WO2004110989A1 - N-hydroxy-7-(arylamino)heptanamide derivatives useful for treating hyper-proliferative disorders - Google Patents

Abstract

This invention relates to novel N-hydroxy-7-(arylamino)heptanamide derivative compounds including salts, carbonates and O-acylated derivatives thereof, pharmaceutical compositions containing such compounds, and the use of those compounds or compositions for treating hyper-proliferative disorders.

Description

N-Hvdroxy-y-farylamino^heptanamide Derivatives Useful for Treating Hvper-Proiiferative Disorders

Field of the Invention This invention relates to novel Λ/-hydroxy-7-(arylamino)heptanamide derivative compounds including salts, carbonates and O-acylated derivatives thereof, pharmaceutical compositions containing such compounds, and the use of those compounds or compositions for treating hyper-proliferative disorders.

Description of the Invention

Compounds of the Invention

One embodiment of this invention relates to a compound of Formula I

(I) wherein

Ar is selected from phenyl, 3-quinolyl, 5-indolyl, and 5-indazolyl;

R is selected from H, O-(CrC₆)alkyl, thienyl, naphthyl, benzofuranyl, benzothiophenyl,

— N V

, and phenyl optionally substituted with up to 3 substituents each selected independently from (C_rC₄)alkyl, O-(C_rC₆)alkyl, and CF₃;

R¹ is selected from H, C(O)W, C(O)NHX, and S(O)₂Y; V is selected from NH, O and CH₂, and when V is NH, N can be optionally substituted with (C_rC₄)alkyl;

W is selected from (C-rC₈)alkyl optionally substituted with 2, (C₃-C₆)cycloalkyl, O-(C_rC₄)alkylphenyl, O-(C_rC₄)alkyl, naphthyl, thienyl, furyl, benzothienyl, phenyl said phenyl being optionally substituted with up to 3 substituents each independently selected from (CrC₄)alkyl, O-(C_rC₄)alkyl, S-(C₁-C₄)alkyl, halo, CF₃, 0-CF₃, phenyl, O-phenyl, O-(C_rC₄)alkyl-phenyl, and isoxazolyl said isoxazolyl being optionally substituted with up to 2 independently selected (C-ι-C₄)alkyl groups; X is selected from (CrC₈)alkyl optionally substituted with Z,

(C₃-C₆)cycloalkyl, naphthyl, thienyl, furyl, benzothienyl, phenyl said phenyl being optionally substituted with up to 3 substituents each independently selected from (CrC₄)alkyl, O-(C_rC₄)alkyl, S-(C₁-C₄)alkyl, halo, CF₃, 0-CF₃, phenyl, O-phenyl, O-(C_rC₄)alkyl-phenyl,

NHC(O)(C_rC₄)alkyl, N[(C_rC₄)alkyl]₂, and isoxazolyl said isoxazolyl being optionally substituted with up to 2 independently selected (C_rC₄)alkyl groups;

Y is selected from (C_rC₈)alkyl optionally substituted with Z, (C₃-C6)cycloalkyl, naphthyl, thienyl, furyl, benzothienyl, phenyl said phenyl being optionally substituted with up to 3 substituents each independently selected from (C_rC₄)alkyl, O-(C_rC₄)alkyl, S-(C_rC₄)alkyl, halo, CF₃, 0-CF₃, phenyl, O-phenyl, O-(C_rC₄)alkyl-phenyl, and isoxazolyl said isoxazolyl being optionally substituted with up to 2 independently selected (C_rC₄)alkyl groups; Z is selected from naphthyl, O-phenyl, O-(d-C₄)alkyl, and phenyl said phenyl being optionally substituted with up to 2 substituents each independently selected from (CrC₄)alkyl, halo and phenyl, or a pharmaceutically acceptable salt, carbonate or an O-acylated derivative thereof.

A preferred embodiment of this invention is a compound of Formula I wherein W is selected from (C₃-C₆)cycloalkyl, O-(C-ι-C₄)alkylphenyl, naphthyl, thienyl, furyl, benzothienyl, (C-|-C₈)alkyl optionally substituted with Z, oxazolyl optionally substituted with up to 2 substituents each selected independently from (CrC₄)alkyl, and phenyl optionally substituted up to 2 substituents each selected independently from (CrC₄)alkyl, O-(C-ι-C₄)alkyl, halo, CF₃, phenyl, and N[(C_rC₄)alkyl]₂;

X is selected from (C-i-C₄)alkyl, (C₁-C₄)alkylphenyl, naphthyl, cyclohexyl, and phenyl said phenyl being optionally substituted with up to 3 substituents each selected independently from phenyl, O-phenyl, O-(CrC₄)alkyl, S-(C_rC₄)alkyl, halo, CF₃, and N[(C_rC₄)alkyl]₂; Y is selected from naphthyl, thienyl, and phenyl said phenyl being optionally substituted with up to 2 substituents each selected independently from (C_rC₄)alkyl, O-(C_rC₄)alkyl, halo, CF₃, OCF₃, phenyl and NHC(O)(C_rC₄)alkyl; and Z is selected from O-(CrC₄)alkyl, O-phenyl, naphthyl and phenyl said phenyl being optionally substituted with up to 2 substituents each independently selected from (CrC₄)alkyl, halo, and phenyl; or a pharmaceutically acceptable salt thereof.

Another preferred embodiment of this invention is a compound of Formula I wherein W is selected from (C₃-C₄)cycloalkyl, naphthyl, thienyl, furyl, benzothienyl,

(C-ι-C₂)alkyl optionally substituted with Z, and phenyl optionally substituted up to 2 substituents each selected independently from (C_rC₂)alkyl, O-(C_rC₂)alkyl, halo, CF₃, phenyl, and N[(C-|-C₂)alkyl]₂; X is selected from (CrC₄)alkyl, (C-ι-C₂)alkylphenyl, naphthyl, cyclohexyl, and phenyl said phenyl being optionally substituted with up to 3 substituents each selected independently from phenyl, O-phenyl, O-(C-ι-C₂)alkyl, S-(C_rC₂)alkyl, halo, CF₃, and Nf(C₁-C₂)BlRyI]₂;

Y is selected from naphthyl, thienyl, and phenyl said phenyl being optionally substituted with up to 2 substituents each selected independently from

(C_rC₂)alkyl, O-(C_rC₂)alkyl, halo, CF₃, OCF₃, phenyl and NHC(O)(C_rC₂)alkyl; and Z is selected from O-(C_rC₂)alkyl, O-phenyl, naphthyl and phenyl said phenyl being optionally substituted with up to 2 substituents each independently selected from (C_rC₂)alkyl, halo, and phenyl; or a pharmaceutically acceptable salt thereof.

