS (DCI / NH 3) m / e 485 (M + NH) + ·

Example 69D (+) - N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-benzyl-4,4-dimethyl- 2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

··

Example 69C (0.62 g, 1.33 mmol) was treated sequentially according to the procedures of Example 2D, 2E and 2F without purification of the intermediates. Purification on a silica gel column eluting with 70% ethyl acetate / hexanes gave 230 mg (0.45 mmol) of the title compound.

1 H NMR (300 MHz, DMSO) 9.95 (s; 0.5H), 9.64 (s; 0.5H), 8.35 (s; 0.5H), 7.94 (s; 0, 5H), d

7.86 (m; 4H); 7.75 (d; 2H; 9 Hz); 7.30 (d; 2H; J = 9 Hz); 7.25 (m; 3H); 7.06 (m; 2H), 4.90 (m; 0.5H), 4.52 (s; 2H), 4.50 (m; 0.5H), 4.18 (m; 2H), 3.82 (m; 1H) 1.62 (m, 1H), 1.22 (s, 6H). MS (DCI / NH 3) m / e 530 (M + NH) ⁺ Example 70 (+) - N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yloxy) methyl] methyl -2- (3,5,5-trimethyl-2,4-dioxo-limidazobdinyl) ethyl] -N-hydroxyformamide

Example 70A 1 - [(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] -3- (3,5,5-trimethyl-2,4-dioxo-1-imidazolidinyl) -2- propanol A solution of 5,5-dimethylhydantoin (2.0 g, 15.6 mmol) in DMF (20 mL) was treated with sodium tert-butoxide (1.5 g, 15.6 mmol), stirred for 10 minutes , then treated with iodomethane (2.2 g, 15.6 mmol), stirred for 3 hours at 40 ° C. The resulting solution was treated with sodium tert-butoxide (1.5 g, 15.6 mmol) followed by 3 - [(4'-cyano- [1,1'-biphenyl] -4-yloxy) - (1,1'-biphenyl] -4-yloxy). 2) -oxirane (1.15 g, 4.58 mmol), stirred for 20 minutes at 100 ° C, then treated with HCl solution (10%) and partitioned between ethyl acetate and brine. The organic layer was dried and concentrated to give 1.35 g (75%) of the title compound as a white solid.

MS (DCI / NH 3) m / e 411 (M + NH) +.

Example 70B

- [(4'-Cyano- [1,1'-biphenyl] -4-yloxy] -3- (3,5,5-trimethyl-2,4-dioxo-1-imidazolidinyl) -2-propanone Example 70A (1.35 g, 3.4 mmol) was treated according to the procedures in Example 2C. Purification on a silica gel column eluting with 30% ethyl acetate gave 1.2 g (3.1 mmol, 90%) of the title compound.

MS (DCI / NH 3) m / e 409 (M + NH) + ·

Example 70C (+) - N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yloxy) methyl] -2- (3,5,5-trimethyl-2, 1 H -pyrido [1,1'-biphenyl] -4-yloxy) methyl] 4-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide

Example A-264890.0-B (1.2 g, 3.07 mmol) was treated sequentially according to the procedures of Example 2D, 2E and 2F without purification of the intermediates. Purification on a silica gel column eluting with 30% ethyl acetate / hexanes gave 380 mg (2.29 mmol) of the title compound. 1 H NMR (300 MHz, DMSO) 9.90 (s; 0.5H), 9.68 (s; 0.5H), 8.38 (s; 0.5H), 7.98 (s; 0) 5H), d 7.88 (m; 4H), 7.72 (d; 2H > 9 Hz), 7.08 (d; 2H; 1 = 9 Hz), 4.92 (m; 0.5H) 4.42 (m; 0.5H), 4.20 (m; 2H), 3.50 (m; 2H), 2.88 (s; 3H), 1.32 (s; 6H).

MS (DCI / NH 3) m / e 454 (M + NH ₄ ) ⁺ .

Calcd for C23H24N4O5: C, 63.30; H, 5.55; N, 12.69. Detected

Example 71

N- [1 - [[4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide;

Example 71A

4'-Methoxy-4-thiomethylbiphenyl

A solution of 4-bromothioanisole (6.15 g, 29.4 mmol) in DMF (60 mL) was sequentially treated with palladium acetate (0.34 g, 1.5 mmol) and tri-o-tolylphosphine (0.94 g). (3.0 mmol) was then treated with 4-methoxyphenylboronic acid (5.06 g, 32.3 mmol) and cesium carbonate (19.2 g, 58.8 mmol). The mixture was stirred at 75 ° C for 8 hours, then at reflux temperature for 15 hours. The resulting suspension was partitioned between water and ether / hexane (2: 1). The organic layer was dried with Mg ₂ SO ₄ and concentrated to give the crude product as a yellow solid. Recrystallization in ether at -20 ° C gave 2.61 g (39%) of the title compound.

MS (ESI) mlz 231 (M + H).

Example 71B

4- (4'-Methoxyphenyl) -phenylmethylsulfone

A solution of Example 71A (2.61 g, 11.3 mmol) in chloroform (100 mL) was treated with m-chloroperbenzoic acid (6.52 g, 22.7 mmol), stirred for 3 hours at room temperature.

0 ° C and then heated at 10 ° C for 1 hour. The mixture was partitioned between dilute aqueous sodium bicarbonate and chloroform, dried (MgSO ₄ ) and concentrated to afford the crude product as a white solid. Recrystallization in dichloromethane and ether gave 1.89 g (64%) of the title compound.

MS (ESI) mlz 263 (M + H) and 280 (M + NH 4).

Example 71C

N- [1 - [[4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide;

A suspension of Example 71B (0.26 g, 1.0 mmol) in THF (40 mL) cooled to -78 ° C under an argon atmosphere was treated with n-BuLi (0.40 mL of a 2.5 M solution in hexane, 1 mL). 0 mmol) and stirred for 3 hours. The resulting suspension was treated with BF 3 * Et ₂ O (0.127 mL, 1.0 mmol) followed by acetaldehyde O-benzyloxime (0.15 g, 1.0 mmol) J. Med. Chem. 1997, vol. 40, number 13, pp. 1955-1968 (Stewart, et al.). [J. Copper. Chem. 1997, vol. 40, 1955-1968 (Stewart, et. Al.).] In THF (10 mL). Stir for 1 hour at -78 ° C, then for 1 hour at reflux temperature. The mixture was partitioned between ether and phosphate buffer at pH 7. The organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated to give the crude product as a white powder, which was purified on a silica gel column eluting with dichloromethane / methanol to give 15 g (36%) of the title compound.

MS (ESI +) mlz 412 (M + H).

/

Example 71D

N- [1 - [[(4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide

A solution of Example 71C (0.11 g, 0.27 mmol) in THF (50 mL) cooled to 0 ° C under argon was treated with marenic acid acetic anhydride (0.24 g, 2.7 mmol), stirred for 5 minutes at 0 ° C and then for 6 hours at reflux temperature. Then partition between 1N HCl and ethyl acetate. The organic extracts were washed with brine, dried (Mg ₂ SO ₄ ) and concentrated to give a crude oil product which was purified on a silica gel column eluting with dichloromethane / methanol to give 114 mg (96%) of the title compound.

MS (ESI +) mlz 263 (M + H) and 280 (M + NH 3).

Example 71E

N- [1 - [[(4'-Methoxy [4'-ifenyl] -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide

A solution of Example 7ID (114 mg, 0.26 mmol) in THF (20 mL) was treated with 10% palladium on activated carbon (35 mg, catalytic amount) and hydrogen gas at atmospheric pressure and stirred at reflux temperature for 18 hours. The suspension is filtered through a pad of Celite and concentrated to give the crude product as a white solid which is collected. purified by trituration in ethyl acetate to give 66 mg (73%) of the title compound, m.p. 197-198 [deg.] C .;

Ή NMR (DMSO-d 6) δ 1.16 (d, I, SH,> 6.6 Hz), 1.22 (d, 1.5H, J = 6.6 Hz), 3.43-3.70 (m,

2H), 3.82 (s, 3H), 4.28-4.41 (m, 0.5H), 4.62-4.76 (m, 0.5H), 7.08 (d, 2H, > 8.7 Hz), 7.74 (d, 2H,> 8.7 Hz), 7.87-7.96 (m, 4.5H), 8.08 (s, 0.5H); 9.47 (s, 0.5H), 9.89 (s, 0.5H);

MS (ESI &lt; + &gt;) m / e 350 (M + H), 367 (M + NH &lt; + &gt;);

Anal Calcd For C 18 H 16 NO 5 S 2 O 2: C, 55.57; H, 5.76; N, 3.81. Found: C, 55.32; H, 5.20; N, 3.67.

Example 72

N- [1 - [[(4'-chloro (1,1'-biphenyl) -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide

The title compound was synthesized according to the procedures described in Example 71, except using 4-chlorophenylboronic acid instead of 4-methoxyphenylboronic acid in Example 71 A. Purification of the crude end product by recrystallization in ethyl acetate yielded 36 mg of the desired compound.

m.p. 178-180 [deg.] C .;

1 H NMR (DMSO-d 6) δ 1.16 (d, 1.5H, J = 6.6 Hz), 1.22 (d, I, SH,> 6.6 Hz), 3.50 (dd, 1H,> 4.8,14.7 Hz), 3.57-3.73 (m, 1H), 4.28-4.41 (m, 0.5H), 4.61-4.77 (m (0.5H), 7.59 (d, 2H, > 8.4 Hz), 7.81 (d, 2H, > 8.4 Hz), 7.91 (s, 0.5H), 7.92 -8.00 (m, 4H), 8.07 (s, 0.5H), 9.45 (s, 0.5H), 9.86 (s, 0.5H);

MS (ESI +) mle 354 (M + H), 376 (M + Na);

Anal Calcd for Ci6Hi6NO ₄ SCl: C, 54.31; H, 4.55; N, 3.95. Found: C, 54.46; H, 4.43; N, 3.85.

Example 73

N- [1 - [[[4- (1,3-benzodioxol-5-yl) phenyl] sulfonyl] methyl] ethyl] -N-hydroxyformamide,

The title compound was synthesized according to the procedures described in Example 71 except that 3,4-methylenedioxybenzeneboronic acid was used in place of 4-methoxyphenylboronic acid in Example 71 A.

m.p. 200-201 ° C.

Ίΐ NMR (DMSO-d 6) δ 1.16 (d, 1.5H,> 6.6 Hz), 1.22 (d, 1.5H,> 6.6 Hz), 3.44-3.70 ( m,

2H), 4.28-4.40 (m, 0.5H), 4.61-4.76 (m, 0.5H), 6.11 (s, 2H), 7.06 (d, 1H; &Gt; 7.8 Hz), 7.29 (d, 1H, > 8.4 Hz), 7.39 (s, 1H), 7.86-7.94 (m, 4, SH), 8.08 ( s, 0.5H), 9.48 (s, 0.5H), 9.90 (s, 0.5H);

MS (ESI +), 364 (M + H), 381 (M + H +);

Calcd for C 11 H 11 NO 6 S: C, 56.19; H, 4.71; N, 3.85. Found: C, 55.97; H, 4.62; N, 3.81.

Example 74

N- [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl] ethyl] -N-hydroxyformamide

Example 74A

4-chlorophenoxyphenylmethylsulfone

A solution of 4-chlorophenol (5.54 g, 43 mmol) in DMSO (75 mL) was treated sequentially with potassium t-butoxide (5.15 g, 46 mmol) followed by a solution of 4-fluorophenylmethylsulfone (5.00 g, 29 mmol). mmol) in DMSO (25 mL), heated at 120 ° C for 2 h, cooled to reflux, then partitioned between dichloromethane and 1 N sodium hydroxide, dried (MgSO ₄ ) and concentrated to give the crude product as white solids. Recrystallization from ethyl acetate and hexane gave 5.44 g (66%) of the title compound.

MS (ESI &lt; + &gt;) m / e 300 (M + NH &lt; + &gt;)

Example 74B

N- [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl] ethyl] -N-hydroxyformamide

The title compound was prepared from Example 74A according to the procedures described in Example 71C-71E. Purification of the crude final compound by recrystallization in ethyl acetate gave 388 mg of the desired compound.

m.p. 144-145 [deg.] C .;

<^ l

1 H NMR (DMSO-d 6) δ 1.15 (d, 1.5H, J = 6.6 Hz), 1.21 (d, 1.5H, J = 6.6 Hz), 3.39-3 68 (m, 2H), 4.25-4.37 (m, 0.5H), 4.60-4.70 (m, 0.5H), 7.16-7.23 (m, 4H) 7.53 (d, 2H, J = 8.9 Hz), 7.837.92 (m, 2.5H), 8.06 (s, 0.5H), 9.45 (s, 0.5H), 9.87 (s, 0.5H);

MS (ESI &lt; + &gt;) 370 (M + H), 387 (M + NH);

Calcd for C 16 H 18 NO 5 SCl: C, 51.96; H, 4.36; N, 3.78. Found: C, 52.22; H, 4.37; N, 3.80.

Example 75

N- [1 - [[(4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] propyl] -N-hydroxyformamide

Example 75A

- (4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl] -2-butanol

A solution of Example 71B (0.70 g, 2.67 mmol) in THF (200 mL) cooled to -78 ° C under argon was treated with n-BuLi (1.17 mL of a 2.5M solution in hexane, 93 mmol), stirred for 4 hours at -78 ° C, then treated dropwise with propionaldehyde (0.40 mL, 5.34 mmol). The resulting reaction mixture was heated at reflux temperature for 1.5 h, quenched with saturated aqueous NHCl (50 mL), partitioned between ether and water, dried (MgSO 4) and concentrated to give 0.90 g of crude product which Purify on a silica gel column eluting with dichloromethane / methanol to give 0.78 g (91%) of the desired compound.

MS (ESI &lt; + &gt;) 321 (M + H), 338 (M + NH).

Example 75B

- (4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl] -2-butene

A solution of Example 75 A (0.45 g, 1.40 mmol) in dichloromethane (40 mL) cooled to

0 ° C was treated dropwise with triethylamine (0.29 mL, 2.11 mmol) and methasulfonyl chloride (0.12 mL, 1.55 mmol) gradually. Stir at reflux for 3 hours, then react with 1, 8-diazabicyclo [5.4.0] undec-7-ene (0.21 mL, 1.40 mmol), reflux for 2 hours The mixture was cooled to reflux and partitioned between dilute sodium bicarbonate solution and dichloromethane. The organic extract was washed with 1N HCl, then brine, dried (Mg ₂ SO ₄ ) and concentrated to give the crude product as a white solid. Recrystallization in ether at -20 ° C afforded 0.34 g (80%) of the title compound.

