CARBONYLAMINO-DERIVATIVES AS NOVEL INHIBITORS OF HISTONE DEACETYLASE

• US 20090042920A1
• Filed: 09/19/2008
• Published: 02/12/2009
• Est. Priority Date: 03/13/2002
• Status: Active Grant

• Current Assignee: Kristof Van Emelen, Leo Jacobus Jozef Backx, Marc Gustaaf Celine Verdonck, Sven Franciscus Anna Van Brandt
• Original Assignee: Kristof Van Emelen, Leo Jacobus Jozef Backx, Marc Gustaaf Celine Verdonck, Sven Franciscus Anna Van Brandt
• Inventors: Van Emelen, Kristof, Verdonck, Marc Gustaaf Celine, Van Brandt, Sven Franciscus Anna, Backx, Leo Jacobus Jozef
• Granted Patent: US 8,071,615 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/402 1-aryl substituted, e.g. piretanide
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/472 Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 : Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 : Antipruritics
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 17/10 : Anti-acne agents
• CPC Class Codes: A61P 17/14 : for baldness or alopecia
• CPC Class Codes: A61P 17/16 : Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 207/09 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 207/14 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 213/78 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 217/02 : with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/16 : substituted by oxygen atoms
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: C12Q 1/34 : involving hydrolase
• CPC Class Codes: C12Q 1/48 : involving transferase
• CPC Class Codes: G01N 2333/98 : acting on amide bonds in linear amides (3.5.1)
• CPC Class Codes: G01N 33/573 : for enzymes or isoenzymes

Abstract

This invention comprises the novel compounds of formula (I)

wherein n, m, t, R¹, R², R³, R⁴, R⁵, L, Q, X, Y and

have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

Claims

1-13. -13. (canceled)

14. A compound of formula (I),

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein

n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended;

m is 0 or 1 and when m is 0 then a direct bond is intended;

t is 0, 1, 2, 3 or 4 and when t is 0 then a direct bond is intended;

each Q is nitrogen or

each X is nitrogen or

each Y is nitrogen or

R¹ is —

C(O)NR⁸R⁹, —

NHC(O)R¹⁰, —

C(O)—

C_1-6alkanediylSR¹⁰, —

NR¹¹C(O)N(OH)R¹¹, —

NR¹¹C(O)C_1-6alkanediylSR¹⁰, —

NR¹¹C(O)C═

N(OH)R¹⁰ or another Zn-chelating-group wherein R⁸ and R⁹ are each independently selected from hydrogen, hydroxy, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl or aminoaryl;

R¹⁰ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, arylC_1-6alkyl, C_1-6alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl;

R¹¹ is hydrogen or C_1-6alkyl;

R² is hydrogen, halo, hydroxy, amino, nitro, C_1-6alkyl, C_1-6alkyloxy, trifluoromethyl, di(C_1-6alkyl)amino, hydroxyamino or naphthalenylsulfonylpyrazinyl;

-L- is a direct bond or a bivalent radical selected from C_1-6alkanediyl, C_1-6alkanediyloxy, amino, carbonyl or aminocarbonyl;

each R³ independently represents a hydrogen atom and one hydrogen atom can be replaced by a substituent selected from aryl;

R⁴ is hydrogen, hydroxy, amino, hydroxyC_1-6alkyl, C_1-6alkyl, C_1-6alkyloxy, arylC_1-6alkyl, aminocarbonyl, hydroxycarbonyl, aminoC_1-6alkyl, aminocarbonylC_1-6alkyl, hydroxycarbonylC_1-6alkyl, hydroxyaminocarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminoC_1-6alkyl or di(C_1-6alkyl)aminoC_1-6alkyl;

R⁵ is hydrogen, C_1-6alkyl, C_3-10cycloalkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, di(C_1-6alkyl)aminoC_1-6alkyl or aryl;

is a radical selected from

wherein each s is independently 0, 1, 2, 3, 4 or 5;

each R⁶ and R⁷ are independently selected from hydrogen;

halo;

hydroxy;

amino;

nitro;

trihaloC_1-6alkyl;

trihaloC_1-6alkyloxy;

C_1-6alkyl;

