CN100546980C

CN100546980C - Benzimidizole derivatives: preparation method and medical applications

Info

Publication number: CN100546980C
Application number: CNB2004800273304A
Authority: CN
Inventors: 陈迪忠; 坎答·山东皮塔; 宋红岩; 艾瑞克T·孙; 余聂芳; 邹勇
Original assignee: SBio Pte Ltd
Current assignee: Mel Pharmaceuticals Ltd By Share Ltd
Priority date: 2003-09-22
Filing date: 2004-09-21
Publication date: 2009-10-07
Anticipated expiration: 2024-09-21
Also published as: AR104985A2; ES2348360T3; CN1860103A; ZA200602181B

Abstract

The present invention relates to histone deacetylase inhibitors hydroxamic acid ester cpds.More particularly, the present invention relates to compound of containing benzoglyoxaline and preparation method thereof.These compounds can be used as treatment proliferative disorders and other relate to, about or with the medicine of the dysregulation diseases associated of histone deacetylase (HDAC).

Description

Benzimidizole derivatives: preparation method and medical applications

Invention field

The present invention relates to can be the hydroxamic acid ester cpds of histone deacetylase inhibitors.More particularly, the present invention relates to compound of containing benzoglyoxaline and preparation method thereof.These compounds can be used as treatment proliferative disorders and other relate to, about or with the medicine of the dysregulation diseases associated of histone deacetylase (HDAC).

Background of invention

Chromatinic local structure generally is identified as the important factor in the genetic expression adjusting.Chromatin, a kind of protein-DNA mixture is to be subjected to its protein member strongly: the influence of translating the back modification of histone.The reversibility acetylize of histone can become the key member of genetic expression in regulating by changing transcription factor to the affinity of DNA.Usually; the raising of acetylation of histone degree is relevant with increasing of transcriptional activity; then relevant [the Wadem P.A.Hum.Mol.Genet.10 of the reduction of acetylation of histone degree with the inhibition of genetic expression; 693-698 (2001); people such as De Ruijter A.J.M.; Biochem.J., 370,737-749 (2003)].In normal cell, histone deacetylase (HDACs) and histone acetyl based transferase are regulated and control the degree of acetylation of histone together to keep balance.The inhibition of HDACs can cause the accumulation of acetylated histones, and it can cause the reaction of various cell pattern dependent cells, and for example: carving dies, necrosis, differentiation, cell survival, inhibition of proliferation and cell static (cytostasis).

The inhibition of HDAC has been studied its curative effect to cancer cells.For example, Vorinostat (suberoylanilide hydroxamic acid, SAHA) effective inductor of dying for the differentiation in Muridae erythrocyte leucocythemia, bladder and the myeloma cell strain and/or carving.[people such as Richon V.M., Proc.Natl.Acad.Sci.USA, 93:5705-5708 (1996), people such as Richon V.M., Proc.Natl.Acad.Sci.USA, 95:3003-3007 (1998)].SAHA has been found can be in vitro with in the growth of in vivo constraining prostate cancer cell people such as [, Cancer Res.60,5165-5170 (2000)] Butler L.M..The hdac inhibitor that other HDAC have been widely studied its antitumour activity is trichostatin A (TSA) and Qu Baixin B (trapoxin B) [people such as Yoshida M., J.Biol.Chem., 265,17174 (1990), people such as Kijima M., J.Biol.Chem., 268,22429 (1993)].Trichostatin A is the reversible inhibitor of a kind of mammals HDAC.Qu Baixin B is a kind of cyclic tetrapeptide, and it is the non-reversibility inhibitor of mammals HDAC.Yet, because these compounds are in intravital unstable, so it is uncomfortable as cancer therapy drug.Recently, other small molecules hdac inhibitors can be used for clinical assessment [US6,552,065].Other HDAC inhibition compound has been reported in document [people such as Bouchain G., J.Med.Chem., 46,820-830 (2003)] and the patent [WO 03/066579A2, WO 01/38322 A1].The activity in vivo vivid of these inhibitor can directly get by the ability of monitoring its amount that makes acetylated histones in biological specimen raising.Hdac inhibitor can be disturbed neurodegenerative process by report, and for example, hdac inhibitor can suppress polyglutamic acid amides dependency nerve degeneration [Nature, 413 (6857): 739-43,18October, 2001].In addition, hdac inhibitor is also known to suppress cytokine known and inflammatory diseases and/or disorder of immune system implication, for example: the production [J.Biol.Chem.1990 of TNF, IFN, IL-1; 265 (18): 10230-10237; Science, 1998; 281:1001-1005; Dinarello C.A. and Moldawer L.L.Proinflammatory andanti-inflammatory cytokines in rheumatoid arthritis.A primer for clinicians. second edition, Amergen Inc., 2000].

Yet, still need provide other to have hdac inhibitor useful, the medicinal properties through improving, for example: carcinostatic agent.

Summary of the invention

One aspect of the present invention provides the compound of formula (I):

Formula I

Wherein:

R ¹Be selected from: H; alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; cycloalkylalkyl; the Heterocyclylalkyl alkyl; aralkyl; heteroaralkyl; aryl alkenyl; the cycloalkyl alkyl of mixing; the aryl alkyl of mixing; the Heterocyclylalkyl alkyl of mixing; the heteroaryl alkyl of mixing; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; the heterocycle alkoxyl group; aryloxy; heteroaryloxy; aralkoxy; amino; alkylamino; aminoalkyl group; amido; arylamino; phenoxy group; benzyloxy; COOH; carbalkoxy; alkyl amino-carbonyl; alkylsulfonyl; alkyl sulphonyl; alkyl sulphinyl; aryl sulfonyl; aryl sulfonyl kia; amino-sulfonyl; SR ⁶And acyl group, it all can not be substituted or be replaced by one or more substituting groups that are selected from down group: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃Alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; the halo alkynyl; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; the alkoxyl group heteroaryl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; cyclenes oxygen base; the heterocycle alkoxyl group; heterocycle alkene oxygen base; aryloxy; heteroaryloxy; aralkyl; heteroaralkyl; aralkoxy; amino; alkylamino; amido; aminoalkyl group; arylamino; alkylsulfonyl; alkyl sulphonyl; aryl sulfonyl; aryl sulfonyl kia; amino-sulfonyl; aminoalkyl group; alkoxyalkyl;-COOH;-C (O) OR ⁵,-COR ⁵,-SH ,-SR ⁶,-OR ⁶And acyl group;

Or R ¹=L;

R ²Be selected from: H; halogen; alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; cycloalkylalkyl; the Heterocyclylalkyl alkyl; aralkyl; heteroaralkyl; aryl alkenyl; the cycloalkyl alkyl of mixing; the Heterocyclylalkyl alkyl of mixing; the heteroaryl alkyl of mixing; the aryl alkyl of mixing; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; the heterocycle alkoxyl group; aryloxy; heteroaryloxy; aralkoxy; amino; alkylamino; aminoalkyl group; amido; arylamino; phenoxy group; benzyloxy; COOH; carbalkoxy; alkyl amino-carbonyl; alkylsulfonyl; alkyl sulphonyl; alkyl sulphinyl; aryl sulfonyl; aryl sulfonyl kia; amino-sulfonyl; SR ⁶And acyl group, it all can not be substituted or be replaced by one or more substituting groups that are selected from down group: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃Alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; the halo alkynyl; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; the alkoxyl group heteroaryl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; cyclenes oxygen base; the heterocycle alkoxyl group; heterocycle alkene oxygen base; aryloxy; heteroaryloxy; aralkyl; heteroaralkyl; aralkoxy; amino; alkylamino; amido; aminoalkyl group; arylamino; alkylsulfonyl; alkyl sulphonyl; aryl sulfonyl; amino-sulfonyl; aminoalkyl group; alkoxyalkyl;-COOH;-COR ⁵,-C (O) OR ⁵,-SH ,-SR ⁶,-OR ⁶And acyl group;

Or R ²=L;

R ³Be selected from H, C ₁-C ₆Alkyl and acyl group; Or be a kind of metal ion that is selected from sodium, calcium, magnesium;

X and Y are identical or different and are selected from respectively: H, halogen ,-CN ,-NO ₂,-CF ₃,-OCF ₃Alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; the halo alkynyl; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; the alkoxyl group heteroaryl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; cyclenes oxygen base; the heterocycle alkoxyl group; heterocycle alkene oxygen base; aryloxy; heteroaryloxy; aralkyl; heteroaralkyl; aralkoxy; amino; alkylamino; amido; aminoalkyl group; arylamino; alkylsulfonyl; alkyl sulphonyl; aryl sulfonyl; amino-sulfonyl; aminoalkyl group; alkoxyalkyl;-COOH;-C (O) OR ⁵,-COR ⁵,-SH ,-SR ⁶,-OR ⁶, acyl group and-NR ⁷R ⁸

R ⁴Be selected from: H, alkyl, alkenyl, alkynyl group, haloalkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, Heterocyclylalkyl alkyl, aralkyl, heteroaralkyl and acyl group;

Each R ⁵Independently be selected from: H, alkyl, alkenyl, alkynyl group, haloalkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, Heterocyclylalkyl alkyl, aralkyl, heteroaralkyl and acyl group;

Each R ⁶Independently be selected from: H, alkyl, alkenyl, alkynyl group, haloalkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, Heterocyclylalkyl alkyl, aralkyl, heteroaralkyl and acyl group;

Each R ⁷And R ⁸All independently be selected from separately: H, alkyl, alkenyl, alkynyl group, haloalkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, Heterocyclylalkyl alkyl, aralkyl, heteroaralkyl and acyl group;

L is selected from:

a)L＝Cy-L ¹-W-

Wherein

Cy is C ₁-C ₁₅Alkyl, aminoalkyl group, Heterocyclylalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, wherein any one can be chosen wantonly by one or more substituting groups that independently are selected from down group and replace: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃Alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; the halo alkynyl; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; the alkoxyl group heteroaryl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; cyclenes oxygen base; the heterocycle alkoxyl group; heterocycle alkene oxygen base; aryloxy; heteroaryloxy; aralkyl; heteroaralkyl; aralkoxy; amino; alkylamino; amido; aminoalkyl group; arylamino; alkylsulfonyl; alkyl sulphonyl; aryl sulfonyl; amino-sulfonyl; aminoalkyl group; alkoxyalkyl;-COOH;-C (O) OR ⁵,-COR ⁵,-SH ,-SR ⁶,-OR ⁶And acyl group.

L ¹Be selected from C ₁-C ₅Alkyl, it can be replaced by one or more substituting groups that independently are selected from down group; Halogen;=O;=S;-CN;-NO ₂Alkyl, alkoxyl group, amido and alkylamino;

W be selected from singly-bound ,-O-,-S-,-S (O)-,-S (O) ₂-,-N (R ⁹)-,-C (O) N (R ⁹)-,-SO ₂N (R ⁹)-, N (R ⁹) C (O)-, N (R ⁹) SO ₂-and-N (R ⁹)-C (O)-N (R ¹⁰)-;

b)L＝Cy-L ¹-W-L ²

Wherein,

Cy is C ₁-C ₁₅Alkyl, aminoalkyl group, Heterocyclylalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, wherein any one can be chosen wantonly by one or more substituting groups that independently are selected from down group and replace: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃Alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; the halo alkynyl; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; the alkoxyl group heteroaryl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; cyclenes oxygen base; the heterocycle alkoxyl group; heterocycle alkene oxygen base; aryloxy; heteroaryloxy; aralkyl; heteroaralkyl; aralkoxy; amino; alkylamino; amido; aminoalkyl group; arylamino; alkylsulfonyl; alkyl sulphonyl; aryl sulfonyl; amino-sulfonyl; aminoalkyl group; alkoxyalkyl;-COOH; C (O) OR ⁵,-COR ⁵,-SH ,-SR ⁶,-OR ⁶And acyl group;

L ¹And L ²Be identical or different and discrete C ₁-C ₅Alkyl, it can replace by one or more substituting groups that independently are selected from down group: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃, alkyl, alkoxyl group, amido and alkylamino;

c)L＝Cy-(CH ₂)m-W-

Wherein,

M is 0,1,2,3,4 or 5;

d)L＝L ¹-W-L ²

L ¹And L ²Identical or different and independently be selected from C ₁-C ₅Alkyl, it can be replaced by one or more substituting groups that independently are selected from down group: halogen;=O;=S;-CN;-NO ₂-CF ₃,-OCF ₃Alkyl, alkoxyl group, amido, alkylamino;

R ⁹And R ¹⁰Identical or different and independently be selected from: H, C ₁-C ₆Alkyl, C ₄-C ₉Cycloalkyl, C ₄-C ₉Heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl; And acyl group;

Z is selected from-CH ₂,-CH ₂CH ₂,-CH=CH-and C ₃-C ₆Cycloalkyl is not substituted or by one or more C that independently are selected from ₁-C ₄The substituting group of alkyl replaces; Or its pharmacy acceptable salt.

A kind of suitable hydroxamic acid compound kind has formula Ia:

Formula Ia

Wherein

Or R ¹=L;

Or R ²=L;

R ³Be selected from: H, C ₁-C ₆Alkyl and acyl group; Or be a kind of metal ion that is selected from sodium, calcium, magnesium;

X and Y are identical or different and are selected from respectively: H, halogen ,-CN ,-NO ₂,-CF ₃,-OCF ₃Alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; the halo alkynyl; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; the alkoxyl group heteroaryl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; cyclenes oxygen base; the heterocycle alkoxyl group; heterocycle alkene oxygen base; aryloxy; heteroaryloxy; aralkyl; heteroaralkyl; aralkoxy; amino; alkylamino; amido; aminoalkyl group; arylamino; alkylsulfonyl; alkyl sulphonyl; aryl sulfonyl; amino-sulfonyl; aminoalkyl group; alkoxyalkyl;-COOH-C (O) OR ⁵,-COR ⁵,-SH ,-SR ⁶,-OR ⁶, acyl group and-NR ⁷R ⁸

Each R ⁷And R ⁸All be selected from separately: H, alkyl, alkenyl, alkynyl group, haloalkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, Heterocyclylalkyl alkyl, aralkyl, heteroaralkyl and acyl group;

L is selected from:

a)L＝Cy-L ¹-W-

Wherein

L ¹Be selected from C ₁-C ₅Alkyl, it can be replaced by one or more substituting groups that independently are selected from down group: halogen;=O;=S;-CN;-NO ₂Alkyl, alkoxyl group, amido and alkylamino;

b)L＝Cy-L ¹-W-L ²

Wherein,

L ¹And L ²Identical or different and independent is C ₁-C ₅Alkyl, it can replace by one or more substituting groups that independently are selected from down group: halogen;=O;=S;-CN;-NO ₂-CF ₃,-OCF ₃, alkyl, alkoxyl group, amido and alkylamino;

c)L＝Cy-(CH ₂)m-W-

Wherein,

M is 0,1,2,3,4 or 5;

d)L＝L ¹-W-L ²

L ¹And L ²Identical or different and independently be selected from C ₁-C ₅Alkyl, it can be replaced by one or more substituting groups that independently are selected from down group: halogen;=O;=S;-CN;-NO ₂-CF ₃,-OCF ₃, alkyl, alkoxyl group, amido, alkylamino;

R ⁹And R ¹⁰Identical or different and independently be selected from: H, C ₁-C ₆Alkyl, C ₄-C ₉Cycloalkyl, C ₄-C ₉Heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl and acyl group;

Z is selected from-CH ₂,-CH ₂CH ₂,-CH=CH-and C ₃-C ₆Cycloalkyl is not substituted or by one or more C that independently are selected from ₁-C ₄The substituting group of alkyl replaces;

Or its pharmacy acceptable salt.

The useful compound of another group has formula Ib:

Formula Ib

Wherein

Or R ¹=L;

Or R ²=L;

X and Y are identical or different and be selected from respectively: H, halogen ,-CN ,-NO ₂,-CF ₃,-OCF ₃Alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; the halo alkynyl; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; the alkoxyl group heteroaryl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; cyclenes oxygen base; the heterocycle alkoxyl group; heterocycle alkene oxygen base; aryloxy; heteroaryloxy; aralkyl; heteroaralkyl; aralkoxy; amino; alkylamino; amido; aminoalkyl group; arylamino; alkylsulfonyl; alkyl sulphonyl; aryl sulfonyl; amino-sulfonyl; aminoalkyl group; alkoxyalkyl;-COOH-C (O) OR ⁵,-COR ⁵,-SH ,-SR ⁶, acyl group and-NR ⁷R ⁸

Each R ⁵Be selected from respectively: H, alkyl, alkenyl, alkynyl group, haloalkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, Heterocyclylalkyl alkyl, aralkyl, heteroaralkyl and acyl group;

Each R ⁶Be selected from respectively: H, alkyl, alkenyl, alkynyl group, haloalkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, Heterocyclylalkyl alkyl, aralkyl, heteroaralkyl and acyl group;

Each R ⁷And R ⁸Be selected from respectively: H, alkyl, alkenyl, alkynyl group, haloalkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, Heterocyclylalkyl alkyl, aralkyl, heteroaralkyl and acyl group;

L is selected from down group:

a)L＝Cy-L ¹-W-

Wherein

b)L＝Cy-L ¹-W-L ²

Wherein,

L ¹And L ²Identical or different and independent is C ₁-C ₅Alkyl, it can be replaced by one or more substituting groups that independently are selected from down group: halogen;=O;=S;-CN;-NO ₂-CF ₃,-OCF ₃, alkyl, alkoxyl group, amido and alkylamino;

c)L＝Cy-(CH ₂)m-W-

Wherein,

Cy is C ₁-C ₁₅Alkyl, aminoalkyl group, Heterocyclylalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, wherein any one can be chosen wantonly by one or more substituting groups that independently are selected from down group and replace: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃Alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; the halo alkynyl; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; the alkoxyl group heteroaryl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; cyclenes oxygen base; the heterocycle alkoxyl group; heterocycle alkene oxygen base; aryloxy; heteroaryloxy; aralkyl; heteroaralkyl; aralkoxy; amino; alkylamino; amido; aminoalkyl group; arylamino; alkylsulfonyl; alkyl sulphonyl; aryl sulfonyl; amino-sulfonyl; aminoalkyl group; alkoxyalkyl;-COOH;-C (O) OR ⁵,-COR ⁵,-SH ,-SR ⁶,-OR ⁶And acyl group;

M is 0,1,2,3,4 or 5;

d)L＝L ¹-W-L ²

Or its pharmacy acceptable salt.

In any group relevant with the compound structure with specific end use, formula (I), (Ia) and compound (Ib) are preferred in its terminal applies.

In some preferred specific embodiments, R ¹Be selected from: C ₁-C ₁₀Alkyl, alkenyl, assorted alkyl, haloalkyl, alkynyl group, aryl, cycloalkyl, Heterocyclylalkyl, heteroaryl, C ₄-C ₉Heterocyclylalkyl alkyl, cycloalkylalkyl, aralkyl and heteroaralkyl, it all can be substituted as described above.

In another embodiment, preferred R ¹Be selected from down group: H, hydroxyalkyl, alkyl, aralkyl, heteroaralkyl, alkoxyalkyl, aminoalkyl group and Heterocyclylalkyl, it all can be substituted as described above.

In another embodiment, preferred R ¹Be selected from down group: H, hydroxyalkyl, alkyl, alkoxyalkyl and aminoalkyl group, it all can be substituted as described above.

In another embodiment, preferably, if R ¹Be alkyl or assorted alkyl, then it can not replaced by cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl.

Particularly preferred R ¹Be:

H, methyl, (pyridine-2-yl) methyl, (pyridin-3-yl) methyl, ethyl, 2-hydroxyl-ethyl, 2-(pyridine-2-yl) ethyl, 2-(pyridin-3-yl) ethyl, 2-phenyl-ethyl, 2-carboxyl-ethyl, 2-(morpholine-4-yl)-ethyl, 2-(piperidines-1-yl)-ethyl, 2-(tetramethyleneimine (pyrollidin)-1-yl)-ethyl, 2-diethylamino-ethyl, propyl group, 2,3-two-hydroxyl-propyl group, 3-hydroxyl-propyl group, 3-methoxyl group-propyl group, 3-isopropoxy-propyl group, 2,2-dimethyl-propyl group, 3-dimethylamino-propyl group, 3-dimethylamino-2,2-dimethyl-propyl group, 3-(2-oxo-tetramethyleneimine-1-yl)-propyl group, 3-(morpholine-4-yl)-propyl group, 3-(imidazoles-1-yl)-propyl group, 3-(4-methyl-piperidines-1-yl)-propyl group, 3-(tetramethyleneimine-1-yl)-propyl group, 4-dimethylamino-butyl, 5-hydroxyl-amyl group, allyl group, benzyl and 3,4,5-trimethoxy benzyl.

In certain preferred aspects, R ²Be selected from: H, halogen, C ₁-C ₁₀Alkyl, alkenyl, assorted alkyl, haloalkyl, alkynyl group, aryl, cycloalkyl, Heterocyclylalkyl, heteroaryl, C ₄-C ₉Heterocyclylalkyl alkyl, cycloalkylalkyl, aralkyl and heteroaralkyl, it all can be substituted as described above.