• φ 9 · • 4 9 4 • 4 4 4 49 9 9 9 94 9 9 4 ' 4 9 4 4 9 4 9 9 4 9 4 4 9 9 4 4 4 4 4 • 9 94

MS (ESI &lt; + &gt;) 303 (M + H), 320 (M + NH).

Example 75C

N- [1 - [[(4'-Methoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] propyl] -N-hydroxyformamide

A solution of Example 75B (0.34 g, 1.12 mmol) in THF (40 mL) was treated with hydroxylamine hydrochloride (0.39g, 5.62 mmol) and potassium carbonate (0.78 g, 5.62 mmol). , reflux for 5 hours, cool to reflux, partition between ether and water, dry (Mg ₂ SO ₄ ) and concentrate to obtain the crude product as a clear, colorless oil. Recrystallization from ethyl acetate and ether gave 0.25 g (67%) of the title compound.

MS (ESI &lt; + &gt;) 336 (M + H).

Example 75D

N- [1 - [[(4'-Methoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] propyl] -N-hydroxyformamide

A solution of Example 75C (0.24 g, 0.72 mmol) in THF (30 mL) cooled to 0 ° C was treated with formic anhydride (64 mg, 0.72 mmol), stirred for 2 hours, partitioned between water and dichloromethane, dried (mg 2 Si ₄₎ and concentrated to give 0.25 g of crude product which was recrystallized in ethyl acetate to obtain 106 mg (41%) of the desired compound.

m.p. 199-200 ° C;

1 H NMR (DMSO-d 6) δ 0.69-0.80 (m, 3H), 1.40-1.69 (m, 2H), 3.41-3.69 (m, 2H), 3, 82 (s, 3H), 3.96-4.07 (m, 0.5H), 4.43-4.54 (m, 0.5H), 7.08 (d, 2H,> 9.0 Hz) ), 7.71-7.78 (m, 2H), 7.87-7.96 (m, 4.5H), 8.17 (s, 0.5H), 9.49 (s, 0.5H) ), 9.84 (s, 0.5H);

MS (ESI +), 364 (M + H), 381 (M + NH);

Calcd for C19H18NO5S: C, 59.48; H, 5.82; N, 3.85. Found: C, 59.67; H, 5.77; N, 3.80.

Example 76

N- [1- [1,1-dimethyl-2 - [(4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyphomiamide

Example 76A

4- (4'-Trifluoromethylphenyl) -phenylmethylsulfone

100 • · t t · i i * * ··· ♦ · * ·· «· ··

The title compound was prepared according to the procedure in Example 73A, substituting 4-trifluoromethylphenylboronic acid for 3,4-methylenedioxybenzeneboronic acid. Purification by recrystallization in ethyl acetate and ether gave 3.70 g (72%) of the title compound.

MS (ESI &lt; + &gt;) m / e 384 (M + NH);

Example 76B (4'-Trifluoromethyl [1,1'-biphenyl] -4-yl) sulfonyl] -2-methyl-2-propanol

The title compound was prepared according to the procedure for EXAMPLE 75A, substituting Example 76A for Example 71B and replacing acetone with propionaldehyde. Purification of the sine product by recrystallization in ethyl acetate, ether and pentane gave 1.40 g (73%) of the title compound. MS (ESI &lt; + &gt;) m / e 376 (M + NH).

Example 76C

N- [1- [1,1-dimethyl-2 - [(4 '- (trifluoromethyl) [1,1-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide

The title compound was prepared from Examples 76B according to the procedures described in Examples 75B, 75C and 75D. Purification of the final product by recrystallization in ethyl acetate and ether gave 17 mg of the desired compound.

m.p. 167-169 ° C 1 H NMR (DMSO-d 6) δ 1.52 (s, 6H), 3.71 (s, 2H), 7.83-8.03 (m, 8.5H), 8.17 (s, 0.5H), 9.43 (s, 0.5H), 10.0 (s, 0.5H);

MS (ESI +), 402 (M + H), 419 (M + NH), 424 (M + Na);

Calcd for C18H18NO4F3SC: C, 53.86; H, 4.52; N, 3.48. Found: C, 53.58; H, 4.48; N, 3.19.

Example 77

N- [1 - [(phenylmethoxy) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide

The title compound was synthesized according to the procedures described in Examples 75A-75D, except for substituting Example 76A for Example 71B and replacing benzyloxyacetaldehyde with propionaldehyde in Example 75A. Purification of the crude end product by recrystallization in ethyl acetate gave 0.53 g of the desired compound.

m.p. 172 [deg.] C .;

»·

101

Ή NMR (DMSO-d 6) δ 3.37-3.61 (m, 3H), 3.61-3.72 (m, 1H), 4.28-4.50 (m, 2.5H), 4 81-4.93 (m, 0.5H), 7.20-7.35 (m, 0.5H), 7.85-8.06 (m, 8.5H), 8.18 (s, 0.5H), 9.57 (s, 0.5H), 9.96 (s, 0.5H);

MS (ESI +), 494 (M + H), 511 (M + NH 4);

Calcd for C24H22NO5F3S: C, 58.41; H, 4.49: N, 2.83. Found: C, 58.43; H, 4.54; N, 2.77.

Example 78

N- [1- (hydroxymethyl) -2 - [[(4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide

A solution of Example 78 (35 mg, 0.07 mmol) in THF (3 mL) and methanol (5 mL) was treated with palladium on charcoal (10%) (30 mg, 0.03 mmol) and hydrogen gas at atmospheric pressure. Stir at reflux temperature for 16 hours, filter through Cebt and concentrate to obtain the crude product. Purification by recrystallization in ethyl acetate, ether and hexane gave 20 mg (70%) of the title compound.

m.p. 159-161 [deg.] C .;

1 H NMR (DMSO-d 6) δ 3.25-3.68 (m, 4H), 3.98-4.10 (m, 0.5H), 4.54-4.66 (m, 0.5H) 4,975.09 (m, 1H), 7.81-8.07 (m, 0.5H), 8.14 (s, 0.5H), 9.44 (s, 0.5H), 9.85 (s, 0.5H);

MS (ESI +) 404 (M + H), 421 (M + NH 4), 426 (M + Na);

Calcd for C17H16NO5F3S: C, 50.61; H, 3.99; N, 3.47. Found: C, 50.57; H, 3.93; N, 3.37.

Example 79

N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazobdinyl) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] -4yl] thio] ethyl] -N-hydroxyformamide

Example 79A

- [(4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] thio] -3- (4,4-dimethyl-2,5-dioxoimidazobdinyl-1-yl) -2-propanone

Example 46A (698 mg, 1.88 mmol), tetrakis (217 mg, 0.19 mmol), 4-trifluorophenylboronic acid (714 mg, 3.76 mmol) and NaOH (1M, 3.76 mL, 3.76 mmol). in DME (20 mL) was refluxed under Ar for 4 hours. The mixture was evaporated to a small volume and partitioned

102

between CH ₂ Cl ₂ / brine. The CH ₂ Cl ₂ layer was combined, dried (Na ₂ SO ₂ ), filtered and evaporated to dryness. Purification of the crude end product on a silica gel column eluting with 20% -40% ethyl acetate / CH ₂ Cl ₂ gave 0.820 g of the title compound.

MS (DCI / NH 3) m / e (M + NH 4 +), 437 (M + H) ⁺ .

Example 79B

N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] -4yl] thio] ethyl] -N-hydroxyformamide

The title compound was obtained according to the procedures in Examples 2D-F (inclusive), but substituting Example 79A (0.82 g, 1.88 mmol) for Example 2C. Purification of the crude end product on a silica gel column eluting with 5% methanol / dichloromethane gave 434 mg of the title compound.

m.p. 172-174 [deg.] C .;

Ή NMR (DMSO-d 6) δ d 9.75 and 9.52 (br s, 1H), 8.37 and 8.33 (s, 1H), 8.31 and 7.77 (s, 1H), 7 90 (d; 2H, J = 8.4 Hz), 7.81 (d, 2H, J = 8.4 Hz), 7.71 (m, 2H), 7.47 (m 2H), 4, 60 and 4.09 (m, 1H), 3.52-3.77 (m, 2H), 3.08-3.46 (m, 2H), 1.28 and 1.25 and 1.23 (s) , 6H),

MS (DCI / NH 3) m / e 499 (M + NH 3) ⁺ , 482 (M + H) ⁺ .

Anal Calcd for C ₂₂ H ₂₂ * 0,5CH3OH N3F3 O4S: C, 54.31; H, 4.86; N, 8.44. Detected:

C, 54.43; H, 4.82; N, 8.08.

Example 80

N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] -4yl] sulfonyl] ethyl] -N-hydroxyformamide

Example 79 is converted to Example 80 according to the procedure described in Example 46D. m.p. 180-182 [deg.] C .;

1 H NMR (DMSO-d 6) δ 9.66 and 9.51 (br s, 1H), 8.39 and 8.35 (s, 1H), 8.10 and 7.73 (s, 1H), 7.798 02 (m, 6H), 7.89 (d, 2H, J = 8.4 Hz), 4.91 and 4.55 (m, 1H), 3.45-3.80 (m, 4H), 1.24 and 1.23 and 1.21 (s, 6H).

MS (DCI / NH 3) m / e 531 (M + NH 3) +, 514 (M + H) ⁺ .

Calcd for C ₂₂ H ₂₂ N ₃ F ₃ O ₆ S * 0.75H ₂ O: C, 50.14; H, 4.49; N, 7.97. Found: C, 50:27; H, 4.49; N, 7.97.

103 • 9 ·· · 9 • 9

999

Example 81

N- [1 - [(2,5-dioxo-1-imidazolidinyl) methyl] -2 - [(4 '- (trifluoromethoxy) [1,1'-biphenyl] 4-yl] oxy] ethyl] N-hydroxyformamide

Example 81A

-bromo-3- (2,5-dioxoimidazolidin-1-yl) propan-2-one

The title compound was prepared according to the procedures in Examples 16A and 16B, but replacing the hydantoin with 1,5,5-trimethylhydantoin.

Example 81B

N- [1 - [(2,5-dioxo-1-imidazolidinyl) methyl] -2 - [(4 '- (trifluoromethoxy) [1,1'-biphenyl] 4-yl] oxy] ethyl] N-hydroxyformamide

The title compound was prepared according to the procedures described in Examples 16C and 16E, but substituting 81A for 16B and 4- (4'-trifluoromethoxy-phenyl) -phenol for 4-bromophenol.

1 H NMR (DMSO-d 6) δ 9.92 (S, 0.5H), 9.60 (BS, 0.5H), 8.31 (S, 0.5H), 8.16 (S, O, 5H), 8.14 (S, 0.5H), 7.92 (S, 0.5H), 7.76-7.72 (Μ, 4H), 7.64-7.62 (D, 4H, J = 8.4 Hz), 7.42-7.40 (D, 4H, J = 8.6 Hz), 7.02-6.98 (Μ, 4H), 4.84-4.82 (M , 0.5H), 4.38-4.35 (M, 0.5H), 4.19-4.04 (MM, 4H).

Calcd for C20H18N3 O ₆ F 3: C, 52.98; H, 4.00; N, 9.13. Found: C, 53.01; H, 4.03; N, 9.13.

Example 82

N- [1 - [[[4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) Ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures described in Example 46A, 46B, 46C, and 46D, except replacing Example 16B with 23A in Example 46A and 4-trifluoromethylbenzeneboronic acid with 4-butyloxybenzeneboronic acid in Example 46B.

1 H NMR (DMSO-d 6) δ 9.70 (s, 0.5H), 9.54 (s, 0.5H), 8.10 (s, 0.5H), 8.05-7.97 ( m, 6H), 7.89 (d, 2H, J = 7.8 Hz), 7.75 (s, 0.5H), 4.97-4.86 (m, 0.5H), 4.60 -4.48 (m, 0.5H), 3.80-, 344 (m, 4H), 2.75 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H) .

MS (ESI) 528 (M + H), 545 (M + NH 4), 526 (M-H).

104

• · J '· • · • '· • · ·· ·· • · • · •. · • 1+ • • · '♦ · • 9 • · · • · · · '· · • · ··

Calcd for C23H24N3O6SF3: C, 52.36; H, 4.58; N, 7.96. Found: C, 52.05; H, 4.70; N, 7.63.

Example 83

N- [1 - [[(4'-butyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] N- hydroxyformamide 1 H NMR (DMSO-d 6) δ 10.00-9.94 (br, 0.5H), 9.64-9.58 (br, 0.5H), 8.34 (s, 0.5H) 7.98 (s, 0.5H), 7.58 (d, 2H,> 8.8 Hz), 7.52 (d, 2H,> 8.6 Hz), 7.24 (d, 2H, > 8.5 Hz), 7.00-6.92 (m, 2H), 4.92-4.79 (m, 0.5H), 4.41-4.30 (m, 0.5H), 4.20-4.03 (m, 2H), 3.95 (d, 2H,> 7.8 Hz), 3.75-3.57 (m, 2H), 2.86 (s, 1.5H) 1.85 (s, 1.5H), 2.60 (t, 2H, J = 7.4 Hz), 1.63-1.51 (m, 2H), 1.39-1.25 ( m, 2H), 0.91 (t, 3H, > 7.4 Hz).

MS (ESI) 440 (M + H), 457 (M + NH 4), 438 (M-H).

Calcd for C24H29N3O5 * 0.25H2O: C, 64.92; H, 6.69; N, 9.46. Found: C, 64.76; H, 6.62; N, 9.29.

Example 84

N- [1 - [(3-methyl-2,5-dioxo-1-imidazobdinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [Ι, Γ-biphenyl] -4yljoxy] ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures in Examples 16C and 16E, except that Example 26A was replaced by 16B and 4- (4'-trifluoromethoxy) phenol was replaced by 4-bromophenol. 1 H NMR (DMSO-d 6) δ 10.02-9.92 (br, 0.5H), 9.64-9.58 (br, 0.5H), 8.35 (s, 0.5H), 7 98 (s, 0.5H), 7.74 (d, 2H, > 8.9 Hz), 7.64 (d, 2H, > 8.8 Hz), 7.41 (d, 2H, > 8) 1.03 Hz), 7.03-6.97 (m, 2H), 4.91-4.82 (m, 0.5H), 4.41-4.31 (m, 0.5H), 4, 21-4.07 (m, 2H), 3.96 (d, 2H, > 7.7 Hz), 3.72-3.57 (m, 2H), 2.86 (s, 1.5H), 2.85 (s, 1.5H).

