TW201006469A - Use of HDAC inhibitors for the treatment of acute myeloid leukemia and/or myelodysplastic syndrome - Google Patents

Abstract

The present invention relates to the use of an HDAC inhibitor, especially an HDAC inhibitor of formula (I): wherein the radicals and symbols have the meanings as defined in the specification, for the preparation of a medicament for the treatment of Acute myeloid leukemia and/or Myelodysplastic syndrome.

Description

201006469 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to the use of an HDAC inhibitor for the preparation of a medicament for treating myeloid leukemia and/or myelodysplastic syndrome (MDS); a treatment for acute myeloid leukemia And/or a method of a warm-blooded animal, particularly a human, of a myelodysplastic syndrome comprising administering to the animal a therapeutically effective amount of a HDAC inhibitor, particularly a compound of formula (1) as defined herein; and a medicament comprising the combination Composition and commercial packaging. SUMMARY OF THE INVENTION Myeloid leukemia includes acute myeloid leukemia and chronic myeloid leukemia. The term "Acute myel〇id leukemia" as used herein relates to a rapidly progressive disease in which too many immature white blood cells (rather than lymphocytes) are found in the blood and bone marrow. It is also known as AML, acute myeloid leukemia, acute bone marrow white blood disease, acute non-lymphocytic leukemia and ANLL. The term "chronic bone: 3⁄4 white blood H-type leukemia form is characterized by an increase in the main bone marrow cells in the bone marrow and accumulation of unregulated cells in the blood. CMLH pure line (four) stem cell disease, in which mature granulocytes are mainly found (neutrophils) White blood cells, eosinophils and blood-stained blood cells (baS〇phiIs) and their progenitors are invited to proliferate. It is a species and is called the fee: dye, body (Philadelphia ehr () m. Translocation-related myeloproliferative diseases. Good syndromes are related to the term "leukemia" as used herein. "Marrow bone marrow development does not produce a group of bones that do not produce adequate healthy white blood cells. 141243.doc 201006469 Prodromal and slow Leukemia. The compound of formula (I) as defined herein is a histone deacetylase inhibitor (HDAC inhibitor). Reversible acetylation of histones is a major regulator of gene expression by altering transcription Factor plays a role in DNA accessibility. In normal cells, histone deacetylase (HDA) and histone acetyltransferase together control the degree of histone deacetylation to maintain Value. HDA inhibition cause excessive accumulation of acetylation of histones, which produce a variety of cellular responses.

Surprisingly, it has now been found that HDAC inhibitors, in particular compounds of formula (I) as defined herein, are suitable for the treatment of acute myeloid leukemia and/or myelodysplastic syndromes. Accordingly, the present invention relates to the use of HDAC inhibitors for the manufacture of a medicament for the treatment of acute myeloid leukemia and/or myelodysplastic syndromes. [Embodiment] HDAC inhibitor compound The HDAC inhibitor compound of particular interest for use in the combination of the present invention is a hydrooxamate compound of the formula (I):

Wherein: R! is H; halo; or a straight-chain Ci-G alkyl, especially methyl, ethyl or n-propyl, the methyl, ethyl and n-propyl substituents are unsubstituted or 141243. Doc 201006469 One or more of the substituents described below with respect to the alkyl substituent; R2 is selected from H; <:!-(:! 〇院基' is preferably C-C6 alkyl, such as methyl , Ethyl or -CHzCHz-OH; CVC; 9 cycloalkyl; C4 'heterocyclic alkyl; C4-C9 heterocycloalkyl: cycloalkyl, such as cyclopropylmethyl. aryl; Aryl; arylalkyl, such as benzyl; heteroaryl, such as "bitomethyl", -(CH2)nC(〇)R6; -(CH2)n〇c(〇)R6; amine group醯-based; HON-qCO-CI^C^R))-aryl-alkyl group; and -(CH2)nR7; R3 and R4 are the same or different 'and independently H; CrC: 6 alkyl; fluorenyl; Or alkylamine; or R3 and R4 together with the carbon to which they are attached represent c=〇, c==s^c=nr· or R2 together with the nitrogen to which it is combined with R3 together with the carbon to which it is bonded to form C4 -C9 heterocycloalkyl; heteroaryl; polyheteroaryl; non-aromatic polyheterocycle; or mixed aryl and non-aryl polyheterocycle; R5 is selected from H^C6 C4_C9 cycloalkyl; C4_C9 heterocycloalkyl; fluorenyl; aryl; heteroaryl, arylalkyl, such as benzyl; heteroarylalkyl, such as pyridylmethyl; aromatic polycyclic Non-aromatic polycyclic; aryl and non-aryl polycyclic; polyheteroaryl; non-aromatic polyheterocycle; and mixed aryl and non-aryl polyheterocycle; η, iM, n2 and n3 are the same Or differently and independently selected, when ~ is K, 'each carbon atom may be optionally and independently substituted; X and Y are the same or different and independently selected from H; from a base; a fluorenyl group, such as CH3 and CF3; 〇2; c(0)Rl; OR9; SR9; CN; and 2^; 141243.doc • 6 - 201006469 R6 is selected from H; CVQ alkyl; C4_C9 cycloalkyl; C4_C9 heterocycloalkyl; cycloalkyl An alkyl group, such as cyclopropylmethyl; aryl; heteroaryl; arylalkyl, such as a benzyl and 2-phenylvinyl; heteroarylalkyl, such as indenyl 0-methyl; 〇Ri2; And NRnR丨4; r7 is selected from or15; sr15; s(0)Rl6; s〇2Ri7; NRnRi4: and NRi2S02R6

R8 is selected from the group consisting of H; 〇R15; NRnRi4; Ci_c6 alkyl; C4_C9 cycloalkyl; cu-c: 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl such as benzyl, and heteroaryl a group, for example, an indenyl group; R9 is selected from a CVC4 alkyl group, such as CH3&CF3; c(〇)alkyl, such as c(o)ch3; and c(o)cf3; R10 and ! ^! identical or different and independently selected from H; Ci_C4 alkyl; and -C(o)-alkyl; R12 is selected from H; Cl-C6 ortho; cvC9 cycloalkyl; heterocycloalkyl;

CcC9 heterocycloalkylalkyl; aryl; mixed aryl and non-aryl polycyclic; heteroaryl; arylalkyl, such as benzyl; and heteroarylalkyl, such as pyridylmethyl;

9 is the same or different and independently selected from H; Ci_c6 alkyl; c4_c cycloalkyl; CcC9 heterocycloalkyl; aryl; heteroaryl; arylalkyl such as a benzyl group; heteroarylalkyl, for example a pyridylmethyl group; an amine-based or R13 and r14 together with the nitrogen to which they are bonded are a C4_C9 heterocycloalkyl; a heteroaryl; a polyheteroaryl; a non-aromatic polyheterocycle; or a mixed aryl group Non-aryl polyheterocycle; 141243.doc 201006469