In another embodiment, preferred R ²Be selected from down group: H, alkyl, aralkyl, aryl, heteroaryl, assorted alkyl, cycloalkyl and L, it all can be substituted as described above.

In another embodiment, preferred R ²Be selected from down group: H, hydroxyalkyl, alkyl, alkoxyalkyl and aminoalkyl group, it all can be substituted as described above.

In another embodiment, preferably, if R ²Be alkyl or assorted alkyl, then it can not replaced by cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl.

Particularly preferred R ²Be: H; methyl; the benzyl amino-methyl; the dibenzyl amino-methyl; [2-(4-fluoro-phenyl)-kharophen]-methyl; [2-(4-methoxyl group-phenyl)-kharophen]-methyl; 4-methoxyl group-benzyl amino-methyl; benzyloxy-methyl; the phenyl acetyl amino-methyl; 1-amino-2-phenyl-ethyl; 2-benzyl amino-ethyl; 2-(3-methoxyl group-phenyl)-ethyl; 2-(pyridin-3-yl) ethyl; 2-(2-phenoxy group kharophen)-ethyl; 2-benzenesulfonyl amino-ethyl; 2-phenyl-ethyl; sec.-propyl; 2-phenyl-propyl group; 3-phenyl-propyl group; 3-phenoxy group-propyl group; 3-(1H-indol-3-yl)-propyl group; 4-methoxyl group-phenyl; 4-fluoro-phenyl; 4-benzyloxy-3-methoxyl group-phenyl; isobutyl-; cyclohexyl; octyl group; benzyl; pyridine-2-base; pyridin-4-yl; thiene-3-yl-; benzylthio-(benzylsulfanyl) and 2-phenyl methylthio group.

If R ¹Or R ²Be substituted, then particularly preferred substituting group is selected from: halogen ,=O ,=S ,-CN ,-NO ₂, alkyl, alkenyl, assorted alkyl, haloalkyl, alkynyl group, aryl, cycloalkyl, Heterocyclylalkyl, heteroaryl, hydroxyl, hydroxyalkyl, alkoxyl group, alkylamino, aminoalkyl group, amido, phenoxy group, alkoxyalkyl, benzyloxy, alkyl sulphonyl, aryl sulfonyl, amino-sulfonyl ,-C (O) OR ⁵, COOH, SH and acyl group.

If X and Y are identical or different and be preferably H, halogen, C ₁-C ₄Alkyl ,-CF ₃,-NO ₂,-C (O) R ⁵,-OR ⁶,-SR ⁶,-CN and NR ⁷R ⁸

X most preferably is H;

Y most preferably is H;

X and Y most preferably are the position 4 and 7 that is positioned at aromatic nucleus.

R ₃Be preferably H, C ₁-C ₆Alkyl or acyl group, more preferably H or C ₁-C ₄Alkyl, most preferably be H;

R ₄Be preferably H or C ₁-C ₄Alkyl, most preferably be H;

R ₅Be preferably C ₁-C ₄Alkyl, assorted alkyl or acyl group, most preferably be methyl;

R ₆Be preferably C ₁-C ₄Alkyl, assorted alkyl or acyl group, most preferably be C ₁-C ₄Alkyl;

R ₇And R ₈Be preferably selected from H, C ₁-C ₆Alkyl, C ₄-C ₉Cycloalkyl, C ₄-C ₉Heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl.

Z partly is preferably the group of formula-CH=CH-.This partly preferably is " E " configuration and is preferably and is positioned at position 5 or 6 positions, most preferably is position 5.

Except the compound of formula I, the specific embodiments that is disclosed is also at the pharmacy acceptable salt of the pharmacy acceptable salt of these compounds, pharmaceutically acceptable prodrug and medicinal activity metabolite and these metabolites.What these compounds, salt, prodrug and metabolite claimed in set sometimes herein is " hdac inhibitor " or " hdac inhibitor ".

The present invention is also about comprising the pharmaceutical composition of compound of the present invention and pharmaceutically acceptable carrier, thinner or vehicle.

Of the present invention provide on the other hand again treatment by the destruction of cell proliferation and/or angiogenesis caused, the method for the related or illness followed, it comprises formula (I) compound for the treatment of significant quantity.

This method preferably includes the compound that is described in herein formula (Ia), the more preferably compound of formula (Ib).

This illness is preferably selected from, but be not limited to, cancer, inflammatory diseases/disorder of immune system, hemangiofibroma, cardiovascular disorder (for example: restenosis, arteriosclerosis), fibrotic disease (for example: hepatic fibrosis), diabetes, autoimmune disorders, chronic and acute neurodegenerative disease be as the infringement of nervous tissue, Huntington Chorea and infectious diseases, as: fungi, bacterium and viral infection.In another embodiment, this illness is a proliferative disorders.This proliferative disorders is preferably cancer.

The present invention also provide in order to treatment by the destruction of cell proliferation and/or angiogenesis caused, the reagent of association or the illness followed, it comprises formula (I) compound that is disclosed in herein.This reagent is preferably a carcinostatic agent.

This reagent preferably contains the compound of formula (Ia), more preferably contains the compound of formula (Ib).

The present invention also about the compound of formula (I) in caused by the destruction of cell proliferation and/or angiogenesis in order to treatment, application in the medication preparation of association or the illness followed.This illness system is preferably proliferative disorders, most preferably is cancer.

Compound of the present invention has hypotoxicity unexpectedly, has the effect of anti-proliferative activity simultaneously.

In another specific embodiments again, the invention provides a kind of methods of treatment of illness, disease or the situation that can treat by the inhibition of histone deacetylase, it comprises the compound of the formula (I) for the treatment of significant quantity.

This illness is preferably selected from but is not limited to: proliferative disorders (for example: cancer); Neurodegenerative disease comprises: Huntington Chorea, polyglutamic acid amides disease, Parkinson's disease, alzheimer's disease, epileptic seizures, striatonigral degeneration, stein-leventhal syndrome, torsional tension is incomplete, spasmodic torticollis and dyskinesia, familial tremor, Tourette syndrome, diffusivity Lay dimension corpusculum disease, stein-leventhal syndrome, Pick's disease, intracranial hemorrhage, primary lateral sclerosis, the spinal cord muscular dystrophy, amyotrophic lateral sclerosis, matter polyneuropathy between hypertrophy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, carrying out property dystaxia and SDShi syndrome (Shy-Drager syndrome); Metabolic disease comprises: diabetes B; The eye degenerative disease comprises: glaucoma, age-related macular degeneration, rubeotic glaucoma; Inflammatory diseases and/or disorder of immune system comprise: rheumatoid arthritis (RA), osteoarthritis, JCA, graft versus host disease (GVH disease), psoriasis, asthma, spinal joint pathology, psoriasis, Crohn's disease, inflammatory bowel, colonic ulcer, alcoholic hepatitis, diabetes, sjogren syndrome (Sjoegrens ' s syndrome), multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, intervertebral disk pain, systemic lupus erythematosus; Relate to the disease of angiogenesis, comprising: cancer, psoriasis, rheumatoid arthritis; The psychology illness comprises: bipolar disorder, schizophrenia, depression and dull-witted; Cardiovascular disorder comprises: heart failure, restenosis and arteriosclerosis; Fibrotic disease comprises: hepatic fibrosis, cystic fibrosis and hemangiofibroma; Infectious diseases, comprise: fungi infestation, for example: Candida albicans (Candida Albicans), infectation of bacteria, viral infection, for example: herpes simplex, protozoan infection, for example: malaria, infections with leishmaniasis, trypanosoma bocagei (Trypanosoma brucei) infection, toxoplasmosis and coccidiosis and hematopoiesis venereal disease disease comprise: Thalassemia, anaemia and sicklemia.

The present invention also provides the reagent of illness, disease or the situation that can be treated by the inhibition of histone deacetylase in order to treatment, and it comprises as the formula that is disclosed in this paper (I) compound.This reagent is preferably a carcinostatic agent.

The present invention is also about the application of compound in the medication preparation of illness, disease or the situation of being treated by the inhibition of histone deacetylase of formula (I).

The present invention also provides a kind of method in order to inhibition of cell proliferation, and it comprises the compound according to formula (I) that gives significant quantity.

More on the other hand, the invention provides the method for a kind of patient's of treatment neurodegenerative disease, it comprises the compound of the formula (I) for the treatment of significant quantity.This method preferably includes the compound that is described in herein formula (Ia), the more preferably compound of formula (Ib).This neurodegenerative disorders is preferably Huntington Chorea.

The present invention also provides the reagent in order to the treatment neurodegenerative disorders, and it comprises as the formula that is disclosed in this paper (I) compound.This reagent is preferably anti-Huntington Chorea agent.

The present invention also about the compound of formula (I) in order to the application in the medication preparation of treatment neurodegenerative disorders.This neurodegenerative disorders is preferably Huntington Chorea.

More on the other hand, the invention provides a kind of patient's of treatment the inflammatory diseases and/or the method for disorder of immune system, it comprises the compound of the formula (I) for the treatment of significant quantity.This method preferably includes the compound that is described in herein formula (Ia), the more preferably compound of formula (Ib).In one embodiment, this inflammatory diseases and/or disorder of immune system are rheumatoid arthritiss.In another embodiment, this inflammatory diseases and/or disorder of immune system are systemic lupus erythematosuses.

The present invention also provides the reagent in order to treatment inflammatory diseases and/or disorder of immune system, and it comprises as the formula that is disclosed in this paper (I) compound.

The present invention also about the compound of formula (I) in order to the application in the medication preparation of treatment inflammatory diseases and/or disorder of immune system.In one embodiment, this inflammatory diseases and/or disorder of immune system are rheumatoid arthritiss.In another embodiment, this inflammatory diseases and/or disorder of immune system are systemic lupus erythematosuses.

Desire detects the effect of these compounds, and the present invention is a kind of to be suitable for to measure and quantitative sample from the mankind or animal species, for example: the method for the acetylated histones amount in tumor tissues, brain and the blood.This method system is according to enzyme-linked immunosorbent assay (ELISA) and can be in order to quantitatively from the sample of cell extraction thing or the mankind or animal species, for example: the acetylated histones in tumor tissues, brain and the blood.ELISA is the superior than legacy system, is because of its format high throughput, and when effect in the individual organisms test macro of the effect of measuring pharmacological agent or medicine, also the quantitative concentration of property mensuration acetylated histones.The general review of habitual elisa technique can be consulted Crowther JR (1995) ELISA theory and practice, Method in molecular biology, the 42nd volume, Humana.

More on the other hand; the invention provides a kind of in order to measure the method for the acetylated histones concentration in the biological specimen; it is to utilize enzyme-linked immunosorbent assay, and this enzyme-linked immunosorbent assay comprises that first capture antibodies or its part and second detect antibody or its combination partly.

First capture antibodies is preferably selected from the group of following composition: anti--the H3 monoclonal antibody, anti--acetylize H3 polyclonal antibody, goat is anti--the H3 polyclonal antibody, goat is anti--acetylize H3 polyclonal antibody and combination thereof.Second detects the group that antibody is preferably selected from following composition: anti--the H3 monoclonal antibody, anti--acetylize H3 polyclonal antibody, goat is anti--the H3 polyclonal antibody, goat is anti--acetylize H3 polyclonal antibody and combination thereof.

In a particularly preferred specific embodiments, first capture antibodies is that the mouse anti-H3 monoclonal antibody and the second detection antibody are rat anti-acetylize H3 polyclonal antibodies.

It is a kind of in order to differentiate the method for histone deacetylase inhibitors in intracellular pharmacological action that the present invention also provides, and this method comprises the following steps:

A) cell that provides histone deacetylase inhibitors to handle;

B) measure intracellular acetylated histones concentration with each described method among the claim 32-35; With

C) this acetylated histones concentration is compared with the acetylated histones concentration of control sample.

In a preferred specific embodiments, control sample system is derived from the cell of handling without histone deacetylase inhibitors.In another preferred specific embodiments, this cell is a tumour cell.

Histone deacetylase inhibitors preferably includes the compound of formula (I).

It is a kind of in order to differentiate the method for the pharmacological action of histone deacetylase inhibitors in object that the present invention also provides, and this method comprises the following steps:

A) obtain the biological sample that histone deacetylase inhibitors is handled from object;

B) measure acetylated histones concentration in this biological sample with the method for the above-mentioned explanation of the present invention; And

This control sample is preferably derived from the biological sample of the object of handling without histone deacetylase inhibitors.

In method of the present invention, this biological sample is preferably selected from: tissue, blood, serum, blood plasma, urine, saliva and combination thereof.

Embodiment describes in detail

The present invention discloses the hydroxamic acid ester cpds, and for example: contain the benzimidazoles of hydroxamic acid in a substituting group, it may be the inhibitor of deacetylase, includes, but are not limited to the inhibitor of histone deacetylase.The hydroxamic acid ester cpds uses together separately or with pharmaceutically acceptable carrier, thinner or vehicle and may be suitable for preventing or treat that destruction by cell proliferation and/or angiogenesis is caused, the related or illness followed.One of these illnesss embodiment is a cancer.

Term as used herein " cancer " generally is meant the illness that is grown to feature widely with the sexual abnormality out of control of cell.

Compound of the present invention is expected can be in order to treat various cancers, include but not limited to: the osteocarcinoma class, comprise: Ewing sarcoma, osteosarcoma, chondrosarcoma and cohorts, brain and cns tumor, comprise: acoustic tumor, neuroblastoma, neuroglia knurl and other cerebral tumors, tumor of spinal cord, breast cancer, colorectal carcinoma, progressive stage colorectum gland cancer, internal secretion cancer class, comprise: adrenocortical carcinoma, the pancreas cancer, the pituitary gland cancer, thyroid carcinoma, the Parathyroid cancer, thymic carcinoma, muitiple endocrine neoplasms, the gastrointestinal cancer class, comprise: cancer of the stomach, esophagus cancer, carcinoma of small intestine, liver cancer, cholangiocarcinoma, stomach and intestine class cancerous tumour, carcinoma of gallbladder, apparatus urogenitalis cancer class, comprise: cover ball cancer, penile cancer, prostate cancer, the gynecological cancer class, comprise: cervical cancer, ovarian cancer, carcinoma of vagina, uterus/carcinoma of endometrium, the private parts cancer, gestational trophoblastic tumor, carcinoma of fallopian tube, sarcoma of uterus, head and tumor colli class, comprise: oral carcinoma, lip cancer, the glandula cancer, the larynx cancer, hypopharyngeal cancer, just swallowing cancer, rhinocarcinoma, nasal sinus cancer, nasopharyngeal carcinoma, the leukemia class, comprise: leukemia of children, kemia, acute myelogenous leukemia, chronic lymphatic leukemia, chronic lymphocytic leukemia, send out shape cellularity leukemia, acute promyelocytic leukemia, the plasma cell leukemia, bone marrow cancer, blood disorder, comprise: marrow poorly differentiated syndrome, the myeloproliferative illness, aplastic anemia, Fanconi anemia, idiopathic macroglobulinemia disease, the lung cancer class, comprise: small cell lung cancer, nonsmall-cell lung cancer, the lymphatic cancer class, comprise: Hodgkin's disease, the non-Hodgkin lymphomas, skin-type T-cell lymphoma, Peripheral T-cell lymphoma, AIDS dependency lymphoma, the cancer eye class, comprise: retinoblastoma, the uveal tract melanoma, the skin carcinoma class, comprise: melanoma, the plain knurl skin carcinoma of non-black, the Merkel's cell cancer, soft tissue sarcoma's class, for example: children soft tissue sarcoma, adult soft tissue sarcoma, kaposi sarcoma, the urinary system cancer comprises: kidney, wilms' tumor, bladder cancer, urethral carcinoma and metastatic cell cancer.

The preferred cancer class that can be treated by compound of the present invention is breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, kidney, stomach and the cancer of the brain.

The preferred cancer class that can be treated by compound of the present invention is skin-type T-cell lymphoma (CTCL) and Peripheral T-cell lymphoma.

The preferred cancer class that can be treated by compound of the present invention is solid-state tumour and blood malignant disease.

This compound also can relate in order to treatment, about or with the dysregulation disorder associated of histone deacetylase (HDAC).

Existing many illnesss are known to be related to or at least a portion is regulated by HDAC is active, and wherein known HDAC activity is for impelling seizure of disease to play the part of certain role, and perhaps these symptoms are known or shown and can have been alleviated by hdac inhibitor.Expection can include but not limited to following by this kind of illness that compound of the present invention is treated: proliferative disorders (for example: cancer); Neurodegenerative disease comprises: Huntington Chorea, polyglutamic acid amides disease, Parkinson's disease, alzheimer's disease, epileptic seizures, striatonigral degeneration, stein-leventhal syndrome, torsional tension is incomplete, spasmodic torticollis and dyskinesia, familial tremor, Tourette syndrome, diffusivity Lay dimension corpusculum disease, stein-leventhal syndrome, Pick's disease, intracranial hemorrhage, primary lateral sclerosis, the spinal cord muscular dystrophy, amyotrophic lateral sclerosis, matter polyneuropathy between hypertrophy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, carrying out property dystaxia and SDShi syndrome; Metabolic disease comprises: diabetes B; The eye degenerative disease comprises: glaucoma, age-related macular degeneration, rubeotic glaucoma; Inflammatory diseases and/or disorder of immune system comprise: rheumatoid arthritis (RA), osteoarthritis, JCA, graft versus host disease (GVH disease), psoriasis, asthma, spinal joint pathology, psoriasis, Crohn's disease, inflammatory bowel, colonic ulcer, alcoholic hepatitis, diabetes, sjogren syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, intervertebral disk pain, systemic lupus erythematosus; Relate to the disease of angiogenesis, comprising: cancer, psoriasis, rheumatoid arthritis; The psychology illness comprises: bipolar disorder, schizophrenia, mania, depression and dull-witted; Cardiovascular disorder comprises: heart failure, restenosis and arteriosclerosis; Fibrotic disease comprises: hepatic fibrosis, cystic fibrosis and hemangiofibroma; Infectious diseases, comprise: fungi infestation, for example: Candida albicans, infectation of bacteria, viral infection, for example: herpes simplex, protozoan infection, for example: malaria, infections with leishmaniasis, trypanosoma bocagei infection, toxoplasmosis and coccidiosis and hematopoiesis venereal disease disease comprise: Thalassemia, anaemia and sicklemia.

Hydroxamate of the present invention has following structure (I):

Formula I

Wherein

Or R ¹=L;

Or R ²=L;

X and Y are identical or different and are selected from respectively: H, halogen ,-CN ,-NO ₂,-CF ₃,-OCF ₃Alkyl; alkenyl; alkynyl group; haloalkyl; haloalkenyl group; the halo alkynyl; assorted alkyl; cycloalkyl; cycloalkenyl group; Heterocyclylalkyl; heterocycloalkenyl; aryl; heteroaryl; hydroxyl; hydroxyalkyl; alkoxyl group; alkoxyalkyl; alkoxy aromatic yl; the alkoxyl group heteroaryl; alkene oxygen base; alkynyloxy group; cycloalkyloxy; cyclenes oxygen base; the heterocycle alkoxyl group; heterocycle alkene oxygen base; aryloxy; heteroaryloxy; aralkyl; heteroaralkyl; aralkoxy; amino; alkylamino; amido; aminoalkyl group; arylamino; alkylsulfonyl; alkyl sulphonyl; aryl sulfonyl; amino-sulfonyl; aminoalkyl group; alkoxyalkyl;-COOH-C (O) OR ⁵,-COR ⁵,-SH ,-SR ⁶, acyl group and-NR ⁷R ⁸

Each R ⁵Independently be selected from: alkyl, alkenyl, alkynyl group, haloalkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, Heterocyclylalkyl alkyl, aralkyl, heteroaralkyl and acyl group;

Each R ⁶Independently be selected from: alkyl, alkenyl, alkynyl group, haloalkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkylalkyl, Heterocyclylalkyl alkyl, aralkyl, heteroaralkyl and acyl group;

L is selected from:

a)L＝Cy-L ¹-W-

Wherein

L ¹Be selected from C ₁-C ₅Alkyl, it can be replaced by one or more substituting groups that independently are selected from down group: halogen ,=O ,=S ,-CN ,-NO ₂, alkyl, alkoxyl group, amido and alkylamino;

b)L＝Cy-L ¹-W-L ²

Wherein,

L ¹And L ²Identical or different and independently be selected from C ₁-C ₅Alkyl, it can be replaced by one or more substituting groups that independently are selected from down group: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃, alkyl, alkoxyl group, amido, alkylamino;

c)L＝Cy-(CH ₂)m-W-

Wherein,

M is 0,1,2,3,4 or 5;

d)L＝L ¹-W-L ²

Or its pharmacy acceptable salt.

Term as used herein " is unsubstituted " and is meant unsubstituted or is only replaced by hydrogen.

" halogen " represents chlorine, fluorine, bromine or iodine.