Another preferred embodiment of this invention is a compound of Formula I wherein R¹ represents S(O)₂Y.

Another preferred embodiment of this invention is a compound of Formula I wherein R¹ represents S(O)₂Y and Y is thienyl.

Another preferred embodiment of this invention is a compound of Formula I wherein R¹ represents C(O)W. Another preferred embodiment of this invention is a compound of Formula I wherein R¹ represents C(O)W and W is thienyl or benzothienyl.

Another preferred embodiment of this invention is a compound of Formula I wherein Ar is phenyl.

Another preferred embodiment of this invention is a compound of Formula I wherein Ar is 5-indolyl.

In another embodiment, the present invention relates to a process of making a compound of formula (I), wherein

[A] a compound of formula (V)

is reacted with hydroxylamine hydrochloride, preferably in the presence of a base, or

[B] a compound of formula (V)

is in a first step reacted with a protected hydroxylamine, such as (O-(tetrahydro-2H- pyran-2-yl)hydroxylamine, preferably in the presence of trimethylaluminum, and in a second step is deprotected, preferably under acidic conditions.

A compound of formula (V) is known or can be prepared as described infra.

The terms identified above have the following meaning throughout:

The term "optionally substituted" means that the moiety so modified may have from none to up to about the highest number of substituents indicated. When there are two or more substituents on any moiety, each substituent is defined independently of any other substituent and can, accordingly, be the same or different.

The terms "(CrC₈)alkyl" and "(C_rC₄)alkyl" mean linear or branched saturated carbon groups having from about 1 to about 8 or about 4 C atoms, respectively. Such groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, ferf-butyl, and the like.

The term "O-(C_rC₄)alkyl" means an O atom substituted with a (CrC₄)alkyl group, where the O-(C_rC₄)alkyl group is attached to the rest of the molecule at the group's O atom. Such groups include methoxy, ethoxy, π-propoxy, f-butoxy and the like.

The term "S-(C_rC₄)alkyl" means an S atom substituted with a (CrC₄)alkyl group, where the S-(C-ι-C₄)a!kyl group is attached to the rest of the molecule at the group's S atom. Such groups include methylthio, ethylthio, n-propylthio, f-butylthio and the like.

The term "O-(C_rC₄)alkylphenyl" means an O atom substituted by a (C_rC₄)alkyl group said alkyl group being itself substituted by phenyl. The O-(C-ι-C₄)alkylphenyl group is attached to the rest of the molecule at the group's O atom. Such groups include benzyloxy, 2-phenethyloxy, 3-phenylpropoxy, 2-phenylbutyloxy and the like.

The term "O-phenyl" means phenoxy, the phenoxy group being attached to the rest of the molecule at the group's O atom. The term "C₃-C₆ cycloalkyl" means a saturated monocyclic alkyl group of from 3 to about 6 carbon atoms and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The term "halo" means an atom selected from Cl, Br, F, and I, where Cl and F are preferred. When "(O)" appears in a chemical formula, it means (=O) (double bonded oxygen atom).

In the chemical formula "N[(CrC₄)alkyl]₂", each of the 2 alkyl groups is selected independently from the other so that they may be the same or different.

Unless the point of attachment of a heterocyclic group is specifically defined, heterocyclic groups such as thienyl, furyl, naphthyl, benzofuranyl, benzothiophenyl, isoxazolyl, and the like, are each attached to the rest of the molecule through any available C atom. Substituents on such heterocycles may be attached to the heterocycle through any available C atom on the heterocycle.

The compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R, S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either =Z- or =E- form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of the present invention. Preferred compounds are those with the absolute configuration of the compound of this invention which produces the more desirable biological activity. Separated, pure and partially purified isomers and racemic mixtures of the compounds of this invention are each included within the scope of the present invention. The purification of said isomers and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.

Pharmaceutically acceptable salts of these compounds are also within the scope of this invention. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. ScL 66: 1-19, 1977.

Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts that are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and Λ/-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. The term "pharmaceutically acceptable carbonate" refers to a relatively non-toxic carbonate derivative of a compound of the present invention where the H atom of an acid hydroxyl group of a compound of Table I has been replaced with a alkoxy-carbonyl group where said alkoxy may be substituted with phenyl, alkoxy, and the like. The carbonates of the compounds of this invention include pharmaceutically acceptable carbonates such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl- or pentyl-carbonate. Other examples of alkoxy-carbonyl groups include -C(=O)OCH₂CH₃ (ethyl carbonate) and -C(=O)OCH(CH₃)₂ (isopropyl carbonate).

The term "pharmaceutically acceptable O-acylated derivative" refers to a relatively non-toxic O-acylated derivative of the present invention where the O atom of the hydroxamic acid group is substituted with an acyl group such as acetyl, propanoyl, butanoyl, benzoyl or toluoyl and the like.

These carbonate and O-acylated derivative(s) may be hydrolyzed at physiological pH values or may be cleaved by endogenous esterases or lipases in vivo to release the parent compound as the active material for treating hyper-proliferative disorders. (See, e.g., U.S. Patent No. 4,942,184, U.S. Patent No. 4,960,790, U.S. Patent No. 5,817,840, and U.S. Patent No. 5824701, all of which are incorporated herein by reference in their entirety, and references therein.)

A sample of representative compounds of this invention are described in Table 1.

Table 1

The compound structures of Table 1 correspond to the IUPAC compound names in Table 2 below.