Ri5 is selected from H; C!-C6 alkyl·r rp A. p 6 丞' cvc; 9 cycloalkyl, C4_c9 heterocycloalkyl; aryl; heteroaryl; aryl 焓. Substyl, heteroarylalkyl; and (CH2)mZR12; 4-(:9heterocycloalkyl; aryl; heteroarylalkyl; and R16 are selected from CKC6 alkyl; alkyl; c, heteroaryl Polyheteroaryl; arylalkyl (CH2) mZR12; selected from Ci-C6 alkyl; c4_c9 cycloalkyl; c4_C9 heterocycloalkyl; aryl; aromatic polycyclic; heteroaryl; aryl a aryl group; a heteroaryl group; a polyheteroaryl group and NR13R14; m is an integer selected from 0 to 6; and z is selected from the group consisting of hydrazine; NR13; S; and s(〇), or a pharmaceutically acceptable thereof Salt, as appropriate, "unsubstituted" means that no substituent or substituent is only hydrogen. The self-substituent is selected from the group consisting of fluorine, gas, bromine and iodine, preferably fluorine or gas. Or, the alkyl substituent includes a straight chain and a branched chain (: 1_(;: 6 alkyl group. Suitable straight chain and branched chain c) - Examples of the alkyl substituent include methyl, ethyl, n-propyl, 2 -propyl, n-butyl, t-butyl, tert-butyl and the like. Further, otherwise, the alkyl substituent includes an unsubstituted alkyl group and an alkyl group substituted with one or more suitable substituents, and the substituents include unsaturation, that is, one or more double bonds or a bond c_c Key 'indenyl; cycloalkyl; yl; oxyalkyl; alkylamino; aminoalkyl; arylamino; and OR 5', such as alkoxy. Preferred substituents for alkyl include teeth a group, a transalkyl group, an alkoxy group, an oxyalkyl group, an alkylamino group, and an aminoalkyl group. 141243.doc 201006469 Unless otherwise stated, a cycloalkyl substituent includes a C3_C9 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group. a group, a cyclopentyl group, a cyclohexyl group, and the like. Unless otherwise stated, a cycloalkyl substituent includes an unsubstituted cycloalkyl group and a cycloalkyl group substituted with one or more suitable substituents, such substitutions. The group includes a c 1 ^5 alkyl group, an i group, a hydroxyl group, an aminoalkyl group, an oxyalkyl group, an alkylamino group, and an anthracene Ri5, such as an alkoxy group. Preferred substituents of the cycloalkyl group include a dentate group, a hydroxyl group, Alkoxy, oxyalkyl, alkylamino and aminoalkyl. The above discussion regarding alkyl and cycloalkyl substituents also applies to a substituent of an alkyl group such as, but not limited to, an alkoxy group, an alkylamine, an alkyl ketone, an arylalkyl group, a heteroarylalkyl group, an alkylsulfonyl group, and an alkyl ester substituent Similar groups. Heterocycloalkyl substituents include 3- to 9-membered aliphatic rings containing from 1 to 3 heteroatoms selected from nitrogen, sulfur, and oxygen, such as 4- to 7-membered aliphatic rings. Suitable heterocyclic rings. Examples of the alkyl substituent include a tweezers, a tetrahydrofuran, a tetrahydrothiocarbamate, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a morpholinyl group, and a diazacycloheptane\1. 4_diazacycloglycine, 14_oxazepine (14. Take 刚) and Μ-milk thiophene (1,4_oxathiapane). Unless otherwise stated, the ring is unsubstituted or substituted on the carbon atom by a plurality of suitable substituents: the substituents include a Cl_C6 alkyl group; a cycloalkyl group; an aryl group; a heteroaryl group; an aryl group 'For example, a aryl group; a heteroaryl group such as a fluorene methyl group; a dentate group, an amine group, an alkylamino group and an anthracene Ri5 such as an alkoxy group. Unless otherwise stated 'other nitrogen heteroatoms are unsubstituted or substituted by: h, Ci-C4, a aryl group, such as a benzyl group; a heteroaryl group, such as a fluorenylmethyl' fluorenyl group , an amine base; a stilbene base; and an aryl continued base. 141243.doc 201006469 A cycloalkylalkyl substituent includes a compound of the formula -(CH2)n5-cycloalkyl, wherein n5 is a number from 1 to 6. Suitable alkylcycloalkyl substituents include cyclopentylmethyl, cyclopentylethyl, cyclohexylfluorenyl and the like. The substituents are unsubstituted or substituted with a suitable substituent in the alkyl moiety or cycloalkyl moiety, including the substituents listed above for the alkyl and cycloalkyl groups. The aryl substituent includes an unsubstituted phenyl group and a phenyl group substituted with one or more suitable substituents including an alkyl group; a cycloalkylalkyl group such as a cyclopropylmethyl group; o (co Alkyl; oxyalkyl; halo; nitro; amine; alkylamino; aminoalkyl; alkyl ketone; nitrile; carboxyalkyl; alkyl sulfonyl; amine sulfonyl; Alkylsulfonyl and or15, such as alkoxy. Preferred substituents include (: 1-<:6 alkyl; cycloalkyl, such as cyclopropylindenyl; alkoxy; oxyalkyl; functional; nitro; amine; alkylamino; amine Alkenyl; carboxyalkyl; alkylsulfonyl; arylsulfonyl and amine based. Examples of suitable aryl groups include Cl_C4 alkylphenyl, Cl_c4 alkoxy stupid, Trifluorodecylphenyl, methoxyphenyl, hydroxyethylphenyl, dimethylaminophenyl, aminopropylphenyl, ethoxycarbonylphenyl, sulfonyl phenyl, and acesulfame a nonylphenyl group. The tricyclic polycyclic ring includes a naphthyl group and a naphthyl group substituted with one or more suitable substituents. The substituents include a CrC6 alkyl group; an alkylcycloalkyl group such as a cyclopropylmethyl group; Oxyalkyl; dentate; nitro; amine; alkylamino; aminoalkyl; fenyl nitrile; carboxyalkyl; alkylsulfonyl; arylsulfonyl; R15, such as alkoxy. Heteroaryl substituents include 5- to 7-membered aromatic ring compounds containing one or more heteroatoms selected from N, 0 and S (eg, 1-4 heteroatoms). Base 141243.doc 201006469 generation Including mercapto, porphinyl, beta-l-butyryl, D-saltyl, trisal, sinyl, oxalyl, pyridyl, pyrimidinyl, isoxazolyl, η-pyrazinyl and Similar groups. Unless otherwise stated, 'other heteroaryl substituents are unsubstituted or substituted on a carbon atom with one or more suitable substituents, including alkyl, alkyl substituents as specified above and Another heteroaryl substituent. The nitrogen atom is unsubstituted or substituted, for example, by a ruler; particularly useful, the substituent includes H, Ci-C4 alkyl, fluorenyl, amino fluorenyl and sulfonyl. The substituent includes a group of the formula -(CH2)n5-aryl, aryl HCHA5-aryl or -(CHdn^CH(aryl)(aryl), wherein the aryl and oxime 5 are as defined above. The isoarylalkyl substituent includes benzyl, 2-phenylethyl ' 1-phenylethyl, fluorenyl phenyl-3-yl, 2-phenylpropyl, diphenyl fluorenyl, 2-di Phenylethyl, 5,5-dimethyl-3-phenylpentyl and the like. The arylalkyl substituent is unsubstituted or in the alkyl or aryl moiety or in the alkyl moiety The aryl moiety is as above for the alkane Substituted as described above for the aryl substituent. The heteroaryl group includes a group of the formula -(CH2)n5.heteroaryl, wherein the heteroaryl and n5 are as defined above and the bridging is The carbon or nitrogen linkage of the aryl moiety 'such as 2-" than dimethylmethyl, 3-" 咬 曱 或 or 4-" than dimethyl thiol, imiline methyl, quinolyl Ethyl and "pyrrolylbutyl. Heteroaryl substituents are unsubstituted or substituted as described above for heteroaryl and alkyl substituents. Aminothio substituents include formulas <:(0) -((:Η2)η-(:(Η)(ΝΙ113Ι114Η(:Η2)η-Ι15 of the group 'where n, R13, R 4 and R5 are as described above. Suitable amine-based substituents include natural and non-natural amino acids such as glycidinyl, D_tryptamine, L-aminoxime, D-homsamine sulfhydryl or L-homsamine thiol, 141243 .doc • 11 - 201006469 4_Aminobutyric acid and spider amine · 4 · dilute base. "Non-aromatic polycyclic substituents include bicyclic and tricyclic fused ring systems wherein each ring may be from 4 to 9 members and each ring may contain zero, one or more double bonds and/or a non-aromatic bond. Suitable examples of the ring include decazinane, octahedral, perhexaphthyl and all hydrogen benzoxanthene. These substituents are unsubstituted or substituted as described above for the cycloalkyl group. - Mixed aryl And non-aryl polycyclic substituents include bicyclic and tricyclic ring systems. Each ring may be from 4 to 9 members and at least one ring is aromatic. Suitable examples of mixed aryl and non-square polycyclic rings include Methyldioxyphenyl, biguanide-methyldioxyphenyl, tetrahydronaphthalene, dibenzocycloheptane, indoline and 9 ugly-. These substituents are unsubstituted or confirmed. Substituted or substituted as described above for a cycloalkyl group. Polyheteroaryl substituents include bicyclic and tricyclic fused ring systems wherein each ring may independently be 5 or 6 members and contain one or more selected from the group consisting of hydrazine, a hetero atom of N*s (for example, 2, 3 or 4 heteroatoms) such that the fused ring system is aromatic. Suitable examples of polyheteroaryl ring systems include quinoline Isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridinium, hydrazine, benzofuran, benzothiazepine, benzoxanthene, benzoxazole, pyrroloquinoline and the like Unless otherwise stated, a polyheteroaryl substituent is unsubstituted or substituted on a carbon atom by one or more suitable substituents, including alkyl groups, alkyl substituents identified above, and a substituent of the formula 0-(CH2CIi=CH(CH3)(CH2))N3H. The nitrogen atom is unsubstituted or substituted, for example, by R13, and particularly useful N substituents include H' Ci-C: 4 alkyl, fluorenyl , Amine-based and sulfonyl. Non-aromatic polyheterocyclic substituents include bicyclic and tricyclic fused ring systems, each of which is 141243.doc -12· 201006469 two 'members to 9 members, containing one or more choices From 〇, a hetero atom of _s (for example, 1, 2, 3 or 4 heteroatoms) and containing zero or one or more 匸<double bonds or ginseng bonds. Suitable examples of non-aromatic polyheterocycles include gambling alcohols, cis-perhydro-cycloheptaindene and (4) groups, decahydrobenzoyl, heptyl, and 28-oxabicyclo[3.3.0] octane Burning, hexahydrophene [32 smoulder perchlorinated [3, 2 external biluo, all hydrogen peak biting, perchlorinated bicyclopentaquinone and heart] Piper. Unless otherwise stated, the non-aromatic polyheterocyclic substituents are unsubstituted or substituted on the carbon atom with one or more substituents including the alkyl group and the above-described thiol substituent. The nitrogen atom is unsubstituted or substituted by, for example, 〜. The N substituent which is particularly useful includes Η%', fluorenyl, fluorenyl, and fluorenyl. Mixed aryl and non-aryl polyheterocyclic substituents include bicyclic and tricyclic anthracene ring systems wherein each ring may be from 4 to 9 members, containing one or more heteroatoms selected from O N" and at least one ring Should be aromatic. Suitable examples of mixed aryl and non-aryl polyheterocycles include 2'3-dihydro(tetra), tetrahydro(tetra), 5,n-dihydro-secretodiphenyl, 4]diazepine, dibenzo-dibenzo(tetra)(1) #氮呼,1,2-Dihydrogen and [3,4仙,5]Benzene two gas, bite with a dinitrogen-to-mouth ratio [2,34][1,4]diazepine_4· _, 12, 3, 4, 6 ι hexahydrobenz [do] mouth bite and [2,3-e] [1,4] diazet _5,. Unless otherwise stated, the mixed aryl and non-aryl polyheterocyclic substituents are unsubstituted or substituted on the carbon atom with one or more suitable substituents including _n〇h, =n 〇h, (d) and the alkyl substituents identified above. The nitrogen atom is unsubstituted or, for example, substituted by 〜; particularly useful N substituents include H, Cl-C4 alkyl, fluorenyl, amine-branched, and extender. 141243.doc •13· 201006469 Amino substituents include primary amines, secondary amines and tertiary amines, and quaternary amines in salt form. Examples of the amino substituent include a monoalkylamino group and a dialkylamino group, a monoarylamino group and a diarylamino group, a monoarylalkylamino group and a diarylalkylamino group, an aryl group- An arylalkylamino group, an alkyl-arylamino group, an alkyl-arylalkylamino group, and the like. The sulfonyl substituent includes an alkylsulfonyl group and an arylsulfonyl group, for example, anthracene, benzenesulfonyl, toluenesulfonyl and the like. The aryl group includes a group of the formula -C(0)-W, -0C(0)-W, _c(o)-o_w or -C^CONR!3!^4, wherein w is R丨6, Η Or a cycloalkylalkyl group. The arylamino substituent includes the formula _n(r12)c(o)-w,