" alkyl " is meant straight chain when being used as the part of a group or a group or divides dendritic aliphatic group group, be preferably C ₁-C ₁₄Alkyl, more preferably C ₁-C ₁₀Alkyl most preferably is C ₁-C ₆, unless otherwise.Suitable straight chain and the dendritic C of branch ₁-C ₆The embodiment of alkyl substituent comprises: methyl, ethyl, n-propyl, 2-propyl group, normal-butyl, second butyl, tributyl, hexyl and cohorts.

" alkylamino " comprises alkyl monosubstituted amino and dialkyl amido, unless otherwise." alkyl monosubstituted amino " is meant-the NH-alkyl group, and " dialkyl amido " is meant-N (alkyl) ₂Group, wherein this alkyl system as above-mentioned definition.This alkyl group is preferably C ₁-C ₆Alkyl group.

" arylamino " comprise list-arylamino and two-arylamino the two, unless otherwise.List-arylamino is meant the group of formula aryl NH-, and two-arylamino is meant formula (aryl) ₂The group of N-, wherein aryl system as above-mentioned definition.

" acyl group " is meant alkyl-CO-group, wherein this alkyl group system as definition herein.The embodiment of acyl group comprises: ethanoyl and this formyl radical.This alkyl group is preferably C ₁-C ₆Alkyl group.

" thiazolinyl " is meant that the aliphatic hydrocarbon group that contains a carbon-to-carbon double bond at least and its can be straight or branched during as the part of a group or a group, and preferably have 2-14 carbon atom in its chain, preferably have 2-12 carbon atom, 2-6 carbon atom most preferably arranged.This group can contain a plurality of pairs of keys and its direction all respectively do for oneself E or Z in its normal, chain.Exemplary alkenyl group includes, but are not limited to: vinyl and propenyl.

" alkoxyl group " is meant-the O-alkyl group, and alkyl system wherein is as the definition of this paper.Preferred person, this alkoxyl group is a C ₁-C ₆Alkoxyl group.Embodiment includes, but are not limited to: methoxyl group and oxyethyl group.

" alkene oxygen base " is meant-the O-alkenyl group, and thiazolinyl system wherein is as the definition of this paper.Preferred alkene oxygen base group is C ₁-C ₆Alkene oxygen base group.

" alkynyloxy group " is meant-the O-alkynyl group, and alkynyl system wherein is as the definition of this paper.Preferred alkynyloxy group group is C ₁-C ₆The alkynyloxy group group.

" carbalkoxy " is meant-C (O)-O-alkyl group, base system wherein such as the definition of this paper.This alkyl is preferably a C ₁-C ₆Alkyl group.Embodiment includes, but are not limited to: methoxycarbonyl and ethoxycarbonyl.

" alkyl sulphinyl " is meant-S (O)-alkyl group, wherein alkyl system as above-mentioned definition.This alkyl is preferably a C ₁-C ₆Alkyl group.Exemplary alkyl sulphinyl group includes, but are not limited to: methylsulfinyl and ethyl sulfinyl.

" alkane alkylsulfonyl " is meant-S (O) ₂-alkyl group, wherein alkyl system as above-mentioned definition.This alkyl is preferably a C ₁-C ₆Alkyl group.Embodiment includes, but are not limited to: methylsulfonyl and ethylsulfonyl.

" alkynyl " is meant that the aliphatic hydrocarbon group that contains a carbon-to-carbon triple bond and its can be straight or branched during as the part of a group or a group, and preferably has 2-14 carbon atom in its chain, and 2-12 carbon atom more preferably arranged, and preferably has 2-6 carbon atom.Exemplary structure includes, but are not limited to: ethynyl and proyl.

" alkyl amino-carbonyl " is meant alkylamino-carbonyl group, wherein alkylamino system as above-mentioned definition.

" cycloalkyl " be meant saturated or partly saturated monocycle or condense or spiral polycyclic carbocyclic ring, be preferably each ring and contain 3 to 9 carbon, for example: and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cohorts, unless otherwise.

The alkyl of above-mentioned discussion and naphthenic substituent also are applicable to other substituent alkyl partly, for example are not limited to: alkoxyl group, alkanamine class, alkane ketone, aralkyl, heteroaralkyl, alkane alkylsulfonyl and alkyl ester substituting group and cohorts.

" cycloalkylalkyl " is meant cycloalkyl-alkyl-group, and cycloalkyl wherein and alkyl be definition as described above partly.Exemplary monocycle alkyl alkyl group comprises: cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl and suberyl methyl.

" Heterocyclylalkyl " is meant and contains a heteroatomic ring that is selected from nitrogen, sulphur, oxygen at least, preferably contain 1 to 3 heteroatoms.Each ring is preferably 3 to 4 yuan, more preferably 4 to 7 yuan.Suitable Heterocyclylalkyl substituting group comprises pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thio-furan base, piperidyl, piperazinyl (piperazyl), THP trtrahydropyranyl, morpholino, 1,3-phenodiazine

(1,3-diazapane), 1, the 4-phenodiazine

(1,4-diazapane), 1,4-Evil nitrogen

(1,4-oxazepane) with 1,4-Evil thiophene nitrogen

(1,4-oxathiapane).

" heterocycloalkenyl " is meant as above-mentioned Heterocyclylalkyl, but contains a two key at least.

" Heterocyclylalkyl alkyl " is meant a Heterocyclylalkyl-alkyl group, and wherein Heterocyclylalkyl and alkyl partly are as described above.Exemplary Heterocyclylalkyl alkyl group comprises: (2-tetrahydrofuran base) methyl, (2-tetrahydrochysene thio-furan base) methyl.

" assorted alkyl " is meant straight or branched alkyl group, and it is preferable over has 2 to 14 carbon in its chain, 2 to 10 atoms more preferably, one of them or a plurality of are the heteroatomss that are selected from S, O and N.Exemplary assorted alkyl comprises alkyl esters, second and trialkyl amines, alkyl sulfinic acid class and cohorts.

" aryl " is meant monocycle that (i) optionally is substituted or fused polycycle, aromaticity carbocyclic ring (annular atoms is the atoll texture of carbon) as the part of a group or a group, is preferably every ring and has 5 to 12 atoms.The embodiment of aryl machine group comprises: phenyl, naphthyl and cohorts; (ii) the part saturability Bicyclic carbocyclic ring that optionally is substituted partly, phenyl wherein and C _5-7Cycloalkyl or C _5-7Cycloalkenyl groups system condenses mutually and forms a ring texture, for example: tetralyl, indenyl or hydrogen indenyl.Aromatic yl group can replace through one or more substituting groups.

" aryl alkenyl " is meant aryl-thiazolinyl-group, and aryl wherein and thiazolinyl system are as described above.Exemplary aryl alkenyl group comprises: the phenyl propenyl.

" aralkyl " is meant that aryl-alkyl-group aryl and alkyl wherein partly is as above-mentioned.Preferred aromatic alkyl group contains a C _1-5Alkyl partly.Exemplary aromatic alkyl group comprises: phenmethyl, styroyl and menaphthyl.

" cycloalkenyl group " is meant non-aromaticity monocycle or the polycyclic ring system that optionally is substituted, and it contains a carbon-to-carbon double bond at least and every ring preferably has 5-10 carbon atom.Exemplary monocycle shape cyclenes basic ring comprises: cyclopentenes, tetrahydrobenzene or suberene.Cycloalkenyl groups can replace through one or more substituting groups.

" heteroaryl " is meant monocycle or condensed polycyclic aromatic heterocycle (being preferably the ring texture of heteroatomic 5 to the 7 yuan of aromatic nucleus that contain one or more N of being selected from, O and S).Typical heteroaryl is got base and is comprised: furyl, thienyl, pyrroles, pyrazoles, triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine, indoles, benzoglyoxaline and cohorts.

" heteroaralkyl " is meant heteroaryl-alkyl group, and heteroaryl wherein and alkyl partly are as above-mentioned.Preferred heteroaralkyl group contains a low alkyl group partly.Exemplary heteroaralkyl group comprises: pyridylmethyl.

" low alkyl group " unless otherwise, be meant the aliphatic hydrocarbon group, it can be straight or branched and have 1 to 6 carbon atom in chain, is preferably 1 to 4 carbon atom, for example: methyl, ethyl, propyl group (n-propyl or sec.-propyl) or butyl (normal-butyl, isobutyl-or tributyl).

Contain a benzoglyoxaline ring system among the formula Ia-Ib of the inferior group that formula I is interior with being defined in formula I compound scope.In these ring systems, but its 4-, 5-, 6-and 7-ring position place are the position of substitution.In each formula I, Ia and Ib, need to connect an acid branch in one of them ring position place.This acid branch can provide certainly, but is not limited to contain a hydroxamic acid group or this sour salt derivative, can provide an acid branch when it is hydrolyzed.In some specific embodiments, this acidity branch can see through hydrocarbyl group, for example-and CH ₂-or-CH ₂CH ₂, or alkenyl group for example-CH=CH-is connected on the ring.Being preferable over the position that connects this acid branch is 5-and 6-ring position.

Known including in the person of family of formula I compound is its isomery pattern, comprising: non-mirror image isomerism thing, mirror image isomerism thing, compounds tautomeric and be " E " or the rotamerism thing of " Z " atroopisomer or be the mixture of E and Z isomer.Saltyly also know some isomery patterns, for example: non-mirror image isomerism thing, mirror image isomerism thing and rotamerism thing can be separated by physics and/or chemical process and by being proficient in those skilled in the art.

Some compounds of specific embodiments through disclosing can be single stereoisomers, and the mixture of raceme and/or mirror image isomerism thing and/or non-mirror image isomerism thing exists.All these single stereoisomerses, raceme and composition thereof tie up in the scope of theme of illustrated and demand.

In addition, formula I is solvation and the non-solvent pattern that contains this compound on using.Therefore, the various compound with specified structure that includes comprises its hydration and anhydrous mould assembly formula.

Except the compound of formula I, the HDAC of different specific embodiments suppresses to comprise: the activation metabolite of pharmacy acceptable salt, prodrug and these compounds and the pharmacy acceptable salt of these metabolites.

Term " pharmacy acceptable salt " is meant the bioactive salt of institute's desire that keeps the above-mentioned compound that defines, and comprises pharmaceutically-acceptable acid addition class and base addition salt class.The pharmaceutically-acceptable acid addition class of suitable formula I compound can prepare from mineral acid or from organic acid.The embodiment of these mineral acids is: hydrochloric acid, sulfuric acid and phosphoric acid.Suitable organic acid can be selected from the organic acid of aliphatics, cycloaliphatic, aromaticity, heterocyclic carboxylic acid and sulfonic acid class, and embodiment is formic acid, acetate, propionic acid, succsinic acid, glycolic acid, gluconic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, FUMARIC ACID TECH GRADE, maleic acid, alkylsulphonic acid, aryl sulfonic acid.The pharmaceutically acceptable base addition salt class of suitable formula I compound comprises: from the metallicity salt of lithium, sodium, potassium, magnesium, calcium, aluminum and zinc manufacturing with from organic bases, for example: the organic salt that choline, diethanolamine, morpholine are made.Other embodiment of organic salt are: ammonium salt class, quaternary salt class, for example: tetramethyl ammonium; The amino acid addition salt class, for example: have glycine and arginic salt.Other data of pharmacy acceptable salt can be referring to Remington ' sPharmaceutical Sciences, and the 18 edition, Mack Publishing Co., Easton, PA 1990.If this reagent is solid, then to be proficient in those skilled in the art and to understand compound of the present invention, reagent and salt and can be different crystallization or polymorphism patterns, it is included in the scope of the present invention and specific formula.

" prodrug " is meant compound, and it can be by metabolic mode in the compound that in vivo transforms (for example: by hydrolysis, reduction or oxidation) accepted way of doing sth I.For example, containing the ester prodrugs of the formula I compound of monohydroxy group can be by hydrolysis in vivo and change into its parent molecule.The ester class of the suitable formula I compound that contains the monohydroxy group for example is: acetic ester, citrate, lactate, tartrate, malonic ester, barkite, salicylate, propionic ester, succinate, fumarate, maleate, methylene radical-bis-beta-hydroxyethyl base naphthoic acid ester, rough gentian acid esters (gentisates), isethionic acid ester, two-right-two pairs of toluyl tartrates, methylmesylate, the sulfonic acid ethyl ester, benzene sulfonate, p-toluenesulfonic esters, cyclohexyl sulfonamide ester and quinate.Among another embodiment, the ester prodrugs that contains the formula I compound of base can be by being transformed into parent molecule in hydrolysis in vivo.(embodiment of ester prodrugs is illustrated in F.J.Leinweber, Drug Metab.Res., 18:379,1987).

Possible hdac inhibitor comprises that the IC50 value is 1 μ M or lower those.

Giving the mankind with the compound in the formula I scope can be by any mode of being used for giving in the intestines accepted, for example: per os or per rectum, or give through intestines by non-, for example: approach in subcutaneous, intramuscular, intravenously and the skin.Injection can be by agglomerate or via constant or intermittent perfusion.The active compound canonical system is contained in pharmaceutically acceptable carrier or the thinner and its consumption is enough to send to the patient treatment effective dose.In various specific embodiments, the inhibitor compound property selected is for quick outgrowth cell, for example: cancerous tumour tool toxicity or its toxicity are bigger to normal cell.

Term " treatment significant quantity " or " therapeutic dose " are the amounts that is enough to produce interests or required clinical effectiveness.Significant quantity can divide one or repeatedly give dispenser in addition.The typical case of significant quantity system is enough to relax, improve, stablize, reverse, slow down or postpone the progress of morbid state.

When using compound of the present invention, the pattern or the pattern that can anyly make this compound can be biological utilisation give.Have the knack of the skill person who makes composite and can select suitable dispensing pattern and pattern according to the particular characteristics of selected compound, the situation of desire treatment, the stage of desire treatment situation and the situation that other suit.We advise that the reader can be with reference to Remingtons Pharmaceutical Sciences, and the 18 edition, Mach Publishing Co. (1990) is to obtain further information.

Compound of the present invention can give separately or to be offerd medicine with pharmaceutically acceptable carrier, thinner or vehicle bonded pharmaceutical composition pattern.Compound of the present invention if itself promptly effectively, can the typical case with the pattern dispensing of its pharmacy acceptable salt, because of these patterns are typically solvability stable, that more easily improved by crystallization and tool.

Yet this compound canonical system uses with the pharmaceutical composition pattern of being allocated according to required dispensing pattern.Provide a pharmaceutical composition in another specific embodiments of the present invention, it comprises compound and a pharmaceutically acceptable carrier, thinner or the excipient of formula (I).Said composition system is made in the method that is known in this skill.

Compound of the present invention can merge use or dispensing in order to the other drug and/or the step (for example: operation, radiotherapy) for chemotherapeutics or hdac inhibitor medicine for the treatment of mentioned condition/disease with one or more.This member can be offerd medicine in identical composite or in the composite that separates.If give in the composite that separates, compound then of the present invention can give in succession or simultaneously with other drug.

Of the present invention non-before the enteral administration pharmaceutical composition comprises pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion agent, suspension agent or emulsifying agent and is used to use just rehydration become the sterilized powder of sterile injectable solution or dispersion liquid.The water-based that is suitable for and the embodiment of non-aqueous carrier, thinner, solvent or supporting agent comprise: water, alcohol, polyalcohols (for example: glycerine, propylene glycol, polyoxyethylene glycol and cohorts), with its suitable mixture, vegetables oil (for example: sweet oil) and the syringeability organosilane ester, for example: ethyl oleate.Keeping of adequate liquidity can be by for example: use the coating material, for example: lecithin, by for example keeping required granular size in the dispersion liquid, and by using interfacial agent.

These compositions also can comprise assistant agent, for example: sanitas, wetting agent, emulsifying agent and dispersion agent.Can be by including various antibacteriums and anti-mycotic agent, for example: p-Hydroxybenzoate (paraben) but, butylene-chlorohydrin, phenol, Sorbic Acid and cohorts to be to guarantee the effect of prophylaxis of microbial.But the prolongation of syringeability medicine pattern absorbs can be by the reagent that includes delayed absorption, for example: aluminum monostearate and gelatin.

If need, and for more effective distribution, can be with compound of the present invention and to discharging at a slow speed or the target transfer system, for example: in polymeric matrix, liposome and the microsphere.

The stabilization of syringeability composite can by: filter is aseptic solid-state composition pattern through bacterium retention filter or by adding, can be dissolved or dispersed in the stablizer in sterilized water or other the aseptic syringeability media before using again at once.

The solid dosage that per os gives usefulness comprises: capsule, lozenge, tablet, powder and particle.In these solid dosages, pharmaceutically acceptable vehicle of one of active compound and at least a inertia or supporting agent, for example: Trisodium Citrate or Lin Suanergai and/or a) weighting agent or extender, for example: starch, lactose, sucrose, glucose, N.F,USP MANNITOL and Whitfield's ointment, b) wedding agent, for example: carboxymethyl cellulose, alginate, the gelatin polyvinylpyrrolidone, sucrose and gum arabic, c) wetting agent, for example: glycerine, d) disintegrating agent, for example: agar glue, lime carbonate, potato or cassava starch, alginic acid, some silicate and yellow soda ash, e) dissolving delayed-action activator, for example: paraffin, f) absorb accelerator, for example: quaternary ammonium compound, g) wetting agent, for example: hexadecanol and glyceryl monostearate, h) sorbent material, for example: kaolin and bentonite, and i) lubricant, for example: talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sulfuric acid sodium laurate and its mixture mix.If capsule, lozenge and tablet, its formulation also can comprise buffer reagent.

The solid-state composition of kindred type also can be used as and for example uses: with lactose or cow's milk carbohydrate and high molecular weight polyethylene glycol and the cohorts weighting agent as the soft or rigid fillibility gelatine capsule of vehicle.

The lozenge of solid dosage, sugar-coat ingot, capsule, tablet and particle can be prepared into has coating or shell, for example: coating and other coatings that is known in medicine allotment skill in the intestines.It can optionally contain opacifying agent and also can be certain part that only can or be preferable in the enteron aisle, optionally discharges the composition of active ingredient with delayed mode.Spendable embedded composition comprises polymerizability material and wax class.

Active compound also can be the micro encapsulation pattern, if appropriate, can have one or more above-mentioned vehicle of mentioning.

The liquid formulation that gives in order to per os comprises pharmaceutically acceptable emulsifying agent, solvent, suspension, syrup and panacea, except active compound, this liquid state formulation can contain the inert diluent that generally is used for this skill, for example: water or other solvents, stablizer and emulsifying agent, for example: ethyl alcohol, isopropyl alcohol, ethyl-carbonate, ethyl acetate, benzylated polyol, the phenylamino benzoic acid methyl esters, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly: cottonseed, Semen arachidis hypogaeae, corn, plumule, olive, Kun fiber crops and sesame oil), glycerine, tetrahydrofuran (THF) alcohol, the fatty acid ester of polyoxyethylene glycol and sorbitol anhydride and its mixture.

Except inert diluent, oral compositions also can comprise: assistant agent, for example: wetting agent, emulsifying agent and suspension agent, sweeting agent, spices and deodorant tune.

In the suspension, except active compound, can contain suspension agent, for example: ethoxyquin iso stearyl alcohols, polyoxyethylene sorbitol and sorbitan ester, Microcrystalline Cellulose, inclined to one side aluminium hydroxide (aluminiummetahydroxide), wilkinite, agar glue and tragacanth gum and its mixture.

Be used for the composition that rectum or vagina give and be preferably suppository, its preparation can be by with compound of the present invention and suitable non-irritating excipient or carrier, for example: theobroma oil, polyoxyethylene glycol or under the room temperature for solid but under body temperature for liquid and thereby can melt and the suppository that disengages active compound mixes with wax in rectum or intravaginal.

The formulation that the topical administration of The compounds of this invention is used comprises: powder, paster, spray, ointment and inhalation.Active compound be under sterile state with pharmaceutically acceptable carrier and required any sanitas, buffer reagent or propellant mixing.

The preferred dosage scope is about 0.01 to 300 milligram of per kilogram of body weight every day.The more preferred dose scope is about 0.1 to 100 milligram of per kilogram of body weight every day, about 0.2 to 80 milligram of per kilogram of body weight every day more preferably, about 0.2 to 50 milligram of per kilogram of body weight every day more preferably again.Suitable dosage can repeatedly divide agent to give every day.

As above-mentioned debater, but be disclosed in compound inhibition of histone deacetylase in the specific embodiments.The enzymic activity of histone deacetylase can utilize known method to be measured [people such as Yoshida M., J.Biol.Chem., 265,17174 (1990), people such as J.Taunton, Science 1996 272:408].In some specific embodiments, histone deacetylase inhibitors can with cell in more than one the histone deacetylase effect and reduce its activity.In some other specific embodiments; histone deacetylase inhibitors can be mainly and a kind of histone deacetylase that belongs to I class HDAC enzyme; for example: HDAC-1, HDAC-3 or HDAC-8 effect also reduce its activity [people such as De Ruijter A.J.M.; Biochem.J.; 370,737-749 (2003)].Some preferred histone deacetylase inhibitors can and reduce its activity with the histone deacetylase effect that participates in the tumour generation, and these compounds may be in order to the treatment proliferative disease.The embodiment of these cell hyperplastic diseases or situation comprises: cancer and/or transfer arbitrarily, psoriasis and restenosis.Compound of the present invention can be especially in order to the treatment tumour, for example: breast cancer, lung cancer, ovarian cancer, prostate cancer, head and/or neck cancer, or rectum, stomach and the cancer of the brain.In addition, compound of the present invention can be in order to treatment for the proliferative disease that has resistance with other amic therapy method treatments; And in order to treat high hyperplasia illness, for example: leukemia, psoriasis, restenosis.