Table 2

Example

IUPAC Name* No

7-[({[4-(dimethylamino)phenyl]amino}carbonyl)(1/-/-indazol-5-yl)amino]-Λ/-

146 hydroxyheptanamide

*The IUPAC name was obtained using the ACD/iLab Web service

Abbreviations and Acronyms

When the following abbreviations are used throughout the disclosure, they have the following meaning: anhyd anhydrous aq aqueous

BOC f-butoxycarbonyl

BOC anhydride (f-butoxycarbonyl)₂O

Celite® registered trademark of Celite Corp. brand of diatomaceous earth

DCM dichloromethane

DMAP 4-(Λ/,/V-dimethyl)aminopyridine

DMF Λ/,Λ/-dimethylformamide

DMSO dimethylsulfoxide

EA elemental analysis

ES electrospray

Et ethyl

Et₂O diethyl ether

EtOAc ethyl acetate

GC-MS Gas chromatography - mass Spectrometry h hour(s)

HPLC High performance liquid chromatography

HEX Hexanes

LC-MS Liquid Chromatography/Mass Spectrometry

Me methyl MeOH methanol min minute(s)

MPLC Medium Pressure Liquid Chromatography

NMR Nuclear Magnetic Resonance Spectroscopy Ph phenyl

PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate

R_f TLC Retention Factor

RT retention time (HPLC) rt room temperature

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

Method of making the compounds of the present invention

The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as whether the amine is substituted or not, the selection of the specific substituents possible at various locations on the molecule, and the like, each play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one of ordinary skill in the art.

In general, the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods. The following preparative methods (Methods A-G) are presented in Reaction Schemes 1-3 to aid the reader in the synthesis of the compounds of the present invention.

For example, as shown in Reaction Scheme 1, compounds of Formula (I) can be prepared in a 3 or 4 step sequence starting from a substituted aniline, represented by

Formula (H) and a 7-haloheptane carboxylic acid ester, such as ethyl 7-bromoheptanoate [Formula (III)]. In the first step, designated as Method A, the aniline of Formula (II) and the bromo ester of Formula (III) are allowed to react in a polar aprotic solvent such as DMF and in the presence of a base such as potassium carbonate, to provide the aryl amino ester of Formula (IV). Depending on the desired R¹ group, the compound of Formula (IV) may be converted to the N-substituted amino ester of Formula (V) by either Method B or Method D. In Method B, the Formula (IV) compound is treated with a sulfonyl chloride [ R¹-CI, where R¹ is Y-SO₂-] in the presence of a non-nucleophilic base such as DMAP, to give the compound of Formula (V). In Method D, the Formula (IV) compound is treated with a chloroformate [R¹ -Cl, where R¹ is W-C(O)-, and W is (C_rC₄)alkoxy or phenyl-(C-i-C₄)alkyl-O-] in the presence of a base such as triethyl amine, in an aprotic solvent such as THF to give the Formula (V) compound. Direct conversion of the Formula (V) compound to the invention compound of Formula (I) can be accomplished by the conditions designated as Method C, namely, treatment of the compound of Formula (V) with hydroxylamine hydrochloride in methanol in the presence of a base such as potassium hydroxide. Alternatively, the Formula (I) compound can be prepared by a multi-step procedure designated as Method E. In the first step of Method E, the compound of Formula (V) is allowed to react with (O-

(tetrahydro-2H-pyran-2-yl)hydroxylamine in the presence of trimethylaluminum in an inert solvent such as methylene chloride, followed by workup in a aqueous phosphate buffer (pH 7) to provide the hydroxamic acid ester of Formula (Vl). This Formula (Vl) ester is converted to the Formula (I) compound by acidic hydrolysis, for example, using 4.0 M HCI in dioxane.

Reaction Scheme 1

nyl

(Vl)

Compounds of Formula (V) where R¹ is -C(O)W or -C(O)NHX are prepared from the compound of Formula (IV) under the conditions described in Reaction Scheme 2 and designated as Methods F and G, respectively. In Method F, the aminoester of Formula (IV) is N-acylated with an acid chloride [R¹CI, where R¹ is WC(O)-], generally in the presence of a base such as triethylamine and in solvent such as THF. In Method G, Formula (IV) compound is treated with an isocyanate of formula XNCO, generally at ambient temperature in an inert solvent such as THF, to produce a Formula (V) compound where R¹ is X- NHC(O)-]. The Formula (V) compound can then be used to prepare the corresponding compound of Formula (I) using Methods C or E, as described in Reaction Scheme 1 , above. Reaction Scheme 2

Method F or Method G

R¹ = -C(O)W R¹ = -C(O)NHX

WC(O)CI or X-NCO

TEA THF

THF

Compounds of Formula (I) where the R is naphthyl, thienyl, naphthyl, benzofuranyl, benzothiophenyl, or an optionally substituted phenyl group, can be prepared from compounds of Formula (VII), as illustrated in Reaction Scheme 3. Using the conditions designated as Method H, the R group is introduced by a palladium-catalyzed coupling reaction of the bromo substituted compound of Formula (VII) with a boronic acid derivative, for example, R-B(OH)₂, in the presence of a Pd catalyst, such as PdCI₂(dppf), and a mild base such as NaHCO₃, to produce the intermediate of Formula (V). The Formula (V) compound can then be used to prepare the corresponding compound of Formula (I) using Methods C or E, as described in Reaction Scheme 1 , above.

Reaction Scheme 3

The following specific preparative examples are presented to illustrate the invention, but they should not be construed as limiting the scope of the invention in any way.

General Experimental Procedures Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 μM coating; 30 m x 0.25 mm). The ion source was maintained at 250 ⁰C and spectra were scanned from 50-800 amu at 2 sec per scan.