-N(R12)C(0)-0-W and -N(R丨2)C(0)-NH0H substituents and R丨2 and W are as defined above. The R2 substituent HON-qcO-CH^Cd)-aryl-alkyl is a group of the formula:

Each substituent preferably includes the following:

Ri is H, halo or linear alkyl; R2 is selected from H, CVC6 alkyl, (: 4-(:9-cycloalkyl, C4_C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl) Alkyl, arylalkyl, heteroarylalkyl, -(CH2)nC(0)R6, aminoguanidino and _(CH2)nR7; R3 is the same or different and independently selected from H&C1-C6 Alkyl; or 141243.doc •14· 201006469 R3 and Han 4 together with the carbon to which they are combined represent C=〇, c=s or c=nr8; R5 is selected from H, Cl-C6 alkyl, c4-c9 Cycloalkyl, c4_C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycyclic, non-aromatic polycyclic, mixed aryl and non-aryl polycyclic, poly a heteroaryl group, a non-aromatic polyheterocyclic ring and a mixed aryl group and a non-aryl polyheterocyclic ring; η, ηι, 112 and n3 are the same or different and independently selected from 〇6, when 〜6 is ,6, each The carbon atom is unsubstituted or independently substituted by R3 and/or &; 乂 is the same or different and is independently selected from H, halo, Cl-(:4 alkyl, CF3, N〇2, 匚 ( 〇 team, 〇r9, SR9, cn&NRi〇rΗ; R6 is selected from the group consisting of hydrazine, CVC6 alkyl, C4-C0f alkyl, C4_C9 heterocycloalkyl, alkane Cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, 〇Rl2 and NR13R14; R7 is selected from the group consisting of OR15, SR15, s(0)Ri6, s〇2Ri7, NR]3Ri4 and NR12SO2R6 9 R8 is selected from the group consisting of H, 〇R15, NRl3R丨4, Ci_c6 alkyl, C4_C^alkyl, φ CVC9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; r9 Selected from cvc4 alkyl and c(o)-alkyl;

Rio is the same as or different from Rn and is independently selected from H, Ci C4 alkyl and _c(〇)_ 'alkyl; heart 2 #' is selected from CVM-based 'c4_C9 ring (iv), a% heterocycloalkyl, aryl , heteroaryl, arylalkyl and heteroarylalkyl; R13 and R" identical or different and independently selected from H, Ci_C6 alkyl, C4_C9 cycloalkyl 'C4_C4 cycloalkyl, aryl, heteroaryl , arylalkyl, 141243.doc 15· 201006469 Heteroarylalkyl and amine fluorenyl; R15 is selected from H, CVQ alkyl, C4-C9 cycloalkyl, C4_C9 heterocycloalkyl, aryl, hetero Aryl, arylalkyl, heteroarylalkyl and (CH2)mZRi2; Ri6 is selected from C-C6 alkyl, c4-c9 cycloalkyl, c4-C9 heterocycloalkyl, aryl, heteroaryl a aryl group, an arylalkyl group, a heteroarylalkyl group, and (CH2)mzR12; R17 is selected from the group consisting of Ci-C6 alkyl, C4-C9 ring, C4-C9 heterocycloalkyl, aryl 'heteroaryl, Arylalkyl, heteroarylalkyl and NR13R14; m is an integer selected from 0-6; and Z is selected from the group consisting of ruthenium, NR丨3, S and S(O); or a pharmaceutically acceptable salt thereof . Useful compounds of the formula (1) include compounds of the formula (I) wherein R, χ, Y, γ and δ are each Η, including compounds of the formula (I) wherein one of Π 2 and η 3 is ruthenium and the other is 1 And especially a compound of formula (I) wherein R 2 is deuterium or -CH 2 -CH 2 -OH. A suitable class of hydroxamic acid amide compounds are compounds of formula (Ia): 〇

Wherein: 114 is 〇_3; R2 is selected from the group consisting of H, Ci-C: 6 alkyl, CU-C9 cycloalkyl, c4-C9 heterocyclic, cycloalkylalkyl, aryl, heteroaryl, Arylalkyl, heteroarylalkyl, -(CH2)nC(0)R6, aminoguanidino and _(CH2)nR7; and 141243.doc •16·201006469 % are heteroaryl; heteroarylalkane Base, methyl group, aromatic polycyclic ring; = polycyclic 'mixed aryl and non-aryl polycyclic; polyhetero; or tolerate "aryl and non-aryl polyheterocycle; or its pharmaceutically acceptable Accept the salt.

Another type of suitable hydroxamic acid vinegar compound is a compound of formula (ia)··

Wherein: 1^4 is 0-3; R2 is selected from H, CVC: 6 alkyl, CVC9 cycloalkyl, C4_C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl ,heteroarylalkyl, -(CH2)nC(0)R6 'amino fluorenyl and cardyl aryl; arylalkyl; aromatic polycyclic; non-aromatic polycyclic; and mixed aryl and non-aromatic a polycyclic ring, especially an aryl group, such as p-fluorophenyl-p-chlorophenyl, p-O-CkCU-alkylphenyl, such as p-methoxyphenyl and p-C4-alkyl-4-phenyl; and arylalkyl, Such as benzyl, o-fluorobenzyl, m-fluorobenzyl or p-fluorobenzyl, o-benzyl, m-benzyl or p-benzyl, o-, m- or p-mono-C-C4 alkyl benzyl, dioxime Cl_c4 alkylbenzyl or tri O-Ci-C: 4 alkylbenzyl (such as o-nonyloxybenzyl, m-decyloxybenzyl or p-methoxybenzyl), meta-p-diethoxy Benzyl, o-, m-p-trimethoxybenzyl and o-, m- or p-Cl_c4 alkyl, a C1-C4 alkyl group or a tri-C1-C4 phenyl group (such as p-methyl 141243. Doc •17- 201006469, m-diethylphenyl); or a pharmaceutically acceptable salt thereof. Another class of concern is the compound of formula (Ib):

(lb)

It is selected from the group consisting of oxime, CVC6, and the like; (VC6 cycloalkyl; cyclodextrin, such as cyclopropylmethyl; (CH2)2_4〇r21, where r "h, methyl, ethyl, propyl and a propyl group; and Μ is unsubstituted 卜3_yl, benzo"_3_yl or (tetra) I group or substituted anthracene group (such as 5n-protonyl or 5-methoxyl, A compound of the formula (Ic): a compound of the formula (Ic): Ο p

(lc) wherein: the non-aromatic rings are saturated or contain no Z, and the ring is an aromatic or non-aromatic ring. 141243.doc 18· 201006469 Saturated ring, Ζι is ο, S or n-r20;

Rl 8 R20

Is HHCl_(10) (methyl, ethyl, tert-butyl); c3_c cycloalkyl; aryl, such as 'unsubstituted phenyl or phenyl substituted with 4-OCH3 or 4-CF3; or heteroaryl, Such as 2_ 吱 基 base, 吩 基 base or 2, ° fixed H base or 4 "bite base; H, (^ (: 6 burnt base; Cl-C6 burnt base _C3_C9 ring yard base, such as cyclopropyl Methyl; aryl; heteroaryl; arylalkyl, such as a benzyl group; heteroarylalkyl, such as pyridylmethyl; fluorenyl, for example, ethyl hydrazino, propyl fluorenyl and phenyl fluorenyl; Sulfhydryl, such as methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl; A! is 1, 2 or 3 substituents, independently H; Ci_C6 alkyl; -OR!9 'halo group; alkylamino group; aminoalkyl group; halogen group; or heteroaryl alkyl group, such as η than butyl group;

Ri9 is selected from the group consisting of H, C-C6 alkyl; CVC9 cycloalkyl; c4-C9 heterocycloalkyl; aryl, heteroaryl; arylalkyl, such as benzyl; heteroaryl, such as pyridine Methyl and -(CHzCH^CHiCHWCHWuH; R2 is selected from H, CVC6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aryl Alkyl, heteroarylalkyl, -(CH2)nC(0)R6, aminoguanidino and -(CH2)nR7; v is 0, 1 or 2; P is 0-3; and q is 1-5 And r is 0; or q is 0 and r is 1-5; 141243.doc • 19· 201006469 or a pharmaceutically acceptable salt thereof. Other variable substituents are as defined above.