MS (ESI) 468 (M + H), 485 (M + NH), 466 (M-H);

Calcd for C 21 H 20 N 3 O 6 F 3: C, 53.96; H, 4.31; N, 8.99. Found: C, 53.85; H, 4.40; N, 8.85.

Example 85

N- [4- [4 - [(4'-chloro [[1,1'-biphenyl] -4-yl) sulfonyl] methyl] tetrahydro-2H-pyran-4-yl] -Nhydroxyformamide

105

·· • 9. • · «· • « 9 · 9 • • . « ♦ • 9 • •  9 9 • «· «· · • 9 * · · 9 9 9 • • 9 9 9.

Example 85A

N_ [fourth [4. [(4 &apos;. _C chloro [[1,1'-biphenyl] -4-yl) sulfonyl] methyl] tetrahydro-2H-pyran-4-yl) Nhydroxyformamid

The title compound was prepared according to the procedure in Example 54A, except that 4'-chloro-40-methylsulfon-biphenyl was used in place of phenoxyphenyl-4-chloro-4'-methylsulfone

Example 85B

N- [4- [4 - [(4'-chloro [[1,1'-biphenyl] -4-yl) sulfonyl] methyl] tetrahydro-2H-pyran-4-yl] N-hydroxyformamide

A solution of 85A (0.436 g, 0.92 mmol) was treated with (CF ₃ CO ₂ ) 3B (4.6 mL, 1M solution in THF, 4.6 mmol) then allowed to stir overnight at room temperature. The solution was concentrated, partitioned between ethyl acetate and aqueous Na ₂ CO _3, and the organic extract was dried (MgSO 4), concentrated, and then purified on a chromatography column to give the desired compound in 51% yield.

Example 85C

N- [4- [4 - [(4'-chloro [[1,1'-biphenyl] -4-yl) sulfonyl] methyl] tetrahydro-2H-pyran-4-yl] N-hydroxyformamide

Example 85B was concentrated to the desired compound using the formylation of Example 2F.

Δ NMR (DMSO-d 6) δ 9.52-9.48 (br, 1H), 8.23 (s, 1H), 7.97 ts, 4H), 7.81 (d, 2H, J = 8, 4 Hz), 7.59 (d, 2H, J = 8.5 Hz), 3.72 (s, 2H), 3.69-3.46 (m, 4H), 2.35-1.94 ( m, 4H).

MS (ESI) 410 (M + H), 427 (M + NF), 432 (M + Na), 408 (M-H).

Example 86

N- [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide,

The title compound was prepared according to the procedures described in Examples 46A, 46C, and 46D, except using 4- (4'-chlorophenoxy) thiophenol instead of 4-bromothiophenol.

¹ H NMR (CDCl 3) δ 9.67 (s, 0.5H), 9.50 (s, 0.5H), 8.36 (d, 1H, J = 13.2 Hz), 8.10 ( s, 0.5H), 7.90 (dd, 2H, J = 8.8, 3.0 Hz), 7.68 (s, 0.5H), 7.53 (d, 2H, J = 8, 8 Hz), 7.20 (d, 4H, J = 8.8 Hz), 4.89-4.77 (m, 0.5H), 4.52-4.40 (m, 0.5H), 3.68-3.38 (m, 4H), 1.251.21 (m, 6H)

106 9 9 9 9 9 9 9 9 9 9 9 9.

9 9 9 9 9 ·· 999

MS (ESI) 496 (M + H), 513 (M + NH), 494 (M-H).

Calcd for C21H2N3O7SCl: C, 50.85; H, 4.47; N, 8.47. Found: C, 50.53; H, 4.58; N, 8.25.

Example 87

N- [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures described in Examples 46A, 46C, and 46D, except using 16B instead of 23A and 4- (4'-chlorophenoxy) thiophenol instead of 4-bromothiophenol.

1 H NMR (d 6 -DMSO) 9.78-9.71 (m, 0.5H), 9.58-9.49 (m, 0.5H), 8.09 (s, 0.5H), 7, 89 (dd, 2H, J = 5.8, 2.9 Hz), 7.68 (s, 0.5H), 7.53 (d, 2H, J = 9.2 Hz), 7.20 (d 4H, J = 8.8 Hz), 4.88-4.78 (m, 0.5H), 4.50-4.38 (m, 0.5H), 3.72-3.40 (m 4H), 2.76 (s, 1.5H), 2.76 (s, 1.5H), 1.26-1.22 (m, 6H).

MS (ESI) 510 (M + H), 527 (M + NH), 508 (M-H).

Calcd for C22H24N3O7SCl: C, 51.81; H, 4.74; N, 8.23. Found: C, 51.61; H, 4.90; N, 7.96.

Example 88

N- [1 - [[(4-butyl [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] - N-hydroxyformamide

The title compound was prepared according to the procedures described in Examples 46A, 46C, and 46D, except using 16B instead of 23A in Example 46A and n-butylbenzeneboronic acid for 4-butyloxybenzeneboronic acid.

1 H NMR (d 6 -DMSO) 9.70 (s, 0.5H), 9.54 (s, 0.5H), 8.10 (s, 0.5H), 7.94 (d, 4H, J = 1.0 Hz), 7.73 (s, 0.5H), 7.69 (dd, 2H, J = 8.1, 2.0 Hz), 7.35 td, 7H, 1 = 8.4 Hz 4.97-4.46 (m, 0.5H), 4.60-4.48 (m, 0.5H), 3.77-3.42 (m, 4H), 2.75 (s) 3H), 2.64 (t, 2H, J = 7.4 Hz), 1.64-1.54 (m, 2H), 1.40-1.27 (m, 2H), 1.24 ( s, 3H) 1.22 (s, 3H), 0.91 (t, 3H, J = 7.5 Hz).

MS (ESI) 516 (M + H), 533 (M + NH), 538 (M + Cl), 514 (M-H).

Calcd for C26H33N3O6S: C, 60.56; H, 6.45; N, 8.14. Found: C, 60.32; H,

6.44; N, 8.09.

Example 89

107

N- [1 - [[(4'-butyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazohdinyl) ethyl] -N -hydroxyformamide,

The title compound was prepared according to the procedure for EXAMPLE 23B, except substituting 4- (4'-ethoxyphenyl) -phenol for 4- (4'-butylphenyl) -phenol.

1 H NMR (d 6 -DMSO) d 0.93 (t, 3H,> 8 Hz), 1.28 (s, 6H), 130-1.39 (m, 2H), 1.50-1.65 ( m, 2H), 2.60 (t, 2H, > 7 Hz), 3.51-3.64 (m, 1H), 3.67-3.80 (m, 1H), 4.03-4, 24 (m, 2H), 4,354.48 (m, 0.5H), 4.78-4.92 (m, 0.5H), 6.99 (dd, 2H,> 3.9 Hz), 7, 25 (d, 2H, > 9 Hz), 7.53 (d, 2H, > 9 Hz), 7.58 (d, 2H, > 9 Hz), 7.94 (s, 0.5H), 8, 34 (d, 1H, > 6 Hz), 8.39 (s, 0.5H), 9.55 (s, 0.5H), 9.87 (s, 0.5H).

MS (ESI -) 452 (M-H) -.

Calcd for C25H31N3O5: C, 66.20; H, 6.88; N, 9.26. Found: C, 65.99; H, 6.71; N, 9.19.

Example 90

N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl 1-N-hydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 23B, except substituting 4- (4'-ethoxyphenyl) -phenol for 4- (3'-cyanomethylphenyl) -phenol.

1 H NMR (d 6 -DMSO) d 2.80 (s, 6H), 3.52-3.83 (m, 2H), 4.10 (s, 2H), 4.12-4.25 (m, 2H), 4.38 (4.46, mH, > 0.5 Hz), 4.80-4.90 (m, 0.5H), 7.03 (dd, 2H, > 3.9 Hz), 7.30 (d, 1H, > 10 Hz), 7.48 (t, 1H, > 10 Hz), 7.57-7.66 (m, 4H), 7.93 (s, 0.5H), 8.34 (d, 1H,> 6 Hz), 8.39 (s, 0.5H), 9.55 (s, 0.5H), 9.88 (s, 0.5H).

MS (ESI -) 435 (M-H) -.

Anal Calcd For C 23 H 40 N 4 O 5 0.25CH 3 CO 2 C 2 H 5: C, 62.87; H, 5.71; N, 12.21. Found: C, 62.85; H, 5.80; N, 12.16.

Example 91

Ν- [1- [4- (2-thienyl) phenoxy] methyl) -2- [1- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

108

• • 44 • 44 44 4 4 • 4 4 4 • · 4 • • 4 4 • 4 4 • 4 4 • * 4 · ♦ · • 444 • • 4 • 4 4 4 4 4 4 4 44 •

The title compound was prepared according to the procedures for EXAMPLES 16C and 16E, except substituting 4- (4 '- (2-thienyl) phenyl) phenol for 4-bromophenol.

¹ H NMR (d 6 -DMSO) d 1.29 (s, 6H), 2.80 (s, 3H), 3.54-3.66 (m, 1H), 3.69-3.84 (m, 1H), 4.04-4.22 (m, 2H), 4.33-4.47 (m, 0.5H), 4.77-4.90 (m, 0.5H), 6.96 ( dd, 2H,> 3.9 Hz), 7,087.13 (m, ~ 1H), 7.38 (d, 1H,> 3 Hz), 7.46 (d, 1H, J = 4 Hz), 7, 59 (d, 2H, > 9 Hz), 7.92 (s, 0.5H), 8.31 (s, 0.5H), 9.54 (s, 0.5H), 9.86 (s, 0.5H).

MS (ESI -) 416 (M-H) -.

Calcd for C ₂₀ H 23 N ₃ O ₅ S * 0.25H 2 O: C, 56.92; H, 5.61; N, 9.95. Found: C, 56.65; H, 5.48; N, 9.77.

Example 92

N- [1 - [[(3-nitro [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazobdinyl) ethyl 1-N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLES 16C and 16E, except substituting 4-phenyl-2-nitrophenol for 4-bromophenol in Example 16C.

1 H NMR (DMSO-d 6) d 1.28 (s, 6H), 2.80 (s, 3H), 3.54-3.65 (m, 1H), 3.70-3.88 (m, 1H), 4.22-4.39 (m, 2H), 4.40-4.50 (m, 0.5H), 4.80-4.91 (m, 0.5H), 7.34- 7.41 (m, 2H), 7.43-7.52 (m, 2H), 7.71 (d, 2H,> 8 Hz), 7.87 (s, 0.5H), 8.0 ( d, 1H, > 9 Hz), 8.16 (dd, 1H, J = 3.6 Hz), 8.29 (s, 0.5H), 9.55 (s, 0.5H), 9.80 (s, 0.5H).

MS (ESI -) 455 (M-H) -.

Calcd for C22H24N4O7: C, 57.88; H, 5.29; N, 12.27. Found: C, 57.62; H; 5.44; N, 11.95.

Example 93

N- [1 - [[(4'-Methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [[3- (methylsulfonyl) amino] phenyl] ethyl] -N-hydroxyformamide

Example 93A

3- (methylsulfonyl) amino-1-bromobenzene

109 m-bromoaniline is dissolved in 40 ml of pyridine and cooled to 0 ° C, then MsCl is added dropwise via syringe. After 10 minutes, the solution was warmed to room temperature and stirred for 4 hours. After concentration in vacuo, the residue was partitioned between 350 mL H ₂ O and 500 mL CH ₂ Cl ₂ in a separator. The organic layers were separated and washed with 100 mL 3N HCl, 200 mL saturated NaHCO 3, and dried over MgSO ₄ . After filtration and concentration in vacuo, a white solid is obtained. This product was recrystallized from CH ₂ Cl ₂ / hexanes to give 6.7g (90%) of 93 A as white needles.

Example 93B

3- (methylsulfonyl) amino-1- (prop-2-enyl) benzene

Use a sealed glass stopper to suspend sulfonamide 93A (3.0 g,

12.1 mmol) in 10 ml of toluene followed by addition of allyltributylSn and under Argon for 5 minutes. To the above suspension was added 280 mg (2 mol%) of Pd (PPh 3) ₄ and the flask was properly fixed with a glass stopper and heated at 120 ° C for 17 hours. After 15 minutes, a homogeneous solution was obtained, which after 30 minutes turned dark brown. After cooling, the filtered washed with CH ₂ Cl ₂ / MeOH catalyst. Concentration of the filtrate followed by purification on a silica gel column eluting with 10% ethyl acetate / hexanes followed by 20% ethyl acetate / hexanes afforded 93B 0.99 g (38%) as a colorless oil, which turned to a solid as a solid.

Example 93C

N- [1 - [[(4'-Methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [[3- (methylsulfonyl) amino] phenyl] ethyl] -N-hydroxyformamide

The title compound was prepared from Example 93B by first epoxidizing as described in Example 5C, opening the 4'-hydroxy-4-biphenylcarbonitrile epoxide as in Example 5F, followed by the procedure described in Examples 2C through 2F.

1 H NMR (DMSO-d 6) d 2.32 (s, 3H), 2.88 (d, 2H,> 6 Hz), 2.96 (s, 1H), 2.98 (s, 3H), 4.034 11.11 (m, 1H), 4.15-4.27 (m, 1.5H), 4.72-4.82 (bs, 0.5H), 6.97-7.10 (m, 4H) 7.05 (s, 1H), 7.20-7.30 (m, 3H), 7.50 (d, 2H, > 9 Hz), 7.57 (d, 2H, > 9 Hz), 7 73 (s, 0.5H), 8.25 (s, 0.5H), 9.18 (s, 0.5H), 10.01 (s, 0.5H).

MS (ESI -) 453 (M-H) -.

F'

110

4 «· • 0 • 0 0 «0 00 0 0 0 0 0 • » 0 Λ «0 0 00 «0

• 0 • ·· 0 • 0 0 0

0 0 0

0 0 0

0 · t ·

Calcd for C24H26N2O5S: C, 63.41; H, 5.76; N, 6.16. Found: C, 63.16; H, 6.12; N, 5.76.

Example 94

N- [1 - [[[3- (diethylamino) carbonyl] phenyl] methyl] -2 - [(4'-methyl [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide

Example 94A

3-Bromo-1- (N, N-diethylcarboxamide) -benzene

Diethylamine (10.0, 97 mmol) was dissolved in 60 mL dry ethyl ether and cooled to

Low: 14 ° C. Benzoyl chloride (3.67 mmol, 28 mmol) was dissolved in 10 mL dry ethyl ether and slowly added dropwise via syringe to the above solution. The resulting slurry after addition and stirring was stirred at 0 ° C for the next 10 minutes, then warmed to room temperature for 1 hour. The mixture was poured into a separator containing 500 mL of ethyl ether and 75 mL of 10% NaOH. The organic layers were separated and washed a second time with 75 mL of 10% NaOH, followed by 75 mL of 10% HCl and 200 mL of water. Finally, it was washed with 100 mL of brine, dried with MgSO ₄ , filtered and then concentrated in vacuo to give compound 94A as a colorless liquid 5.9g (83%) which was used without further purification.