High pressure liquid chromatography-electrospray mass spectra (LC-MS) were obtained using either a:

(A) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes, or (B) Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215

Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2 x 23mm, 120 A), and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. Spectra were scanned from 120-800 amu over 1.5 seconds. ELSD (Evaporative Light Scattering Detector) data was also acquired as an analog channel. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018%

TFA. Gradient elution from 10% B to 90% over 3.5 minutes at a flowrate of 1.5 mL/min was used with an initial hold of 0.5 minutes and a final hold at 90% B of 0.5 minutes. Total run time was 4.8 minutes. An extra switching valve was used for column switching and regeneration. Routine one-dimensional NMR spectroscopy was performed on 300 MHz Varian

Mercury-plus spectrometers. The samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs, and transferred to 5mm ID Wilmad NMR tubes. The spectra were acquired at 293 K. The chemical shifts were recorded on the ppm scale and were referenced to the appropriate solvent signals, such as 2.49 ppm for DMSO-c/₆, 1.93 ppm for CD₃CN, 3.30 ppm for CD₃OD, 5.32 ppm for CD₂CI₂ and 7.26 ppm for CDCI₃ for ¹H spectra, and 39.5 ppm for DMSO-Cf₆, 1.3 ppm for CD₃CN, 49.0 ppm for CD₃OD, 53.8 ppm for CD₂CI₂ and 77.0 ppm for CDCI₃ for ¹³C spectra.

The Methods A-G generally described in Reaction Schemes 1 ,2 and 3 are described in the specific procedures found in the following Examples and Steps: Method A: Example 1, Step 1

Method B: Example 1, Step 2 Method C: Example 1 , Step 3 Method D: Example 2, Step 2 Method E: Example 2, Steps 3 and 4 Method F: Example 3, Step 2

Method G: Example 4, Step 1 Method H: Example 5, Step 3

Preparative Sequence. The compounds in Table I that have data in the TLC and/or LC MS columns (columns 3 and 4) of Table I were prepared using the methods analogous to those described in the Specific Experimental Procedures section below by following the sequence listed in the "Preparative Sequence" column (column 5) of Table I, and by substituting appropriate starting materials or other reagents as would be obvious to one to skilled in the art. For example, an entry of "A, F, C" in the Preparative Sequence column of Table I indicates that the preparation route started with General Method A, followed by General Method F, then followed by general Method C. In general, each reaction was monitored by TLC and stopped when conversion to products had occurred.

The compounds without data in the TLC and/or LC MS columns may be prepared using the methods analogous to those described in the Specific Experimental Procedures section below and as noted in the Preparative Sequence column, by substituting the appropriate starting materials or other intermediate reagents, also as would be obvious to one skilled in the art. Specific Experimental Procedures

Example 1

Preparation of Λ/-Hvdroxy-7-ri H-indol-5-yl(2-thienylsulfonyl)amino]heptanarnide

Step 1 : Preparation of Ethyl 7-(1/-/-indol-5-ylamino)heptanoate

A mixture of 5-aminoindole (6.22 g, 47.1 mmol), ethyl 7-bromoheptanoate (8.59 g, 46.2 mmol) and potassium carbonate (10.0 g, 72.4 mmol) in 100 ml_ of anhydrous DMF was heated with stirring under argon at 65 ⁰C for 5 h. The reaction mixture was diluted with ether, filtered through Celite^®, the Celite^® was rinsed down with additional ether and the combined filtrate was evaporated in vacuo at up to 50 °C to solvents. The dark oily residue was chromatographed in several portions on a Flash 40 Biotage silica gel column using EtOAc/hexane (25:75) as eluent to yield 5.25 g (50.3%) of pure product.

Step 1 of Example 1 constitutes General Method A for the preparation of aminoester intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples.

Step 2: Preparation of Ethyl 7-ri/-/-lndol-5-yl(2-thienylsulfonyl)aminolheptanoate

A solution of ethyl 7-(1H-indol-5-ylamino)heptanoate (3.05 g, 10.58 mmol), 2- thiophenesulfonyl chloride (2.12 g, 11.6 mmol) and 4-dimethylaminopyridine (2.58 g, 21.2 mmol) in 100 ml_ of anhyd dichloromethane was heated under argon at 50 ⁰C for 14.25 h and then cooled. The resulting reaction mixture was washed first with 2 N HCI, then water, and finally saturated aqueous sodium bicarbonate. The extract was then dried over MgSO4, evaporated in vacuo and the residue was chromatographed on a Biotage flash 40 silica gel column to yield 4.0 g (87%) of pure product.

Step 2 of Example 1 constitutes General Method B for the preparation of sulfonamide intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples. Step 3: Preparation of /V-Hvdroxy-7-HH-indol-5-yl(2-thienylsulfonyl)aminolheptanamide

A solution of hydroxylamine hydrochloride (5.76 g, 82.8 mmol) in 40 ml_ of MeOH was stirred as potassium hydroxide (9.11 g, 138 mmol) was added resulting in a thick slurry. This slurry was added to a solution of ethyl 7-[1 H-indol-5-yl(2- thienylsulfonyl)amino]heptanoate (4.00 g, 9.20 mmol) in 100 ml. of MeOH which was stirred under argon at ambient temperature overnight. The resulting mixture was filtered and the solid was washed with methanol and then the filtrate containing crude product was evaporated in vacuo and chromatographed in three portions on a Biotage flash 40 silica gel column using 5% MeOH in dichloromethane. The yield of pure title compound Λ/-hydroxy-7- [1/-/-indol-5-yl(2-thienylsulfonyl)amino]heptanamide was 2.6 g which formed a hard foam upon pumping under high vacuum: LC-MS [M+H]⁺ 422, RT 2.49 min; ¹H-NMR (DMSO-Cf₆) δ

11.2 (s, 1 H), 10.3 (s, 1 H), 8.6 (s, 1H), 7.95 (d, 1H), 7.3-7.5 (m, 3H), 7.2 (m, 2H), 6.7 (d, 1H), 6.4 (s, 1H), 3.5 (m, 2H), 1.9 (m, 2H) and 1.1-1.5 ppm (m, 8H).