Other compounds that are disclosed in each specific embodiments in this paper can be in order to treatment neurodegenerative disease and inflammatory diseases and/or disorder of immune system.

This illness is preferably selected from: cancer, inflammatory diseases and/or disorder of immune system (for example: rheumatoid arthritis, systemic lupus erythematosus), hemangiofibroma, cardiovascular disorder, fibrotic disease, diabetes, autoimmune disorders, chronic and acute neurodegenerative disease, as: Huntington Chorea, Parkinson's disease, nervous tissue infringement and infectious diseases, as: fungi, bacterium and viral infection.In another embodiment, this illness is a proliferative disorders.

Histone deacetylase inhibitors of the present invention has significant anti-proliferative effect and promotes differentiation, G1 or the cell cycle of G2 phase to suppress, and apoptosis.

Synthesizing of deacetylase inhibitors

The reagent of each specific embodiments can utilize reaction path or the synthetic schemes that is described as follows, and uses the technology that can get in this skill, is prepared with obtainable starting raw material.The preparation of the specific compound of specific embodiments is described in more detail in the following example; but those who familiarize themselves with the technology knows that illustrated chemical reaction is applicable to many other reagent in the different specific embodiments of preparation; for example: the synthetic of non-example compound can successfully be implemented by being proficient in the obvious modification of those skilled in the art; for example: by protection suitably disturb group, by changing over known other suitable reagent in this technology, or modify by the routine of carrying out reaction conditions.The tabulation of the due care group in organic synthesis can be referring to the Protective Groups inOrganic Synthesis of T.W.Greene, John Wiley ﹠amp; Sons, 1981.Perhaps, disclose herein or this skill in known other reactions can be identified as the suitability that has in order to other compounds that prepare each specific embodiments.

Can be obtained or prepared according to known technology in this skill in order to the reagent of synthetic compound.

In the following example, unless otherwise, all temperature in the following explanation are degree centigrade and institute is important and per-cent is weight ratio, unless otherwise.

Various initial substances and other reagent are all available from the available commercial merchant, for example: Aldrich Chemical Company or Lancaster Synthesis Ltd. and without being further purified direct use, unless otherwise.Tetrahydrofuran (THF) (THF) and N, dinethylformamide (DMF) are available from Aldrich, and it is the bottled and direct use of sealing.All solvents all use the standard method purifying in addition in this skill, unless otherwise.

Following reaction is in the malleation of nitrogen, argon or has under the drying tube, in room temperature (unless otherwise), in anhydrous solvent, and reaction flask is connected in order to carry out under the rubber diaphragm separator that imports matrix and reagent via injection tube.With glassware through oven drying and/or heat drying.Carry out on silica gel 60 F of glass back plate 254 flat boards (EMerck (0.25mm)) that analytical thin layer look is analysed and with appropriate solvent ratio (v/v) molten in addition from.With the TLC analytical reaction and when definite initial substance exhausts terminated.

Absorb or with can be by UV, or observe the TLC sheet by dyeing in the iodine groove through the right-aubepine spray or the Sonnenschein's reagent (Aldrich Chemical, 20 weight % are dissolved in alcohol) of thermal activation.Subsequent disposal to be the typical case washed (unless otherwise) by the specified aqueous solution of 25% volume ratio that with reaction solvent or extraction solvent reaction volume is doubled and to re-use the extraction volume.Product solution through anhydrous sodium sulfate dehydration, is filtered and on rotatory evaporator again, under decompression with solvent evaporation and notice that solvent is in very aerial removal.Rapid column chromatography [people such as Still, J.Org.Chem., 43,2923 (1978)] be to use quick silica gel of E Merck-level (47-61mm) and silica gel: the roughage ratio is about 20: 1 to 50: 1, except as otherwise noted.Hydrogenolytic cleavage is to carry out under specified pressure or constant pressure.

1H NMR collection of illustrative plates is to be recorded in the Bruker instrument of operating under the 400MHz, and ¹³The C-NMR collection of illustrative plates is to be recorded in operator under the 100MHz.The NMR collection of illustrative plates is with CDCl ₃Obtain (being unit with ppm) during solution, optionally use chloroform as reference standard (7.25ppm and 77.00ppm) or CD ₃OD (3.4 and 4.8ppm and 49.3ppm), or tetramethylsilane internal standard (0.00ppm).Other NMR solvent system optionally uses.If point out the wave crest multiplicity, use then that following abbreviation: s=is unimodal, the doublet of d=doublet, t=triplet, m=multiplet, br=doublet that broaden, the dd=doublet, dt=triplet.When if coupling constant is provided, its unit is a hertz.

Mass spectral obtaining is to utilize LC/MS, and it can be ESI or APCI.The equal unmodified of all melting points.

The purity of all end products is all greater than 90% (recording under the wavelength of 220nm and 254nm by HPLC).

The following example is the specific embodiments that is disclosed in order to explanation, and may not be interpreted as its restriction.But the compound different with other compounds under being illustrated in also operation instruction in following reacting flow chart or its suitable variation or modify and prepared.

Synthetic

Schema I explanation is in order to the step of the compound of synthesis type Ib, and wherein X and Y are hydrogen, and the compound of formula Ia (VI) can be prepared by similar step, for example: by selecting suitable parent material for use.For example, if Z be-CH=CH-and be connected in the C of formula Ib ₅During-position, this compound can be by the similar approach that is illustrated in schema I, with the styracin that is substituted (for example: trans-the 3-nitro-4-chloro-styracin, suitable amine compound (R ¹NH ₂), aldehyde or carboxylic acid composition (R ²CHO or R ²COOH) and suitable azanol or N-alkyl azanol (NHR ³OH, wherein R ³As the definition among the above-mentioned formula Ia) begin to be synthesized.

Schema I

Specifically, hydroxamic acid ester cpds formula Ib can be synthesized by the route of synthesis that shows among the schema I.Trans-4-chloro-3-nitrocinnamic acid (I) at a kind of alkali (for example: under existence triethylamine), can get (II) with the amine reaction in appropriate solvent.In acid catalyst (for example: in methyl alcohol, handle (II) sulfuric acid) and can carry out esterification and produce (III).(III) nitryl group can by suitable reductive agent (for example: tin chloride) reduced and with the phenylenediamine that produces with aldehyde in addition cyclisation to obtain (V).The acquisition of hydroxamic acid ester cpds (VI) can by a known synthetic method (J.Med.Chem., 2002,45,753-757).In order to the alternative method system of preparation (VI) by with suitable acid and (IV) coupling and again by the cyclisation with the acetic acid heating (J.Med.Chem.2001,44,1516-1529).

Schema II

The another kind of compound in order to preparation formula Ib of schema II explanation, wherein X and Y are hydrogen, R ²=Cy-L ¹-W-L ²Substituting step.For example: if Z is-CH=CH-and be connected in the C of formula Ib ₅During-position, this compound (XV) can be by the similar approach that is illustrated in schema II, begins to be synthesized with suitable (III), suitable Fmoc protective amino acid, suitable sour muriate or aldehydes and azanol.

More specific person, for example: hydroxamic acid ester cpds formula Ib, wherein X and Y are hydrogen, R ²=Cy-L ¹-W-L ²And Z is connected in C ₅-position, it can be synthesized by the route of synthesis that is shown in schema II.Suitable intermediate (III) can be reduced into corresponding two amines (VII) by tin chloride.Can produce two kinds of coupling product (VIII) and (IX) with the suitable coupled reaction of Fmoc protective amino acid under PyBOP exists.Do not need further separation, can make (VIII) and (IX) directly under acidic conditions, carry out cyclization also to produce (X).The acquisition of crucial intermediate (XI) can be by handling (X) with 20% piperidines.With suitable sour muriate or suitable alkylsulfonyl chloride treatment (XI) can obtain (XII) and target compound (XIII) can obtain by use is similar to the method for above-mentioned explanation.

If (XI) (NaBH (OAc) under reductive condition ₃/ CH ₃COOH) can obtain (XIV) and can be changed into corresponding hydroxamic acid derivs (XV) with suitable aldehyde reaction by the method identical with above-mentioned exponent.

Schema III

Formula I hydroxamic acid ester cpds also can be prepared by solid-phase synthesis.Synthesizing of the hydroxamic acid ester cpds of schema III formula Ib.For example, as Z be-CH=CH-and be connected in the C of formula Ib ₅During-position, this compound (VI) can be by the similar approach that is illustrated in schema III, with SASRIN resin, suitable azanol (for example: O-(2,4-dimethoxy-phenyl)-azanol), suitable styracin (for example: trans-4-chloro-3-nitro-styracin), suitable amine and aldehyde begin to be synthesized.

Specifically, for example: hydroxamic acid ester cpds (VI) formula Ib can be synthesized by the route of synthesis that is shown in schema IV.With the SASRIN resin in appropriate solvent, at reductive condition (NaBH ₃CN/CH ₃COOH) under with O-(2,4-dimethoxy-phenyl)-azanol) handled and can be obtained corresponding compound (XVI).(XVI) under existing, 4-dimethylaminopyridine can be produced (XVII) with trans-4-chloro-3-nitro-styracin reaction.Further handle (XVII) and can obtain (XVIII) with suitable amine.(XIX) be by (XVIII) cracking of corresponding resin is got.Need not be further purified, use aforesaid method that (XIX) changed into corresponding hydroxamic acid ester cpds (VI).

Schema IV

Schema IV explanation another kind is in order to the step of the hydroxamic acid ester cpds of preparation formula I.For example, as Z be-CH=CH-and be connected in the C of formula Ib ₅During-position, this compound (VI) can be by the similar approach that is illustrated in schema IV, with suitable intermediate (V) beginning, synthesized and can again the compound (XX) that is produced be changed into the hydroxamic acid ester cpds (XXI) of corresponding formula Ib via reductive action.Compound (XXIII), Z wherein are cyclopropylene groups

And be connected in the C of formula Ib ₅-position person can be by with (CH ₃) ₃S (O) I handles and to be prepared from V, and according to the above description in order to the method for preparing hydroxamic acid the cyclopropyl derivatives (XXII) of gained is changed into corresponding hydroxamic acid derivs (XXIII).

Schema V

Schema V explanation another kind is in order to the step of the hydroxamic acid ester cpds of preparation formula I.For example, as Z be-CH=CH-and be connected in the C of formula Ib ₅During-position, this compound can be by the similar approach that is illustrated in schema V, with suitable intermediate (II) beginning, via reductive action synthesize and again with the compound (XXIV) that produced without being further purified in addition cyclisation with must (XXV).In mineral alkali (for example: yellow soda ash) under the existence, in appropriate solvent, handle (XXV) to obtain (XXVI) with suitable alkyl halide.Can produce (XXVIII) with the hydrogen peroxide treatment (XXVI) that is dissolved in acetic acid.Use method as hereinbefore, can be with (XXVI) and (XXVIII) change into corresponding hydroxamic acid ester cpds (XXVII) and (XXIX) respectively.

Following preparation and embodiment are for being proficient in the theme that those skilled in the art were well understood to and implemented this paper more.It can not be identified as the restriction of the scope that discloses, and only is made for the usefulness of its explanation and representative.

Embodiment 1

N-hydroxyl-3-[1-(3-hydroxyl-propyl group)-2-(2-phenyl-propyl group)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (1)

Step 1

(1.0g 4.4mmol) adds triethylamine (2mL), 3-amino-1-propyl alcohol (1.5mL) in the solution in the trans-4-chloro-3-nitrocinnamic acid that is dissolved in diox (10mL) of pre-stirring.The solution of gained is heated to 85 ℃ kept 19 hours and be cooled to again room temperature.In vacuum with removal of solvents.Water (100mL) added in the residue and with pH transfer to 1-1.5.Collecting precipitation thing and with twice of cold water washing and exsiccant.Product 3-[3-nitro-4-(hydroxyl the propylamine)-phenyl that can be yellow solid]-vinylformic acid (1.10g, 95%).MS(m/z)：267(MH) ⁺。

Step 2

The vitriol oil (0.5mL) is added to trans-4-(3-hydroxyl propylamine)-3-nitrocinnamic acid, and (1.10g is 3.9mmol) and in the solution of MeOH (15mL).With the vlil of gained 18 hours.Under-10 ° to-15 ℃, make reaction mixture cooling 3 hours.Collection is 3-[3-nitro-4-(hydroxyl the propylamine)-phenyl of crystallization yellow solid]-methyl acrylate (1.06g, 91%).MS(m/z)：281(MH) ⁺。

Step 3

In the trans-4-that is dissolved in Glacial acetic acid (5mL) of pre-stirring (3-hydroxyl propylamine)-3-nitrocinnamic acid methyl esters (280mg, 1.0mmol) and 3-phenyl butyraldehyde (500mg, 3.4mmol) add in the solution tin chloride (1.18g, 10.0mmol).The solution of gained is heated to 45 ℃ kept 17 hours and be cooled to again room temperature.In vacuum with removal of solvents.Add to water (20mL) and methylene dichloride (20mL) in the residue and stirred 30 minutes.With organic layer dehydration (MgSO ₄), filter and be condensed into the oily residue.Adding 100mL diethyl ether cake stirred 4 hours.Can get product 3-[1-(3-hydroxyl-propyl group)-2-(2-phenyl-propyl group)-1H-benzoglyoxaline-5-yl]-methyl acrylate, its productive rate is 34.9% (132.0mg).MS(m/z)：379(MH) ⁺。

Step 4

With first sodium oxide (30% is dissolved in methyl alcohol) (782mg, 4.1mmol) add to 3-[1-(3-hydroxyl-propyl group)-2-(2-phenyl-propyl group)-1H-benzoglyoxaline-5-yl through pre-stirring]-methyl acrylate (130mg, 0.34mmol and in the solution of azanol hydrogenchloride (242mg, 3.4mmol are dissolved in MeOH (1.5mL)).Reaction mixture continuously stirring under room temperature was also poured in the frozen water solution that contains the 1.0mL concentrated hydrochloric acid in 40 minutes again.With this mixture of dichloromethane extraction.With this organic layer dehydration (MgSO ₄), filter and concentrate.HPLC separates required product with anti-phase preparation property.After freeze dried, can obtain Powdered N-hydroxyl-3-[1-(3-hydroxyl-propyl group)-2-(2-phenyl-propyl group)-1H-benzoglyoxaline-5-yl of 7.8mg (6%)]-acrylamide.HPLC:96%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ manage notes; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 7.22 minutes; 92%. ¹H NMR(400MHz，DMSO-d ₆)δ1.35(3H，d，J＝6.5Hz)，1.83(2H，m)，3.00-4.00(6H，m)，4.33(2H，t，J＝7.1Hz)，6.55(1H，d，J＝15.8Hz)，7.19-7.33(5H，m)，7.62(1H，d，J＝15.8Hz)，7.70(1H，d，J＝8.60Hz)，7.82(1H，d，J＝8.60Hz)，7.92(1H，s)，10.15(1H，bs)，10.33(1H，bs)。MS(m/z)：380[MH] ⁺。

Embodiment 2

N-hydroxyl-3-[1-(3,4,5-trimethoxy phenmethyl)-2-(2-phenyl-ethyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (2)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (2) HPLC:91%; t _R=(LC/PDA:Phenomenex Luna C182.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 7.22 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ3.08(2H，t，J＝7.72Hz)，3.48(2H，t，7.72Hz)，3.63(3H，s)，3.67(6H，s)，5.58(2H，s)，6.59(2H，s)，7.22-7.31(7H，m)，7.63(1H，d，J＝15.78Hz)，7.71(1H，d，J＝8.76Hz)，7.83(1H，d，J＝8.76Hz)，7.98(1H，s)，11.00(2H，bs)。MS(m/z)：488[MH] ⁺。

Embodiment 3

N-hydroxyl-3-[2-(4-benzyloxy-3-methoxyl group-phenyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-preparation of acrylamide (3)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (3) HPLC:92%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 7.32 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ3.87(3H，s)，4.01(3H，s)，5.24(2H，s)，6.56(1H，d＝15.80Hz)，7.32-7.50(8H，m)，7.74(1H，d，J＝8.72Hz)，7.88(1H，d，J＝8.72Hz)，7.94(1H，s)，10.85(1H，bs)。MS(m/z)：431[MH] ⁺。

Embodiment 4

N-hydroxyl-3-[2-(4-benzyloxy-3-methoxyl group-phenyl)-1-(3-hydroxyl-propyl group)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (4)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (4) HPLC:95%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 6.82 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.96(2H，m)，3.88(3H，s)，4.48(2H，t，J＝7.12Hz)，5.24(2H，s)，6.56(1H，d，J＝15.76Hz)，7.32-7.50(8H，m)，7.65(1H，d，J＝15.76Hz)，7.74(1H，d，J＝8.60Hz)，7.91(1H，d，J＝8.60Hz)，7.95(1H，s)，10.85(1H，bs)。MS(m/z)：474[MH] ⁺。

Embodiment 5

N-hydroxyl-3-[1-(2-hydroxyl-ethyl)-2-(4-methoxyl group-phenyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (5)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (5) HPLC:98%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 4.12 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ3.80(2H，t，J＝5.36Hz)，3.87(3H，s)，4.39(2H，t，J＝5.36Hz)，6.56(1H，d，15.72Hz)，7.17(2H，d，J＝8.88Hz)，7.61(1H，d，J＝8.52Hz)，7.62(1H，d，J＝15.72Hz)，7.78(1H，d，J＝8.52Hz)，7.88(1H，d，J＝8.88Hz)，7.90(1H，s)，10.77(1H，bs)。MS(m/z)：354[MH] ⁺。

Embodiment 6

N-hydroxyl-3-[1-(2,3-hydroxyl-propyl group)-2-(4-methoxyl group-phenyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (6)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (6) HPLC:98%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.39 minutes.NMR (400MHz, DMSO-d ₆) δ 3.90 (3H, s), 4.01 (1H, m), 4.35 (2H, m), 4.58 (2H, dd, J=2.48 and 14.48Hz), 6.62 (1H, d, J=15.84Hz), 7.27 (2H, d, J=8.92Hz), 7.68 (1H, d, J=15.84Hz), 8.01 (4H, m), 10.13 (1H, bs).MS(m/z)：383[M] ⁺。

Embodiment 7

N-hydroxyl-3-[2-(4-benzyloxy-3-methoxyl group-phenyl)-1-(2,3-hydroxyl-propyl group)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (7)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (7) HPLC:100%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.06 minutes.NMR(400MHz，DMSO-d ₆)δ4.04-4.38(3H，m)，4.05(3H，s)，4.49(2H，m)，5.22(2H，s)，6.55(1H，d，J＝15.72Hz)，7.29-7.94(11H，m)，8.01(1H，s)。MS(m/z)：490[MH] ⁺。

Embodiment 8

N-hydroxyl-3-[1-(2,3-hydroxyl-propyl group)-2-(2-pyridyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (9)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (9) HPLC:93.7%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.61 minutes.NMR(400MHz，DMSO-d ₆)δ3.20-3.37(4H，m)，3.90(1H，m)，4.90-4.95(2H，m)，6.54(1H，d，J＝15.52Hz)，7.98(1H，s)，8.04(1H，m)，8.27(1H，m)，9.73(1H，d，J＝8.0Hz)。MS(m/z)：355[MH] ⁺。

Embodiment 9

N-hydroxyl-3-[1-(2-hydroxyl-ethyl)-2-(4-pyridyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (10)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (10) HPLC:97.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.14 minutes.NMR(400MHz，DMSO-d ₆)δ3.78(2H，t，J＝5.80Hz)，4.43(2H，t，J＝5.80Hz)，6.50(1H，d，J＝15.80Hz)，7.82(2H，d，J＝8.56Hz)，7.94(1H，s)，8.00(2H，d，J＝5.97Hz)，8.81(2H，d，J＝5.97Hz)。MS(m/z)：325[MH] ⁺。

Embodiment 10

N-hydroxyl-3-[1-(3-hydroxyl-propyl group)-2-(4-pyridyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (11)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (11) HPLC:98.2%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.61 minutes.NMR(400MHz，DMSO-d ₆)δ1.91(2H，m)，3.37(2H，t，J＝5.84Hz)，4.49(2H，t，J＝7.84Hz)，6.54(1H，d，J＝15.52Hz)，7.98(1H，s)，8.06(2H，d，J＝6.26Hz)，8.90(2H，d，J＝626Hz)。MS(m/z)：339[MH] ⁺。