C_1-6alkyl substituted with aryl and

C_3-10cycloalkyl;

C_1-6alkyloxy;

C_1-6alkyloxyC_1-6alkyloxy;

C_1-6alkylcarbonyl;

C_1-6alkyloxycarbonyl;

C_1-6alkylsulfonyl;

cyanoC_1-6alkyl;

hydroxyC_1-6alkyl;

hydroxyC_1-6alkyloxy;

hydroxyC_1-6alkylamino;

aminoC_1-6alkyloxy;

di(C_1-6alkyl)aminocarbonyl;

di(hydroxyC_1-6alkyl)amino;

(aryl)(C_1-6alkyl)amino;

di(C_1-6alkyl)aminoC_1-6alkyloxy;

di(C_1-6alkyl)aminoC_1-6alkylamino;

di(C_1-6alkyl)aminoC_1-6alkylaminoC_1-6alkyl;

arylsulfonyl;

arylsulfonylamino;

aryloxy;

aryloxyC_1-6alkyl;

arylC_2-6alkenediyl;

di(C_1-6alkyl)amino;

di(C_1-6alkyl)aminoC_1-6alkyl;

di(C_1-6alkyl)amino(C_1-6alkyl)amino;

di(C_1-6alkyl)amino(C_1-6alkyl)aminoC_1-6alkyl;

di(C_1-6alkyl)aminoC_1-6alkyl(C_1-6alkyl)amino;

di(C_1-6alkyl)aminoC_1-6alkyl(C_1-6alkyl)aminoC_1-6alkyl;

aminosulfonylamino(C_1-6alkyl)amino;

aminosulfonylamino(C_1-6alkyl)aminoC_1-6alkyl;

di(C_1-6alkyl)aminosulfonylamino(C_1-6alkyl)amino;

di(C_1-6alkyl)aminosulfonylamino(C_1-6alkyl)aminoC_1-6alkyl;

cyano;

thiophenyl;

thiophenyl substituted with di(C_1-6alkyl)aminoC_1-6alkyl(C_1-6alkyl)aminoC_1-6alkyl, di(C_1-6alkyl)aminoC_1-6alkyl, C_1-6alkylpiperazinylC_1-6alkyl, hydroxyC_1-6alkylpiperazinylC_1-6alkyl, hydroxyC_1-6alkyloxyC_1-6alkylpiperazinylC_1-6alkyl, di(C_1-6alkyl)aminosulfonylpiperazinylC_1-6alkyl, C_1-6alkyloxypiperidinyl, C_1-6alkyloxypiperidinylC_1-6alkyl, morpholinylC_1-6alkyl, hydroxyC_1-6alkyl(C_1-6alkyl)aminoC_1-6alkyl, or di(hydroxyC_1-6alkyl)aminoC_1-6alkyl;

furanyl;

furanyl substituted with hydroxyC_1-6alkyl;

benzofuranyl;

imidazolyl;

oxazolyl;

oxazolyl substituted with aryl and C_1-6alkyl;

C_1-6alkyltriazolyl;

tetrazolyl;

pyrrolidinyl;

pyrrolyl;

piperidinylC_1-6alkyloxy;

morpholinyl;

C_1-6alkylmorpholinyl;

morpholinylC_1-6alkyloxy;

morpholinylC_1-6alkyl;

morpholinylC_1-6alkylamino;

morpholinylC_1-6alkylaminoC_1-6alkyl;

piperazinyl;

C_1-6alkylpiperazinyl;

C_1-6alkylpiperazinylC_1-6alkyloxy;

piperazinylC_1-6alkyl;

naphtalenylsulfonylpiperazinyl;

naphtalenylsulfonylpiperidinyl;

naphtalenylsulfonyl;

C_1-6alkylpiperazinylC_1-6alkyl;

C_1-6alkylpiperazinylC_1-6alkylamino;

C_1-6alkylpiperazinylC_1-6alkylaminoC_1-6alkyl;