Step 3 of Example 1 constitutes General Method C for the preparation of final hydroxamic acids of this invention as indicated in the table of all Examples. Example 2

Preparation of Benzyl 7-(hvdroxyamino)-7-oxoheptylf4-(1-piperidinvπphenyl1carbamate

Step 1 : Preparation of Ethyl 7-([4-(1-piperidinvπphenyllamino>heptanoate

To a mixture of 4-(1-piperidino)aniline (4 g, 22.68 mmol), potassium carbonate

(12.55 g, 90.77 mmol) and potassium iodide (0.753 g, 4.54 mmol) in absolute EtOH (80 mL) was added dropwise ethyl-7-bromoheptanoate (4.56 mL, 22.69 mmol). The reaction mixture was heated at reflux under argon for 4 h. After cooling to rt, the mixture was filtered to remove solids. The filtrate was concentrated by rotary evaporation and the resulting crude residue was purified by column chromatography using 25:75 v/v EtOAc-hexane as eluent to give the title compound (1.8 g, yield 23%) as a brown oil. TLC R_f=0.7 (40:60 v/v EtOAc- hexane), LC-MS 332 [M]⁺.

Step 2: Preparation of Ethyl 7-(f(Benzyloxy)carbonyn[4-(1-piperidinyl)phenyllamino) heptanoate

To a solution of ethyl 7-{[4-(1-piperidinyl)phenyl]amino}heptanoate (1.34 g, 4.02 mol) and triethylamine (0.56 mL, 4.02 mmol) in THF (30 mL) was added, dropwise, benzyl chloroformate (0.66 mL, 4.42 mmol). After addition, the mixture was stirred at rt under argon for 18 h. TLC showed complete conversion. The mixture was filtered to give a brown solution, which was concentrated by rotary evaporation to give the title compound (1.8 g, yield 95%). TLC R_f =0.80 (10:90 v/v EtOAc-hexane), LC-MS 466 [M]⁺, 467 [M+H]⁺.

Step 2 of Example 2 constitutes General Method D for the preparation of carbamate intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples

Step 3: Preparation of Benzyl 7-Oxo-7-r(tetrahvdro-2/-/-pyran-2-yloxy)aminolheptylf4-(1- piperidinvPphenvUcarbamate

A mixture of ethyl 7-{[(benzyloxy)carbonyl][4-(1-piperidinyl)phenyl]amino} heptanoate (0.500 g, 1.07 mmol) and (O-(tetrahydro-2/-/-pyran-2-yl)hydroxylamine (0.489 g, 4.18 mmol) in CH₂CI₂ anhydrous (15 mL) was stirred at rt for 30 min before 2.0 M trimethylaluminum (2.09 mL, 4.18 mmol) was added dropwise. After being stirred for 7 h, the reaction mixture was quenched carefully by addition of phosphate buffer (pH=7, 15 mL) and extracted with CH₂CI₂ (3x20 mL). The combined extracts were dried (Na₂SO₄), evaporated and purified on column chromatography with 5:95 v/v MeOH-CH₂CI₂ to give the title compound (0.350 g, yield 60.4%). TLC R_f =0.28 (5:95 v/v EtOAc-hexane), LC-MS 537[M]⁺, 538 [M+H]⁺. Step 4: Preparation of Benzyl 7-(Hvdroxyamino)-7-oxoheptvir4-(1-piperidinyl)phenvπ- carbamate

Benzyl 7-oxo-7-[(tetrahydro-2H-pyran-2-yloxy)amino]heptyl[4-(1- piperidinyl)phenyl]carbamate (258 mg, 0.48 mmol) was treated with 4.0 M hydrogen chloride in 1 ,4-dioxane (7.6 mL). After stirring at ambient temperature for 1.5 h, the solvent was evaporated to give a brown residue, which was dissolved in CH₂CI₂ and washed with saturated aq NaHCO₃. The organic solution was dried over Na₂SO₄, and purification on preparative TLC plate with 7:93 MeOH-CH₂CI₂ afforded the title compound (50 mg, yield 23%). TLC R_f =0.2 (5:95 v/v MeOH-CH₂CI₂), LC-MS 453 [M]⁺, 454 [M+H]⁺; ¹H-NMR (Acetone-c/e) δ 7.2-7.4 (m, 5H), 7.15 (d, 2H), 6.9 (d, 2H), 5.1 (s, 2H), 3.6 (m, 2H), 3.1 (m, 4H), 2.1 (m, 2H under solvent/water peaks) and 1.2-1.7 ppm (m, 14H). Steps 3 and 4 of Example 2 constitutes General Method E for the preparation of final hydroxamic acids of this invention as indicated in the table of all Examples.

Example 3

Preparation of /V-r7-(hvdroxyaminoV7-oxoheptvπ-Λ/-(4-metho^χyphenyl)-2- thiophenecarboxamide

Step 1 : Preparation of Ethyl 7-f(4-Methoxyphenyl)aminolheptanoate

Ethyl 7-[(4-methoxyphenyl)amino]heptanoate was prepared from 4-methoxyaniline and ethyl 7-bromoheptanoate using General Method A as described in Example 1 , Step 1 above.

Step 2: Preparation of Ethyl 7-[(4-Methoxyphenyl)(2-thienylcarbonyl)amino1heptanoate

A mixture of ethyl 7-[(4-methoxyphenyl)amino]heptanoate (0.5 g, 1.79 mmol), TEA (0.36 g, 3.58 mmol), and 2-thiophenecarbonyl chloride (0.34 g, 2.32 mmol) in anhyd THF was stirred overnight at rt. The resulting white precipitate was filtered, and the filtrate was concentrated in vacuo. The crude product was purified on a silica gel column using 5 to 50% ethyl acetate in hexanes as eluent to give desired product (0.64 g, 91%).

Step 2 of Example 3 constitutes General Method F for the preparation of amide intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples.

Step 3: Preparation of ΛM7-(hvdroxyaminoV7-oxoheptyπ-/V-(4-methoχyphenvO-2- thiophenecarboxamide

The above product of Step 2 was converted to the title compound using General Method C as found in Example 1 , Step 3 and purified either on a Biotage flash 40 silica column as in Example 1 or by reverse phase chromatography on C18 columns from YMC using gradient elution from 10 to 90 % acetonitrile in water with 0.5% trifluoroacetic acid.