Embodiment 11

N-hydroxyl-3-[1-(3-pyridylmethyl)-2-(2-phenyl-ethyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (12)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (12) HPLC:97.9%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.32 minutes.NMR(400MHz，DMSO-d ₆)δ3.11(2H，t，J＝8.40Hz)，5.71(2H，s)，6.51(1H，d，J＝15.80Hz)，7.20-7.31(6H，m)，7.43(1H，m)，7.40-7.57(4H，m)，7.94(1H，s)，8.57(1H，s)。MS(m/z)：399[MH] ⁺。

Embodiment 12

N-hydroxyl-3-[1-(3-hydroxyl-propyl group)-2-(2-pyridyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (13)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (13) HPLC:98.3%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.37 minutes.NMR(400MHz，DMSO-d ₆)δ1.98(2H，m)，3.30(2H，m)，4.86(2H，t，J＝7.00Hz)，6.51(1H，d，J＝15.76Hz)，7.77(2H，d，J＝8.56Hz)，7.94(1H，s)，8.05(1H，m)，8.30(1H，d，J＝7.92Hz)，8.78(1H，d，J＝4.28Hz)。MS(m/z)：339[MH] ⁺。

Embodiment 13

N-hydroxyl-3-[1-(3-hydroxyl-propyl group)-2-styroyl-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (14)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (14) HPLC:97.3%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.63 minutes.NMR(400MHz，DMSO-d ₆)δ1.87(2H，m)，3.18(2，t，J＝7.40Hz)，4.41(2H，t，J＝7.0Hz)，6.57(1H，d，J＝17.60Hz)，7.15(5H，m)，7.64(1，d，J＝17.60Hz)，7.89(1H，d，J＝8.64Hz)，7.95(1H，s)。MS(m/z)：366[MH] ⁺。

Embodiment 14

The preparation of N-hydroxyl-3-(2-styroyl-1-(pyridine-2-yl) methyl isophthalic acid H-benzoglyoxaline-5-yl)-acrylamide (16)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (16) HPLC:99.7%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.11 minutes.NMR(400MHz，DMSO-d ₆)δ3.31(2H，t，J＝7.56Hz)，5.81(2H，s)，6.57(1H，d，J＝17.60Hz)，7.20-7.36(6H，m)，7.52(1H，m)，7.64(1H，d，J＝17.60Hz)，7.68(1H，d，J＝8.48Hz)，7.77(1H，d，J＝8.48Hz)，7.87(1H，m)，8.44(1H，d，J＝3.92Hz)。MS(m/z)：399[MH] ⁺。

Embodiment 15

N-hydroxyl-3-[1-(3-dimethylamino-2,2-dimethyl-propyl group)-2-styroyl-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (17)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (17) HPLC:100%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.13 minutes.NMR(400MHz，DMSO-d ₆)δ1.08(6H，s)，2.89(6H，s)，4.30(2H，s)，6.54(1H，d，J＝15.80Hz)，7.03(1H，s)，7.16(1H，s)，7.22-7.32(6H，m)，7.65(1H，d，J＝15.80Hz)，7.91(1H，s)。MS(m/z)：421[MH] ⁺。

Embodiment 16

The preparation of N-hydroxyl-3-[2-benzyloxymethyl-1-(3-hydroxyl-propyl group-1H-benzoglyoxaline-5-yl)-acrylamide (19)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (19) HPLC:98.6%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 4.50 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.94(2H，m)，3.43(2H，t，J＝5.8Hz)，4.42(2H，t，J＝7.2Hz)，4.67(2H，s)，4.97(2H，s)，6.53(1H，d，J＝15.8Hz)，7.38(5H，m)，7.63(1H，d，J＝15.8Hz)，7.67(1H，d，J＝9.1Hz)，7.80(1H，d，J＝8.6Hz)，7.90(1H，s)，10.77(1H，bs)。MS(m/z)：382[MH] ⁺。

Embodiment 17

N-hydroxyl-3-[1-(3-hydroxyl-propyl group)-2-thio phenyl-3-base-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (20)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (20) HPLC:97.9%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV254): 3.06 minutes. ¹H NMR(400MHz，DMSO-d ₆)，δ1.98(2H，m)，3.49(2H，t，J＝5.8Hz)，4.56(2H，t，J＝7.2Hz)，6.56(1H，d，J＝15.8Hz)，7.65(1H，d，J＝15.8Hz)，7.69(1H，d，J＝8.7Hz)，7.75(1H，dd，J＝5.1Hz，1.2Hz)，7.89(2H，m)，7.93(1H，s)，8.42(1H，dd，J＝2.6Hz)，10.90(1H，bs)。MS(m/z)：344[MH] ⁺。

Embodiment 18

N-hydroxyl-3-[1-(3-hydroxyl-propyl group)-2-isobutyl--1H-benzoglyoxaline-5-yl]-preparation of acrylamide (21)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (21) HPLC:100%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.14 minutes. ¹H NMR(400MHz，DMSO-d ₆)，δ1.01(6H，d，J＝6.6Hz)，1.94(2H，m)，2.28(1H，m)，3.04(2H，d，J＝7.4Hz)，3.47(2H，t，J＝5.8Hz)，4.46(2H，t，J＝7.1Hz)，6.56(1H，d，J＝15.8Hz)，7.65(1H，d，J＝15.8Hz)，7.73(1H，d，J＝8.6Hz)，7.89(1H，d，J＝8.6Hz)，7.94(1H，s)。MS(m/z)：318[MH] ⁺。

Embodiment 19

Preparation N-hydroxyl-3-[1-(3-hydroxyl-propyl group)-2-octyl group-1H-benzoglyoxaline-5-yl]-acrylamide (23)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (23) HPLC:99.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 7.38 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ0.86(3H，t，J＝6.8Hz)，1.32(10H，m)，1.83(2H，m)，1.94(2H，m)，3.12(2H，t，J＝7.7Hz)，3.46(2H，t，J＝5.8Hz)，4.44(2H，t，J＝7.0Hz)，6.56(1H，d，J＝15.8Hz)，7.64(1H，d，J＝15.8Hz)，7.71(1H，d，J＝8.6Hz)，7.87(1H，d，J＝8.6Hz)，7.92(1H，s)。MS(m/z)：374[MH] ⁺。

Embodiment 20

The preparation of N-hydroxyl-[2-cyclohexyl-1-(3-hydroxyl-propyl group)-1H-benzoglyoxaline-5-yl]-acrylamide (24)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (24) HPLC:98.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 7.38 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.28-2.03(12H，m)，3.33(1H，m)，3.47(2H，t，J＝5.7Hz)，4.51(2H，t，J＝6.9Hz)，6.58(1H，d，J＝15.8Hz)，7.65(1H，d，J＝15.8Hz)，7.76(1H，d，J＝8.6Hz)，7.92(1H，d，J＝8.7Hz)，7.93(1H，s)，10.85(1H，bs)。MS(m/z)：344[MH] ⁺。

Embodiment 21

The preparation of N-hydroxyl-3-(2-isobutyl--1-styroyl-1H-benzoglyoxaline-5-yl)-acrylamide (25)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (25) HPLC:99.1%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 6.51 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ0.90(6H，d，J＝6.6Hz)，2.10(1H，m)，2.70(2H，d，J＝7.3Hz)，3.11(2H，t，J＝7.0Hz)，4.66(2H，t，J＝7.0Hz)，6.57(1H，d，J＝15.8Hz)，7.14(2H，m)，7.26(3H，m)，7.64(1H，d，J＝15.8Hz)，7.70(1H，d，J＝8.8Hz)，7.86(1H，d，J＝8.6Hz)，7.92(1H，s)； ¹³C NMR(100MHz，DMSO-d ₆)δ22.0，26.9，33.3，34.5，45.8，113.0，114.3，119.7，123.7，126.9，128.5，129.0，132.2，132.7，137.2，137.8，154.4，162.5。MS(m/z)：364[MH] ⁺。

Embodiment 22

The preparation of N-hydroxyl-3-(1,2-two styroyls-1H-benzoglyoxaline-5-yl)-acrylamide (26)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (26) HPLC:98.3%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 7.68 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ2.99(4H，m)，3.09(2H，m)，4.59(2H，t，J＝6.9Hz)，6.56(1H，d，J＝15.8Hz)，7.07(2H，m)，7.23(6H，m)，7.31(2H，m)，7.64(1H，d，J＝15.5Hz)，7.66(1H，d，J＝7.2Hz)，7.78(1H，d，J＝8.6Hz)，7.92(1H，s)； ¹³C NMR(100MHz，DMSO-d ₆)δ27.0，31.9，34.5，45.6，112.7，114.7，119.4，123.5，126.5，126.9，128.3，128.5，129.0，131.8，133.0，137.3，138.0，139.5，154.6，162.6。MS(m/z)：412[MH] ⁺。

Embodiment 23

The preparation of N-hydroxyl-3-(2-styroyl-1-(2-pyridin-3-yl-ethyl)-1H-benzoglyoxaline-5-yl)-acrylamide (27)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (27) HPLC:99.9%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.42 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ3.10(4H，m)，3.28(2H，t)，4.63(2H，t)6.53(1H，d)，7.22-7.33(7H，m)，7.54-7.74(4H，m)，8.55(2H，d)，10.88(1H，bs)。MS(m/z)：413[MH] ⁺。

Embodiment 24

N-hydroxyl-3-[1-(3-hydroxyl-propyl group)-2-isobutyl--1H-benzoglyoxaline-5-yl]-preparation of propionic acid amide (29)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (29) HPLC:99.6%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.88 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.00(6H，d，J＝6.4Hz)，2.06(2H，m)，2.27(1H，m)，2.42(2H，t，J＝7.6Hz)，3.05-3.11(4H，m)，3.57(2H，t，J＝6.0Hz)，4.52(2H，t，J＝7.2Hz)，7.45(1H，d，J＝8.0Hz)，7.56(1H，s)，7.78(1H，d，J＝8.0Hz)； ¹³C NMR(100MHz，MeOD)δ20.6(2C)，27.2，30.4，30.6，32.7，33.5，41.5，57.0，112.0，112.3，112.4，126.3，129.9，139.6，152.3，169.4。MS(m/z)：320[MH] ⁺。

Embodiment 25

N-hydroxyl-3-{1-[3-(tetramethyleneimine-1-yl)-propyl group]-2-styroyl-1H-benzoglyoxaline-5-yl }-preparation of acrylamide (30)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (30) HPLC:99.7%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.88 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.84(4H，m)，3.14-3.41(8H，m)，4.29(2H，t，J＝7.04Hz)，6.54(1H，d，J＝15.76Hz)，7.21-7.33(5H，m)，7.62(1H，d，J＝15.76Hz)，7.71(1H，d，J＝8.36Hz)，7.84(1H，d，J＝8.36Hz)，7.93(1H，s)。MS(m/z)：433[MH] ⁺。

Embodiment 26

The preparation of N-hydroxyl-3-[1-(3-morpholine-4-propyl group]-2-styroyl-1H-benzoglyoxaline-5-yl)-acrylamide (31)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (31) HPLC:99.7%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.16 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ2.12(2H，m)，3.11(6H，m)，3.39(2H，t，J＝7.44Hz)，4.39(2H，t，J＝7.01Hz)，6.56(1H，d，J＝15.8Hz)，7.23-7.33(5H，m)，7.62(1H，d，J＝15.8Hz)，7.71(1H，d，J＝8.60Hz)，7.85(1H，d，J＝8.60Hz)，7.95(1H，s)。MS(m/z)：435[MH] ⁺。

Embodiment 27

3-[5-(2-hydroxyl carbamyl-vinyl)-2-styroyl-benzoglyoxaline-1-yl]-preparation of propionic acid (32)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (32) HPLC:95.6%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.55 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ2.74(2H，t，J＝6.68Hz)，4.49(2H，t，J＝6.68Hz)，3.16(2H，t，J＝7.44Hz)，6.52(1H，d，J＝15.76Hz)，7.22-7.33(5H，m)，7.62(1H，d，J＝15.76Hz)，7.66(1H，d，J＝8.56Hz)，7.82(1H，d，J＝8.56Hz)，7.89(1H，s)，11.00(1H，s)。MS(m/z)：380[MH] ⁺。

Embodiment 28

N-hydroxyl-3-(1-phenmethyl-2-styroyl-1H-benzoglyoxaline-5-yl }-preparation of acrylamide (33)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (33) HPLC:99.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 7.82 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ3.08(2H，t，J＝7.4Hz)，3.34(2H，t，J＝7.5Hz)，5.62(2H，s)，6.50(1H，d，J＝15.8Hz)，7.14(2H，m)，7.30(8H，m)，7.63(3H，m)，7.92(1H，s)，10.78(1H，br)； ¹³C NMR(100MHz，DMSO-d ₆)δ27.8，32.2，46.8，112.1，115.9，118.6，123.0，126.4，126.8，127.9，128.3，128.4，128.9，131.0，134.4，135.7，138.4，139.9，155.3，162.7。MS(m/z)：398[MH] ⁺。

Embodiment 29

N-hydroxyl-3-(1-phenmethyl-2-isobutyl--1H-benzoglyoxaline-5-yl }-preparation of acrylamide (34)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (34) HPLC:89.2%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 6.07 minutes. ¹H NMR(400MHz，CDCl ₃)δ0.92(6H，d，J＝6.6Hz)，2.13(1H，m)，3.02(2H，d，J＝7.4Hz)，5.72(2H，s)，6.54(1H，d，J＝15.8Hz)，7.21(2H，m)，7.35(3H，m)，7.66(3H，m)，7.96(1H，s)； ¹³C NMR(100MHz，CDCl ₃)δ22.0，27.2，34.0，47.2，112.8，114.9，119.4，123.7，126.8，128.0，128.9，131.9，133.6，135.3，138.0，155.0，162.6。MS(m/z)：350[MH] ⁺。

Embodiment 30

The preparation of N-hydroxyl-3-(1-phenmethyl-1H-benzoglyoxaline-5-yl)-acrylamide (35)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (35) HPLC:97.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.69 minutes. ¹H NMR(400MHz，CD ₃OD)δ5.68(2H，s)，6.54(1H，d，J＝15.7Hz)，7.37(5H，m)，7.66(1H，d，J＝15.8Hz)，7.75(2H，s)，7.94(1H，s)，9.36(1H，br)； ¹³C NMR(100MHz，CD ₃OD)δ51.7，114.8，116.1，120.6，126.5，129.2，130.2，130.4，135.0，135.3，140.1，165.6。MS(m/z)：294[MH] ⁺。

Embodiment 31

N-hydroxyl-3-(2-styroyl-1-propyl group-1H-benzoglyoxaline-5-yl }-preparation of acrylamide (36)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (36) HPLC:93.9%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 6.05 minutes. ¹H NMR(400MHz，CD ₃OD)δ0.90(3H，t，J＝7.4Hz)，1.70(2H，m)，3.20(2H，m)，3.48(2H，t，J＝7.1Hz)，4.21(2H，t，J＝7.4Hz)，6.54(1H，d，J＝15.7Hz)，7.20(5H，m)，7.65(1H，d，J＝15.7Hz)，7.75(1H，d，J＝8.8Hz)，7.79(1H，d，J＝8.6Hz)，7.84(1H，s)； ¹³C NMR(100MHz，CD ₃OD)δ11.2，23.6，28.7，34.0，47.7，114.4，114.6，120.5，126.3，128.3，129.5，130.0，132.7，134.0，135.2，139.9，140.1，155.5，165.6。MS(m/z)：350[MH] ⁺。

Embodiment 32

The preparation of N-hydroxyl-3-(1-propyl group-1H-benzoglyoxaline-5-yl)-acrylamide (37)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (37) HPLC:95.2%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.92 minutes. ¹H NMR(400MHz，CD ₃OD)δ0.97(3H，t，J＝7.4Hz)，1.98(2H，m)，4.42(2H，t，J＝7.3Hz)，6.55(1H，d，J＝15.8Hz)，7.68(1H，d，J＝15.8Hz)，7.79(1H，d，J＝8.7Hz)，7.88(1H，d，J＝8.7Hz)，7.92(1H，s)，9.24(1H，s)； ¹³C NMR(100MHz，CD ₃CD)δ11.1，23.8，48.4，114.3，116.1，120.3，126.4，133.8，134.9，135.0，140.3，143.5，165.7。MS(m/z)：246[MH] ⁺。

Embodiment 33

N-hydroxyl-3-(1-ethyl-2-styroyl-1H-benzoglyoxaline-5-yl }-preparation of acrylamide (38)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (38) HPLC:99.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 5.06 minutes. ¹H NMR：(400MHz，CD ₃OD)δ1.37(3H，t，J＝7.3Hz)，3.26(2H，t，J＝7.6Hz)，3.53(2H，t，J＝7.5Hz)，4.78(2H，dd，J＝7.3Hz)，6.60(1H，d，J＝15.8Hz)，7.21-7.31(5H，m)，7.72(1H，d，J＝15.8Hz)，7.83-7.89(3H，m)。MS(m/z)：336[MH] ⁺。

Embodiment 34

N-hydroxyl-3-(1-ethyl-1H-benzoglyoxaline-5-yl }-preparation of acrylamide (39)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (39) HPLC:99.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.86 minutes. ¹H NMR：(400MHz，CD ₃OD)δ1.64(3H，t，J＝7.3Hz)，4.55(2H，dd，J＝7.3Hz)，6.61(1H，d，J＝15.8Hz)，7.72(1H，d，J＝15.8Hz)，7.86-7.97(3H，m)，9.38(1H，s)。MS(m/z)：232[MH] ⁺。

Embodiment 35

The preparation of 1-(3-hydroxyl-propyl group)-2-styroyl-1H-benzoglyoxaline-5-carboxylic acid hydroxamides (40)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (40) HPLC:96.0%. ¹H NMR(400MHz，CD3OD，δ)：1.88(2H，m)，3.16(2H，t，J＝7.2Hz)，3.46(4H，m)，4.34(2H，t，J＝7.2Hz)，7.12-7.21(5H，m)，7.82(2H，m)，8.05(1H，s)。MS(m/z)：340[MH] ⁺。

Embodiment 36

N-hydroxyl-3-[1-(2-pyridine-2-base-ethyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (42)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (42) HPLC:98.4%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.05 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ3.43(2H，t)，4.84(2H，t)，6.53(1H，d)，7.41(2H，m)，7.64(2H，m)，7.77-7.95(4H，m)，8.56(1H，s)，9.16(1H，s)。MS(m/z)：309[MH] ⁺。

Embodiment 37

The preparation of N-hydroxyl-3-(1-ethyl-2-methyl isophthalic acid H-benzoglyoxaline-5-yl)-acrylamide (43)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (43) HPLC:96.5%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.52 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.38(3H，t)，2.85(3H，s)，4.42(2H，t)，6.58(1H，d)，7.31(1H，m)，7.50(1H.d)，7.88(2H，m)，10.31(1H，bs)，11.18(1H，bs)。MS(m/z)：246[MH] ⁺。

Embodiment 38

N-hydroxyl-3[1-(3-hydroxyl-propyl group)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (47)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (47) HPLC:＞99%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.02 minutes. ¹H NMR(400MHz，CD ₃OD)δ2.12(2H，m)，3.58(2H，t，J＝5.7Hz)，4.57(2H，t，J＝6.9Hz)，6.55(1H，d，J＝15.8Hz)，7.67(1H，d，J＝15.8Hz)，7.79(1H，d，J＝8.7Hz)，7.89(1H，d，J＝8.9Hz)，7.92(1H，s)，9.22(1H，s)； ¹³C NMR(100MHz，MeOD)δ32.7，45.3，59.2，114.3，116.1，120.3，126.4，135.0，140.3，143.8，165.7。MS(m/z)：262[MH] ⁺。

Embodiment 39

The preparation of N-hydroxyl-3-(1-methyl-2-styroyl-1H-benzoglyoxaline-5-yl)-acrylamide (48)

Title compound (48) is according to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare HPLC:99%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 4.53 minutes. ¹H NMR：(400MHz，CD ₃OD)δ3.18(2H，t，J＝7.5Hz)，3.47(2H，t，J＝7.4Hz)，3.76(3H，s)，6.54(1H，d，J＝15.8Hz)，7.10-7.26(5H，m)，7.65(1H，d，J＝15.8Hz)，7.75-7.82(3H，m)。MS(m/z)：322[MH] ⁺。

Embodiment 40

The preparation of N-hydroxyl-3-(2-styroyl-1H-benzoglyoxaline-5-yl)-acrylamide (50)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (50).HPLC:99%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 4.36 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ3.16(2H，t，J＝7.5Hz)，3.36(2H，t，J＝7.9Hz)，6.53(1H，d，J＝15.8Hz)，7.17-7.29(5H，m)，7.58(1H，d，J＝15.8Hz)，7.66-7.87(3H，m)。MS(m/z)：308[MH] ⁺。

Embodiment 41

The preparation of N-hydroxyl-3-(1H-benzoglyoxaline-5-yl)-acrylamide (51)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (51).HPLC:99%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 0.99 minute. ¹H NMR(400MHz，DMSO-d ₆)δ6.62(1H，d，J＝15.8Hz)，7.74(1H，d，J＝15.8Hz)，7.85-7.99(3H，m)，9.32(1H，s)。MS(m/z)：204[MH] ⁺。