Example 94B

N- [1 - [[[3- (diethylamino) carbonyl] phenyl] methyl] -2 - [(4'-methyl [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedure in Examples 93B and 93C, with the exception of substituting 94A for 93A.

1 H NMR (DMSO-d 6) d 0.98-1.20 (bd, 6H), 2.32 (s, 3H), 2.93 (d, 2H, J = 6 Hz), 3.11-3, 48 (bd, 4H), 4.0-4.13 (m, 1H), 4.16-4.30 (m, 1.5H), 4.74-4.86 (bs, 0.5H), 6.98 (d, 2H, J = 9Hz), 7.137.40 (m, 6H), 7.50 (d, 2H,> 8Hz), 7.56 (d, 2H, J = 9Hz), 7.73 (s, 0.5H), 8.23 (s, 0.5H), 9.63 (s, 0.5H), 10.02 (s, 0.5H).

MS (ES +) 461 (M + H); · *

111

• « ·· • ·· • · • · • ·· • ·· • · • · ·· • ♦ • · • • · • • · • · ·· ··· ·· ··· ·· • Φ

Anal Calcd for C28H32N2O * ₄ 1.5H ₂ O: C, 68.97; H, 7.23; N, 5,7.1. Found: C, 68.96; H, 7.09; N, 5.42.

Example 94C

N- [1 - [[[3- (diethylamino) carbonyl] phenyl] methyl] -2 - [(4'-methyl [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedure in Examples 93B and 93C, except that 94A was replaced by 93A.

1 H NMR (DMSO-d 6) d 0.98-1.20 (bd, 6H), 2.32 (s, 3H), 2.93 (d, 2H, J = 6 Hz), 3.11-3, 48 (bd, 4H), 4.0-4.13 (m, 1H); 4.16-4.30 (m, 1.5H), 4.7-4.86 (bs, 0.5H) 6.98 (d, 2H,> 9 Hz), 7.137.40 (m, 6H), 7.50 (d, 2H, J = 8 Hz), 7.56 (d, 2H,> 9 Hz), 7.73 (s, 0.5H), 8.23 (s, 0.5H), 9.63 (s, 0.5H), 10.02 (s, 0.5H).

MS (ESI &lt; + &gt;) 461 (M + H).

Calculated for C ₂ 8H32N2O ₄ * 1.5H ₂ O: C, 68.97; H, 7.23; N, 5.74. Found: C, 68.96; H, 7.09; N, 5.42.

Example 95 ^% N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [(4'-cyano [1,1'-biphenyl] - 4-yl) oxy] ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures of Examples 5F, 5G, and 5H, except using Example 3B instead of 5E.

1 H NMR (DMSO-d 6) d 4.18-4.36 (m, 4H), 4.43-4.57 (bs, 0.5H), 4.97-5.03 (bs, 0.5H) 7.10 (d, 4H, J = 9 Hz); 7.77 (d, 4H, J = 9Hz), 7.81-7.95 (m, 8H), 8.13 (s, 0.5H), 8.42 (s, 0.5H), 9 75 (s, 0.5H), 10.15 (s, 0.5H),

MS (DCI / NH 3) M + H (490), M + 18 (507).

Calcd for C ₃₀ H ₂₃ N ₃ O ₄ * 0.25 H ₂ O: C, 72.93; H, 4.79; N, 8.50. Found: C, 72.80; H, 4.74; N, 8.26.

Example 96

112

N- [1 - [[(4'-Cyano [1,1-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyphonamide

The title compound was prepared according to the procedure for EXAMPLE 23B, except substituting 4- (4'-ethoxyphenyl) -phenol for 4- (4'-cyanophenyl) -phenol.

1 H NMR (DMSO-d 6) d 1.27 (s, 6H), 3.50-3.66 (m, 1H), 3.67-3.82 (m, 1H), 4.08-4, 28 (m, 2H), 4.38-4.50 (m; 0.5H), 4.80-4.93 (m, 0.5H), 7.06 (dd, 2H, J = 3.9 Hz), 7.73 (d, 2H, J = 9Hz), 7.82-7.93 (m, 4H), 7.94 (s, 0.5H), 8.35 (d, 1H, J = 6 Hz), 8.40 (s, 0.5H), 9.56 (s, 0.5H), 9.87 (s, 0.5H).

MS (ESI -) 421 (M-H) -.

Calcd for C22H22N * ₄ O5 0.25H2 O: C, 61.89; H, 5.31; N, 13.12. Found: C, 61.82; H; 5.34; N, 12.82.

Example 97

N- [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (2-methoxyethoxy) [1,1'-biphenyl) 4-yl] oxy ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 23B, substituting 4 (4 '- (2-methoxyethoxy) -phenyl) -phenol for 4- (4'-ethoxyphenyl) -phenol.

1 H NMR (DMSO-d 6) d 1.26 (s, 6H), 3.33 (s, 3H), 3.50-3.64 (m, 1H), 3.66-3.69 (m, 2H) ), 3.70-3.81 (m, 1H), 4.03-4.22 (m, 4H), 4.35-4.48 (m, 0.5H), 4.78-4.90 (m, 0.5H), 6.98 (dd,

4H, J = 3.9Hz), 7.55 (dd, 4H, J = 3.6Hz), 7.91 (s, 0.5H), 8.33 (d, 1H, J = 7Hz) , 8.40 (s, 0.5H), 9.55 (s, 0.5H), 9.86 (s, 0.5H).

MS (ESI -) 470 (M-1).

Calcd for C24H29N3O7: C, 61.13; H, 6.19; N, 8.91. Found: C, 60.86; H, 6.41; N, 8.65.

Example 98

N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [(4'-propoxy [1,1'-biphenyl] -4-yl) oxy] ethyl] - N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLE 23B, except substituting 4- (4'-ethoxyphenyl) -phenol for 4- (4'-propyloxyphenyl) -phenol. m.p. 158-160 ° C υ

113

Calcd for C24H29N3O6: C, 63.28; H, 6.42; N, 9.22. Found: C, 63.25; H, 6.48; N, 9.29.

MS (ESI): +456 (m + 1), + 473 (m + 18), -454 (m-1), -490 (m + 35) 1 H NMR (DMSO-d 6): 0.90 (3H) t, J = 6 Hz), 1.17 (2.4H, s), 1.20 (3.6H, s), 1.65 (2H, sextet, J = 6Hz), 3.46-3 55 (1H, m), 3.59-3.74 (1H, m), 3.86 (2H, t, J = 6Hz), 3.96-4.06 (1H, m), 4, 06-4.14 (1H, m), 4.28-4.38 (0.6H, m), 4.72-4.51 (0.4H, m), 6.88 (4H, d, J) = 4.8 Hz), 7.42 (2H, d, J = 4.8 Hz), 7.44 (2H, d, J = 4.8 Hz), 7.83 (0.4H, s) 8.24 (1H, s), 8.28 (0.6H, s), 9.43 (0.6H, s), 9.74 (0.4H, s), ¹³ C NMR (DMSO-d 6) ): 10.4; 22.0; 24.4; 24.5; 36.0; 36.4; 52.1; 56.1; 57.8; 57.9; 64.7; 65.0; 69.0; 114.8; 115.0; 127.2; 132.0; 132.8; 132.9; 155.0; 155.2; 157.0; 157.1; 157.9; 158.2; 163.1; 177.2; 177.3.

Example 99

N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [(4'-pentyloxy [1,1'-biphenyl] -4yl) oxy] ethyl] - N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLE 23B, substituting 4- (4'-pentylyloxy-phenyl) -phenol for 4- (4'-ethoxy-phenyl) -phenol.

1 H NMR (300 MHz, DMSO-d 6) d 0.90 (t, 3H,> 6.9 Hz), 1.27 (s, 6H), 1.3-1.5 (m, 4H), 1, 71.8 (m, 2H), 3.5-3.8 (m, 2H), 3.98 (t, 2H,> 6.9 Hz), 4.0-4.2 (m, 2H), 4.35-4.45 (m, 0.5H), 4.8-4.9 (m, 0.5H), 6.9-7.0 (m, 4H), 7.5-7.6 (m, 4H), 7.92 (s, 0.5H), 8.3-8.4 (m, 1.5H), 9.53 (s, 0.5H), 9.84 (s, 0) , 5H).

MS (ESI) 484 (M + H), 501 (M + NH 4).

Calcd for C 26 H 33 N 3 O 6: C, 64.57: H, 6.87; N, 8.68. Found: C, 64.27; H, 6.85; N, 8.60.

Example 100

N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl] sulfonyl] methyl] -3- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) propyl) -N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLE 61 but using EXAMPLE 61

23A instead of Example 16B and 4'-thiol-3-cyanomethylbiphenyl instead of 4'-thiol-4-biphenylcarbonitrile in Example 61 A.

114

1 H NMR (300 MHz, DMSO-d ₆ ) d 9.98 (br, 0.5H), 9.63 (br, 0.5H), 8.31 (s, 0.5H), 8.23 (br, s, 0.5H), 8.12 (s, 0.5H), 7.99-7.92 (m, 4H), 7.82 (s, 0.5H), 7.74 (m, 2H) 7.57 (t, 1H), 7.46 (d, 1H), 4.52 (m, 0.5H), 4.14 (s, 2H), 4.00 (m, 0.5H), 3.69-3.57 (m, 2H), 3.42-3.28 (m, 2H), 2.02-1.88 (m, 1H), 1.78-1.64 (m, 1H) 1.21 (s, 6H);

MS (ESI) mlz 499 (M + 1) ⁺ .

Calcd for C24H26N4O6S: C, 57.82: H, 5.26; Ν, 11.24. Found: C, 57.56; H, 5.41; N, 10.89.

Example 101

N- [1 - [[[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl 1-N-hydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 46, excluding substituting 16B for 23A in Example 46A and 4-trifluoromethoxybenzeneboronic acid for 4-butoxybenzeneboronic acid in Example 46B.

1 H NMR (300 MHz, dfDMSO) δ 9.72 (br, 0.5H), 9.56 (br, 0.5H), 8.10 (s, 0.5H), 7.99 (m, 4H) ), 7.94-7.88 (m, 2H), 7.74 (s, 0.5H), 7.53 (d, 2H), 4.91 (m, 0.5H), 4.54 (s) m, 0.5H), 3.753.44 (m, 4H), 2.75 (s, 3H), 1.24-1.22 (m, 6H);

MS (ESI) mle 544 (M + 1) ⁺ .

Calcd for C23H24F3N3O7S: C, 50.83; H, 4.45; N, 7.73. Found: C, 51.17; H, 4.77; N, 7.29.

Example 102

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (3-methyl-2,5-dioxo-limidazolidinyl) ethyl] -N- hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLE 61 but EXAMPLE 26A was used instead of EXAMPLE 16B for EXAMPLE 61 A.

1 H NMR (300 MHz, d 6 -DMSO) δ 9.83 (s, 0.5H), 9.58 (s, 0.5H), 8.09 (s, 0.5H), 8,048.00 ( m, 8H), 7.80 (s, 0.5H), 4.94-4.85 (m, 0.5H), 4.53-, 4.43 (m, 0.5H), 3.91 -3.88 (m, 2H), 3.78-3.44 (m, 4H), 2.80 (s, 1.5H), 2.79 (s, 1.5H);

MS (ESI) mlz 457 (M + 1) ⁺ .

115

Calcd for C21H20N4O6S: C, 55.26: H, 4.42; N, 12.27. Found: C, 54.99; H, 4.38; N, 12.07.

Example 103

N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 46, excluding substituting Example 16B for 23A in Example 46A and 3-cyanomethylbenzeneboronic acid for 4-butoxybenzeneboronic acid in Example 46B.

The desired compound is prepared in a conventional manner from α-bromoketone and 4-bromothiophenol.

1 H NMR (300 MHz, δ-DMSO) δ 9.71 (s, 0.5H), 9.56 (s, 0.5H), 8.10 (s, 0.5H), 8.03-7 94 (m, 4H), 7.75 (m, 2.5H), 7.57 (t, 2H), 7.46 (d, 2H), 4.96-4.88 (m, 0.5H) 4.59-4.49 (m, 0.5H),

4.14 (s, 2H), 3.69-3.48 (m, 4H), 2.75 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H);

MS (ESI) mlz 499 (M + 1) ⁺ .

Calcd for C24H26N4O6S: C, 57.82; H, 5.26; N, 11.24. Found: C, 57.73; H, 5.36; N, 10.95.

Example 104

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxyl] methyl] -2- (1,6-dihydro-3-methyl-6-oxo-1 pyridazinyl) ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures of Examples 3C and 3D, except substituting 6-methyl-3 (2H) -pyridazinone (generated in situ with potassium carbonate) for potassium phthalimide in Example 3C.

1 H NMR (300 MHz, CD ₃ OD) δ 8.31 (s, 0.5H), 7.91 (s, 0.5H), 7.76 (s, 4H), 7.67-7.64 (d, 2H), 7.38 (dd, 1H), 7.08 (d, 2H), 6.94 (dd, 1H), 5.20-5.11 (m, 0.5H), 4, 64-4.52 (m, 2H), 4.42-4.32 (m, 2H), 4.27-4.19 (m 0.5H), 2.35 (s, 1.5H), 2 34 (s, 1.5H);

MS (ESI) mlz 405 (M + 1) ⁺ .

Calcd for C22H20N4O4: C, 65.34; H, 4.98; N, 13.85. Found: C, 64.85 H,

5.36; N, 13.44.

-τ

116

Example 105

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLE 61 but EXAMPLE 47A was used instead of EXAMPLE 16B for EXAMPLE 61 A.

Δ NMR (300 MHz, d 6 -DMSO) δ 9.98 (s, 0.5H), 9.62 (s, 0.5H), 8.31 (s, 0.5H), 8.22 (s,

0.5H), 8.12 (s, 0.5H), 8.05-7.96 (m, 8H), 7.82 (s, 0.5H), 4.55-4.46 (m, 0.57), 4.07-3.97 (m, 0.5H), 3.70-3.56 (m, 2H), 3.32-3.24 (m, 2H), 2.02- 1.88 (m, 0.5H), 1.76-1.64 (m, 0.5H), 1,211.18 (m, 6H);

MS (ESI) mlz 485 (M + 1) ⁺ .