Particularly useful compounds of formula (1C) are those of formula (Ic) wherein the rule 2 is _(ch2)pCH2OH (wherein p is 1-3), especially the compound of formula (Ic) wherein Ri&h; such as its center! And X and Y are each H and wherein q is 1_3 and 1 is 〇 or a compound of formula (Ic) wherein q is 0 and !* is U, especially wherein z is NR2. (c). Things. In these compounds, & is preferably Η or cH2_cH2〇H and the sum of q and r is preferably 1. Another type of hydrochloroproline vinegar compound that attracts attention is the formula (egg chelating compound:

Wherein: Ζι is Ο, S or N-R2Q; Ri8 is Η; halo; c^c 1-C6 alkyl (methyl, ethyl

a fluorenyl group; an aryl group; a heteroaryl group; a tributyl group; a c3-c7 group, such as an unsubstituted stupid group or a 4-OCH3 group

Phenylsulfonic acid and toluenesulfonyl; alkyl-CVC9 cycloalkyl, such as cyclopropylaryl, arylalkyl, such as benzyl; heteroarylmethyl, fluorenyl, for example, ethyl hydrazino, propyl hydrazine, for example Sulfonyl, ethyl sulfonyl, 141243.doc 201006469 A! 2 or 3 substituents, or halo; independently h, Ci_c6, 〇Ri9~ selected from η; cvc6 alkyl ; cvC9 ring · ; c4_C9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, such as a benzyl group; and heteroarylalkyl, such as pyridylmethyl; P is 0-3;

q is 1-5 and r is 0; or q is 0 and r is 1-5; or a pharmaceutically acceptable salt thereof. Other variable substituents are as defined above. Particularly useful compounds of formula (Id) are those of formula (Id) wherein r2 is 1^ or _(CH2)pCH2〇H (wherein P is 1-3), especially a compound of formula (Id) having a center of 11; A compound of the formula (Id) wherein R丨 is Η and X and Y are each H and wherein q is 1-3 and 1 is hydrazine or wherein q is 0 and r is 1-3. Among these compounds, Han 2 is preferably ruthenium or CH 2 _CH 2 -OH and the sum of q and r is preferably 1. The invention further relates to compounds of formula (Ie):

Or a pharmaceutically acceptable salt thereof. Variable substituents are as defined above. Particularly useful compounds of formula (Ie) are those wherein R18 is H, fluoro, silane, bromo, deuterated, substituted CrC* alkyl, C3-C7 cycloalkyl, unsubstituted phenyl, 141243.doc • 21 201006469 A compound of formula (k) in the para position, a left-substituted base or a heteroaryl (eg, n-bite) ring. Another useful group of compounds of the formula (Ie) are those of the formula (Ie) wherein Η or •(CH 2 )pCH 2 〇H (wherein Ρ is I·3), especially the compound of the formula (Ie) wherein 1 Η is Η; A compound of the formula (Ie) wherein R is Η and X and Y are each Η and wherein q is 1_3 and 1' is 〇 or wherein q is 〇 and r is 1-3, "R2 is preferred in such compounds" It is H or _CH2_CH2_〇H and the sum of 9 and r is preferably 1. In these compounds, P is preferably 1 and R3 and R4 are preferably ruthenium. Another useful group of compounds of formula (Ie) are those wherein R1S is H, methyl, ethyl, decyl butyl, trifluoromethyl, cyclohexyl, phenyl, 4-methoxyphenyl, 4-tri Fluorylphenyl, 2-furyl, 2-thienyl or 2-acridinyl, 3·pyridinyl or 4-pyridyl, wherein the 2, furanyl, 2-thienyl or 2-pyridyl The 3-pyridyl or 4-pyridyl substituent is unsubstituted or substituted as described above for the heteroaryl ring; R2 is oxime or -(CH2)pCH2〇H (wherein p is 1-3) (ie a compound; in particular, a compound of the formula (Ie) wherein the rule 1 is 11 and wherein: ^ and γ are each H, and wherein q is i_3&r is hydrazine or wherein q is 0 and r is 1-3. In these compounds, R.sup.2 is preferably hydrazine or -CH2_CH2-OH and the sum of q and r is preferably a sigma wherein R2〇 is Η or C^C:6 alkyl, especially 彼( Le) The compound is an important member of each subclass of the compound of the above formula (Ie) ^ - Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1//·吲哚-3-yl)) Ethyl]-amine·yl]methyl]phenyl]-2£-2-propanylamine, hydrazine-perylene-3-[4-[[[2·(ΐ//-弓布朵-3 -yl)ethyl]-amino]methyl]phenyl]·2£_2· acrylamide and hydrazine-3·[4-[[[2-(2-曱基〇朵_3·) _Ethyl]•Amino]methyl]phenyl]-2£-2-propenylamine or a pharmaceutically acceptable salt thereof is an important compound of the formula 141243.doc-22. 201006469 (Ie). The invention further relates to a compound of formula (If):

Or a pharmaceutically acceptable salt thereof. Variable substituents are as defined above. Useful compounds of the formula (If) include compounds of the formula (If) wherein R 2 is hydrazine or -(CH 2 )pCH 2 OH (wherein P is s), in particular wherein 1 is a compound of the formula (If); And X and Y are each deuterium, and a compound of the formula (If) wherein q is 1-3 and r is deuterium or wherein q is 0 and r is 1-3. In these compounds, r2 is preferably hydrazine or -CH2-CH2-OH and the sum of q and r is preferably 1. #-经基-3-[4-[[[2-(benzofuran]-3-yl)-ethyl]-amino]methyl]phenyl]-2penta-2-propenylamine or its A pharmaceutically acceptable salt is an important formula (if). The above compounds are usually used in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts include, where appropriate, pharmaceutically acceptable base addition salts and acid addition salts, such as metal salts (such as alkali metal and alkaline earth metal salts), ammonium salts, organic amine addition salts. And amino acid addition salts and sulfonates. Acid addition salts include inorganic acid addition salts such as hydrochlorides, sulfates and phosphates; and organic acid addition salts such as alkyl sulfonates, aryl sulfonates, acetates, methacrylates , fumarate, tartrate, citrate and lactate. Examples of metal salts are alkali metal salts such as lithium salts, sodium salts and potassium salts; 14I243.doc -23- 201006469 alkaline earth metal salts such as magnesium salts and calcium salts; aluminum salts and zinc salts. Examples of ammonium salts are ammonium salts and tetradecyl ammonium salts. An example of an organic amine addition salt is a salt formed with morpholine and piperidine. Examples of the amino acid addition salt are salts formed with glycine, amphetamine, glutamic acid and lysine. Sulfonic acid salts include methanesulfonate, tosylate and besylate. Other HDAC compounds within the scope of Formula (I) and their synthesis are disclosed in WO 02/22577, published on Mar. 21, 2002, which is incorporated herein in its entirety. Two preferred compounds within the scope of WO 02/22577 are:

iV-hydroxy-3-[4-[(2-hydroxyethyl){2-(1//--indol-3-yl)ethyl]-amino]indolyl]phenyl]-2-5-2 - acrylamide or a pharmaceutically acceptable salt thereof, and