C_1-6alkylpiperazinylsulfonyl;

aminosulfonylpiperazinylC_1-6alkyloxy;

aminosulfonylpiperazinyl;

aminosulfonylpiperazinylC_1-6alkyl;

di(C_1-6alkyl)aminosulfonylpiperazinyl;

di(C_1-6alkyl)aminosulfonylpiperazinylC_1-6alkyl;

hydroxyC_1-6alkylpiperazinyl;

hydroxyC_1-6alkylpiperazinylC_1-6alkyl;

C_1-6alkyloxypiperidinyl;

C_1-6alkyloxypiperidinylC_1-6alkyl;

piperidinylaminoC_1-6alkylamino;

piperidinylaminoC_1-6alkylaminoC_1-6alkyl;

(C_1-6alkylpiperidinyl)(hydroxyC_1-6alkyl)aminoC_1-6alkylamino;

(C_1-6alkylpiperidinyl)(hydroxyC_1-6alkyl)aminoC_1-6alkylaminoC_1-6alkyl;

hydroxyC_1-6alkyloxyC_1-6alkylpiperazinyl;

hydroxyC_1-6alkyloxyC_1-6alkylpiperazinylC_1-6alkyl;

(hydroxyC_1-6alkyl)(C_1-6alkyl)amino;

(hydroxyC_1-6alkyl)(C_1-6alkyl)aminoC_1-6alkyl;

hydroxyC_1-6alkylaminoC_1-6alkyl;

di(hydroxyC_1-6alkyl)aminoC_1-6alkyl;

pyrrolidinylC_1-6alkyl;

pyrrolidinylC_1-6alkyloxy;

pyrazolyl;

thiopyrazolyl;

pyrazolyl substituted with two substituents selected from C_1-6alkyl or trihaloC_1-6alkyl;

pyridinyl;

pyridinyl substituted with C_1-6alkyloxy, aryloxy or aryl;

pyrimidinyl;

tetrahydropyrimidinylpiperazinyl;

tetrahydropyrimidinylpiperazinylC_1-6alkyl;

quinolinyl;

indole;

phenyl;

phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, C_1-6alkyl, C_1-6alkyloxy, hydroxyC_1-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC_1-4alkyloxy, C_1-4alkylsulfonyl, C_1-4alkyloxyC_1-4alkyloxy, C_1-4alkyloxycarbonyl, aminoC_1-4alkyloxy, di(C_1-4alkyl)aminoC_1-4alkyloxy, di(C_1-4alkyl)amino, di(C_1-4alkyl)aminocarbonyl, di(C_1-4alkyl)aminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)amino(C_1-4alkyl)amino, di(C_1-4alkyl)amino(C_1-4alkyl)aminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl(C_1-4alkyl)amino, di(C_1-4alkyl)aminoC_1-4alkyl(C_1-4alkyl)aminoC_1-4alkyl, aminosulfonylamino(C_1-4alkyl)amino, aminosulfonylamino(C_1-4alkyl)aminoC_1-4alkyl, di(C_1-4alkyl)aminosulfonylamino(C_1-4alkyl)amino, di(C_1-4alkyl)aminosulfonylamino(C_1-4alkyl)aminoC_1-6alkyl, cyano, piperidinylC_1-4alkyloxy, pyrrolidinylC_1-4alkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC_1-4alkyl, di(C_1-4alkyl)aminosulfonylpiperazinyl, di(C_1-4alkyl)aminosulfonylpiperazinylC_1-4alkyl, hydroxyC_1-4alkylpiperazinyl, hydroxyC_1-4alkylpiperazinylC_1-4alkyl, C_1-4alkyloxypiperidinyl, C_1-4alkyloxypiperidinylC_1-4alkyl, hydroxyC_1-4alkyloxyC_1-4alkylpiperazinyl, hydroxyC_1-4alkyloxyC_1-4alkylpiperazinylC_1-4alkyl, (hydroxyC_1-4alkyl)(C_1-4alkyl)amino, (hydroxyC_1-4alkyl)(C_1-4alkyl)aminoC_1-4alkyl, di(hydroxyC_1-4alkyl)amino, di(hydroxyC_1-4alkyl)aminoC_1-4alkyl, furanyl, furanyl substituted with —