Example 106

N- [1 - [[[4- (4-fluorophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 61 but EXAMPLE 26A was used instead of EXAMPLE 16B and 4- (4'-fluorophenoxy) -benzenethiol instead of 4-thiol-4-biphenylcarbonitrile in EXAMPLE 61 A.

1 H NMR (300 MHz, d 6 -DMSO) δ 9.66 (s, 0.5H), 9.50 (s, 0.5H), 8.39 (s, 0.5H), 8.35 (s 0.58), 8.10 (s, 0.5H), 7.88 (dd, 2H), 7.68 (s, 0.5H), 7.36-7.30 (m, 2H), 7.26-7.20 (m, 2H), 7.15 (d, 2H), 4.88-4.80 (m, 0.5H), 4.51-4.41 (m, 0.5H) 3.70-3.39 (m, 4H), 1.24-1.22 (m,

6H);

MS (ESI) mlz 480 (M + 1) ⁺ .

Calcd for C21H22FN3O7S: C, 52.60; H, 4.62; N, 8.76. Found: C, 52.79; H, 4.57; N, 8.68.

Example 107

N- [1 - [[4- (4-pyridinyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinylethyl] -N-hydroxyformamide

117 1 H NMR (DMSO-d 6): d 9.53-9.97 (c, 1H), 8.55-8.60 (c, 7H), 8.32 (s, 1 / 2H), 7, 92 (s, 1 / 2H);

7.77 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.64 (s, 1H), 7.01-7.08 (c, 2H), 4 82-4.89 (c, 1 / 2H)

4.39-4.46 (c, 1H), 4.18-4.25 (c, 1H), 4.08-4.17 (c, 1H), 3.71-3.83 (c 1H), 3.57-3.66 (c, 1 H),

2.78 (s, 1.5H), 2.77 (s, 1, SH), 1.27 (s, 3H), 1.26 (s, 3H):

MS (ESI (+)) 413 (M + H), 435 (M + Na), 847 (2M + Na).

Calcd for C ₂₁ H ₂₄ N ₄ O ₅ * 0.5 H ₂ O: C, 59.84; H, 5.98; N, 13.29. Found: C, 60.18; H, 6.05; N, 13.10.

Example 108 (S) -N- [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4- yl] oxy] ethyl] -N-hydroxyformamide

Example 108A (R) - (4- (4 '- (Trifluoromethoxy) phenoxy) -3-benzyloxy-2-propanol

A solution of 4- (4'-trifluoromethoxyphenyl) -phenol (1.85 g, 7.3 mmol) and (S) -2 (benzyloxymethyl) -oxirane (1.0 g, 6.1 mmol) in DMF (15 mL) was added. was treated with potassium carbonate (1.007g, 7.3 mmol) then stirred overnight at 80 ° C. The reaction mixture was then cooled to reflux temperature, poured into water (100 mL) and extracted twice with ethyl acetate (200 mL x 2). The combined organic layers were washed with saturated aqueous NH ₄ Cl, water, brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by flash column chromatography on silica gel, eluting with 20-25% ethyl acetate / hexane to afford 2.03g (80% yield) of 108A as a white solid.

Example 108B

A solution of Example 108A (1.505 g, 3.6 mmol), di-Boc-hydroxylamine (1.007 g, 4.3 mmol), triphenylphosphine (1.23 g, 4.7 mmol) in THF (15 mL) was allowed to react with diethyl azodicarboxylate (0.735 mL, 4.7 mmol) at room temperature, stirred for 1 hour, then concentrated. The crude product was purified by column chromatography eluting with 10% ethyl acetate / hexane to afford 1.16 g (50%) of compound 108B.

118

Example 108C

A solution of Example 108B (248 mg, 0.4 mmol) in THF (3 mL) was hydrogenated overnight (H ₂ balloon) in the presence of 23 mg of 10% Pd on charcoal. The reaction mixture was filtered, concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate / hexane to give 180mg (85%) of the desired compound.

• 9 · · 4 · 4 · · a a a a a a a a 4 4 4 4 4 4 4 4 ··

Example 108D

A solution of Example 108C (228 mg, 0.42 mmol), 5,5-dimethylhydantoin (94 mg, 0.73 mmol) and triphenylphosphine (165 mg, 0.63 mmol) in THF (4 mL) was treated with diethyl azodicarboxalate. (0.1 mL, 0.63 mmol) is added dropwise via syringe. The resulting pale yellow solution was stirred at reflux temperature for 45 mih, concentrated and chromatographed on a silica gel column eluting with 25% ethyl acetate / hexane to afford 193 mg (71%) of 108D.

Example 108E (S) -N- [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4- yl] oxy] ethyl] -N-hydroxyformamine

A solution of Example 108D (191 mg, 0.29 mmol) in methylene chloride (3 mL) was treated with TFA (1.5 mL) which was added dropwise via syringe. The reaction was stirred at reflux temperature for 40 minutes, then concentrated and the residue partitioned between ethyl acetate and aqueous NaHCO ₃ . The organic extracts were washed with brine, dried (Na ₂ SO 4) and concentrated to give 113 mg (86%) of compound 108E as a white solid.

Example 108F (S) -N- [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1' biphenyl] - 4-yl] oxy] ethyl] -N-hydroxyformamide

The title compound was prepared from 108E according to the procedure for EXAMPLE 2F MS (ESI) m / e 482 (M + H) ⁺ .

· · · · · · · · · · · · · · · · · ·

Example 109 (R) -N- [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1' biphenyl] - 4-yl] oxy] ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLE 108, except using (R) -2 (benzyloxymethyl) -oxirane instead of using (S) -2- (benzyloxymethyl) -oxirane.

@ 1 H NMR (DMSO-d6) .delta.9.86 (s, 0.5H), 9.55 (s, 0.5H), 8.39 (s, 0.5H), 8.35 (s, 0, 5H), 8.33 (s, 0.5H), 7.93 (s, 0.5H), 7.76-7.73 (m, 2H), 7.64 (d, 2H), 7.42 (d, 2H), 7.02 (dd, 2H), 4.91-4.80 (m, 0.5H); 4.47-4.38 (m, 2H), 4.23-4.06 (m, 2H), 3.79-3.50 (m, 2H), 1.27 (s, 1.5H) 1.26 (s, 1.5H);

MS (ESI) mlz 482 (M + 1) ⁺ .

Example 110

N- [1 - [[[4 '- (trifluoromethoxy)] [1,1'-biphenyl] -4-yl] oxy] methyl] -3- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) (propyl) -N-hydroxyformamide

The title compound was prepared according to the procedures of Example 5, except avoiding methylation in Example 5B and substituting 4- (4'-trifluoromethoxyphenyl) phenol for 4'-hydroxy-4-biphenylcarbonitrile in Example 5F.

mp 197.1-197.9 ° C ^! HNMR (DMSO-d 6) δ; 1.27 (s, 6H), 1.70-2.00 (m, 2H), 3.35-3.46 (2H), 3.97-4.16 (m, 2.75H), 4, 51 (br s, 0.25H), 7.00-7.03 (d, 2H, J = 9 Hz); 7.39-7.42 (d, 2H, > 9 Hz), 7.60-7.63 (d, 2H, J = 9 Hz), 7.72-7.75 (d, 2H, J = 9) Hz), 8.25-8.35 (2H), 9.55 (s, 0.75H), 9.95 (br s, 0.25H).

MS (ESI) mlz 496 (M + H) ⁺ , 518 (m + Na), 494 (mH) -, 530 (m + Cl) -.

Calcd for C23H24F3N3O6: C, 55.75; H, 4.88; N, 8.48. Found: C, 55.72; H, 5.07; N, 8.59.

Example 111

N- [1- [4 - [(4-pyridinylthio) phenoxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

120

The title compound was prepared according to the procedure for EXAMPLE 23B, except substituting (prepared by adding 4-hydroxythiophenol to 4-chloropyridine) to 4- (4'-butyloxyphenyl) -phenol.

1 H NMR (DMSO-d 6) δ; 1.258-1.272 (s + s, 6H), 3.492-3.793 (m, 2H), 4.082-4.248 (m, 2H), 4.437 (m, 0.5H), 3.861 (m, 0.5H), 5.759 (s , 1H), 6.927-6.948 (dd, 2H, &gt; 1.5.4.8 Hz), 7.0637.102 (dd, 2H, > 3. 8.7 Hz), 7.529-7.557 (d, 2H, > 8.4 Hz), 7.939 (s, 0.5H), 8.323-8.343 (dd, 2H,> 1.2.4.8 Hz), 8.391 (s, 0.5H), 9.555 (s, 0, 5H), 9.866 (s, 0.5H),

MS (ESI) mle 431 (M + H) ⁺ , 453 (m + Na) ⁺ , 429 (mH) -, 465 (m + Cl) -.

Example 112

N- [1 - [[[(4-chlorophenoxy) phenyl] sulfonyl] methyl] -3- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) propyl] -N-hydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 61, substituting for 4 (4'-chloro-phenoxy) -benzenethol for 4'-thiol-4-biphenyl-carbonitrile and Example 47A for Example 16B in Example 61A.

1 H NMR (d 6 -DMSO) 9.94 (s, 0.5H), 9.58 (s, 0.5H), 8.23 (d, 0.5H,> 9.5 Hz), 8.11 ( s, 0.5H), 8.05 (d, 0.5H,> 9.2 Hz), 7.89-7.83 (m, 2H), 7.76 (s, 0.5H), 7, 54-7.50 (m, 2H), 7.22-7.16 (m, 4H), 4.52-4.41 (m, 0.5H), 4.10-3.92 (m, 0) 1 H, 3.66-3.37 (m, 2H), 3.31-3.24 (m, 3H), 1.961.84 (m, 1H), 1.74-1.62 (m, 1H) 1.28-1.21 (m, 6H).

MS (ESI) 508 (M-H), 510 (M + H), 532 (M + Na).

Example 113

N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxyl) methyl] -2- (1,6-dihydro-6-oxo-1-pyridazinylethyl) -N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLE 104, except that pyridazinone was substituted for 6-methyl-3 (2H) -pyridazinone.

1 H NMR (d 6 -DMSO) 9.99 (s, 0.5H), 9.64 (s, 0.5H), 8.28 (s, 0.5H), 7.96-7.83 (m , 0.5H), 7.757.71 (m, 2, OH), 7.47-7.41 (m, 1H), 7.07-6.95 (m, 3H), 5.11-5.00 (m, 0.5H), 4.62-4.12 (m, 4.5H),

MS (ESI) 391 (M + H), 413 (M + Na), 389 (M-H).

Anal Calcd for C2iHi8N ₄ * 0,5H2O O4: C, 63.15; H, 4.79; N, 14.02. Found: C, 63.33; H, 4.66; N, 13.68.

121

Example 114

N- [1 - [[[4 '- (aminosulfonyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1) imidazobdinyl) ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLES 16C and 16E, except substituting 4- (4'-sulfonamide-phenyl) -phenol for 4-bromophenol. mp 203-205 ° C 1 H NMR (DMSO-d 6): d 9.88 (bs, 1 / 2H), 9.54 (bs, 1 / 2H), 8.32 (s, 1 / 2H), 7 56-8.01 (c, 5L / 2H), 7.34 (s, 1H), 7.00-7.14 (c, 4H), 4.78-4.97 (c, 1 / 2H) ), 4.34-4.50 (c, 1 / 2H), 4.06-4.27 (c, 2H), 3.69-3.85 (c, 1H), 3.57-3.68 (c, 1H), 2.78 (s, 3H), 1.17-1.28 (c, 6H), ¹³ C NMR (DMSO-d 6): d 176.5; 176.2; 163.1; 158.1; 154.2; 154.1; 128.3; 128.2; 128.0; 127.0; 126.8; 126.2; 115.2; 64.8; 60.7; 36.7; 36.4; 24.2; 21.4.

MS (ESI (+)) 491 (M + H), 508 (M + NH 4), 513 (M + Na).

Example 115

N- [1 - [[[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazobdinyl) ethyl 1-N-hydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 46, substituting 4-trifluoromethoxy-benzeneboronic acid for 4-butyloxy-benzeneboronic acid in Example 46B.

m.p. Mp 195-197 ° C

1 H NMR (DMSO-d 6): d 9.62 (bs, 1H), 8.29-8.43 (c, 1H), 8.10 (s, 1 / 2H), 7.95-8.05 (c, 4H), 7.92 (d, 1H, J = 3Hz), 7.88 (d, 1H, J = 3Hz), 7.74 (s, 1 / 2H),

7.54 (s, 1H); 7.49 (s, 1H); 4.87-4.99 (c, 1 / 2H); 4.50-4.63 (c, 1 / 2H); 43-3.80 (c, 4H), 1.22 (s,

6 H), ¹³ C NMR (DMSO-d 6): d 177.2; 177.1; 162.3; 157.1; 155.0; 154.8; 148.7; 144.0; 143.9; 138.0; 137.8; 137.5; 129.2; 128.6; 128.4; 127.9; 127.7; 121.5; 118.4; 57.8; 53.3; 53.0; 51.3; 47.5; 38.8; 38.1; 24.31; 24.30.

MS (ES &lt; + &gt; (+)) 530 (M + H), 547 (M + NH4), 552 (M + Na), 1076 (2 &lt; + &gt;); , l 193

122

Calcd for C22H22F3N3O7S: C, 49.90; H, 4.19; N, 7.94; F, 10.76; S, 6.06.

Found: C, 49.58; H, 4.10; N, 7.75 J ⁷ , 11.04; S, 5.96.

Example 116

N- [1- [4 - ((4-pyridinyloxy) phenyl] sulfonyl]] ethyl] -N-hydroxyformamide

Example 116 A

4- [4- (methylsulfonyl) phenoxy] pyridine

A mixture of 4-methylsulfonylphenol (2.93 g, 17 mmol) and 4-chloropyridine hydrochloride (2.93 g, 19.5 mmol) was heated to 150 ° C resulting in slow melting. At this temperature, ie. Stir 150 ° C for 4 hours, then partition the mixture between ethyl acetate and 1N NaOH. The organic extract was dried over MgSO ₄ and concentrated to 1.3 g of a yellow solid. The solid was recrystallized from ethyl acetate-ether to give 0.81 g of the desired compound as a white solid.