Embodiment 42

N-hydroxyl-3-[1-methyl-2-(3-phenyl-propyl group)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (52)

Step 1

In the trans-4-(methylamine) that is dissolved in 40mL methyl alcohol and 10mL Glacial acetic acid-3-nitrocinnamic acid methyl esters (1.0g, 4.0mmo through pre-stirring; Prepared as the explanation among the embodiment 1) add in the solution tin chloride (3.0g, 16.0mmol).The solution of gained is heated to 55 ℃ kept 24 hours and be cooled to again room temperature.With removal of solvents and with sodium bicarbonate mixture is neutralized to pH=8.Crude product is extracted 3 times with methylene dichloride (20mL).Organic extract merged and wash once and further with Na with water (10mL) washed twice and with salt solution (10mL) ₂SO ₄Dewatered 1 hour, and filtered and concentrate.Obtain product: the productive rate of trans-4-(methylamine)-3-amino-cinnamic acid methyl esters is 82.5% (726mg).MS(m/z)：207[MH] ⁺。

Step 2

In a 25mL round-bottomed flask with the 4-phenylbutyric acid (68mg, 0.41mmol), trans-4-(methylamine)-3-amino-cinnamic acid methyl esters (85mg, 0.40mmol) and PyBOP (236mg 0.46mmol) mixes with the 10mL anhydrous methylene chloride.The mixture of gained was stirred 5 minutes under logical nitrogen.(288uL is 1.62mmol) and with gained mixture restir 4 hours under room temperature to inject DIEA.Progress with the TLC monitoring reaction.Through column chromatography (solvent systems: ethyl acetate: hexane=1: 1) purifying after can get coupling product: 3-{3-amino-4-[methyl-(4-phenyl-butyryl radicals) amino]-phenyl-methyl acrylate and 3-[4-methylamino-3-(4-phenyl-butyryl radicals amino)-phenyl]-methyl acrylate.MS(m/z)：353[MH] ⁺。

Step 3

(59mg 0.17mmol) heated 4 hours under 70 ℃ with the 5mL Glacial acetic acid with above-mentioned coupling product.Be cooled to room temperature after, the quantitative property acquisition pure products by in vacuum, removing Glacial acetic acid: 3-[1-methyl-2-(3-phenyl-propyl group)-1H-benzoglyoxaline-5-yl]-methyl acrylate. ¹H NMR(400MHz，DMSO-d ₆)δ2.14(2H，m)，2.75(2H，t)，3.14(2H，t)，3.95(3H，s)，6.58(1H，d)，7.16-7.30(5H，m)，7.65(1H.d)，7.72(1H，d)，7.90(2H，m)。MS(m/z)：335[MH] ⁺。

Step 4

According to being illustrated among the embodiment 1 in order to prepare the step of hydroxamic acid, by using suitable starting raw material to prepare title compound (52).HPLC:99.8%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 5.01 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ2.14(2H，m)，2.75(2H，t)，3.14(2H，t)，3.95(3H，s)，6.58(1H，d)，7.16-7.30(5H，m)，7.65(1H.d)，7.72(1H，d)，7.90(2H，m)，10.89(1H，bs)。MS(m/z)：336[MH] ⁺。

Embodiment 43

N-hydroxyl-3-[1-(3-imidazoles-1-base-propyl group)-2-styroyl-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (56)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (56).HPLC:98.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.50 minutes. ¹H NMR(400MHz，CD ₃OD)δ2.20(2H，m)，3.19(2H，m)，3.39(2H，t，J＝7.6Hz)，4.28(4H，t，J＝7.6Hz)，6.52(1H，d，J＝16.0Hz)，7.17(5H，m)，7.52(1H，t，J＝1.5Hz)，7.58(1H，t，J＝1.6Hz)，7.65(1H，d，J＝16.0Hz)，7.68(2H，s)，7.85(1H，s)，8.84(1H，s)； ¹³C NMR(100MHz，CD ₃OD)δ29.3，30.7，34.4，42.4，47.6，113.0，116.2，119.2，121.6，123.1，125.7，128.0，129.6，129.9，133.7，135.1，136.6，137.2，140.7，140.9，156.5，166.0。MS(m/z)：416[MH] ⁺。

Embodiment 44

N-hydroxyl-3-[1-(4-dimethylamino-butyl)-2-styroyl-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (57)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (57).HPLC:97.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H2O that contains 0.1% trifluoroacetic acid; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.70 minutes. ¹H NMR(400MHz，CD ₃OD)δ1.71(4H，m)，2.82(6H，s)，3.05(2H，t，J＝7.1Hz)，3.21(2H，t，J＝7.6Hz)，3.44(2H，t，J＝7.5Hz)，4.27(2H，t，J＝7.5Hz)，6.53(1H，d，J＝16.0Hz)，7.20(5H，m)，7.65(1H，d，J＝16.0Hz)，7.73(2H，m)，7.85(1H，s)； ¹³C NMR(100MHz，CD ₃OD)δ22.8，27.3，29.1，34.2，43.5，45.1，58.3，113，5，115.6，119.6，125.9，128.1，129.5，130.0，134.2，134.7，140.4，140.6，156.2，162.7，165.9。MS(m/z)：407[MH] ⁺。

Embodiment 45

N-hydroxyl-3-[1-(3-hydroxyl-propyl group)-2-isobutyl--1H-benzoglyoxaline-5-yl]-preparation of acrylamide (29)

Step 1

3-[1-(3-hydroxyl-propyl group)-2-isobutyl--1H-benzoglyoxaline-5-yl that utilizes logical hydrogen to spend the night and will be dissolved in 10mLMeOH]-methyl acrylate is (according to embodiment 1, step 1-3 is prepared) (126.6mg, 0.4mmol) and 10%Pd/C (40mg) hydrogenation in addition.After the short column filtered through silica gel, permeate is evaporated under decompression to get 3-[1-(3-hydroxyl-propyl group)-2-isobutyl--1H-benzoglyoxaline-5-yl of the quantitative property of tool productive rate]-propionic acid methyl ester (127mg): MS m/z (M+H) ⁺: 319; ¹H NMR (400MHz, MeOD) δ 0.95 (6H, d, J=6.4Hz), 1.92 (2H, m), 2.19 (1H, m), 2.60 (2H, t, J=8.0Hz), 2.74 (2H, d, J=7.2Hz), 2.96 (2H, t, J=7.6Hz), 3.50 (2H, t, J=4.1Hz), 3.54 (3H, s), 4.25 (2H, t, J=7.2Hz), 7.05 (1H, d, J=8.0Hz), 7.30-7.40 (2H, m); ¹³C NMR (100MHz, MeOD) δ 20.9 (2C), 27.3,30.1,31.5,34.6,35.3,39.5,50.1,57.4,109.1,116.4,122.1,132.6,134.2,141.3,154.2,173.2.

Step 2

Prepare title compound (29) according to previously described in order to the method for preparing hydroxamic acid: MS m/z (M+H) ⁺: 320; ¹H NMR (400MHz, MeOD) δ 1.00 (6H, d, J=6.4Hz), 2.06 (2H, m), 2.27 (1H, m), 2.42 (2H, t, J=7.6Hz), and 3.05-3.11 (4H, m), 3.57 (2H, t, J=6.0Hz), 4.52 (2H, t, J=7.2Hz), 7.45 (1H, d, J=8.0Hz), 7.56 (1H, s), 7.78 (1H, d, J=8.0Hz); ¹³C NMR (100MHz, MeOD) δ 20.6 (2C), 27.2,30.4,30.6,32.7,33.5,41.5,57.0,112.0,112.3,112.4,126.3,129.9,139.6,152.3,169.4.

Embodiment 46

N-hydroxyl-3-[2-(phenmethyl amino-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-preparation of acrylamide (60)

Step 1

With 3-[2-(N-Fmoc-amino methyl)-1 methyl isophthalic acid H-benzoglyoxaline-5-yl]-methyl acrylate (by using suitable starting raw material, according to embodiment 42, step 1-3 is prepared for 43mg, 0.176mmol) is dissolved in the 10mL methylene dichloride.Handle the solution of gained with the 2.0mL piperidines.All solvents of removal and piperidines can get 3-(2-aminomethyl-1,2-methyl isophthalic acid H-benzoglyoxaline-5-yl)-methyl acrylate in vacuum.MS(m/z)：246[MH] ⁺。

Step 2

With phenyl aldehyde (47mg, 0.445mmol), 3-(2-aminomethyl-1,2-methyl isophthalic acid H-benzoglyoxaline-5-yl)-methyl acrylate (109mg, 80%, 0.445mmol) and acetic acid (27mg 0.445mmol) is dissolved in the 15mL methylene dichloride.This mixture was stirred under room temperature 1 hour.With sodium triacetoxy borohydride (142mg, 95%, 0.668mmol) add in the above-mentioned solution.This reacts on 12 hours back fully and with saturated NaHCO ₃(10mL) twice of organic layer of washing, wash once and again through Na with salt solution (10mL) ₂SO ₄Dehydration.After filtering, can obtain crude product (100mg, 67.6% productive rate): 3-[2-(phenmethyl amino-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl by removing solvent]-methyl acrylate.MS(m/z)：336[MH] ⁺。

Step 3

Title compound (60) is according to being illustrated in the step of the step 4 of embodiment 1, by using 3-[2-(phenmethyl amino-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-methyl acrylate prepared as starting raw material.HPLC:89.6%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.68 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ3.78(3H，s)，4.37(2H，s)，4.58(2H，s)，6.48(1H，d)，7.46(3H，m)，7.55(3H，m)7.64(2H，t)7.88(1H，s)，9.88(1H，bs)，10.74(1H，bs)。MS(m/z)：337[MH] ⁺。

Embodiment 47

N-hydroxyl-3-[1-(3-dimethylamino-propyl group)-2-styroyl-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (63)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (63).HPLC:100%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.52 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ2.09(2H，m)，2.75(3H，s)，2.76(3H，s)，3.12-3.22(4H，m)，3.37(2H，b)，4.50(2H，b)，6.55(1H，d，J＝15.76Hz)，7.22-7.34(5H，m)，7.63(1H，d，J＝15.76Hz)，7.66(1H，d，J＝7.80Hz)，7.82(1H，d，7.80Hz)，7.92(1H，s)。MS(m/z)：393[MH] ⁺。

Embodiment 48

N-hydroxyl-3-[2-(phenmethyl amino-methyl)-ethyl-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (64)

Title compound (64) is by using suitable starting raw material, being prepared according to the step that is illustrated in embodiment 46.HPLC:98.5%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.52 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.31(3H，t)3.37(2H，m)，3.50(2H，t)，4.28(4H，m)，6.48(1H，d)，7.43-50(3H，m)，7.55(3H，m)7.73-7.83(2H，t)7.95(1H，s)，9.25(1H，bs)，10.76(1H，bs)。MS(m/z)：351[MH] ⁺。

Embodiment 49

Preparation N-hydroxyl-3-(preparation of 2-(phenmethyl-1-methyl-3-oxo-1H-benzoglyoxaline-5-yl)-acrylamide (65)

Title compound (65) is by using suitable starting raw material, being prepared according to the step that is illustrated in embodiment 42.HPLC:99%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 4.48 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ3.87(3H，s)，4.59(2H，s)，6.57(1H，d，J＝15.9Hz)，7.09-7.36(5H，m)，7.62(1H，d，J＝15.8Hz)，7.73-7.95(3H，m)。MS(m/z)：309[MH] ⁺。

Embodiment 50

N-hydroxyl-3-[1-(2-diethylamino-ethyl)-2-styroyl-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (66)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (66).HPLC:100%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.72 minutes. ¹H NMR(400MHz，CD ₃OD)δ1.29(6H，t，J＝7.3Hz)，3.26(8H，m)，3.40(2H，t，J＝7.5Hz)，4.60(2H，t，J＝8.0Hz)，6.50(1H，d，J＝16.0Hz)，7.21(5H，m)，7.62(1H，d，J＝16.0Hz)，7.70(2H，m)，7.85(1H，s)； ¹³C NMR(100MHz，CD ₃OD)δ9.0，29.4，34.3，39.9，48.4，50.3，112.7，116.6，119.3，125.8，128.1，129.6，130.0，133.9，134.9，137.6，140.8，157.0，166.0。

MS(m/z)：407[MH] ⁺。

Embodiment 51

N-hydroxyl-3-[2-styroyl-1-(piperidines-1-base-ethyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (67)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (67).HPLC:100%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.90 minutes. ¹H NMR(400MHz，CD ₃OD)δ1.86(6H，br s)，3.26(8H，m)，3.40(2H，t，J＝7.5Hz)，4.62(2H，t，J＝7.9Hz)，6.50(1H，d，J＝16.0Hz)，7.23(5H，m)，7.62(1H，d，J＝16.0Hz，)，7.70(2H)，7.84(1H，s)； ¹³C NMR(100MHz，CD ₃OD)δ22.5，24.2，29.4，34.3，39.6，54.4，54.9，112.7，116.6，119.2，125.7，128.1，129.6，130.0，133.8，134.9，137.8，140.8，157.0，166.0。MS(m/z)：419[MH] ⁺。

Embodiment 52

N-hydroxyl-3-[2-styroyl-1-(2-tetramethyleneimine-1-base-ethyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (72)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (72).HPLC:100%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.71 minutes. ¹H NMR(400MHz，CD ₃OD)δ2.06(4H，br)，3.21(2H，t，J＝7.4Hz)，3.26(4H，m)，3.37(2H，t，J＝7.7Hz)，3.42(2H，t，J＝7.5Hz)，4.57(2H，t，J＝7.4Hz)，6.47(1H，d，J＝16.0Hz)，7.21(5H，m)，7.58(1H，d，J＝16.0Hz)，7.67(1H，d，J＝8.6Hz)，7.74(1H，d，J＝8.6Hz)，7.83(1H，s)； ¹³C NMR(100MHz，CD ₃OD)δ24.1，29.4，34.3，41.1，52.8，55.7，112.9，116.5，119.2，125.8，128.1，129.6，130.0，133.9，134.9，137.2，140.7，140.8，157.0，165.9。MS(m/z)：405[MH] ⁺。

Embodiment 53

N-hydroxyl-3-[2-(2-phenmethyl amino-ethyl)-1-ethyl-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (74)

Title compound (74) is by using suitable starting raw material, being prepared according to the step that is illustrated in embodiment 42.HPLC:98.5%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 3.52 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.31(3H，t)3.37(2H，m)，3.50(2H，t)，4.28(4H，m)，6.48(1H，d)，7.43-50(3H，m)，7.55(3H，m)7.73-7.83(2H，t)7.95(1H，s)，9.25(1H，bs)，10.76(1H，bs)。MS(m/z)：365[MH] ⁺。

Embodiment 54

N-hydroxyl-3-[2-styroyl-1-(3-tetramethyleneimine-1-base-propyl group)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (82)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (82).HPLC:100%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.18 minutes. ¹H NMR(400MHz，CD ₃OD)δ2.01(2H)，2.17(4H)，3.03(2H)，3.26(4H)，3.48(2H)，3.62(2H)，4.37(2H)，6.60(1H)，7.27(5H)，7.71(1H)，7.78(2H)，7.91(1H)。MS(m/z)：419[MH] ⁺。

Embodiment 55

N-hydroxyl-3-[1-(3-dimethylamino-2,2-dimethyl-propyl group)-2-(2-pyridin-3-yl-ethyl)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (86)

Title compound (86) is by using suitable starting raw material, being prepared according to the step that is illustrated in embodiment 42.HPLC:90.4%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV254): 1.24 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.00(6H，s)，2.94(6H，s)，3.32(2H，m)，3.38(4H，m)4.35(2H，m)，6.52(1H，d)，7.58-7.86(5H，m)8.20(1H，d)，8.65(1H，m)8.77(1H，s)，9.50(1H，s)。MS(m/z)：422[MH] ⁺。

Embodiment 56

2-[2-styroyl-1-(3,4,5-trimethoxy-phenmethyl)-1H-benzoglyoxaline-5-yl]-preparation of cyclopropane-carboxylic acid oxyamide (88)

Step 1

Under room temperature and logical nitrogen, in (the CH that is dissolved in anhydrous DMSO (1mL) ₃) ₃S (O) I (132mg, 0.6mmol) add sodium hydride (28mg in the solution, 60% in mineral oil), after 10 minutes, add the compound (244mg that is dissolved in the anhydrous THF of 4mL again, 0.5mmol), 3-[2-styroyl-1-(3,4,5-trimethoxy-phenmethyl)-1H-benzoglyoxaline-5-yl]-solution of methyl acrylate (according to embodiment 1, step 1-3 is prepared).Again the solution of gained is stirred under room temperature and spend the night.After the water-based subsequent disposal, obtain residue (135mg) as oil, it is used in the next step without being further purified.

Step 2

In the solution of the above-mentioned crude product that is dissolved in 0.5mL MeOH, add previously prepared 2.0M NH as our preceding making ₂OH mother liquor (2mL).The mixture of gained was stirred under room temperature 4 hours.After TFA (0.4mL) stopped reaction, reaction mixture is carried out the title compound (88) of HPLC purifying to obtain 10mg.HPLC:99%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65% B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 6.36 minutes. ¹H NMR(400MHz，CD ₃OD)δ1.21-1.29(1H，m)，1.45-1.52(1H，m)，1.75-1.79(1H，m)，2.48-2.55(1H，m)，2.99(2H，t，J＝8.0Hz)，3.45(2H，t，J＝8.0Hz)，3.61(6H，s)，3.64(3H，s)，5.42(2H，s)，6.40(2H，s)，7.00-7.18(5H，m)，7.26(1H，d，J＝8.4Hz)，7.45(1H，s)，7.59(1H，d，J＝8.4Hz)。MS(m/z)：502[MH] ⁺。

Embodiment 57

N-hydroxyl-3-[2-phenmethyl sulfhedryl-1-(3-dimethylamino-2,2-dimethyl-propyl group)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (89)

Step 1

With 3-[4-(3-dimethylamino-2,2-dimethyl-propyl group amino)-3-nitro-phenyl]-vinylformic acid (1.93g, 6.0mmol is as embodiment 1, the explanation of step 1 is prepared), tin chloride (13.5g, 60mmol) and MeOH (50mL) mix and to be incorporated under 45 ℃ heating 20 hours.Reaction mixture is cooled to room temperature and removes solvent under decompression.In this residue, add 100mL methylene dichloride and 100mL water.With strong aqua pH is transferred to 10.With level separately and with 100mL dichloromethane extraction water.Merge organic phase, through the sodium sulfate dehydration, filter and under decompression, remove solvent.In the residue of gained, add MeOH (100mL), CS ₂(18mL) and potassium hydroxide (3.4g).Reaction mixture was heated 16 hours under 80 ℃, be cooled to room temperature again and under decompression, remove solvent.Crude product recrystallize in MeOH with gained.This product: 3-[1-(3-dimethylamino-2,2-dimethyl-propyl group)-2-sulfo--2,3-dihydro-1H-benzoglyoxaline-5-yl]-vinylformic acid can obtain in two steps, and productive rate is 75% (1.5g).MS(m/z)：334[MH] ⁺。

Step 2

With 3-[1-(3-dimethylamino-2,2-dimethyl-propyl group)-2-sulfo--2,3-dihydro-1H-benzoglyoxaline-5-yl]-vinylformic acid (100mg, 0.3mmol), cylite (360mg, 3.6mmol) and salt of wormwood (0.83g) mix with 10mL DMF.The mixture of gained stirred under 45 ℃ spend the night.By the required product of preparation property HPLC purifying: 3-[2-phenmethyl sulfhedryl-1-(3-dimethylamino-2,2-dimethyl-propyl group)-2,3-dihydro-1H-benzoglyoxaline-5-yl]-benzyl acrylate ester: 150mg (productive rate: 76.6%). ¹H NMR(400MHz，DMSO-d ₆)δ1.08(6H，s)，2.88(3H，s)，2.89(3H，s)，3.30(2H)，4.11(2H，s)，4.65(2H，s)，5.24(2H，s)，6.72(2H，d，J＝15.96Hz)，7.26-7.47(10H，m)，7.68(2H，bs)，7.83(1H，d，J＝15.96Hz)，8.00(1H，s)。MS(m/z)：514[MH] ⁺。

Step 3

The acquisition of title compound (89) system is by according to previously described method (step 4) processing 3-[2-phenmethyl sulfhedryl-1-(3-dimethylamino-2 of embodiment 1 in order to prepare hydroxamic acid, 2-dimethyl-propyl group)-2,3-dihydro-1H-benzoglyoxaline-5-yl]-the benzyl acrylate ester.HPLC:99%; t _R=(LC/PDA:Phenomenex Luna C182.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65% B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.87 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.09(6H，s)，2.88(3H，s)，2.89(3H，s)，3.26(2H)，4.11(2H，s)，4.65(2H，s)，6.48(2H，d，J＝15.79Hz)，7.26-7.47(6H，m)，7.58(1H，d，J＝15.79Hz)，7.65(1H，d，J＝8.48Hz)，7.80(1H，s)。MS(m/z)：439[MH] ⁺。