CH═

CH—

CH═

CH—

, pyrrolidinylC_1-4alkyl, pyrrolidinylC_1-4alkyloxy, morpholinyl, morpholinylC_1-4alkyloxy, morpholinylC_1-4alkyl, morpholinylC_1-4alkylamino, morpholinylC_1-4alkylaminoC_1-4alkyl, piperazinyl, C_1-4alkylpiperazinyl, C_1-4alkylpiperazinylC_1-4alkyloxy, piperazinylC_1-4alkyl, C_1-4alkylpiperazinylC_1-4alkyl, C_1-4alkylpiperazinylC_1-4alkylamino, C_1-4alkylpiperazinylC_1-4alkylaminoC_1-6alkyl, tetrahyfropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylC_1-4alkyl, piperidinylaminoC_1-4alkylamino, piperidinylaminoC_1-4alkylaminoC_1-4alkyl, (C_1-4alkylpiperidinyl)(hydroxyC_1-4alkyl)aminoC_1-4alkylamino, (C_1-4alkylpiperidinyl)(hydroxyC_1-4alkyl)aminoC_1-4alkylaminoC_1-4alkyl, pyridinylC_1-4alkyloxy, hydroxyC_1-4alkylamino, hydroxyC_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC_1-4alkyloxy, or thiophenylC_1-4alkylamino;

each R⁶ and R⁷ can be placed on the nitrogen in replacement of the hydrogen;

aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.

15. A compound as claimed in claim 14 wherein

R⁸ and R⁹ are each independently selected from hydrogen, hydroxy, hydroxyC_1-6alkyl, aminoC_1-6alkyl or aminoaryl;

R⁵ is hydrogen, C_1-6alkyl, C_3-10cycloalkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl or di(C_1-6alkyl)aminoC_1-6alkyl;

is a radical selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-27), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42) (a-43) or (a-44);

and each R⁶ and R⁷ are independently selected from hydrogen;

halo;

hydroxy;

amino;

nitro;

trihaloC_1-6alkyl;

trihaloC_1-6alkyloxy;

C_1-6alkyl;

C_1-6alkyloxy;

C_1-6alkyloxyC_1-6alkyloxy;

C_1-6alkylcarbonyl;

C_1-6alkylsulfonyl;

cyanoC_1-6alkyl;

hydroxyC_1-6alkyl;

hydroxyC_1-6alkyloxy;

hydroxyC_1-6alkylamino;

aminoC_1-6alkyloxy;

di(C_1-6alkyl)aminocarbonyl;

di(hydroxyC_1-6alkyl)amino;

arylC_1-6alkyl)amino;

di(C_1-6alkyl)aminoC_1-6alkyloxy;

di(C_1-6alkyl)aminoC_1-6alkylamino;

arylsulfonyl;

arylsulfonylamino;

aryloxy;

arylC_2-6alkenediyl;

di(C_1-6alkyl)amino;

di(C_1-6alkyl)aminoC_1-6alkyl;

di(C_1-6alkyl)aminoC_1-6alkyl(C_1-6alkyl)aminoC_1-6alkyl;

cyano;

thiophenyl;

thiophenyl substituted with di(C_1-6alkyl)aminoC_1-6alkyl(C_1-6alkyl)aminoC_1-6alkyl, di(C_1-6alkyl)aminoC_1-6alkyl, C_1-6alkylpiperazinylC_1-6alkyl or di(hydroxyC_1-6alkyl)aminoC_1-6alkyl;

furanyl;

imidazolyl;

C_1-6alkyltriazolyl;

tetrazolyl;

pyrrolidinyl;

piperidinylC_1-6alkyloxy;

morpholinyl;

C_1-6alkylmorpholinyl;

morpholinylC_1-6alkyloxy;

morpholinylC_1-6alkyl;

C_1-6alkylpiperazinyl;

C_1-6alkylpiperazinylC_1-6alkyloxy;

C_1-6alkylpiperazinylC_1-6alkyl;