Example 116B

N- [1- [4 - ((4-pyridinyloxy) phenyl] sulfonyl]] ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLE 75, substituting for Example 116Aza71Ba acetaldehyde for propionaldehyde.

m.p. Mp 180-181 ° C

Ή NMR, 400MHz (DMSO-d _s): d 9.71 (bs, 1H), 8.54 (d, 2H,> 3 Hz), 8.05 (s, 1 / 2H), 7.97 (d (2H,> 6 Hz), 7.84 (s, 1 / 2H), 7.49 (d, 2H,> 6 Hz), 7.03-7.13 (c, 2H), 4.63-4 73 (c, 1 / 2H), 4.28-4.39 (c, 1 / 2H), 3.59-3.78 (c, 1H), 3.48 (dd, 1H,> 3.10) 1.5 Hz, 1.20 (dd, 3H, > 4.5,10.5)

Hz), ¹³ C NMR (DMSO-d 6): d 162.62; 162.61; 161.33; 158.33; 158.31; 156.74; 151.77; 135.40;

135.13; 130.74; 130.45; 120.56; 120.34; 113.27; 56.50; 49.69; 45.02, 19.05, 17.71.

MS (ES &lt; + &gt; (+)) 337 (M + H), 359 (M + Na), 391 (M + Na &lt; + &gt; MeOH), 695 (2M + Na)

Calcd for C ₁₅ H ₁₆ N ₂ O ₅ S * 0.5H 2 O: C, 52.16; H, 4.96; N, 8.11, S, 9.28. Found: C, 52.32; H, 4.78; N, 7.98, S, 9.45.

123

Example 117

N- [1 - [[[(4-cyanophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

The title compound was prepared according to the procedures for EXAMPLE 61, substituting 4- (4'-cyanophenoxy) -benzenethiol for 4-thiol-4-biphenyl-carbonitrile and Example 23A for Example 16B in Example 61A.

Δ NMR, 400MHz (DMSO-d 6) δ 9.70 (s, 0.5H), 9.50 (s, 0.5H), 8.39 (s, 0.5H), 8.34 (s, 0) 5H), 8.10 (s, 0.5H), 7.98-7.91 (m, 4H), 7.68 (s, 0.5H), 7.37-7.27 (m, 4H) ), 4.88-4.77 (m, 0.5H), 4.52-4.41 (m, 0.5H), 3.78-3.39 (m, 4H), 1.24-1 .22 (m, 6H);

MS (ESI) mlz 487 (M + 1) ⁺ .

Calcd for C22H22N4O7S: C, 54.31; H, 4.56. Found: C, 54:17; EI, 4.79.

Example 118

N- [1 - [[4 - [[4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] methyl] -3- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) propyl] -N-hydroxyformamide

The title compound was prepared according to the procedure for EXAMPLE 61, substituting 4- (4'-trifluoromethoxy-phenoxy) -benzenethiol for 4'-thiol-4-biphenyl-carbonitrile and Example 47A for Example 16B in Example 61 A.

1 H NMR (d6 -DMSO) 9.96 (s, 0.5H), 9.60 (s, 0.5H), 8.32 (s, 0.5H), 8.23 (s, 0.5H) 8.11 (s, 0.5H), 7.93-7.86 (m, 2H), 7.75 (s, 0.5H), 7.48 (d, 0.5H,> 8.8) Hz), 7.25 (dd, 4H,> 22.8, 8.8 Hz), 4.53-4.42 (m, 0.5H), 4.04-3.93 (m, 0.5H) ), 3.65-3.46 (m, 2H), 3.34-3.22 (m, 2H), 2.021.62 (m, 2H), 1.26 (s, 3H), 1.23 ( s, 3H).

MS (ESI) 560 (M + H), 577 (M + NH 3), 582 (M + Na), 558 (M-H).

Calcd for C23H24N3O8SF3: C, 49.37; H, 4.32; N, 7.51. Found: C, 49.46; H, 4.23; N, 7.47.

Example 119

N- [1 - [[4 - [[4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide

124 - / ΛΓ ··· * ....... ·· “

The title compound was prepared according to the procedures for EXAMPLE 61, substituting 4- (4'-trifluoromethoxy-phenoxy) -benzenethiol for 4'-thiol-4-biphenyl-carbonitrile in Example 61A. ¹ H NMR (d 6 -DMSO) 9.51 (s, 0. 5H), 9.70 (s, 0.5H), 8.09 (s, 0.5H), 7.91 (dd, 2H, J = 8.9, 3.1 Hz), 7.68 (s 0.57), 7.47 (d, 2H, J = 9.2 Hz), 7.31-7.21 (m, 4H), 4.90-4.78 (m, 0.5H), 4.514.40 (m, 0.5H), 3.74-3.40 (m, 4H), 2.76 (d, 3H, J = 1.7 Hz), 1.27-1.22 (m, 6H).

MS (ESI) 558 (M-H), 560 (M + H), 577 (M + NH 3), 582 (M + Na).

Calcd for C23H24N3O8SF3: C, 49.37; H, 4.32; N, 7.51. Found: C, 49.41; H, 4.29; N, 7.36.

Claims (18)