(III) iV-hydroxy-3-[4-[[[2-(2-mercapto-1/f-indol-3-yl)-ethyl]-amino]indenyl]phenyl]-2E -2-Propanylamine or a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to a method for treating acute myeloid leukemia and/or myelodysplastic syndrome comprising administering to a warm-blooded animal in need thereof (especially 141243.doc-24-201006469 humans thereof) a therapeutically effective amount of hdac The inhibitor, preferably a warm-blooded animal, preferably a human, in need thereof, is administered a therapeutically effective amount of a compound of formula (I) as defined above or a salt of the compound having at least one salt-forming group. The term "treatment J" as used herein includes treatment of a patient suffering from acute myeloid leukemia and/or myelodysplastic syndrome or in a pre-stage of the disease, the effect of which is to delay the progression of the disease in such patients. The present invention provides a treatment A method of acute myeloid leukemia and/or myelodysplastic syndrome comprising administering to a warm-blooded animal in need thereof a therapeutically effective amount of an HDAC inhibitor against acute myeloid leukemia and/or myelodysplastic syndrome. The relevant test mode is selected to confirm the beneficial effects of the compounds inhibiting HDAC activity mentioned above and below on acute osteoblastic leukemia and/or myelodysplastic syndromes, for example in a suitable clinical study or by means of the following examples' To demonstrate the pharmacological activity of a compound which inhibits the rib from being active. The invention also provides the use of a compound of formula (1) as defined herein for the manufacture of a medicament for the treatment of acute (tetra) leukemia and/or (d) dysplasia syndromes' In the combination of the invention (combination OF the INVENT) Uses for the treatment of acute (d) leukemia and/or (d) 0 adverse syndromes. Combination partners include anti-proliferative compounds including, but not limited to, aromatase inhibitors; antiestrogens; topological differences Enzyme inhibitors; topoisomerase inhibitors; microtubule active compounds; basalization 141243.doc • 25- 201006469 compounds; histone deacetylase inhibitors; compounds that induce cell differentiation; Oxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-neoplastic antimetabolites; platinum compounds; compounds that target/lower protein or lipid kinase activity and other anti-angiogenic compounds; target, reduce or inhibit proteins or lipids Phosphatase active compound; gonadotropin agonist; antiandrogen; methionine amine peptidase inhibitor; bisphosphonate; biological response modifier; antiproliferative antibody; heparinase (heparanase) Inhibitor; Ras oncogenic isoform inhibitor; telomerase inhibitor; proteasome inhibitor; compound for the treatment of hematological malignant diseases; Compounds that are low or inhibit Flt-3 activity; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC3 3 05 07), 17-DMAG (17-two) Nonylaminoethylamino-17-desmethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (from Conforma Therapeutics); temozolomide (TEMODAL) ®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 (from GlaxoSmithKline), or pentamidine/chlorpromazine (from CombinatoRx); MEK inhibitors such as ARRY 1428 86 (from Array PioPharma), AZD6244 (from AstraZeneca), PD181461 (from Pfizer) and formazan leucovorin. The term "aromatase inhibitor" as used herein relates to a compound which inhibits the production of estrogen (i.e., inhibits the conversion of the receptor androstenedione and the testosterone to estrone and estradiol, respectively). The term includes, but is not limited to, steroids, particularly atamestane, exemestane, and fumes 141243.doc -26-201006469 stan (formestane); and especially non-steroids, especially amine rumimi (aminoglutethimide), roqueimimide (roglethimide), pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole ), 法屈" sitting (fadrozole), anastrozole (anastrozole) and come to sit (letrozole). Exemestane can be administered, for example, in the form as it is marketed, for example, under the trademark AROMAS IN. Formestane can be administered, for example, in the form as it is marketed, for example, under the trademark LENTARON. The fadrozole can be administered, for example, in the form as it is marketed, for example, under the trademark AFEMA. Anastrozole can be administered, for example, in the form as it is marketed, for example, under the trademark ARIMIDEX. The koji can be administered, for example, in the form of, for example, the trademark FEMARA or FEMAR. Amine can be administered, e.g., in the form as it is marketed, e.g. under the trademark ORIMETEN. Combinations of the invention comprising a chemotherapeutic agent as an aromatase inhibitor are particularly useful for treating hormone receptor positive tumors, such as breast tumors. The term "antiestrogens" as used herein relates to a compound which antagonizes the estrogen effect at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen can be administered, for example, in the form as it is marketed, for example, under the trademark NOLVADEX. Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA. Fulvestrant can be formulated as disclosed in U.S. Patent 4,6 5 9,5, or it can be administered, for example, in the form of, for example, the trade name FASLODEX. Combinations of the invention comprising a chemotherapeutic agent as an antiestrogens are particularly useful for treating estrogen receptor positive tumors, such as breast tumors. The term "antiandrogen" as used herein relates to any substance capable of inhibiting the biological effects of male stimulating 141243.doc -27-201006469 and includes, but is not limited to, bicalutamide (CASODEX), which may for example As defined in US 4,636,505, the term "gonados agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is disclosed in U.S. Patent No. 4,100,274, the disclosure of which is incorporated herein by reference in its entirety in its entirety. Abex can be formulated, for example, as disclosed in U.S. Patent 5,843,901. The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian, and Analogs, 9-decylcamptothecin and macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO 99/17804). Irinotecan can be administered, for example, in the form as it is marketed, for example, under the trademark CAMPTOSAR. Topotecan can be administered, for example, in the form as it is marketed, for example, under the trademark HYCAMTIN. The term "topoisomerase purine inhibitor" as used herein includes, but is not limited to, anthracycline, such as doxorubicin (including liposome formulations such as CAELYX), and Doxorubicin Daunorubicin, epirubicin, idarubicin, and nemombicin; anthraquinone, mitoxantrone, and losoxantrone ; and podophillotoxine, etoposide and teniposide. The docking ring can be administered, for example, in the form of, for example, the trademark ETOPOPHOS. Teniposide can be administered, for example, in the form as it is marketed, for example, under the trademark VM 26-BRISTOL. Doxorubicin 141243.doc -28 - 201006469 can be administered, for example, in the form of, for example, the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, for example, in the form as it is marketed, for example, under the trademark farm 〇 rubicin. The choline can be administered, for example, in the form as it is marketed, for example, under the trademark ZAVEDOS. Mitoxantrone can be administered, for example, in the form as it is marketed, for example, under the trademark NOVANTRON. The term "microtubule active compound" relates to microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubule polymerization inhibitors, including but not limited to: taxanes such as paclitaxel and polydextrose ( Docetaxel); vinca alkaloid, such as vinblastine (especially sulphuric acid sulphate), vincristine (especially vinca sulphate) and vinorelbine; Descendé Discodermolide; cochicine; and epothilone and its derivatives, for example, epothilone B or epothilone D or a derivative thereof. Pacific paclitaxel can be administered, for example, in the form as it is marketed, for example, under the trademark TAXOL. Docetaxel can be administered, for example, in the form as it is marketed, for example, under the trademark TAXOTERE. Vinblastine sulfate can be administered, for example, in the form as it is marketed, for example, under the trademark VINBLASTIN R.P. The vincosine sulfate test can be obtained, for example, in the form of, for example, the trademark FARMISTIN, which is commercially available, for example, as disclosed in U.S. Patent 5,010,099. Epothilone derivatives are also disclosed, which are disclosed in WO 98/10121, US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461, and WO 00/31247. Particularly preferred is epothilone A and/or epothilone B. The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan 141243.doc •29-201006469 (melphalan) or ashishiji Urea (nitrosourea) (BCNU or Gliadel). Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTIN. The ifosfamide can be administered, for example, in the form as it is marketed, eg under the trademark HOLOXAN. As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cisplatin, shunming ( Cisplatinum) and oxaliplatin. The card name can be administered, for example, in the form of, for example, the trademark CARBOPLAT. Osliplatin can be administered, for example, in the form as it is marketed, e.g., under the trademark ELOXATIN. The term "targeting/reducing protein or lipid kinase activity; or a protein or lipid phosphatase activity compound; or other anti-angiogenic compound" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine And/or a sulphate kinase inhibitor or a lipid kinase inhibitor, for example: a) a compound that targets, decreases or inhibits the activity of platelet-derived growth factor receptor (PDGFR), such as a compound that targets, decreases or inhibits PDGFR activity, Compounds that specifically inhibit the PDGF receptor, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668, and GFB-111; b) targeting, reducing or inhibiting fibroblasts a compound that is active in growth factor receptor (FGFR); c) a compound that targets, decreases or inhibits the activity of insulin-like growth factor receptor I (IGF-IR), such as a compound that is dry, reduces or inhibits IGF-IR activity, especially Compounds that inhibit the kinase activity of the IGF-I receptor, such as those disclosed in WO 02/092599, or extracellular to the IGF-I receptor or its 141243.doc • 30-201006469 growth factor a domain antibody; d) a compound that is dry, reduces or inhibits the activity of the Trk receptor retinoic acid kinase family, or an ephrin B4 inhibitor; e) a compound that is dry, reduces or inhibits the activity of the Axl receptor valine kinase family; f) a compound that redirects, reduces or inhibits the activity of the Ret receptor valine kinase; g) a compound that targets, reduces or inhibits the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; I h) targeting a compound that reduces or inhibits the activity of the C-kit receptor tyrosine kinase (part of the PDGFR family), such as a compound that targets, decreases or inhibits the activity of the c-Kit receptor tyrosine kinase family, particularly inhibits c-Kit Compounds such as imatinib; i) compounds that target, reduce or inhibit c-Abl family members, their gene fusion products (eg, BCR-Abl kinase), and mutant activities, such as targeting, reducing or inhibiting c - Abl family members and their gene fusion product activities - compounds such as N-phenyl-2-, biting-amine derivatives such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (from ParkeDavis); Or dasatinib (BMS-354825); j) targeting, reducing or inhibiting protein kinase C (PKC) members and members of the serine/threonine kinase Raf family, MEK, SRC, JAK, FAK, Compounds of PDKJ, PKB/Akt members and members of the Ras/MAPK family and/or members of the cyclin-dependent kinase family (CDK), and in particular those derived from Staurosporine disclosed in US 5,093,330 141243.doc -31- 201006469, such as rice betaostaurin; examples of other compounds include, for example, UCN-01, safingol, BAY 43-9006, Bryostatin 1 Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compound, such as disclosed in WO 00/09495 ; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) 瘳 compounds that target, reduce or inhibit protein-tyrosine kinase inhibitor activity, such as targeting, reducing or inhibiting protein-case Amino acid kinase inhibitor active compound Yue comprising imatinib mesylate (GLEEVEC®) or tyrphostin. Tyrphostin is preferably a low molecular weight (Mr < 1500) compound or a pharmaceutically acceptable salt thereof, especially selected from the group consisting of benzalmalononitrile or S-aryl phenylmalononitrile or double acceptor quinoline A compound of the compound, more particularly any compound selected from the group consisting of: Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) pair Opids; Tyrphostin AG 555 ; AG 494 ; Tyrphostin AG 556 , AG957 and · adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid acetonide vinegar; NSC 680410, adaphostin); l) targeting, reducing or inhibiting the epidermal growth factor family of receptor tyrosine kinases (in the form of homodimers or heterodimers, EGFR, ErbB2

Compounds of ErbB3, ErbB4) and their mutants, such as targeting, 141243.doc-32-201006469 Compounds that reduce or inhibit the activity of the epidermal growth factor receptor family are particularly members of the EGF receptor tyrosine kinase family (eg, EGF receptor, ErbB2, ErbB3 and ErbB4) or a compound, protein or antibody that binds to an EGF or EGF-related ligand, and in particular WO 97/02266 (for example a compound of Example 39), or EP 0 564 409, WO 99/ 03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5,747, 498 'WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and especially WO 96/3 0347 ( For example, compounds such as CP 3 5 8774), WO 96/3 3980 (eg compound ZD 1839) and WO 95/03283 (eg compound ZM105 180) are generally and specifically disclosed for their compounds, proteins or monoclonal antibodies; for example Trastuzumab (HerceptinTM), cetuximab (ErbituxTM), Iressa, Tarceva, OSI -774, CI-103 3, EKB-5 69, GW-2016, E1. E2.4, E2.5, E6.2, E6.4, E2 .ll, E6.3 or E7.6.3, and 7H-pyrrolo[2,3-d]pyrimidine derivatives, disclosed in WO 03/013541; and m) targeting, reducing or inhibiting c-Met receptors An active compound such as a compound that targets, decreases or inhibits c-Met activity, particularly a compound that inhibits the kinase activity of the c-Met receptor, or an antibody that targets the extracellular domain of c-Met or binds to HGF. Other anti-angiogenic compounds include compounds that have additional mechanisms of activity (eg, unrelated to protein or lipid kinase inhibition), such as 'thalidomide (THALOMID) and TNP-470 °, targeting, reducing or inhibiting proteins or lipids Compound Example of Phosphatase Activity 141243.doc • 33· 201006469 For example, a phosphatase 1 inhibitor, a phosphatase 2A inhibitor or a CDC25 inhibitor, such as okadaic acid or a derivative thereof. Compounds that induce cell differentiation processes are, for example, retinoic acid, alpha-tocopherol, gamma-tocopherol or delta-tocopherol or alpha-tocotrienol, gamma-tocotrienol or delta-tocotrienol phenol. The term cyclooxygenase inhibitor as used herein includes, but is not limited to, for example, a Cox-2 inhibitor, a 5-alkyl substituted 2-arylaminophenylacetic acid, and a derivative such as celecoxib. (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid (eg, 5-mercapto-2) -(2'-Gas-6'-fluoroanilino)phenylacetic acid), Lumiracoxib. The term "bisphosphonate" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid. ), alendronic acid, ibandronic acid, risedronic acid and. Sit zoledronic acid. "Etoxin acid" can be administered, for example, in the form as it is marketed, for example, under the trademark DIDRONEL. "Colaphosphonic acid" can be administered, for example, in the form as it is marketed, for example, under the trademark BONEFOS. "Tirolic acid" can be administered, for example, in the form as it is marketed, for example, under the trademark SKELID. "Pamidronic acid" can be administered, for example, in the form as it is marketed, for example, under the trademark AREDIATM.