Example 4 Preparation of 7-rr(Benzylamino)carbonvN(4-methoxyphenv0amino1-/V-hvdroχyheptanamide

Step 1: Preparation of Ethyl 7-rr(Benzylamino)carbonyll(4-rnethoxyphenv0aminolheptanoate

A mixture of ethyl 7-[(4-methoxyphenyl)amino]heptanoate (0.1 g, 0.36 mmol) and benzyl isocyanate (0.07 g, 0.54 mmol) in THF (4 ml_)was stirred overnight at rt. The crude product, which was a single spot by TLC, was isolated by concentration of solvent in vacuo and used in the final step without further purification. Step 1 of Example 4 constitutes General Method G for the preparation of urea intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples.

Step 2: Preparation of 7-rr(Benzylaminotoarbonyll(4-methoxyphenvnaminoy/V- hvdroxyheptanamide

The above product of Step 1 was converted to the title compound using General Method C as found in Example 1 , Step 3 and purified as described above in Example 3.

Example 5 Preparation of 7-rr4-(1-benzofuran-2-vl)phenvπ(2-thienvlsulfonvDarnino1-Λ/- hydroxyheptanamide

Step 1 : Ethyl 7-[(4-bromophenyl)amino]heptanoate was prepared from 4- bromoaniline and ethyl 7-bromoheptanoate using General Method A as described in Example 1 , Step 1 above.

Step 2: This material was then converted to ethyl 7-[(4-bromophenyl)(2- thienylsulfonyl)amino]heptanoate using General Method B as described in Example 1, Step 2.

Step 3: A mixture of ethyl 7-[(4-bromophenyl)(2-thienylsulfonyl)amino]heptanoate (103 mg, 0.22 mmol), benzofuran-2-boronic acid (53 mg, 0.33 mmol), and NaHCO₃ (55 mg,

0.65 mmol) in DME/H₂O was degassed with argon for 10 min. PdCI₂(dppf) was added to the reaction mixture and the resulting solution was heated to reflux overnight. The reaction mixture was cooled and concentrated and the crude product was purified on silica gel column using 20% ethyl acetate/hexanes as eluent. Step 3 of Example 5 constitutes General Method H for the preparation of biaryl intermediates used in the synthesis of various compounds of this invention as indicated in the table of all Examples.

Step 4: The product of Step 3 was converted to the title compound using General Method C as described in Example 1 , Step 3.

Other compounds identified in Table 1 were made using General Methods A - H as described above in examples 1 - 5 by substituting appropriate chemical matter as required, as would be apparent to one skilled in the art.

Salts of the compounds identified herein can be obtained by isolating the compounds as hydrochloride salts, prepared by treatment of the free base with anhydrous

HCI in a suitable solvent such as THF. Generally, a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art. Or, a desired salt can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. These methods are conventional and would be readily apparent to one skilled in the art.

Carbonates of this invention in general may be made by conventional methods well known in the art. For example, the hydroxyl group of the hydroxamic acid moiety of a compound of Formula I may be converted to a carbonate by reacting the compound with, for example, an alkyl haloformate such as ethyl chloroformate in the presence of a base.

O-Acylated derivatives of this invention in general may be made by conventional methods well known in the art. For example, the hydroxyl group of the hydroxamic acid moiety of a compound of Formula I may be converted to an O-acylated derivative by reacting the compound with an acyl halide or anhydride, such as acetyl chloride or benzoic anhydride and the like, in the presence of a base such as triethylamine.

Such methods would be initiated either after synthesis of the desired compound or at another place in the synthetic route that would be readily apparent to one skilled in the art.

Additionally, sensitive or reactive groups on the compound of this invention may need to be protected and deprotected during any of the above methods. Protecting groups in general may be added and removed by conventional methods well known in the art (see, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999). Compositions of the compounds of this invention

The compounds and prodrugs of this invention can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. The present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, prodrug, or salt thereof, of the present invention. A pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, otically, sublingually, rectally, vaginally, and the like.

For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present. The pharmaceutical compositions of this invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as sόy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin. Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1-dioxolane-4-methanol, ethers such as poly( ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants. Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.

The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca- ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

In one embodiment, the invention relates to intravenous (i.v.) application of the active compound, e.g. as bolus injection (that is as single dose, e.g. per syringe), infusion over a short period of time (e.g. for up to one hour) or infusion over a long period of time

(e.g. for more than one hour). The application can also be done by intermittent dosing. The applied volume can vary dependent on the conditions and usually is 0.5 to 30, preferably 1 to 20 ml for bolus injection, 25 to 500, preferably 50 to 250 ml for infusion over a short period of time and 50 to 1000, preferably 100 to 500 ml for infusion over a long period of time.

The application forms have to be sterile and free of pyrogens. They can be based on aqueous solvents or mixtures of aqueous and organic solvents. Examples are ethanol, polyethyleneglycol (PEG) 300 or 400, aqueous solutions containing cyclodextrins or emulsifiers, such as lecithin, Pluronic F68®, Solutol HS15® or Cremophor®. Aqueous solutions are preferred.

For intravenous application the solutions are generally isotonic and euhydric, for example with a pH of 3 to 11 , preferably 6 to 8 and most preferred about 7.4. Glass or plastic containers can be employed as packaging for i.v.-solutions, e.g. rubber seal vials. They can contain liquid volumes of 1 to 1000, preferably 5 to 50 ml. The solution can directly be withdrawn from the vial to be applied to the patient. For this purpose, it can be advantageous to provide the active compound in solid form (e.g. as lyophilisate) and dissolve by adding the solvent to the vial directly before administration. Solutions for infusion can advantageously be packaged in containers made from glass or plastic, for example bottles or collapsible containers such as bags. They can contain liquid volumes of 1 to 1000, preferably 50 to 500 ml. A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such material are, for example, cocoa butter and polyethylene glycol.

Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued

June 11, 1991, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations which are known in the art. It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011 ,472, issued April 30, 1991.