C_1-6alkylpiperazinylsulfonyl;

aminosulfonylpiperazinylC_1-6alkyloxy;

aminosulfonylpiperazinyl;

aminosulfonylpiperazinylC_1-6alkyl;

di(C_1-6alkyl)aminosulfonylpiperazinyl;

di(C_1-6alkyl)aminosulfonylpiperazinylC_1-6alkyl;

hydroxyC_1-6alkylpiperazinyl;

hydroxyC_1-6alkylpiperazinylC_1-6alkyl;

C_1-6alkyloxypiperidinyl;

C_1-6alkyloxypiperidinylC_1-6alkyl;

hydroxyC_1-6alkyloxyC_1-6alkylpiperazinyl;

hydroxyC_1-6alkyloxyC_1-6alkylpiperazinylC_1-6alkyl;

(hydroxyC_1-6alkyl)(C_1-6alkyl)amino;

(hydroxyC_1-6alkyl)(C_1-6alkyl)aminoC_1-6alkyl;

pyrrolidinylC_1-6alkyloxy;

pyrazolyl;

thiopyrazolyl;

pyrazolyl substituted with two substituents selected from C_1-6alkyl or trihaloC_1-6alkyl;

pyridinyl;

pyridinyl substituted with C_1-6alkyloxy or aryl;

pyrimidinyl;

quinolinyl;

indole;

phenyl;

phenyl substituted with one, two or three substituents independently selected from halo, amino, C_1-6alkyl, C_1-6alkyloxy, hydroxyC_1-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC_1-4alkyloxy, C_1-4alkyloxyC_1-4alkyloxy, aminoC_1-4alkyloxy, di(C_1-4alkyl)aminoC_1-4alkyloxy, di(C_1-4alkyl)amino, di(C_1-4alkyl)aminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl(C_1-4alkyl)aminoC_1-4alkyl, piperidinylC_1-4alkyloxy, pyrrolidinylC_1-4alkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC_1-4alkyl, di(C_1-4alkyl)aminosulfonylpiperazinyl, di(C_1-4alkyl)aminosulfonylpiperazinylC_1-4alkyl, hydroxyC_1-4alkylpiperazinyl, hydroxyC_1-4alkylpiperazinylC_1-4alkyl, C_1-4alkyloxypiperidinyl, C_1-4alkyloxypiperidinylC_1-4alkyl, hydroxyC_1-4alkyloxyC_1-4alkylpiperazinyl, hydroxyC_1-4alkyloxyC_1-4alkylpiperazinylC_1-4alkyl, (hydroxyC_1-4alkyl)(C_1-4alkyl)amino, (hydroxyC_1-4alkyl)(C_1-4alkyl)aminoC_1-4alkyl, pyrrolidinylC_1-4alkyloxy, morpholinylC_1-4alkyloxy, morpholinylC_1-4alkyl, C_1-4alkylpiperazinyl, C_1-4alkylpiperazinylC_1-4alkyloxy, C_1-4alkylpiperazinylC_1-4alkyl, hydroxyC_1-4alkylamino, di(hydroxyC_1-4alkyl)amino, di(C_1-4alkyl)aminoC_1-4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC_1-4alkyloxy, or thiophenylC_1-4alkylamino

16. A compound as claimed in claim 14 wherein t is 0;

m is 0;

R¹ is —

C(O)NR⁸R⁹, —

C(O)—

C_1-6alkanediylSR¹⁰, —

NR¹¹C(O)N(OH)R¹¹, —

NR¹¹C(O)C_1-6alkanediylSR¹⁰, —

NR¹¹C(O)C═

N(OH)R¹⁰ or another Zn-chelating-group wherein R⁸ and R⁹ are each independently selected from hydrogen, hydroxy, hydroxyC_1-6alkyl or aminoC_1-6alkyl;

R² is hydrogen, halo, hydroxy, amino, nitro, C_1-6alkyl, C_1-6alkyloxy, trifluoromethyl or di(C_1-6alkyl)amino;

-L- is a direct bond or a bivalent radical selected from C_1-6alkanediyl, C_1-6alkanediyloxy, amino or carbonyl;

R⁴ is hydrogen, hydroxy, amino, hydroxyC_1-6alkyl, C_1-6alkyl, C_1-6alkyloxy, arylC_1-6alkyl, aminocarbonyl, aminoC_1-6alkyl, C_1-6alkylaminoC_1-6alkyl or di(C_1-6alkyl)aminoC_1-6alkyl;