"Alendronic acid" can be administered, for example, in the form as it is marketed under the trademark FOSAMAX. "Ibandronic acid" can be administered, for example, in the form as it is marketed, for example, under the trademark BONDRANAT. "Risedronic acid" can be administered, for example, in the form as it is marketed, for example, under the trademark ACTONEL. "Zoledronic acid" can be administered, for example, in the form as it is marketed, for example, under the trademark ZOMETA 141243.doc • 34-201006469. The term "mTOR inhibitor" relates to a compound that inhibits the mammalian target of rapamycin (mT〇R) and has antiproliferative activity, such as sirolimus (Rapamune) (g )), everolimus (CerticanTM), CCI_779 and ABT578. The term "heparinase inhibitor" as used herein refers to a compound which is dry, reduces or inhibits the degradation of heparin sulfate. The term includes, but is not limited to, pi_88. As used herein, "a biological response modifier" refers to lymphokine or interferon, such as interferon gamma. The term "Ras oncogenic isoform inhibitor" (eg, H-Ras, K-Ras or N-Ras) as used herein refers to a compound that targets, decreases or inhibits the carcinogenic activity of Ras, eg, "Fani A famesyl transferase inhibitor, such as L-744832, DK8G557 or R115777 (Zamestra). The term "telomerase inhibitor" as used herein refers to a compound which targets, decreases or inhibits telomerase activity. Compounds which dry, reduce or inhibit telomerase activity φ are especially compounds which inhibit telomerase receptors, such as telomestatin. The term "methionine amine peptidase inhibitor" as used herein refers to a compound that is dry, 'reducing or inhibiting the activity of anthracycline aminopeptidase. The compound which is dry, reduced or • inhibits the activity of methionine peptidase is, for example, bengamide or a derivative thereof. The term "proteasome-inhibiting maiko" as used herein refers to a compound which is dry, reduces or inhibits the activity of protease Zhao. Compounds which coarsely, reduce or inhibit the activity of the proteasome include, for example, Bettézil (Vicat 141243. doc-35. 201006469 (Velcade)TM) and MLN 341. The term "matrix metalloproteinase inhibitor" or ("ΜΜΡ" inhibitor) as used herein includes, but is not limited to, a collagen peptide mimetic and a non-peptide mimetic inhibitor, a tetracycline derivative such as hydrogengrass. Amine ester peptide mimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), beauty Metastat (NSC 683551), BMS-27925, BAY 12-9566, TAA21, MMI270B or AAJ996. The term "compound for the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, such as targeting, reducing or inhibiting FMS-like tyrosine kinase receptors (Flt-3R). Active compounds; interferons, sputum-bD-arabinoside ara-c and bisulfan; and ALK inhibitors, for example, targeting, reducing or inhibiting pleomorphic lymphoma a compound of a kinase. A compound that targets, reduces or inhibits the activity of the FMS-like tyrosine kinase receptor (FU-3R), particularly a compound, protein or antibody that inhibits members of the Flt-3R receptor kinase family, such as PKC412, militalin, and spores A bacteriocin derivative, SU11248 and MLN518. The term "HSP90 inhibitor" as used herein includes, but is not limited to, compounds that target, decrease or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteasome pathway . A compound that targets, decreases or inhibits the intrinsic ATPase activity of HSP90, particularly a compound, protein or antibody that inhibits the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin ( 17AAG) (a kind of geldanamycin derivative); other geldanamycin related 141243.doc • 36- 201006469 compound; radicicol; and HDAC inhibitor. The term "anti-proliferative antibody" as used herein includes, but is not limited to, trastuzumab (HejiapingTM), trastuzumab-DM1, Erbitux, bevacizumab (cancer) AvastinTM), rituximab (Rituxan®), PR064553 (anti-CD40) and 2C4 antibodies. An antibody means, for example, an intact monoclonal antibody, a plurality of antibodies, a multispecific antibody formed of at least two intact antibodies, and an antibody fragment which exhibits desired biological activity. The term "anti-leukemia compound" includes, for example, Ara-C (a mouth bite analog) which is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the analogs of hypoxanthine, 6-mercaptopurine (6-indene), and fludarabine phosphate. As used herein, a somatostatin receptor antagonist refers to a compound that targets, processes or inhibits the somatostatin receptor, such as octreotide and SOM230. Tumor cell destruction methods refer to methods such as ionizing radiation. The term "ionized radiation" as referred to above and hereinafter means ionizing radiation in the form of electromagnetic radiation (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Heilman, Principles of Radiation Therapy, Cancer, Praci/ce 〇/ 0 «co/og, Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993). The term EDG-binding agent as used herein refers to a class of immunosuppressive agents that modulate lymphocyte recirculation, such as FTY720. The term ribonucleotide reductase inhibitor refers to pyrimidine or purine nucleoside analogous to 141243.doc-37-201006469, including but not limited to fiudarabine and/or cytosine arabinoside (ara-C) ), 6-thiopurine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL) and / or pent〇statin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1β-isoindole-1,3-dione derivatives such as Nandy et al, jcia, Vol. 33, No. 8, 953- PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned on page 961 (1994). The term "adenosine methionine decarboxylase inhibitor" as used herein includes, but is not limited to, the compounds disclosed in U.S. Patent 5,461,076. Also included are compounds, proteins or monoclonal antibodies of the VEGF disclosed in WO 98/35958, for example, xenon 4-anilino)-4-(4.pyridylfluorenyl)pyridazine or its medicinal An acceptable salt (e.g., succinate), or such VEGF as disclosed in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, and EP 0 769 947 Compound, protein or monoclonal antibody; eg, Prewett et al., Cancer '第59^- » % 5209-5218^ (1999) Ϊ Yuan^ A > Proc Natl Acad Sci, Vol. 93, pp. 14765-14770 (1996) ; Zhu et al., Cancer, vol. 58, pp. 3209-3214 (1998); and Mordenti et al., Corpse^"/2〇/, Vol. 27, No. 1, pp. 14-21 (1999) ; such compounds, proteins or monoclonal antibodies of VEGF as described in WO 00/37502 and WO 94/10202; ANGIOSTATIN, by O'Reilly et al, Ce//, vol. 79, 315-328 (1994); Endostatin (ENDOSTATIN), described by O'Reilly et al, Ce / /, 88 141243. doc • 38 · 201006469, pp. 277-285 (1997); adjacent Amidoxime; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibody or anti-VEGF receptor antibody, such as rhuMAb and RHUFab, VEGF aptamer, such as Macugon; FLT- 4 inhibitor, FLT-3 inhibitor, VEGFR-2 IgG1 antibody, angiase (Angiozyme) (RPI 46 1 0) and bevacizumab (cancer TM). Photodynamic therapy as used herein refers to a therapy for treating or preventing cancer using certain chemicals known as photosensitizing compounds. Examples of photodynamic therapy include treatment with a compound such as VISUDYNE and porfimer sodium. Angiostatic steroid, as used herein, refers to a compound that blocks or inhibits angiogenesis, such as anacontave, triamcinolone, hydrocortisone, ll-α- Hydrogen cortisol (11-oc-epihydrocotisol), 11-deoxycorticol (cortexolone), 17α-pyridinone, corticosterone, deoxycorticosterone, tamoxifen, dexamethasone and dexamethasone ). A corticosteroid-containing implant refers to a compound such as fluocinolone or dexamethasone. Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA Or a hybrid compound or a compound having other or unknown mechanisms of action. The compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drugs such as anti-inflammatory drugs, bronchodilators or antihistamines, 141243.doc-39-201006469, especially for the treatment of such as mentioned above Obstructive or inflammatory airway diseases, for example, as therapeutic therapeutic potentiators of such drugs or as a means of reducing the required dose or potential side effects of such drugs. The compound of the present invention may be mixed with other drugs in the form of a fixed pharmaceutical composition or may be administered separately before other drugs, simultaneously with other drugs or after other drugs. Accordingly, the invention includes a combination of a compound of the invention as described above with an anti-inflammatory agent, a bronchodilator, an antihistamine or a cough suppressant, the compound of the invention and the drug being in the same or different pharmaceutical compositions. Suitable anti-inflammatory drugs include steroids, especially such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate. a glucocorticosteroid of (mometasone furoate), or WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (particularly examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101, WO 03/035668,