The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M. F. et al, "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics

Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al, "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171. Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples.include but are not limited to carbon dioxide, CCI₂F₂, F₂CIC-CCIF₂ and CCIF₃) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene- butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerol); solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono- palmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

It is believed that one skilled in the art, using the preceding information, can utilize the present invention to its fullest extent. Nevertheless, the following are examples of pharmaceutical formulations that can be used in the composition of the present invention. They are for illustrative purposes only, and are not to be construed as limiting the invention in any way.

Pharmaceutical compositions according to the present invention can be illustrated as follows:

Intravenously administrable solution 1:

Composition: 100-200 mg of the compound of Example 1 , 15 g polyethylenglykol 400 and 250-g water, in saline optionally with up to 15 % Cremophor EL, and optionally up to 15% ethyl alcohol, and optionally up to 2 equivalents of a pharmaceutically suitable acid such as lactic acid, citric acid or hydrochloric acid.

Preparation:

The compound of Example 1 and the polyethylenglykol 400are dissolved in the water with stirring. The solution is sterile filtered (pore size 0.22 μm) and filled into heat sterilized infusion bottles under aseptical conditions. The infusion bottles are being sealed with rubber seals.

Intravenously administrable solution 2: Composition: 100-200 mg of the compound of Example 1 , saline solution, optionally with up to 15 % by weight of Cremophor EL, and optionally up to 15% by weight of ethyl alcohol, and optionally up to 2 equivalents of a pharmaceutically suitable acid such as lactic acid, citric acid or hydrochloric acid.

Preparation:

The compound of Example 1 is dissolved in the saline solution with stirring. Optionally Cremophor EL, ethyl alcohol or acid are added. The solution is sterile filtered (pore size 0.22 μm) and filled into heat sterilized infusion bottles under aseptical conditions. The infusion bottles are being sealed with rubber seals

Intravenously administrable solution 3:

A 5 mg/mL solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over 60 minutes. Lvophilized powder for IV administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 min.

Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN 80 9 mg/mL sodium chloride 9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two- piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.

Method of treating hvper-proliferative disorders

The present invention relates to a method of using the compounds described above, including salts and esters thereof and corresponding compositions thereof, to treat mammalian hyper-proliferative disorders. This method comprises administering to a patient an amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, which is effective to treat the patient's hyper-proliferative disorder. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular hyper-proliferative disorder. Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.

Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal / nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.

The utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below. The link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art. For example, the therapeutic utility of taxol (Silvestrini et al. Stem Cells 1993, 11(6), 528-35), taxotere (Bissery et al. Anti Cancer Drugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al. Cancer Chemother. Pharmacol. 1996, 37(5), 385-93) was demonstrated with the use of in vitro tumor proliferation assays.

The following assay is one of the methods by which compound activity relating to treatment of the disorders identified herein can be determined.

In vitro tumor cell proliferation assay

The adherent tumor cell proliferation assay used to test the compounds of the present invention involves a readout called Cell Titre-Glo developed by Promega (Cunningham, BA "A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth" The Scientist 2001 , -/5(13), 26, and Crouch, SP et al., "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity" Journal of

Immunological Methods 1993, 160, 81-88). HCT116 cells (colon carcinoma, purchased from ATCC) or A549 (lung carcinoma, purchased from ATCC) are plated in 96-well plates at 3000 cells/well in complete media with 10% Fetal Calf Serum and incubated 24 h at 37 ⁰C. Twenty-four h after plating, test compounds are added over a final concentration range of 10 nM to 20 μM in serial dilutions at a final DMSO concentration of 0.2 %. Cells are incubated for 72 h at 37 ⁰C in complete growth media after addition of the test compound. On day 4, using a Promega Cell Titer GIo Luminescent^® assay kit, the cells are lysed and 100 microliters of substrate/buffer mixture is added to each well, mixed and incubated at room temperature for 8 min. The samples are read on a luminometer to measure the amount of ATP present in the cell lysates from each well, which corresponds to the number of viable cells in that well. Values read at 24 h incubation are subtracted as Day 0. For determination of IC50's, a linear regression analysis can be used to determine drug concentration which results in a 50% inhibition of cell proliferation using this assay format. Representative compounds of this invention, as shown in the table below, showed a significant inhibition of tumor cell proliferation in the assays with HCT116 cells and representative compounds were also studied with the A549 cells and found to be active.

MDA-MB-231 (breast adenocarcinoma, purchased from ATCC), LnCaP (prostate carcinoma, purchased from ATCC)₁ H460 (lung carcinoma, purchased from ATCC), or HeIa (cervix adenocarcinoma) cells can also be used in similar assays. Based upon the above and other standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from

0.01 to 200 mg/kg. The daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof. Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11^th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6- mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine. Other anti-hyper-proliferative agents suitable for use with this invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2', 2'- difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5- fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, Λ/-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine. Other anti- hyper-proliferative agents suitable for use with this invention include but are not limited to other anti-cancer agents such as epothilone, irinotecan, raloxifen and topotecan.

It is believed that one skilled in the art, using the preceding information, can utilize the present invention to its fullest extent.

It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein.

Claims

Claims

1. A compound of formula (I)

(D wherein

Ar is selected from phenyl, 3-quinolyl, 5-indolyl, and 5-indazolyl; R is selected from H,

O-(C-ι-C₆)alkyl, thienyl, naphthyl, benzofuranyl, benzothiophenyl,

— N V

, and phenyl optionally substituted with up to 3 substituents each selected independently from (CrC₄)alkyl, O-(C_rC₆)alkyl, and CF₃; R¹ is selected from H, C(O)W, C(O)NHX, and S(O)₂Y; V is selected from NH, O and CH₂, and when V is NH, N can be optionally substituted with (C_rC₄)alkyl; W is selected from

(Ci~C₈)alkyl optionally substituted with Z, (C₃-C₆)cycloalkyl, O-(C_rC₄)alkylphenyl,

O-(C_rC₄)alkyl, naphthyl, thienyl, furyl, benzothienyl, phenyl optionally substituted with up to 3 substituents each independently selected from (C_rC₄)alkyl, O-(C_rC₄)alkyl, S-(C_rC₄)alkyl, halo, CF₃, 0-CF₃, phenyl, O-phenyl, and O-(d-C₄)alkyl-phenyl, and isoxazolyl optionally substituted with up to 2 independently selected (C-ι-C₄)alkyl groups; X is selected from