00 99 (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo) -1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- ( 2-methoxyethoxy) [1,1-biphenyl) -4-yl] oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)] methyl] -2 - [(4'-propoxy [1,1'-biphenyl] -4yl) oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [(4,4-dimethyl-2,5) -dioxo-1-imidazolidinyl) methyl] -2 - [(4'-pentyloxy [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[3] 1- (cyanomethyl) [1,1'-biphenyl] -4-yl] sulfonyl) methyl] -3- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) propyl] -N-hydroxyformamide, (±) -N- [1 - [[[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazo Udinyl) ethyl N-Hydroxyformamide, (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (3-methyl-2,5) -dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-d ioxol-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) oxyl] methyl] -2- (1,6) -dihydro-3-methyl-6-oxo-1-pyridazinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[4- (4-fluorophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[4- (4-pyridinyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] N-hydroxyformamide, (S) -N- [1 - [(4,4-dimethyl-2,5-dioxo)] -1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] oxy] ethyl] -N-hydroxyformamide, (R) -N- [1 - [(4, 4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] oxy] ethyl] -N-hydroxyformamide, N- [1 - [[[4 '- (trifluoromethoxy)] [1,1'-biphenyl] -4-yl] oxy] methyl] -3- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) propyl] - N-hydroxyformamide; N- [1- [4 - [(4-pyridinylthio) phenoxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide; 152 N- [1 - [[4 - [[4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] methyl] -3- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) propyl] -N-hydroxyformamide; and N- [1 - [[4 - [[4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide . PATENT REQUIREMENTS 44 1. A compound of formula (I): OH ^{1 R} 1, S? ^Y -Ar ₂ or a pharmaceutically acceptable salt or prodrug thereof, wherein A is hydrogen; index n is zero; R 1 and R 3 are independently selected from the group consisting of (1) hydrogen (2) alkyl having from 1 to 6 carbon atoms; R2 and R4 are independently selected from the group consisting of (1) hydrogen; (2) alkyl having from 1 to 6 carbon atoms; 2,4-dioxo-1-imidazolidinyl) propyl] -N-hydroxyformamide; (±) -N- [1 - [[(3'-Cyanomethyl- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-ethyl-4,4-dimethyl-2,5-dioxo) -1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-benzyl-4,4-dimethyl-2,5-dioxo) -1-imidazolidinyl) ethyl] -N-hydroxyformamide; 144 ............... (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,5,5-trimethyl-2,4-dioxo-1) (imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [(2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] oxy] ethyl] -N -hydroxyformamide; (±) -N- [1 - [[[4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo) 1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[(4'-Butyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl 1-N-hydroxyformamide; (±) - N - [1 - [(3-Methyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '(trifluoromethoxy) [1,1-biphenyl] -4-yl] oxy (ethyl) -N-hydroxyformamide (±) -N- [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1- imidazolidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[(4-Butyl [1,1-biphenyl] -4-yl) sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazo) lidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1- [4- (2-Thienylphenoxy] methyl] -2- [1- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(3-Nitro [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxol-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[[4 '- (trifluoromethoxy) [[, Γ-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-cyano [Ι, Γ-biphenyl] -4-yl) sulfonyl] methyl] -2- (3-methyl-2,5-dioxol-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(3 '- (cyanomethyl) [1,1-biphenyl] -4-yl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo) 1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[4- (4-pyridinyl) phenosyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo) (imidazolidinyl) ethyl] -N-hydroxyformamide; N- [1 - [[4 '- (Aminosulfonyl) [1,1'-biphenyl) -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) (ethyl) -N-hydroxyformamide; and N- [1 - [[4 - [[4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide. 145 (2) phenoxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms and wherein the phenyl group is unsubstituted or substituted; The compound of claim 1, wherein A is hydrogen; R _b, R 3 and R 4 are independently selected from hydrogen or alkyl having from 1 to 6 carbon atoms; ; • · 136 substituent X is selected from the group consisting of (1) -θ-, (2) -S (O) _p -, and (3) -NR ₅ SO ₂ -; and Ar 1 is phenyl, which is optionally substituted. (2) pyridyl; (2) NR 5 SO 2 -; (3) - (alkylene) -S (O) _p -phenyl wherein the alkylene group has from 1 to 6 carbon atoms, the p index is zero and the phenyl group is unsubstituted or substituted; The compound of claim 2, wherein R ₂ is alkyl having from 1 to 6 carbon atoms. (3) pyrazinyl; (3) -S (O) _p -; and (4) -C (O) -; wherein each group is drawn with its left-hand end that is attached to the alkylene group and its right-hand end that is attached to the Ari; Ar 1 is phenyl, which is optionally substituted with one or two substituents independently selected from the group consisting of (and) alkyl having from 1 to 6 carbon atoms; (b) perfluoroalkyl having from 1 to 6 carbon atoms; (C) halogen; (d) haloalkyl having from 1 to 6 carbon atoms; (E) alkoxy groups having from 1 to 6 carbon atoms; ω hydroxy groups; (G) hydroxyalkyl having from 1 to 6 carbon atoms; (h) alkoxyalkyl wherein the alkyl and alkylene group independently have from 1 to 6 carbon atoms; (and) nitro groups; the substituent Y is selected from the group consisting of (1) covalent bonds; (2) -O-; (3) alkylene having from 2 to 4 carbon atoms;  (4) piperidinyl, (5) alkenylene having 2 carbon atoms; (6) alkynylene having 2 carbon atoms; (Ό - S (O) _P - a (8) -WHAT)-; and 133 (3) thiomorpholinylsulfone; (3) alkenyl having from 1 to 6 carbon atoms; (4) - (alkylene) -S (O) _p -alkyl; A compound according to claim 3 selected from the group consisting of (±) -N- [1 - [[[3 '- (cyanomethyl) - [1,1'-biphenyl] -4-yl] oxy] methyl] pentyl] -Nhydroxyformamide, (±) -N- [1 - [[(4-cyano- [1,1'-biphenyl) -4-yl) oxy] methyl] -3-methylbutyl] -Nhydroxyformamide, (±) -N- [ 1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2-methylbutyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'- cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] pentyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl]] - 4-yl) oxy] methyl] ethyl] -N-hydroxyformamide, (±) - N - [2 - [(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] -1-methylpropyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-methoxy- [1,1'-biphenyl] -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-chloro- [1,1'-biphenyl] -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide, (±) - N - [1 - [[[4- ( 1,3-benzodioxol-5-yl) phenyl] sulfonyl] methyl] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl] ethyl] -N - hydroxyformamide, (±) -N- [1-f [(4'-methoxy- [1,1'-biphenyl] -4-yl) sulfonyl] methyl] propyl] -Nhyd Roxyformamide, (±) -N- [1- [1,1-Dimethyl-2 - [(4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide, (± ) -N- [1- [4 - [(4-pyridinyloxy) phenyl] sulfonyl] ethyl] -N-hydroxyformamide, 137 (4) pyridazinyl; (4) pyrrolidinyl; (4) alkynyl having from 1 to 6 carbon atoms; (5) hydroxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms; The compound of claim 2, wherein R 2 is hydrogen. (5) furyl; (5) piperazinyl; (5) alkoxyalkyl; (6) - (alkylene) -N (R 5) SO 2 -phenyl wherein the alkylene group has from 1 to 6 carbon atoms, the phenyl group being unsubstituted or substituted; and R ₅ is selected from the group consisting of (a) hydrogen (b) alkyl having from 1 to 6 carbon atoms; A compound according to claim 5 having the formula N- [2 - [(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide. (6) thienyl; (6) piperidinyl; (6) alkoxycarbonylalkyl, wherein the alkylene and alkyl groups independently have from 1 to 6 carbon atoms; (7) phenylalkoxyalkyl, wherein the alkylene and alkyl groups independently have from 1 to 6 carbon atoms and the phenyl group is unsubstituted or substituted; The compound of claim 2, wherein R 2 is selected from the group consisting of (1) phenyl, wherein the phenyl group is unsubstituted or substituted; (7) isoxaloyl; (7) succinimidyl; (7) haloalkyl having from 1 to 6 carbon atoms; A compound according to claim 7 selected from the group consisting of (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2-phenoxyethyl] -Nhydroxyformamide; (±) - N - [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (phenylthio) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4-methylphenylethyl) -N-hydroxyformamide; (±) - N - [2 - [(4'-Cyano- [11'-biphenyl] -4-yl) oxy] -1- (4'-fluorophenylethyl) -N-hydroxyformamide; (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4-fluorophenyl) ethyl] -N · hydroxyformamide; (±) -N- [1 - [[(3'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- [methyl [(4-methylphenyl) sulfonyl] amino] ethyl] -N -hydroxyformamide; (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [[(2-methoxycarbonyl) phenyl] thio) ethyl] -N- hydroxyformamide; (±) - N - [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -5 - [(4-methyl-2-oxo-2H-1-benzopyran-6)] -yl) oxy] pentyl] -N-hydroxyformamide; (±) - N - [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -4 - [(4-methyl-2-oxo-2H-1-benzopyran-6)] -yl) oxy] butyl] -N-hydroxyformamide; (±) - N - [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -4 - [(4-methyl-2-oxo-2H-1 benzopyran) -7-yl) oxy] butyl] -N-hydroxyformamide; (±) - N - [1 - [[(4-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -5 - [(4-methyl-2-oxo-2H-1 benzopyran- 7-yl) oxy] pentyl] -N-hydroxyformamide; (±) - N - [1 - [((4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2-isopropylthioethyl] -N-hydroxyformamide; (±) - N - [1 - [(phenylmethoxy) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide; (±) - N - [1- (hydroxymethyl) -2 - [[(4 '- (trifluoromethyl) [1,1-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [[3- (methylsulfonyl) amino] phenyl] ethyl] -N -hydroxyformamide; • · 139 (±) - N - [1 - [[[3- (Diethylamino) carbonyl] phenyl] methyl] -2 - [(4'-methyl] [1,1-biphenyl] 4-yl) oxy] ethyl] - N-hydroxyformamide; N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [(4'-cyano [1,1'-biphenyl] -4yl) oxy] ethyl] -N-hydroxyformamide; N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxyl] methyl) -2- (1,6-dihydro-3-methyl-6-oxo-1-pyridazinyl) ethyl] -N-hydroxyformamide; and N- [1 - [[(4-cyano [1,1'-biphenyl] -4-yl) oxyl) methyl] -2- (1,6-dihydro-6-oxo-1 pyridazinyl) ethyl] -N- hydroxyformamide. (8) - (alkylene) -heterocycle, wherein the heterocycle is unsubstituted or substituted by (9) (heterocycle) oxyalkyl, wherein the alkylene group has from 1 to 6 carbon atoms and the heterocycle is unsubstituted or substituted and (10) - (alkylene) -phenyl wherein the phenyl group is unsubstituted or substituted. • · • fc fc · • · • fc • fc • fc • • • • • · • • • • • • · • • fc fc ·· · • fcfc fcfc • · · • · • · (8) oxazolyl; (8) maleimidyl; (9) glutarimidyl; (8) hydroxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms; The compound of claim 2, wherein R 2 is - (alkylene) -NR 6 R 6 -. The compound of claim 9, wherein -NR e R ₇ is • · • · • • • • • • · • • · • * • • • · • • • • • • • • • • 9 • • · • · · ·· • · · • · • · (9) thiazolyl and (10) isothiazolyl, wherein the aryl group is optionally substituted with one, two or three substituents independently selected from the group consisting of (a) alkyl having from 1 to 6 carbon atoms; (b) alkoxy groups having from 1 to 6 carbon atoms; (c) alkoxy groups having from 1 to 6 carbon atoms substituted with alkoxy groups having from 1 to 6 carbon atoms; (d) -alkyl-CO ₂ R ₅ ; (e) -alkyl-NR _x R _y ; (f) alkoxyalkyl wherein the alkyl group has from 1 to 6 carbon atoms and the alkylene group has from 1 to 6 carbon atoms; (g) cyano groups; (h) cyanoalkyl groups having from 1 to 6 carbon atoms; (i) halogen; (j) haloalkyl having from 1 to 6 carbon atoms; (k) hydroxy groups; (1) hydroxyalkyl groups having from 1 to 6 carbon atoms; (m) hydroxyalkyl groups wherein the alkyl group has from 1 to 6 carbon atoms; (n) thioalkoxy groups having from 1 to 6 carbon atoms; 134 (o) thioalkoxyalkyl wherein the alkyl group has from 1 to 6 carbon atoms and the alkylene group has from 1 to 6 carbon atoms; (p) phenylalkoxy groups wherein the alkylene group has from 1 to 6 carbon atoms; (q) phenoxy groups; (r) phenoxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms; (s) (heterocyclic) oxy groups; (t) (heterocycle) oxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms; (u) perfluoroalkyl having from 1 to 6 carbon atoms; (v) perfluoroalkoxy groups, wherein the perfluoroalkyl moiety has from 1 to 6 carbon atoms; (w) sulfinylalkyl, wherein the alkyl moiety has from 1 to 6 carbon atoms; (x) sulfonylalkyl, wherein the alkyl moiety has from 1 to 6 carbon atoms; TO K (y) wherein X is selected from -CH 2 -, -CH 2 O-, and -O and Y is selected from -C (O) - and - (C (R ") 2) v, wherein the substituent R is hydrogen or alkyl having from 1 to 4 carbon atoms and the index v is 1-3; (z) -N (R ₅ ) SO ₂ R ₅ -, wherein R 5 is as defined above and R 5 'is selected from the group consisting of (i) hydrogen and (ii) alkyl having from 1 to 6 carbon atoms; and (aa) -SO ₂ N (R ₅ ) (R ₅ '), wherein for (s) and (t) the heterocyclic moieties (heterocyclic) of the oxy group of the (heterocyclic) oxyalkyl are selected from the group consisting of (i) pyridyl ; (ii) pyrazinyl; (iii) pyridazinyl; (iv) furyl; (v) thienyl; • · 135 t (vi) of isoxazolyl; (vii) oxazolyl; (viii) thiazolyl and (ix) isothiazolyl and wherein for (s) and (t) the heterocyclic moieties of the (heterocyclic) oxy group and the (heterocyclic) oxyalkyl are optionally substituted with one or two substituents independently selected from the group consisting of (i) alkyl having from 1 to 6 carbon atoms; (ii) alkoxy groups having from 1 to 6 carbon atoms; (iii) perfluoroalkyl having from 1 to 6 carbon atoms; (iv) halogen; (v) cyano groups; (vi) cyanoalkyl; (vii) haloalkyl having from 1 to 6 carbon atoms; (viii) alkanoyl having from 1 to 6 carbon atoms; wherein for (q) and (r) the phenyl portion of the phenoxy group and the phenoxyalkyl are optionally substituted with one or two substituents independently selected from the group consisting of (i) alkyl having from 1 to 6 carbon atoms; (ii) alkoxy groups of 1 to 6 carbon atoms; (iii) perfluoroalkyl having from 1 to 6 carbon atoms; (iv) halogen; (v) cyano groups; (vi) cyanoalkyl; (vii) haloalkyl having from 1 to 6 carbon atoms; (viii) alkanoyl having from 1 to 6 carbon atoms; • • ·· • ·· ·· ·· ·· • · • 9 • • * • • • · • • • • fl « • • • · • • • • fl ··· 1 ·· * · ··· «· ·· Ar ₂ is an aryl group selected from the group consisting of (1) phenyl; • • · ·· • · • · • • • · • • • • • • • • • • ·. * • • · • • 9 • • • • • 9 ··· • · · • • ·· · ·· 99 wherein for (f) and (g) the phenyl and phenyl portion of the phenylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of (i) alkyl having from 1 to 6 carbon atoms; (ii) alkoxy groups having from 1 to 6 carbon atoms; (iii) perfluoroalkyl having from 1 to 6 carbon atoms; (iv) halogen; (v) haloalkyl having from 1 to 6 carbon atoms and (vi) alkanoyl having from 1 to 6 carbon atoms; or R e and R 7 are taken together with the nitrogen atom to which they are attached to form a defined group selected from the group consisting of (1) morpholinyl (2) thiomorpholinyl; (9) - (alkylene) -S (O) _p -alkyl wherein the alkylene has from 1 to 6 carbon atoms and the alkyl has from 1 to 6 carbon atoms; (10) phthalimidyl; (10) phenyl; A compound according to claim 10 selected from the group consisting of (±) -N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4 4-dimethyl-2,5-dioxol-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [(4'-ethoxy [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide; (±) -N- [1 - [[4- (1,3-benzodioxol-5-yl) phenoxy] methyl] -2- (4,4-dimethyl-2,5-dioxol-imidazobdinyl) ethyl] -N -hydroxyformamide; (±) -N- [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '(trifluoromethoxy) [1,1'-biphenyl] -4- yl] oxy] ethyl] -N-hydroxyformamide; (±) - N - [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '(trifluoromethyl) [1,1'-biphenyl] -4- yl] oxy] ethyl] -N-hydroxyformamide; (±) -N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl) -4-yl] oxy] methyl] -3- (4,4-dimethyl-2,5-dioxo-1) -imidazolidinyl) propyl] -N-hydroxyformamide 140 (±) - N - [1 - [[(4'-Butoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-diethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -3- (4,4-dimethyl-2,5-dioxol-imidazolidinyl) propyl] -N-hydroxyformunide; (±) -N- [1 - [[[4 '- (methylsulfonyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1) (imidazolidinyl) ethyl] -N-hydroxyformamide; (±) - N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '(trifluoromethyl) [1,1'-biphenyl] -4- yl] thio] ethyl] -N-hydroxyformamide; (±) - N - [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '(trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazohdinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Butyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxol-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (4,4-dimethyl-2,5-dioxoimidazoidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1) imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (2-methoxyethoxy) [1,1'-biphenyl] -4- yl] oxy] ethyl] -N-hydroxyformamide; (±) - N - [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [(4'-propoxy [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide: N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl] methyl] -2 - ((4'-pentyloxy [1,1-biphenyl] -4-yl) oxy] ethyl) -N-hydroxyformamide; (±) -N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl] sulfonyl] methyl] -3- (4,4-dimethyl-2,5-dioxo-1) (imidazoidinyl) propyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1) (imidazolidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [([4- (4-Fluorophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazohdinyl) ethyl] -N-hydroxyformamide ; 141 (S) -N- [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '(trifluoromethoxy) [1,1'-biphenyl] -4] -yl) oxy] ethyl) -N-hydroxyformamide; (R) -N- [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '(trifluoromethoxy) [1,1'-biphenyl] -4-yl] [oxy] ethyl] -N-hydroxyformamide; N- [1 - [[[4 '- (trifluoromethoxy)] [1,1'-biphenyl] -4-yl] oxy] methyl] -3- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) propyl 1-N-hydroxyformamide; N- [1- [4 - [(4-pyridinylthio) phenoxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide; N- [1 - [[[(4-chlorophenoxy) phenyl] sulfonyl] methyl] -3- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) propyl] -N-hydroxyformamide; N- [1 - [[[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl 1-N-hydroxyformamide; N- [1 - [[[(4-cyanophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide; and N- [1 - [[4 - [[4- (trifluoromethoxy) phenoxy] phenyl] sulfonyl] methyl] -3- (4,4-methyl-2,5-dioxo-1-imidazolidinyl) propyl] -N-hydroxyformamide. (11) naphthalimidyl; O ^ ^N \ ^ O N-N H, C CH, (13) fc ' 131 a wherein for (1) - (23), the groups defined by R 6 and R 7 are taken together with the nitrogen atom to which they