WO 03/048181, WO 03/062259, WO 03/064445, WO

Steroids as described in G 03/072592, such as non-steroidal glucocorticoids as described in WO 00/00531, WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229 Receptor agonists; LTB4 antagonists such as those described in LY293111, CGS025019C, .CP-195543, SC-53228, BIIL 284, ΟΝΟ 4057, SB 209247 and US 545 1700; LTD4 antagonists, such as Meng Montelukast and zifirlukast; PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline), roflus 141243.doc -40- 201006469

Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659/PD168787 (Parke- Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene)' SelCID(TM) CC-10004(Celgene)>VM554/UM565 (Vernalis), T-440(Tanabe) 'KW-4490( Kyowa Hakko Kogyo), and WO 92/19594, WO 93/19749, WO 93/19750, WO 93/1975, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205 , WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449 , WO 04/018450, WO 04/01845, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607, and WO 04/037805; A2a agonist, For example, EP 409 595 A2, EP 1052264, EP 1241176, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/2445, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265 WO 01/67266, WO 00/23 457, WO 00/77018, WO 00/78774, WO 01/23399 'WO 01/27130' WO 01/27131 'WO 01/60835 ' WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, WO 03/086408 'WO 04/039762, WO 04/039766, WO 04/045618 and WO 04/046083; A2b antagonists, such as in WO 02/42298 Revealer; and β-2 adrenergic receptor agonist, 141243.doc -41- 201006469 such as albuterol (salbutamol), metaproterenol, terbutaline ( Terbutaline), salmeterol, fenoterol, procaterol and especially formoterol and its pharmaceutically acceptable salts, and WO 0075114 (the literature) A compound of formula I (in free form or in the form of a salt or a solvate) incorporated herein by reference, preferably a compound of its kind, especially a compound of the formula:

And pharmaceutically acceptable salts thereof, and compounds of formula I in WO 04/16601 (in free form or in salt or solvate form), and compounds of WO 04/033412. Suitable bronchodilators include anticholinergic or anticonvulsant compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salt, and CHF 4226 (Chiesi) And glycopyrrolate, and WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03 /53966, EP 424021, US 5171744, US 37143 57, WO 03/33495 and WO 04/01 8422. Suitable antihistamines include cetirizine hydrochloride. Cetirizine hydrochloride, acetaminophen, antibutanic acid 141243.doc -42- 201006469 clemastine fumarate, promethazine, loratidine ), desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, gas drawing Azelastine, ebastine, epinastine, _ »sit; mizolastine and tefenadine and WO 03/099807, WO 04/026841 And as described in JP 2004107299. Other useful combinations of the compounds of the invention and anti-inflammatory drugs are with chemokine receptors (eg, CCR), CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, Combinations of CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5) antagonists, especially CCR-5 antagonists (such as Schering-Plough Antagonist Sword SC-351125, 8 (: 11-5 5700 and 8 (:11-〇), butyl & 1 <^(1& antagonist (such as]^-[[4-[[[6,7-dihydro-2-(4-methyl) Phenyl)_5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-indole, fluorenyl-dimercapto-2H-pyran-4-hythium chloride ( TAK-770)) and in US 6166037 (especially technical solutions 18 and 19), WO 00/66558 (especially technical solution 8), WO 00/66559 (particularly technical solution 9), WO 04/018425 and WO 04/026873 Said CCR-5 antagonist. It can be from the current version of the standard summary "The Merck Index" or from, for example, the International Patent (International) (for example, 'IMS World Publications') The database obtains the structure of the active compound identified by the number, common name or trade name. The above-mentioned compounds which can be used in combination with the compound of the formula (i) are prepared and administered as described in the art (such as in the literature cited above). The compound of the formula (I) may also advantageously Knowing therapeutic methods, for example, in combination with hormones or especially light shots. The compound of formula (1) can be especially useful as a radiation sensitizer, especially for treating tumors that exhibit poor sensitivity to radiation therapy. "Combination" means a dosage unit. a fixed combination of forms; or where the compound of formula (1) and the combination partner can be administered simultaneously or separately during a time interval, especially if such time intervals allow the combined conjugate to exhibit a synergistic (eg, synergistic) effect, It means a kit of parts for combined administration. The AML cell line KG-1 used in the example: KG-1 cell line is derived from erythroblastic leukemia which develops acute osteogenic leukemia 59 Caucasian male bone extract. KG-1 a: KG-1 a cell line is a derivative of KG-1 cell line and does not respond to community stimulating factors in soft agar culture and does not Now sample antigen 13. KG-1 a sigh cells induced giant cell phorbol diesters of differentiation and proliferation of resistant cells and the like from the operation of the presence of phorbol diacetate. THP-1: THP-1 cells are phagocytic cells with no surface and cytoplasmic immunoglobulin. The phorbol ester 12-0-tetradecyl phorbol 13·acetate (τρα) induces monocyte differentiation. LAMA-84: Cell line HL60 derived from acute myeloid leukemia mother cells · Cell line derived from acute bone marrow leukemia mother cells 141243.doc • 44- 201006469 Basic principle of DAC inhibition of AML/MDS • In AML, such as t( 8,21), t(ll,17) and the oncogenic translocation of CBP-MLL recruit HDAC to suppress the transcription of bone marrow differentiation genes. • The deacetylation of HDAC6 to hsp90 is required for concomitant protein activity and stabilization of leukemia proteins such as Bcr-Abl in CML and mutant FLT-3 in AML. • Prove the cross-talk between histone deacetylation and DNA thiolation in genetic silencing beyond tumor suppressor. • Since the combination of a DAC inhibitor and a demethylating agent synergizes to inhibit tumor suppressor factors such as pi 6, such combinations will be clinically beneficial for demethylatoring. AML/MDS for drug efficacy. LBH589 data in MDS/AML • LBH589 is a potent single agent in many AML cell lines and new isolated cells from AML patients. • The anti-leukemia effect of LBH589 is mediated by anti-proliferative and pro-apoptotic mechanisms. • The combination of Panobinostat with Cytarabine, Fludarabine, Bortezomib and major doxorubicin enhances the anti-leukemia efficacy of each individual agent. • The combination of pabisstat with doxorubicin + cytarabine fludarabine and four recombinants may be an interesting treatment option for patients with relapsed/refractory AML. • Treatment of AML cells with LBH589 + 5-azacytidine resulted in higher apoptosis compared with treatment with either single agent 141243.doc -45· 201006469. • DNMT1 (target of 5-azacytidine) is an HSP90 client protein that is degraded after treatment of AML cell lines with LBH589. • Co-treatment with LBH589+17-AAG against imatinib-born CML-BC and AML cells with activated FLT-3 mutations induced co-cell killing. Table 1. Single agent anti-tumor activity of LBH589 in live AML cell line. Cell line type IC50/nM LD50/nM LD90/nM HL-60 AML - 1.4 5.6 KG-1 AML 0.5 2.2 8.7 KG-la AML 3.0 7.1 14.8 THP-1 AML 1.0 13.4 > 10,000 IC50: concentration of LBH589 required to inhibit cell growth by 50% LD50: concentration of LBH589 required to kill 50% of the cell population: LD90: kill the cell population The concentration of LBH589 required for 90% death AML cell lines HL60, KG, KGla and THP-1 were treated with increasing concentrations of LBH589, incubated for 72 hours and the resulting cell growth was assessed using the MTS assay. Calculate IC50, the concentration required to inhibit cell growth by 50%; LD50, the concentration of LBH589 required to reduce the initial inoculum of the cells by 50%; and LD90, to kill the cell population almost completely (>90%) The concentration of LBH589. As can be seen from Table 1, all AML cell lines were highly sensitive to LBH589-induced cell growth inhibition and death (IC50 and LD50 were low nanomolar concentrations). The AML cell line LAMA84 and nascent AML mother cells isolated from the patient were treated with LBH589 alone or in combination with decitabine or with the hsp90 inhibitor 17-DMAG. Cell lysates were prepared from the treatment group and the control group by 141243.doc -46-201006469 cells, and the concentration of DNMT1 was analyzed by Western immunoblotting, which is the current MDS study drug decitabine and 5 - Aza-cytidine (vidaza) target. Evaluate other targets EZH2 and hsp70. Β-actin was used as a loading control. As can be seen in Figure 1, treatment of these cells with LBH589 alone or in combination with decitabine or treatment with 17-DMAG resulted in cell depletion of DNMT1 and EZH2. Increased hsp70 levels indicate that target depletion occurs via hsp90 inhibition. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows N-hydroxy-3-[4-[[[2-(2-mercapto-1H-indol-3-yl)-ethyl]-amino]methyl]benzene ]]2E-2-propenylamine causes degradation of DNMT1 (DNMTI is the target of the MDS drugs Vidaza and decitabine) in leukemia mother cells. 141243.doc -47-

Claims (1)