(C-ι-C₈)alkyl optionally substituted with Z, (C₃-C₆)cycloalkyl, naphthyl, thienyl, furyl, benzothienyl, phenyl optionally substituted with up to 3 substituents each independently selected from (C_rC₄)alkyl, O-(C_rC₄)alkyl, S-(C_rC₄)alkyl, halo, CF₃, 0-CF₃, phenyl, O-phenyl, O-(C_rC₄)alkyl-phenyl, NHC(O)(C₁-C₄)alkyl, and N[(C_rC₄)alkyl]₂, and isoxazolyl optionally substituted with up to 2 independently selected (CrC₄)alkyl groups; Y is selected from

(C_rC₈)alkyl optionally substituted with Z, (C₃-C₆)cycloalkyl, naphthyl, thienyl, furyl, benzothienyl, phenyl optionally substituted with up to 3 substituents each independently selected from (C_rC₄)alkyl, O-(CrC₄)alkyl, S-(C_rC₄)alkyl, halo, CF₃, 0-CF₃, phenyl, O-phenyl, O-(C_rC₄)alkyl-phenyl, NHC(O)(C_rC₄)alkyl, and N[(C_rC₄)alkyl]₂ where each alkyl group is selected independently from the other, and ^' isoxazolyl optionally substituted with up to 2 independently selected (C₁-C₄)alkyl groups; Z is selected from naphthyl, O-phenyl, O-(C_rC₄)alkyl, and phenyl optionally substituted with up to 2 substituents each independently selected from (Ci-C₄)alkyl, halo and phenyl, or a pharmaceutically acceptable salt, carbonate or an O-acylated derivative thereof.

2. The compound of Claim 1, wherein

W is selected from

(C₃-C₆)cycloalkyl, O-(C_rC₄)alkylphenyl, naphthyl, thienyl, furyl, benzothienyl,

(C-ι-C₈)alkyl optionally substituted with Z, oxazolyl optionally substituted with up to 2 substituents each selected independently from (CrC₄)alkyl, and phenyl optionally substituted up to 2 substituents each selected independently from (C_rC₄)alkyl, O-(C₁-C₄)alkyl, halo, CF₃, phenyl, and N[(C_rC₄)alkyl]₂; X is selected from (C_rC₄)alkyl,

(C_rC₄)alkylphenyl, naphthyl, cyclohexyl, and phenyl optionally substituted with up to 3 substituents each selected independently from phenyl, O-phenyl, O-(C_rC₄)alkyl,

S-(C_rC₄)alkyl, halo, CF₃, and N[(C_rC₄)alkyl]₂; Y is selected from naphthyl, thienyl, and phenyl optionally substituted with up to 2 substituents each selected independently from (C_rC₄)alkyl, O-(C_rC₄)alkyl, halo, CF₃, OCF₃, phenyl and NHC(O)(C_rC₄)alkyl; and Z is selected from

O-(C_rC₄)alkyl, O-phenyl, naphthyl, and phenyl optionally substituted with up to 2 substituents each independently selected from (C_rC₄)alkyl, halo, and phenyl; or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1, wherein W is selected from

(C₃-C₄)cycloalkyl, naphthyl, thienyl, furyl, benzothienyl,

(C-ι-C₂)alkyl optionally substituted with Z, and phenyl optionally substituted up to 2 substituents each selected independently from (Ci-C₂)alkyl, O-(CrC₂)alkyl, halo, CF₃, phenyl, and N[(CrC₂)alkyl]₂; X is selected from (C_rC₄)alkyl, (C₁-C₂)alkylphenyl, naphthyl, cyclohexyl, and phenyl optionally substituted with up to 3 substituents each selected independently from phenyl, O-phenyl, O-(CrC₂)alkyl, S-(C_rC₂)alkyl, halo, CF₃, and N[(C_rC₂)alkyl]₂; Y is selected from naphthyl, thienyl, and phenyl optionally substituted with up to 2 substituents each selected independently from (C-ι-C₂)alkyl, O-(C_rC₂)alkyl, halo, CF₃, OCF₃, phenyl and

NHC(O)(C_rC₂)alkyl; and Z is selected from

O-(C_rC₂)alkyl, O-phenyl, naphthyl and phenyl optionally substituted with up to 2 substituents each independently selected from

halo, and phenyl; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R¹ represents S(O)₂Y.

5. The compound of claim 1 wherein R¹ represents S(O^Y and Y is thieπyl.

6. The compound of claim 1 wherein R¹ represents C(O)W.

7. The compound of claim 1 wherein R¹ represents C(O)W and W is thienyl or benzothieπyi.

8. The compound of claim 1 wherein Ar is phenyl.

9, The compound of claim 1 whsreiπ Ar is 5-indolyl.

10. A process for making a compound of claim 1, wherein

[A] a compound of formula (V)

is reacted with hydroxylamine hydrochloride, or

[B] a compound of formula (V)

is in a first step reacted with a protected hydroxylamine, and in a second step is deprotectad.

11. The process of claim 10 wherein in said protected hydroxylamine is (O-(tetrahydro-2/^ pyran-2-yl)hydroxylamine.

12. The compound of claim 1 for the treatment and/or prophylaxis of disorders.

13. A pharmaceutical composition comprising a compound according to claim 1.

14. A pharmaceutical composition comprising a compound of claim 1 in combination with at least one pharmaceutically acceptable, pharmaceutically safe carrier or excipient.

15. A process for preparing the pharmaceutical composition of claim 14, comprising combining at least one compound of claim 1 with at least one pharmaceutically acceptable, pharmaceutically safe carrier or excipient, mixing the combination and bringing the combination into a suitable administration form.

16. The use of a compound according to claim 1 for manufacturing a pharmaceutical composition for the treatment and/or prophylaxis of cancer.

17. The pharmaceutical composition according to Claim 13 for the treatment and/or prophylaxis of cancer.

18. A method of treating a disease or condition in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound according to the formula

(I).