R⁵ is hydrogen;

is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);

each s is independently 0, 1, 2, 3 or 4;

R⁶ is hydrogen;

halo;

hydroxy;

amino;

nitro;

trihaloC_1-6alkyl;

trihaloC_1-6alkyloxy;

C_1-6alkyl;

C_1-6alkyloxy;

C_1-6alkylcarbonyl;

C_1-6alkyloxycarbonyl;

C_1-6alkylsulfonyl;

hydroxyC_1-6alkyl;

aryloxy;

di(C_1-6alkyl)amino;

cyano;

thiophenyl;

furanyl;

furanyl substituted with hydroxyC_1-6alkyl;

benzofuranyl;

imidazolyl;

oxazolyl;

oxazolyl substituted with aryl and C_1-6alkyl;

C_1-6alkyltriazolyl;

tetrazolyl;

pyrrolidinyl;

pyrrolyl;

morpholinyl;

C_1-6alkylmorpholinyl;

piperazinyl;

C_1-6alkylpiperazinyl;

hydroxyC_1-6alkylpiperazinyl;

C_1-6alkyloxypiperidinyl;

pyrazoly;

pyrazolyl substituted with one or two substituents selected from C_1-6alkyl or trihaloC_1-6alkyl;

pyridinyl;

pyridinyl substituted with C_1-6 alkyloxy, aryloxy or aryl;

pyrimidinyl;

quinolinyl;

indole;

phenyl;

or phenyl substituted with one or two substituents independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl;

and R⁷ is hydrogen;

halo;

hydroxy;

amino;

nitro;

trihaloC_1-6alkyl;

trihaloC_1-6alkyloxy;

C_1-6alkyl;

C_1-6alkyloxy;

C_1-6alkylcarbonyl;

C_1-6alkyloxycarbonyl;

C_1-6alkylsulfonyl;

hydroxyC_1-6alkyl;

aryloxy;

di(C_1-6alkyl)amino;

cyano;

pyridinyl;

phenyl;

or phenyl substituted with one or two substituents independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl.

17. A compound as claimed in claim 14 wherein n is 1;

m is 0 or 1;

t is 0.1 or 2;

each Q is

R¹ is —

C(O)NH(OH);

R² is hydrogen or C_1-6alkyl;

-L- is a direct bond;

R⁴ is hydrogen;

R⁵ is hydrogen;

is a radical selected from (a-1), (a-20), (a-25), (a-27), (a-28), (a-29), (a-41) or (a-42);

each s is independently 0, 1 or 2; and

each R⁶ is independently selected from hydrogen, halo, C_1-6alkyl or C_1-6alkyloxy;

18. A compound as claimed in claim 14 wherein n is 1;

m is 0 or 1;

t is 0, 1 or 2;

each Q is

R¹ is —

C(O)NH(OH);

R² is hydrogen;

-L- is a direct bond;

R⁴ is hydrogen;

R⁵ is hydrogen;

is a radical selected from (a-1), (a-20), (a-27), (a-28), (a-29), (a-41) or (a-42);

each s is independently 0, 1 or 2; and

each R⁶ is independently selected from hydrogen, halo, C_1-6alkyl or C_1-6alkyloxy.

19. A compound according to claim 14 wherein the compound is the following compound No. 3.

20. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 14.

21. A process of preparing a pharmaceutical composition as claimed in claim 20 wherein the pharmaceutically acceptable carriers and the compound are intimately mixed.

22. The method of treating proliferative disease comprising administering to a patient in need of such treatment, an anti-proliferative disease-effective amount of a compound of claim 14.

23. A process for preparing a compound as claimed in claim 14, characterized by reacting an intermediate of formula (II) with an appropriate acid, such as for example, trifluoro acetic acid (CF₃COOH), yielding a hydroxamic acid of formula (I-a), wherein R¹ is —

C(O)NH(OH).

24. A method of detecting or identifying a histone deactylase (HDAC) in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound as defined in claim 14 and a HDAC.

25. A combination of an anti-cancer agents and a compound of claim 14.