Embodiment 58

N-hydroxyl-3-[1-(3-dimethylamino-2,2-dimethyl-propyl group)-2-phenyl methanesulfonamide acyl group-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (91)

Step 1

Under 0 ℃, 3-[2-phenmethyl sulfhedryl-1-(3-dimethylamino-2 with 118mg, 2-dimethyl-propyl group)-2,3-dihydro-1H-benzoglyoxaline-5-yl]-benzyl acrylate ester (according to embodiment 57, step 1-2 is prepared), 1.0mL hydrogen peroxide (30%) and 10mL acetic acid mixes in ice bath.Do not need to add again ice, reaction mixture stirred spend the night, quantitative this product of property acquisition: 3-[1-(3-dimethylamino-2,2-dimethyl-propyl group)-2-phenylmethane base sulfinyl-2,3-hydrogen-1H-benzoglyoxaline-5-yl]-the benzyl acrylate ester.MS(m/z)：530[MH] ⁺。

Step 2

The acquisition of title compound (91) system is by according to previously described method (step 4) processing 3-[1-(the 3-dimethylamino-2 of embodiment 1 in order to prepare hydroxamic acid; 2-dimethyl-propyl group)-and 2-phenylmethane base sulfinyl-2,3-hydrogen-1H-benzoglyoxaline-5-yl]-the benzyl acrylate ester.HPLC:77.1%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.46 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.11(6H，s)，2.90(3H，s)，2.91(3H，s)，3.12(2H，s)，3.82(2H，s)，4.79(2H，s)，6.56(1H，d，J＝15.80Hz)，7.15-7.32(5H，m)，7.59-7.66(2H，m)，7.87(1H，d，J＝8.68Hz)，8.06(1H，s)。MS(m/z)：455[MH] ⁺。

Embodiment 59

The preparation of N-hydroxyl-3-(2-phenmethyl-1-ethyl-1H-benzoglyoxaline-5-yl)-acrylamide (92)

Title compound (92) is by using suitable starting raw material, being prepared according to the step that is illustrated in embodiment 42.HPLC:97.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.60 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.17(3H，t，J＝7.1Hz)，4.34(2H，dd，J＝6.8Hz)，4.56(2H，s)，6.55(1H，d，J＝15.8Hz)，7.31-7.40(5H，m)，7.63(1H，d，J＝15.8Hz)，7.85-7.93(3H，m)。MS(m/z)：322[MH] ⁺。

Embodiment 60

N-hydroxyl-3-{1-ethyl-2-[3-(1H-indol-3-yl)-propyl group]-1H-benzoglyoxaline-5-yl }-preparation of acrylamide (93)

Title compound (93) is by using suitable starting raw material, being prepared according to the step that is illustrated in embodiment 42.HPLC:98.5%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.98 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.33(3H，t)，2.22(2H，m)，2.87(2H，t)，3.16(2H，m)，4.37(2H，m)，6.53(1H，d)，6.98(1H，m)7.06(1H，m)7.19(1H，s)，7.33(1H.d)，7.54-7.88(5H，d)，10.82(2H，bs)。MS(m/z)：389[MH] ⁺。

Embodiment 61

N-hydroxyl-3-{1-(3-dimethylamino-2,2-dimethyl-propyl group)-2-[2-(3-methoxyl group-phenyl)-ethyl]-1H-benzoglyoxaline-5-yl }-preparation of acrylamide (94)

Title compound (94) is by using suitable starting raw material, being prepared according to the step that is illustrated in embodiment 42.HPLC:99.7%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.34 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.03(6H，s)，2.90(6H，s)，3.19(2H，t)，3.34(4H，s)3.71(3H，s)4.29(2H，t)，6.52(1H，d)，6.80(1H，m)6.88(2H，d)7.22(1H，m)，7.62(2H，m)，7.83-7.89(2H，m)，9.34(1H，s)，10.77(1H，bs)。MS(m/z)：451[MH] ⁺。

Embodiment 62

N-hydroxyl-3-[1-ethyl-2-(3-phenoxy group-propyl group)-1H-benzoglyoxaline-5-yl]-preparation of acrylamide (96)

Title compound (96) is by using suitable starting raw material, being prepared according to the step that is illustrated in embodiment 46.HPLC:99.6%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.83 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ1.36(3H，t)，2.32(2H，m)，3.34(2H，m)，4.12(2H，m)，4.46(2H，m)，6.58(1H，d)，6.73(2H，d)6.90(1H，m)7.22(2H，m)，7.65(1H.d)，7.80(1H，d)，7.94(2H，m)。MS(m/z)：366[MH] ⁺。

Embodiment 63

N-hydroxyl-3-(2-{[2-(4-methoxyl group-phenyl)-kharophen]-methyl }-1-methyl-H-benzoglyoxaline-5-yl)-acrylamide (99)

Title compound (99) is by using suitable starting raw material, being prepared according to the step that is illustrated in embodiment 42.HPLC:97.0%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 2.75 minutes. ¹H NMR(400MHz，DMSO-d ₆)δ3.48(2H，s)，3.67(3H，s)，3.87(3H，s)，4.71(2H，m)，6.55(1H，d)，6.86(3H，m)7.18(3H，m)7.84-7.92(2H，m)，10.77(1H，s)。MS(m/z)：395[MH] ⁺。

Embodiment 64

The preparation of 2-(1-methyl-2-styroyl-1H-benzoglyoxaline-5-yl)-cyclopropane-carboxylic acid oxyamide (100)

Title compound (100) is by using suitable starting raw material, being prepared according to the step that is illustrated in embodiment 56.HPLC:99%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 6.36 minutes ¹H NMR (400MHz, CDCl ₃, add a d ₆-DMSO-d ₆) δ 1.25 (1H, m), 1.64 (1H, m), 1.88 (1H, m), 1.98 (3H, s), 2.63 (1H, m), 3.23 (2H, t, J=8.0Hz), 3.52 (2H, t, J=8.0Hz), 7.08-7.45 (7H, m), 7.57 (1H, s).MS(m/z)：336[MH] ⁺。

Embodiment 65

The preparation of N-hydroxyl-3-(1-methyl isophthalic acid H-benzoglyoxaline-5-yl)-acrylamide (49)

According to the step that is illustrated among the embodiment 1, by using suitable starting raw material to prepare title compound (49).HPLC:99%; t _R=(LC/PDA:Phenomenex Luna C18 2.0x150mm 5 μ posts; 0.8mL/ minute, gradient 5-65%B is through 15.5 minutes, solvent orange 2 A: the H that contains 0.1% trifluoroacetic acid ₂O; Solvent B: the acetonitrile that contains 0.1% trifluoroacetic acid; UV 254): 1.05 minutes. ¹H NMR：(400MHz，CD ₃OD)δ4.05(3H，s)，6.52(1H，d，J＝15.8Hz)，7.62(1H，d，J＝15.8Hz)，7.77-7.89(3H，m)，9.19(1H，s)。MS(m/z)：218[MH] ⁺。

Following compounds is some representative example with method that is disclosed in above embodiment 1-65 or similar approach preparation:

Table 1

By being similar to the method that is disclosed in, can prepare the formula I compound of extensive variation, those that it includes, but are not limited to list in the table 2 (a):

Table 2 (a)

By being similar to the method that is disclosed in, can prepare the formula I compound of extensive variation, those that it includes, but are not limited to list in the table 2 (b) by the parent material that change is used in synthesizing:

Table 2 (b)

Biological test and enzyme analysis

Reorganization GST-HDAC1 protein expression and purifying

The human cDNA of the SW620 cell preparation of utilization through cultivating storehouse.From then on to the expression vector pDEST20 and pFASTBAC of baculovirus (GATEWAY CloningTechnology, Invitrogen Pte Ltd) grown in changeing respectively that also incite somebody to action human HDAC1 of cDNA storehouse amplification and HDAC8 coding region.Confirm that by the DNA sequencing pDEST20-HDAC1 and pFASTBAC-HTGST-HDAC8 construct body.Explanation (Invitrogen Pte Ltd) according to manufacturers utilizes the Bac-To-Bac legal system to be equipped with recombinant baculovirus.Record baculovirus concentration with the analysis of bacteriolyze spot and be about 10 ⁸PFU/ml.

Carried out the expression of GST-HDAC1 or HTGST-HDAC8 in 48 hours by pDEST20-HDAC1 or pFASTBAC-GST-HDAC8 baculovirus infection SF9 cell (Invitrogen Pte Ltd) with MOI=1.The cytolysis thing of solubility and the glutathione S epharose 4B pearl (Amersham) of pre-equilibration were put under 4 ℃ 2 hours altogether.Wash this pearl 3 times with the PBS damping fluid.By containing 50mM Tris, pH 8.0,150mM NaCl, and 1% Triton X-100 and 10mM or 20mM are molten molten from GST-HDAC1 protein or GST-HDAC8 protein from damping fluid through the reductive gsh.To contain 10mM Tris, pH 7.5,100mM NaCl and 3mM MgCl ₂The purified GST-HDAC1 protein of HDAC storage buffer dialysis or purified GST-HDAC8 protein.Be stored in-80 ℃ before, in purified GST-HDAC1 protein or purified GST-HDAC8 protein, add 20% glycerine.

Analyze in order to the in vitro HDAC that measures the IC50 value

In 96 orifice plates, analyze and carry out fluorescent substrate HDAC activation analysis.The composition of analysis buffer comprises 25mM Tris pH 7.5,137mM NaCl, 2.7mM KCl, 1mM MgCl ₂, the general matrix of 500 μ M Flur de lys used of the 200 μ M Flur de lys p53 peptide matrix used of 1mg/ml BSA, test-compound, 500nM HDAC8 enzyme or 600nM HDAC1 enzyme, HDAC8 enzyme or HDAC1 enzyme and under room temperature, putting 2 hours subsequently.Add Flur de lys developping agent and this reaction was carried out 10 minutes.In brief, the deacetylation of matrix can make it to the developping agent sensitivity, and it can produce fluorophorre (mark) again.This fluorophorre can be excited and be detected its emission light (460nm) by 360nm light on fluorescent screen reader (Tecan Ultra Microplate detection system, Tecan Group Ltd.).

Operational analysis software: Prism 3.0 produces IC among a series of data ₅₀The HDAC enzyme of representative compounds suppresses the results are shown in table 3.

Table 3

Compound	HDAC1 enzymic activity IC ₅₀(μM)	HDAC8 enzymic activity IC ₅₀(μM)
Compound	HDAC1 enzymic activity IC ₅₀(μM)	HDAC8 enzymic activity IC ₅₀(μM)	1	0.051	0.119
2	0.026	0.355	1	0.051	0.119
2	0.026	0.355	3	1.37	1.71
4	1.34	0.790	3	1.37	1.71
4	1.34	0.790	5	4.32	0.401
6	1.38	0.262	5	4.32	0.401
6	1.38	0.262	7	1.52	0.336
8	0.286	0.454	7	1.52	0.336
8	0.286	0.454	9	1.34	0.344
10	2.66	0.883	9	1.34	0.344
10	2.66	0.883	11	0.846	0.161
12	0.131	0.202	11	0.846	0.161
12	0.131	0.202	13	0.385	0.141
14	0.171	0.251	13	0.385	0.141
14	0.171	0.251	15	0.206	0.313
16	0.194	0.366	15	0.206	0.313
16	0.194	0.366	17	0.024	0.353
18	0.438	0.290	17	0.024	0.353
18	0.438	0.290	19	0.165	0.145
20	1.91	0.537	19	0.165	0.145
20	1.91	0.537	21	0.064	0.238
22	1.326	0.234	21	0.064	0.238
22	1.326	0.234	23	0.529	0.402
24	3.24	0.203	23	0.529	0.402
24	3.24	0.203	25	1.32	0.601
26	0.876	1.005	25	1.32	0.601
26	0.876	1.005	27	0.092	0.329
28	0.206	0.300	27	0.092	0.329

29	49.06	33.96
29	49.06	33.96	30	0.195	0.724
31	0.246	1.09	30	0.195	0.724
31	0.246	1.09	32	2.21	1.89
33	0.449	1.45	32	2.21	1.89
33	0.449	1.45	34	1.46	0.846
35	0.371	0.412	34	1.46	0.846
35	0.371	0.412	36	0.227
37	0.897		36	0.227
37	0.897		38	0.218	0.148
39	1.22	0.201	38	0.218	0.148
39	1.22	0.201	40	3.30	0.441
41	0.195	0.159	40	3.30	0.441
41	0.195	0.159	42	0.479	0.237
43	0.947	0.192	42	0.479	0.237
43	0.947	0.192	44	0.268	0.345
45	0.167		44	0.268	0.345
45	0.167		46	1.67
47	1.09		46	1.67
47	1.09		48	0.356	0.291
49	1.40		48	0.356	0.291
49	1.40		50	0.173
51	0.896		50	0.173
51	0.896		52	0.160
53	1.85		52	0.160
53	1.85		54	0.100
55	0.137		54	0.100
55	0.137		56	0.158
57	0.153		56	0.158
57	0.153		58	1.14
59	0.382		58	1.14
59	0.382		60	0.116
61	0.196		60	0.116
61	0.196		62	0.234

63	0.162
63	0.162		64	0.230
65	0.062		64	0.230
65	0.062		66	0.072	0.255
67	0.039	0.254	66	0.072	0.255
67	0.039	0.254	68	0.294
69	0.146		68	0.294
69	0.146		70	0.923
71	0.167		70	0.923
71	0.167		72	0.052
73	0.560		72	0.052
73	0.560		74	0.371
75	0.290		74	0.371
75	0.290		76	1.03
77	0.570		76	1.03
77	0.570		78	＞100
79	1.26		78	＞100
79	1.26		80	1.69
81	1.60		80	1.69
81	1.60		82	0.304
83	0.071		82	0.304
83	0.071		84	0.054
85	0.131		84	0.054
85	0.131		86	0.400
87	0.517		86	0.400
87	0.517		88	0.297
89	0.116		88	0.297
89	0.116		90	0.166
91	0.030		90	0.166
91	0.030		92	0.168
93	0.065		92	0.168
93	0.065		94	0.052
95	0.061		94	0.052
95	0.061		96	0.125

In order to measure GI ₅₀The property hyperplasia is analyzed at the bottom of the cell based of value

Human colon's JEG-3 (Colo205 and HCT116), human breast cancer cell strain (MDA-MB435 and MDA-MB231) and Human Lung Cancer cell strain (A549) are available from ATCC.With the Colo205 cell cultures in the RPMI 1640 that contains 2mM L-glutaminate, 5%FBS, 1.0mM Sodium.alpha.-ketopropionate.With A549 and MDA-MB231 cell cultures in the RPMI 1640 that contains 2mM L-glutaminate, 5%FBS.The MDA-MB435 cell is incubated among the DMEM that contains 2mM L-glutaminate, 5%FBS.With the HCT116 cell cultures in the IMEM that contains 2mM L-glutaminate, 5%FBS.In the 96-orifice plate, every hole is respectively 2000 and 5000 cells with A549 and Colo205 cell inoculation.MDA-MB435, HCT116, MDA-MB231 carefully are inoculated in the 96-orifice plate, and every hole is 6000 cells.This is coiled in 37 ℃, 5%CO ₂Under cultivated 24 hours.With cell with the compound treatment of different concns 96 hours.Re-use the cyquant cell and increase the growth of planting analysis (Invitrogen Pte Ltd) monitoring cell.Use XL-fit to draw dose response curve to measure its GI ₅₀Value.

The cytoactive of representative compounds the results are shown in table 4.Table 5 is the selected compounds of arrangement, comprises the antiproliferative activity of its different salts for other JEG-3.These data point out that compound of the present invention has high activity for the inhibition of growth of tumour cell.

Table 4

Compound	GI50 (Colo 205，μM)	GI50 (MDA-MB435，μM)
Compound	GI50 (Colo 205，μM)	GI50 (MDA-MB435，μM)	1	0.52	1.64
2	0.43	0.32	1	0.52	1.64
2	0.43	0.32	4	29.87	25.70
5	＞100		4	29.87	25.70
5	＞100		6	＞100
7	＞100		6	＞100
7	＞100		8	41.36	58.42
9	＞100	＞100	8	41.36	58.42
9	＞100	＞100	11	＞100	＞100
12	0.38	1.07	11	＞100	＞100
12	0.38	1.07	13	12.32	14.05
14	3.07	5.99	13	12.32	14.05
14	3.07	5.99	15	1.99	4.07

16	0.94	0.98
16	0.94	0.98	17	0.06	0.56
18	4.69	6.16	17	0.06	0.56
18	4.69	6.16	19	4.10	3.97
20	30.86	37.22	19	4.10	3.97
20	30.86	37.22	21	25.91	30.26
22	13.47	13.35	21	25.91	30.26
22	13.47	13.35	23	3.65	3.72
24	30.70	35.02	23	3.65	3.72
24	30.70	35.02	25	8.10	6.82
26	8.79	6.67	25	8.10	6.82
26	8.79	6.67	27	2.23	3.44
28	2.53	5.15	27	2.23	3.44
28	2.53	5.15	30	11.44	19.85
31	1.87	4.06	30	11.44	19.85
31	1.87	4.06	33	1.54	3.38
35	1.89	6.76	33	1.54	3.38
35	1.89	6.76	36	2.29	2.17
37	7.82	7.90	36	2.29	2.17
37	7.82	7.90	38	1.47	1.53
39	11.68	12.05	38	1.47	1.53
39	11.68	12.05	40	25.62	30.97
41	1.65	1.91	40	25.62	30.97
41	1.65	1.91	42	14.41	15.75
43	9.18	8.62	42	14.41	15.75
43	9.18	8.62	44	2.82	3.65
45	2.41	1.90	44	2.82	3.65
45	2.41	1.90	48	1.45	1.78
50	4.29	5.19	48	1.45	1.78
50	4.29	5.19	52	2.04	3.58
54	4.47	5.92	52	2.04	3.58
54	4.47	5.92	55	＞100	＞100

56	＞100	＞100
56	＞100	＞100	57	1.11	1.39
59	2.72	3.69	57	1.11	1.39
59	2.72	3.69	60	2.47	3.60
61	2.69	3.05	60	2.47	3.60
61	2.69	3.05	62	11.65	19.80
63	2.00		62	11.65	19.80
63	2.00		64	1.70
65	36.89		64	1.70
65	36.89		66	0.22
67	0.08		66	0.22
67	0.08		68	0.73
69	7.16		68	0.73
69	7.16		70	2.90
71	7.09		70	2.90
71	7.09		72	0.18
73	6.67		72	0.18
73	6.67		74	2.07
75	2.88		74	2.07
75	2.88		82	0.72
83	0.25		82	0.72
83	0.25		84	0.17
85	1.65		84	0.17
85	1.65		86	13.13
87	47.71		86	13.13
87	47.71		88	1.26
89	0.12		88	1.26

Table 5

The histone H 3 acetylize is analyzed

The feature that histone deacetylase (HDAC) suppresses is that the degree of acetylation of histone improves.Acetylation of histone comprises: H3, H4 and H2A, this mensuration can be by immunoblotting (Western blotting).Get about 1.5x10 ⁶The Colo205 cell inoculation of individual cell/10 centimeter dish was cultivated 24 hours and is that the hdac inhibitor of 0.1,1,5 and 10 μ M is handled with final concentration subsequently in aforesaid substratum.After 24 hours, collecting cell is also dissolved according to the explanation of Sigma mammalian cell dissolving cover group.With BCA method (Sigma Pte Ltd) that protein concn is quantitative in addition.What 4-12% pair-tris SDS-PAGE colloid (Invitrogen Pte Ltd) isolated protein solute of use was also incited somebody to action is transferred on the pvdf membrane (BioRad Pte Ltd).This film used respectively acetylize H3, acetylize H4 or the narrow spectrum first antibody of acetylize H2A tool (Upstate Pte Ltd) are surveyed.Use detection antibody according to the explanation of manufacturers: with HRP bonded goat anti-rabbit antibodies (Pierce Pte Ltd).Behind film removal detection antibody, will add on the film in order to the enhancing chemistry cold light matrix (Pierce Pte Ltd) that detects HRP.Remove this matrix after, on X-exographX (Kodak), expose this film to the open air 1 second-20 minute.Use X-exographX handler that the X-exographX is developed.Use UVP Bioimaging software (UVP, Inc, Upland, CA) density of each cross band of analysis on the video picture egative film.The density that again this numerical value is contrasted the Actin muscle in the corresponding sample in addition normalization to know this protein expression.

Use the immunoblotting of histone deacetylase H3, H4 and H2A antibody to the results are shown in table 6.

Table 6

But these data confirm compound inhibition of histone deacetylase of the present invention, thereby cause accumulating of acetylated histones.

Histone H 3 acetylize analysis-ELISA method

Enzyme-linked immunosorbent assay (ELISA) can be used with the acetylated histones 3 (AcH3) in the protein solute of the cancer cells that detects the hdac inhibitor processing of also quantitatively hanging oneself.