201006469 VII. Scope of Application: 1. The use of an HDAC inhibitor for the preparation of a drug for (4) a disease selected from the group consisting of acute osteonechotic leukemia and (4) m-money group. 2. The use of claim 1, wherein the HDAC inhibitor is a compound of formula (1): Ο R Ri is Η; halo; or straight-chain Ci_C6 alkyl, especially mercaptoethyl or n-propyl, the methyl, ethyl and n-propyl substituents are unsubstituted or one or more of the following about dazzling &gt Substituent substituent substituted; K.2 is selected from hydrazine; C--C丨0 alkyl, preferably 匚丨-匸6 alkyl, such as methyl, ethyl or -CH2CH2-OH C4-C9 cycloalkyl; C4-C9 heterocycloalkyl, CU-Cs»heterocyclic alkyl; cycloalkyl, such as cyclopropyl fluorenyl; aryl; heteroaryl; aryl An alkyl group, such as a benzyl group; a heteroarylalkyl group such as pyridyl fluorenyl; -(CH2)nc(C〇R6; -(CH2)n0C(0)R6; an amine fluorenyl; HON-CCOXl^C^ R,)-aryl-alkyl-; and _(CH2)nR7; 'R3 is the same or different from R.sup.4, and independently H; C--C6 alkyl; stearyl; or mercaptoamine; Or R3 and Κ4 together with the carbon to which they are combined represent C=〇, <C=NR8; or R2 together with the nitrogen and R3 to which it is combined, together with the carbon to which it is bonded 141243.doc - 1 - 201006469 c4- C9 heterocycloalkyl; heteroaryl s succinyl, non-aromatic polyheterocyclic, or mixed aryl and non-aryl polyheterocycle; R5 CVC6 alkyl; cc 4 C9 cycloalkyl, C4-C9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, eg, benzyl; heteroaryl fluorenyl, eg, (tetra)ylmethyl; Aromatic polycyclic; non-aromatic polycyclic; mixed aryl and non-aryl polycyclic; polyheteroaryl; non-aromatic polyheterocycle; and mixed aryl and non-aryl polyheterocycle; η, ηι, n2An3 The same or different and independently selected from 〇·6, when u, each carbon atom may be optionally substituted by ^ and / (4); X and γ are the same or different and independently selected from Η; _ base; Ci C4 Institute Bases, such as CH3 and CF3; N〇2; c(〇)Ri; 〇R9; recognize 9; CN; and NR10Rn; Κ·6 are selected from Η; Cj-Cf; Hyun. p r1 broadcast a Gan. 6 play 丞, L4_C9 cycloalkyl; c4-C9 heterocyclic: group; cycloalkylalkyl, such as cyclopropylmethyl; aryl; heteroarylarylalkyl, such as benzyl and 2-phenylethylene Heteroarylalkyl, such as pyridylmethyl; ORi2; &NRi3r"; R7 ❹ Is selected from or15; sr15; s(o)r16; so2R17; NR]3Ri4; and nr12so2r6; Rs is selected from H; OR15; NR丨3Ri4; Ci-C6 alkyl; c4-c9 cycloalkyl'·CcC9 a cycloalkyl, an aryl group; a heteroaryl group; an arylalkyl group such as a benzyl group; and a heteroarylalkyl group such as n to a dimethyl group; the R9 group is selected from a CVC4 alkyl group such as CH3 and cf3; (o)-alkyl, such as c(o)ch3; and c(o)cf3; R丨0 is the same or different and independently selected from Η; c丨-C4 alkyl; and 141243.doc 201006469 -c (o)-alkyl; R12 is selected from fluorene; (VC6 alkyl; (: 4-(: 9 ring t I . r Λ . r ^ group, c4-c9 heterocycloalkyl, CrC: 9 heterocycloalkane) An alkyl group; an aryl group, a mixed aryl group and a non-radical polycyclic ring; a heteroaryl group; an arylalkyl group, such as benzyl; and a heteroarylalkyl group such as pyridylmethyl R13 and R14 are the same or different and are independently selected from (b), c, -c6 alkyl; C4_C9 ring-based; C4-C9 heterocycloalkyl; aryl; heteroaryl; aryl a group such as benzyl; heteroarylalkyl, such as pyridylmethyl; amine-based; or ~ and R" together with the nitrogen to which they are combined, is a C4_C9 heterocycloalkyl; heteroaryl; polyaromatic | Non-aromatic polyheteropolycycloalcohol mixed aryl and non-aryl polyheterocycle; ~ is selected from oxime; Cl_c6 alkyl; C4_C9 cycloalkyl; C4_C9 heterocycloalkyl; aryl; heteroaryl; aryl Alkyl; heteroarylalkyl; and (CH2)mZR12; R16 is selected from the group consisting of (VC6 alkyl; C4_C9 cycloalkyl; C4_C9 heterocycloalkyl; aryl; heteroaryl; polyheteroaryl; arylalkyl; heteroarylalkyl; and (CH2)mZR12; Rw Is selected from CVC6 alkyl; C4_C9 cycloalkyl; C4_C9 heterocycloalkyl; aryl 'aromatic polycyclic; heteroaryl; arylalkyl; heteroarylalkyl; polyheteroaryl and NR13R14; An integer selected from 0 to 6; and Z is selected from the group consisting of hydrazine; NR13; S; and 8 (〇), or a pharmaceutically acceptable salt thereof. 141243.doc 201006469 3. The use of claim 2 The compound of the formula (1) is a pyridyl group of the formula (4)-3-[4-[[[2-(2-methyl- 韵 朵 _3_yl)ethyl]amino]methyl] phenyl]-2 -2-propanol amine: (III), or a pharmaceutically acceptable salt thereof. The use of any one of the items (1), wherein the warm-blooded animal is a human. The material is selected from the group consisting of acute (four) autoimmune diseases and (4) developmental syndrome, and the method of the disease includes the warm blood to the need The animal is administered a therapeutically effective amount of an HDAC inhibitor. 6. The method of claim 5, which comprises administering to the warm-blooded animal in need thereof a therapeutically effective amount of a compound of formula (I): (I) where R is! a dentate group; or a linear Ci_C6 alkyl group, especially methyl ethyl or n-propyl, the methyl, ethyl and n-propyl substituents being unsubstituted or via one or more of the following alkyl substituents Substituted substituents; R2 is selected from H; C _ Cl 〇 alkyl, preferably 〇 1 < 0 alkyl, such as a 141243.doc 201006469 base, ethyl or -ch2ch2-oh; c4-c9 naphthenic C4-C9 heterocycloalkyl; C4_C: 9 heterocycloalkylalkyl; cycloalkylalkyl, such as cyclopropylindenyl; aryl; heteroaryl; arylalkyl, eg benzyl; Arylalkyl, for example pyridylmethyl; _(CH2)nC(〇)Re; _(CH2)n0C(0)R6; amine fluorenyl; h〇n_c(〇)_ch=c(Ri) aryl -alkyl-; and -(CH2)nR7; & same or different from h, and independently H; Ci_C6 alkyl; fluorenyl; or decylamino; or R3 and R4 together with the carbon to which they are attached represent c=〇, c=s or C=NR8 Or R2 together with the nitrogen and R3 to which it is bonded, together with the carbon to which it is bonded, may form a C:C9 heterocycloalkyl group; a heteroaryl group; a polyheteroaryl group; a non-aromatic polyheterocyclic ring, or a mixed aryl group and a non-aromatic group; a polyheterocyclic ring; R5 is selected from H; CVC6 alkyl; C4_C9 cycloalkyl; heterocycloalkyl fluorenyl; aryl '. heteroaryl; arylalkyl, such as a benzyl group; , for example, _ylmethyl; aromatic polycyclic; non-aromatic polycyclic; mixed aryl and non-aryl polycyclic; polyheteroaryl; non-aromatic polyheterocycle; and mixed aryl and non-aryl poly η, 111, 〜, and 〜 are the same or different and independently selected from 〇-6, when ... is 66, each rabbit atom may be as appropriate and independent (4) taken the same or different and independently selected from H; _; ci_c4 Base, such as CH4CF3; n〇2; c(〇)Ri; 〇r9; sr9Cn; and NRjoR]]; R6 is selected from H; c, basic meaning M; CVC9 heterocyclic 141243.doc 201006469 base; naphthenic Alkyl group, such as cyclopropyl fluorenyl; aryl; hetero An arylalkyl group such as a benzyl group and a 2-phenylvinyl group; a heteroarylalkyl group such as a carbyl methyl group; 0R 2; &NRi3R"; R? is selected from or15; sr15; (0) R,6; s〇2Ri7; NRi3Ri4; and nr12so2r6; R8 is selected from H; OR15; NR13R14; Cl_c6 alkyl; c4 c9 cycloalkyl, C4-C9 heterocycloalkyl; aryl; heteroaryl An arylalkyl group, such as a benzyl group; and a heteroarylalkyl group, such as pyridylmethyl; R9 is selected from the group consisting of c]-c4 leuco, such as chaCF3; c(〇)alkyl such as c(o)ch3; And c(0)cf3; R1〇 is the same as or different from R11 and is independently selected from H; Ci_c4 alkyl; and -C(O)-alkyl; ~: selected from H; Cl_C6 alkyl; C4_C9 cycloalkyl; C4 ring-burned soil, CVC9 heterocyclic ruthenium; aryl; mixed aryl and non-aryl polycyclic; heteroaryl; arylalkyl, for example, ^ ^ such as benzyl; and heteroaryl Pyridylmethyl; R!3 is the same or different and independently selected from the RM 4 1 ^§H, CVC6 alkyl; c4_c9% of the base; CVC9 heterocycloalkyl; Fangm. «. 'heteroaryl; a base group such as a benzyl group; a heteroarylalkyl group; an alkyl group; or Methyl; amines Ri3 & RH together with the nitrogen to which they are combined. Insult C4-C9 heterocycloalkyl; heteroaryl polyheterocycle; #, or mixed aryl and non-R15 are selected from H; Cl_c6 alkane Base; c4_c long base; c4-c9 heterocycloalkane 141243.doc 201006469 base; aryl; heteroaryl; arylalkyl; heteroarylalkyl; and (CH2)mZR12; R16 is selected from C- C6 alkyl; (34-(:9-cycloalkyl; c4-c9 heterocycloalkyl; aryl; heteroaryl; polyheteroaryl; arylalkyl; heteroarylalkyl; and (CH2)mZR12 ; R" is selected from the group consisting of Cl_C6 alkyl; C4_C9 cycloalkyl; c4_C9 heterocycloalkyl; aryl; aromatic polycyclic; heteroaryl; arylalkyl; heteroarylalkyl; B polyheteroaryl and Nr13r14; m is an integer selected from the group consisting of; and Z is selected from 0; NR13; S; and S(0), or eight pharmaceutically acceptable salts. 141243.doc