are attached, optionally substituted by one or two substituents independently selected from the group consisting of (a) halogen, (b) alkyl, (c) alkoxy groups, (d) phenoxy groups, (e) phenylalkyl, and (f) benzyloxy groups; or R 1 and R 2 are taken together with the carbon atom to which they are attached to form a ring selected from the group consisting of (1) a spiroalkyl having from 3 to 8 carbon atoms of (2) tetrahydropyranyl; or R 3 and R 4 are linked to the carbon atom to which they are attached to form a spiroalkyl group having from 3 to 8 carbon atoms; or R 1 and R 3 are taken together with the carbon atom to which they are attached to form a 5-, 6-, or 7-membered ring; ΦΦ 132 substituent X is selected from the group consisting of (1) -O-; (11) phenylalkoxyalkyl, wherein the alkylene and alkyl groups independently have from 1 to 6 carbon atoms; 127 (12) phenylalkyl, wherein the alkylene group has from 1 to 6 carbon atoms; A compound according to claim 9 selected from the group consisting of (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2 3-dihydro-1,3-dioxol-1H-isoindol-2-yl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl) -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1) -yl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1) -yl) propyl] -N-hydroxyformamide; (±) -N- [1- [4 - [(2-E-Phenylethenyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide ; (±) - N - [1 - [[4- (2-Furanyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1- imidazolidinyl) ethyl] -N-hydroxyformamide; 142 (±) -N- [1 - [[(4'-Fluoro [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxole) (imidazobdinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [(3,4,4-trimethyl-2,5-dioxo-1-imidazobdinyl) methyl] -2 - [[4 '- (trifluoromethyl) [U'-biphenyl] - 4-yl) oxy] ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Methoxy [1,1'-biphenyl) -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1) (imidazobdinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5'-dioxo) 1-imidazobdinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-butoxy [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-1-imidazobdinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[4- (3-Thienyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[([1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-imidazobdinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(3'-chloro-4'-fluoro [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl2,5) (dioxo-1-imidazobdinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[(2'-Methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1- imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-imidazobdinyl) ethyl] -N-hydroxyformamide ; (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (1,1-dioxido-3-oxo-1,2-benzisothiazole- 2 (3H) -yl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[4- (4-Phenyl-1-piperidinyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazobdinyl) ethyl] -N -hydroxyformamide; (±) - N - [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- [4,4-dimethyl-2,5-dioxo 3 - ( 3-pyridinylmethyl) -1-imidazolidinyl] ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(3'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1- imidazobdinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[[4 '- (methylthio) [1,1'-biphenyl) -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo) -1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1- [4 - [[4- (trifluoromethyl) phenoxy] phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N- hydroxyformamide; 143 • · • 0 • · 0 0 • · 0 0 0 0 00 0 0 0 0 0 • 0 0 0 0 0 0 0 0 0 ·· · • 0 0 00 0 0 0 0 0 0 0 (±) -N- [1 - [[(4 '- (Trifluoromethoxy) [1,1-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl) ethyl] -2-N-hydroxyphonamide; (±) -N- [1 - [[[4 '- (methylsulfonyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo) 1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[[3 '- (cyanomethyl) -4'-methoxy] [1,1'-biphenyl] -4-yl] oxy] methyl] -2 (3,4,4-trimethyl- 2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[(3'-Cyano [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide ; (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,6-dioxo-1-piperidinyl) ethyl] -N-hydroxyformamide; N- [1S - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide; N- [1R - [[(4'-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-ethyl-3-methyl-2,5-dioxo-1- pyrrolidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (5,5-dimethyl-2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[(4'-Cyano [Ι, Γ-biphenyl] -4-yl) sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1) (imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-chloro- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl) -2,5-dioxo 1-imidazolidinyl) ethyl] -N-hydroxyformamide; (±) - N - [1 - [[(3'-Cyanomethyl- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,5,5-trimethyl) The compound of claim 1, wherein R 1 and R 2 are taken together with the carbon atom to which they are attached to form a ring selected from (1) a spiroalkyl having from 3 to 8 carbon atoms and (2) tetrahydropyranyl. (13) phenoxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms; A compound according to claim 13 selected from the group consisting of N- [4- [4 - [[(4-chlorophenoxy) phenyl] sulfonyl] methyl] tetrahydro-2H-pyran-4-yl] -N-hydroxyformamide. N- [4- [4 - [[(4'-chloro [1,1'-biphenyl] -4-yl) sulfonyl] methyl] tetrahydro-2H-pyran-4-yl] -N-hydroxyformamide. (14) - (alkylene) -N (R ₅ ) SO 2 -phenyl, wherein the alkylene group has from 1 to 6 carbon atoms and the substituent R ₅ is selected from the group consisting of (a) hydrogen and (b) alkyl having from 1 up to 6 carbon atoms; A compound selected from the group consisting of (±) -N- [1 - [[(4'-cyano- [1,1-biphenyl] -4-yl) oxy] methyl] -2-phenoxyethyl] -N- hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (phenylthio) ethyl] -N-hydroxyformamide, (± ) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,3-dihydro-1,3-dioxo-1H- isoindol-2-yl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- ( 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl]] - 4-yl) oxy] methyl] -3- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) propyl] -N-hydroxyformamide, (±) -N- [1 - [[[3 '- (cyanomethyl)] (1-) - [1,1'-biphenyl] -4-yl) oxy] methyl] pentyl) -N-hydroxyformamide, (±) -N- [1 - [((4'-cyano - [1, 1Aiphenyl]) - 4-yl) oxy] methyl] Amethylbutyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] - 2-methylbutyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1-biphenyl] -4-yl) oxy] methyl] pentyl] -N-hydroxyformamide, ( ±) -N- [1 - [[(4'-Cyano- [ 1,1'-biphenyl) -4-yl) oxy] methyl] -2- (4-methylphenyl) ethyl] -N-hydroxyformamide, (±) -N- [2 - [(4'-cyano- [1,1'- biphenyl] -4-yl) oxy] -1- (4-fluorophenyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1'-biphenyl]] - 4-yl) oxy] methyl] -2- (4-fluorophenyl) ethyl] -N-hydroxyformamide, 146 «· 99 99 9 9 • 9 • 9 99 9 9 • · 99 9 9 • « • · • 9 • · • · · 999 ·· 999 99 • · (±) - N - [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] ethyl] -N-hydroxyformamide, N- [2 - [(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyacetamide, N- [2 - [(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide, (±) -N- [1- [4 - [(2E- phenylethenyl) phenoxy) methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[4- (2-furanyl) (phenoxy) methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] N-hydroxyformamide, (±) - N - [[- (4'-butoxy [ 1,1'-biphenyl) -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-fluoro [1,1'-biphenyl) -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N -hydroxyformamide, (±) -N- [1 - [(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethyl) [Ι, if-biphenyl] -4-yl] oxy] ethyl] -N-hydroxyformamide, (±) - N - [1 - [[(4'-methoxy [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-methyl [1,1'-biphenyl] -4] -yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-butoxy) [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [(4,4-dimethyl-2,5-dioxo-1)] -imidazolidinyl) methyl] -2 - [(4'-ethoxy [1,1'-biphenyl] -4-yl) oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[4- (1, 2, 3, 4, 3, 4, 3, 4, 3, 4, 3, 4, 3, 4, 3, 3, 3, 3, 3); 3-Benzodioxol-5-yl) phenoxy] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[( 4'-Hutoxy [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N - [1 - [[4- (3-thienyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N - [1 - [[([1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(3'-chloro-4'-fluoro- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl- 2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, 147 ·· · 99 ·· • · • · • 99 9 · • · 9 9 9 • · • · 9 9 9 • · • · 99 9 99 · 99 999 ·· • · (±) - N - [1 - [[(2'-Methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo- (±) -N- [1 - [[(4'-cyano [4'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo- (limidazobdinyl) ethyl) -N-hydroxyformamide 1-Imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano (1,1'-biphenyl] -4-yl) oxy] methyl] -2- (1,1- dioxido-3-oxo-1,2-benzisothiazol-2 (3H) -yl) ethyl] -N-hydroxyformamide, (± -N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazobdinyl)) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] oxy) ethyl] -N-hydroxyformamide (±) -N- [1 - [[4- (4-phenyl-1)] -piperidinyl) phenoxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazobdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - ((4,4-dimethylethyl) -2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] 4-yl] oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(3'-Cyano (1,1'-biphenyl] -4-yl) oxy] methyl] -2- [methyl [(4-methylphenyl) sulfonyl] amino] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- [4,4-dimethyl-2,5-dioxo-3- (3-pyridinylmethyl) ) -1-imidazo people nyl] ethyl] -N-hydroxyformamide, (±) -N- [2 - [(4'-cyano [1,1'-biphenyl] -4-yl) oxy] -1-methylpropyl] -N-hydroxyformamide, (± ) -N- [1 - [[(3-cyano [1,4-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazotidinyl) ethyl] -N-hydroxyformamide; (±) -N- [1 - [[[4 '- (methylthio) [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5- dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1- [4 - [[4- (trifluoromethyl) phenoxy] phenoxy] methyl] -2- (3,4,4-trimethyl-2; 5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[4 '- (trifluoromethoxy) [1,1-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -2-N-hydroxyformamide, (±) -N- [1 - [([4 '- (methylsulfonyl)] [1,1] 1-Biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazohinyl) ethyl] -N-hydroxyformamide, (±) -N- [1- [[[3 '- (cyanomethyl) -4'-methoxy [1,1'-biphenyl] -4-yl] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -3- (4,4-dimethyl) -2,5-dioxo-limidazolidinyl) propyl] -N-hydroxyphomiamide 148 (±) - N - [1 - [[(4'-Butoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) (ethyl) -N-hydroxyfonnainide, (±) -N- [1 - [[(4 + cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -3- (4,4-dimethyl-2) (5-dioxo-limidazolidinyl) propyl] -N-hydroxyformamide, (±) -N- [1 - [[[4 '- (methylsulfonyl) [1,1'-biphenyl] -4-yl] oxy] methyl] -2 - (4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(3'-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl] (oxy) methyl] -2- (4,4-dimethyl-2,6-dioxo-1-piperidinyl) ethyl] -N-hydroxyformamide; N- [1S - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide, N- [1R - [[(4'-Cyano [1,1'-biphenyl) -4-yl) oxy] methyl] -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -N-hydroxyformamide, (± ) -N- [1 - [[(4'-Cyano [1,1'-biphenyl) -4-yl) oxy] methyl] -2- (3-ethyl-3-methyl-2,5-dioxo-1) pyrrolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [4- [4 - [[(4-chlorophenoxy) phenyl] sulfonyl] methyl] tetrahydro-2H-pyran-4-yl) -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [[(2-methoxycarbonyl) phenyl) thio] ethyl] -N hydroxyformamide, (±) - N - [1 - [[(4'-Cyano [1,1'-biphenyl) -4-yl) oxy] methyl] -5 - [(4-methyl-2-oxo-2H-1 -) - benzopyran-6-yl) oxy] pentyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -4- [ (4-Methyl-2-oxo-2H-1-benzopyran-6-yl) oxy] butyl] -N-hydroxyformamide, (±) - N- [1 - ([(4 + cyano [1,1 + biphenyl] -4- yl) oxy] methyl] -4 - [(4-methyl-2-oxo-2H-1-benzopyran-7yl) oxy] butyl) -N-hydroxyformamide, (±) -N- [1 - [[(4 ') -cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -5 - [(4-methyl-2-oxo-2H-1-benzopyran-7-yl) oxy] pentyl] -N-hydroxyformamide, (± ) -N- [1 - [[(4'-Cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (5,5-dime) thyl-2,4-dioxo-3-oxazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide; 149 (±) - N - [1 - [[(4'-Cyano [1,1'-biphenyl) -4-yl) oxy] methyl] -2- (3-methyl-2,5-dioxo-limidazobdinyl) ethyl -N-hydroxyformamide. (±) -N- [1 - [[(4'-Cyano (1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazobdinyl) (ethyl) -N-hydroxyformamide, (±) -N- [1 - [[(4'-chloro- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,4,4) -trimethyl-2,5-dioxo-limidazobdinyl) ethyl] -N-hydroxyformainide, (±) -N- [1 - [[(3'-cyanomethyl- [1,1'-biphenyl] -4-yloxy) methyl] methyl -2- (3,5,5-trimethyl-2,4-dioxo-limidazobdinyl) propyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [1,1 '] -biphenyl] -4-yl) oxy] methyl] -2-isopropylthioethyl] -N-hydroxyformamide, (±) -N- [1 - [[(3'-cyanomethyl- [1,1'-biphenyl] -4-yl)] oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-cyano- [ 1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-ethyl-4,4-diethyl-2,5-dioxo-limidazobdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-Cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3-benzyl-4,4-dimethyl-2,5-dioxo-1-imidazobdinyl) ethyl N - [1 - [[(4'-cyano- [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (3,5,5-) trimethyl-2,4-dioxo-limidazolinyl-ethyl] -N-hydroxyform amide, (±) - N - [1 - [[4'-Methoxy [1,1'-biphenyl] -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide; (±) -N- [1 - [[(4'-chloro (1,1'-biphenyl] -4-yl) sulfonyl] methyl] ethyl] -N-hydroxyformamide (±) -N- [1 - [[[ 4- (1,3-benzodioxol-5-yl) phenyl] sulfonyl] methyl] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[4- (4-chlorophenoxy) phenyl] sulfonyl] methyl ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl) methyl] propyl] -N-hydroxyformamide, (±) ) -N- [1- [1,1-dimethyl-2 - [(4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide, (±) -N- [1 - [(phenylmethoxy) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide, (±) -N- [1- (hydroxymethyl) ) -2 - [[(4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [(4,4-dimethyl- 2,5-dioxo-1-imidazobdinyl) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] 4-yl] thio] ethyl] -N-hydroxyformamide; 150 (±) - N - [1 - [(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] -4-yl] sulfonyl] ethyl] -N-hydroxyformamide, (±) -N- [1 - [(2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1' - biphenyl] -4-yl] oxy] ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[4 '- (trifluoromethyl) [1,1'-biphenyl] -4-ylsulfonyl] methyl] -2- (3 , 4,4-trimethyl-2,5-dioxol-imidazolidinyl) ethyl] -N-hydroxyphonamide, (±) -N- [1 - [[(4'-butyl [1,1'-biphenyl] -4-yl) (oxy) methyl] -2- (3-methyl-2,5-dioxo-1 imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [(3-methyl-2,5-dioxo-) 1-imidazolidinyl) methyl] -2 - [[4 '- (trifluoromethoxy) [1,1'-biphenyl] -4-yl] oxy] ethyl] -N-hydroxyformamide, (±) -N- [4- [4 - [( 4'-chloro [1,1'-biphenyl] -4-yl) sulfonyl] methyl] tetrahydro-2H-pyran-4-yl) N-hydroxyformamide, (±) -N- [1 - [[[4- (4- chlorophenoxy) phenyl] sulfonyl] methyl] -2- (4,4-dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[4- (4- chlorophenoxy) phenyl] sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydro xyformamide, (±) -N- [1 - [[(4-butyl [1,1'-biphenyl] -4-yl) sulfonyl] methyl] -2- (3,4,4-trimethyl-2,5-dioxo) -limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [((4'-butyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4- dimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[[3 '- (cyanomethyl) [1,1'-biphenyl] -4-yl) oxy] methyl] -2- (4,4-dimethyl-2,5-dioxolanudazohdinyl) ethyl] -N-hydroxyformamide, (±) -N- [1- [4- (2-thienyl) phenoxy] methyl) -2 - [1- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(3-nitro [1,1-biphenyl]] -4-yl) oxy] methyl] -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) ethyl] -N-hydroxyformamide, (±) -N- [1 - [[(4 1-methyl [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [[3- (methylsulfonyl) amino] phenyl] ethyl] N-hydroxyformamide, (±) -N- [1- [ [[3- (diethylamino) carbonyl] phenyl] methyl] -2 - [(4'-methyl- [1,1'-biphenyl] -4-yl) oxy] ethyl] N-hydroxyformamide, N- [1 - [[(4'-cyano [1,1'-biphenyl] -4-yl) oxy] methyl] -2 - [(4'-cyano [1,1'-biphenyl] -4yl) oxy ethyl] -N-hydroxyformamide, 151 0 · 0 • 0 0 0 0 0 0 0 * 0 • 0 0 • 0 00 0 000 00 00 ► 0 · I (15) (heterocycle) oxyalkyl wherein the alkylene group has from 1 to 6 carbon atoms; A compound according to claim 15 having the formula (S) -N- [1 - [(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl) methyl] -2 - [[4 '(trifluoromethoxy) [ 1,1'-biphenyl] -4-yl] oxy] ethyl] -N-hydroxyformamide. (16) - (alkylene) -S (O) _p -heterocycle, wherein the alkylene group has from 1 to 6 carbon atoms; ((17) - (alkylene) - heterocycle wherein the alkylene group has from 1 to 6 carbon atoms; and (18) - (alkylene) -NR ₆ R ₇ wherein the alkylene group has from 1 to 6 carbon atoms; - (17) is a heterocycle selected from the group consisting of (a) pyridyl, (b) pyrazinyl, (c) pyridazinyl, (d) furyl, (e) thienyl, (f) isoxazolyl, (g) oxazolyl, (h) thiazolyl, (i) isothiazolyl, and wherein for (10) - (17) there are phenyl, phenyl portions of phenylalkoxyalkyl, phenylalkyl, - (alkylene) -N (R ₅ ) SO 2 -phenyl, phenoxyalkyl, and - (alkylene) -S (O) ) _p- phenyl, and heterocycle, heterocyclic moieties (heterocycle) oxyalkyl, - (alkylene) heterocycle and - (alkylene) -S (O) _p -heterocycle optionally substituted with one, two or three substituents independently selected from the group consisting of (and ) alkyl having from 1 to 6 carbon atoms; (b) alkoxy groups having from 1 to 6 carbon atoms; (c) alkoxyalkyl, wherein the alkyl group and the alkylene group independently have from 1 to 6 carbon atoms; (d) halogen; 128 (e) haloalkyl having from 1 to 6 carbon atoms; (f) hydroxy groups; (g) hydroxyalkyl having from 1 to 6 carbon atoms; (h) - (alkylene) -heterocycle; In (i) - (alkylene) -phenyl, (j) -N (R ₅ ) SO ₂ -alkyl, (k) phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of with (i) a cyano group (ii) a nitro group and (iii) a halogen, (1) -C (O) OR ₅ ; and (m) -C (O) NR _x R _y , wherein R _x and R _y are independently selected from the group consisting of (i) alkyl having 1 to 6 carbon atoms, (ii) phenyl and (iii) phenylalkyl, wherein for (ii) and (iii) the phenyl and phenyl moiety of the phenylalkyl are optionally substituted with substituents independently selected from the group consisting of halo and alkoxy of from 1 to 6 carbon atoms; wherein for (18), R 1 and R _{7 are} independently selected from the group consisting of (a) a hydrogen atom; (b) alkyl having from 1 to 6 carbon atoms; (c) cycloalkyl having from 3 to 8 carbon atoms; (d) cycloalkylalkyl, wherein the cycloalkyl group has from 3 to 8 carbon atoms and the alkylene group has from 1 to 10 carbon atoms; (e) an alkanoyl having from 1 to 10 carbon atoms; (i) phenyl and (g) phenylalkyl, wherein the alkylene group has from 3 to 10 carbon atoms, 129 Use of a compound according to claim 1 for the preparation of a medicament for inhibiting matrix metalloproteinases in a mammal in need of such treatment. .18. A composition for inhibiting matrix metalloproteinases comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.