Elisa assay is developed in order to measure the AcH3 content through the Colo205 colon cancer cell line of 10 μ M HDAC inhibition compound treatment.As the above-mentioned protein solute of obtaining unprocessed or treated Colo205.Use the protein concn of BCA method (Sigma-Aldrich Pte Ltd) mensuration from dissolved cell.

Investigation can be used as the different antibody combination (referring to table 7) of first antibody (capture antibodies) or second antibody so that determine suitable antibody and make antibody concentration and the analysis condition optimization.We find mouse anti H3 monoclonal antibody and the anti-AcH3 polyclonal antibody of rabbit (Lys9/14) combination can with antigen, no matter be that the hang oneself peptide or the protein solute of the Colo205 colon cancer cell line that hdac inhibitor handles produces most preferably combination.Do not observe background.The detection antibody that is used in this ELISA is and the anti-rabbit antibody of peroxidase bonded donkey.

Measure the EC that acetylated histones 3 was induced at 50% o'clock ₅₀, with the Colo205 cell with 1.5x10 ⁵Individual cells/well was cultivated 24 hours in 96 orifice plates.Handle Colo205 cell (two repeat, and 9 kinds of treatment dosage are from 4 times of 100 μ M dilutions) with the hdac inhibitor of various dose subsequently.Handle 24 hours after, cell dissolved and measured protein concn.

Under 4 ℃, ELISA dish (immulon 2HB dish, Biolaboratories Pte Ltd) coating 4 μ g/mL mouse anti H3 monoclonal antibodies are spent the night.Remove mouse anti H3 monoclonal antibody after, wash this dish and under 37 ℃, blocked 1 hour with the PBS damping fluid that contains 0.05%Tween-20 with super blocking solution (Pierce Pte Ltd).Remove this super blocking solution and wash this dish with the PBS damping fluid that contains 0.05%Tween.The AcH3 peptide, H3 peptide and the protein solute that add the Colo205 of the hdac inhibitor processing of hanging oneself.Under 37 ℃, make first antibody and antigen: the histone 3 in the sample carried out catching reaction 1 hour.Behind the removal sample, wash this dish with the PBS damping fluid that contains 0.05%Tween.Add second antibody: the 0.5 anti-AcH3 polyclonal antibody of μ g/mL rabbit (Lys9/14), detect acetylize H31 hour under 37 ℃.After the removal second antibody, to wash this dish with the PBS damping fluid that contains 0.05%Tween.Add to detect antibody under 37 ℃, to detect the second antibody 30 minutes of having caught the AcH3 in the sample.Add matrix: 1-step Turbo TMB (Pierce Pte Ltd) 30 minutes until colour generation.Use 1M H ₂SO ₄Termination reaction.Use Spectromax reader (Molecular Devices Corporation, Sunnyvale, CA) light absorption value at mensuration OD450nm place.

The drawing standard curve also utilizes AcH3 concentration [(Lys9/14), μ g/ml] in the Softmax software working sample in the Spectromax.According to the AcH3 content in the following formula calculation sample:

AcH3 (Lys9/14), the pg/ gross protein,

(ID Business Solution, Emeryville CA) draw dose response curve to record the EC of compound to utilize XL-fit ₅₀Value.[table 8]

Table 7: the antibody that is used for test of species cross reactivity and combinatorial antibody research

As first or the antibody of second antibody	Detect antibody with HRP (horseradish peroxidase) bonded
As first or the antibody of second antibody	Detect antibody with HRP (horseradish peroxidase) bonded	The anti-AcH3 polyclonal antibody of rabbit (Lys9/14; Upstate Pte Ltd),	The anti-rabbit of donkey (Pierce Pte Ltd)
The anti-AcH3 polyclonal antibody of rabbit (Lys14; Upstate	Goat antirabbit (Pierce Pte Ltd)		The anti-rabbit of donkey (Pierce Pte Ltd)

Pte Ltd)，
Pte Ltd)，		The anti-AcH3 polyclonal antibody of rabbit (Lys9, Upstate Pte Ltd),	The anti-ageing mouse of goat (Pierce Pte Ltd)
The anti-AcH3 polyclonal antibody of goat (Lys9/14, Santa Cruz Pte Ltd),	The anti-goat of rabbit (Pierce Pte Ltd)		The anti-ageing mouse of goat (Pierce Pte Ltd)
	The anti-goat of rabbit (Pierce Pte Ltd)	The anti-H3 polyclonal antibody of goat (N-20, Santa Cruz Pte Ltd)	Mouse anti goat (Pierce Pte Ltd)
Mouse anti H3 monoclonal antibody (Upstate Pte Ltd)			Mouse anti goat (Pierce Pte Ltd)

The data presentation of selecting compound for use is in table 8, with the concentration (EC of the acetylize ([AcH3 (lys9/14)]) that can effectively bring out 50% histone 3 ₅₀) expression.

Table 8

In vivo preventing tumor (or antitumor) effect of hdac inhibitor:

In the data that does not show, test selected compound in the intravital maximum tolerated dose of normal mouse and find that it quite can stand (it can be＞200 milligrams/kg/day) no visible toxicity mark or side effect in the dosage range of using for mouse.

Can re-use in vivo animal xenotransplantation research and measure the effect of The compounds of this invention.

In these researchs, the subcutaneous implantation of flank of the female atymic nude mouse (Harlan) that 12-14 week is big is suspended in the 5x10 of 50%Matrigel ⁶The HCT116 of individual cell or 1x10 ⁶The Colo205 human colon cancer of individual cell is when the tumour size reaches 100mm ³, should heteroplastic nude mouse pairing be divided into each treatment group.Selected hdac inhibitor is dissolved in suitable supporting agent, for example: also give this through intraperitoneal every day in the 10% DMA/10%Cremophore/80% water and implemented altogether 14 days through heteroplastic nude mouse.For the agent volume is the 0.2ml/20g mouse., it is prepared into is dissolved in 10% ethanol/10%Cremophore/80% water and gives as positive control group with taxol (Paclitaxol) for intravenously.The confession agent volume of taxol is the 0.015-ml/g mouse.All calculated gross tumor volume in back per two days of injection: gross tumor volume (mm with following formula ³)=(w ²Xl)/2, the wherein width of w=HCT116 or Colo205 cancer and l=length, its unit is: mm.Tested The compounds of this invention can show significant gross tumor volume and reduce for the control group that handled by supporting agent.If measure the activity of histone deacetylase, it should be lowered and with respect to the control group of handling through supporting agent, it can cause accumulating of acetylated histones.

The details that is illustrated in specific embodiment of the present invention is not in order to be inferred to be its restriction.Can not carry out various synonyms and modification from essence of the present invention and scope, and known these synonym specific embodiments some that is the present invention.

Claims

1. the compound of a formula (I) or its pharmacy acceptable salt:

Formula I

Wherein

R ¹Be selected from: H, C _1-14Alkyl, C _2-14Alkenyl, C _2-14Assorted alkyl, C _4-7Heterocyclylalkyl, C _4-7Heterocyclylalkyl C _1-14Alkyl, C _5-12Aryl C _1-14Alkyl, heteroaryl C _1-14Alkyl, hydroxyl C _1-14Alkyl, C _1-6Alkoxy C _1-14Alkyl and amino C _1-14Alkyl, it is not substituted separately or is replaced by one or more substituting groups that are independently selected from down group: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃,-CO ₂H, OH, C _1-14Alkyl, C _2-14Assorted alkyl, C _3-9Cycloalkyl, C _4-7Heterocyclylalkyl, C _1-6Alkoxyl group, C _5-12Aryl C _1-14Alkyl, heteroaryl C _1-14Alkyl, C _5-12Aryl C _1-6Alkoxyl group, amino and C _1-14Alkylamino;

R ²Be selected from: H, C _1-14Alkyl, C _2-14Assorted alkyl, C _3-9Cycloalkyl, C _5-12Aryl, heteroaryl, C _3-9Cycloalkyl C _1-14Alkyl, C _4-7Heterocyclylalkyl C _1-14Alkyl, C _5-12Aryl C _1-14Alkyl, heteroaryl C _1-14Alkyl, heteroaryl C _2-14Assorted alkyl, C _5-12Aryl C _2-14Assorted alkyl and C _1-6Alkoxy C _5-12Aryl, it is not substituted separately or is replaced by one or more substituting groups that are independently selected from down group: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃, CO ₂H, OH, C _1-14Alkyl, C _2-14Assorted alkyl, C _3-9Cycloalkyl, C _4-7Heterocyclylalkyl, C _1-6Alkoxyl group, C _5-12Aryl C _1-14Alkyl, heteroaryl C _1-14Alkyl, C _5-12Aryl C _1-6Alkoxyl group, amino and C _1-14Alkylamino;

R ³Be H;

X and Y are H;

R ⁴Be H; With

Z is-CH=CH-, and is connected in ring position 5,

Wherein, heteroaryl is meant monocycle or condensed polycyclic aromatic heterocycle, and described aromatic heterocycle contains the ring texture of heteroatomic 5 to 7 yuan of aromatic nucleus of one or more N of being selected from, O and S.

2. compound as claimed in claim 1, wherein, R ¹Be selected from: H, hydroxyl C _1-14Alkyl, C _1-14Alkyl, C _2-14Assorted alkyl, C _5-12Aryl C _1-14Alkyl, heteroaryl C _1-14Alkyl, C _1-6Alkoxy C _1-14Alkyl, amino C _1-14Alkyl and C _4-7Heterocyclylalkyl, it is not substituted separately or is replaced by one or more substituting groups that are independently selected from down group: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃,-CO ₂H, OH, C _1-14Alkyl, C _2-14Assorted alkyl, C _3-9Cycloalkyl, C _4-7Heterocyclylalkyl, C _1-6Alkoxyl group, C _5-12Aryl C _1-14Alkyl, heteroaryl C _1-14Alkyl, C _5-12Aryl C _1-6Alkoxyl group and amino and C _1-14Alkylamino.

3. compound as claimed in claim 1, wherein, R ¹Be selected from: H, methyl, (pyridine-2-yl) methyl, (pyridin-3-yl) methyl, ethyl, 2-hydroxyl-ethyl, 2-(pyridine-2-yl) ethyl, 2-(pyridin-3-yl) ethyl, 2-phenyl-ethyl, 2-carboxyl-ethyl, 2-(morpholine-4-yl)-ethyl, 2-(piperidines-1-yl)-ethyl, 2-(tetramethyleneimine-1-yl)-ethyl, 2-diethylamino-ethyl, propyl group, 2,3-two-hydroxyl-propyl group, 3-hydroxyl-propyl group, 3-methoxyl group-propyl group, 3-isopropoxy-propyl group, 2,2-dimethyl-propyl group, 3-dimethylamino-propyl group, 3-dimethylamino-2,2-dimethyl-propyl group, 3-(2-oxo-tetramethyleneimine-1-yl)-propyl group, 3-(morpholine-4-yl)-propyl group, 3-(imidazoles-1-yl)-propyl group, 3-(4-methyl-piperidines-1-yl)-propyl group, 3-(tetramethyleneimine-1-yl)-propyl group, 4-dimethylamino-butyl, 5-hydroxyl-amyl group, allyl group, benzyl, with 3,4,5-trimethoxy benzyl.

4. compound as claimed in claim 1, wherein, R ²Be selected from H, C _1-14Alkyl, C _5-12Aryl C _1-4Alkyl, C _5-12Aryl, heteroaryl, C _2-14Assorted alkyl, C _3-9Cycloalkyl, it is not substituted separately or is replaced by one or more substituting groups that are independently selected from down group: halogen ,=O ,=S ,-CN ,-NO ₂,-CF ₃,-OCF ₃, CO ₂H, OH, C _1-14Alkyl, C _2-14Assorted alkyl, C _3-9Cycloalkyl, C _4-7Heterocyclylalkyl, C _1-6Alkoxyl group, C _5-12Aryl C _1-14Alkyl, heteroaryl C _1-14Alkyl, C _5-12Aryl C _1-6Alkoxyl group, amino and C _1-14Alkylamino.

5. compound as claimed in claim 1, wherein, R ²Be selected from down group: H; methyl; the benzyl amino-methyl; the dibenzyl amino-methyl; [2-(4-fluoro-phenyl)-kharophen]-methyl; [2-(4-methoxyl group-phenyl)-kharophen]-methyl; 4-methoxyl group-benzyl amino-methyl; benzyloxy-methyl; phenyl acetylaminohydroxyphenylarsonic acid methyl; 1-amino-2-phenyl-ethyl; 2-benzyl amino-ethyl; 2-(3-methoxyl group-phenyl)-ethyl; 2-(pyridin-3-yl) ethyl; 2-(2-phenoxy group kharophen)-ethyl; 2-benzenesulfonyl amino-ethyl; 2-phenyl-ethyl; sec.-propyl; 2-phenyl-propyl group; 3-phenyl-propyl group; 3-phenoxy group-propyl group; 3-(1H-indol-3-yl)-propyl group; 4-methoxyl group-phenyl; 4-fluoro-phenyl; 4-benzyloxy-3-methoxyl group-phenyl; isobutyl-; cyclohexyl; octyl group; benzyl; pyridine-2-base; pyridin-4-yl; thiene-3-yl-; benzylthio-and 2-phenyl methylthio group.

6. compound as claimed in claim 1, wherein, described compound is selected from following compound, and pharmacy acceptable salt:

7. pharmaceutical composition, it comprises each described compound and pharmaceutically acceptable thinner, vehicle or carrier among the claim 1-6.

8. the purposes of the described compound of claim 1, it is used to prepare, and the destruction that is used for the treatment of by cell proliferation and/or angiogenesis is caused, the medicine of or the illness followed related with this destruction.

9. purposes as claimed in claim 8, wherein, described illness is a proliferative disorders.

10. purposes as claimed in claim 9, wherein, described proliferative disorders is a cancer.

11. the purposes of the described compound of claim 1, it is used for external modification deacetylation enzymic activity.

12. purposes as claimed in claim 11, wherein, described deacetylation enzymic activity is the histone deacetylase activity.

13. purposes as claimed in claim 12, wherein, described deacetylation enzymic activity is an I class histone deacetylase activity.

14. purposes as claimed in claim 13, wherein, described histone deacetylase is a histone deacetylase 1.

15. purposes as claimed in claim 13, wherein, described histone deacetylase is a histone deacetylase 8.

16. the purposes of the described compound of claim 1, it is used to prepare the medicine that is used for the treatment of the illness that can be treated by the histone deacetylase that suppresses the patient.

17. purposes as claimed in claim 16, wherein, described illness is selected from: proliferative disorders; Neurodegenerative disease; Metabolic disease; The eye degenerative disease; Inflammatory diseases; Disorder of immune system; The disease that relates to angiogenesis; The psychology illness; Cardiovascular disorder; Fibrotic disease; Infectious diseases; And hematopoiesis venereal disease disease.

18. the purposes of the described compound of claim 1, it is used to prepare the medicine of the neurodegenerative disorders that is used for the treatment of the patient.

19. purposes as claimed in claim 18, wherein, described neurodegenerative disorders is a Huntington Chorea.

20. the purposes of the described compound of claim 1, it is used to prepare the medicine that is used for the treatment of inflammatory diseases or disorder of immune system.

21. purposes as claimed in claim 20, wherein, described inflammatory diseases or disorder of immune system are rheumatoid arthritiss.

22. purposes as claimed in claim 21, wherein, described inflammatory diseases or disorder of immune system are systemic lupus erythematosuses.

23. one kind is used enzyme-linked immunosorbent assay to measure with each described compound among the claim 1-6 or comprises the method for acetylated histones concentration in the biological sample that the pharmaceutical composition of described compound handled, described enzyme-linked immunosorbent assay comprises a part of and second combination that detects antibody or its some of first capture antibodies or its.

24. method as claimed in claim 23, wherein, described first capture antibodies is selected from: anti--the H3 monoclonal antibody, anti--acetylize H3 polyclonal antibody, goat is anti--the H3 polyclonal antibody, goat is anti--acetylize H3 polyclonal antibody and combination thereof.

25. method as claimed in claim 23, wherein, described second detects antibody is selected from: anti--the H3 monoclonal antibody, anti--acetylize H3 polyclonal antibody, goat is anti--the H3 polyclonal antibody, goat is anti--acetylize H3 polyclonal antibody and combination thereof.

26. method as claimed in claim 23, wherein, described first capture antibodies is mouse anti-H3 monoclonal antibody, and the second detection antibody is rat anti-acetylize H3 polyclonal antibody.

27. each described compound or comprise the method for pharmacological action of the pharmaceutical composition of described compound among the claim 1-6 in the identification of cell, this method comprises the following steps:

A) provide with each described compound among the claim 1-6 or comprise the cell that the pharmaceutical composition of described compound is handled;

B) concentration of the interior acetylated histones of each described method mensuration cell among the usefulness claim 23-26; With

C) concentration of this acetylated histones is compared with the acetylated histones concentration of control sample.

28. method as claimed in claim 27, wherein, described control sample is derived from the cell of handling without histone deacetylase inhibitors.

29. method as claimed in claim 27, wherein, described cell is a tumour cell.

30. the method for pharmacological action of differentiating in the object each described compound among the claim 1-6 or comprising the pharmaceutical composition of described compound, this method comprises the following steps:

A) obtain with each described compound the claim 1-6 or comprise the biological sample of the pharmaceutical composition processing of described compound from object;

B) measure acetylated histones concentration in this biological sample with each described method among the claim 23-26; And

31. method as claimed in claim 30, wherein, described control sample is the biological sample derived from the object of handling without histone deacetylase inhibitors.

32. method as claimed in claim 23, wherein, described biological sample is selected from: tissue, blood, serum, blood plasma, urine, saliva and combination thereof.

33. method as claimed in claim 30, wherein, described biological sample is selected from: tissue, blood, serum, blood plasma, urine, saliva and combination thereof.

34. each described compound is used for regulating the purposes of the active medicine of deacetylase among the claim 1-6 in preparation.

35. purposes as claimed in claim 34 is characterized in that, described deacetylation enzymic activity is the histone deacetylase activity.

36. purposes as claimed in claim 34, wherein, described deacetylation enzymic activity is an I class histone deacetylase activity.

37. purposes as claimed in claim 35, wherein, described histone deacetylase is a histone deacetylase 1.

38. purposes as claimed in claim 35, wherein, described histone deacetylase is a histone deacetylase 8.

39. purposes as claimed in claim 17, it is characterized in that described neurodegenerative disease is selected from: Huntington Chorea, polyglutamic acid amides disease, Parkinson's disease, alzheimer's disease, epileptic seizures, striatonigral degeneration, stein-leventhal syndrome, torsional tension is incomplete, spasmodic torticollis and dyskinesia, familial tremor, Tourette syndrome, diffusivity Lay dimension corpusculum disease, stein-leventhal syndrome, Pick's disease, intracranial hemorrhage, primary lateral sclerosis, the spinal cord muscular dystrophy, amyotrophic lateral sclerosis, matter polyneuropathy between hypertrophy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, carrying out property dystaxia and Shy-Drager syndrome.

40. purposes as claimed in claim 17 is characterized in that, described metabolic disease is a diabetes B.

41. purposes as claimed in claim 17 is characterized in that, described eye degenerative disease is selected from: glaucoma, age-related macular degeneration and rubeotic glaucoma.

42. purposes as claimed in claim 17, it is characterized in that described inflammatory diseases and/or disorder of immune system are selected from: rheumatoid arthritis, osteoarthritis, JCA, graft versus host disease (GVH disease), psoriasis, asthma, spinal joint pathology, psoriasis, Crohn's disease, inflammatory bowel, colonic ulcer, alcoholic hepatitis, diabetes, sjogren syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, intervertebral disk pain and systemic lupus erythematosus.

43. purposes as claimed in claim 17 is characterized in that, the described disease that relates to angiogenesis is selected from: cancer, psoriasis and rheumatoid arthritis.

44. purposes as claimed in claim 17 is characterized in that, described proliferative disorders is a cancer.

45. purposes as claimed in claim 17 is characterized in that, described psychological illness is selected from: bipolar disorder, schizophrenia, mania, depression and dull-witted.

46. purposes as claimed in claim 17 is characterized in that, described cardiovascular disorder is selected from: heart failure, restenosis and arteriosclerosis.

47. purposes as claimed in claim 17 is characterized in that, described fibrotic disease is selected from: hepatic fibrosis, cystic fibrosis and hemangiofibroma.

48. purposes as claimed in claim 17 is characterized in that, described infectious diseases is selected from: fungi infestation, infectation of bacteria, viral infection and protozoan infection.

49. purposes as claimed in claim 48 is characterized in that, described infectious diseases is selected from: Candida albicans, herpes simplex, malaria, infections with leishmaniasis, trypanosoma bocagei infection, toxoplasmosis and coccidiosis.

50. purposes as claimed in claim 17 is characterized in that, described hematopoiesis venereal disease disease is selected from: Thalassemia, anaemia and sicklemia.